JP2007530633A - VEGF receptor tyrosine kinase inhibitor coated stent - Google Patents

Abstract

  The present invention relates to the topical administration of vascular endothelial growth factor receptor tyrosine kinase inhibitors or pharmaceutically acceptable salts, optionally in combination with one or more other active ingredients, and devices suitable for such topical administration. About.

Description

Detailed Description of the Invention

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

  Many humans suffer from circulatory diseases caused by the progressive blockage of blood vessels that perfuse the heart and other major organs. Such severe vascular blockade in humans often leads to ischemic injury, hypertension, stroke or myocardial infarction. Atherosclerotic lesions that restrict or occlude coronary or peripheral blood flow are a major cause of ischemic disease-related morbidity and mortality, including coronary heart disease and stroke. Percutaneous transluminal coronary angioplasty (PCTA), percutaneous transluminal angioplasty to stop disease progression and prevent more advanced disease states where the myocardium or other organs are at risk Medical revascularization methods are used, such as (PTA), atherectomy, bypass surgery or other types of vascular grafting.

  Atherosclerotic coronary restenosis (restenosis) after various revascularization methods occurs in 10-80% of patients subjected to this procedure, depending on the method used and the arterial site. In addition to arterial openings occluded by atherosclerosis, revascularization also damages endothelial and smooth muscle cells within the vessel wall, thus initiating thrombotic and inflammatory responses. Cell-derived growth factors such as platelet-derived growth factor, infiltrating macrophages, leukocytes or smooth muscle cells themselves cause proliferative and migratory responses in smooth muscle cells. Simultaneous with local proliferation and migration, inflammatory cells can also enter the site of vascular injury and migrate to deeper layers of the vessel wall. Proliferation / migration usually occurs 1-2 days after injury and lasts days to weeks depending on the revascularization method used.

  Cells both in atherosclerotic lesions and in the transport medium 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 point proliferation slows in the intima. The newly formed tissue is called neointimal, intimal thickening or restenotic lesion and usually results in narrowing of the vessel lumen. Furthermore, luminal narrowing can occur by constitutive remodeling, such as vascular remodeling, leading to further intimal thickening or hyperplasia.

  Thus, effective treatment and drug delivery to prevent and treat intimal thickening or restenosis that occurs after injury, such as occurs in the heart or other grafts, including, for example, surgical injury, eg, revascularization-induced injury There is a need for a system.

  A 4-pyridylmethyl-phthalazine derivative that is a selective inhibitor of VEGF (vascular endothelial growth factor) receptor tyrosine kinase is described, for example, in US Pat. No. 6,258,812, which is incorporated herein by reference. Included. Such compounds are useful for the treatment of diseases associated with deregulated angiogenesis, especially neoplastic diseases (solid tumors) such as breast cancer, colon cancer, lung cancer, especially small cell lung cancer, and prostate cancer. It has been reported.

  Surprisingly, according to the present invention, a VEGF receptor tyrosine kinase inhibitor, in particular a compound of formula I as defined herein, and in particular PTK787, optionally in combination with other active compounds, for example antiproliferative compounds, It was found to have a beneficial effect when applied topically to the lesion site.

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

The VEGF receptor tyrosine kinase inhibitors used in the present invention are in particular compounds or antibodies that inhibit VEGF receptor tyrosine kinase or VEGF receptor, or compounds that bind to VEGF, such as WO98 / 35958 (eg 1- (4-chloroanilino ) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof), or WO00 / 09495, WO00 / 27820, WO00 / 59509, WO98 / 11223, WO00 / 27819, WO00 / 37502, WO94 / 10202. And the proteins, small molecules or monoclonal antibodies generally and specifically described in EP 0769947, M. Prewett et al in Cancer Research 59 (1999) 5209-5218, F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770, Dec. 1996, Z. Zhu et al i n Cancer Res. 58, 1998, 3209-3214, as described by J. Mordenti et al in Toxicologic Pathology, Vol. 27, no. 1, pp 14-21, 1999, MS O'Reilly et al, Cell 79 , 1994, Angiostatin ^TM described by 315-328, MS O'Reilly et al, Cell 88, 1997, may be selected from Endostatin ^TM described by 277-285.

〔式中、
ｒは０から２であり、
ｎは０から２であり、
ｍは０から４であり、
Ｒ_１およびＲ_２は、(ｉ)低級アルキルであるか、または
(ii)一体となって、部分式Ｉ^＊

(架橋は２個の末端炭素原子を介して達成される)
の架橋を形成するか、または
一体となって、部分式Ｉ^＊＊

(式中、１個または２個の環員Ｔ_１、Ｔ_２、Ｔ_３およびＴ_４は窒素であり、そして他方はいずれの場合もＣＨであり、そして架橋はＴ_１およびＴ_４を介して達成される)
の架橋を形成し；
Ａ、Ｂ、Ｄ、およびＥは、互いに独立して、ＮまたはＣＨ。ただし、２個を超えるこれらのラジカルがＮではなく； Preferably, the present invention is a method for the treatment or prevention of intimal thickening or restenosis that occurs after an injury, such as occurs in a heart or other graft, including, for example, a surgical injury, such as a revascularization-induced injury, Therapeutically effective amount of Formula I

[Where,
r is from 0 to 2,
n is from 0 to 2,
m is from 0 to 4,
R ₁ and R ₂ are (i) lower alkyl, or
(ii) Combined, partial formula I ^*

(Bridges are achieved through two terminal carbon atoms)
Form a cross-link of or together form the partial formula I ^**

(Wherein one or two ring members T ₁ , T ₂ , T ₃ and T ₄ are nitrogen, and the other is in each case CH, and the bridge is via T ₁ and T ₄ Achieved)
Forming a crosslink of
A, B, D, and E are independently of each other N or CH. However, more than two of these radicals are not N;

G is lower alkylene, lower alkylene substituted by acyloxy or _{hydroxy, -CH 2 -O -, - CH} 2 -S -, - CH 2 -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 di-substituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro , Cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N, N-di-substituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl -Lower alkyl sulfinyl or alkylphenyl sulfinyl, wherein the substituents Z are identical or different from each other when two or more radicals Z are present;
And the bonds characterized by the wavy lines are either single or double bonds, when present. ]
Or an N-oxide of a defined compound (wherein one or more N atoms carry an oxygen atom) or a salt of such a compound having at least one salt-forming group, in particular succinic acid It relates to a method comprising administering a salt to a warm-blooded animal in need thereof, preferably a human.

The radicals and symbols used in the definition of compounds of formula I have the meanings described in US Pat. No. 6,258,812.
A preferred compound of formula I is PTK787.

As used herein, “PTK787” is such that r, n and m are each 0, R ₁ and R ₂ together form a bridge of partial formula I ^* , and A, B, D and E are Means a compound of formula I, each of which is CH, G is methylene, X is imino, Y is 4-chlorophenyl and the bond characterized by the wavy line is a double bond;

  According to the present invention, a VEGF receptor tyrosine kinase inhibitor is the only active ingredient or an immunosuppressive agent such as a calcineurin inhibitor such as cyclosporine such as cyclosporin A, or FK506, EDG-receptor agonist such as FTY720, Anti-inflammatory agents such as steroids such as corticosteroids such as dexamethasone or prednisone, NSAIDs such as cyclooxygenase inhibitors such as COX-2 inhibitors such as celecoxib, rofecoxib, etlicoxib or valdecoxib, or ascomycin such as ASM981, antithrombotic agents Or anticoagulants such as heparin, IIb / IIIa inhibitors, antiproliferative agents such as taxanes such as taxol, paclitaxel or docetaxel, bins Alkaloids such as vinblastine, especially vinblastine sulfate, vincristine, especially vincristine sulfate, and vinorelbine, discodermride, or epothilone or derivatives thereof such as, but not limited to, microtubule stabilization or desorption Stabilizers, tyrosine kinase inhibitors that are not inhibitors of VEGF, such as staurosporine and related small molecules such as UCN-01, BAY 43-9006, bryostatin 1, Perifosine, Limofosine, midostaurin, RO318220, RO320432, GO6976, Isis3521 Inhibits PDGF receptor tyrosine kinase, such as LY333531, LY379196, SU5416, SU6668, AG1296 Compound or antibody or compound that binds to PDGF or decreases PDGF receptor expression, eg, EGF such as STI571, CT52923, RP-1776, GFB-111, pyrrolo [3,4-c] -beta-carboline-dione Compounds or antibodies that inhibit receptor tyrosine kinases, or compounds that bind to EGF or reduce EGF receptor expression, such as compounds described in WO 97/02266, such as the compound of Example 39, retinoic acid, ZD1839 (Iressa) , Alpha-, gamma- or delta-tocopherol or alpha-, gamma- or delta-tocotrienol, or compounds that act on GRB2, IMC-C225, such as statins, eg having HMG-CoA reductase inhibitory activity Tachin, lovastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, pitavastatin, rosuvastatin or nivastatin, a compound, protein, growth factor or compound that stimulates growth factor production that would promote endothelial regrowth of the luminal endothelium, such as FGF, IGF, matrix metalloproteinase inhibitors such as batimistat, marimistat, trocade, CGS27023, RS130830 or AG3340, modulators of kinases (ie antagonists or agonists) such as JNK, ERK1 / 2, Compounds that stimulate the release of MAPK or STAT, or (NO) or NO donors, such as diazeniumdiolate, S-nitrosothio It can be applied in combination mesoionic oxatriazole, a combination of isosorbide.

  The present invention also provides a calcineurin inhibitor as described above, for example an EDG-receptor agonist as described above, such as a microtubule stabilization or destabilizer as described above, such as a PDGF receptor tyrosine kinase as described above. A compound or antibody that binds to or reduces PDGF receptor expression, such as a compound or antibody that inhibits EGF receptor tyrosine kinase as described above or binds to EGF or expresses EGF receptor. Compounds that reduce, eg, statins as described above, eg, compounds, proteins, growth factors or compounds, eg, matrices as described above, that stimulate growth factor production that would promote endothelial regrowth of luminal endothelium as described above Metalloproteinase inhibitors, such as quinas as described above Ze modulators (i.e. antagonists or agonists), or for example in combination with compounds which stimulate the release of (NO) or NO donors as described above, provides a local administration or delivery of the VEGF receptor tyrosine kinase inhibitors.

In accordance with certain discoveries of the present invention, the following are provided:
1. A method of preventing or treating smooth muscle cell proliferation and migration in a hollow tube, or increased cell proliferation or decreased apoptosis or increased matrix deposition, comprising a therapeutically effective amount of a VEGF receptor tyrosine kinase inhibitor. Optionally including topical administration in combination with one or more other active ingredients, eg, as described above.

2. A method of treating intimal thickening of a vascular wall, wherein a therapeutically effective amount of a VEGF receptor tyrosine kinase inhibitor from any catheter-based device or intraluminal medical device, optionally as described above, for example, A method comprising controlled delivery in combination with one or more other active ingredients.

  Preferably, the disease to be treated is stenosis, for example restenosis after revascularization or neovascularization, and / or inflammation and / or thrombosis.

3. a) a medical device suitable for local administration or administration into a hollow tube, eg a catheter-based delivery device or an intraluminal medical device, and b) releasably secured to the catheter-based delivery device or medical device, respectively. A pharmaceutical delivery device or system comprising a therapeutic dose of a VEGF receptor tyrosine kinase inhibitor, optionally in combination with a therapeutic dose, eg, one or more other active ingredients as described above.

  Such local delivery devices or systems are for revascularization, bypass or transplantation performed at all vascular sites, including coronary, carotid, renal, peripheral, cerebral or any other arterial or venous site. To reduce stenosis or restenosis as an adjunct, to reduce anastomic stenosis as in the case of arterio-venous dialysis access with or without polytetrafluoroethylene implantation and with or without stent placement, Or it can be used in combination with any other heart or transplantation method, or congenital vascular intervention.

  VEGF receptor tyrosine kinase inhibitors are hereinafter referred to as “drugs”. Other active ingredients that may be used in combination with a VEGF receptor tyrosine kinase inhibitor, eg, as described above, are hereinafter collectively referred to as “adjuvants”. Drug (s) shall mean drug or drug + adjuvant.

Local administration is preferably performed at or near the site of vascular lesions.
Administration can be by one or more of the following routes: intranasally, intrabronchially, intraperitoneally or esophagus via a catheter or other intravascular delivery system. Hollow tubes are circulatory vessels, blood vessels (arteries or blood vessels), tissue lumens, lymphatic vessels, gastrointestinal tracts including respiratory canals, respiratory organs, excretory tubes, genital tubes and ducts, body lumen tubes Etc. Local administration or application of the drug (s) allows for concentrated delivery of the drug (s) and achieves tissue levels in the target tissue that are not obtainable via other routes of administration.

  The local drug delivery means to the hollow tube may be by delivery of the drug to either the inside or the outside of the hollow tube. Local drug delivery includes catheter delivery systems, local infusion devices or systems or indwelling devices. Such devices or systems can be stents, coated stents, intraluminal sleeves, stent grafts, liposomes, controlled release matrices, polymeric intraluminal paving, or other intravascular devices, embolic delivery particles, affinity-based delivery. Cell targeting, internal patches around hollow tubes, external patches around hollow tubes, hollow tube cuffs, external paving, external stent sleeves, and the like. Eccleston et al. (1995) Interventional Cardiology Monitor 1: 33-40-41 and Slepian, NJ (1996) Intervente. Cardiol. 1: 103-116 or Regar E, Sianos, the disclosure of which is incorporated herein by reference. G, Serruys PW. Stent development and local drug delivery. See Br Med Bull 2001, 59: 227-48.

  “Biocompatible” means a substance that does not elicit or minimally induce negative tissue reactions, including, for example, thrombus formation and / or inflammation.

  Delivery or administration of the drug (s) can be performed using a stent or sleeve or sheath. An intraluminal stent made of or coated with a polymer or other biocompatible material, or a porous ceramic, such as a nanoporous ceramic, in which the drug (s) are filled or incorporated Can be used. Such stents are biodegradable or can be made of metals or alloys such as Ni and Ti, or other stable materials when intended for permanent use. The drug (s) may also be incorporated into the metal of the stent or graft body that has been modified to include a porosity or groove. Also, luminal and / or antiluminal coatings or external sleeves made from polymers or other biocompatible materials, including drug (s), can be used for local delivery.

  Stents are generally used as tubular structures that remain inside the lumen of a tube to reduce occlusion. They are inserted into the lumen of the lumen in an unexpanded form, and then spontaneously (self-stretching stents) to shear and break the occlusion associated with the vessel wall composition and obtain an enlarged lumen Alternatively, it can be inflated with the aid of an angioplasty balloon mounted in situ on a second device, eg, a constricted blood vessel or a catheter that expands within a body passage.

  For example, the drug (s) can be incorporated into or secured to the stent in a number of ways and using any biocompatible material; it can be inserted, for example, into a polymer or polymerizable matrix and external to the stent May be sprayed on. A mixture of drug (s) and polymerizable material is prepared in a solvent or solvent mixture and applied to the surface of the stent by dip coating, brush coating and / or dip / spin coating, the solvent is evaporated and encapsulated A thin film with the applied drug (s) may be left. For stents where drug (s) are delivered from micropores, struts or grooves, a solution of polymer can be further applied as an outer layer to control drug (s) release; It may be included in the struts or grooves, and the adjuvant may be included in the outer layer, and vice versa. The drug may also be secured to the inner layer of the stent and the adjuvant to the sheath, or vice versa. The drug (s) may also be covalently bound to the stent surface (eg, ester, amide or anhydride), including chemical derivatization. The drug (s) may also be incorporated into a biocompatible porous ceramic coating, such as a nanoporous ceramic coating.

  Examples of polymerizable materials are biocompatible degradable materials such as lactone based polyesters or copolyesters such as polylactides; polylactide-glycolides; polycaprolactone-glycolides; polyorthoesters; polyanhydrides; polyamino acids; polysaccharides; Phosphazenes; poly (ether-ester) copolymers, such as PEO-PLLA, or mixtures thereof; and biocompatible non-degradable materials, such as polydimethylsiloxane; poly (ethylene-vinyl acetate); acrylate-based polymers or copolymers, such as Polybutylmethacrylate, poly (hydroxyethylmethyl methacrylate); polyvinylpyrrolidinone; fluorinated polymers such as polytetrafluoroethylene; cellulose esters.

  When using a polymerizable matrix, it has two layers, for example a base layer in which the drug (s) is incorporated, such as ethylene-co-vinyl acetate and polybutyl methacrylate, and no drug and drug (s) ), Which can serve as a diffusion control, for example polybutylmethacrylate. Alternatively, the drug may be included in the base layer and the adjuvant may be incorporated in the outer layer, or vice versa. The synthetic thickness of the polymerizable matrix can be about 1 to 20μ or more.

  By the method of the invention or the device or system of the invention, the drug (s) can be eluted passively, actively or under activation, eg photoactivation.

  The drug (s) elutes from the drug substance or stent from the drug over time and enters the surrounding tissue, for example, for about one month to one year. Local delivery according to the present invention allows a high concentration of drug (s) to the disease site with low concentrations of circulating compounds. The dose of agent (s) used for topical delivery application will vary depending on the compound used, the condition to be treated and the desired effect. For the purposes of the present invention, a therapeutically effective amount will be administered. A therapeutically effective amount is taken to be an amount sufficient to inhibit cell proliferation and result in prevention and treatment of a disease state. Specifically, local delivery may require fewer compounds than systemic administration, eg, for prevention or treatment of restenosis after revascularization, or for anti-tumor treatment.

  The usefulness of the drug (s) can be demonstrated, for example, in animal testing methods as well as clinically according to the following method. The following examples illustrate the invention without limiting it.

A1. Inhibition of late neointimal lesion formation at day 28 in rat carotid balloon injury model Many compounds have been shown to inhibit vascular intimal formation at 2 weeks in rat balloon-treated carotid artery model However, few compounds have proven effective at 4 weeks. Compounds of formula I are tested in the following rat model.

  Rats are administered orally with a placebo or VEGF receptor tyrosine kinase inhibitor, such as a compound of formula I, such as PTK787. Daily dosing starts 3 days before surgery and continues for 31 days. Rat carotid arteries are injured with a balloon using the method described in Clowes et al. Lab. Invest. 1983; 49; 208-215. After killing 28 days after balloon injury, the carotid artery is removed and processed for histological and morphological evaluation. In this assay, it can be shown that the ability of compounds of formula I significantly inhibit neointimal lesion formation after balloon injury.

A2. Day 28 Restenosis Inhibition in Rabbit Ilium Bone Stent Model Combined angioplasty and stent placement is performed on New Zealand white rabbit iliac arteries. Iliac artery balloon injury is performed by inflating a 3.0 × 9.0 mm angioplasty balloon in the middle of the artery and then “pulling back” one balloon length catheter. The balloon injury is repeated twice and a 3.0 × 12 mm stent is deployed in the iliac artery for 30 seconds at 6 atmospheres. Balloon injury and stent placement are then performed in the same manner on the contralateral iliac artery. Angiography is performed after stent deployment. All animals receive oral aspirin 40 mg / day daily as an antiplatelet treatment and are fed on a standard low cholesterol rabbit diet. After 28 days of stent placement, the animals are anesthetized and killed, and the arterial tree is perfused with lactated Ringer at 100 mmHg for several minutes and then at 100 mmHg for 15 minutes with 10% formalin. A blood vessel section between the peripheral aorta and the proximal femoral artery is removed and the periadventitial tissue is removed from the arterial vessel. Arterial stented sections are embedded in plastic and sections are taken from the proximal, middle, and distal of each stent. All sections are stained with hematoxylin-eosin and Movat pentachrome stain. The area is measured by a computer to determine the areas of the inner elastic plate (IEL), the outer elastic plate (EEL) and the lumen. Neointimal and neointimal thickness are measured both at and between the stent struts. Vessel area is measured as the area within the EEL. Data are shown as mean ± SEM. Statistical analysis of histological data is performed using analysis of variance (ANOVA) due to the fact that it measures with two stented arteries per animal and the average production per animal. P <0.05 is considered statistically significant.

  PTK787 is orally administered by oral gavage as the first dose one day before stent placement, and then 50% of the first dose is administered from the date of stent placement to 27 days after stent placement. In this model, a significant decrease in the degree of restenosis lesion formation in the presence of PTK787 can be seen on day 28, while placebo-treated animals consist of large amounts of smooth muscle cells in the proteoglycan / collagen matrix, And there is considerable neointimal formation with apparently complete endothelial healing lesions.

A3. Manufacture of stents Stents are weighed and then mounted for coating. While rotating the stent, a solution of polylactide glycolide, 0.75 mg / ml PTK787 and 0.0015 mg / ml 2,6-di-tert.-butyl-4-methylphenol dissolved in a mixture of methanol and tetrahydrofuran was added to the solution. Spray on top. The coated stent is then removed from the spray and allowed to air dry. After final weighing, determine the amount of coating on the stent.

A4. Release of PTK787 from polymer coating in aqueous solution Four 2 cm sections of a coated stent as described above are placed in 100 mL phosphate buffer (PBS) having a pH of 7.4. Another 4 sections from each series are placed in 100 mL of polyethylene glycol (PEG) / water solution (40/60 v / v, MW of PEG = 400). The stent sections are incubated at 37 ° C. in a shaker. The buffer and PEG solutions are changed daily and different assays are performed on the solutions to determine the released PTK787 concentration. By such a method, stable release of PTK787 from the coated stent can be demonstrated. The term “stable PTK787 release” means that less than 10% variation in drug release rate is observed.

A5. Release of PTK787 from polymer coating into plasma The release of PTK787 into plasma can also be tested. A 1 cm section of the coated stent is placed in 1 mL of citrated human plasma (from Helena Labs.) Reconstituted in lyophilized form by addition of 1 mL of sterile deionized water. Three sets of stent plasma solutions are incubated at 37 ° C. and the plasma is changed daily. A different assay is performed on the solution to determine the released PTK787 concentration. By such a method, stable PTK787 release from the coated stent to plasma can be demonstrated. The term “stable PTK787 release” means that less than 10% variation in drug release rate is observed.

A6. Stability of PTK787 in a pharmaceutically acceptable polymer at body temperature A PDGF stimulated receptor tyrosine kinase assay can be performed on the last section of each sample to determine PTK787 activity. Similar tests can be performed with free PTK787. In vitro inhibition of PDGF-stimulated receptor tyrosine kinase activity is described in the PDGF receptor immune complex of BALB / c3T3 cells, as described by E. Andrejauskas-Buchdunger and U. Regenass in Cancer Research 52 , 5353-5358 (1992). It can be measured according to the method. In this way, the stability of free PTK787 and PTK787 in polymer coatings can be compared.

Claims (13)

  a) a medical device suitable for local administration or administration into a hollow tube, such as a catheter-based delivery device or an intraluminal medical device, and b) a therapeutic dose of VEGF receptor tyrosine that is releasably secured to the medical device A pharmaceutical delivery device or system comprising a kinase inhibitor.   The device of claim 1, comprising PTK787.   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.   The device according to claim 1, wherein the device is a coated stent.   A method of preventing or treating smooth muscle cell proliferation and migration within a hollow tube or increased cell proliferation or decreased apoptosis or increased matrix deposition in a mammal in need thereof, wherein the therapeutically effective amount of vascular endothelial cell proliferation A method comprising locally administering a factor (VEGF) receptor tyrosine kinase inhibitor.   A method of treating intimal thickening of a vascular wall comprising the controlled delivery of a therapeutically effective amount of a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor from a catheter-based device or an intraluminal medical device. Including. The VEGF receptor tyrosine kinase inhibitor is of formula I

[Where,
r is from 0 to 2,
n is from 0 to 2,
m is from 0 to 4,
R ₁ and R ₂ are (i) lower alkyl, or
(ii) Combined, partial formula I ^*

(Bridges are achieved through two terminal carbon atoms)
Form a crosslink of
(iii) Combined, partial formula I ^**

(Wherein one or two ring members T ₁ , T ₂ , T ₃ and T ₄ are nitrogen, and the other is in each case CH, and the bridge is via T ₁ and T ₄ Achieved)
Forming a crosslink of
A, B, D, and E are independently of each other N or CH. However, more than two of these radicals are not N;
G is lower alkylene, lower alkylene substituted by acyloxy or _{hydroxy, -CH 2 -O -, - CH} 2 -S -, - CH 2 -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 di-substituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, Nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N, N-di-substituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, Phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, the substituent Z being the same or different from each other when two or more radicals Z are present;
And the bonds characterized by the wavy lines are either single or double bonds, when present. ]
Or an N-oxide of a defined compound, wherein one or more N atoms carry an oxygen atom, or a salt of such a compound having at least one salt-forming group.   The method according to claim 5 or 6, wherein the administration or delivery is intravascular, intranasal, intrabronchial, intraperitoneal or esophagus.   7. The method of claim 5 or 6, wherein the administration or delivery is performed using a catheter delivery system, a local infusion device, an indwelling device, a stent, a coated stent, a sleeve, a stent graft, a polymerizable intracavitary paving or a controlled release matrix.   6. The method of claim 5, wherein the VEGF receptor tyrosine kinase inhibitor is administered from a stent or a coating applied to the stent.   7. The method of claim 6, wherein the VEGF receptor tyrosine kinase inhibitor is delivered from a stent or a coating applied to the stent.   6. A method according to claim 5 for the treatment of stenosis, restenosis or inflammation.   7. A method according to claim 6 for the treatment of stenosis, restenosis or inflammation.