MXPA97001820A - Compounds of pirazolo [3,4-g] quinoxaline queinhiben protein tyrosine kinase receptor dep - Google Patents

Abstract

The present invention relates to a compound according to the formula: wherein: ----- can be a double bond, R1 or R2 is hydrogen, acyl, 1,2-dihydroxyethyl, 1,2-dihydroxyprop-3- ilo, or R5 (CR) x-X; R3 or R4 is Y-Ar with the other being hydrogen, R5n is H, alkyl, hydroxy, alkoxy, carboxy or carbamoyl, R is hydrogen or alkyl, X is hydrogen-alkyl C4-C6, alkenyl, hydroxy, 1,2-dihydroxyethyl, 1,2-dihydroxyprop-3-yl, alkoxy, carboxy, carbalkoxy, acyl, acyloxy, amino, mono- or di-alkyl-amino, acylamino, cyano, carbamoyl , acylcarbamoyl, mono- or di-alkylcarbamoyl, thiocarbamoyl, mono- or di-alkylthio-carbamoyl, acylthiocarbamoyl, 2,2-dialkyl-1,3-dioxolan-5-yl, 5-tetrazolyl, piperidinyl, pyridyl, phenyl, or substituted phenyl wherein the substitution may be one or two groups independently selected from alkyl, alkoxy, carboxy, carbalkoxy, carbamoyl, mono- or di-alkylcarbamoyl, thiocarbamoyl, mono- or di-alkylthiocarbamoyl, halogen or halogen oalkyl; Y is a bond, (CH2) 1-3, (CH2) nO (CH2) m, (CH2) nS (CH2) m, or (CH2) nNR (CH2) m; n and m are independently 0-3 and n + m = 0-3, x is 1-3, Ar is phenyl, substituted phenyl, thienyl, substituted thienyl, pyridyl, substituted pyridyl, alpha or p-naphthyl or substituted alpha or p-naphthyl wherein the substitution may be one or two groups independently selected from alkyl, hydroxy, alkoxy, halogen, haloalkyl or cyano; or a pharmaceutically acceptable salt thereof;

Description

COMPOUNDS OF PIRñZOLQC3, 4-q] QUINOXflLINfl INHIBIT PROTEINfl TIROSINfl QUINflSfl RECEPTOR OF PDGF FIELD OF THE INVENTION This invention relates to the inhibition of cell proliferation. More specifically, this invention relates to the use of pyrazoloyl 3,4-j: iquinoxaline compounds to inhibit cell proliferation, including compounds that are useful inhibitors of protein tyrosine kinase (PTK). directed by the exposure of the cell substrate to one or more growth factors, examples of which are insulin, epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) .These growth factor receptors are embedded in and penetrate through the cell membrane The initiation of cell reproduction is thought to occur when a growth factor binds the corresponding receptor on the outer surface of the cell membrane This growth factor-receptor binding alters the chemical characteristics of that portion of the receptor that exists within the cell and that functions as an enzyme to catalyze the phosphorylation of a substrat or intracellular or the receptor itself, the latter being referred to as autophosphorylation. Examples of such phosphorylation enzymes include tyrosine kinases, which catalyze the phosphorylation of amino acid residues from shots! a of substrate proteins. The initiation of autophosphorylation, that is, phosphorylation of the growth factor receptor itself, and the phosphorylation of a host of intracellular substrates are some of the biochemical events that are involved in mitogenesis and cell proliferation. Phosphorylation of substrate proteins by other receptors are the earliest identifiable biochemical hormone responses. The compounds described in this invention can be applied to the treatment of various disease states that are characterized by uncontrolled cell proliferation. These disease states involve a variety of cell types and include disturbances such as restenosis that occurs after angioplasty, atherosclerosis, lukarsia, rheumatoid arthritis, transdermal atheroeclerosis, glornerolonephritis, or tumors / cancer. The application of compounds as selective inhibitors of protein tyrosine kinase activation can interfere with this cell growth-mediated hyperplasia which results in a therapeutic agent for the treatment of the aforementioned disturbances. The compounds of this invention are novel as selective inhibitors of the protein tyrosine kinase of PDGF-R and can be applied as potential therapeutic agents for various disease states that are characterized by uncontrolled cell proliferation.

REGISTERED DEVELOPMENTS Protein tyrosine kinases (PTKs) are a group of enzymes that play a crucial role in the regulation of cell proliferation. These enzymes catalyze the transfer of OTP t-phosphate to specific tyrosine residues on several intracellular protein substrates as well as the ligand-induced autophosphorylation of trane-embrane receptors. This enzymatic activity has been detected in several viral and cellular oncogene products and is associated with a variety of growth factor receptors, including platelet-derived growth factor (PDGF). The interaction of PDGF with specific cell surface receptors stimulates the associated activity of tyrosine kinase. This enzyme activity is believed to be an important initial event of the signal translation mechanisms that control cell proliferation. Coronary artery restenosis after balloon angioplasty is due to intimate hyperplasia of vascular soft muscle cells and is the main problem limiting the long-term efficacy of this procedure. Compounds that inhibit PDGF receptor tyrosine kinase may be useful as potential therapeutic agents for the control of this and other hyperproliferative disorders. International Publication No. WO92 / 206462 to Rhone-Poulenc Rorer International (Holdings) Inc. discloses mono- and bicyclic aryl and heteroaryl bis which inhibit EGF and / or PDGF receptor tyrosine kinase.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, the compounds are provided which possess properties that are capable of inhibiting abnormal cell proliferation in a patient suffering from a disturbance characterized by said proliferation. In addition, the present invention provides a method for treating such disturbances comprising administering to a patient a PDGF receptor that inhibits the effective amount of a? Irazole C3.4 gKquinoxaline compound exhibiting protein tyrosine kinase inhibition activity where In addition, an aryl or heteroaryl group is added to the quinoxalinyl portion of the molecule. Said compounds being optionally substituted or polysubstituted. Another aspect of the present invention relates to pharmaceutical compositions comprising, together with a pharmaceutically acceptable carrier, a pharmaceutically effective amount of a novel compound of the aforementioned type. Another aspect of this invention comprises novel compounds useful in the practice of the present method. More specifically, the compounds of this invention can be described by the compounds of the formula I: Formula 1 where: it can be a double bond; Rl or R2 is hydrogen, acyl, 1, -dihydroxyethyl, 1,2-d? Hydroxyprop-3-yl, or Rs: CR) "~ X; R3 or R «is Y-flr the other being H torogen; R5 is hydrogen, alkyl, hydroxy, alkoxy, carboxy, carbalkoxy or carbamoyl; R is hydrogen or alkyl X is hydrogen, C 1 -Ce alkyl, alkenyl, hydroxy, alkoxy, carboxy, carbalkoxy, acyl, acyloxy, amino, mono- or di-alkyl-a, acylamino, cyano, carbamoyl, acylcarba oyl , mono- or di-alkylcarbarnoyl, t -carba- oyl, mono- or di-alkyl-ocarba-oyl, acylthio-carbamoyl, 2,2-dialkyl, 3-dioxolan-5-yl, 5-tetrazolyl, piperdinol, pyridyl, phenyl or substituted phenyl wherein the substitution may be one or two groups independently selected from alkyl, alkoxy, carboxy, carbalkoxy, carbamoyl, mono- or di-alkylcarbamoyl, mono- or di-alkylthiocarbamoyl, halo or haloaluyl; Y is a bond, (CH2) -3, (CH2) n 0 (CH2), (CH-2) nS (CH2) m, O (CH2) nNR (CH2) m; n and m are independently 0-3 and n + rn = 0-3; x is 1-3; Ar is phenyl, substituted phenyl, thienyl, substituted thienyl, pyridyl, substituted pyridyl, naphthyl or β or substituted a or β-naphthyl wherein the substitution may be one or two groups independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl or cyano; or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION AND PREFERRED MODALITIES The pyrazoloL "3,4-g] quinoxaline nomenclature used in this invention is as follows: As used above and through this description, the following terms, unless otherwise indicated, should be understood to have the following meanings: "Alkyl" means a saturated, branched or straight aliphatic hydrocarbon. The preferred alkyl is "lower alkyl" having from about 1 to about 6 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, butyl, e-butyl, t-butyl, pentyl and hexyl. "ñlquemlo" refers to an unsaturated or partially unsaturated hydrocarbon group containing from 2 to approximately 7 carbon atoms which may be in rec + a or branched chain. Rilo is preferred. "Alkoxy" refers to an alkyl-0- group. Preferred alkoxy groups are "lower alkoxy" having from about 0 to about 6 carbon atoms. Examples include ethoxy, ethoxy, propoxy, i-propoxy, butoxy and t-butoxy. "Acyl" refers to any organic radical derived from an organic acid by the removal of its J-hydroxy group, such as form, ace + yl, propionyl, 1-proponylo, butyryl, and t-butyl. "Acylarnino" refers to an in-substituted group with an acyl radical. "illociloxy" refers to an acyl-Q- group. Preferred acyloxy groups include acetyloxy, propionyloxy, i-propiomloxy, butyryloxy and t-butyloxy. "Carboxi" means -C00H. "Carbalkoxy" means an alkyl ester of a carboxylic acid. "Carba oyl" refers to any organic radical derived from an organic acid by the removal of its hydroxy group and replacing it with an amine or substituted amine. Preferred carbamoyl groups include carbamoyl, mono- and di-alkylcarbane and acylcarbamoyl. "Thiocarbarnoyl" means a carbamoyl wherein the oxygen has been replaced with sulfur. Preferred thiocarbamoyl groups include thiocarbamoyl, rnonono- or di-alkylthiocarbamoyl and acylthiocarbamoyl. "Halo" means halogen. Preferred halogens include chloride, bromide and fluoride. The preferred haloalkyl g is trifluoro ethyl. The most preferred compounds of this invention include those compounds of the formulas TI-V.

Formula II formula Formula IV Still the most preferred compounds are described by the formulas II-V wherein: R is hydrogen or lower alkyl; X is hydrogen, hydroxy, lower alkoxy, carboxy, lower carbalkoxy, phenyl or substituted phenyl wherein the substitution may be one or two groups independently selected from lower alkyl, lower alkoxy, carboxy, lower carbalkoxy, carbamoyl, chlorine, fluorine or trifluoroethyl; Y is a bond, (CH2)? -3 or 0 (CH2>? -3; Ar is phenyl, substituted phenyl, thienyl or substituted thienyl wherein the substitution may be one or two groups independently selected from lower alkyl, hydroxy, lower alkoxy, chloro, fluoro or trifluoromethyl The most preferred compounds are described by the formulas VI-XIII.

Formula X Formula XI wherein: Ri or R2 is hydrogen, acyl, 1,2-dihydroxyethyl, 1,2-dihydroxy? rop-3-yl, or R is hydrogen or lower alkyl; X is hydrogen, hydroxy, lower alkoxy, carboxy, lower carbalkoxy, phenyl or substituted phenyl wherein the substitution may be one or two groups independently selected from alkyl, alkoxy, carboxy or lower carbalkoxy and carbamoyl; x is 1-3; R 'and R "are independently selected from lower alkyl, hydroxy, lower alkoxy, halo or rforomethyl, Representative compounds include the following: 7- (5-chlorothien-2-yl) -lH-pyrazoloC3, 4-g] quinoxaline l-methyl-7- (5-chlorothien-2-yl) -lH-pyrazoloC3, 4-g] quinoxaline 2 ~ rnetyl-7- (5-chlorothien-2-yl) -2H-pyrazolof3, 4-g3 uinoxaline 7- (3-fluoro-4-rnetoxy phenyl) -lH-pyrazoloC3, 4-g3quinoxaline l-rnetil-7- (3-fluoro-4-methoxyphenyl) -lH-pi only C3, 4-g] quinoxaline 2-rnethyl-7- (3-fluoro-4-methoxyphenyl) -2H-pyrazoloC3, -gluquinoxaline l-acetyl-7- ( 3-fluoro-4-methoxyphenyl) -lH-pyrazoloC3,4-glquinoxalma 2-acet? L-7- (3-fluo or-4-methox? Feml) -2H - ?? razoloC3,4-g] qu? Noxal ? n l-al? l-7- (3-fluoro-4-rnetox? in? l) -lH-p? razolo [3,4-g] qu? noxal? na 2-al? l ~ 7- ( 3-fluoro-4-methoxyphen? L) -2H-p? just C 3, -g] qumoxal? to 1-et? L -7- (3-fluoro-4-methoxyphen? L) -lH-p? RazoloC3,4-g] qu? Noxal? Na 2-et? L-7- (3-fluoro-4-methox? Phen? L) -2H-p? RazoloC3,4-g] qu? Noxaline l-benc? L-7- (3-fluoro-4-) methox? phen? l) -lH-p? razoloC3, 4-g] qumoxal? na 2-benz? l-7- (3-fluoro-4-methox? phen? l) -2H - ?? razoloC3, 4- g) qu? noxal? na 2- (2-t-bu? lox? methyl) -7- (3-fiuoro-4-rr »ethoxy? in? l) - 2H-p? razolo [3,4- g) qu? noxal? n l- (2-t-bu ryloxy ethyl) -7- (3-fluoro-4-methox? phen?) - 1H-p? razoloC3,4-g] qu? noxal na 2 - (2-t-but? R? Lox? Met? L) -6- (3-fluoro-4-meto? Phen? L) -2H - ?? razoloC3,4-g] qu? Noxai? Na l- (2-t-but r? Lox? Methyl) -5- (3-fluoro-4-methox? Phen? L) -1H-p? RazoloC3,4-g] qu? Noxal? to 1-carboe + or imet? 1-7- (3-fluoro-4-rnetox? Phen? L) -lH-p? RazoloC3, 4-g] qu? Noxal? Na 2-carboethox? Met? L-7- (3-fluoro-4-) rnetox? phen? l) -2H-p? razo] oC3, 4-g] qu? noxalma 6- (3-fluoro-4-methox? phen?) - 1H-? loc 3, 4 -glqumoxali na l- (2 ~ aceoxy l) -7- (3 ~ fluoro-4-methox? phenyl) ~! H-? irazolor3, 4-g] qu? noxaline 2- (2- acetoxiet? l) -7- (3-fluoro-4-methox phenyl) -lH-pyrazoloC3, 4-g] quinoxal? na 1-carbox? methyl -7- (3-fluoro-4-methox? phenyl) -lH -p? razoloC, 4-glquinoxaline 2-carbox? methyl-7- (3? fluoro-4-methoxyphenyl) -2H-pyrazoloC3,4-g] qu? noxal na l-cyanornet? l-7- (3-fluoro) ~ 4-methoxyphen? L) -lH-pirazoJoC3, 4-g] qu? Noxalma 2-c? Anomet? L-7 ~ (3- luoro-4-methoxyphen? L) -2H-p? RazoloL ~ 3.4 -gJqumoxaJ ina 1 ~ L ~ 2 ~ h? drox? et 13-7- (3-fluoro-4-rnetox? phenyl) -lH-pi razo] oC 3,4-g] qu? noxalma 2-C2 -hi Roxy Ethyl] -7- (3-fluoro-4-ethoxy phenyl) -2H-? i Razo loC 3,4-gD-chloroaline-2-C2-hydroxyethyl] -6- (3-fluoro-4-methoxyphenyl) -2H- ? irazoloC3, 4-glquinoxalma l- (Np? perd? nilet? l) -7- (3-fluoro-4-methox? feml) -IH-p? razoloC3,4-g3qu? noxal? a 2- (Np? pep? n? let? l) -7- (3-fluoro-4-methoxyfen) - 2H-p? razoloC3,4-g] qu? noxal? na l - [(4R) - 2,2-d? Met? L- [l, 33dioxolan-4-? Lmet? L3-7- (3-fluoro-4-methox? In? L) -lH-?? razoloC, 4-glqu? Noxali a 2-C (4R) -2,2-dimethyl-Cl, 3] dioxolan-4-ylmethyl] -7- (3-fluoro-4- etho i feml) ~ 2H ~ p? RazoloC, 4-g] what? noxal? na 1- C (2R) - l, 2-d? H? Droxiprop-3-yl) -7- (3-fluoro-4-methox? Phen? L) - 1 H-p! Razolo [3,4-gl u? Noxaline 2-C (2R) -l, 2-d? hydroxyprop-3-yl) -7- (3-fluoro-4-methox? phen?) -2H- ?? razoloC3,4-g3quinoxal ma 7- (3-fluorophenyl) -lH- p? razoloC3,4- qu? no a? na 7- (t? en -3?) l-lH ~ ?? razoloC3, 4- 3 u? noxaJ ina l-methyl-7- (tien-3 ~ il ) -lH-p? razolo 3,4- 3q i oxal ina 2-met? l-7- (thien-3? l) -2H-pyrazoloC3,4-g] qu? noxaline 7-phenet? l-lH -p? razolo [, 4-g3quinoxal? na 6- (t? en-3-yl) -lH-pyrazoloC3,4-g] quinoxaline 1 - (2-methox? et l) -7- (t? en- 3-? L) -lH-p? Razolor3,4-g] which oxaJ a 2- (2-methox? Et? L) -7- (thien-3-yl) -2H-p? RazoloE3, 4-g ] what? noxalma l-acetam? do-7-. { thien-3-? l) -lH-pyrazolo [3,4-gl u? noxaline 2-acetam do-7- (t? en-3-yl) -2H-pyrazoloL ~ 3, -g3 uinoxali a l- ( p? pd-3-? lmet? l) -7- (3-fluoro-4-methox? phenyl) -lH-pyrazoloI.3,4-gjquinoxaline 2- (pipd-3? memethyl) -7- (3 -fluoro-4-methoxyphenyl? ~ 2H - ?? razoloC3,4-g3qu? noxal? na J- (p? r? d-2-? lmet? l) -7- (3-fluorofen? l) -lH- ? irazoloC3, -g3qu? noxal? 2- (p? id-2-ylmethyl) -7- (3-fluorophenyl) -2H-p? razolo [3,4-glqumoxalma 1 -h? dro til? ~ 7- (thien-3-yl) -lH-pi azolo [3,4-g3-quinine aline 2-hydroxyl-ethyl-7- (thien-3-yl) -2H-pyrazoloC3, 4-g3-chloroalkyl 1- (2 -N, N-diethylacetamido) -7- (3-fluo-ro-4-methoxy fem) -1H-p? RazoloC3,4-g] quinoxali to 2- (2-N, N-diet? Lacetamido) -7 - (3-fluoro-4-rethoxyphenyl) -2H-pyrazoloL-3,4-g] quinoxallan l- (3-thiopropionamido) -7- (3-fluorophenyl) -lH-pyrazoloC3,4-g3quinoxaline 2- (3-thioproionamido) -7- (3-fluorophenyl) -2H-pyrazoloC3, -gD-quinoxaline 1- (3-c boxi ti1) -7- (3- f1uoropheni1) -1H-pi only [3,4- l-kinoxaiin 2- (3-carboxyethyl) -7- (3-fluorophenyl) -2H-? IrazoloC3,4 ~ g] quinoxaline l- ( 2-N, N-dimethylaminoethyl) -7- (3-fluoro-methoxyphenyl) -lH-pyrazoloC3,4-g3quinoxaline 2- (2-N, N-imethylaminoethyl) -7- (3-fluoro-4-methoxyphenyl) -2H-pirazoloC3, -g] quino lina The compounds of this invention can be prepared by the following general reaction schemes.

STAGE fl STAGE Ba STAGE Bb Re X J 1) NaH, THF, 0 ° C < XCL & 2) R6I, r.t. -cco ^ STAGE C STAGE Da STAGE Db STAGE Ea STAGE Eb STAGE Fa STAGE Fb wherein: Re is defined as Ri and R2 and is other than hydrogen and acyl and R7 is acyl. Condensation as shown in step A of 5,6-dia inhindazole with a glyoxyloylthiophene in the presence of absolute alcohol gives or results in ring formation of a mixture of 6-t? Eml-lH-p? RazoloC3,4 -g3qu? noxal? na and 7-t? in? l-lH-p? razoloC3, 4-g) what? noxalma. These positional isomers can be separated by normal procedures, such as column chromatography. A similar preparation as shown in step C can be carried out to obtain feml-lH - ?? razolol.3,4-g3qu? Noxal? Na 6-subst? Tu? Da and fen? L-lH-p? RazoloC , 4-glqumoxaline 7-subst? Tu? Da. When the 6-t-emuls or 7-t? In? LlHp? RazoloC3,4-glquinoxalmas as shown in steps Ba and Ab are reacted with sodium hydride in a polar medium, such as THF at reduced temperatures, followed by treatment with a substituted alkyl halyide at room temperature results in a mixture of the 5-thienyl or 7-thienyl-1H-pyrazoloC3,4-g] 1-substituted quinoline and 6-thienyl or 7-thienyl-2H -pirazoloC3, 4-g] 2-substituted quinoxaline. If desired, a tosylate or alkyl mesylate may be employed instead of the alkyl halide. These positional isomers can also be separated by normal procedures, such as a columnar column. A similar preparation as shown in the stages Da and Db can be carried out to obtain 1-substituted-6-substituted phenyl or phenyl-1H-? IrazoloC3.4-g] 7-eubstituted quinoxaline and 2-substituted-d-eubstituted phenyl or phenyl-2H-pyrazoloC3,4 -g3 7-substituted uinoxaline. When it is desired to have an eubetitute in position 1 or 2 consisting of an aryl group as shown in steps Ea and Eb then 6-thienyl or 7-thienyl-lH-pyrazoloC3,4-g] quinoxaline is reacted, as shown above, with sodium hydride in a polar medium, such as THF at reduced temperature, followed by treatment, with the appropriate anhydrous at room temperature gives 6-thienyl or 7-thienyl-lH-pyrazoloC3, -g3quinoxaline 1-substiuide and 6-thienyl or 7-thienyl-2H-? irazoloC3.4-g3quinoxaline 2-substituted. These positional isomers can be separated by normal procedures, such as column chromatography. A similar preparation as shown in steps Fa and Fb is carried out to obtain 6-phenyl or 7-phenyl-1H-β-irazoloC3,4-g3-1-substituted-3-phenyl or 7-phenyl-2H-pyrazolo 3 , 2-substituted 4-g3quinoxaline. The starting materials of this invention are known or can be prepared by known methods using readily available materials. Thus, for example, a substituted acetylthiophene when treated with seienium oxide in an aqueous dioxane medium at elevated temperatures results in the corresponding substituted glyoxyloylthiophene. Likewise, the substituted glyoxyloylbenzenes can be prepared.

The compounds of this invention may be useful in the form of the free base, in the form of salts and as a hydrate. All forms are within the scope of this invention. Acid addition salts can also be formed and are simply a more convenient way to be used, and in practice, the use of the salt form inherently equals the use of the base form. The acids that can be used to prepare the addition salts preferably include those which, when combined with the free base, produce pharmaceutically acceptable salts, that is, salts whose amons are not toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial properties inherent in the free base are not vitiated by lateral effects attributed to the amones. Although pharmaceutically acceptable salts of said basic compound are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product, or, for example, when the salt is formed only for purification and identification purposes. , or when an intermediary is used to prepare a pharmaceutically acceptable salt by ion exchange processes. Pharmaceutically acceptable salts within the scope of the invention include those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and eulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, ethansulonic acid, ethanedic acid, benzenesulphonic acid, p-toluene sulfonic acid, cyclohexylsulfaric acid, chemical acid, and the like.

'.Y? The corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfarnate, acetate, citrate, lactate, tartrate, methanesulfonate, ethansulonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl sulfate and quinate, respectively. The acid addition salts of the compounds of this invention are prepared by dissolving the free base in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid or by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which the salt directly separates or can be obtained by the concentration of the solution. Certain compounds dr > This invention can have at least one asymmetric carbon atom. As a result, those compounds of this invention can be obtained as racemic mixtures, diastereomeric mixtures or co or individual enantiomers.The product can be synthesized as a mixture of the isomers and then the desired isomer is separated by conventional techniques such as chromatography or fractional crystallization. On the other hand, the synthesis can be carried out by known stereospecific methods using the desired form of the intermediate which would result in obtaining the desired stereospecificity It should be understood that the scope of this invention comprises not only the different isomers that may exist if not also the different mixtures of isomers that may be formed The resolution of the compounds of this invention and their starting materials may be carried out by known methods The incorporation by reference is made herein to the four-volume pendio Optical Resolution Procedures for Chemical Compounds: Optical Reeolution Information Center, Manhattan College, Riverdale, New York. Said methods are useful in the practice of this invention. Another useful reference is Enantio ers, Racernates and Resolutions: 3ean 3acques, Andre Collet and Samuel H. Uilen; John Uiley 8 Sons, Inc., New York, 1981. Basically, the resolution of compounds is based on differences in the physical properties of the distereros. The conversion of racernates into a mixture of diastereomers by adding an enantiomerically pure moiety results in forms that are separable by frictional crystallization, distillation or chromatography. Various substitutes in the novel present compounds may be present in the starting compounds, added to any of the intermediates or added after the formation of the final products by known methods of substitution or conversion reactions. If the substitutes themselves are reactive, then the substitutes can themselves be protected in accordance with techniques known in the art. A variety of protecting groups known in the art can be employed. Examples of many of these possible groups can be found in "Protective Groups in Organic Synthesis" by T.U. Green, 3ohn Wiley & Sons, 1981. For example, the nitro groups can be added by nitration and the nitro group converted to other groups, such as amino by reduction, and halo by diazotization of the amino group and replacement of the diazo group. The acyl groups can be added by Friedel-Crafts acylation. The acyl groups can then be transformed into the corresponding alkyl groups by different methods, including the Wolff-Kiehner reduction and the Clem-enson reduction. The amino groups can be alkylated to form nono- and di-alkylamino groups; and the mercapto and hydroxy groups can be alkylated to corresponding ethers. The primary alcohols can be oxidized by means of oxidizing agents known in the art to form carboxylic acids. In this way, substitution or alteration reactions can be employed to provide a variety of substitutes through the starting material molecule, intermediates, or the final product. The compounds of this invention can be prepared by employing procedures known in the literature starting from known compounds or readily preparable intermediates. Examples of general procedures are found below. The compounds of the present invention can be prepared by the following representative examples.

EXAMPLE 1 6- (5-chlorothien-2-yl) -lH-pyrazoloC3, 4-gIquinoxaline 7- < 5-chlorothien-2-yl) -lH-pyrazoloC3,4-g] quinoxaline STAGE A 2-chloro-5-glyoxyloylthiophene The selenium oxide (6.88%) is heated to dissolve in 100 ml aqueous dioxane (95: 5 dioxane: H2?). The 2-acetyl-5-chlorothiophene (5.00 g) is added to the mixture. The resulting mixture is refluxed overnight, then cooled. The precipitated selenium metal is filtered after solvent removal of a resulting coarse brown oil that solidifies at rest. The solid is heated to dissolve in 400 ml of filtered hot water and allowed to cool to room temperature. The precipitate was collected by filtration, washed with fresh H2O and dried to obtain a light brown bean. The second crop is obtained by extracting the mother liquor with ethyl acetate, separating, drying (MgSOi) and concentrating in vacuo to give a light yellow solid that at the time of HPLC treatment gives 2-chloro-5-glyoxy-thiophene, which is used directly in the next stage.

STAGE B BIS-chlorothien-1-D-lH-pyrazoloCS ^ -glquinoxaline 7- (5-chlorothien-2-yl) -lH-pyrazolo [3,4-gH-quinhoxaline To a mixture of 5,6-diaminoinda-. A solution of 2-chloro-5-glyoxyloylthiophene (0.72 g) and 20 ml of ethanol is added slowly to (0.5 g) in 30 ml of absolute ethanol. The resulting mixture is stirred at room temperature for 4.5 hours. The yellow solid that forms is filtered, washed with ethanol then with hexane and air dried overnight. The products are separated and purified by column chromatography on silica gel using 3%, 6% after 9% ethylacetate in methylene chloride as eluent to obtain 6- (5-chlorothien-2-yl) -lH-pyrazoloC3, 4-g3quinoxaline and 7- (5-chlorothien-2-yl) -lH-? IrazoloC3,4 -g3quinoxaline (mp> 300 ° C).

EXAMPLE 2 6- (Thien-3-yl) -lH-pyrazoloC3,4-g3quinoxaline 7- (thien-3-yl) -lH-pyrazoloC3,4-gJquinoxaline When the procedure of Example 1 is followed and 2-acetyl-5-chlorothiophene is replaced with 3-acetylthiophene, then the prepared products are 6- (thien-2-yl) -lH-pyrazoloC3,4-glquinoxaline and 7- (thien). -2-il) -lH-pi azoloC3,4- 3-quinoxaline.

EXAMPLE 3 6- (3-Fluoro-4-methoxy-enyl) -lH-pyrazoloC3, 4-gH-quinhoxaline 7- (3-fluoro-4-methoxy-enyl) -lH-pyrazolo-3,4-g3quinoxaline STAGE A l-methoxy-2-fluoro-4-glyoxyloylbenzene The selenium oxide (4,953 g) is heated to dissolve the 100 ml aqueous dioxane (95: 5 dioxane: H2?). The 3-f luoro-4-rnetoxiacetophenone (5.00 g) is added to the mixture. The resulting mixture is refluxed overnight after cooling. The precipitated selenium metal is filtered. The filtrate is concentrated in vacuo to give a thick brown gum. It is recycled from -200 ml of hot H2O, filtered hot and allowed to stand at room temperature overnight. The pale pink precipitated flake is filtered, washed with H2O and air dried to give l-methoxy-2-fluoro-4-glyoxyloylbenzene, which is used directly in the next step.

STAGE B 6- (3-fluoro-4-roetoxyphenyl) -lH-pyrazolo [3,4-g3-quinoxaline 7- (3-fluoro-4-methoxyphenyl) -lH-pyrazolo [3,4-g] quinoxaline To an ice-cooled mixture of 5,6-diaminoindazole (0.5 g) in 20 rnl of absolute ethanol is slowly added a solution of l-methoxy-2-fluoro-4-glyoxyloxy i 2 ene (0.75 g) in 30 rnl of ethanol. The resulting mixture is stirred at room temperature overnight. The solid that forms is filtered, washed with a small amount of ethanol then with hexane and air dried to give a yellow material. The products are separated and purified by silica gel column chromatography using 3%, 6% and then 9% ethylacetate in methylene chloride as eluent to obtain 7- (3-fluoro-4-methox? Fem) -lH- p? razoloC3,4-g] qumoxal? na (pt 283-285 ° 0) and then with 20%, 30% and 40% ethylacetate in methylene chloride as eluent to obtain 6- (3-fluoro-4-methoxy) ? l) -lH-p? razolot.3, 4-g3qu? noxalma (mp 250 ° C).

EXAMPLE 4 l-methyl-7- (5-chlorothien-2-yl) -lH-pyrazoloC3, -g] quinoxalirva 2-methyl-7- (5-chlorothien-2-yl) -2H-pyrazolol.3, 4- g3quinoxaline To an ice-cooled suspension of NaH (0.062 g) in 20 ml of anhydrous THF or 2 is added 7- (5-chlorot? En- -? L) -lH-p? RazoloC3.4-g] qu? Noxal ? na (0.63 g). The orange-ro mixture is stirred at the same temperature for 5 minutes, then lodonetano (0.374 g) is added in the form of drops to the orange- or a-mixture. The resulting mixture is stirred at room temperature overnight, then poured into water, extracted with methylene chloride, separated, dried (tleSO), concentrated in vacuo to give a yellow sol. Purification is by chromatography by eluting first with 5% ethyl acetate in hexane, then gradually up to 30% ethyl acetate in hexane to isolate l-rnet? L-7- (5-chlorothien-2-L!) -! Hp? RazoloC3 , -g3quinoxaline (mp 225-227 ° C), then up to 10% hexane in ethyl acetate to isolate 2-methyl-7- (5-chlorothien-2-yl) -2H-pyrazoloC3,4-g3quinoxaline (mp 222-224) ° C).

EXAMPLE 5 l-Methyl-7- (3-fluoro-4-methoxy enyl) -lH-pyrazolo [3,4- gUquinoxaline 2-roethyl-7- (3-fluoro-4-methoxy enyl) -2H-pyrazoloC3,4 - glquinoxaline When the procedure of Example 4 is followed and 7- (5-chlorothien-2-yl) -lH-pyrazoloC3,4-g] quinoxaline is replaced with 7- (3-fluoro-4-methoxyphenyl) -lH-p? RazoloC3 , 4-g quinoxaline, then the products prepared are l-met? L-7- (3-f luoro- -rnetox? Feml) -lH-p? RazoloC3,4-g3quinoxal? Na (mp 229-231 ° C) and 2-rnetyl-7- (3-luoro-4-methoxy phenyl) -2H ~ p? just C 3, 4-g qumoxaline (m.p. 201-205 ° C).

EXAMPLE 6 l-ethyl-7- (3-f luoro-methoxy phenyl) -lH-pyrazolo I.3,4-g3quinoxaline 2-ethyl-7- (3-luoro-4-roetoxyphenyl) -2H-pyrazoloC3,4- g] quinoxaline When the procedure of the example is followed and iodonetane is replaced with iodetane, then the prepared products are l-ethyl-7- (3-fluoro-4-methoxyphenyl) -lH-pyrazoloC3,4-g3quinoxaline (mp 164-171 ° C) and 2-ethyl-7- (3-fluoro-4-methoxyphenyl) -2H-pyrazoloC3, 4-g quinoxaline (mp 185-189 ° C).

EXAMPLE 7 l-acetyl-7- (3-fluoro-4-roetoxyphenyl-lH-pyrazolo [.3,4-glquinoxaline 2-acetyl-7- (3-fluoro-methoxyphenyl) -2H-pyrazoloC3.4- gjquinoxaline To a cold-cooled NaH solution (0.029 g) in 30 ml of anhydrous THF under N2 was added 7- (3-fluoro-4-methoxyphenyl) -1H-pyrazoloC3,4-g3quinoxaline. The orange-red mixture is stirred at the same temperature for 5 minutes, then anhydrous acetic acid (0.122 g) is added as drops to the mixture. A yellow solid is formed during additions of anhydrous acetic acid. The resulting mixture is stirred at room temperature overnight. The mixture is poured into water. The yellow solid is filtered, washed with water then with ether and dried. The product is purified by column chromatography by eluting with 15% ethyl acetate in hexane, 25% ethyl acetate in hexane then 5% ethyl acetate in methylene chloride to obtain 1-acetyl-7- (3-fluoro-methoxy phenyl) -lH-pyrazoloC 3, 4-g3quinoxaline (mp 261-265 ° C) and l-ac < -t.il-7- (3-fluoro-4- rnetoxy feni I) -2H-pi only C 3, 4 -g3 quinoxal i na.

EXAMPLE ? l-allyl-7- (3-luoro-4-roetoxyphenyl) -lH-pyrazoloC3J4-g3quinoxaline 2-allyl-7- (3-fluoro-4-methoxyphenyl) -2H-pyrazolo [3,4-g quinoxaline To a suspension of 0.50 g of 7- (3 ~ fluoro-4-? Netoxyphenyl) -. LH-pyrazoloC3,4-g3quinoxaline, 30 ml of anhydrous THF is added 0.061 g of 60% NaH. It is stirred at room temperature for 10 minutes, then alyl bromide of 0.206 g is added in the form of drops in the red mixture. The resulting mixture is stirred at room temperature overnight then poured into water, extracted with methylene chloride and the organic layer is separated, dried (2S0), concentrated in vacuo to give a yellow crude product. This is purified by silica gel column chromatography using rnetylene chloride, then changed to% -4% acetone / methylene chloride as the solvent system to obtain 1-allyl-7- (3-fluoro-4-methoxy) phenyl) -lH-pi razóloC 3,4-g3quinoxalina (mp 121-124 ° C) and 2-allyl-7- (3-fluoro-4-methoxyphenyl) -2H-pyrazoloC3,4-g3quinoxalina (mp 196-200 ° C).

EXAMPLE 9 l-benzyl-7- (3-f luoro-4-methoxy enyl) -lH-pyrazoloC 3, 4- g3quinoxaline 2-benzyl-7- (3-luoro-4-methoxyphenyl) -2H-pyrazoloC3,4- gjquinoxalina To a suspension of 0.50 g of 7- (3-fluoro-4-rnetoxifem) -lH-p? RazoloC3,4-g] quinoxaline, 30 ml of anhydrous THF is added 0.061 g of 60% NaH. The red-orange mixture is stirred at room temperature for 10 minutes, then 0.255 g of benzyl iodide is added and stirred at room temperature overnight. The mixture is filtered, washed with CH2Cl2. The filtrate and the washing of CH 2 Cl 2 are combined and mixed with water, extracted with CH 2 Cl 2, separated, dried (N 2 O 2) and concentrated in vacuo to give a crude yellow solid. It is purified by column chromatography with silica gel using the combination of ethyl acetate: exan: methylene chloride as solvent to obtain 1-benzyl-7- (3-fluoro-4-rnetoxifem) -! H-pyrazoloC3, 4-g3quinixali na (mp 149-155 ° C) and 2-benzyl-7- (3-fluoro-4-methox? Pheny1) -2H-p? RazoloC3,4-glqu? Noxaline (mp 225-227 ° C ).

EXAMPLE 10 l- (2-Butyryl) -6- (3-fluoro-4-methoxyphen-1) -2H-pyrazoloC3,4-g3quinoxaline 2- (2-t-butyryloxymethyl) -6- (3-fluoro-4-methoxyphenyl) ) -1H- pyrazolol.3,4-q3-quinoxaline NaH (60%, 1.84 g) is added slowly to the mixture of 15.04 g of β- (3-fluor-o-4-methox-fem) -lH-p? RazoloC3,4-glqumoxaline in 150 ml of anhydrous THF. This is stirred at room temperature for 15 minutes, then 7.7 g 2-t-butyloxodide iodide is added slowly dropwise into the mixture. The mixture is then stirred at room temperature. The mixture is filtered and the filtrate is washed with water, extracted with ethylene chloride, separated, dried (Na2SO.j) and concentrated in vacuo to give 13.46 g of crude yellow solid, which is purified by column chromatography. with silica gel using ethyl acetate: methylene chloride: hexane or eluent starting with the combination ratio of 1: 3: 6, respectively, and changing the ratio of the methylene chloride and hexane to the cause of the acetate. ethylene (e.g., 1: 3.5: 5.5; 1: 4: 5 1: 6: 3) to obtain 2- (2-t-butynyl? x? rnet? l) -6- (3-fluoro-4-) methox? feml) -lH-p? razolor3,4-g3-qu? noxal? na (mp 199-201 ° C).

EXAMPLE 11 l- (2-t-butyryl) -7- (3-fluoro-4-methoxyphenyl) -2 H -pyrrazoloC3,4-g3-quinoxaline 2- (2-t-butyryloxiroethyl) -7- ( 3-fluoro-4-methoxy enyl) -lH-5 pyrazoloC3, 4-g3-quinoxaline When the procedure of Example 10 is followed and 6- (3-fluoro-4-methox? Fem) -lH-p? RazoloC3, 4- glquinoxal ina is replaced by 7- (3-fluoro-4-methoxy phenyl) - IH-pi, ≤ 3, 4-10 qumoxaline, then the prepared products are l ~ (2-t-but? R? L) -7- (3-fluoro-4-methox? Feml) -2H-p? only l3, 4-g3-qumoxal na (mp 193-194 ° C) and 2- (2-t-butylox? rnet l) -7- (3-fluoro-4-meto? feml) -lH-? irazoloC3, 4-g -qu? Noxal? Na (mp 161-163 ° C). EXAMPLE 12 1- (2-acetoxyethyl) -7- (3-luoro-4-methoxyphenyl) -lH-pyrazoloC3, 4- g3qu noxaline 2- (2-acetoxyethyl- [7- 3-fluoro-4-methoxyphenyl) - 2H-pyrazoloC3,4-¿0 g3quinoxaline NaH (60%, 0.35 g) is added to a stirring solution of 2.14 g of 7- (3-fluoro-4-methox? Feml) -1H- ?? razoloC3,4-g] which is noxal in 30 my DMF anhydrous and stirred ^ 5 for 15 minutes, then add 1.34 g of 2-bromoetyl to the mixture slowly. The resulting mixture is stirred at room temperature for 2 1/2 hours, then it is poured into water and the product is filtered off, washed with water and dried. This is purified by column chromatography using 5% 20% ethyl acetate in ethylene color or as eluent to obtain 1- (2-acetoxy? Et? L) -7- (3-fluoro-methoxy? Phen) -IH-p? RazoloC3,4-g3qumoxal? Na (.f. 164-166 ° C) and 2- (2-acetoxietii) -7- (3-fluoro ~ 4-methox? Feml) -2H- ?? reason [3, í-g3qu? noxalma (p.f. 175-178 ° C). When 6- (3-fluoro-4-rnetox? Feml) - 1H-p? RazoloC3,4-g3qu? Noxalma is used in the above procedure, the prepared products are l- (2-acetox? Et? L) - 6- (3-fluoro-4-rnetoxy phenyl) -lH ~ p? RazoloC3, 4-g qu? Noxalma and 2- (2-acetox? Et? L) -6- (3-fluoro-4-methox? Feml ) -2H-p? Razolol3,4- what? Noxal? Na.

EXAMPLE 13 l-Carboethoxymethyl-7- (3-fluoro-4-methoxyphenyl) -lH-pyrazoloC3,4-g3qu? Noxaline 2-carboethoxymethyl-7- (3-fluoro-4-roetox? Phenyl) -2H-pyrazoloC3,4 - g3quinoxaline When the procedure of Example 12 is followed and the acetoxyethyl bromide is replaced with bro-ethyium acetate, then the prepared products are l-carboethoxetho-7 - (3-fluoro-4-methoxy? In? L) -lH - ?? razoloC3,4-g3qu? noxal? a (mp 179-181 ° C) and 2-carboethoxy? met? l-7- (3-fluoro-4-rnetox? -feml) -2H-p? razoloC3,4-g] qu? noxal? na EXAMPLE 14 l-carboxymethyl-7 (3-luoro-4-methoxy-enyl) -lH-pyrazoloC3,4-g3quinoxaline 2-carboxymethyl-7- (3-luoro-4-methoxy-phenyl) -lH-pyrazoloC3, -g3quinoxaline Add 1-carboethoxymethyl-7- (3-fluoro-4-rnetoxy? Phen?) -lH-?? razoloC3,4-g3qu? Noxaline (0.3 g) to a solution of KOH (0.22 g) in 15 ml of methanol The mixture is stirred at room temperature for 1 1/2 hours, then heated at 60 ° C for 2 hours. The mixture is concentrated in vacuo and the residue is stirred in 20 mL of 0.6 N aqueous HCl for 1/2 hour, then the solid is filtered, washed with water and ether and air dried to obtain 1-carbox? J -7- (3-fluoro ~ 4-methox? Phenyl) -lH-p? RazoloC3,4-g3quinoxal? Na (pf > 260 ° C). When the above procedure is followed and 1-carboethoxymethyl-7- (3-fluoro-4-methox-fem) -12H-p? RazoloC3,4-g3qu? Noxal? Na is replaced by 2-carboethoxy? Methyl-7 - (3-fluoro-4-methox? Phenyl) -lH-p? RazoloC3,4-g3qu? Noxal? Na, then the product prepared is 2-carbox? Met? L-7- (3-fluoro-4-methox) ? feml) -lH-p? razoloC3,4-g qu? noxalina.

EXAMPLE 15 l-Cyanomethyl-7- (3-fluoro-4-methoxyphenyl) -lH-pyrazolo 3,4 g3quinoxaline 2-cyanomethyl-7- (3-luoro-4-methoxyphenyl) -2H-pyrazoloE3,4-g3quinoxaline NaH (0.082 g) is added to a solution of 0.5 g of 7- (3-fluoro-4-methoxyphenyl) -lH-? IrazoloC3.4-g] quinoxaline and 10 ml of anhydrous DMF. The mixture is stirred for 15 minutes, then 0.22 g of bromine acetonitrite is slowly added to the mixture. The resulting mixture is stirred at room temperature for 48 hours, then poured into water. The product is collected by filtration, washed with water and dried with air and purified by chromatography using 5% -20% ethyl acetate in rnetylene chloride as eluent to obtain 1-cyanornetyl-7- (3-fluoro). -4-methoxy-phenyl-1) -lH-pyrazoloC, 4-glquinoxaline (mp 248-252 ° C) and 2-cyanomethyl-7- (-fluoro-4-rnetoxyphenyl) -2H-pi azoloC3,4-g quinoxaline.

EXAMPLE 16 l-r 2 -hydroxyethyl 3-7- (3-fluoro-4-methoxypheniH-lH-pyrazoloC3,4-gjquinoxaline To a mixture of 0.36 g of l- (2-acetoxyethyl) -7 ~ (3-fluoro-4-methoxyphenyl) -lH-pyrazoloC3,4-g3quinoxaline in 50 ml of THF: MeOH: H2? (3: 1: 1) 0.39 g of is added and the resulting mixture is stirred at room temperature overnight. The MeOH and THF m are stripped off and the yellow crystalline solid is precipitated out of the aqueous solution. More water is added to the mixture and cooled in a bath with ice for 1/2. The product is collected by filtration, washed with water and dried with air. The product is recpstalised from ethyl acetate, collected and dried with air to obtain 1-C2-hydroxyl and 3-3-7- (3-fluoro-4-methoxyl) -lH-?? razoloC3, - g] what? noxal? na (mp 192 ~ 195 ° C). EXAMPLE 17 2- [2-Hydroxyethyl 3-6- (3-fluoro-4-roetoxy) -2H-pyrazoloC3J4-g3quinoxaline When the procedure of example 15 is followed and l- (2-acetoxy? Et? L-7- (fluoro- -methoxyphenyl) -1H- pi razo lo C3, 4- qumoxal? A is replaced by 2- (2 -acetox? - »ll- 6- (3-fluoro-4-methoxyphenyl) -lH - ?? razolol.3, 4-g3qu? noxalma, then the product prepared is 2-C2-hydrox? et? l3- 6- (3-fluoro-4- 0 methox? Feml) -2H - ?? razoloC3,4-g3qu? Noxal? Na (mp 210-212 ° C).

EXAMPLE 18 lCi4R) -2,2-Dimethyl- [l-33-dioxolan-4-ylmethyl-3- (3-fluoro-4-methoxyphenyl) -lH-pyrazoloE3,4-g3quinoxaline 2C (4R) -2,2-dimethyl- [. l, 33-dioxolan-4-ylmethyl-3- (3-fluoro-methoxyphenyl) -2H-pyrazol C3,4-g3quinoxaline NaH (0.08 g) is added to stirring solutions of 0.5 g of 7- (3-fluoro-4-methoxyphenyl) -lH-pyrazoloyl-3,4-gjquinoxaline and 20 ml of anhydrous DMF. After 10 minutes of stirring, 0.393 g of (R) - (-) - 2,2-di-dialnetium-1,3-dioxalan-4-methanol mesylate is added to the mixture. The resulting mixture is stirred at room temperature for 2.5 hours, after which it is heated to gentle reflux for 2 hours. The mixture is poured into water and the precipitate is filtered off, washed with water and dried with air. The pro is purified - -_ >; by chromatography with silica gel using 5% -20% < ethyl acetate in rnetylene chloride as eluent to obtain 1C (4R) -2,2-dirnethyl-3,1-dioxolan-4-ylmethyl-3- (3-fluoro-4-methoxy) -lH-pyrazoloC3 , 4-g3quinoxaline (mp 145-151 ° C) and 2-L "(4R) -2, 2-dirnethyl-Cl, 33-dioxolan-4-ylmethyl-3- (3-fluoro-4-methoxyphenyl) -2H-pyrazoloC3 , 4-g3quinoxaline (mp 175-179 ° C).

EXAMPLE 19 1-C (2R) -l, 2Jd hydroxprop-3-yl) -7- (3-fluoro-4-roethoxyphenyl) -1) -lH-pyrazolo-C3,4-g3qu? Noxaline 2-C ( 2R) -l, 2-di-idroxiprop-3-yl) -7-t3-fluoro-4-methoxyphenyl) -2H-pyrazolo-C3,4-g3quinoxaline A mixture of 0.24 g of 1 C (4R) -2,2-d? Met? Li: 33 d? Oxolan-4? Lmet? I] -7- (3-fluoro-4) is refluxed overnight. -metox feml) -lH-p? razoloC3,4-g3qu? noxal? na (0.05 g) of p-toluene sulfate pipdimo and 20 ml of aqueous acetone (1: 4) H2?: Acetone). The acetone m is then stripped and the residue is mixed with ether, filtered and the yellow solid is treated with saturated NaHCO 3, filtered, washed with water and dried with air. It is recrystallized with ethyl acetate, filtered and dried overnight. This is then recrystallized from CHCl3 and the resulting product is purified by column chromatography using 3% MeOH in methylene chloride to obtain l-C2R) -l, 2-d? H? Drox? Prop-3-l) -? - (3-fluoro-4-methox? Phen? L) -lH-?? razolo-C3,4-g3qu? Noxal? Na (p.f. 228-234 ° C) and 2-L "(2R) - 1, 2-d? H? Drox? Prop-3 ~? L) -7- (3-f luoro-4 ~ methox? Phen? -2H-p? Razolo-C3,4-glqu? Noxal? Na.

EXAMPLE 20 l- (2-piperdin-1-ylethyl) -7- (3-fluoro-4-methoxyphenyl) -lH-pyrazoloC3,4-g3quinoxaline STEP A 1- (2-Toyosyloxyethyl) -7- (3-fluoror- 4-roethoxyphenyl) -lH-? IrazoloE3,4-g3quinoxaline Pyridine (0.83 g) is added slowly to a mixture of 1- (2-? Iperdin-1-yl) -7- (3-fluoro-4-methoxy phenyl) -1H-μirazoloC3, 4-g3qu? Noxal? Na (1.42 g), p-tosyl chloride (0.96 g) in 50 rnl of anhydrous CH 2 Cl 2. The resulting mixture is stirred at room temperature overnight. The TLC shows that the reaction is proceeding slowly so that 2.6 eq. of Et3 to the mixture and stirred overnight. The filtering salt is separated, washed with CH 2 Cl 2 and the filtrate is washed with water. The organic layer is separated, dried (Na2-S0u), concentrated in vacuo which recrystallizes upon standing. This is purified by chromatography using 5% ethyl acetate and methylene chloride as eluent to obtain J- (2-tosyloxyl) -7- (3-fluoro-4-methoxyphenyl) -lH-pi only C 3, 4-g3q? Inoxaline.

STEP B l- (2-piperdin-l-ylethyl) -7- (3-luoro-4-methoxyphenyl) -lH-pyrazoloC3,4-g3-quinnoxaline A mixture of l- (2- osi Joxiet il) -7- (3-fluoro-4-methoxy fem) -lH-pyrazolo [3,4-g 3 -quinhoxaline (0.3 g), piperdma (0.11 g) and 20 ral is stirred. of anhydrous DMF at room temperature overnight. The mixture is heated to gentle reflux for 2 1/2 hours. After cooling, it is poured into water and the precipitate is filtered, washed with water and dried with air. This is then purified by chromatography using (3: 7-1: 9) methylene chloride in ethyl acetate as eluent, 0.220 g of the desired product to obtain l- (2-??? l) -7- (3-fluoro-4-methox? feml) -lH-?? razoloC3,4-g3dqu? noxal? na (mp 117-120 ° C (dec)).

EXAMPLE 21 When the procedures of the preceding examples are followed, the following representative compounds can be prepared. 6- (3-fluorofeml) -lH - ?? razoloL ~ 3,4-g u? ox l? a 7 - (3-fluoro phenyl) -IH-pi razoloT3, 4-g] qu? oxal? a 6- (3-chlorophen? l) -1H-pi razoloL ~ 3, 4-g] qu? noxal na 7 - (3-chlorofeml) -lH-p? razoloL "3,4-gu? noxalma 6- (3-brornofeml) -lH - ?? razolo [" 3, 4-g3qumoxal i na 7- (3- chlorofen? l) -lH-p? razoloC3,4-g3 u? noxalma 6- (3-tr? fluorornet? lfen? l) -lH-p? razoloC3,4-g3qu noxal? na 7- (3-tr? fluoromet? lfeml) -lH-p? razoloC3, 4-g qu? noxalma 6- (3, 5-d? chloro in? l) -lH-p? razoloC3, 4-g qumoxal ina 7- (3,5-d? chlorofeml) -lH-p? razoloC3, 4-gu? noxal? a 6- (3-methox? feml) -lH- ?? razoloC3, 4-glqu? noxal? na 7- (3-rethoxyphenyl) -lH-pyrazoloC3, 4-g uinoxaline 6 - (4-methoxy phenyl) ~ lH ~ picazole C3, 4-g quinoxaline 7- (4-methoxyphenyl) -lH-? irazoloC3,4- quinoxaline 6- (3-ethoxy phenyl) -lH-pyrazoloC 3,4-quinoxal ina 7- (3-ethoxy. .1) -lH-pyrazoloC3, 4-g3quinoxaline 6- (3, 4-dimethoxy phenyl) -lH-pyrazoloC3, 4-g.lquinoxaline 7- (3, -dimethoxy phenyl) -lH-pyrazoloyl-3,4-g3quinoxaline 6- (3,5-dimethoxyphenyl) -lH -pyrazolole C3,4-g quinoxaline 7- (3, 5-dimethoxyphenyl) -lH-pi R 4, 4-g3qui oxali to 6- (2,6-dimethoxyphenyl) -lH-pyrazoloC3, -] quinoxali a 7- (2,6-di-ethoxyphenyl) -lH-pyrazoloyl "3,4-quinoxaline 6- (2,5-dimethoxyphenyl) -lH-pyrazoloC3,4-g3quinox lina 7- (2,5-dimethoxyphenyl) -lH -pirazoloC3,4-g quinoxaline 6- (3-fluoro-4-ethoxyphenyl) -lH-pyrazoloC3, 4-g3quinoxali to 7- (3-fluoro-4-ethoxyphenyl) -lH-pyrazoloC 3, -g3quinoxaline 6- (3 -chloro-4-methoxyphenyl) -lH-? irazoloC3,4-g3 uinoxaline 7- (3-chloro-4-ethoxyphenyl) -lH-pyrazoloC3, 4-g3quinoxaline 6-benzyl-lH-pyrazoloC3,4-g uinoxali a 7 -benzyl-lH-pyrazoloC3,4-g quinoxaline 6-phenethyl-lH-pyrazoloC3,4-g3quinoxaline 7-phenethyl-lH-pyrazoloC3,4-g3 uinoxaline 6-benzyloxy-lH-pyrazoloC3, 4-g uinoxali to 7-benzyloxy -lH-pyrazoloC3,4-g quinoxaline 6-phenoxy-lH-pyrazoloC3,4-g3quinoxaline 7-phenoxy-lH-pyrazoloC, 4-g] quinoxaline 6-anilino-lH-? irazoloC3,4-g3 uinoxaline 7-amlino- lH-pyrazoloC3,4-g quinoxaline 6-phenytoin-lH-pyrazoloC3,4-g3quinoxaline 7-phenylthio-lH-pyrazoloC3,4-g quinoxaline 6-pyrid-2-yl-lH-pyrazolo [3,4-g quinoxali a 7-pyrid-2-yl-lH-pyrazoloC3, 4- lquinoxaline 6-pi id-3-yl-lH-pyrazole loC3,4-g quinoxaline 7-pyrid-3-yl-yl-pyrazoloC3,4-g quinoxali to 6-naphth-i-yl-iH-pyrazolo [3,4-g3-quinxoaline 7-naphth-l-yl-lH -pi azoloC3,4-g3 uinoxaline 6-naphth-2-yl-lH-pi azoloC3, 4-g3 uinoxaline 7-naphth-2-yl-lH-pyrazoloC3,4-quinoxaline - (N-methylbenzylamino) -lH-pyrazoloC3 , 4-g quinoxali a - (N-methylbenzylamino) -lH-pyrazoloC3,4-g quinoxaline 6-benzyloxymethyl-lH-pyrazoloC3,4-g3quinoxaline 7-benzyloxymethyl-lH-pyrazolo [3,4-g3quinoxaline 6-Phenylthiomethyl-1H-pyrazoloC3,4-g quinoxin 7-phenylthiomethyl-1-lH-? IrazoloC3,4-g uinoxaline 6-phenoxymethyl-1H-pyrazolo 3,4-g quinoxaline 7-phenoxyrnethyl-1-lH-pyrazoloC3 , 4-g3quinoxaline 6- (2-ethylphenyl) -lH-pyrazoloC3,4-g quinoxaline 7- (2-methylphenyl) -lH-pyrazoloC3,4-g] quinoxaline 6- (3-methylphenyl) -lH-pyrazoloC, 4-g quinoxaline 7- (3-methylphenyl) -lH-pyrazoloC3,4-g3q? Inoxaline 6- (4-methylphenyl) -lH-pyrazolo [3,4- qui-oxaline 7- (4-methylphenyl) -lH-pyrazoloC3,4-g quinoxaline 6- (2, 4-dimethylphenyl) -lH-pyrazolo £ 3,4-g quinoxaline 7- (2,4-d? Rnet? Lfen? L) -lH-? razoloC3, 4-g3qu? noxal? a 6- (3, 4-d? met? lfe l) ~ lH-p? razoloC3, 4-g qu? noxalma 7- (3,4-d? met? lfeml) -lH-p? razoloC3, 4- g3qu? noxal? na 6- (3-c? anoteml) -lH-p? razoloC3,4-lqu? noxal na 7- (3-c? anofen? l) -lH-p? razolo [3,4-g3qu ? noxal? na 6- (4-c? anofeml) -lH-pyrazoloC3,4-g3qu? noxal? na 7- (3-c? anofen 1) -lH-p? 1., 4-g3qu? noxalma l-met? l-7- (t? en -3? l) -lH-p? razoloC3,4-g qu? noxal? na 2-met? l-7- (t? en -3? l) -2H-p? razoloC3,4-gu? nox l ina l- (2-methox? et? l) -7- (t? en -3? l) -lH -p? razolor3,4-gu? noxal? na 2- (2-rnetox? Et? L) -7- (t? En -3? L) -2H-p? RazoloC3,4-g qu? Noxal? Na l-acetam? Do-7- (t? in-3-? l) -lH-p? razoloC3,4-gu noxal? na 2-acetam? do-7- (t? en -3? l) -2H - ?? razoloC3,4-g3qu? noxal ? n l- (p? r? d -3? lmet? l) -7- (3-fluoro-4-methox? feml) -lH-p? razoloC3,4-g3qu? noxal? na 2- (p ? r? d -3? lmet? l) -7- (3-fluoro-4-methox? feml) -2H-p? azoloC3,4-glqumoxal i na l- (p? pd-2-? lmet? l) -7- (3-fluorofen? l) -lH-p? razoloC3, 4- g3qumoxal? na 2- (p? pd- 2-? Lmet? L) -7- (3 ~ luorofen? L) -2H-p? RazoloC3,4-glquinoxaline lh? Drox? Et? L-7- (t? En -3? L) -lH- ??? razoloC3,4-g qu? noxalma 2-h? drox? et? l-7- (t? en -3? l) -2H-p? razoloC3,4-g3qu? noxal? na l- (2 -N, Nd? Et? L cetamido) -7- (3-fluoro-4-methox? Fe l) -lH- p? RazoloC3,4-g3-qu? Noxal? Na 2- (2-N, Nd? Et lacetamido) -7- (3-fluoro-4-methox? Phen l) -2H- pyrazoloC3,4-quinoxaline l- (3-thio? Roranoquin) -7- (3-fluorophenyl) -lH- pyrazoloC, 4- g3quinoxaline 2- (3-thio-roranoquin) -7- (3-fluorophenyl) -2H-pyrazolo [3, 4- g3quinoxaline l- (3-carboxyethyl) -7- (3-f-fluorophenyl) -lH -pi razólo C3, - g3quinoxalina 2- (3-carboxietil) -7- (3-fluorophenyl) -2H-pirazoloC3,4- g qui oxalina 1- (2-N, N-dimethylarninoethyl) -7- (3- fluoro- -methoxy phenyl) -1H- pyrazolo-C3,4-g3quinoxaline 2- (2-N, -dimethylaminoethyl -7 (3-fluoro-4-methoxy phenyl) -2H-pyrazolo-C3, 4-glquinoxaline3 PREPARATION OF PHARMACEUTICAL COMPOSITIONS AND SECTION PHARMACOLOGY OF TESTS Compounds within the scope of this invention exhibit significant activity as inhibitors of the protein tyrosine kinase and possess therapeutic value as cellular antiproliferative agents for the treatment of certain conditions including psoriasis damage., ateróeselerosie and restenosis. The invention is expected to be particularly applicable to the treatment of atherosclerosis. With regard to the treatment of some conditions, for example, atherosclerosis, certain people can be identified as being at high risk, for example, due to genetic, environmental or historical factors. Compounds within the scope of the present invention exhibit modulation and / or inhibition of cell signaling, cell proliferation, cellular inflammatory response, control of abnormal cell growth and can be used to prevent or delay the appearance or reappearance of such conditions or treat the condition. To determine the efficacy of the compounds of this invention, the following pharmacological tests described below are used, which are accepted in the art and recognized to correlate with pharmacological activity in mammals. The compounds within the scope of the invention have been subjected to these various tests, and it is believed that the results obtained correlate with the useful cellular antipoliferative activity. The tests described below are useful for determining the inhibition activities of the EGF receptor kinase, the PDGF receptor kinase, and the insulin receptor kinase of the compounds described herein. It is believed that the results of these tests provide sufficient information to persons skilled in the pharmacological and medicinal chemistry techniques to determine the parameters for using the compounds studied in one or more of the therapies described herein. In order to test the present compounds as inhibition, the following pro is used. tion that uses PDGF stimulation. "IC50", as used below, refers to the concentration of inhibitor (mM) at which the afo-phospholation ratio is reduced by half, compared to media containing no inhibitor.

Inhibition of PDG-R autophosphorylation One third of the NTH 3T3 cells were diluted in Triton free pH buffer and stimulated with PDNF / rnL of PDGF for 30 minutes at 4 ° C. The equivalent of 1/15 of a 175 cm2 plate was used per sample. With polyclonal antibodies the rabbit anti-PDGF receptor cultured against a synthetic peptide from the COOH terminal region (amino acids 1094-1106) or the human β subunit of the PDGF receptor was added to growing concentrations of the test compound of the present invention. After 10 minutes at 4 ° C, 10 μCi of Ct-32p] pjP were added and further incubated for 10 minutes at 4 ° C. The samples were separated by SDS-PAGE on b% gels.

Inhibition of Cell Proliferation as Measured by Inhibition of DNA Synthesis Overexpression cells (HER14) of the EGF receptor were seeded at a rate of 1 x 10 5 cells per dish in Costar dishes of 24 receptacles coated with human fibronectin (incubating for 30 minutes). minutes at room temperature with 10 ug / 0.5 ml / receptacle). The cells are grown to confluence for 2 days. The medium is changed to DMEM containing 0.5 of the calf serum for 36-48 hours and the cells are then incubated with EGFÍToyobo, New York, NY) (20 ng / ml), PDGF CArngen) (20ng / ml) a serum ( 10% calf serum, FCS) and different concentrations of the compound of the present invention. Thymidine C3H3 (NEN, Boston, MA) is added 16-24 hours later at 0.5uCi / ml for 2 hours. Quantitative material is quantified in TCA by scintillation counting (4 ° C). The results of this test are determined. The "IC50" of the concentration of the inhibitor (nM) is calculated, to which the thymidine incorporation is divided in half [3H, in comparison with the means that do not contain a pH regulator. Since FCS contains a wide range of growth factors, the ICso values for PDGF should be lower than for FCS, which indicates that the compounds of the present invention do not act as general inhibitors. These results of these tests indicate that the compounds within the scope of the invention inhibit the PDGF receptors of the growth factor. The following tables show examples of representative compounds of this invention and the results of their tests as determined by the above inhibition by the cell-free self-consolidation procedure of PDGF-R.

COMPOUNDS Inhibition of cell-free autophosphorylation of PDGF-R IC50 Í) The results obtained by the above experimental methods demonstrate the useful inhibitory properties of the tyrosine protein kmase of the compounds within the scope of the present invention and possess a therapeutic value as cellular proliferating agents. The above results of pharmacological tests can be used to determine the dosage and mode of administration of the particular therapy sought. The compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, i.e. orally or parenterally. Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intersmodial, t ransepi telial including transderrnica, optalmic, sublingual and buccal; Topical including ophthalmic, dermal, ocular, rectal and nasal inhalation by means of insufflation and aerosol and recto-sistemica. The active compound can be administered orally, for example, with an inert diluent or with an edible assimilable carrier, or it can be included in gelatin capsules with a hard or soft layer, or it can be compressed into tablets, or it can be directly incorporated with the diet food. For oral therapeutic administration, the active compound can be incorporated with excipient and used in the form of mgendable tablets., oral tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions and preparations can be varied, of course, and can conveniently be between about 2 and about 6% of the weight of the unit. The amount of the active compound in such therapeutically useful compositions is such that adequate dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that a unit form for oral dosage contains between about 1 and 1,000 mg of the active compound. The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as calcium phosphate; a disintegrating agent such as corn starch, potato starch, algic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin can be added or a sabotating agent such as peppermint, pyrogenic or cherry oil. When the unit dosage form is a capsule, it may contain, in addition to the ingredients of the above type, a liquid carrier. Various other ingredients may be present with coating or modifying the physical form of the dosage unit. For example, tablets, pills or capsules can be coated with lacquer, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, ethyl- and propylparabens as preservatives, a dye and sabopzante such as cherry or orange flavor. Of course, any ingredient in the preparation of any unit dosage form must be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into the sustained release preparations and formulations. The active compound can also be administered parenterally and intraperitoneally. Solutions of the active compound can be prepared as a free base or pharmacologically acceptable salt in water suitably mixed with a surfactant such as hydroxypropylcellulose. The dispersion in glycerol, liquid polyethylene glycols and mixtures thereof and in oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative agent to prevent the growth of microorganisms. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that there is easy injection capacity. It can be stable under manufacturing and storage conditions and must be preserved against the contaminating action of rnic oorga smoe such as bacteria or fungi. The carrier may be a solvent medium or dispersion containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures thereof, and vegetable oils. Fluidity itself can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be produced by various agents against bacteria and fungi, for example, parabens, chlorobutanol, phenol, soric acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be produced by the use of agents that delay absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with several of the other ingredients made above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and the other ingredients required from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying technique which produce a powder of the active ingredient with any other desired ingredient of the solution thereof. previously filtered until sterilized. The therapeutic components of this invention can be administered to a mammal, alone or in combination with pharmaceutically acceptable carriers, as indicated above, the proportion of which is determined by the solubility and chemical nature of the compound, the route of administration chosen and the established pharmaceutical practice. The dosage of the present therapeutic agents which will be very suitable for prophylaxis and treatment will vary with the form of administration, the particular-chosen compound and the physiological characteristics of the particular patient under treatment. Generally, small dosages will be used and if necessary, they will be increased in small increments until the optimum effect is reached under the circumstances. The human therapeutic dosage, based on physiological studies using rats, will generally be from about 0.01 mg to about 100 mg per kg of body weight per day or from about 0.4 mg to about 10 mg or more, although it can be administered in several different units of dosage one to several times a day. Oral administration requires higher dosages.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound according to the formula: where: it can be a double bond; i or R2 is hydrogen, acyl, 1,2-dihydroxyethyl ,. 1, 2-dihydroxyprop-3-yl, or R5 (CR) X-X; R3 or 4 is v - Ar being the other hydrogen; Rsn is H, alkyl, hydroxy, alkoxy, carboxy or carba oyl; R is hydrogen or alkyl; X is hydrogen-C-C-alkyl, alkenyl, hydroxy, 1,2-dihydroxy-thio, 1,2-dihydroxy-3-yl, alkoxy, carboxy, carbalkoxy, acyl, acyloxy, amino, mono- or di-alkyl- amino, acylamino, cyano, carbamoyl, acylcarbamoyl, mono- or di-alkylcarbamoyl, thiocarba oyl, mono- or di-alkylthiocarba oyl, acylthiocarbamoyl, 2,2-dialkyl-1, 3-dioxolan-5-yl, -tetrazolyl, piperidinyl, pyridyl, phenyl, or substituted phenyl wherein the substitution may be one or two groups independently selected from alkyl, alkoxy, carboxy, carbalkoxy, carbamoyl, mono- or di-alkylcarbamoyl, thiocarba oyl, mono- or di- alkylthiocarbamoyl, halogen or haloalkyl; Y is a bond, (CH2H-3., (CH2) nO (CH2), (CH2) nS (CH2) m, or (CH2) nNR (CH2) m; ny or are independently 0-3 and n + m = 0-3; x is 1-3; Ar is phenyl, substituted phenyl, thienyl, substituted thienyl, pipdyl, substituted pyridyl, - or β-naphthyl or a- or. {3-naphthyl) substituted where the substitution may be being one or two groups independently selected from alkyl, hydroxy, alkoxy, halogen, haloalkyl or cyano, or a pharmaceutically acceptable salt thereof 2. A compound according to claim 1 of the formula: R1 3. - A compound according to claim 1 of the formula: 4. - A compound according to claim 1 of the formula: 5. - A compound according to claim 1 of the formula: 6. - A compound in accordance with the claim 2 of the formula: ? . - A compound according to claim 2 of the formula: R? 8. - A compound of cor. i. tnity with claim 3 of the formula: 9. - A compound in accordance with the claim 3 of the formula: 10. - A compound according to claim 4 of the formula: 11. - A compound according to claim 4 of the formula: 12. - A compound according to claim 5 of the formula: 13. - A compound according to claim 5 of the formula: 14. - A compound according to claim 6 of the formula: 15. - A compound according to claim 7 of the formula: 16. - A compound according to claim 11 of the formula: 17. - A compound according to claim 11 of the formula: 18. - A compound according to claim 11 of the formula: CH CH 19. - A compound according to claim 11 of the formula:? H 20. - A compound according to claim 11 of the formula: H3 21. - A compound according to claim 11 of the formula: 22. - A co-operation in accordance with claim 7 of the formula: 23. - A pharmaceutical composition for inhibiting cell proliferation consisting of an amount effective to inhibit the PDGF receptor of a compound according to claim 1 which is mixed with a pharmaceutically acceptable vehicle. 24. The use of a pharmaceutical composition according to claim 23, in the preparation of a medicament for inhibiting cell proliferation in a patient suffering from a disorder characterized by such a roliferation.