MXPA99011026A - Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases - Google Patents

Abstract

This invention is directed to quinoline/quinoxaline compounds which inhibit platelet-derived growth factor or p56lck tyrosine kinase activity, to pharmaceutical compositions comprising these compounds, and to the use of these compounds for treating a patient suffering from or subject to disorders/conditions involving cellular differentiation, proliferation, extracellular matrix production or mediator release and/or T cell activation and proliferation

Description

QUINOLINE AND QUINOXALINE COMPOUNDS THAT INHIBIT GROWTH FACTOR DERIVED FROM PLATELETS AND / OR p56 ** TIROSINE KINASES BACKGROUND OF THE INVENTION 1. Field of the invention This invention is directed to the inhibition of cell proliferation and / or cell matrix production and / or cell movement (chemotaxis) and / or activation and proliferation of T cells using quinoline / quinoxaline compounds that tyrosine kinase inhibitors (TKI) are useful. Cell signaling is mediated through a system of interactions that include contact between cells or contact between cell and matrix or contact between extracellular receptor and substrate. The extracellular signal is commonly communicated to other parts of the cell by means of a tyrosine kinase-mediated phosphorylation event that affects the substrate proteins downstream of the membrane of the cell bound to the signaling complex. A specific set of receptor enzymes such as the insulin receptor, the epidermal growth factor receptor (EGF-R) or the platelet-derived growth factor receptor (PDGF-R) are examples of tyrosine kinase enzymes that are involved in cell signaling. The autophosphorylation of the enzyme is required for efficient enzyme-mediated phosphorylation of substrate proteins containing tyrosine residues. It is known that these substrates are responsible for a variety of cellular events including cell proliferation, cell matrix production, cell migration and apoptosis to name a few. It is understood that a large number of disease states is caused either by the uncontrolled reproduction of cells or by matrix overproduction or programmed poorly regulated cell death (apoptosis). These disease states include a variety of cell types and include disorders such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, atherosclerosis and restenosis subsequent to angioplasty of the coronary, femoral or kidney arteries, or fibroproliferative diseases such as arthritis, fibrosis of the lung, kidney and liver. In addition, dysregulated cell proliferative conditions continue after coronary bypass surgery. It is believed that the inhibition of tyrosine kinase activity has utility in the control of uncontrolled cell reproduction or in overproduction of matrix or poorly regulated programmed cell death (apoptosis). It is also known that certain tyrosine kinase inhibitors can interact with more than one type of tyrosine kinase enzyme. Several tyrosine kinase enzymes are critical for the normal functioning of the body. For example, it would not be desirable to inhibit the action of insulin in most normal circumstances. Therefore, compounds that inhibit the activity of PDGF-R tyrosine kinase at concentrations lower than the effective concentrations for inhibiting insulin receptor kinase could provide valuable agents for the selective treatment of diseases characterized by cell proliferation and / or production of cell matrix and / or movement of cells (chemotaxis) such as restenosis. This invention relates to the modulation and / or inhibition of cell signaling, cell proliferation, extracellular matrix production, chemotaxis, the control of abnormal cell growth and the inflammatory response of cells. More specifically, this invention relates to the use of substituted quinoxaline compounds that exhibit selective inhibition of differentiation, proliferation or mediating release by effectively inhibiting tyrosine kinase activity and / or Lck tyrosine kinase activity of the growth factor receptor derived from platelet (PDGF-R). 2. BACKGROUND OF THE INVENTION A number of literature reports describe tyrosine kinase inhibitors that are selective for tyrosine kinase receptor enzymes such as EGF-R or PDGF-R or non-receptor cytosolic tyrosine kinase enzymes such as v-abl., p56lck or c-src. Recent articles by Spada and Myers (Exp. Opin. Ther.Patents 1995, 5 (8), 805) and Baridges (Exp. Opin. Ther.Patents 1995, 5 (12), 1245) summarize the literature for tyrosine kinase inhibitors and selective EGF-R inhibitors respectively. In addition, Law and Lydon have condensed the anticancer potential of tyrosine kinase inhibitors (Emerging Drugs: The Prospect For Improved Medicines 1996, 241-260). The known inhibitors of the tyrosine kinase activity of PDGF-R include the quinoline-based inhibitors reported by Maguire et al. (J. Med. ChemA994, 37, 2129) and by Dolle et al (J. Med. Chem. 1994, 37, 2627). A class of phenylamino-pyrimidine-based inhibitors was recently reported by Traxler et al in EP 564409 and by Zimmerman, J. and Traxler, P. et al. (Biorg. & Med. Chem. Lett. 1996, 6 (11), 1221-1226) and by Buchdunger, E. et al. (Proc. Nat. Acad. Sci. 1995, 92, 2558). Despite progress in the field, there are no agents of these classes of compounds that have been approved for use in humans to treat proliferative diseases. The correlation between the multifactorial disease of restenosis with PDGF and PDGF-R is well documented throughout the scientific literature. However, recent developments in the understanding of fibrotic diseases of the lung (Anoniades, H. N. et al J. Clin. Invest. 1990, 86, 1055), kidney and liver (Peterson, T.C. Hepatology, 1993, 17, 486) have also implicated PDGF and PDGF-R as playing an important role.

For example, glomerulonephritis is a major cause of renal failure and PDGF has been identified as a potent mitogen for mesangial cells in vitro, as demonstrated by Shultz et al. (Am. J. Physiol. 1988, 255, F674) and by Floege, et al (Clin. Exp. Imnun., 1991, 86, 334). It has been reported by Thornton, S.C. et al (Clin. Exp. Imnun., 1991, 86, 79) that FNT-alpha and PDGF (obtained from human patients with rheumatoid arthritis) are the main cytokines involved in the proliferation of synovial cells. In addition, specific types of tumor cells have been identified (see Silver, BJ, Biofactors, 1992, 3, 217) such as glioblastoma and Kaposi's sarcoma, which overexpress either the protein or the PDGF receptor thereby leading to uncontrolled growth of cancer cells by an autocrine or paracrine mechanism. Therefore, it is anticipated that a PDGF tyrosine kinase inhibitor would be useful for treating a variety of apparently unrelated human disease conditions that could be characterized by the involvement of PDGF and / or PDGF-R in its etiology. The role of various non-receptor tyrosine kinases such as p56 / c / c (hereinafter "Lck") under conditions related to inflammation involving the activation and proliferation of T cells has been reviewed by Hanke, et al (Inflamm Res. , 44, 357) and by Bolen and Brugge (Ann. Re. Immunol., 1997, 15, 371). These inflammatory conditions include allergy, autoimmune diseases, rheumatoid arthritis and rejection of transplants. Another recent review concludes several classes of tyrosine kinase inhibitors, including compounds that have Lck inhibitory activity (Groundwater, et al Progress in Medicinal Chemistry, 1996, 3, 233). Inhibitors of Lck tyrosine kinase activity include several natural products that are generally non-selective tyrosine kinase inhibitors such as staurosporine, genistein, certain flavones and erbstatin. Damnacantol was recently reported as a low nM Lck inhibitor (Faltynek, et al Biochemintry, 1995, 34, 12404). Examples of synthetic Lck inhibitors include: a series of dihydroxy-isoquinoline inhibitors reported to have low micromolar activity at submicromolar activity (Burke, et al J. Med. Cem. 1993, 36, 425) and a quinoline derivative which was found it was much less active with an IC50 of Lck of 610 micromolar. Researchers have also described a series of 4-substituted quinazolines that inhibit Lck on the low micromolar and submicromolar scale (Myers et al, WO 95/15758 and Myers, et al Bioorg, Med.Chem.Lett.R. 1997, 7, 417) . Researchers at Pfizer (Hanke, et al J. Biol. Chem. 1996, 271, 695) have described two specific pyrazolopyrimidine inhibitors known as PP1 and PP2, which have low nanomolar potency against Lck and Fyn (another Src family of kinase) . No inhibitory activity of Lck has been reported that refers to quinoline or quinoxaline-based compounds. ThusIt is anticipated that an inhibitor of LK tyrosine kinase activity based on quinoline or quinoxaline would be useful to treat a variety of morbidly unrelated human disease conditions that could be characterized by the involvement of Lck tyrosine kinase signaling in its etiology.

BRIEF DESCRIPTION OF THE INVENTION This invention is directed to a compound to the formula wherein R-a is optionally substituted alkyl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy, optionally substituted heterocyclylcarbonyloxy or halogen; Rib is hydrogen, optionally substituted alkyl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy, optionally substituted heterocyclylcarbonyloxy or halogen; R-ic is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocyclylcarbonyloxy, halogen, cyano, RßRßN- or acylR5N-; R3 is hydrogen, or ortho or for fluoro, or meta lower alkyl, lower alkoxy, halogen or carbamoyl; Rt is hydrogen or lower alkyl; R5 and R6 are independently hydrogen or alkyl, or R5 and Rβ taken together with the nitrogen atom to which R5 and R3 are attached form azaheterocyclyl; Za is N or CH; and Z is NH or O, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof or salt thereof, provided that R-? a and R-ib are not both optionally substituted alkyl. Another aspect of the invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula I and a pharmaceutically acceptable carrier. The invention is also directed to intermediates useful for preparing compounds of the formula I, to methods for the preparation of the intermediates and compounds of the formula I, and to the use of a compound of the formula I to treat a patient suffering from, or be subject to, disorders / conditions that involve cell differentiation, cell proliferation, production of extracellular matrix or mediator release.

DETAILED DESCRIPTION OF THE INVENTION As used above and throughout the description of the invention, it should be understood that the following terms have the following meanings, unless otherwise indicated: Definitions "Patient" refers to a mammal including a human. "Effective amount" means an amount of compound of the present invention effective to inhibit tyrosine kinase activity of PDGF-R and / or Lck tyrosine kinase activity, thereby producing the desired therapeutic effect. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched chain and having about 1 to about 10 carbon atoms. The alkyl that is preferred is "lower alkyl" having about 1 to about 3 carbon atoms; most preferably it is methyl. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl group is also optionally substituted by alkoxy, halogen, carboxy, hydroxy or R5RβN- (wherein R5 and Rß are independently hydrogen or alkyl, or R5 and R taken together with the nitrogen atom to which R5 and Rβ are attached form azaheterocyclyl ); preferably optionally substituted by fluoro. Examples of alkyl include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl. "Aryl" means an aromatic carbocyclic radical containing about 6 to about 10 carbon atoms. Exemplary aryl includes phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents which may be the same or different, wherein "aryl group substituent" includes hydrogen, hydroxy, halogen, alkyl, alkoxy, carboxy, alkoxycarbonyl or Y1Y2NCO-, wherein Y1 and Y2 are independently hydrogen or alkyl. "Eteroaryl" means an aromatic monocyclic or multicyclic hydrocarbon ring system of 5 to about 10 members in which one or more of the carbon atoms in the ring system is or are non-carbon elements, eg nitrogen, oxygen The "heteroaryl" can also be substituted by one or more of the "aryl group substituents" mentioned above Exemplary heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl. , furazanyl, pyrrolyl, imidazo [2,1-bjthiazolyl, benzofurazinyl, indolyl, azaindoyl, benzimidazolyl, benzothienyl, quinolyl, imidazolyl and substituted izoquinolinyl.

"Heterocyclyl" means a monocyclic or multicyclic ring system of about 4 to about 7 members in which one or more of the atoms in the ring system is an element that is not a carbon, chosen from nitrogen, oxygen or sulfur. The designation of the prefix aza or oxa as a prefix before heterocyclyl defines that at least one atom of nitrogen, or oxygen is present respectively as a ring atom. Monocyclic heterocyclyl groups include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Exemplary heterocyclic moieties include quinuclidinyl, pentamethylene sulfide, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydrofuranyl, or 4-piperidinopiperidine. "Heterocyclycarbonyloxy" means a heterocyclyl-C (O) O- group in which the heterocyclyl is as defined herein. An exemplary heterocyclylcarbonyloxy group is [1, 4 '] - biperidin-1' -carbonyloxy (4-piperidinopiperid-1-ylcarbonyloxy). "Acyl" means a group H-CO- or alkyl-CO- in which the alkyl group is as described above. The preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and caproyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. The preferred alkoxy is "lower alkoxy" having about 1 to about 3 carbon atoms; the most preferred is methoxy. The alkoxy can be optionally substituted by one or more of alkoxy, carboxy, alkoxycarbonyl, carboxiaryl, or R5RβN- (wherein R5 and Rβ are as defined above). Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, / -propoxy, n-butoxy, heptoxy, 2- (morpholin-4-yl) ethoxy, 2- (ethoxy) ethoxy. "Cycloalkyloxy" means a cycloalkyl-O- group in which the cycloalkyl group is as previously described. Exemplary cycloalkyloxy groups include cyclopentyloxy or cyclohexyloxy. "Heterocyclyloxy" means a heterocyclyl-O- group in which the heterocyclyl group is as previously defined. Exemplary heterocyclyloxy groups include pentamethyleneoxy sulfide, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy. "Aryloxy" means an aryl-O- group in which the aryl group is as previously defined. "Heteroaryloxy" means a heteroaryl-O- group in which the heteroaryl group is as previously described. "Acyloxy" means an acyl-O- group in which the acyl group is as previously described. "Carboxy" means a group HO (0) C- (carboxylic acid). "R5R6N-" means a substituted or unsubstituted amino group, wherein R5 and Rβ are as described above. Exemplary groups include amino (H2N-), methylamino, ethylmethylamino, dimethylamino and diethylamino.

"R5RβNCO-" means a substituted or unsubstituted carbamoyl group, wherein R5 and R6 are as previously described. Exemplary groups are carbamoyl (H2NCO-), and dimethylaminocarbamoyl (Me2NCO-). "ACÍI0R5N-" means an acylamino group in which R5 and acyl are as defined herein. "Halogen" means fluoro, chloro, bromo or iodo. Fluoro, chloro or bromo are preferred, and more fluoro or chloro is preferred. "Prodrug" means a form of the compound of formula I suitable for administration to a patient without undue toxicity, irritation, allergic response and the like, and effective for its desired dose, including ketal, ester and zwitterionic forms. A prodrug is transformed in vivo to produce the parent compound of the above formula, for example by hydrolysis in the blood. A careful description is provided in T. Higuchi and V. Stella. Pro-drugs as Novel Deliverv Systems. Vol. 14 of A.C.S. Symposium Series, and in Edward B. Roche, ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent binding, including hydrogen bonding.

In certain cases, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated into the crystalline structure of the crystalline solid. "Solvate" covers solvates of both phase in solution and isolates. Representative solvates include ethanolates, methanolates and the like. "Hydrate" is a solvate in which the solvent molecule is or are H2O.

Preferred Modes One aspect of the compound that is preferred in the invention is a compound of the formula I wherein R a is optionally substituted lower alkoxy, optionally substituted monocyclic cycloalkyloxy, or optionally substituted monocyclic oxaheterocyclyloxy; most preferably R-a is optionally substituted lower alkyl or monocyclic oxaheterocyclyloxy optionally substituted; and still most preferably R, a is methoxy, ethoxy, 2- (ethoxy) ethoxy, 2- (4-morpholinyl) ethoxy or furanyloxy. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R 1 is hydrogen, optionally substituted lower alkoxy, optionally substituted monocyclic cycloalkyloxy, optionally substituted heterocyclylcarbonyloxy or optionally substituted monocyclic oxaheterocyclyloxy; most preferably it is hydrogen or optionally substituted lower alkoxy; and still very preferably R- | is methoxy or ethoxy. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R a and Ri are lower alkoxy; preferably, lower alkoxy is methoxy or ethoxy.

Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R-? C is hydrogen or optionally substituted alkoxy; most preferably R? c is hydrogen, methoxy or ethoxy. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R2 is Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R2 is Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R3 is hydrogen, ortho or para fluoro, or metamethyl, trifluoromethyl, methoxy, fluoro, chloro, bromo or carbamoyl. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein R 4 is hydrogen or methyl; Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Za is N. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Za is CH.

Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Zb is NH. Another aspect of the compound that is preferred in the invention is a compound of the formula I wherein Zb is O. The preferred compounds according to the invention are selected from the following species: 2-anilino-6-quinoxaolin; 2 - ((R) -a-methylbenzylamino) -6,7-diethoxyquinol; 2-anilino-6-isopropoxyquinoxaline; 2-phenoxy-6-methoxyquinolaline; (3-bromobenzyl) - (6,7-dimethoxyquinolalin-2-yl) -amine; 2- (3-carbamoylphenylamino) -6-methoxyquinoline; 2- (2-fluorophenylamino) -6,7-dethoxyquinoxaline; 2- (3-trifluoromethylphenylamino) -6,7-diethoxyquinoline; Phenyl- [6- (tetrahydrofuran-3 (R) -yloxy) quinoxalyn-2-yl] amine; Benzyl- (6,7-d¡methoxyquinolalin-2-yl) -amine; 2 - ((S) -a-methylbenzyl-amino) -6,7-diethoxyquinolone; 2-benzylamino-6,7-diethoxyquinol; (6-methoxyquinolalin-2-yl) - (3-methylphenyl) -amine; 6-methoxy-2-phenylamino-quinoxaline; 2-anilino-6-etoxiquinoxaline; 2- (3-methoxyphenylamino) -6,7-diethoxyquinolaline; 2- (4-fluorophenylamino) -6,7-diethoxyquinolaline; 6,7-diethoxy-2-phenoxyquinolaline; 2-phenylamino-6,7-diethoxyquinoxaline; (6,7-dimethoxyquinolalin-2-yl) - (3-phuorophenyl) -amine; 2- (3-fluorophenylamino) -6,7-diethoxyquinolaline; (3-bromophenyl) - (6,7-dimethoxyquinolaln-2-yl) -amine; (6,7-dimethoxy-quinotoxalin-2-yl) -phenyl-amine; and (3-chlorophenyl) -) (6,7-dimethoxyquinolalin-2-yl) -amine. The most preferred species are the following: Phenyl- [6- (tetrahydrofuran-3 (R) -yloxy) quinoxalin-2-yl] amine; Benzyl- (6,7-dimethoxyquinolalin-2-yl) amine; 2 - ((S) -a-methylbenzyl-amino) -6,7-diethoxyquinolaline; 2-benzylamino-6,7-diethoxyquinolaline; (6-methoxyquinolalin-2-yl) - (3-methylphenyl) -amina; 6-methoxy-2-phenylamino-quinoxaline; 2-amino-6-etoxiquinoxaline; 2- (3-methoxyphenylamine) -6,7-diethoxyquinoline; 2- (4-fluorophenylamino) -6,7-diethoxyquinolaline; 6,7-diethoxy-2-phenoxyquinolone; 2-phenylamino-6,7-diethoxyquinolaline; (6,7-dimethoxyquinolaln-2-yl) - (3-fluorophenyl) -amine; 2- (3-fluorophenylamino) -6,7-diethoxyquinoline; (3-bromophenyl) - (6,7-dimethoxyquinol-2-yl) -amina; (6,7-dimethoxy-quinotoxalin-2-yl) -phenyl-amine; and (3-chlorophenyl) - (6,7-dimethoxyquinolalin-2-yl) amine. It should be understood that this invention covers all suitable combinations of the particular and preferred groupings mentioned herein. The compounds of this invention can be prepared using procedures known in the literature starting from known compounds or easily prepared intermediates. Following are exemplary general procedures. In addition, the compounds of the formula I are prepared according to the following schemes I-VI, wherein the variables are as described above, except those variables that one skilled in the art would appreciate were inconsistent with the described method.

SCHEME I SCHEME II SCHEME III SCHEME IV , cat. d SCHEME V SCHEME VI is lower alkoxy centaurea, oxaheterocyclyl or optionally substituted SCHEME VII 1 sust your or optm ona mind wherein R1a and R1b are acyloxy, alkoxy Optionally substituted, optionally substituted cycloalkyoxy, optionally substituted oxaheterocyclyloxy or optionally substituted heterocyclylcarbonyloxy.

I. GENERAL PROCEDURES 1. - Duplication of 2-chloro substituted quinoxaline and amines or anilines A mixture of 2-chloro-6,7-dimethoxyquinolaline (1 eq.) And an amine (about 1 to about 5 eq.) Was heated to about 160 to about 180 ° C for about 3 hours or overnight. The dark brown residue was dissolved in methanol / methylene chloride (0% -10%) and subjected to chromatography on silica gel eluted with hexane / ethyl acetate or methanol / methylene chloride (0% -100%) to give the desired product. The desired product can also be purified by recrystallization from methanol, methylene chloride or methanol / water. 2. - Duplication of 2-chloro substituted quinoxaline and alcohols or phenols A suspension of an alcohol or mercaptan (1 eq.) And sodium hydride (about 1 to about 3 eq.) In anhydrous DMF / THF (0% -50%) it was refluxed for 1 hour before adding 2-chloro-6,7-dimetixoquinoxaline (1 eq.). The resulting mixture was refluxed for 1 hour at about 4 hours. The suspension was neutralized to a pH of 5-8 and separated between methylene chloride and brine. After concentration, the methylene chloride residue was chromatographed on silica gel eluted with hexane / ethyl acetate or methanol / methylene chloride (0% -100%) to give the desired product. 3. - Reaction by reductive amination with amino-quinolines and aldehydes or ketones An appropriately substituted 3-aminoquinoline (1 eq.) Was stirred with 1 eq. of aldehyde or appropriate ketone in methanol (or other suitable solvent mixture) until the CCD indicated that mine formation was complete. Excess NaCNBH or NaBH4, or other suitable reducing agent was added and the mixture was stirred until the CCD showed intermediate consumption. The mixture was concentrated and the residue was chromatographed on silica gel with hexane / ethyl acetate (0-100%) or chloroform / methanol (0-20%) to give the desired product. 4. - Coupling reaction of 3-amino substituted quinolines and bromophenyl compounds An appropriately substituted 3-aminoquinoline (1 eq.) Was stirred with -1.4 eq. of a strong base such as sodium f-butoxide, 1 eq. of the suitable bromophenyl compound, and catalytic amounts of 2,2'-bis (diphenylphosphino) -1-1'-biphenyl (S-BINAP) and bis (dibenzyl dacetone) -Paladium (Pd (dba) 2) were mixed in a solvent Inert organic such as toluene under an inert atmosphere such as argon and heated to about 80 ° C overnight. The mixture was cooled, diluted with a solvent such as ether, filtered, concentrated and chromatographed with 50% EtOAc / hexane to give the desired product.

. - Formation of ether from 3-hydroxy substituted quinolines by Mitsunobu conditions A THF solution of a suitably substituted hydroxyquininoaline (from 0 to about 25 ° C) was treated with 1 eq. of each desired alcohol, triphenylphosphine and finally diethylazodicarboxylate (DEAD) or an appropriate equivalent. The progress of the reaction is monitored through CCD and after concluding the reaction (from 1 to about 24 hours) the mixture was concentrated and the residue was chromatographed on silica gel to give the desired product. 6. - Desalkylation of a quinoline or quinoxaline substituted with lower alkoxy, and subsequent alkylation A quinoline or quinoxaline substituted with suitable lower alkoxy (1 eq.) In DMF was treated with excess sodium enantiolate (usually about 2 or more equivalents) and the The reaction mixture was stirred with heating for 1 to about 24 hours. The mixture was separated between water and ethyl acetate. Extraction treatment followed by chromatography, if necessary, provides the corresponding suitable product of quinoline or hydroxy substituted quinoxaline.

The quinoline or hydroxy substituted quinoxaline product can be alkylated using the conditions for the Mitsunobu reaction as described above. Alternatively, simple alkylation using methods well known in the art with a reactive alkyl or benzyl halide using NaH or other appropriate base in a suitable solvent provides the desired alkylated product. 7. Oxidation of a nitrogen in a quinoline or quinoxaline for the corresponding N-oxide A portion of mine (= N-) in a quinoline or quinoxaline compound of formula (I), can be converted to the corresponding compound wherein the imine moiety is oxidized to an N-oxide, preferably by reaction with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at High temperature. The compounds of the present invention are useful in the free base or acid form or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention. If the compound of the present invention is substituted with a basic portion, acid addition salts are formed and are simply a more convenient form of use; and in practice, the use of the salt form is inherently equivalent to the use of the free base form. Acids which can be used to prepare the acid addition salts preferably include those which, when combined with free bases, produce pharmaceutically acceptable salts, that is, salts whose anions are not toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on PDGF inherent in the free base are not vitiated by side effects attributable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, by itself, is used only as an intermediate product such as, for example, , when the salt is formed only for purposes of purification, and identification, or when it is used as an intermediate to prepare pharmaceutically acceptable salt by ion exchange processes. The pharmaceutically acceptable salts within the scope of the invention are those that come from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalogenides, for example hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, cetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene bis-β-hydroxynaphthoates, gentisatos, mesylates, isethionates and di-p-toluoyltartrates methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl sulfamate and quinate, respectively. According to a further feature of the invention, the acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous solution or aqueous alcohol or other suitable solvents containing the appropriate acid and by isolating the salt by evaporating the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt is separated directly or can be obtained by concentration of the solution. The compounds of the invention can be regenerated from the acid addition salts by the application or adaptation of known methods. For example, the compounds of origin of the invention can be regenerated from their acid addition salts by treatment with an alkali, for example aqueous sodium bicarbonate solution or aqueous ammonia solution. When the compound of the invention is substituted with an acidic portion, the basic addition salts can be formed and are simply a more convenient form of use.; and in practice, the use of the salt form is inherently equivalent to the use of the free acid form. The bases which can be used to prepare the basic addition salts preferably include those which, when combined with a free acid, produce pharmaceutically acceptable salts, that is, salts whose cations are not toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on PDGF inherent in the free acid are not vitiated by the side effects attributable to the cations. Within the scope of the invention, the pharmaceutically acceptable salts, including for example alkali salts or alkaline earth metal salts, are those which are derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, hydroxide aluminum, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonic, triethylammonic, ethylenediamine, n-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, n-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, and the like. The metal salts of the compounds of the present invention can be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the selected metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or any mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Said reactions are normally carried out at room temperature, however, if desired, they can be carried out with heating. The amine salts of compounds of the present invention can be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. The amino acid salts can be prepared in a similar manner. The compounds of this invention can be regenerated from the basic addition salts by the application or adaptation of known methods. For example, the compounds of origin of the invention can be regenerated from their basic addition salts by treatment with an acid, for example, hydrochloric acid. In addition to being able to be used by themselves as active compounds, the salts of the compounds of the invention are useful for purification purposes of the compounds, for example by taking advantage of differences in solubility between the salts and the compounds of origin, products secondary and / or starting materials by techniques known to those skilled in the art. The compounds of the present invention may comprise asymmetric centers. These asymmetric centers may be independently in the R or S configuration. It will also be evicient for those skilled in the art that certain compounds of formula I may exhibit geometric shape. Geometric isomers include the cis and trans forms of compounds of the invention, ie, compounds having alkenyl substituent portions in the ring systems. In addition, the bicyclic ring systems include endo and exo isomers. The present invention comprises the individual geometric isomers, stereoisomers, enantiomers and mixtures thereof. Said isomers can be separated from their mixtures, by application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are prepared separately from the appropriate isomers of their intermediates, for example, by applying or adapting methods described herein. The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods that are described in the reference examples or their obvious chemical equivalents, or by methods described in accordance with the present invention. The present invention is also exemplified but not limited by the following illustrative examples that describe in the preparation of the compounds according to the invention. In addition, the following examples are representative of the procedures used to synthesize the compounds of this invention.

EXAMPLE 1 2- (3-Fluorophenylamino) -6.7-diethoxyquinolaline To 0.25 g (0.989 mmol) of 2-chloro-6,7-diethoxyquinoline was added 2 mL of m-fluoroaniline. This mixture was heated under nitrogen overnight at 120 ° C. The resulting mixture was subjected to chromatography (30: 1 CH2Cl2: EtOH) to give the partially purified product. This solid was triturated with ethyl acetate to give 0.175 g of the product as a brown yellow solid in 54.1% yield (mp 193 ° C). Anal. cale, for C18H18N3O2F.0.25 H2O: C, 65.15; H, 5.62; N, 12.66. Found: C, 65.30; H, 5.30; N, 12.41.

EXAMPLE 2 2-Anilino-6-methoxy-quinoxaiine hydrochloride To 2-chloro-6-methoxy-quinoxaline (0.93 g, 4.8 mmol) under argon was added aniline (1.3 mL, 14.3 mmol). The reaction mixture was heated at 120 ° C for 2 hours, then at 150 ° C for 1.5 hours. The mixture was cooled and CH2Cl2 was added. The resulting suspension was stirred and the orange solid was filtered, washed with CH2Cl2 / Et2, then vigorously stirred in H2O for 40 minutes, filtered, and washed with Et2O to provide a bright yellow solid.

The following compounds are prepared in a similar manner starting with the appropriate starting material. 2- (3-Carbamoylphenylamino) -6-methoxy-quinotoxaline, m.p. 247 ° C, Anal. cale, for C16H14N4O2 «0.25 H2O: C, 64.31; H, 4.89; N, 18.75. Found: C, 64.24; H, 5.04; N, 18.75; 2- (2-Fluorophenylamino) -6,7-d-ethoxyquinxaine, m.p. 184 ° C, Anal, cale, for C18H18FN3O2: C, 66.04; H, 5.54; F, 5.80; N, 12.84. Found: C, 65.75; H, 5.61; N, 12.68; 2- (3-Trifluoromethylphenylamino) -6,7-diettoquininoxaline, m.p. 158 ° C, Anal. cale, for C19H18F3N3? 2; C, 60.47; H, 4.81; F, 15.10; , 1 1.14. Found: C, 60.27; H, 4.84; N, 10.97; (6-Methoxyquinolalin-2-yl) - (3-methylphenyl) -amine, m.p. 133-135 ° C, Anal. cale, for C 16 H 15 N 3 O: C, 72.43; H, 5.70; N, 15.84. Found: C, 7243; H, 5.79; N, 15.77; 6-Methoxy-2-phenylamino-quinoxaline, m.p. 152-153 ° C, Anal. cale, for C15H13N3O: C, 71.70; H, 5.21; N, 16.72. Found; C, 71.70; H, 5.16; N, 16.80; 2-Anilino-6-etoxiquinoxalin, p.f. 118-120 ° C, Anal. cale, for C16H15N3O »0.63 H2O: C, 69.48; H, 5.92; , 15.19. Found; C, 69.24; H, 5.97; N, 15.14; 2- (3-Methoxyphenylamino) -6,7-diethoxyquinolaline, m.p. 173 ° C, Anal.

Cale, for C19H21N3O3: C, 67.24; H, 6.24; N, 12.38. Found; C, 67.02; H, 6.23; N, 12.21; 2- (4-Fluorophenylamino) -6,7-diethoxyquinoline, m.p. 242 ° C, Anal. Cale, for C18H18FN3? 2 »0.50 H2O: C, 64.27; H, 5.69; N, 12.49. Found: C, 64.21; H, 5.39; , 12.24; 2-Phenylamino-6,7-diethoxyquinolaline, m.p. 239 ° C; (6,7-Dimetoxiquinoxalin-2-yl) - (3-fluorophenyl) -amine, m.p. 99-100 ° C, Anal. cale, for C 16 H 4FN 3 O 2: C, 64.21; H, 4.71; F, 6.35; N, 14.04. Found: C, 64.35; H, 4.61; N, 13.84; 2- (3-Fluorophenylamino) -6,7-diethoxyquinolaline, m.p. 193 ° C, Anal. cale, for C? 8H18FN3O2 «0.25 H2O: C, 65.15; H, 5.62; N, 12.66. Found: C, 65.30; H, 5.30; N, 12.41; (3-Bromophenyl) - (6,7-dimethoxyquinolaln-2-yl) -amine, m.p. 197-198 ° C, Anal. Cale for C16H? 4BrN302: C, 53.35; H, 3.92; Br, 22.18; N, 11.67. Found: C, 53.39; H, 3.82; N, 11.64; (6,7-Dimetoxiquinoxalin-2-yl) -phenyl-amine, m.p. 88-90 ° C, Anal. cale, for C 16 H 15 N 3 O 2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.02; H, 5.52; N, 14.91; Y (3-Chlorophenyl) - (6,7-dimethoxyquinolalin-2-yl) amine, m.p. 187-188 ° C, Anal. cale, for: C? 8H14CIN3O2: C, 60.86; H, 4.47; Cl 11.23; N, 13.31. Found: C, 60.85; H, 4.59; N, 13.26.

EXAMPLE 3 2-Benzylamino-6,7-diethoxyquinoline To 0.3 g (1.19 mmoles) of 2-chloro-6,7-diethoxyquinoline was added 2 mL of benzylamine. This mixture was heated under nitrogen overnight at 120 ° C. The resulting mixture was separated between CH Cl2 and saturated NaHCO3 solution. The organic layer was concentrated, and the residue was subjected to chromatography (30: 1 CH2Cl2: EtOH) to give 0.337 g of the product as a yellow solid in 87.6% yield (mp 136 ° C). Anal. cale, for C19H2iN3O2: C, 70.57; H, 6.54; N, 12.99. Found: C, 70.54; H, 6.66; N, 12.80.

The following compounds are prepared in the same way starting with the appropriate starting materials. (3-Bromobenzyl) - (6,7-dimethoxyquinolalin-2-yl) amine, m.p. 199-206 ° C, Anal. cale, for: C17H16BrN3O2: C, 54.56; H, 4.31; Br, 21.35, N, 1 1.23. Found: C, 49.90; H, 4.00; N, 10.14.

Benzyl- (6,7-dimethoxyquinolaln-2-yl) amine, m.p. 210-214 ° C, Anal, cale, for: C17H? 7N302: C, 69.14; H, 5.80; N, 14.23. Found: C, 61.78; H, 5.47; N, 12.64; Y 2- (Benzylamino) -6,7-diethoxyquinol, p.f. 136 ° C, Anal. cale, for: C19H2? N3O2: C, 70.57; H, 6.55; N, 12.99. Found: C, 70.54; H, 6.66; N, 12.80.

EXAMPLE 4 2 - ((R) -a-Methylbenzylamino-6,7-diethoxyquinolaline To 0.3 g (1.19 mmol) of 2-chloro-6,7-diethoxyquinoline was added 2 mL of (R) -a - (+) - methylbenzylamine. This mixture was heated for three days under nitrogen at 120 ° C. The resulting mixture was separated between CHCl3 and saturated NaHCO3 solution. The organic layer was concentrated, and the residue was subjected to chromatography (30: 1 CH2CI2: EtOH) to give 0.118 g of the product as a yellow solid in 29.4% yield (mp 53-56 ° C). Anal. cale, for C2oH23N3O2 * 0.25 H2O: C, 70.26; H, 6.93; N, 12.29. Found: C, 70.56; H, 6.80; N, 12.35. The following compound was prepared in a similar manner, starting with the appropriate starting materials. 2 - ((S) -a-Methylbenzylamino-6,7-diethoxyquinoline, mp 55-58 ° C). Anal. cale, for C2oH23N3O2 »0.25 H2O: C, 70.26; H, 6.93; N, 12.29. Found: C, 70.49; H, 6.89; N, 12.23.

EXAMPLE 5 2,7-Bis-cyclohexyloxy-β-methoxy-quinoxaline To a solution of DMF (5 mL) of NaH (0.32 g, 8 mmol) under argon, cyclohexanol was added dropwise (0.7 mL, 6.7 mmol). The mixture was stirred at room temperature for 25 minutes, then 2-chloro-6,7-dimethoxyquinolaline was added in portions. The reaction was stirred for 15 minutes at room temperature, at 90 ° C for two hours, and at 110 ° C for one hour. The mixture was cooled, quenched with H2O, and separated between EtOAc / H2O. The organic layer was washed with H2O and brine, dried (MgSO4), and chromatographed (10% EtOAc / hexanes) to give a white waxy solid (mp 75-78 ° C) Anal. cale, for: C21H28N203: C, 70.76; H, 7.92; N, 7.86. Found: C, 70.81; H, 7.79; N, 7.70. The following compounds are prepared in the same way starting with the appropriate starting materials. 2-phenoxy-6-methoxyquinolaline, m.p. 79-81 ° C; and 6,7-diethoxy-2-phenoxyquinoline, m.p. 130-131 ° C; Anal. cale, for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03; found: C, 69.53; H, 5.82; N, 8.91.

EXAMPLE 6 Cyclohexyl- (6,7-dimethoxyquinolalin-2-ylmethyl) -amine To a solution of 6,7-dimethoxy-2-quinoxaline carboxaldehyde at 0.067 M in 2: 1 MeOH / 1,2-dichloroethane (7.5 ml, 0.5 mmol), cyclohexylamine (0.11 ml, 0.9 mmol) is added. The reaction is allowed to stir at room temperature overnight, then NaBH4 (0.038 g, 1 mmol), and the reaction mixture is stirred overnight. The mixture is then concentrated and chromatographed (50% EtOAc / hexanes, approximately 5% MeOH in 50% EtOAc / hexanes). The oil dissolves in EtOAc / hexanes and treated with HCl in EtOH. The resulting solution is concentrated, and the solids are triturated with isopropanol to give a white solid after drying under vacuum at 60 ° C (mp 185-190 ° C.). Anal. cale, for C17H23N3O2 «HCl: C, 60.44; H, 7.16; N, 12.44; found: C, 60.48; H, 6.88; N, 12.07.

EXAMPLE 7 Cyclohexyl- (6-methoxy-7-morpholin-4-l-quinoxalin-2-yl) -amine This preparation is based on an adaptation of the method described by Buchwaid et al., J. Am Chem. Soc, 1996, 118, 7215. To a toluene solution of 2-cyclohexylamino-6-methoxy-7-bromo-quinoxaline (0.1 g) , 0.3 mmoles) under argon, morpholine (0.1 g, 0.3 mmol), sodium tert-butoxide (0.04 g, 0.42 mmol), S - (-) - BINAP (cat., 0.001 g) and Pd (dba) 2 are added. (cat., 0.001 g). The reaction mixture is heated at 80 ° C overnight. The mixture is cooled, diluted with Et2O, filtered, concentrated and chromatographed (50% EtOAc / hexanes). The product is recrystallized from EtOAc / hexanes to provide, in two batches, a yellow solid (mp 194-196 ° C). Anal. cale, for C? 9H26N4O2: C, 66.64; H, 7.65; N, 16.36; Found: C, 66.60; H, 7.60; N, 16.51.

EXAMPLE 8 3-Cyclohexyloxy-6,7-dimethoxyquinoline To a THF solution (30 ml) at 0 ° C is added 3-hydroxy-6,7-dimethoxyquinoline (0.237 g, 1.15 mmole), cyclohexanol (0.347 g, 3.46 mmole) and Ph3P (0.908 g, 3.46 mmole). Diethyl azodicarboxylate is added in portions until the solution retains a dark red color (0.663 g, 3.81 mmol). After 4 hours, the solution is concentrated and the residue is chromatographed (50% EtOAc in hexanes). The product is recrystallized from isopropanol / hexanes as the HCl salt as a white solid (mp 229-232 ° C, dea).

EXAMPLE 9 2-anilino-6-quinoxaIinol By the method of Feutrill, G. I .; Mirrington, R. N. 7ef. Lett. 1970, 1327, the methyl ether of aryl is converted to the phenol derivative. To 2-anilino-6-methoxy-quinoxaline (0.27 g, 1.07 mmol) under argon in DMF is added the sodium salt of ethanediol (0.19 g, 2 mmol). The reaction mixture is heated at 110 ° C overnight. The mixture is concentrated and separated between EtOAc and H2O / tartaric acid at 5%, so that the pH of the aqueous layer is about 4. The organic layer is washed with H2O (4X) and then with 2.5% NaOH ( 4X). The basic layers are combined, washed with EtOAc (2X), acidified again with 5% tartaric acid, and washed with multiple portions of EtOAc. The organic layers are combined, washed with brine, dried (Na2SO4), and concentrated. The resulting solid is chromatographed (50% EtOAc / hexanes). An analytical sample is obtained by triturating the product with Et 2 O to provide a yellow powder (mp 211-213 ° C). Anal. cale, for C 14 HnN 3 O: C, 70.88; H, 4.67; N, 17.71; found: C, 70.64; H, 4.85; N, 17.58.

EXAMPLE 10 Phenyl-r6- (tetrahydrofuran-3- (R) -yl-oxy) quinoxalin-2-inamine To a solution of THF at 0 ° C under argon is added 2-anilino-6-quinoxalinol (0.23 g, 0.97 mmol), (S) - (+) - 3-hydroxytetrahydrofuran (0.086 ml, 1.3 mmol) and triphenylphosphine (0.31 g). g, 1.2 mmol). It is added in portions DEAD (0.18 ml, 1.2 mmol). The reaction is allowed to warm to room temperature and is stirred for 1.5 hours. The mixture is concentrated and separated between EtOAc and H2O. The organic layer is washed with H2O, brine, dried (MgSO4) and concentrated. The resulting yellow oil is chromatographed (50% EtOAc / hexanes) and taken up in Et2O / IPA (isopropanol). HCl / Et20 solution is added dropwise, and the resulting red-orange powder is dried in vacuo. The powder is freed from the base by shaking in MeOH with basic ion exchange resin (3X H2O, 5X MeOH) washed. The mixture is stirred for 30 minutes, filtered, concentrated and recrystallized from EtOAc / hexanes to provide, in two batches, the product (mp 173-175 ° C). Anal, cale, for C18H17N3O2: C, 70.35; H, 5.57; N, 13.67; found: C, 70.19; H, 5.60; N, 13.66.

EXAMPLE 11 2-Anilino-6-isopropoxy-quinoxaline hydrochloride To NaH (0.033 g, 0.84 mmol) under argon is added 1 ml of DMF. 2-Anilino-6-quinoxalinol (0.1 g, 0.42 mmol) in 1.5 ml of DMF is added in portions. After 30 minutes, 2-bromopropane is added in portions, and the solution is heated at 50 ° C for 1.5 hours. The cooled reaction mixture is quenched with water and separated between EtOAc and H2O, washed with H2O (3X), brine, dried (MgSO) and concentrated. The resulting residue is chromatographed (30% EtOAc / hexanes) to provide 0.05 g of dialkylated product and 0.1 g of the title compound. An analytical sample of the HCl salt is obtained by the addition of IPA / HCl to an Et 2 O / IPA solution of the free base to provide HCl salt (mp 205-210 ° C, dea). Anal, cale, for d7H17N3O * HCI: C, 64.65; H, 5.74; N, 13.31; found: C, 64.51; H, 5.90; N, 13.09.

EXAMPLE 12 1-3-Cyclohexyloxy-6,7-dimethoxyquinolaline oxide A mixture of 2-cyclohexyloxy-6,7-dimethoxyquinolutin (110 mg, 0. 38 mmol) and meta-chlorobenzoic acid (70%, 113 mg, 0.46 mmol) in 10 ml of methylene chloride are stirred at room temperature for 1 day. After filtration, the solution is concentrated, and the residue is chromatographed on silica gel (20% ethyl acetate / hexanes) to provide the desired product (mp 167-169 ° C). Similarly, rans-4- (6,7-dimethoxy-4-oxy-quinoxalin-2-ylamino) -cyclohexanol is prepared in the same manner (mp 220-222 ° C). Anal. cale, for C16H2? N3O4 »0.2 of H2O: C, 59.42; H, 6.69; N, 12.99; found: C, 59.43; H, 6.64; N, 12.95.

INTERMEDIARY EXAMPLE 1 4-bromo-5-methoxy-becene-1,2-diamine dihydrochloride To a solution of EtOAc (50 ml) and 5-bromo-4-methoxy-2-nitro-phenylamine (2.5 g, 10 mmol) under argon, Pd at 5% / C (0.5 g) is added. The reaction mixture is hydrogenated at 3515 kg per cm2 for 1 hour. The mixture is filtered through Celite in an HCI / IPA / EtOAc solution, and the pad washed with additional EtOAc. The resulting precipitate is filtered to provide a white solid.

EXAMPLE OF INTERMEDIARY 2 7-bromo-6-methoxy-quinoxalin-2-ol and 6-bromo-7-methoxyquininoalin-2-ol To a solution of MeOH (15 ml) under argon, pellets of Powdered NaOH (0.86 g, 21 mmol) and 4-bromo-5-methoxy-benzene-1,2-diamine dihydrochloride (2.7 g, 9.3 mmol). The mixture is stirred for 10 minutes, and then a solution of 45% ethyl glyoxylate or in toluene (2.7 g, 12 mmol) is added in portions. The reaction mixture is refluxed for 1 hour, and then cooled. Water is added, and then the suspension is filtered. The resulting solid is washed successively with H2O, MeOH, IPA and Et2O to provide a yellow powder.

EXAMPLE OF INTERMEDIARY 3 7-bromo-2-chloro-6-methoxy-quinoxaline and 6-bromo-2-chloro-7-methoxy-quinoxaline To a mixture of 7-bromo-6-methoxy-quinoxalin-2-ol and 6-bromo-7-methoxy-quinoxalin-2-ol (1 g, 3.9 mmol) is added POCI3 (5 mL). The reaction mixture is refluxed for 1 hour, poured into ice water, filtered and then washed with water to provide a light tan solid. The ratio of 7-bromo-2-chloro-6-methoxy-quinoxaline: 6-bromo-2-chloro-7-methoxy-quinoxaline is about 7: 1 by 1 H NMR.

EXAMPLE OF INTERMEDIARY 4 5-chloro-4-methoxy-2-nitroaniline To a solution of N- (5-chloro-4-methoxy-2-nitrophenyl) -acetamide (2 g, 8.2 mmol) in HCl at 5N (20 ml), 1,4-dioxane (10 ml) is added, and The mixture is stirred at 60 ° C for 1.5 hours. The reaction mixture is concentrated and separated between EtOAc / NaOH at 2N. The aqueous layers are washed with EtOAc (3x), brine, dried (MgSO4), adsorbed on silica gel, and chromatographed (70% EtOAc / hexanes) to provide an orange powder.

INTERMEDIARY EXAMPLE 5 4-Chloro-4-methoxy-benzene-1,2-diamine dihydrochloride To a solution of EtOAc (25 ml) and 5-chloro-4-methoxy-2-nitro-phenylamine (1.6 g, 7.9 mmol) under argon is added Pd at 5% / C (0.5 g). The reaction mixture is hydrogenated at 3515 kg / cm2 for 1 hour. The mixture is filtered under N2 through Celite in a solution of 1 N HCl / Et2O in EtOAc, and the pad washed with additional EtOAc. The resulting precipitate is filtered to provide a white solid.

EXAMPLE OF INTERMEDIARY 6 7-chloro-6-methoxy-quinoxalin-2-ol v 6-chloro-7-methoxy-quinoxalin-2-ol To a solution of 4-chloro-5-methoxy-benzene-1,2-diamine dihydrochloride (1.8 g, 7.2 mmol) in EtOH (15 mL) under argon is added TEA (2.5 mL, 18 mmol) at 0 ° C. . The mixture is stirred for 20 minutes, and then a solution of 45% ethyl glyoxylate in toluene (2.1 g, 9.3 mmol) is added portionwise. The reaction mixture is warmed to room temperature, refluxed for 1.5 hours, and then cooled. Water is added, and then the suspension is filtered and washed successively with H2O, IPA and Et2O to provide a light yellow powder. The product is azeotropically treated several times with toluene, and dried in vacuum before use.

EXAMPLE OF INTERMEDIARY 7 2-Dichloro-6-methoxy-quinoxane and 2,6-dichloro-7-methoxy-quinoxaline To a mixture of 7-chloro-6-methoxy-quinoxalin-2-ol and 6-chloro-7-methoxy-quinoxalin-2-ol (1 g, 4.7 mmol) under a CaCl2 drying tube is added POCI3 (5 g). ml). The reaction mixture is refluxed for 30 minutes, poured into cold saturated NaHCO3 solution, filtered and washed with water to provide a solid. The ratio of 2,7-dichloro-6-methoxy-quinoxaline: 2,6-dichloro-7-methoxy-quinoxaline is about 6: 1 by 1 H NMR.

The compounds of formula I described herein exhibit inhibition of cell proliferation and / or cell matrix production and / or cell movement (chemotaxis) by inhibition of the tyrosine kinase activity of PDGF-R. A large number of disease states are caused by the uncontrolled reproduction of cells, or the overproduction of programmed matrix or programmed cell death (apoptosis). These disease states involve a variety of cell types, and include disorders such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, atherosclerosis and disorders that occur subsequent to angioplasty of the coronary, femoral or renal arteries. , or fibroproliferative disease, such as in arthritis and fibrosis of the lung, kidney and liver. In particular, it has been reported that PDGF and PDGF-R are implicated in specific types of cancers and tumors such as brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma and malignant melanoma, as well as deregulated cell proliferative conditions following coronary bypass surgery. It is thought that the inhibition of tyrosine kinase activity has utility in the control of reproduction without cell control, overproduction of matrix or programmed cell death poorly regulated (apoptosis). This invention relates to the modulation and / or inhibition of cellular signaling, cell proliferation and / or cell matrix production and / or cell movement (chemotaxis), the control of abnormal cell growth and the cellular inflammatory response. More specifically, this invention relates to the use of quinoline and quinoxaline substituted compounds which exhibit selective inhibition of differentiation, proliferation, matrix production, chemotaxis or mediator release, effectively inhibiting the factor receptor receptor tyrosine kinase activity of PDGF-R. of growth derived from platelets. The initiation of autophosphorylation, that is, the phosphorylation of the growth factor receptor itself, and the phosphorylation of a number of intracellular substrates, are some of the biochemical events involved in signaling, proliferation, matrix production, chemotaxis and release of cellular mediator. By effectively inhibiting Lck tyrosine kinase activity, the compounds of this invention are also useful in the treatment of transplantation resistance and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, in transplant rejection, in graft disease. against host, in hyperproliferative disorders such as tumors and psoriasis, and diseases in which cells receive pro-inflammatory signals, such as in asthma, inflammatory bowel disease and pancreatitis. In the treatment of resistance to transplantation, a compound of this invention can be used prophylactically or in response to an adverse reaction by the human subject to a transplanted organ or tissue. When used prophylactically, a compound of this invention is administered to the patient or to the tissue or organ to be transplanted, in advance of the transplant operation. Prophylactic treatment may also include administration of the drug after the transplant operation, but before signs of adverse reaction or transplantation are observed. When administered in response to an adverse reaction, a compound of this invention is administered directly to the patient to treat resistance to transplantation after external signs of resistance have manifested.

In accordance with a further feature of the invention, a method is provided for the treatment of a patient suffering from, or subject to, conditions that can be ameliorated or prevented by the administration of an inhibitor of PDGF-R tyrosine kinase activity. and / or Lck tyrosine kinase activity, for example, conditions as described above, which comprises administering, to the patient, an effective amount of the compound of formula I or a composition containing a compound of formula I, or a pharmaceutically acceptable salt thereof. It should be understood that the reference to the treatment herein includes prophylactic therapy, as well as the treatment of established conditions. The present invention also includes within its scope, pharmaceutical compositions comprising a pharmaceutically acceptable amount of at least one of the compounds of formula I, in association with a pharmaceutically acceptable carrier, for example, an adjuvant, diluent, coating and excipient. In practice, the compounds or compositions for treatment according to the present invention can be administered in any variety of suitable forms, for example, by inhalation, topically, parenterally, rectally or orally; preferably orally. More specific routes of administration include intravenous, intramuscular, subcutaneous, infraocular, intrasynovial, colonic, peritoneal, transepithelial including transdermal, ophthalmic, sublingual, buccal, dermal, ocular, nasal inhalation by insufflation, and aerosol. The compounds of formula I can be presented in forms that allow their administration by the most suitable route, and the invention also relates to pharmaceutical compositions containing at least one compound according to the invention and which are suitable for use as a medicament in a patient. These compositions can be prepared according to customary methods using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and different non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more agents selected from the group comprising sweeteners such as sucrose, lactose, fructose, saccharin. or Nutrasweet®, flavors such as peppermint oil, wintergreen oil or cherry or orange flavors, colorants, or stabilizers such as methyl- or propylparaben, to obtain pharmaceutically acceptable preparations. The choice of the vehicle and the content of active substance therein is generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions that will be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc, they can be used to prepare tablets, troches, pills, capsules and the like. To prepare a capsule, it is advantageous to use lactose and a liquid carrier such as high molecular weight polyethylene glycols. Various other materials may be present as coatings or otherwise to modify the physical form of the dosage unit. For example, tablets, pills or capsules can be coated with lacquer, sugar, or both. When aqueous suspensions are used, they may contain emulsifying agents or agents that facilitate the suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol can also be used., propylene glycol and glycerol, and chloroform or mixtures thereof. In addition, the active compound can be incorporated into sustained release preparations and formulations. For oral administration, the active compound can be administered, for example, with an inert diluent or with an edible assimilable carrier, or it can be included in gelatin capsules of hard or soft shell, or it can be compressed into tablets, or it can be incorporated directly with the food of the diet, or it can be incorporated with excipient or used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. For parenteral administration, emulsions, suspensions or solutions of the compounds according to the invention are used in vegetable oil, for example sesame oil, peanut oil or olive oil, or aqueous organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as also sterile aqueous solutions of the pharmaceutically acceptable salts. The injectable forms must be fluid to the extent that they can be easily injected, and an adequate fluidity 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. Prolonged absorption of the injectable compositions can be achieved by the use of agents that delay absorption, for example, aluminum monostearate and gelatin. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. A dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Aqueous solutions, which also comprise solutions of the salts in pure distilled water, can be used for intravenous administration with the proviso that their pH is adjusted appropriately, that they are thoroughly regulated in their pH, and that they are made isotonic with a sufficient amount of glucose or sodium chloride, and which are sterilized by heating and radiation, microfiltration and / or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with several of the other ingredients listed above, as required, followed by sterilization with filtration. In general, the dispersions are prepared by incorporating the different sterilized active ingredients in a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and the freeze dehydration technique, which produce a powder of the active ingredient plus some other desired ingredient of the previously sterile filtered solution of the same. For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention can be used. The compounds of the invention can also be incorporated in a matrix or gel base for application in a patch, which would allow the controlled release of the compound through the transdermal barrier. For administration by inhalation, the compounds of the The invention may be dissolved or suspended in a vehicle suitable for use in a nebulizer or aerosol in solution or suspension, or may be adsorbed or absorbed onto a solid carrier suitable for use in a dry powder inhaler. Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I. The compositions according to this invention can also be formulated in a manner that resists rapid depuration of the vascular wall. (arterial or venous) by convection and / or diffusion, thus increasing the residence time of the viral particles at the desired site of action. A periadventive deposit comprising a compound according to the invention can be used for sustained release. Said depot useful for administering a compound according to the invention may be a copolymer matrix, such as ethylene-vinyl acetate, or a polyvinyl alcohol gel surrounded by a Silastic sheath. Alternatively, a compound according to the invention can be supplied locally from a silicone polymer implanted in the adventitia. An alternative method for minimizing entrainment of a compound according to the invention during percutaneous and transvascular delivery comprises the use of non-diffusible drug eluting microparticles. The microparticles can be formed from a variety of synthetic polymers, such as polylactide for example, or natural substances, including proteins or polysaccharides. These microparticles allow the strategic manipulation of variables that include the total dose of drug and the kinetics of its release. The microparticles can be effectively injected into the arterial or venous wall through a porous balloon catheter or a balloon onto a stent, and be retained in the vascular wall and the periadventive tissue for at least about two weeks. Formulations and methodologies for the intravascular and site-specific local delivery of the therapeutic agents are described in Reissen et al (J. Am. Coil, Cardiol., 1994; 23: 1234-1244), whose contents are incorporated in their entirety in the present as a reference. A composition according to the invention may also comprise a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polymer of polyacrylic acid which can function as a drug-absorbing sponge. Such polymers have been described, for example, in the application WO93 / 08845, the contents of which are hereby incorporated by reference in their entirety. Some of them, such as, in particular, those obtained from ethylene and / or propylene oxide, are commercially available. During the use of the compounds according to the invention to treat pathologies that are linked to hyperproliferative disorders, the compounds according to the invention can be administered in different ways. For the treatment of restenosis, the compounds of the invention are administered directly to the wall of the blood vessel by means of an angioplasty balloon which is coated with a hydrophilic film (for example, a hydrogel), which is saturated with the compound , by means of any other catheter containing an infusion chamber for the compound which can be precisely applied in this way to the site to be treated, and allows the compound to be released locally and efficiently at the site of the cells that they will be treated. Advantageously, this method of administration makes it possible for the compound to rapidly come into contact with the cells in need of treatment. The method of treatment of the invention preferably consists of introducing a compound according to the invention into the site to be treated. For example, a hydrogel containing the composition can be directly deposited on the surface of the tissue to be treated, for example during a surgical intervention. Advantageously, the hydrogel is introduced into the desired intravascular site by coating a catheter, for example a balloon catheter, and supplying it to the vascular wall, preferably during angioplasty. In a particularly advantageous form, the saturated hydrogel is introduced into the site which will be treated by means of a balloon catheter. The balloon may be accompanied by a protective sheath as the catheter is advanced toward the target vessel, to minimize drug disposal after the catheter is introduced into the bloodstream. Another embodiment of the invention provides a compound according to the invention that will be administered by means of perfusion balloons. These perfusion balloons, which make it possible to maintain a blood flow and thus decrease the risks of myocardial ischemia, during inflation of the balloon, also allow the compound to be supplied locally at normal pressure for a relatively long time, more than 20 minutes, which may be necessary for your optimal action. Alternatively, a balloon catheter with channels ("balloon angioplasty catheter with channels", Mansfield Medical, Boston Scientific Corp., Watertown, MA) can be used. The latter consists of a conventional balloon covered with a layer of 24 perforated channels which are perfused by an independent lumen through an additional infusion orifice. Various types of balloon catheters, such as double balloon, porous balloon, microporous balloon, balloon with channels, balloon on stent and hydrogel catheter, all of which can be used to practice the invention, are described in Reissen et al. (1994), whose contents are incorporated herein in their entirety as a reference. The use of a balloon catheter for perfusion is especially advantageous, since it has the advantages of keeping the balloon inflated for a longer period by requiring the properties of facilitated slippage and specificity of the hydrogel site. Another aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the invention and poloxamer, such as Poloxamer 407, which is a commercially available biocompatible, non-toxic polyol (BASF, Parsippany, NJ).A poloxamer impregnated with a compound according to the invention can be deposited directly on the surface of the tissue to be treated, for example, during a surgical intervention. The poloxamer has essentially the same advantages as the hydrogel, but has a lower viscosity. The use of a balloon catheter with channels, with a poloxamer impregnated with a compound according to the invention, is especially advantageous. In this case, the advantages of keeping the balloon inflated for a longer period are simultaneously obtained, while retaining the properties of facilitated slippage and specific character of the poloxamer site. The percentage of active ingredient in the compositions of the invention can be varied, being necessary that it should constitute a proportion such that a suitable dosage can be obtained. Obviously, several dosage unit forms can be administered at almost the same time. The dose used can be determined by a qualified physician or medical professional, and depends on the desired therapeutic effect, the route of administration, the duration of treatment and the patient's condition. In the adult, the doses are generally from about 0.001 to about 50, preferably from about 0.001 to about 5, milligrams per kilogram of body weight per day by inhalation, from about 0.01 to about 100, preferably from 0.1 to 70, more especially from 0.5 to 10, milligrams per kilogram of body weight per day by oral administration, and from about 0.001 to about 10, preferably from 0.01 to 10, milligrams per kilogram of body weight per day by intravenous administration. In each particular case, the doses are determined in accordance with the factors that distinguish the patient to be treated, such as age, weight, general state of health and other characteristics that may influence the efficacy of the compound according to the invention. The compounds / compositions according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose, and may find adequate maintenance doses much weaker. For other patients, it may be necessary to carry out long-term treatments at a rate of 1 to 4 doses per day, in accordance with the physiological requirements of each patient in particular. In general, the active product can be administered orally 1 to 4 times a day. In fact, for other patients, it will be necessary to prescribe no more than one or two doses per day. The compounds of the present invention can also be formulated to be used in conjunction with other therapeutic agents such as agents or in relation to the application of therapeutic techniques to highlight pharmacological conditions that can be ameliorated by the application of a compound of formula I, such as in the following: The compounds of the present invention can be used in the treatment of restenosis or angioplasty using any device such as a balloon, ablation or laser techniques. The compounds of the present invention can be used in the treatment of restenosis following stent placement in the vasculature such as 1) primary treatment of vascular blockage, or 2) in the case where the anglioplasty using any device fails to find a visible artery. . The compounds of the present invention can be used orally, by parenteral administration, or the compound can be applied topically by the intervention of a specific device or as a suitably formulated coating on a stent device. The compounds of the present invention can be used in the treatment of restenosis in combination with any anticoagulant, antiplatelet, antithrombotic or profibrinolytic agent. Frequently, patients are treated concurrently before, during and after interventional procedures with agents of these classes to safely perform the intervention procedure, or to prevent detrimental effects of thrombus formation. Some examples of classes of agents that are known to be anticoagulant, antiplatelet, antithrombotic or prophylactic agents include any formulation of heparin, low molecular weight heparin, pentasaccharides, fibrinogen receptor antagonists, thrombin inhibitors, factor Xa inhibitors or inhibitors of Vlla factor The compounds of the present invention can be used in combination with any antihypertensive agent or cholesterol or lipid regulating agent, in the treatment of restenosis or atherosclerosis concurrently with the treatment of high blood pressure or atherosclerosis. Some examples of agents that are useful in the treatment of high blood pressure include compounds of the following classes: beta blockers, ACE inhibitors, calcium channel blockers and alpha receptor antagonists. Some examples of agents that are useful in the treatment of elevated cholesterol levels or regulated lipid levels, include compounds known to be inhibitors of HMGCoA reductase, compounds of the fibrate class. The compounds of the present invention can be used in the treatment of various forms of cancer, alone or in combination with compounds known to be useful in the treatment thereof. It is understood that the present invention includes combinations of compounds of this invention with one or more of the agents of the therapeutic groups mentioned above. Compounds within the scope of the present invention exhibit remarkable pharmacological activities in accordance with tests described in the literature, whose test results are thought to correlate with pharmacological activity in humans and other mammals. The following in vitro and in vivo pharmacological test results are typical for characterizing the compounds of the present invention.

PREPARATION OF PHARMACEUTICAL COMPOSITIONS AND SECTION OF PHARMACOLOGICAL TESTS Compounds within the scope of this invention exhibit significant activity as tyrosine kinase inhibitors, and possess therapeutic value as cellular antiproliferative agents for the treatment of certain conditions including psoriasis, atherosclerosis and restenosis damage. Compounds within the scope of the present invention exhibit modulation and / or inhibition of cellular signaling and / or cell proliferation and / or matrix production and / or chemotaxis and / or cellular inflammatory response, and can be used to prevent or delay the incidence or recidivism of said conditions, or otherwise to treat the condition. To determine the efficacy of the compounds of this invention, the pharmacological tests described below are used, which are accepted in the art and recognized to correlate with pharmacological acfivity in mammals. The compounds within the scope of the present invention have been subjected to these different tests, and it is thought that the results obtained correlate with the useful activity of mediating cell differentiation. It is believed that the results of these tests provide sufficient information for experts in pharmacology and chemical medicine techniques to determine the parameters for the use of the compounds studied in one or more of the therapies described herein. 1. ELISA test for the autophosphorylation of the tyrosine kinase of PDGF-R The titer test is carried out as described by Dolle et al. (J. Med. Chem. 1994, 37, 2627), citation incorporated herein by reference , except that used cells derived from human aortic smooth muscle cells (HAMSC) are used, as described below: 2. General procedure of the mitogenesis test to. Cell culture Human aortic smooth muscle cells (4 to 9 passages) are deposited in 96-well plates in a growth support medium at 6000 cells / well, and allowed to grow for 2 to 3 days. At a confluence of about 85%, growth of the cells is stopped with serum free media (SFM). b. Mitogenesis test After serum deprivation for 24 hours, the medium is removed and replaced with test / vehicle compound in SFM (200 μl / well). The compounds are solubilized in DMSO for cell culture at a concentration of 10 mM, and further dilutions are made in SFM.

After preincubation for 30 minutes with compound, the cells are stimulated with PDGF at 10 ng / ml. Determinations are made in duplicate with stimulated and unstimulated wells at the concentration of each compound. Four hours later, 1 μCi of 3H thymidine / well is added. The cultures are terminated 24 hours after the addition of the growth factor. The cells are raised with trypsin, and harvested on a filter mat using an automated cell harvester (Wallac Machi 196). The counting of the filter mat is done in a scintillation counter (Wallac Betaplate) to determine the mark incorporated into the DNA. 3. Guimiotaxis test Human aortic smooth muscle cells (HASMC) are obtained in previous passages of the ATCC. The cells are grown in Clonetics SmGM 2 SingleQuots (media and cells are used in passages 4 to 10). When the cells are 80% confluent, a calcein AM fluorescent probe (5 mM, molecular probe) is added to the media, and the cells are incubated for 30 minutes. After washing with saline solution regulated in its pH with HEPES, the cells are raised with trypsin, and neutralized with pH regulator MCDB 131 (Gibco) with 0.1% BSA, 10 mM glutamine and 10% fetal bovine serum . After centrifugation, the cells are washed once more and resuspended in the same pH buffer without bovine fetal serum at 30,000 cells per 50 ml. The cells are incubated with different concentrations of a compound of formula I (final concentration of DMSO = 1%) for 30 minutes at 37 ° C. For chemotaxis studies, modified 96-well Boyden chambers (Neuroprobe, Inc.) and a polycarbonate membrane with an 8-mm pore size (Poretics, CA) are used. The membrane is coated with collagen (Sigma C3657, 0.1 mg / ml). It is placed in the lower chamber PDGF-ßß (3 ng / ml) in pH regulator with and without a compound of formula I. 30,000 cells, with and without inhibitor, are placed in the upper chamber. The cells are incubated for 4 hours. The filter membrane is removed, and the cells on the upper side of the membrane are removed. After drying, the fluorescence on the membrane is determined using Cytofluor II (Millipore) at excitation / emission wavelengths of 485/530 nm. In each experiment, an average cell migration is obtained from 6 replicates. The percent inhibition is determined from control values treated with DMSO. Based on concentration-dependent inhibitions of 5 points, the value of the IC5rj is calculated. The results are presented as an ± SEM average of 5 of said experiments. 4. Purification of EGF receptor The purification of the EGF receptor is based on the procedure of Yarden and Schlessinger. A431 cells are grown in 80 cm2 flasks to confluence (2 x 107 cells per flask). Cells are washed twice with PBS and harvested with PBS containing 11.0 mmoles of EDTA (1 hour at 37 ° C), and centrifuged at 600g for 10 minutes. The cells are solubilized in 1 ml by 2 x 10 7 pH regulator cells for cold solubilization (50 mmol of pH regulator HEPES, pH 7.6, Triton X-100 at 1%, 150 mmol of NaCl, 5 mmol of EGTA, 1 mmol of PMSF, 50 mg per ml of aprotinin, 25 mmol of benzamidine, 5 mg per ml of leupeptin and 10 mg per ml of soybean trypsin inhibitor) for 20 minutes at 4 ° C. After centrifugation at 100,000g for 30 minutes, the supernatant is loaded onto a WGA-agarose column (100 ml of resin packed by 2 x 10 7 cells) and stirred for 2 hours at 4 ° C. The unabsorbed material is removed, and the resin is washed twice with pH regulator HTN (50 mmoles of HEPES, pH 7.6, Triton X-100 at 0.1%, 150 mmoles of NaCl), twice with pH regulator HTN containing NaCl at 1 M, and twice with pH regulator HTNG (50 mmoles of HEPES, pH 7.6, Triton X-100 at 0.1%, 150 mmoles of NaCl and glycerol at 10%). The EGF receptor is eluted intermittently with pH regulator HTNG containing N-acetyl-D-glucosamine at 0.5 M (200 ml per 2 x 10 7 cells). The eluate is stored in aliquots at -70 ° C and diluted before use with TMTNG pH regulator (50 mmol Tris-Mes pH regulator, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl, 10% glycerol).

. Inhibition of EGF-R autophosphorylation A431 cells are grown to confluence on tissue culture plates coated with human fibronectin. After washing twice with ice-cold PBS, the cells are lysed by the addition of 500 ml per pH regulator plate for lysis (50 mmoles of HEPES, pH 7.5, 150 mmoles of NaCl, 1.5 mmoles of MgCl 2, 1 mmoles of EGTA, glycerol at 10%, triton X-100 at 1%, 1 mmol of PMSF, 1 mg per ml of aprotinin, 1 mg per ml of leupeptin), and incubating for 5 minutes at 4 ° C. After stimulation of EGF (500 mg / ml, 10 minutes at 37 ° C), immunoprecipitation is carried out with anti-EGF-R (Ab 108), and the autophosphorylation reaction (aliquots of 50 ml, 3 mCi of [ g "32 P] ATP) is carried out in the presence of 2 or 10 mM of the compound of the present invention, for two minutes at 4 ° C. The reaction is stopped by the addition of a pH regulator for hot electrophoresis. Analysis of SDA-PAGE (7.5%) is followed by autoradiography, and the reaction is quantified by densitometry screening of the X-ray films. to. Cell culture Cells designated HER 14 and K721A are prepared by transfecting NIH3T3 cells (clone 2.2) (from C. Fryling, NCI, NIH), which lack endogenous EGF receptors with wild-type EGF receptor cDNA constructs or EGF receptor mutant lacking tyrosine kinase activity (in which Lys 721 at the ATP binding site is replaced by an Ala residue, respectively). All cells are cultured in DMEM with 10% calf serum (Hyclone, Logan, Utah). 6. The selectivity against PKA and PKC is determined using commercial equipment a. Colorimetric equipment for PKA Pierce test, format Spinzyme Brief protocol: 1 U of PKA enzyme (bovine heart) / test tube. Peptide peptide substrate (labeled with dye). 45 minutes at 30 ° C. Absorbance at 570 nm. b. Colorimetric equipment for PKA Pierce test, format Spinzyme Brief protocol: 0.025 U of PKC enzyme (rat brain) / test tube Neurogranin peptide substrate (dye-labeled) 30 minutes at 30 ° C. Absorbance at 570 nm. 7. Measurements of p56 Ick tyrosine kinase inhibition activity The tyrosine kinase inhibition activity of p56lck is determined in accordance with a procedure described in the US patent. No. 5,714,493, incorporated herein by reference.

In the alternative, the tyrosine kinase inhibition activity is determined according to the following method. A substrate (substrate containing tyrosine, Biot- (ß Ala) 3-Lys-Val-Glu-Lys-lle-Gly-Glu-Gly-Thr-Tyr-Glu-VaI-Val-Tyr-Lys- (NH2) recognized per p56lck, 1 μM) is first phosphorylated in the presence or absence of a given concentration of the test compound, by a given amount of enzyme (the enzyme is produced by expressing the p56lck gene in a yeast construct) purified from a cloned yeast (the purification of the enzyme is carried out following classical methods) in the presence of ATP (10 μM), MgC (2.5 mM), MnCl2 (2.5 mM), NaCl (25 mM), DTT (0.4 mM) in Hepes at 50 mM, pH 7.5, for 10 minutes at room temperature. The total reaction volume is 50 μl, and the reactions are carried out in a 96-well black fluoroplate. The reaction is stopped by the addition of 150 μl of stop buffer (100 mM Hepes, pH 7.5, KF at 400 mM, EDTA at 133 mM, 1 g / L BSA), containing a selected anti-tyrosine antibody labeled with the Europium cryptate (PY20-K) at 0.8 μg / ml and streptavidin labeled with allophycocyanin (XL665) at 4 μg / ml. The labeling of streptavidin and anti-tyrosine antibodies was carried out by Cis-Bio International (France). The mixture is counted using a Discovery Packard counter, which is capable of measuring the homogenous transfer of resolved fluorescence with time (excitation at 337 nm, reading at 620 nm and 665 nm). The signal ratio of 665 nm / 620 nm signal, is a measure of the concentration of phosphorylated tyrosine. White is obtained by replacing the enzyme with a pH regulator. The specific signal is the difference between the ratio obtained without inhibitor and the relationship with the target. The percentage of specific signal is calculated. The IC50 is calculated with 10 concentrations of inhibitor in duplicate using Xlfit soft. The reference compound is staurosporine (Sigma), and exhibits an IC5o of 30 + 6 nM (n = 20). The results obtained by the above experimental methods show that the compounds within the scope of the present invention possess useful properties of inhibition of tyrosine kinase of the PDGF receptor or tyrosine kinase inhibition properties of p56lck, and that in this way they possess therapeutic value. The above pharmacological test results can be used to determine the dosage and mode of administration for the particular therapy sought. The present invention can be described in other specific forms without departing from the spirit or the essential attributes thereof.

Claims (38)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula wherein R1a is optionally substituted alkyl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy, optionally substituted heterocyclylcarbonyloxy or halogen; R-ib is hydrogen, optionally substituted alkyl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy, optionally substituted heterocyclylcarbonyloxy or halogen; R c is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocyclylcarbonyloxy, halogen, cyano, R5RßN- or acylR5N-; R2 is R3 is hydrogen, or ortho or for fluoro, or meta lower alkyl, lower alkoxy, halogen or carbamoyl; R 4 is hydrogen or lower alkyl; R5 and R6 are independently hydrogen or alkyl, or R5 and R8 together with the nitrogen atom to which R5 and R6 are attached form azaheterocyclyl; Za is N or CH; and Zb is NH or O, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof or salt thereof, provided that R a and R y are not both optionally substituted alkyl.

2. The compound according to claim 1, further characterized in that R a is optionally substituted lower alkoxy, optionally substituted monocyclic cycloalkyloxy, optionally substituted heterocyclylcarbonyloxy, or optionally substituted monocyclic oxaheterocyclyloxy.

3. The compound according to claim 2, further characterized in that R a is optionally substituted lower alkoxy or optionally substituted monocyclic oxaheterocyclyloxy.

4. The compound according to claim 3, further characterized in that R1a is methoxy, ethoxy, 2- (ethoxy) ethoxy, 2- (4-morpholinyl) ethoxy or furanyloxy.

5. The compound according to claim 1, further characterized in that R-ib is hydrogen, optionally substituted lower alkoxy, optionally substituted monocyclic cycloalkyloxy, optionally substituted heterocyclylcarbonyloxy, or optionally substituted monocyclic oxaheterocyclyloxy.

6. The compound according to claim 5, further characterized in that R ^ is hydrogen or optionally substituted lower alkoxy.

7. The compound according to claim 6, further characterized in that Rib is methoxy or ethoxy.

8. The compound according to claim 1, further characterized in that R a and Rib are lower alkoxy.

9. The compound according to claim 8, further characterized in that R a and R-ib are methoxy or ethoxy.

10. The compound according to claim 1, further characterized in that R-? C is hydrogen or optionally substituted lower alkoxy.

11. The compound according to claim 10, further characterized in that R-? C is hydrogen, methoxy or ethoxy.

12. The compound according to claim 1, further characterized in that R2 is

13. - The compound according to claim 1, further characterized in that R2 is

14. The compound according to claim 1, further characterized in that R3 is hydrogen, fluoro s ortho or para, or methyl, trifluoromethyl, methoxy, fluoro, chloro, bromo or carbamoyl meta.

15. The compound according to claim 1, further characterized in that R4 is hydrogen or methyl.

16. The compound according to claim 1, further characterized in that Za is N.

17. The compound according to claim 1, further characterized in that Za is CH.

18. The compound according to claim 1, further characterized in that Zb is NH.

19. The compound according to claim 1, further characterized in that Z is O.

20.- A compound according to claim 1, further characterized in that it is selected from the following species: 2-anilino-6-quinoxaIinol; 2 - ((R) -a-methylbenzyl-amino) -6,7-diethoxyquinoline; 2- ani-Iino-6-isopropoxyquinoxaline; 2-phenoxy-6-methoxyquinolaline; (3-bromobenzyl) - (6,7-dimethoxyquinoxaln-2-yl) -amine; 2- (3-carbamoylphenylamino) -6-methoxyquinolaline; 2- (2-fluorophenylamino) -6,7-dethoxyquinolaline; 2- (3-trifluoromethylfenylamino) -6,7-diethoxyquinolaline; phenyl- [6- (tetrahydrofuran-3 (R) -yloxy) quinoxalin-2-yl] amine; benzyl- (6,7-dimethoxyquinolalin-2-yl) -amine; 2 - ((S) -a-methylbenzyl-amino) -6,7-diethoxyquinolaline; 2-benzylamino-6,7-diethoxyquinolaline; (6-methoxyquinolalin-2-yl) - (3-methylphenyl) -amine; 6-methoxy-2-phenylamino-quinoxaline; 2-anilino-6-etoxiquinoxaline; 2- (3-methoxyphenylamino) -6,7-diethoxyquinolaline; 2- (4-fluorophenylamino) -6,7-dethoxyquinolaline; 6,7-diethoxy-2-phenoxyquinolaline; 2-phenylamino-6,7-diethoxyquinolaline; (6,7-dimethoxyquinolalin-2-yl) - (3-fluorophenyl) -amine; 2- (3-fluorophenylamino) -6,7-diethoxyquinolaline; (3-bromophenyl) - (6,7-dimethoxyquinolalin-2-yl) -amina; (6,7-dimethoxy-quinotoxalin-2-yl) -phenyl-amine; and (3-chlorophenyl) -) (6,7-dimethoxyquinolalin-2-yl) -amine, or an N-oxide thereof, hydrate thereof, sulfate thereof, prodrug thereof or pharmaceutically acceptable salt thereof. the same.

21. A compound according to claim 1, further characterized in that it is selected from the species: phenyl- [6- (tetrahydrofuran-3 (R) -yloxy) quinoxalin-2-yl] amine; benzyl- (6,7-dimethoxyquinolalin-2-yl) amine; 2 - ((S) -a-methylbenzyl-amino) -6,7-dethoxyquinolalin; 2-benzylamino-6,7-diethoxyquinolaline; (6-methoxyquinolalin-2-yl) - (3-methylphenyl) -amine; 6-methoxy-2-phenylamino-quinoxaline; 2-anilino-6-etoxiquinoxaline; 2- (3-methoxyphenylamino) -6,7-diethoxyquinolaline; 2- (4-fluorophenylamino) -6,7-dimethoxyquinol; 6,7-diethoxy-2-phenoxyquinolaline; 2-phenylamino-6,7-diethoxyquinolaline; (6,7-dimethoxyquinolalin-2-yl) - (3-fluorophenyl) -amine; 2- (3-fluorophenylamino) -6,7-diethoxyquinolaline; (3-bromophenyl) - (6,7-dimethoxyquinolalin-2-yl) -amine; (6,7-dimethoxy-quinotoxalin-2-yl) -phenyl-amine; and (3-chlorophenyl) - (6,7-dimethoxyquinolalin-2-yl) amine, or an N-oxide thereof, hydrate thereof, sulfate thereof, prodrug thereof or pharmaceutically acceptable salt thereof .

22. The compound according to claim 1, further characterized in that it is phenyl- [6- (tetrahydrofuran-3 (R) -yloxy) quinoxalin-2-yl] amine, or an N-oxide thereof, hydrate of the same, solvate thereof, prodrug thereof or pharmaceutically acceptable salt thereof.

23. The compound according to claim 1, further characterized in that it is benzyl- (6,7-dimethoxyquinolalin-2-yl) -amine, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug of the same or pharmaceutically acceptable salt thereof.

24. The compound according to claim 1, further characterized in that it is (6,7-dimethoxyquinolalin-2-yl) - (3-fluorophenyl) -amine, or an N-oxide thereof, hydrate thereof, solvate of the same, prodrug thereof or pharmaceutically acceptable salt thereof.

25. The compound according to claim 1, further characterized in that it is (3-bromophenyl) - (6,7-dimethoxyquinolalin-2-yl) -amine, or an N-oxide thereof, hydrate thereof, solvate of the same, prodrug thereof or pharmaceutically acceptable salt thereof.

26. - The compound according to claim 1, further characterized in that it is (3-chlorophenyl) - (6,7-dimethoxyquinolalin-2-yl) -amine, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof or pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition, characterized in that it comprises the compound according to claim 1 and a pharmaceutically acceptable vehicle.

28. A method for inhibiting the tyrosine kinase activity of PDGF, characterized in that it comprises contacting a compound according to claim 1, with a composition containing a tyrosine kinase of PDGF.

29. A method for inhibiting the tyrosine kinase activity of Lck, characterized in that it comprises contacting a compound according to claim 1 with a composition containing an Lck tyrosine kinase.

30. The use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the proliferation, differentiation or release of cellular mediator, in a patient.

31.- The use of the compound in accordance with the claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a pathology linked to a hyperproliferative disorder in a patient.

32. The use according to claim 31, wherein said pathology is restenosis.

33. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating inflammation in a patient.

34. The use according to claim 32, wherein the compound of claim 1 is administered by a coating on a stent device, and wherein the coating comprises a compound according to claim 1.

35.- The use according to claim 31, wherein the pathology linked to a hyperproliferative disorder is a cancer susceptible to treatment by inhibition of PDGF tyrosine kinase.

36. The use according to claim 35, wherein the cancer is brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma or malignant melanoma.

37. The use according to claim 30, wherein the disorder is leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, arthritis, fibrosis of the lung, fibrosis of the kidney, fibrosis of the liver, atherosclerosis or Restenosis that occurs subsequent to angioplasty of the coronary, femoral or renal arteries. 38.- The use of an inhibitory amount of Lck tyrosine kinase of the compound according to claim 1, in the manufacture of a medicament for the treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, asthma, Inflammatory bowel disease or pancreatitis, in a patient.