WO2005094916A1

WO2005094916A1 - Vegf receptor tyrosine kinase inhibitor coated stent

Info

Publication number: WO2005094916A1
Application number: PCT/EP2005/003459
Authority: WO
Inventors: Margaret Forney Prescott; Jeanette Marjorie Wood
Original assignee: Novartis Ag.; Novartis Pharma Gmhbh
Priority date: 2004-04-02
Filing date: 2005-04-01
Publication date: 2005-10-13
Also published as: CN1929882A; AU2005229566A1; KR20070004795A; JP2007530633A; EP1735026A1; BRPI0509566A; CA2559756A1

Abstract

The invention relates to the local administration of a vascular endothelial growth factor receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt, optionally in conjunction with one or more other active ingredients, and a device adapted for such local administration.

Description

VEGF RECEPTOR TYROSINE KINASE INHIBITOR COATED STENT

The present invention relates to drug delivery systems for the prevention and treatment of proliferative diseases, particularly vascular diseases.

Many humans suffer from circulatory diseases caused by a progressive blockage of the blood vessels that perfuse the heart and other major organs. Severe blockage of blood vessels in such humans often leads to ischemic injury, hypertension, stroke or myocardial infarction. Atherosclerotic lesions which limit or obstruct coronary or periphery blood flow are the major cause of ischemic disease related morbidity and mortality including coronary heart disease and stroke. In order to stop the disease process and prevent the more advanced disease states in which the cardiac muscle or other organs are compromised, medical revascularization procedures such as percutaneous transluminal coronary angioplasty (PCTA), percutaneous transluminal angioplasty (PTA), atherectomy, bypass grafting or other types of vascular grafting procedures are used.

Re-narrowing (restenosis) of an artherosclerotic coronary artery after various revascularization procedures occurs in 10-80% of patients undergoing this treatment, depending on the procedure used and the aterial site. Besides opening an artery obstructed by atherosclerosis, revascularization also injures endothelial cells and smooth muscle cells within the vessel wall, thus initiating a thrombotic and inflammatory response. Cell derived growth factors such as platelet derived growth factor, infiltrating macrophages, leukocytes or the smooth muscle cells themselves provoke proliferative and migratory responses in the smooth muscle cells. Simultaneous with local proliferation and migration, inflammatory cells also invade the site of vascular injury and may migrate to the deeper layers of the vessel wall. Proliferation/migration usually begins within one to two days post-injury and, depending on the revascularization procedure used, continues for days and weeks.

Both cells within the atherosclerotic lesion and those within the media migrate, proliferate and/or secrete significant amounts of extracellular matrix proteins. Proliferation, migration and extracellular matrix synthesis continue until the damaged endothelial layer is repaired at which time proliferation slows within the intima. The newly formed tissue is called neointima, intimal thickening or restenotic lesion and usually results in narrowing of the vessel lumen. Further lumen narrowing may take place due to constructive remodeling, e.g. vascular remodeling, leading to further intimal thickening or hyperplasia.

Accordingly, there is a need for effective treatment and drug delivery systems for preventing and treating intimal thickening or restenosis that occurs after injury, e.g. vascular injury, including e.g. surgical injury, e.g. revascularization-induced injury, e.g. also in heart or other grafts.

4-Pyridylmethyl-phthalazine derivatives that are selective inhibitors of VEGF (vascular endothelial growth factor) receptor tyrosine kinase are described, for example, in U.S. Patent No. 6,258,812, which is here incorporated by reference. Such compounds have been reported to be useful for treating diseases associated with deregulated angiogenesis, especially neoplastic diseases (solid tumors), such as breast cancer, cancer of the colon, lung cancer, especially small cell lung cancer, and cancer of the prostrate.

Surprisingly, it has now been found that VEGF receptor tyrosine kinase inhibitors, especially the compounds of formula I as defined herein and, in particular, PTK787, optionally in conjunction with other active compounds, e.g. antiproliferative compounds, have beneficial effects when locally applied to the lesions sites.

Hence, the invention relates to a method of treating for preventing and treating intimal thickening or restenosis that occurs after injury, e.g. vascular injury, including e.g. surgical injury, e.g. revascularization-induced injury, e.g. also in heart or other grafts, comprising administering a therapeutically effective amount of a VEGF receptor tyrosine kinase inhibitor to a warm-blooded animal in need thereof.

The VEGF receptor tyrosine kinase inhibitor employed in the present invention can, in particular, be selected from a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, e.g. proteins, small molecules or monoclonal antibodies generically and specifically disclosed in WO 98/35958, e.g. 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 00/37502, WO 94/10202 and EP 0 769 947, those as described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770, Dec. 1996, by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, by J. Mordenti et al in Toxicologic Pathology, Vol. 27, no. 1, pp 14-21 , 1999, AAnnggiioossttaattiinn™™,, ddeessccrriibbeedd bbyy MM.. SS.. OO''RReeiillllyy eett aall,, CCeellll 7799,, 11994, 315-328, Endostatin™ described by M. S. O'Reilly et al, Cell 88, 1 997, 277-285.

Preferably, the invention relates to a method of treating for preventing and treating intimal thickening or restenosis that occurs after injury, e.g. vascular injury, including e.g. surgical injury, e.g. revascularization-induced injury, e.g. also in heart or other grafts, comprising administering a therapeutically effective amount of a compound of formula I

wherein r is 0 to 2, n is 0 to 2, m is 0 to 4, Ri and R₂ (i) are lower alkyl or (ii) together form a bridge in subformula I^*

the binding being achieved via the two terminal carbon atoms, or (iii) together form a bridge in subformula I*^*

\ τ₂ (I-) τ₄=τ_s wherein one or two of the ring members T^ T₂, T₃ and T are nitrogen, and the others are in each case CH, and the binding is achieved via Ti and T₄; A, B, D, and E are, independently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N; G is lower alkylene, lower alkylene substituted by acyloxy or hydroxy, -CH₂-O-, -CH₂-S-, -CH₂-NH-, oxa (-O-), thia (-S-), or imino (-NH-); Q is lower alkyl; R is H or lower alkyl; X is imino, oxa, or thia; Y is unsubstituted or substituted aryl, pyridyl, or unsubstituted or substituted cycloalkyl; and Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present; and wherein the bonds characterized, if present, by a wavy line are either single or double bonds; or an N-oxide of the defined compound, wherein 1 or more N atoms carry an oxygen atom, or the salt of such compound having at least one salt-forming group, in particular a succinate, to a warm-blooded animal, preferably a human, in need thereof.

The radicals and symbols as used in the definition of a compound of formula I have the meanings as disclosed in U.S. Patent No. 6,258,812.

A preferred compound of formula I is PTK787.

The term "PTK787" as used herein means a compound of formula I wherein r, n and m are each 0, R₁ and R₂ together form a bridge of subformula I^*, A, B, D and E are each CH, G is methylene, X is imino, Y is 4-chlorophenyl, and the bonds characterized by a wavy line are double bonds.

According to the invention, the VEGF receptor tyrosine kinase inhibitor may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, e.g. a calcineurin inhibitor, e.g. a cyclosporin, for example cyclosporin A, or FK506, an EDG- Receptor agonist, e.g. FTY720, an anti-inflammatory agent, e.g. a steroid, e.g. a corticosteroid, e.g. dexamethasone or prednisone, a NSAID, e.g. a cyclooxygenase inhibitor, e.g. a COX-2 inhibitor, e.g. celecoxib, rofecoxib, etoricoxib or valdecoxib, or an ascomycin, e.g. ASM981 , an anti- thrombotic or anti-coagulant agent, e.g. heparin, a llb/llla inhibitor, etc. an antiproliferative agent, e.g. a microtubule stabilizing or destabilizing agent including but not limited to taxanes, e.g. taxol, paclitaxel or docetaxel, vinca alkaloids, e.g. vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides or epothilones or a derivative thereof.e.g. epothilone B or a derivative thereof, a tyrosine kinase inhibitor which is not an nhibito of VEGF, e.g. staurosporin and related small molecules, e.g. UCN-01 , BAY 43-9006, Bryostatin 1 , Perifosine, Limofosine, midostaurin, RO318220, RO320432, GO 6976, Isis 3521 , LY333531 , LY379196, SU5416, SU6668, AG1296 etc., a compound or antibody which inhibits the PDGF receptor tyrosine kinase or a compound which binds to PDGF or reduces expression of the PDGF receptor e.g. STI571 , CT52923, RP-1776, GFB-111 , pyrrolo[3,4-c]-beta-carboline-diones, etc., a compound or antibody which inhibits the EGF receptor tyrosine kinase or a compound which binds to EGF or reduces expression of the EGF receptor e.g. the compounds disclosed in WO97/02266, e.g. the compound of example 39, retinoic acid, ZD1839 (Iressa), alpha-, gamma- or delta-tocopherol or alpha-, gamma- or delta-tocotrienol, or compounds affecting GRB2, IMC-C225, a statin, e.g. having HMG-CoA reductase inhibition activity, e.g. fluva- statin, lovastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, pitavastatin, rosuvastatin or nivastatin, a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, e.g. FGF, IGF, a matrix metalloproteinase inhibitor, e.g. batimistat, marimistat, trocade, CGS 27023, RS 130830 or AG3340, a modulator (i.e. antagonists or agonists) of kinases, e.g. JNK, ERK1/2, MAPK or STAT, or a compound stimulating the release of (NO) or a NO donor, e.g. diazeniumdiolates, S-nitrosothiols, mesoionic oxatriazoles, a combination of isosorbide.

The present invention also provides the local administration or delivery of a VEGF receptor tyrosine kinase inhibitor in conjunction with a calcineurin inhibitor, e.g. as disclosed above, an EDG-Receptor agonist, e.g. as disclosed above, a microtubule stabilizing or destabilizing agent, e.g. as disclosed above, a compound or antibody which inhibits the PDGF receptor tyrosine kinase or a compound which binds to PDGF or reduces expression of the PDGF receptor, e.g. as disclosed above, a compound or antibody which inhibits the EGF receptor tyrosine kinase or a compound which binds to EGF or reduces expression of the EGF receptor, e.g. as disclosed above, a statin, e.g. as disclosed above, a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, e.g. as disclosed above, a matrix rnetalloproteinase inhibitor, e.g. as disclosed above, an inhibitor of a modulator (i.e. antagonists or agonists) of kinases, e.g. as disclosed above, or a compound stimulating the release of (NO) or a NO donor, e.g. as disclosed above.

In accordance with the particular findings of the present invention, there is provided:

1. A method for preventing or treating smooth muscle cell proliferation and migration in hollow tubes, or increased cell proliferation or decreased apoptosis or increased matrix deposition in a mammal in need thereof, comprising local administration of a therapeutically effective amount of a VEGF receptor tyrosine kinase inhibitor, optionally in conjunction with one or more other active ingredients, e.g. as disclosed above.

2. A method for the treatment of intimal thickening in vessel walls comprising the controlled delivery from any catheter-based device or intraluminal medical device of a therapeutically effective amount of a VEGF receptor tyrosine kinase inhibitor, optionally in conjunction with one or more other active ingredients, e.g. as disclosed above.

Preferably the disease to be treated is stenosis, restenosis, e.g. following revascularization or neovascularization, and/or inflammation and/or thrombosis.

3. A drug delivery device or system comprising a) a medical device adapted for local application or administration in hollow tubes, e.g. a catheter-based delivery device or intraluminal medical device, and b) a therapeutic dosage of a VEGF receptor tyrosine kinase inhibitor, optionally in conjunction with a therapeutic dosage of one or more other active ingredients, e.g. as disclosed above, each being releasably affixed to the catheter- based delivery device or medical device.

Such a local delivery device or system can be used to reduce stenosis or restenosis as an adjunct to revascularization, bypass or grafting procedures performed in any vascular location including coronary arteries, carotid arteries, renal arteries, peripheral arteries, cerebral arteries or any other arterial or venous location, to reduce anastomic stenosis such as in the case of arterial-venous dialysis access with or without polytetrafluoro- ethylene grafting and with or without stenting, or in in conjunction with any other heart or transplantation procedures, or congenital vascular interventions.

A VEGF receptor tyrosine kinase inhibitor will be referred to hereinafter as "drug". The other active ingredients which may be used in conjunction with the VEGF receptor tyrosine kinase inhibitor, e.g. as disclosed above, will be referred to hereinafter collectively as "adjunct". Drug(s) shall mean drug or drug plus adjunct.

The local administration preferably takes place at or near the vascular lesions sites.

The administration may be by one or more of the following routes: via catheter or other intravascular delivery system, intranasally, intrabronchially, interperitoneally or eosophagal. Hollow tubes include circulatory system vessels such as blood vessels (arteries or veins), tissue lumen, lymphatic pathways, digestive tract including alimentary canal, respiratory tract, excretory system tubes, reproductive system tubes and ducts, body cavity tubes, etc. Local administration or application of the drug(s) affords concentrated delivery of said drug(s), achieving tissue levels in target tissues not otherwise obtainable through other administration route.

Means for local drug(s) delivery to hollow tubes can be by physical delivery of the drug(s) either internally or externally to the hollow tube. Local drug(s) delivery includes catheter delivery systems, local injection devices or systems or indwelling devices. Such devices or systems would include, but not be limited to, stents, coated stents, endolumenal sleeves, stent-grafts, liposomes, controlled release matrices, polymeric endoluminal paving, or other endovascular devices, embolic delivery particles, cell targeting such as affinity based delivery, internal patches around the hollow tube, external patches around the hollow tube, hollow tube cuff, external paving, external stent sleeves, and the like. See, Eccleston et al. (1995) Interventional Cardiology Monitor 1:33-40-41 and Slepian, N.J. (1996) Intervente. Cardiol. 1:103-116, or Regar E, Sianos G, Serruys PW. Stent development and local drug delivery. Br Med Bull 2001 ,59:227-48 which disclosures are herein incorporated by reference.

By "biocompatible" is meant a material which elicits no or minimal negative tissue reaction including e.g. thrombus formation and/or inflammation. Delivery or application of the drug(s) can occur using stents or sleeves or sheathes. An intraluminal stent composed of or coated with a polymer or other biocompatible materials, e.g. porous ceramic, e.g. nanoporous ceramic, into which the drug(s) has been impregnated or incorporated can be used. Such stents can be biodegradable or can be made of metal or alloy, e.g. Ni and Ti, or another stable substance when intented for permanent use. The drug(s) may also be entrapped into the metal of the stent or graft body which has been modified to contain micropores or channels. Also lumenal and/or ablumenal coating or external sleeve made of polymer or other biocompatible materials, e.g. as disclosed above, that contain the drug(s) can also be used for local delivery.

Stents are commonly used as a tubular structure left inside the lumen of a duct to relieve an obstruction. They may be inserted into the duct lumen in a non-expanded form and are then expanded autonomously (self-expanding stents) or with the aid of a second device in situ, e.g. a catheter-mounted angioplasty balloon which is inflated within the stenose vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.

For example, the drug(s) may be incorporated into or affixed to the stent in a number of ways and utilizing any biocompatible materials; it may be incorporated into e.g. a polymer or a polymeric matrix and sprayed onto the outer surface of the stent. A mixture of the drug(s) and the polymeric material may be prepared in a solvent or a mixture of solvents and applied to the surfaces of the stents also by dip-coating, brush coating and/or dip/spin coating, the solvent (s) being allowed to evaporate to leave a film with entrapped drug(s). In the case of stents where the drug(s) is delivered from micropores, struts or channels, a solution of a polymer may additionally be applied as an outlayer to control the drug(s) release; alternatively, the drug may be comprised in the micropores, struts or channels and the adjunct may be incorporated in the outlayer, or vice versa. The drug may also be affixed in an inner layer of the stent and the adjunct in an outer layer, or vice versa. The drug(s) may also be attached by a covalent bond, e.g. esters, amides or anhydrides, to the stent surface, involving chemical derivatization. The drug(s) may also be incorporated into a biocompatible porous ceramic coating, e.g. a nanoporous ceramic coating.

Examples of polymeric materials include biocompatible degradable materials, e.g. lactone- based polyesters or copolyesters, e.g. polylactide; polylactide-glycolide; polycaprolactone- glycolide; polyorthoesters; polyanhydrides; polyaminoacids; polysaccharides; polyphospha- zenes; poly(ether-ester) copolymers, e.g. PEO-PLLA, or mixtures thereof; and biocompatible non-degrading materials, e.g. polydimethylsiloxane; poly(ethylene-vinylacetate); acrylate based polymers or coplymers, e.g. polybutylmethacrylate, poly(hydroxyethyl methyl- methacrylate); polyvinyl pyrrolidinone; fluorinated polymers such as polytetrafluoethylene; cellulose esters.

When a polymeric matrix is used, it may comprise 2 layers, e.g. a base layer in which the drug(s) is/are incorporated, e.g. ethylene-co-vinylacetate and polybutylmethacrylate, and a top coat, e.g. polybutylmethacrylate, which is drug(s)-free and acts as a diffusion-control of the drug(s). Alternatively, the drug may be comprised in the base layer and the adjunct may be incorporated in the outlayer, or vice versa. Total thickness of the polymeric matrix may be from about 1 to 20μ or greater.

According to the method of the invention or in the device or system of the invention, the drug(s) may elute passively, actively or under activation, e.g. light-activation.

The drug(s) elutes from the polymeric material or the stent over time and enters the surrounding tissue, e.g. up to ca. 1 month to 1 year. The local delivery according to the present invention allows for high concentration of the drug(s) at the disease site with low concentration of circulating compound. The amount of drug(s) used for local delivery applications will vary depending on the compounds used, the condition to be treated and the desired effect. For purposes of the invention, a therapeutically effective amount will be administered. By therapeutically effective amount is intended an amount sufficient to inhi it cellular proliferation and resulting in the prevention and treatment of the disease state. Specifically, for the prevention or treatment of restenosis e.g. after revascularization, or antitumor treatment, local delivery may require less compound than systemic administration.

Utility of the drug(s) may be demonstrated in animal test methods as well as in clinic, for example in accordance with the methods hereinafter described. The following examples are illustrative of the invention without limitating it. A1. Inhibition of late neointimal lesion formation in the 28 day rat carotid artery balloon injury model

Numerous compounds have been shown to inhibit intimal lesion formation at 2 weeks in the rat ballooned carotid model, while only few compounds prove effective at 4 weeks. Compounds of formula I are tested in the following rat model.

Rats are dosed orally with placebo or a VEGF receptor tyrosine kinase inhibitor, e.g. a compound of formula I, e.g. PTK787. Daily dosing starts 3 days prior to surgery and continues for 31 days. Rat carotid arteries are balloon injured using a method described by Clowes et al. Lab. Invest. 1983;49; 208-215. Following sacrifice at 28 days post-balloon injury, carotid arteries are removed and processed for histologic and morphometric evaluation. In this assay the ability of the compounds of formula I can be demonstrated to significantly reduce neointimal lesion formation following balloon injury.

A.2 Inhibition of restenosis at 28 days in the rabbit iliac stent model

A combined angioplasty and stenting procedure is performed in New Zealand White rabbit iliac arteries. Iliac artery balloon injury is performed by inflating a 3.0 x 9.0 mm angioplasty balloon in the mid-portion of the artery followed by "pull-back" of the catheter for 1 balloon length. Balloon injury is repeated 2 times, and a 3.0 x 12 mm stent is deployed at 6 atm for 30 seconds in the iliac artery. Balloon injury and stent placement is then performed on the contralateral iliac artery in the same manner. A post-stent deployment angiogram is performed. All animals receive oral aspirin 40 mg/day daily as anti-platelet therapy and are fed standard low-cholesterol rabbit chow. Twenty-eight days after stenting, animals are anesthetized and euthanized and the arterial tree is perfused at 100 mmHg with lactated Ringer's for several minutes, then perfused with 10% formalin at 100 mmHg for 15 minutes. The vascular section between the distal aorta and the proximal femoral arteries is excised and cleaned of periadventitial tissue. The stented section of artery is embedded in plastic and sections are taken from the proximal, middle, and distal portions of each stent. All sections are stained with hematoxylin-eosin and Movat pentachrome stains. Computerized planimetry is performed to determine the area of the internal elastic lamina (IEL), external elastic lamina (EEL) and lumen. The neointima and neointimal thickness is measured both at and between the stent struts. The vessel area is measured as the area within the EEL. Data are expressed as mean + SEM. Statistical analysis of the histologic data is accomplished using analysis of variance (ANOVA) due to the fact that two stented arteries are measured per animal with a mean generated per animal. A P < 0.05 is considered statistically significant.

PTK787 is administered orally by gavage at an initial dose one day prior to stenting, then dosed at 50 % of the initial dose from the day of stenting until day 27 post-stenting. In this model a marked reduction in the extent of restenotic lesion formation in the presence of PTK787 can be shown, whereas there is extensive neointimal formation in placebo-treated animals at 28 days, with the lesions consisting of abundant smooth muscle cells in proteoglycan/collagen matrix and apparent full endothelial healing.

A.3 Manufacture of a stent

A stent is weighed and then mounted for coating. While the stent is rotating, a solution of polylactide glycolide, 0.75 mg/ml of PTK787 and 0.0015 mg/ml 2,6-di-tert.-butyl-4- methylphenol dissolved in a mixture of methanol and tetrahydrofuran, is sprayed onto it. The coated stent is removed from the spray and allowed to air-dry. After a final weighing the amount of coating on the stent is determined.

A.4 PTK787 release from polymer coatings in aqueous solution

Four 2 cm pieces of coated stents as described above are placed into 100 mL of phosphate buffer solution (PBS) having a pH of 7.4. Another 4 pieces from each series are placed into 100 mL of polyethylene glycol (PEG)/water solution (40/60 v/v, MW of PEG=400). The stent pieces are incubated at 37° C. in a shaker. The buffer and PEG solutions are changed daily and different assays are performed on the solution to determine the released PTK787 concentrations. By such method a stable PTK787 release from coated stents can be shown. The term "stable PTK787 release" means that less than 10% of variation of the drug release rate is observed. A.5 PTK787 release from polymer coatings in plasma

Release of PTK787 in plasma can also be studied. 1 cm pieces of a coated stent are put into 1 mL of citrated human plasma (from Helena Labs.) in lyophilized form and reconstituted by adding 1 mL of sterile deionized water. Three sets of stent plasma solutions are incubated at 37° C and the plasma is changed daily. Different assays are performed on the solution to determine the released PTK787 concentrations. By such method a stable PTK787 release from coated stents in plasma can be demonstrated. The term "stable PTK787 release" means that less than 10% of variation of the drug release rate is observed.

A.6 PTK787 stability in pharmaceutically acceptable polymers at body temperature

PDGF-stimulated receptor tyrosine kinase assay can be performed on the last piece of each sample to determine the PTK787 activity. A similar test can be performed with free PTK787. The inhibition of PDGF-stimulated receptor tyrosine kinase activity in vitro can be measured in PDGF receptor immunocomplexes of BALB/c 3T3 cells, analogously to the method described by E. Andrejauskas-Buchdunger and U. Regenass in Cancer Research 52, 5353- 5358 (1992). By such approach the stability of free PTK787 and PTK787 in polymer coatings can be compared.

Claims

1. A drug delivery device or system comprising a) a medical device adapted for local application or administration in hollow tubes, e.g. a catheter-based delivery device or an intraluminal medical device, and b) a therapeutic dosage of a VEGF receptor tyrosine kinase inhibitor being releasably affixed to the medical device.

2. The device according to claim 1 comprising PTK787.

3. The device according to claim 1 or 2 which is a catheter delivery system, a local injection device, an indwelling device, a stent, a stent-graft or a sleeve.

4. A device according to claim 1 or 2 which is a coated stent.

5. A method for preventing or treating smooth muscle cell proliferation and migration in hollow tubes or increased cell proliferation or decreased apoptosis or increased matrix deposition in a mammal in need thereof, comprising local administration of a therapeutically effective amount of a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor.

6. A method for the treatment of intimal thickening in vessel walls comprising the controlled delivery from a catheter-based device or an intraluminal medical device of a therapeutically effective amount of a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor.

7. The method according to claim 5 or 6 wherein the VEGF receptor tyrosine kinase inhibitor is a compound of formula I

wherein r is 0 to 2, n is 0 to 2, m is 0 to 4, Ri and R₂ (i) are lower alkyl or (ii) together form a bridge in subformula I*

the binding being achieved via the two terminal carbon atoms, or (iii) together form a bridge in subformula I^**

\. (I**) τ₄-τ₃ wherein one or two of the ring members T_1f T₂, T₃ and T₄ are nitrogen, and the others are in each case CH, and the binding is achieved via Ti and T₄; A, B, D, and E are, independently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N; G is lower alkylene, lower alkylene substituted by acyloxy or hydroxy, -CH₂-O-, -CH₂-S-, -CH₂-NH-, oxa (-O-), thia (-S-), or imino (-NH-); Q is lower alkyl; R is H or lower alkyl; X is imino, oxa, or thia; Y is unsubstituted or substituted aryl, pyridyl, or unsubstituted or substituted cycloalkyl; and Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present; and wherein the bonds characterized, if present, by a wavy line are either single or double bonds; or an N-oxide of the defined compound, wherein 1 or more N atoms carry an oxygen atom, or the salt of such compound having at least one salt-forming group.

8. The method according to claim 5 or 6 wherein the administration or delivery is intra- vascular, intranasal, intrabronchial, interperitoneal or eosophagal.

9. The method according to claim 5 or 6 wherein the administration or delivery is made using a catheter delivery system, a local injection device, an indwelling device, a stent, a coated stent, a sleeve, a stent-graft, polymeric endoluminal paving or a controlled release matrix.

10. The method according to claim 5 wherein the VEGF receptor tyrosine kinase inhibitor is administered from a stent or from a coating applied to a stent.

11. A method according to claim 6 wherein the VEGF receptor tyrosine kinase inhibitor is delivered from a stent or from a coating applied to a stent.

12. A method according to claim 5 for the treatment of stenosis, restenosis or inflammation.

13. A method according to claim 6 for the treatment of stenosis, restenosis or inflammation.