Title of Invention

QUINOLINE AND QUINOXALINE COMPOUNDS OF FORMULA I AND A STENT DEVICE COMPRISING THE SAME

Abstract

This invention is directed to quinoline/quinoxaline compounds of formula (I) wherein X is L1OH or L2Z2; L1 is (CR3aR3b)r or (CR3aR3b)m-Z3-(CR3'aR3'b)n; L2 is (CR3aR3b)p-Z4-(CR3'aR3'b)q or ethenyl; Z1 is CH or N; Z2 is optionally substituted hydroxycycloalkyl, optionally substituted hydroxycycloalkenyl, optionally substituted hydroxyheterocyclyl or optionally substituted hydroxyheterocyclenyl; Z3 is O, NR4, S, SO or SO2; Z4 is O, NR4, S, SO, SO2 or a bond; m is 0 or 1; n is 2 or 3, and n + m = 2 or 3; p and q are independently 0, 1, 2, 3 or 4, and p + q = 0, 1, 2, 3 or 4 when Z4 is a bond, and p + q = 0, 1, 2 or 3 when Z4 is other than a bond; r is 2, 3 or 4; 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.

Full Text

This is a continuation of U.S. patent application No. 09/198,720, filed November 24, 1998, which, in turn, is a continuation-in-part of International Patent Application No. PCT/US98/11000, filed May 28, 1998, which, in turn, is a continuation-in-part of U.S. Ser. No. 08/972,614, filed Nov. 18, 1997, now abandoned, which, in turn, is a continuation-in-part of U.S. Ser. No. 08/864,455, filed May 18, 1997, now abandoned. 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 T cell activation and proliferation using of quinoline/quinoxaline compounds which are useful protein tyrosine kinase inhibitors (TKIs). Cellular signaling is mediated through a system of interactions which include cell-cell contact or cell-matrix contact or extracellular receptor-substrate contact. The extracellular signal is often communicated to other parts of the cell via a tyrosine kinase mediated phosphorylation event which affects substrate proteins downstream of the cell membrane bound signaling complex. A specific set of receptor-enzymes such as the insulin receptor, epidermal growth factor receptor (EGF-R) or platelet-derived growth factor receptor (PDGF-R) are examples of tyrosine kinase enzymes which are involved in cellular signaling. Autophosphorylation of the enzyme is required for efficient enzyme-mediated phosphorylation of substrate proteins containing tyrosine residues. These substrates are known to be responsible for a variety of cellular events including cellular proliferation, cellular matrix production, cellular migration and apoptosis to name a few. It is understood that a large number of disease states are caused by either uncontrolled reproduction of cells or overproduction of matrix or poorly regulated 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 restenosis occurring subsequent to angioplasty of the coronary, femoral or kidney arteries or, fibroproliferative disease such as in arthritis, fibrosis of the lung, kidney and liver. In addition, deregulated cellular proliferative conditions follow from coronary bypass surgery. The inhibition of tyrosine kinase activity is believed to have utility in the control of uncontrolled reproduction of cells or 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 function of the body. For instance, it would be undesirable to inhibit insulin action in most normal circumstances. Therefore, compounds which inhibit PDGF-R tyrosine kinase activity at concentrations less than the concentrations effective in inhibiting the insulin receptor kinase could provide valuable agents for the selective treatment of diseases characterized by cell proliferation and/or cell matrix production and/or cell movement (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 cell inflammatory response. More specifically, this invention relates to the use of substituted quinoxaline compounds which exhibit selective inhibition of differentiation, proliferation or mediator release by effectively inhibiting platelet-derived growth factor-receptor (PDGF-R) tyrosine kinase activity and/or Lck t>TOsine kinase activity. 2. Reported Developments A number of literature reports describe tyrosine kinase inhibitors which 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 reviews by Spada and Myers {Exp. Opin. Thei\ Patents 1995, 5(8), 805) and Bridges {Exp. Opin. Ther. Patents 1995, 5{12) 1245) summarize the literature for tyroine kinase inhibitors and EGF-R selective inhibitors respectively. Additionally Law and Lydon have summarized the anticancer potential of tyrosine kinase inhibitors {Emerging Drugs: The Prospect For Improved Medicines 1996, 241-260). Known inhibitors of PDGF-R tyrosine kinase activity includes quinoline-based inhibitors reported by Maguire et al. (./. Med, Chem. 1994, 37, 2129), and by Dolle et al. (./ 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 the progress in the field there are no agents from these classes of compounds that have been approved for use in humans for treating proliferative disease. The correlation between the multifactorial disease of restenosis with PDGF and PDGF-R is well-documented throughout the scientific literature. However, recent developments into the understanding of fibrotic diseases of the lung (Antoniades, H. N.; et al. J. Clin. Invest. 1990, 86, 1055), kidney and liver (Peterson, T. C. Hepatology, 1993, 77, 486) have also implicated PDGF and PDGF-R as playing a role. For instance glomerulonephritis is a major cause of renal failure and PDGF has been identified to be 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. Immim. 1991, 86, 334). It has been reported by Thornton, S. C; et al. {Clin. Exp. Immiin. 1991, 86, 79) that TNF-alpha and PDGF (obtained from human rheumatoid arthritis patients) are the major cytokines involved in proliferation of synovial cells. Furthermore, specific tumor cell types have been identified (see Silver, B. J., BioFactors, 1992, i, 217) such as glioblastoma and Kaposi's sarcoma which overexpress either the PDGF protein or receptor thus leading to the uncontrolled growth of cancer cells via an autocrine or paracrine mechanism. Therefore, it is anticipated that a PDGF tyrosine kinase inhibitor would be useful in treating a variety of seemingly unrelated human disease conditions that can be characterized by the involvement of PDGF and or PDGF-R in their etiology. The role of various non-receptor tyrosine kinases such as p56KK (hereinafter "Lck") in inflammation-related conditions involving T cell activation and proliferation has been reviewed by Hanke, et al {Injlamm. Res, 1995. 44, 357) and by Bolen and Brngge (Am. Rev, immunol, 1997,15, 371). These inflammatory conditions include allergy, autoimmune disease, rheumatoid arthritis and transplant rejection. Another recent review summarizes various classes of tyrosine kinase inhibitors including compounds having Lck inhibitory activity (Groundwater, et. al Progress in Medicinal Chemistry, 1996,35,233). Inhibitors of Lck tyrosine kinase activity include several natural products which are generally non-selective tyrosine kinase inhibitors such as staurosporine, genistein. certain flavones and crbstatin. Damnacanthoi was recently reported to be a low nM inhibitor of Lck (Faltynek. ct. al, Biochemisiry, 1995,34. 12404). Examples of synthetic Lck inhibitors include: a scries of dihydroxy-isoquinoline inhibitors reported as having low micromoiar to submicromolar activity (Burke, et, al J, Med Chem, 1993,36.425); and a quinoline derivative found to be much less active having an Lck Ic50 of 610 micromoiar. Researchers have also disclosed a series of 4-substituted quinazolines that inhibit Lck in the iow micromoiar to submicromolar range (Myers et a!, W095/15758 and Myers, et. ai Bioorg. Med Chem. Lett. 1997. 7,417). Researchers al Pfizer (Hanke. et, al 1 Biol. Chem. 1996,27/, 695) have disclosed two specific pyrazolopyrimidine inhibitors known as PPl and PP2 which have low nanomolar potency against Lck and Fyn. (another Src-family kinase). No Lck inhibitory has been reported regarding quinoline or quinoxaline based compounds. Therefore, it is anticipated that a quinoline or quinoxaline based inhibitor of Lck tyrosine kinase activity could be useful in treating a variety of .seemingly unrelated human disease conditions that can be characterized by the involvement of Lck tyrosine kinase signaling in their etiology. n is 2 or 3 and n + m = 2 or 3; p and q are independently 0, 1. 2» 3 or 4, and p + q = 0, 1,2,3, or 4 when Z4 is a bond, and p + q = 0, 1, 2 or 3 when Z4 Is other than a bond; r is 2, 3 or 4; R1a and R1b, are, independently: « (i) an aliphatic hydrocarbon group which may be branched- or straight-chained, having 1 to 10 carbon atoms, and optionally substituted by S3 (hereinafter referred to as "alkyl"); (ii) an aromatic carbocyclic radical containmg6 to 10 carbon atoms and optionally substituted by S3 (hereinafter referred to as "aryl"); (iii) a 5- to lO-membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is nitrogen, oxygen or sulftjr, optionally substituted by* S3 (hereinafter referred to as "heteroaryl") (iv) hydroxy; (v) acyl-O-, wherein acyl is H-CO- or alkyl-CO- (hereinafter referred to as "acyloxy"); (vi) an alkyl-0- group optionally substituted by S4 (hereinafter referred to as "alkoxy"); (vii) a cycloalkyl-0- group optionally substituted by S1 (hereinafter referred to as Another aspect of the invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention is also directed to intermediates useful in preparing compounds of formula I, methods for the preparation of the intermediates and compounds of formula I, and the use of compound of formula I 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. Definitions "Patient" includes both human and other mammals. "Effective amount" means an amount of compound of the present invention effective in inhibiting PDGF-R tyrosine kinase activity and/or Lck tyrosine kinase activity, and thus producing the desired therapeutic effect. "AJkyl" means aliphatic hydrocarbon group which may be branchcd-or straight-chained having about 1 to about 10 carbon atoms. Preferred alkyi is "loweralkyi" having about 1 to about 6 carbon atoms. Branched means that one or more lower alky! groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl group is also optionally substituted by alkoxy, halo, carboxy. hydroxy or R2R6N-. Examples of alkyl include methyl, fluoromethyk difluoromethyl. trifluoromethyi. ethyl, n-propvl. isopropyl butyl, sec-butyl, t-butyi, amy! and hexyl. "Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 10 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 6 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkenyl group may be substituted by carbalkoxy. Exemplary alkenyl groups include ethenyl, propenyl, w-butenyl, /-butenyl, 3-niethylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl. "Ethylenyl" means a -CH=CH- group. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms. The cycloalkyl group may be substituted by one or more, preferably one to three, more preferably one to two, of the following "'cycloalkyl substituents", alkyl, hydroxy, acyloxy. alkoxy, halo, R5R6N-, acylR5N-, carboxy or R5R6NCO- substituents, more preferred substituents are alkyl, hydroxy, acyloxy, alkoxy. and R5R6NCO-. Furthermore, when the cycloalkyl group is substituted with at least two hydroxy substituents, then at least two of the hydroxy substituents may be ketalated or acetalated with an aldehyde or ketone of one to six carbon atoms to form the corresponding ketal or acetal. "Hydroxycycloalkyl" means HO-cycloalkyl wherein the cycloalkyl may be substituted as noted. When the hydroxycycloalkyl group is derived from a cycloalkyl group which is also substituted with hydroxy, two of the hydroxy substituents may be ketalated or acetalated with an aldehyde or ketone of one to six carbon atoms to form the corresponding ketal or acetal. Ketalization of a gen-diol results in formation of a spiro fused ring system. A preferred spiro cycloalkyl ring is l,4-dioxaspiro[4,5]dec-8-yl. Preferred unsubstituted or substituted monocyclic cycloalkyl rings include cyclopentyl. hydroxycyclopentyl, fiuorocyclopentyl, cyclohexyl, hydroxycyclohexyl, hydroxymethylcyclohexyl and cycloheptyl; more preferred are hydroxycyclohexyl and hydroxycyclopentyl. Exemplary multicyclic cycloalkyl rings include 1-decalin, adamant-(l- or 2-)yl, [2.2.]]bicycloheptanyl (norbornyl), hydroxy[2.2.1]bicycloheptanyl (hydroxynorbomyl), [2.2.2]bicyclooctanyl and hydroxy[2.2.2]bicyclooctanyl: more preferred are hydroxy[2.2.1]bicycloheptanyl (hydroxynorbornyl), and hydroxy[2.2.2]bicyclooctanyl. "Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms. The cycloalkenyl group may be substituted by one or more, preferably one to three, more preferably one to two cycloalkyl substituents as described above. "Hydroxycycloalkenyl" means HO-cycloalkenyl wherein the cycloalkyl may be substituted as noted. Preferred unsubstituted or substituted monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, hydroxycyclopentenyl, hydroxycyclohexenyl and cycloheptenyl; more preferred is hydroxycyclopentenyl and hydroxycyclohexenyl. Preferred multicyclic cycloalkenyl rings include [2.2.1]bicycloheptenyl (norbornenyl) and [2.2.2]bicyclooctenyl. "Aryl" means aromatic carbocyclic radical containing about 6 to about 10 carbon atoms. Exemplary aryl include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes hydrogen, hydroxy, halo, alkyl, alkoxy, carboxy. alkoxycarbonyl or Y'Y^NCO-, wherein Y' and Y" are independently hydrogen or alkyl. Preferred aryl group substituents include hydrogen, halo and alkoxy. "Heteroaryl" means about a 5- to about a 10- membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. The "heteroaryl" may also be substituted by one or more of the above-mentioned "aryl group substituents". Exemplary heteroaryl groups include substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo[2,l-b]thiazolyl5 benzofurazanyl, indolyl, azaindolyl benzimidazolyl benzothienyl, quinolinyl, imidazolyl and isoquinolinyl. "Heterocyclyl" means an about 4 to about 10 member monocyclic or multicyclic ring system wherein one or more of the atoms in the ring system is an element other than carbon chosen amongst nitrogen, oxygen or sulfur. The heterocyclyl group may be substituted by one or more, preferably one to three, more preferably one to two cycloalkyl substituents as described above. "Hydroxyheterocyclyl" means HO-heterocyclyl wherein the heterocyclyl may be substituted as noted. "Azaheterocyclyl' means a heterocyclyl as noted herein wherein at least one of the ring atoms is nitrogen. Exemplary- heterocyclyl moieties include quinuclidyL pentamethylenesulfide, tetrahydropyranyl. tetrahydrothiophenyl, pyrrolidinyl, tetrahydrofuranyl or 7-oxabicyclo[2.2.1]heptanyl. "Cycloalkyloxy" means a cycloalkyl-O- group in which the cycloalkyl group is as previously described. Exemplary cycloalkyloxy groups include cyclopentyloxy, cyclohexyloxy, hydrocyclopentyloxy and hydroxycyclohexyloxy. "Heterocyclyloxy" means a heterocyclyl-O- group in which the heterocyclyl group is as previously described. Exemplary heterocyclyloxy groups include quinuclidyloxy, pentamethylenesulfideoxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy or 7-oxabicyclo[2.2.1]heptanyloxy, hydroxytetrahydropyranyloxy and hydroxy-7-oxabicyclo[2.2.1]heptanyloxy. "Aryloxy" means aryl-0- group in which the aryl group is as previously described. "Heteroaryloxy" means heteroaryl-0- group in which the heteroaryl group is as previously acceptable salt thereof. Another preferred compound aspect of the invention is a compound of formula I wherein R1a and R1b are independently optionally hydroxy substituted lower alkyl, hydroxy, lower alkoxy, cycloaikyloxy, heterocyclyloxy, or one of R1a and R1b is hydrogen or halo and the other of R1a, and R1b, is optionally hydroxy substituted lower alkyl, hydroxy, lower alkoxy, cycloaikyloxy, heterocyclyloxy. Another preferred compound aspect of the invention is a compound of formula 1 wherein R1a and Rih are independently heterocyclylcarbonyloxy or optionally substituted lower alkoxy; more preferably, the lower alkoxy is methoxy or ethoxy. Another preferred compound aspect of the invention is a compound of formula 1 wherein Ri^ and R,i, are lower alkyl; more preferably the lower alkyl is methyl or ethyl. Another preferred compound aspect of the invention is a compound of formula 1 wherein one of R,a and R,,, is lower alkoxy, and the other of R,a and R,,, is halo: more preferably the lower alkoxy is methoxy or ethoxy, and the halo is chloro or bromo. Another preferred compound aspect of the invention is a compound of formula I wherein one of R1a and R1b is lower alkyl, and the other of R1a and R1b is lower alkoxy; more preferably the lower alkoxy is methoxy or ethoxy, and the lower alkyl is methyl or ethyl. Another preferred compound aspect of the invention is a compound of formula 1 wherein one of R1a,, and R1b is lower alkoxy, and the other of R1a and R1b, is cycloalkyloxy; more preferably the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy. Another preferred compound aspect of the invention is a compound of formula I wherein one of R1a and R1b is hydrogen, and the other of R1a and R1b is lower alkoxy, cycloalkyloxy or heterocyclyloxy; more preferably the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy, and the heterocyclyloxy is furanyloxy. Another preferred compound aspect of the invention is a compound of formula I wherein R,,, and R1b, are lower alkoxy wherein the lower alkoxy is optionally substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. Another preferred compound aspect of the invention is a compound of formula 1 wherein one of R1a and R1b is unsubstituted lower alkoxy and the other of R1a, and R1b, optionally substituted heterocyclylcarbonyloxy or is lower alkoxy substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. Another preferred compound aspect of the invention is a compound of formula I wherein one of R1a and R1b is methoxy and the other of R1a and R1b, is [l,4']-bipiperadin-1-ylcarbonyloxy, 2-(ethoxy)ethoxy, 2-(4-morpholinyl)ethoxy, 2-(4-methylpiperazin-l -yl)ethoxy, carboxymethoxy, methoxycarbonylmethoxy, aminocarbonylmethoxy, N-methylaminocarbonylmethoxy or N,N-dimethylaminocarbonylmethoxy. Another preferred compound aspect of the invention is a compound of formula I wherein Ri^ is hydrogen, lower alkyl or lower alkoxy; more preferably the lower alkoxy is methoxy or ethoxy. Another preferred compound aspect of the invention is a compound of formula 1 wherein Z, is CH. Another preferred compound aspect of the invention is a compound of formula 1 wherein Z, is N. Another preferred compound aspect of the invention is a compound of formula 1 wherein Z^ is optionally substituted hydroxycycloalkyl. Another preferred compound aspect of the invention is a compound of formula 1 wherein p and q are 0. Another preferred compound aspect of the invention is a compound of formula I wherein p + q-1. Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is O. Another preferred compound aspect of the invention is a compound of formula 1 wherein Z4 is O, and p and q are 0. Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is O, and p + q = 1. V Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is NR4. Another preferred compound aspect of the invention is a compound of formula 1 wherein Z4 is NR4, and p and q are 0. Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is NR4, and m + n = 1. Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is S. Another preferred compound aspect of the invention is a compound of formula I wherein Z4 is S, and p and q are 0. Another preferred compound aspect of the invention is a compound of formula I wherein Z., is S, and p + q = 1 ■ Another preferred compound aspect of the invention is a compound of formula I wherein Z2 is (hydroxy or alkyl) substituted hydroxycycloalkyi, more preferred is (lower alkyl)hydroxycycloalkyl. The compounds of this invention may be prepared by employing procedures known in the literature starting from known compounds or readily prepared intermediates. Exemplary general procedures follow. In addition, compounds of formula I are prepared according to the following Schemes 1-X herein the variables are as described above, excepting those variables which one skilled in the art would appreciate would be incongnient with the method described. In Schemes VI. VII and VIII. R represents a precursor group to R1a, R1b or R1c as defined herein, such that reaction of RBr, ROH, or RCOCI with the aromatic hydroxy group under the conditions described in Schemes Vl, VII and VIII results in formation of R13, R1b or R1c. Representative RBr include bromoacetic acid and methyl and ethyl bromoacetate. Representative ROH include 2-ethoxyethanol. 2-(4-morphollnyl)ethanol and 3-(4-methylpiperazinyl)propanol. A representative RCOCI is [1,4']-bipiperid!n-1'-ylcarbonyl chloride. 1 General Procedures: 1. Coupling of 2-chloro substituted quinoxaline and amines or anilines A mixture of 2-chloro-6,7-dimethoxyquinoxaline (1 eq.) and an amine (about 1 to about 5 eq.) is heated at about 160 to about 180 °C from about three hours to overnight. The dark-brown residue is dissolved in methanol/ methylene chloride (0%-10%) and chromatographed on silica gel eiuted with hexane/ethyl acetate or methanol/methylene chloride (0%-100%) to yield the desired product. The desired product may be purified further through recrystallization in methanol, methylene chloride or methanol/water. 2. Coupling of 2-chloro substituted quinoxaline and alcohols or phenols A suspension of an alcohol or mercaptan (1 eq.) and sodium hydride (about I to about 3 eq.) in anhydrous DMF/THF (0%-50%) is refluxed for 1 hour before addition of 2-chioro-6,7-dimethoxyquinoxaline (1 eq.). The resulting mixture is refluxed for about one to about four hours. The suspension is neutralized to about pH 5-8 and partitioned between methylene chloride and brine. The residue after concentration of methylene chloride is chromatographed on silica gel eiuted with hexane/ethyl acetate or methanol/methylene chloride (0%-100%) to give the desired product. 3. Reductive amination reaction with amino-quinolines and aldehydes or ketones. An appropriately substituted 3-amino quinoline (i eq.) is stirred with 1 eq. of the appropriate aldehyde or ketone in methanol (or another suitable solvent mixture) until TLC indicates imine formation is complete. Excess NaCNBH4 or NaBH4, or another suitable reducing agent is added and the mixture is stirred until TLC shows consumption of the intermediate imine. The mixture is concentrated and the residue is 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-amino quinoline (1 eq.) is stirred with -1.4 eq. of a strong base such as sodium /-butoxide, I eq. of the appropriate bromophenyl compound, and catalytic amounts of 2,2'-bis(diphenylphosphino)-I-i'-binaphthyl (S-BINAP)and bis(dibenzylideneacetone)-Palladium (Pd(dba)2) are mixed in an inert organic solvent such as toluene under an inert atmosphere such as argon and heated to about 80°C overnight. The mixture is cooled, diluted with a solvent such as ether, filtered, concentrated and chromatographed with 50% EtOAc/hexane to give the desired product, 5. Ether formation from 3-hydroxy substituted quinolines via Mitsunobu conditions, A THF solution of an appropriately substituted hydroxyquinoxaline (at about 0 to about 25 °C) is treated with 1 eq. each of the desired alcohol, triphenylphosphine and finally diethylazodicarboxylate (DEAD) or a suitable equivalent. The reaction progress is monitored via TLC and upon completion of the reaction (about 1 to about 24 hours) the mixture is concentrated and the residue is chromatographed on silica gel to yield the desired product. 6. Dealkylation of a lower alkoxy substituted quinoline or quinoxaline, and subsequent alkylation. An appropriate lower alkoxy substituted quinoline or quinoxaline (1 eq.) in DMF is treated with excess sodium ethanthiolate (usually about 2 or more eq.) and the reaction mixture is stirred with heating from about 1 to about 24 hours. The mixture is partitioned between water and ethyl acetate. Extractive workup followed by chromatography, if necessary, provides the corresponding desired hydroxy substituted quinoline or quinoxaline product. The hydroxy substituted quinoline or quinoxaline product can be alkylated using the conditions for the Mitsunobu reaction as detailed above. Alternatively, simple alkylation using methods well-known in the art with a reactive alkyl- or benzyl- halide using NaH or another appropriate base in a suitable solvent provides the desired alkylated product. 7. Oxidation of a nitrogen in a quinoline or quinoxaline to the corresponding N-oxide. An imine (=N-) moiety in a quinoline or quinoxaline compound of formula (1), may be converted to the coiTesponding compound wherein the imine moiety is oxidized to an N-oxide, preferably by reacting 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 elevated temperature. The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof All fonns are within the scope of the invention. Where the compound of the present invention is substituted with a basic moiety, acid addition salts are formed and are simply a more convenient form for use: and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base. pharmaceutically acceptable salts, that is, salts whose anions are non-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 ascribable 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, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those derived 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, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively. According to a further feature of the invention, 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 or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution. The compounds of this invention can be regenerated from the acid addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution. Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-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 side effects ascribable to the cations. Pharmaceutically acceptable salts, including for example alkali and alkaline earth metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonia, triethylammonia, ethylenediamine, n-methyl-glucamine, lysine, arginine. ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, n-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethyiammonium hydroxide, and the like. Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a 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. Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating. Amine salts of compounds of the present invention may 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. Amino acid salts may be similarly prepared. The compounds of this invention can be regenerated from the base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g., hydrochloric acid. As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art. Compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in either the R or S configuration. It will also be apparent to those skilled in the art that certain compounds of formula I may exhibit geometrical isomerism. Geometrical isomers include the cis and trans forms of compounds of the invention, i.e., compounds having alkenyl moieties or substituents on the ring systems. In addition, bicyclo ring systems include endo and exo isomers. The present invention comprises the individual geometrical isomers, stereoisomers, enantiomers and mixtures thereof Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein. The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents, or by methods described according to the invention herein. The present invention is further exemplified but not limited by the following illustrative examples which describe the preparation of the compounds according to the invention. Further, the following examples are representative of the processes used to synthesize the compounds of this invention. EXAMPLE 1 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), Ph3P (0.908 g, 3.46 mmole). Diethylazodicarboxylate is added portionwise until the solution retained a deep red color (0.663 g, 3,81 mmole). After 4 hours the solution is concentrated and the residue chromatographed {50% EtOAc in hexanes). The product is recrystallized from isopropanol/hexanes as the HCl salt as a white solid (m.p. 229-232°C. dec). chromatographed (50% EtOAc/hexanes) and taken up in Et2O/IPA. HCl/ Et2O solution is added dropwise and the resulting red-orange powder is dried in vacuo. The powder is free-based by stirring in MeOH with washed (3X H2O, 5X MeOH) basic ion exchange resin. The mixture is stirred 30 minutes, filtered, concentrated, and recrystallized from EtOAc/hexanes to provide, in two crops, the product (m.p. 173-175^C). Anal. Calcd. for C,8H,7N302: C, 70.35; H, 5.57; N, 13.67; Found: C, 70.19; H, 5.60; N, 13.66. EXAMPLE 12 trans-4-(6,7-Dimethoxyquinoxaiin-2-ylamino)-cyclohexanoI trans- 4-aminocyclohexanol (0.11 g, 2 eq.) and 2-chloro-6,7-dimethoxyquinoxaline (O.I g, 1 eq.) are combined and heated to 160-180°C for a period of 4-8 hours. The dark-brown suspension is filtered and concentrated. The residue is purified on a flash column eluted with 3% methanol/methylene chloride to provide the product as a yellow powder with m,.p. of 119- 123°C. Anal. Calcd. for C16H21N303: C, 62.33; H, 7.05; N, 13.63; Found: C 62.35; R 7.09: N, 13.18. The compound could be recrystallized by the following method. Starting with 0.2 g of yellow powder in a mixture of 2.5 mL of water and 1.25 mL of methanol a clear orange-colored solution is obtained upon reflux. The hot solution is left standing and cooled gradually. Orange-colored needle-like crystals are collected by filtration and dried under high vacuum to give a yellow solid (m.p. 119-120 °C). Alternatively, the HCI salt of the title compound is prepared as follows: To a solution of trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexanol in isopropanol is added a solution of HCI at 0°C. The mixture is stirred for 15 minutes before filtration. The solid collected is dried under a high vacuum to provide the trans--4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexanol hydrochloric acid salt. Anal. Calcd. for C16H32CIN30., •1.2 H,0: C, 53.19: H. 6.80; N, 11.63; CK 9,81: Found: C, 53.14: H. 6.85; N, 11.24: CI 10.28. Procedure B: A mixture of 2-chIoro-6,7-dimethoxyquinoxaline (9 g, 40.! mmole) and (±)-exo-norbomyl-2-amine (5.77 g, 52 mmole), Sodium t-butoxide (4.22 g, 44 mmole). 2,2'-bis(diphenylphosphino)-l-r-binaphthyl (BINAP, 120 mg) and bis(dibenzylideneacetone)-palIadium Pd(dba)2, 40 mg in 80 niL of toluene is heated at 80°C for eight hours. Another portion of BINAP (60 mg) and Pd(dba)2(20 mg) is added and the mixture is heated at 100°C overnight. After being diluted with 200 mL of methylene chloride, the reaction mixture is washed with IN NaOH (100 mL). The organic layer is dried over magnesium sulfate and filtered. The residue after concentration is chromatographed on silica gel eluted with hexane/ethyl acetate (80%) to provide the desired product as a light-yellow solid (m.p. 188-189°C). Anal. Calcd. for C7H21N3O3,: C, 68.20; H, 7.07; N. 14.04; Found: C. 68,18: R 7.03; N, 14.03. The following compounds are prepared similarly beginning with the appropriate starting material (procedure A). EXAMPLE 16 cis/trans-4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanecarboxylic acid. A mixture of cis/trans-4-hydroxy-cyclohexanecarboxylic acid (144 mg, 1 mmole) and NaH (60%, 160 mg, 4 mmole) in anhydrous THF/DMF( 10 mL/2 mL) is refluxed for one hour before addition of 2-Chloro-6,7-dimethoxyquinoxaiine (225 mg, 1 mmole). The resulting mixture is continued to refluxed for four hours. The reaction mixture is neutralized to pH 5 and extracted with ethyl acetate (2x50 mL). The combined organic solutions are dried over magnesium sulfate and filtered, The residue after concentration is chromatographed on silica gel (ethyl acetate, followed by methanol) to provide the desired product as a white solid (m.p, 90-93 °C). Anal. Calcd. for C17H20N2O5 •O.5 H2O: C, 59.89; H, 6.19; N. 8.22; Found: C. 59.91; R 6.62; N, 7.90. The following compounds are prepared similarly beginning with the appropriate starting material 4-(6,7-Dimethoxyquinoxalin-2-yloxymethyl)-cyclohexanol (m.p. 118-12 PC). Anal. Calcd. for CnH22N204 •0.3 H.O: C, 63.15; H, 7.03; M, 8.66; Found: C, 63.13; H, 6.65; N, 9.01. 3-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol (m.p. 151-153°C). Anal. Calcd. for Ci6H2oN.O^: C\ 63.14; a 6.62; N, 9.20; Found: C, 62.56; H, 6.58; N, 8.67. 4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol (m.p. 162-164'C). Anal. Calcd. for C]6H2oN204: C, 63.14; H, 6.62; N, 9.20: Found: C, 62.52; H 6.80; N, 8.88. EXAMPLE 20 3-Cyclohexyloxy-6,7-dimethoxyquinoxaline 1 -oxide. A mixture of 2-cyclohexyloxy-6,7-dimethoxyquinoxaline (110 mg, 0.38 mmole) and meta-chlorobenzoic peracid (70%, 113 mg, 0.46 mmole) in 10 mL of methylene chloride is stirred at room temperature for one day. The solution after filtration is concentrated and the residue is chromatographed on silica gel (20% ethyl acetate/hexane) to provide the desired product (m.p. 167-169 °C). trans-4-(6,7-Dimethoxy-4-oxy-quinoxalin-2-ylamino)-cyclohexanol (m.p. 220-222°C) is prepared similarly. Anal. Calcd. for C16H21N2O4 •0.2 H2O: C, 59.42; H, 6.69; N, 12.99; Found: C, 59.43; H, 6.64; N, 12.95. EXAMPLE 21 Acetic acid trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexyl ester A mixture of trans-4-(6,7-dimethoxyquinoxalin-2-yiamino)-cyclohexanol (303 mg, 1 mmol), acetic anhydride (2 mL) and pyridine (2 mL) in 10 mL of dichloromethane is stirred at room temperature overnight. The mixture is quenched with water (5 mL) and extracted with dichloromethane (2x 30 mL), After drying over magnesium sulfate and filtration, the solution is concentrated on a rotovap. The residue is chromatographed on silica gel (ethyl acetate) to provide the desired acetate as a light yellow solid (m.p. 176-177°C). Anal. Calcd. for C18H23N304: C 62.59; H, 6.71; N, 12.17; Found: C. 62.89: R 6.67; N, 11.95. EXAMPLE 22 (2exo,5exo)-5-(6,7-Dimethoxyquinoxa]ine-2-ylamino)-bicyclo[2.2.1]heptan-2-ol A mixture of (2exo,5exo)-5-aminobicyclo[2.2.1 ]heptan-2-acetate (127 mg, 0.75 mmol) and 2-chloro-6,7-dimethoxyquinoxaline (224 mg, 1 mmol ) is heated to 1 180°C for six hours. After which time, the mixture is cooled to room temperature, dissolved in methylene chloride and purified via flash column. The recovered product (20 mg, 7.5 % yield) is dissolved in methanol (2 mL), and a fresh solution of 1 N sodium methoxide (0.063 mL, 0.063 mmol) is added. The reaction mixture is refluxed for ninety minutes. The crude mixture is purified by preparative thin layer chromatography to provide the product as a yellow solid with a m.p. of 97-lOO^C. C,7H21N.,03 (m/z ): 315. The following compounds are prepared similarly beginning with the appropriate starting material (2endo5exo)-5-(6,7-Dimethoxyquinoline-2-ylamino)-bicyclo[2.2.1]heptan-2-ol, as a yellow solid. C17H21N3O3 (m/z ): 315. {2exo, 6exo;)-6-(6,7-Dimethoxy-quinolin-2-ylamino)-bicyclo[2.2.1]heptan-2-o], as a yellow solid (30 mg, overall 21 %). C,7H2,N30.. (m/z ): 315. Anal. Calcd. for C17H21N3O3: C 64.74; H.6.7]:N. 13.32; Found C 58.42; H, 6.26; N, 11.56. EXAMPLE 23 (2trans.4cis)-4-(6,7-Dimethoxyquinoxaline-2-ylamino)-2-methyl-cyclohexanol and(2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol A mixture of 2-chioro-6,7-dimethoxy quinoxaline (1.08 g, 4.81 mmol) and (2trans)-4-amino-2-methylcyclohexanot (620 mg, 4.81 mmol) is heated to 180°C for six hours. The reaction yielded two diastereomers. The major isomer is isolated as a yellow solid, assigned as (ItransA trans-4--(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol (240 mg, 0.76 mmol. C17H23N3O3. (m/z ): 317. Anal. Calcd. for C17H23NA •2H2O: C 58.00; H, 7.69; N, 11.94; Found C 58.0; H, 6,58; "N. 11.24. EXAMPLE 26 Biotransformative Preparation of (1 S,2R.4S,5R)-5-(6,7-DimethoxyquinoxaIin-2- ylamino)-Bicyclo[2.2.1 ]heptan-2-ol Fungi Strain F 2052 ( Mortierella isabellina ) is purchased from the Northern Utilization Research and Development Division (NRRL). The fungi is stored at -25°C. 250 mL conical flasks each containing 50 mL seed culture medium ( medium 216 ) are inoculated with 2 mL of fungi suspension and incubated on a rotary shaker ( 200 rpm ) at 23°C for 3 days. 250 mL conical flasks each containing 50 mL of the same medium were inoculated EXAMPLE 29 2-[2-(^ram-4-Hydroxy-cyclohexylamino)-7-methoxy-quinoxalin-6-yloxyl]-N,N- dimethyl-acetamide and 2-[2-(//'a^7A-4-Hydroxy-cyclohexylamino)-6-methoxy-quinoxalin-7-yloxyl]-N,N-dimethyl-acetamide The title compound is prepared by aminolysis of the compound of Example 28 using dimethylamine. INTERMEDIATE EXAMPLE 1 4-Bromo-5-methoxy-benzene-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 is added 5% Pd/C (0.5 g). The reaction mixture is hydrogenated at 50 psi for 1 hour. The mixture is filtered through Celite into a solution of HCl/lPA/EtOAc. and the pad is washed with additional EtOAc. The resulting precipitate is filtered off to provide white solid. INTERMEDIATE EXAMPLE 2 7-Bromo-6-methoxy-quinoxaiin-2-ol and 6-Bromo-7-methoxy- quinoxalin-2-ol To a solution of MeOH (15 mL) under argon is added pulverized NaOH pellets (0.86 g, 21 mmol) and 4-bromo-5-methoxy-benzene-l,2-diamine dihydrochloride (2.7 g, 9.3 mmol). The mixture is stin-ed for 10 minutes, then a solution of 45% ethyl giyoxylate in toluene (2.7 g, 12 mmol) is added portionwise. The reaction mixture is refluxed for 1 hour, then cooled. Water is added, then the suspension is filtered. The resulting solid is washed successively with H20, MeOH, IPA, and Et.O to provide a yellow powder. INTERMEDIATE EXAMPLE 3 7-Bromo-2-chloro-6-methoxy-quinoxaline and 6-Bronio-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 FOCI:, (5 mL). The reaction mixture is refluxed 1 hour, poured into ice water, filtered, then washed with water to provide a light-tan solid. Ratio of 7-bromo-2-chloro-6-methoxy-quinoxaline : 6-bromo-2-chioro-7-methoxy-quinoxaline is approximately 7:1 by 'HNMR. INTERMEDIATE EXAMPLE 4 5-Chloro-4-methoxv-2-nitroaniline To a solution of N-(5-chloro-4-methoxy-2-nitrophenyl)-acetamide (2 g, 8.2 mmol) in 5N HCl (20 mL) is added 1,4-dioxane (10 mL), and the mixture is stirred at 60°C for 1.5 hours. The reaction mixture is concentrated and partitioned between EtOAc/2 N NaOH. The aqueous layers are washed with EtOAc (3X), brine, dried (MgSO4), adsorbed onto silica gel, and chromatographed (70% EtOAc/hexanes) to provide an orange powder. minutes, poured into cold saturated 'NaHC03 solution, filtered, then washed with water to provide a solid. The ratio of 2,7-dichloro-6-methoxy-quinoxaline : 2,6-dichloro-7-methoxy-quinoxaline is approximately 6:1 by^HNMR. INTERMEDIATE EXAMPLE 8 cis-4-Aminocyclohexanol cis-4-aminocyclohexanol is made according to the literature procedure with minor modification [./ Med Chem. 18(6) 634 1975]. (2encio, 6exo)-6-amino-bicyclo[2.2.1]heptan-2-ol, and (2exo, 6exo))-6-amino-bicyclo[2.2.1 ]heptan-2-ol The titled compounds are prepared from proper starting material by application of above procedure of INTERMEDIATE EXAMPLE 11. INTERMEDIATE EXAMPLE 13 2-Methyl-6,7-dimethoxyquinoxaline The title compound is prepared using an adaptation of the published method of Tamao, et al. Tetrahedron, 1982, iS, 3347-3354. To a THF solution under argon is added 2-Chloro-6,7-dimethoxyquinoxaline (5 g, 26 mmol) and NiCl2(dppp) (0.14 g, 0.26 mmol). The reaction mixture is cooled to 0°C, and a 3 M solution of MeMgBr in Et2O (13 mL, 39 mmol) is added portionwise. The reaction mixture is allowed to warm to room temperature, stirred for 1 hour, then refluxed for 1.5 hours. The mixture is cooled, quenched with 10% HCl, stirred 10 minutes, then made basic with 5% NaOH. CH3CI3 and H2O are added to the reaction, and the mixture stirred overnight. Additional CH2Cl2,H30, and NaCl are then added and the mixture is filtered. The resulting solution is poured into a separatory funnel, and the aqueous layers are washed 3X with CHsCl2. The organic layers are combined, washed with brine, dried (MgSO4), concentrated onto silica gel, and chromatographed (50%-80% EtOAc/hexanes) to provide a orange solid (49% yield). A mixture of the above solid (300 mg, 1 mmol ) and hydrazine (0.126 mL, 2.2 mmo!) in 5 mL of methanol is heated to reflux for six hours. After removal of methanol, dichloromethane (3x 30 mL) is used to extract the residue. Concentration of the solvent affords (exo,exo)-5-aminobicyclo[2.2.1 ]heptan-2-acetate (127 mg, 75%) which is used in the coupling reaction without further purification. Similarly, (lendo,5exo)-5-am'mob\cyc\o[2.2.] ]heptan-2-acetate, (2endo,6exoy6-aminobicyclo[2.2.1 ]heptan-2-acetate and (2ew,6.vo)-6-aminobicyclo[2.2.1 ]heptan-2-acetate are prepared from proper starting material. INTERMEDIATE EXAMPLE 16 (2trans)-4-Amino-2-methylcyclohexanol A mixture of 3-methyl-2-cycIohexenone (4 g, 36.36 mmol), toluenesulfonic acid (100 mg) and ethylene glycol (7 mL) in 100 mL of toluene is refluxed overnight and water fonned is removed by Dean-Stark trap. The residue after concentration is chromatographed on silica gel (10% ethyl acetate/hexane) to give 3.36 g (62%) of 7-methyl-K4-dioxa-spiro[4.5]dec-7-ene. To a stirred solution of 7-methyl-l,4-dioxa-spiro[4.5]dec-7-ene (3.36 g, 22.47 mmol) in tetrahydrofuran (THF) (125 mL) is added a IM solution of borane in THF (22.47 mL, 22.47 mmol) at room temperature. The mixture stirred for one hour, and the reaction is quenched by adding H2O (10 mL) at OT followed by sodium perborate tetrahydrate (lO.Og, 66 mmol). The mixture is left to stir overnight. The two layers are separated, and the aqueous layer is washed several times with ethyl acetate (4 X 150 mL). The desired alcohol is obtained as a clear liquid after flash column chromatography. The above alcohol (1.8 g, 10.5 mmol) is dissolved in methanol (50 mL) and IN HCl (16 mL). The reaction mixture is left to stir overnight. The acidic solution is neutralized with IN sodium hydroxide (18 mL) and normal aqueous work-up followed. The crude mixture is purified by flash column (50% ethyl acetate) to give tram 4-hydroxy-3-methyl-cyclohexanone. To a solution of tram 4-hydroxy-3-methyl-cyclohexanone (780 mg, 6.1 mmol) water (3 mL) is added hydroxylamine hydrochloride (550 mg, 7.92 mmol), followed by the slow addition of a saturated solution of sodium carbonate (326 mg, 3.8 mmol) in water (1.02 mL). After stirring for thirty minutes, ether is added to the reaction mixture, and the two layers are separated. The organic layer is condensed and dissolved in ethanol (10 mL). To the refluxing ethanol solution is added sodium (1.8 g, 78.3 mmol) over a period of one hour and the resulting mixture is heated for additional 2.5 hours. After removal of ethanol, n-propanol (10 mL), ether (25 mL), and water (3 mL) is added. The organic solution is dried over magnesium sulfate and filtered. Concentration of solvents affords a mixture of (2trans)4-amino-2-methylcyclohexanol as a white solid. INTERMEDIATE EXAMPLE 17 2-methoxy-4,5-diaminophenol dihydrochloride The title compound is prepared by hydrogenation of 2-methoxy-4,5-dinitrophenol according to the procedure of Ehrlich et al., J. Org.Chem., 1947,12, 522. INTERMEDIATE EXAMPLE 18 7-hydroxy-6-methoxy-quinoxaline-2-ol and 6-hydroxy-7-methoxy-quinoxaline-2-ol. The title compounds are prepared from 4-niethoxy-5-hydroxybenzene-l,2-diamine dihydrochloride by reaction with NaOH and ethyl glyoxalate using the procedure of Intermediate Example 2. INTERMEDIATE EXAMPLE 19 7-hydroxy-6-methoxy--2-chloroquinoxaline and 6-hydroxy-7-methoxy-2-chloroquinoxaiine. The title compounds are prepared from 7-hydroxy-6-methoxy-quinoxaline-2-ol and 6-hydroxy-7-methoxy-quinoxaline-2-ol by reaction with POCK using the procedure of Intermediate Example 3. The compounds of formula 1 as described herein inhibit inhibition of cell proliferation and/or cell matrix production and/or cell movement (chemotaxis) via inhibition of PDGF-R tyrosine kinase activity. A large number of disease states are caused by either uncontrolled reproduction of cells or overproduction of matrix or poorly regulated 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 occurring subsequent to angioplasty of the coronary, femoral or kidney arteries or, fibroproliferative disease such as in arthritis, fibrosis of the lung, kidney and liver. In particular, PDGF and PDGF-R have been reported to be 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. In addition, deregulated cellular proliferative conditions follow from coronary bypass surgery. The inhibition of tyrosine kinase activity is believed to have utility in the control of uncontrolled reproduction of cells or overproduction of matrix or poorly regulated programmed cell death (apoptosis). This invention relates to the modulation and/or inhibition of cell signaling, cell proliferation and/or cell matrix production and/or cell movement (chemotaxis), the control of abnormal cell growth and cell inflammatory response. More specifically, this invention relates to the use of substituted quinoline and quinoxaline compounds which exhibit selective inhibition of differentiation, proliferation, matrix production, chemotaxis or mediator release by effectively inhibiting platelet-derived growth factor-receptor (PDGF-R) tyrosine kinase activity. Initiation of autophosphorylation, i.e., phosphorylation of the growth factor receptor itself, and of the phosphorylation of a host of intracellular substrates are some of the biochemical events which are involved in cell signaling, cell proliferation, matrix production, chemotaxis and mediator release. By effectively inhibiting Lck tyrosine kinase activity, the compounds of this invention are also useful in the treatment of resistance to transplantation and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, in transplant rejection, in graft vs. host disease, in hyperproliferative disorders such as tumours and psoriasis, and in diseases in which cells receive pro-inflammatory signals such as asthma, inflammatory bowel disease and pancreatitis. In the treatment of resistance to transplantation, a compound of this invention may be used either 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 transplantation operation. Prophylactic treatment may also include administration of the medication after the transplantation operation but before any signs of adverse reaction to transplantation are observed. When administered in response to an adverse reaction, a compound of this invention is administered directly to the patient in order to treat resistance to transplantation after outward signs of the resistance have been manifested. According to a further feature of the invention there is provided a method of inhibiting PDGF tyrosine kinase activity comprising contacting a compound according to claim 1 with a composition containing a PDGF tyrosine kinase. According to a further feature of the invention there is provided method of inhibiting Lck tyrosine kinase activity comprising contacting a compound according to claim 1 with a composition containing a Lck tyrosine kinase. According to a further feature of the invention there is provided a method for the treatment of a patient suffering from, or subject to, conditions which may 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 hereinbefore described, which comprises the administration to the patient of an effective amount of compound of formula 1 or a composition containing a compound of formula 1 or a pharmaceutically acceptable salt thereof. Reference herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions. The present invention also includes within its scope pharmaceutical compositions which comprise 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 compounds or compositions for treating according to the present invention may administered in any variety of suitable forms, for example, by inhalation, topically, parenterally, rectally or orally; more preferably orally. More specific routes of administration include intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, colonical. peritoneal, transepithelial including transdermal, ophthalmic, sublingual, buccal, dermal, ocular, nasal inhalation via insufflation, and aerosol. The compounds of formula 1 may be presented in forms permitting administration by the most suitable route and the invention also relates to pharmaceutical compositions containing at least one compound according to the invention which are suitable for use as a medicament in a patient. These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various 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 chosen from the group comprising sweeteners such as sucrose, lactose, fructose, saccharin or Nutrasweet®, flavorings such as peppermint oil, oil of wintergreen. or cherry or orange flavorings, colorings, or stabilizers such as methyl- or propylparaben in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions to 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 may be used for preparing tablets, troches, pills, capsules and the like. To prepare a capsule, it is advantageous to use lactose and liquid carrier, such as high molecular weight polyethylene glycols. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof may also be used. In addition, the active compound may be incorporated into sustained-release preparations and formulations. For oral administration, the active compound may be administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet, or may be incorporated with excipient and 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 in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The injectable forms must be fluid to the extent that it can be easily syringed, and proper 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 brought about by use of agents delaying 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 hydroxypropyl-cellulose. Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, iiradiation, 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 various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof. Topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may be also incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through transdermal barrier. For administration by inhalation, compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier 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 1. Compositions according to the invention may also be formulated in a manner which resists rapid clearance from the vascular (arterial or venous) wall by convection and/or diffusion, thereby increasing the residence time of the viral particles at the desired site of action. A periadventitial depot comprising a compound according to the invention may be used for sustained release. One such useful depot 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 shell. Alternatively, a compound according to the invention may be delivered locally from a silicone polymer implanted in the adventitia. An alternative approach for minimizing washout of a compound according to the invention during percutaneous, transvascular delivery comprises the use of nondiffusible, drug-eluting microparticles. The microparticles may be comprised of a variety of synthetic polymers, such as polylactide for example, or natural substances, including proteins or polysaccharides. Such microparticles enable strategic manipulation of variables including total dose of drug and kinetics of its release. Microparticles can be injected efficiently into the arterial or venous wall through a porous balloon catheter or a balloon over stent, and are retained in the vascular wall and the periadventitial tissue for at least about two weeks. Formuiations and methodologies for local, intravascular site-specific delivery of therapeutic agents are discussed in Reissen et al. (./ Am. Coll. Cardiol. 1994; 23: 1234-1244), the entire contents of which are hereby incorporated by 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 polyacrylic acid polymer that can act as a drug absorbing sponge. Such polymers have been described, for example, in application WO93/08845, the entire contents of which are hereby incorporated by reference. Certain of them, such as, in particular, those obtained from ethylene and/or propylene oxide are commercially available. In the use of compounds according to the invention for treating pathologies which 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 arc administered directly to the blood vessel wall by means of an angioplasty balloon which is coated with a hydrophilic film (for example a hydrogel) which is saturated with the compound, or by means of any other catheter containing an infusion chamber for the compound, which can thus be applied in a precise manner to the site to be treated and allow the compound to be liberated locally and efficiently at the location of the cells to be treated. This method of administration advantageously makes it possible for the compound to contact quickly the cells in need of treatment. The treatment method of the invention preferably consists in introducing a compound according to the invention at the site to be treated. For example, a hydrogel containing composition can be deposited directly onto the surface of the tissue to be treated, for example during a surgical intervention. Advantageously, the hydrogel is introduced at the desired intravascular site by coating a catheter, for example a balloon catheter, and delivery to the vascular wall, preferably at the time of angioplasty. In a particularly advantageous manner, the saturated hydrogel is introduced at the site to be treated by means of a balloon catheter. The balloon may be chaperoned by a protective sheath as the catheter is advanced toward the target vessel, in order to minimize drug washoff after the catheter is introduced into the bloodstream. Another embodiment of the invention provides for a compound according to the invention to be administered by means of perfusion balloons. These perfusion balloons, which make it possible to maintain a blood flow and thus to decrease the risks of ischaemia of the myocardium, on inflation of the balloon, also enable the compound to be delivered locally at normal pressure for a relatively long time, more than twenty minutes, which may be necessary for its optimal action. Alternatively, a channelled balloon catheter ("channelled balloon angioplasty catheter", Mansfield Medical, Boston Scientific Corp., Watertown, MA) may be used. The latter consists of a conventional balloon covered with a layer of 24 perforated channels which are perfused via an independent lumen through an additional infusion orifice. Various types of balloon catheters, such as double balloon, porous balloon, microporous balloon, channel balloon, balloon over stent and hydrogel catheter, all of which may be used to practice the invention, are disclosed in Reissen et al. (1994), the entire contents of which are hereby incorporated by reference. The use of a perfusion balloon catheter is especially advantageous, as it has the advantages of both keeping the balloon inflated for a longer period of time by retaining the properties of facilitated sliding and of site-specificity of the hydrogel, are gained simultaneously. Another aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the invention and poloxamer, such as Poloxamer 407 is a non-toxic, biocompatible polyol, commercially available (BASF, Parsippany, NJ). A poloxamer impregnated with a compound according to the invention may be deposited directly on the surface of the tissue to be treated, for example during a surgical intervention. Poloxamer possesses essentially the same advantages as hydrogel while having a lower viscosity. The use of a channel balloon catheter with a poloxamer impregnated with a compound according to the invention is especially advantageous. Jn this case, the advantages of both keeping the balloon inflated for a longer period of time, while retaining the properties of facilitated sliding, and of site-specificity of the poloxamer, are gained simultaneously. The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. A dose employed may be determined by a physician or qualified medical professional, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10. mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 10, mg/kg body weight per day by intravenous administration. In each particular case, the doses are determined in accordance with the factors distinctive to the patient to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the compound according to the invention. The compounds/compositions according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for other patients, it will be necessary to prescribe not more than one or two doses per day. The compounds of the present invention may also be formulated for use in conjunction with other therapeutic agents such as agents or in connection with the application of therapeutic techniques to address pharmacological conditions which may be ameliorated through the application of a compound of formula 1, such as in the following: The compounds of the present invention may be used in the treatment of restenosis post angioplasty using any device such as balloon, ablation or laser techniques. The compounds of the present invention may be used in the treatment of restenosis following stent placement in the vasculature either as 1) primary treatment for vascular blockage, or 2) in the instance where angioplasty using any device fails to give a patent artery. The compounds of the present invention may be used either orally, by parenteral administration or the compound could be applied topically through the intervention of a specific device or as a properly formulated coating on a stent device. In one aspect, the coating on a stent device is formed by applying polymeric material in which the compound of the invention is incorporated to at least one surface of the stent device. Polymeric materials suitable for incorporating the compound of the invention include polymers having relatively low processing temperatures such as polycaprolactone, poly(ethylene-co-vinyl acetate) or poly(vinyl acetate or silicone gum rubber and polymers having similar relatively low processing temperatures. Other suitable polymers include non-degradable polymers capable of carrying and delivering therapeutic drugs such as latexes, urethanes, polysiloxanes, styrene-ethylene/butylene-styrene block copolymers (SEBS) and biodegradable, bioabsorbable polymers capable of carrying and delivering therapeutic drugs, such as poly-DL-lactic acid (DL-PLA), and poly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, and polyphosphazenes. A porosigen may also be incorporated in the drug loaded polymer by adding the porosigen to the polymer along with the therapeutic drug to form a porous, drug loaded polymeric membrane. "Porosigen" means as any moiety, such as microgranules of sodium chloride, lactose, or sodium heparin, for example, which will dissolve or otherwise be degraded when immersed in body fluids to leave behind a porous network in the polymeric material. The pores left by such porosignes can typically be a large as 10 microns. The pores formed by porosignes such as polyethylene glycol (PEG), polyethylene oxide/polypropylene oxide (PEO/PPO) copolymers, for example, can also be smaller than one micron, although other similar materials which form phase separations from the continuous drug loaded polymeric matrix and can later be leached out by body fluids can also be suitable for forming pores smaller than one micron. The polymeric material can be applied to the stent while the therapeutic drug and porosigen material are contained within the polymeric material, to allow the porosigen to be dissolved or degraded by body fluids when the stent is placed in a blood vessel, or alternatively, the porosigen can be dissolved and removed from the polymeric material to form pores in the polymeric material prior to placement of the polymeric material combined with the stent within a blood vessel. If desired, a rate-controlling membrane can also be applied over the drug loaded polymer, to limit the release rate of the compound of the invention. The rate-controlling membrane can be added by applying a coating form a solution, or a lamination. The rate-controlling membrane applied over the polymeric material can be formed to include a uniform dispersion of a porosigen in the rate-controlling membrane, and the porosigen in the rate-controlling membrane can be dissolved to leave pores in the rate-controlling membrane typically as large as 10 microns, or as small as 1 micron, for example, although the pores can also be smaller than 1 micron. The porosigen in the rate-controlling membrane can be, for example sodium chloride, lactose, sodium heparin, polyethylene glycol, polyethylene oxide/polypropylene oxide copolymers, and mixtures thereof. In another aspect, the coating on the stent device can be formed by applying the compound of the invention to at least one surface of the stent device to form a bioactive layer and then applying one or more coats of porous polymeric material over the bioactive layer, such that the porous polymeric material has a thickness adequate to provide a controlled release of the compound. In one aspect, the porous polymeric material is composed of a polyamide, parylene or a parylene derivative applied by catalyst-free vapor desposition. "Parylene" refers to a polymer based on p-xylylene and made by vapor phase polymerization as described in U.S. Pat. "No. 5,824,049, incorporated herein by reference. Alternatively, the porous polymeric material is applied by plasma deposition. Representative polymers suitable for plasm deposition include poly(ethylene oxide), poly(ethylene glycol), poly(propylene oxide), and polymers of methane, silicone, tetrafluoroethylene tetramethyldisiloxane, and the like. Other suitable polymer systems include polymers derived from photopolymerizable monomers such as liquid monomers preferably having at least two cross linkable C-C (Carbon to Carbon) double bonds, and being a non-gaseous addition polymerizable ethylenically unsaturated compound, having a boiling point above 100 °C, at atmospheric pressure, a molecular weight of about 100-1500 and being capable of forming high molecular weight addition polymers readily. More preferably, the monomer is preferably an addition photopolymerizable polyethylenically unsaturated acrylic or methacrylic acid ester containing two or more acrylate or methacrylate groups per molecule or mixtures thereof Representative examples of such multifuntional acrylates are ethylene glycol diacrylate. ethylene glycol dimethacrylate, trimethylopropane triacrylate, trimethylopropane trimethacrylate. pentaeryhritol tetraacrylate or pentaerythritol tetramethacrylate, 1,6-hexanediol dimethacrylate, and diethyleneglycol dimethacrylate, Also useful in some special instances are monoacrylates such as n-butyl-acrylate. n-butyl methacrylate, 2-ethylhexyl acrylate, lauryl-acrylate. and 2-hydroxy-propyl acrylate. Small quantities of amides of (meth)acrylic acid such as N-methylol methacrylamide butyl ether are also suitable, N-vinyl compounds such as N-vinyl pyrrolidone, vinyl esters of aliphatic monocarboxylic acids such as vinyl oleate, vinyl ethers of diols such as butanedioI-l,4-divinyl ether and allyl ether and allyl ester are also suitable. Also included are other monomers such as the reaction products of di- or polyepoxides such as butanediol-1, 4-diglycidyl ether or bisphenol A diglycidyl ether with (meth)acrylic acid. The characteristics of the photopolymerizable liquid dispersing medium can be modified for the specific purpose by a suitable selection of monomers or mixtures thereof Other useful polymer systems include a polymer that is biocompatible and minimizes irritation to the vessel wall when the stent is implanted. The polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability. Bioabsorbable polymers that could be used include poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly (hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(gIycolic acid), poly(D, L-lactic acid), poly(glycolic acid-cotrimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly (iniinocarbonate), copoly(ether-esters) (e.g., PEO/PLA), polyalkylene oxlates, polyphoosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid. Also, biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters could be used and other polymers could also be used if they can be dissolved and cured or polymerized on the stent such as polyolefms, polyisobutylene and ethylene-alphaolefine copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile. polyvinyl ketones, polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitril-styrene copolyers, ABS resins, and ethylene-vinyl acetate copolymers; polyamides, such as Nylone 66 and polycaprolactam; alkyl reins, polycarbonates; polyoxymethylenes; polyimides, polyethers; epoxy reins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate buryrate; cellophane, cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose. In addition to plasma deposition and vapor phase deposition, other techniques for applying the various coatings on the stent surfaces may be employed. For example, a polymer solution may be applied to the stent and the solvent allowed to evaporate, thereby leaving on the stent surface a coating of the polymer and the therapeutic substance. Typically, the solution can be applied to the stent by either spraying the solution onto the stent or immersing the stent in the solution. The compounds of the present invention may be used in the treatment of restenosis in combination with any anticoagulant, antiplatelet, antithrombotic or profibrinolytic agent. Often patients are concurrently treated prior, during and after interventional procedures with agents of these classes either in order to safely perform the interventional procedure or to prevent deleterious effects of thrombus formation. Some examples of classes of agents known to be anticoagulant, antiplatelet, antithrombotic or profibrinolytic agents include any formulation of heparin, low molecular weight heparins, pentasaccharides, fibrinogen receptor antagonists, thrombin inhibitors. Factor Xa inhibitors, or Factor VIIa inhibitors. The compounds of the present invention may 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 antagonists and alpha-receptor antagonists. Some examples of agents that are useful in the treatment of elevated cholesterol levels or disregulated lipid levels include compounds known to be HMGCoA reductase inhibitors, compounds of the fibrate class, The compounds of the present invention may be used in the treatment of various forms of cancer either alone or in combination with compounds known to be useful in the treatment of cancer. It is understood that the present invention includes combinations of compounds of the present invention with one or more of the aforementioned therapeutic class agents Compounds within the scope of the present invention exhibit marked pharmacological activities according to tests described in the literature which tests results are believed to correlate to pharmacological activity in humans and other mammals. The following pharmacological in vitro and in vivo test results are typical for characterizing compounds of the present invention. Preparation of Pharmaceutical Compositions and Phanmacological Test Section Compounds within the scope of this invention exhibit significant activity as protein tyrosine kinase inhibitors and possess therapeutic value as cellular antiproliferative agents for the treatment of certain conditions including psoriasis, atherosclerosis and restenosis injuries. Compounds within the scope of the present invention exhibit the modulation and/or inhibition of cell signaling and/or cell proliferation and/or matrix production and/or chemotaxis and/or cell inflammatory response, and can be used in preventing or delaying the occurrence or reoccurrence of such conditions or otherwise treating the condition. To determine the effectiveness of compounds of this invention, the pharmacological tests described below, which are accepted in the art and recognized to correlate with pharmacological activity in mammals, are utilized. Compounds within the scope of this invention have been subjected to these various tests, and the results obtained are believed to correlate to useful cellular differentiation mediator activity. The results of these tests are believed to provide sufficient information to persons skilled in the pharmacological and medicinal chemistry arts to determine the parameters for using the studied compounds in one or more of the therapies described herein. 1. PDGF-R Tyrosine Kinase Autophosphorylation ELISA assay The titled assay is performed as described by Dolle et al. (./. Med. Chem. 1994, 37, 2627), which is incorporated herein by reference, with the exception of using the cell lysates derived from Human aortic smooth muscle cells (HAMSC) as described below. 2. Mitogenesis Assay General Procedure a. Cell Culture Human aortic smooth muscle cells (passage 4-9) are plated in 96 well plates in a growth supporting medium at 6000 cells/well and allowed to grow 2-3 days. At approximately 85% confluence, cells are growth arrested with serum free media (SFM). b. Mitogenesis Assay After 24 hour serum deprivation, medium is removed and replaced with test compound/vehicle in SFM (200 jal/well). Compounds are solubilized in cell culture DMSO at a concentration of 10 mM and further dilutions are made in SFM. After 30 min preincubation with compound, cells are stimulated with PDGF at 10 ng/mL. Determinations are performed in duplicate with stimulated and unstimulated wells at each compound concentration. Four hours later, 1 µCi 3H thymidine/well is added. Cultures are terminated 24 hours after addition of growth factor. Cells are lifted with trypsin and harvested onto a filter mat using an automated cell harvester (Wallac MachII96). The filter mat is counted in a scintillation counter (Wallac Betaplate) to determine DNA-incorporated label. 3. Chemotaxis Assay Human aortic smooth muscle cells (HASMC) at earlier passages are obtained from ATCC. Cells are grown in Clonetics SniGM 2 SingleQuots (media and cells at passages 4-10 are used. When cells are 80% confluent, a fluorescent probe, calcein AM (5 mM, Molecular Probe), is added to the media and cells are incubated for 30 minutes. After washing with HEPES buffered saline, cells are lifted with trypsin and neutralized with MCDB 131 buffer (Gibco) with 0.1% BSA, 10 mM glutamine and 10% fetal bovine serum. After centrifugation, cells are washed one more time and resuspended in the same buffer without fetal bovine serum at 30000 cells/50 mL. Cells are incubated with different concentrations of a compound of formula I (final DMSO concentration = 1 %) for 30 min at 37°C. For chemotaxis studies, 96 well modified Boyden chambers (Neuroprobe, Inc.) and a polycarbonate membrane with 8 mm pore size (Poretics, CA) are used. The membrane is coated with collagen (Sigma C3657, 0.1 mg/mL). PDGF-PP (3 ng/mL) in buffer with and without a compound of formula I are placed in the lower chamber. Cells (30,000), with and without inhibitor, are placed in the upper chamber. Cells are incubated for 4 hours. The filter membrane is removed and cells on the upper membrane side are removed. After drying, fluoresce 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 six replicates. Percent inhibition is determined from DMSO treated control values. From five points concentration-dependent inhibitions, IC50 value is calculated. Results are presented as a mean±SEM from five such experiments. 6. Selectivity vs. PKA and PKC is determined using commercial kits: a. Pierce Colorimetric PKA Assay Kit, Spinzyme Format Brief Protocol: PKA enzyme (bovine heart) 1 U/assay tube Kemptide peptide (dye labeled) substrate 45 minutes @ 30°C Absorbance at 570 nm b. Pierce Colorimetric PKC Assay kit, Spinzyme Format Brief Protocol: PKC enzyme (rat brain) 0.025U/assay tube Neurogranin peptide (dye labeled) substrate 30 minutes® 30°C Absorbance at 570 nm 7, p56ICK Tyrosine Kinase Inhibition Activity Measurements p56ICK Tyrosine kinase inhibition activity is determined according to a procedure disclosed in United States 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 (tyrosine-containing substrate, Biot-(P Ala)3-Lys-Val-Glu-Lys-Ile-Gly-Glu-Giy-Thr-Tyr-Glu-Val-Val-Tyr-Lys-CNH2) recognized by P56ICK, I jiM) is first phosphorylated in presence or absence of a given concentration of the test compound, by a given amount of enzyme (enzyme is produced by expression of P56'ICK gene in a yeast construct) purified from a cloned yeast (purification of the enzyme is done by following classical methods) in the presence of ATP (lOµM) MgC12( 2.5mM), MnC12 (2.5mM) NaCl (25mM), DTT (0.4mM) in Hepes 50mM, pH 7.5, over 10 min at ambient temperature. The total reaction volume is 50µ1, and the reactions are performed in a black 96-well fluoroplate. The reaction is stopped by addition of 150µ1 of stopping buffer (lOOmM Hepes pH7.5. KF 400mM, EDTA 133 mM, BSA lg/1.) containing a selected anti tyrosine antibody labelled with the Europium cryptate (PY20-K) at 0.8µg/ml and allophycocyanine-labelled streptavidin (XL665) at 4µg/ml. The labelling of Streptavidin and anti-tyrosine antibodies were performed by Cis-Bio International (France). The mixture is counted using a Packard Discovery counter which is able to measure time-resolved homogeneous fluorescence transfer (excitation at 337 nm, readout at 620 nm and 665 nm). The ratio of the 665 nm signal / 620nm signal is a measure of the phosphorylated tyrosine concentration. The blank is obtained by replacing enzyme by buffer. The specific signal is the difference between the ratio obtained without inhibitor and the ratio with the blank. 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 it exhibits an IC50 of 30± 6 nM (n=20). 8. Measurement of In Vitro Tumor Inhibition The inhibition of tumor growth in vitro by the compounds of this invention is determined as follows: C6 rat glioma cell line (provided by ATCC) is grown as monolayers in Dubelcco's Modified Eagle Medium containing 2 mM L-glutamine, 200 U/ml penicillin, 200 Hg/ml streptomycin and supplemented with 10% (v/v) heat inactivated foetal calf serum. Cells in exponential phase of growth are trypsinized, washed with PBS and diluted to a final concentration of 6500 cells/ml in complete medium. Drug to be tested or control solvent are added to the cell suspension (2.5 ml) under a volume of 50 µ1 and 0.4 ml of 2.4% Noble Difco agar maintained at 45 °C are added and mixed. The mixture is immediately poured into Petri dishes and left standing for 5 minutes at 4 °C. The number of cellular clones (>60 cells) are measured after 12 days of incubation at 37 °C under 5% CO2 atmosphere. Each drug is tested at 10, 1, 0.1, and O.OI µlg/ml (final concentration in the agar) in duplicate. Results are expressed in percent inhibition of clonogenicity relatively to untreated controls. lC5o's are determined graphically from semi-logarithmic plots of the mean value determined for each drug concentration. 9. Measurement of Tumor Inhibition In Vivo The inhibition of tumor growth in vivo by the compounds of this invention is determined using a subucatenous xenograft model as described in U.S. Pat. Nos. 5,700,823 and 5,760,066, in which mice are implanted with C6 glioma cells and tumor growth is measured using venier calipers. The results obtained by the above experimental methods evidence that the compounds within the scope of the present invention possess useful PDGF receptor protein tyrosine kinase inhibition properties or p56ICK tyrosine kinase inhibition properties, and thus possess therapeutic value. The above pharmacological test results may be used to determine the dosage and mode of administration for the particular therapy sought. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. WE CLAIM: 1. A compound of formula (I) wherein (i) HO-cycloaikyL wherein cycloalkyl is a non-aromatic mono- or multicyclic ring system of 3 to ] 0 carbon atoms (hereinafter referred to as "hydroxycycloalkyi"); (ii) HO-cycloalkenyl, wherein cycloalkenyl is a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having 3 to 10 carbon atoms (hereinafter referred to as "hydroxycycioalkenyr'); (iii) HO-heteroc3'clyl, wherein heterocyclyl is a 4- to lO-member monocyclic or multicyclic ring system wherein one or more of the atoms in the ring system is an element other than carbon chosen amongst nitrogen, oxygen and sulfur (hereinafter referred to as "hydroxyheterocyclyl"); or (iv) HO-heterocyclenyl, wherein heterocyclenyl is a heterocyclyl which contains at least a carbon-carbon or carbon-nitrogen double bond (hereinafter referred to as "hydroxyheterocyclenyl"); any of which is optionally substituted by one or more S^ Z3 isO, NR4.S, SO or SO.; Z4 is O, NR4, S, SO, SO2 or a bond; m is 0 or 1; n is 2 or 3 and n + m = 2 or 3; p and q are independently 0, 1, 2, 3 or 4, and p + q = 0, 1, 2, 3, or 4 when Z4 is a bond, and p + q = 0, 1, 2 or 3 when Z4 is other than a bond; r is 2, 3 or 4; R1a and R1b, are, independently: (i) an aliphatic hydrocarbon group which may be branched- or straight-chained, having I to 10 carbon atoms, and optionally substituted by S2 (hereinafter referred to as "alkyl"); (ii) an aromatic carbocyclic radical containing 6 to 10 carbon atoms and optionally substituted by S (hereinafter referred to as "'aryl"); (iii) a 5- to i 0-membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is nitrogen, oxygen or sulfur, optionally substituted by* S:, (hereinafter referred to as "heteroaryl") (iv) hydroxy; (v) acyl-0-, wherein acyl is H-CO- or alkyl-CO- (hereinafter referred to as "acyloxy"); (vi) an alkyl-0- group optionally substituted by S4 (hereinafter referred to as "alkoxy"); (vii) a cycloalkyi-0- group optionally substituted by S1 (hereinafter referred to as "cycloalkyloxy"); (viii) a heterocyclyl-0- group optionally substituted by S1 (hereinafter referred to as "heterocyclyioxy"); an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or a pharmaceuticaliy acceptable salt thereof 4. The compound of claim I wherein Z1 is CH. 5. The compound of claim 1 wherein Z\ is "N. 6. The compound of claim 1 wherein Z. is hydroxycycloalkyi optionally substituted by S,. 7. The compound of claim 1 wherein p and q are 0. 8. The compound of claim 1 wherein p + q = 1 - 9. The compound of claim 1 wherein Z4 is O. 10. The compound of claim 1 wherein Z4 is O, and p and q are 0. 11. The compound of claim I wherein Z4 is O, and p + q = I. 12. The compound of claim 1 wherein Z4 is NR4. 13. The compound of claim 1 wherein Z4 is NR4 and p and q are 0. 14. The compound of claim 1 wherein Z4 is NR4 and p + q = i. 15. The compound of claim 1 wherein Z4 is S. 16. The compound of claim 1 wherein Z4 is S, and p and q are 0. 17. The compound of claim I wherein Z4 is S, and p + q = I. 18. The compound of claim 1 wherein R^ and R|b are independently optionally hydroxy substituted lower alkyl, hydroxy, alkoxy having 1 to 6 carbon atoms optionally substituted by S4 (hereinafter referred to as "lower alkoxy'\ cycloalkyloxy, heterocyclyioxy, or one of R|a and Rib is hydrogen or halo and the other of Ria and Rib is optionally hydroxy substituted lower alkyi, hydroxy, lower alkoxy, cycloalkyloxy or heterocycloxy. 19. The compound of claim 1 wherein Ria and Rib are independently heterocyclylcarbonyloxy or lower alkoxy. 20. The compound of claim 19 wherein the lower aikoxy is methoxy' or ethoxy. 21. The compound of ciaim 1 wherein R1a and R1b are lower aikyi. 22. The compound of claim 21 wherein the lower alkyl is methyl or ethyl. 23. The compound of claim 1 wherein one of R1a and R1b is lower alkoxy, and the other of R1and R1b is halo. 24. The compound of claim 23 wherein the lower aikoxy is methoxy or ethoxy, and the halo is chloro or bromo. 25. The compound of claim I wherein one of R1a and R1b is lower alkyl, and the oilier of R1a and R1b is lower alkoxy. 26. The compound of claim 25 wherein the lower alkoxy is methoxy or ethoxy, and the lower alky! i^ methyl or ethyl 27. The compound of claim 1 wherein one of R1a and R1b is lower alkoxy, and the other of R1a and R1b is cycloalkyloxy. 28. The compound of claim 27 wherein the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy. 35. The compound of claim 19 wherein the lower alkoxy is optionally substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. 36. The compound of claim 35 wherein one of R,, and R1b is unsubstituted lower alkoxy and the other of R1a and R1b is optionally substituted heterocyclylcarbonyloxy or lower alkoxy substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. 37. The compound of claim 36 wherein one of R,, and R,b is roethoxy and the other of R1a, and R1b is [1,4]-bipiperadin-l'-yicarbonyloxy, 2-(ethoxy)ethoxy, 2-(4-morpboiinyI)etbox\; 2-{4-methylpiperazin-]-yl)ethoxyl, carboxymethoxy, methoxycarbonylmethoxy, aminocarbonylmethoxy. N-methylaminocarbonylmethox}' or N,N-dimethylaminocarbonylmethoxy (lS.2R,4S3R)-5-(6,7-DimethoxyquinoxaIin-2-ylammo)-Bicyclo[2.2.1]-heptan-2-o1 an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceuticaily acceptable sah thereof. 39. The compound according to claim 1 which is trans--4-(6.7-dimethoxy-quimoxa;on-2-ylamino)- cyclohexanoK or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 40. The compound according to claim 1 which is cis-4-(6,7-dimethoxy-quinoxalin-2-ylamino)-cyclohexanoL or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof 41. The compound according to claim 1 which is 4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyciohexanol. or an "N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable sah thereof 48 • A stent device having a polymeric coating, characterized in that the polymeric coating incorporates a compound of formula I substituted heteoaryl, hydroxy, acyloxy, optionally substitated alkoxy, optionally substituted cycloalkyioxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclyicarbonyioxy, optionally substituted aryloxy, optionally substituted R4 is hydrogen ,or an N-oxide thereof hydrate thereof, solvate thereof prodrug thereof or pharmaceutically accaptable salt thereof. 80. The stent device of claim 48 wherein the polymeric coating comprises one or more polymers selected from the group consisting of polycaprolactone, poly(ethylene-co-vinyl acetate) paloy(vmyi acetate) and alicone gum rubber. 68- The strat device of claim 48 "wherein the compound of formula I is incorporated into the polymeric coating by applying tbe ompound of formula I to at least one surface of the stent device to form a bioactive layer and then applying one or more coats of porous polymeric material over the bioactive layer. 78, The accrding to claim 77 wherein said restenosis is the result of mechanical injury to zn aterial wall produced by treatment of an atherosclerotic lesion by ang;oplasty. Dated this 22 day of June 2001

Documents:

in-pct-2001-878-che-abstract.pdf

in-pct-2001-878-che-assignement.pdf

in-pct-2001-878-che-claims filed.pdf

in-pct-2001-878-che-claims granted.pdf

in-pct-2001-878-che-correspondnece-others.pdf

in-pct-2001-878-che-correspondnece-po.pdf

in-pct-2001-878-che-description(complete) filed.pdf

in-pct-2001-878-che-description(complete) granted.pdf

in-pct-2001-878-che-form 1.pdf

in-pct-2001-878-che-form 26.pdf

in-pct-2001-878-che-form 3.pdf

in-pct-2001-878-che-form 5.pdf

in-pct-2001-878-che-other documents.pdf

in-pct-2001-878-che-pct.pdf