WO2005063251A1 - Tuteur modifie utile pour liberer des medicaments le long du support du tuteur - Google Patents

Tuteur modifie utile pour liberer des medicaments le long du support du tuteur Download PDF

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Publication number
WO2005063251A1
WO2005063251A1 PCT/IB2004/004031 IB2004004031W WO2005063251A1 WO 2005063251 A1 WO2005063251 A1 WO 2005063251A1 IB 2004004031 W IB2004004031 W IB 2004004031W WO 2005063251 A1 WO2005063251 A1 WO 2005063251A1
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alkyl
amino
alkoxy
alkylamino
trifluoromethyl
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PCT/IB2004/004031
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English (en)
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Paul Steven Changelian
Anderson See Gaweco
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Pfizer Products Inc.
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Publication of WO2005063251A1 publication Critical patent/WO2005063251A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus

Definitions

  • JIELD OF THE INVENTION Delivery of a Janus Kinase 3 (JAK3) inhibitor locally, particularly from an intravascular stent, directly from micropores in the stent body or mixed or bound to a polymer coating applied on stent, to inhibit neointimal tissue proliferation and thereby prevent restenosis.
  • This invention also facilitates the performance of the stent in inhibiting restenosis.
  • Re-narrowing (restenosis) of an artherosclerotic coronary artery after percutaneous transluminal coronary angioplasty occurs in 10-50% of patients undergoing this procedure and subsequently requires either further angioplasty or coronary artery bypass graft. While the exact hormonal and cellular processes promoting restenosis are still being determined, our present understanding is that the process of PTCA, besides opening the artherosclerotically obstructed artery, also injures resident coronary arterial smooth muscle cells (SMC).
  • SMC coronary arterial smooth muscle cells
  • adhering platelets, infiltrating macrophages, leukocytes, or the smooth muscle cells (SMC) themselves release cell derived growth factors with subsequent proliferation and migration of medial SMC through the internal elastic lamina to the area of the vessel intima.
  • Further proliferation and hyperplasia of intimal SMC and, most significantly, production of large amounts of extracellular matrix over a period of 3-6 months results in the filling in and narrowing of the vascular space sufficient to significantly obstruct coronary blood flow.
  • Heparin is the best known and characterized agent causing inhibition of SMC proliferation both in vitro and in animal models of balloon angioplasty-mediated injury.
  • the mechanism of SMC inhibition with heparin is still not known but may be due to any or all of the following: 1 ) reduced expression of the growth regulatory protooncogenes c-fos and c-myc, 2) reduced cellular production of tissue plasminogen activator; are 3) binding and dequestration of growth regulatory factors such as fibrovalent growth factor (FGF).
  • FGF fibrovalent growth factor
  • angiopeptin a somatostatin analog
  • calcium channel blockers angiotensin converting enzyme inhibitors
  • angiotensin converting enzyme inhibitors captopril, cilazapril
  • cyclosporin A trapidil
  • trapidil an antianginal, antiplatelet agent
  • terbinafine antifungal
  • colchicine and taxol antitubulin antiproliferatives
  • PDGF SMC mitogen platelet derived growth factor
  • PTCA percutaneous transiuminal coronary angioplasty
  • CABG coronary to artery bypass graft
  • a major difficulty with PTCA is the problem of post- angioplasty closure of the vessel, both immediately after PTCA (acute reocclusion) and in the long term (restenosis).
  • the mechanism of acute reocclusion appears to involve several factors and may result from vascular recoil with resultant closure of the artery and/or deposition of blood platelets along the damaged length of the newly opened blood vessel followed by formation of a fibrin/red blood cell thrombus.
  • intravascular stents have been examined as a means of preventing acute reclosure after PTCA.
  • Endoplasmic reticulum, golgi bodies, and free ribosomes are few and located in the perinuclear region.
  • Extracellular matrix surrounds SMC and is rich in heparin-like glycosylaminoglycans which are believed to be responsible for maintaining SMC in the contractile phenotypic state.
  • PDGF platelet derived growth factor
  • bFGF basic fibroblast growth factor
  • EGF epidermal growth factor
  • PDGF platelets adhering to the damaged arterial luminal surface, invading macrophages and/or leukocytes, or directly from SMC (i.e., BFGF) provoke a proliferation and migratory response in medial SMC.
  • SMC i.e., BFGF
  • the present invention relates to astent comprising: a generally thin walled cylinder, said cylinder containing a plurality of struts, said struts expandable struts having a generally uniform thickness; and a channel formed in at least one of said struts, said channel having a closed perimeter on all sides and an open top, and said channel smaller in all dimensions than said strut, said channel containing a compound of the formula
  • R 1 is a group of the formula
  • R 4 is selected from the group consisting of hydrogen, (C C 6 )alkyl, (C
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (C ⁇ -C 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C C 6 )acyloxy, (C ⁇ -C 6 )acylamino, (C C 6 )alkylamino, ((C C 6 )alkyl) 2 amino, cyano, cyano(C 1 -C 6 )alkyl, trifluoromethyl(C C 6 )alkyl, nitro, nitro(C ⁇ -C 6 )alkyl or (CrC ⁇ acylamino; R 12 is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C C 6 )alkyl, trifluoro
  • C 6 )alkylamino ((C C 6 )alkyl) 2 amino, amino(C ⁇ -C 6 )alkyl, (C C 6 )alkoxy-CO-NH, (C r C 6 )alkylamino-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (CrC 6 )alkylamino, hydroxy(C 1 - C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C C 6 )alkyl, halo(C- ⁇ -C 6 )alkyl, nitro(C C 6 )alkyl, trifluoromethyl, trifluoromethyl(C ⁇ -C 6 )alkyl, (C C 6 )acylamino, (C
  • the coating material should not contribute to any adverse response by the body (i.e., should be non-thrombogenic, non-inflammatory, etc.).
  • FIGS. 1 and la are top views and section views of a stent containing reservoirs as described in the present invention
  • FIGS. 3a and 3b are similar views of an alternate embodiment of the stent with open ends;
  • FIGS. 3a and 3b are further alternate figures of a device containing a grooved reservoir;
  • FIG. 4 is a layout view of a device containing a reservoir as in FIG. 3.
  • reaction 1 of Preparation A the 4-chloropyrrolo[2,3-d]pyhmidine compound of formula XXI, wherein R is hydrogen or a protecting group such as benzenesulfonyl or benzyl, is converted to the 4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, wherein Y is chloro, bromo or iodo, by reacting XXI with N- chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide.
  • the reaction mixture is heated to reflux, in chloroform, for a time period between about 1 hour to about 3 hours, preferably about 1 hour.
  • reaction 1 of Preparation A the 4- chloropyrrolo[2,3-d]pyrimidine of formula XXI, wherein R is hydrogen, is converted to the corresponding 4-chloro-5-nitropyrrolo[2,3-d]pyrimidine of formula XX, wherein Y is nitro, by reacting XXI with nitric acid in sulfuric acid at a temperature between about - 10°C to about 10°C, preferably about 0°C, for a time period between about 5 minutes to about 15 minutes, preferably about 10 minutes.
  • reaction 2 of Preparation A the 4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, wherein R is hydrogen, is converted to the corresponding compound of formula XIX, wherein R 2 is (C C 6 )alkyl or benzyl, by treating XX with N- butyllithium, at a temperature of about -78°C, and reacting the dianion intermediate so formed with an alkylhalide or benzylhalide at a temperature between about -78°C to room temperature, preferably room temperature.
  • the dianion so formed is reacted with molecular oxygen to form the corresponding 4-chloro-5- hydroxypyrrolo[2,3-d]pyrimidine compound of formula XIX, wherein R 2 is hydroxy.
  • the compound of formula XX, wherein Y is bromine or iodine and R is benzenesulfonate is converted to the compound of formula XIX, wherein R 2 is (C 6 - C 12 )aryl or vinyl, by treating XX with N-butyllithium, at a temperature of about -78°C, followed by the addition of zinc chloride, at a temperature of about -78°C.
  • reaction 3 of Preparation A the compound of formula XIX is converted to the corresponding compound of formula XVI by treating XIX with N-butyllithium, lithium diisopropylamine or sodium hydride, at a temperature of about -78°C, in the presence of a polar aprotic solvent, such as tetrahydrofuran.
  • a polar aprotic solvent such as tetrahydrofuran.
  • the anionic intermediate so formed is further reacted with (a) alkylhalide or benzylhalide, at a temperature between about -78°C to room temperature, preferably -78 °C, when R 3 is alkyl or benzyl; (b) an aldehyde or ketone, at a temperature between about -78°C to room temperature, preferably -78°C, when R 3 is alkoxy; and (c) zinc chloride, at a temperature between about -78°C to room temperature, preferably -78°C, and the corresponding organozinc intermediate so formed is then reacted with aryliodide or vinyl iodide in the presence of a catalytic quantity of palladium.
  • reaction mixture is stirred at a temperature between about 50°C to about 80°C, preferably about 70°C, for a time period between about 1 hour to about 3 hours, preferably about 1 hour.
  • the anion so formed is reacted with molecular oxygen to form the corresponding 4-chloro-6-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XVI, wherein R 3 is hydroxy.
  • reaction 1 of Preparation B the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI is converted to the corresponding compound of formula XXII, according to the procedure described above in reaction 3 of Preparation A.
  • reaction 2 of Preparation B the compound of formula XXII is converted to the corresponding compound of formula XVI, according to the procedures described above in reactions 1 and 2 of Preparation A.
  • reaction 1 of Scheme 1 the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVII is converted to the corresponding compound of formula XVI, wherein R is benzenesulfonyl or benzyl, by treating XVII with benzenesulfonyl chloride, benzylchloride or benzylbromide in the presence of a base, such as sodium hydride or potassium carbonate, and a polar aprotic solvent, such as dimethylformamide or tetrahydrofuran.
  • a base such as sodium hydride or potassium carbonate
  • a polar aprotic solvent such as dimethylformamide or tetrahydrofuran.
  • reaction mixture is stirred at a temperature between about 0°C to about 70°C, preferably about 30°C, for a time period between about 1 hour to about 3 hours, preferably about 2 hours.
  • reaction 2 of Scheme 1 the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVI is converted to the corresponding 4-aminopyrrolo[2,3-d]pyrimidine compound of formula XV by coupling XVI with an amine of the formula HNR 4 R 5 .
  • the reaction is carried out in an alcohol solvent, such as tert-butanol, methanol or ethanol, or other high boiling organic solvents, such as dimethylformamide, triethylamine, 1,4- dioxane or 1 ,2-dichloroethane, at a temperature between about 60°C to about 120°C, preferably about 80°C.
  • Typical reaction times are between about 2 hours to about 48 hours, preferably about 16 hours.
  • R 5 is a nitrogen containing heterocycloalkyl group, each nitrogen must be protected by a protecting group, such a benzyl.
  • Removal of the R 5 protecting group is carried out under conditions appropriate for that particular protecting group in use which will not affect the R protecting group on the pyrrolo[2,3-d]pyrimidine ring. Removal of the R 5 protecting group, when benzyl, is carried out in an alcohol solvent, such as ethanol, in the present of hydrogen and a catalyst, such as palladium hydroxide on carbon.
  • the R 5 nitrogen containing hetrocycloalkyl group so formed may be further reacted with a variety of different electrophiles of formula II.
  • electrophiles of formula II such as isocyanates, carbamates and carbamoyl chlorides are reacted with the R 5 nitrogen of the heteroalkyl group in a solvent, such as acetonitrile or dimethylformamide, in the presence of a base, such as sodium or potassium carbonate, at a temperature between about 20°C to about 100 °C for a time period between about 24 hours to about 72 hours.
  • a solvent such as acetonitrile or dimethylformamide
  • electrophiles of formula II such as acylchlorides and sulfonyl chlorides
  • a solvent such as methylene chloride
  • a base such as pyridine
  • Amide formation may also be carried out by reacting a carboxylic acid with the heteroalkyl group in the presence of a carbodiimide such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide in a solvent such as methylene chloride at ambient temperatures for 12-24 hours.
  • electrophiles of formula II such as ⁇ , ⁇ -unsaturated amides, acids, nitriles, esters, and ⁇ -halo amides, are reacted with the R 5 nitrogen of the heteroalkyl group in a solvent such as methanol at ambient temperatures for a time period between about 12 hours to about 18 hours.
  • Alkyl formation may also be carried out by reacting aldehydes with the heteroalkyl group in the presence of a reducing agent, such as sodium cyanoborohydride, in a solvent, such as methanol, at ambient temperature for a time period between about 12 hours to about 18 hours.
  • a reducing agent such as sodium cyanoborohydride
  • reaction 3 of Scheme 1 removal of the protecting group from the compound of formula XV, wherein R is benzenesulfonyl, to give the corresponding compound of formula I, is carried out by treating XV with an alkali base, such as sodium hydroxide or potassium hydroxide, in an alcohol solvent, such as methanol or ethanol, or mixed solvents, such as alcohol/tetrahydrofuran or alcohol/water.
  • an alkali base such as sodium hydroxide or potassium hydroxide
  • an alcohol solvent such as methanol or ethanol
  • mixed solvents such as alcohol/tetrahydrofuran or alcohol/water.
  • reaction 3 of Scheme 2 the compound of formula XXIII is converted to the corresponding compound of formula XV, according to the procedure described above in reaction 3 of Preparation A.
  • reaction 1 of Scheme 3 the compound of formula XVII is converted to the corresponding compound of formula I, according to the procedure described above in reaction 2 of Scheme 1.
  • the compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention.
  • Such non- toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
  • These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • Pharmacological attempts to prevent restenosis by pharmacologic means have thus far been unsuccessful and all involve systemic administration of the trial agents. Neither aspirin-dipyridamole, ticlopidine, acute heparin administration, chronic warfarin (6 months) nor methylprednisolone have been effective in preventing restenosis although platelet inhibitors have been effective in preventing acute reocclusion after angioplasty.
  • the calcium antagonists have also been unsuccessful in preventing restenosis, although they are still under study.
  • thromboxane inhibitors include thromboxane inhibitors, prostacyclin mimetics, platelet membrane receptor blockers, thrombin inhibitors and angiotensin converting enzyme inhibitors.
  • thromboxane inhibitors include thromboxane inhibitors, prostacyclin mimetics, platelet membrane receptor blockers, thrombin inhibitors and angiotensin converting enzyme inhibitors.
  • antiproliferative (or anti- restenosis) concentrations may exceed the known toxic concentrations of these agents so that levels sufficient to produce smooth muscle inhibition may not be reached (Lang et al., 42 Ann. Rev. Med., 127-132 (1991); Popma et al., 84 Circulation, 1426-1436 (1991 )).
  • balloon- expandable slotted metal tubes (usually but not limited to stainless steel), which when expanded within the lumen of an angioplastied coronary artery, provide structural support to the arterial wall. This support is helpful in maintaining an open path for blood flow.
  • stents were shown to increase angiographic success after PTCA, increase the stenosed blood vessel lumen and to reduce the lesion recurrence at 6 months (Serruys et al., 331 New Eng Jour. Med, 495, (1994); Fischman et al., 331 New Eng Jour. Med, 496-501 (1994).
  • heparin coated stents appear to possess the same benefit of reduction in stenosis diameter at follow-up as was observed with non-heparin coated stents. Additionally, heparin coating appears to have the added benefit of producing a reduction in sub-acute thrombosis after stent implantation (Serruys et al., 93 Circulation, 412-422, (1996).
  • sustained mechanical expansion of a stenosed coronary artery has been shown to provide some measure of restenosis prevention
  • coating of stents with heparin has demonstrated both the feasibility and the clinical usefulness of delivering drugs to local, injured tissue off the surface of the stent.
  • EXPERIMENTS Agents 3- ⁇ (3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- amino]-piperidin-1-yl ⁇ -3-oxo-propionitrile. Delivery Methods: These can vary: Local delivery of such agents (3- ⁇ (3R,4R)-4- Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl ⁇ -3-oxo- propionitrile) from the struts of a stent, from a stent graft, grafts, stent cover or sheath.
  • Polymers are biocompatible (i.e., not elicit any negative tissue reaction or promote mural throm 3o bus formation) and degradable, such as lactone-based polyesters or copolyesters, e.g., polylactide, polycaprolactonlycolide.polyorthoesters, polyanhydrides; polyaminoacids; polysaccharides; polyphosphazenes; poly (ether-ester) copolymers, e.g., PEO-PLLA, or blends thereof.
  • lactone-based polyesters or copolyesters e.g., polylactide, polycaprolactonlycolide.polyorthoesters, polyanhydrides; polyaminoacids; polysaccharides; polyphosphazenes; poly (ether-ester) copolymers, e.g., PEO-PLLA, or blends thereof.
  • Nonabsorbable biocompatible polymers are also suitable candidates.
  • Polymers such as polydimethylsiolxane; poly(ethylene-vingylacetate); acrylate based polymers or copolymers, e.g., poly(hydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone; fluorinated polymers such as polytetrafluoroethylene; cellulose esters.
  • Bulking agents typically comprise inert materials. Suitable bulking agents are known to those skilled in the art.
  • Polymers suitable to form a polymeric matrix of the sustained release composition of this invention are biocompatible polymers which can be either a biodegradable or non-biodegradable polymer, or blends or copolymers thereof.
  • Biodegradable as defined herein, means the composition will degrade or erode in vivo to form smaller chemical species. Degradation can result, for example, by enzymatic, chemical and physical processes.
  • Suitable biocompatible, biodegradable polymers include, for example, poly (lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid- coglycolic acid)s, poly caprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, poly (p- dioxanone), poly(alkylene oxalate)s, biodegradable polyurethanes, blends and copolymers thereof.
  • Biocompatible, nonbiodegradable polymers suitable for the modulated release composition of this invention include non-biodegradable polymers selected from the group consisting of polyacrylates, polymers of ethylene-vinyl acetates and other acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, blends and copolymers thereof.
  • non-biodegradable polymers selected from the group consisting of polyacrylates, polymers of ethylene-vinyl acetates and other acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, blends and copolymers thereof.
  • a polymer, or polymeric matrix is biocompatible if the polymer, and any degradation products of the polymer, are non-toxic to the recipient and also present no significant deleterious or untoward effects on the recipient's body, such as an immunological reaction at the injection site.
  • the terminal functionalities of a polymer can be modified.
  • polyesters can be blocked, unblocked or a blend of blocked and unblocked polymers.
  • a blocked polymer is as classically defined in the art, specifically having blocked carboxyl end groups. Generally, the blocking group is derived from the initiator of the polymerization and is typically an alkyl group.
  • An unblocked polymer is as classically defined in the art, specifically having free carboxyl end groups.
  • Acceptable molecular weights for polymers used in this invention can be determined by a person of ordinary skill in the art taking into consideration factors such as the desired polymer degradation rate, physical properties such as mechanical strength, and rate of dissolution of polymer in solvent. Typically, an acceptable range of molecular weights is of about 2,000 Daltons to about 2,000,000 Daltons.
  • the polymer is a biodegradable polymer or copolymer.
  • the polymer is a poly(lactide-co- glycolide) (hereinafter "PLGA”) with a lactide:glycolide ratio of about 1 :1 and a molecular weight of about 5,000 Daltons to about 70.000 Daltons.
  • PLGA poly(lactide-co- glycolide)
  • the molecular weight of the PLGA used in the present invention has a molecular weight of about 10,000 Daltons.
  • Polymer/drug mixture is applied to the surfaces of the stent by either dip- coating, or spray coating, or brush coating or dip/spin coating or combinations thereof, and the solvent allowed to evaporate to leave a film with entrapped 3- ⁇ (3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl ⁇ -3- oxo-propionitrile. 2.
  • the dipping solution can also be compressed to improve the 55 loading efficiency.
  • the stent is dipped briefly in fresh solvent to remove excess surface bound drug.
  • a solution of polymer, chosen from any identified in the first experimental method, is applied to the stent as detailed above. This outerlayer of 60 polymer will act as diffusion-controller for release of drug. . 3.
  • any stent strut 10, 20, 30 can be modified to have a certain reservoir or channel 11 , 21 , 31. Each of these reservoirs can be open or closed as desired. These reservoirs can hold the drug to be delivered.
  • FIG. 4 shows a stent 40 with a reservoir 45 created at the apex of a flexible strut.
  • this reservoir 45 is intended to be useful to deliver 3- ⁇ (3R,4R)-4-Methyl-3-[methyl-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl ⁇ -3-oxo-propionitrile or any other drug at a specific point of flexibility of the stent. Accordingly, this concept can be useful for "second generation" type stents. In any of the foregoing devices, however, it is useful to have the drug dosage applied with enough specificity and enough concentration to provide an effective dosage in the lesion area. In this regard, the reservoir size in the stent struts must be kept at a size of about 0.0005" to about 0.003".

Abstract

Libération locale d'un inhibiteur de Janus Kinases 3 (JAK3), surtout au moyen d'un tuteur intravasculaire, l'inhibiteur étant contenu directement dans des micropores du corps du tuteur ou étant mélangé ou lié au revêtement polymère appliqué sur le tuteur, afin d'inhiber la prolifération de tissus néointimaux et de prévenir ainsi la resténose. L'invention améliore également la capacité du tuteur d'inhiber la resténose.
PCT/IB2004/004031 2003-12-17 2004-12-06 Tuteur modifie utile pour liberer des medicaments le long du support du tuteur WO2005063251A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8299084B2 (en) 2009-04-20 2012-10-30 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of Janus kinase 3
US8500794B2 (en) 2007-08-02 2013-08-06 Flexible Stenting Solutions, Inc. Flexible stent
US9149376B2 (en) 2008-10-06 2015-10-06 Cordis Corporation Reconstrainable stent delivery system
US9592137B2 (en) 2005-04-04 2017-03-14 Flexible Stenting Solutions, Inc. Flexible stent

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0795556A1 (fr) * 1996-02-29 1997-09-17 PHARMACIA & UPJOHN S.p.A. Pyrrolopyrimidines 4-substituées comme inhibiteurs de tyrosine kinase
EP0950386A2 (fr) * 1998-04-16 1999-10-20 Cordis Corporation Stent permettant l'administration locale de rapamycine
WO2001042246A2 (fr) * 1999-12-10 2001-06-14 Pfizer Products Inc. Composes a base de pyrrolo[2,3-d]pyrimidine
WO2002102800A1 (fr) * 2001-06-15 2002-12-27 Vertex Pharmaceuticals Incorporated 5-(2-aminopyrimidine-4-yl) benzisoxazoles en tant qu'inhibiteurs de proteine kinases
WO2003055882A1 (fr) * 2001-12-24 2003-07-10 Merck Patent Gmbh Pyrrolopyrimidines en tant d'agents d'inhibition de phosphodiesterase-vii

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0795556A1 (fr) * 1996-02-29 1997-09-17 PHARMACIA & UPJOHN S.p.A. Pyrrolopyrimidines 4-substituées comme inhibiteurs de tyrosine kinase
EP0950386A2 (fr) * 1998-04-16 1999-10-20 Cordis Corporation Stent permettant l'administration locale de rapamycine
WO2001042246A2 (fr) * 1999-12-10 2001-06-14 Pfizer Products Inc. Composes a base de pyrrolo[2,3-d]pyrimidine
WO2002102800A1 (fr) * 2001-06-15 2002-12-27 Vertex Pharmaceuticals Incorporated 5-(2-aminopyrimidine-4-yl) benzisoxazoles en tant qu'inhibiteurs de proteine kinases
WO2003055882A1 (fr) * 2001-12-24 2003-07-10 Merck Patent Gmbh Pyrrolopyrimidines en tant d'agents d'inhibition de phosphodiesterase-vii

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9592137B2 (en) 2005-04-04 2017-03-14 Flexible Stenting Solutions, Inc. Flexible stent
US8500794B2 (en) 2007-08-02 2013-08-06 Flexible Stenting Solutions, Inc. Flexible stent
US9149376B2 (en) 2008-10-06 2015-10-06 Cordis Corporation Reconstrainable stent delivery system
US10010438B2 (en) 2008-10-06 2018-07-03 Flexible Stenting Solutions, Inc. Reconstrainable stent delivery system
US8299084B2 (en) 2009-04-20 2012-10-30 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of Janus kinase 3
US8962638B2 (en) 2009-04-20 2015-02-24 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of janus kinase 3
US9493469B2 (en) 2009-04-20 2016-11-15 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of Janus kinase 3
US9856261B2 (en) 2009-04-20 2018-01-02 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of Janus kinase 3

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