WO2004056353A2

WO2004056353A2 - Device and method for delivering mmp inhibitors

Info

Publication number: WO2004056353A2
Application number: PCT/EP2003/014602
Authority: WO
Inventors: David Saul Cohen; Margaret Forney Prescott
Original assignee: Novartis Ag; Novartis Pharma Gmbh
Priority date: 2002-12-20
Filing date: 2003-12-19
Publication date: 2004-07-08
Also published as: WO2004056353A3; AU2003294917A1

Abstract

The invention relates to the local administration of a matrix metalloproteinase inhibitor of formula (I), or a pharmaceutically acceptable salt thereof, optionally in conjunction with one or more other active ingredients, and a device adapted for such local administration.

Description

Device and method for delivering MMP inhibitors

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. 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.

It is also an object of this invention to provide a drug-containing medical device which allows sustained delivery of the pharmaceutical or sufficient pharmaceutical activity at or near the coated surfaces of the devices.

Also, it is an object of the invention to provide medical devices with stabilized complexed drug coatings and methods for making such devices.

Additionally, it is an object of the invention to provide a drug-releasing coating stents or medical devices to allow the timed or prolonged application of the drug to body tissue. It is a further object of the invention to provide methods for making a drug-releasing medical device, which permit timed-delivery or long-term delivery of a drug. Thus, there is a need for improved bio-compatible complexed drug coatings which enhance the biostability, abrasion- resistance, lubricity and bio- activity of the surface of implantable medical devices, especially complexed drug coatings which contain heat-sensitive biomolecules. In particular, there is a need for improved, cost efficient complexed drug coatings and devices, which have antithrombogenic and/or anti-restenosis and/or anti-inflammatory properties and for more efficient methods of providing the same. The present invention is directed to meeting these and other needs.

It has now been surprisingly found that certain MMP inhibitors, optionally in conjunction with other active compounds, e.g. compounds having mTOR inhibiting properties or compounds having anti-inflammatory properties, have beneficial effects when locally applied to the lesions sites. It has particularly been found that certain MMP inhibitors are surprisingly well adapted for delivery especially controlled delivery from a catheter-based device or an intraluminal medical device. The pharmaceutically acceptable polymers do not alter or adversely impact the therapeutic properties of certain MMP inhibitors. On the contrary, certain MMP inhibitors are particularly stable in any pharmaceutically acceptable polymers at body temperature and in human plasma, permitting an unexpected long storage in a coated stents. Certain MMP inhibitors are particularly well adapted because they are easily secured to the medical device by the polymer and the rate at which it is released from coating to the body tissue can be easily controlled. Furthermore, MMP inhibitor coated stents permit long-term delivery of the drug. It is particularly worthwhile to control the bioeffectiveness of the MMP inhibitor coated stent in order to obtain the same biological effect as a liquid dosage. Additionally, it has now been found that certain MMP inhibitors have a beneficial effect on restenosis and stenosis following transplantation, in particular restenosis following revascularisation.

The preparation of MMP inhibitors and the use thereof, especially as an antiproliferative agent, is described in EP 606046, EP766672, EP873312, US5646167, WO 98/14424 and WO 98/42662.

It will be understood that references to MMP inhibitors is meant to also include the pharmaceutically acceptable salts. MMP inhibitors or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.

According to the invention in a first aspect, a MMP inhibitor of formula I

wherein

Ar is carbocyclic or heterocyclic aryl;

R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly- halo-lower alkyl, C₃- C - cycloalkyl, C -C -cycloalkyl- lower alkyl, (oxa or thia)-C₃-C - cycloalkyl, [(oxa or thia)- C₃-C₆- cycloalkyl] -lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl; Ri is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃- Cio- cycloalkyl, C₃-C -cycloalkyl- lower alkyl, (lower alkyl, cycloalkyl, carbocyclic-lower alkyl, lower alkoxy-lower alkyl or halogen-lower alkyl and (4-OH or lower-alkoxy))- cyclohexyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, (carbocyclic or heterocyclic aryl)-lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, (N-lower alkyl-piperazino or N- carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl, acylamino-lower alkyl, piperidyl, (N-acyl-piperidyl)-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acyl or N-lower alkylpiperidyl)- (hydroxy or lower alkoxy)-lower alkyl, pyrrolidinyl, hexahydroazepinyl, N- lower alkyl- (piperidyl, hexahydroazepinyl or pyrrolidinyl), N-acyl- (hexahydroazepinyl, piperidyl or pyrrolidinyl), C₅- C₁₀-oxacycloalkyl, C₅-C₁₀-thiacycloalkyl, (hydroxy or oxo)-C₅ -C₁₀- cycloalkyl, (hydroxy or oxo)-C ₅-C₁₀-thiacycloalkyl, (hydroxy or oxo)-C₅-C₁o-oxacycloalkyl, (amino, mono- or di-lower alkylamino or acylamino)-C5-C₁o-cycloalkyl, 2-oxo-(pyrrolidinyl, piperidyl or hexahydroazepinyl), (carbocyclic or heterocyclic aryl)-(thio, sulfinyl or sulfonyl)- lower alkyl; R₂ is hydrogen or lower alkyl;

(b) or wherein Ri and R₂ together with the chain to which they are attached form a 1,2,3,4- tetrahydro-isoquinoline, piperidine, oxazolidine, thiazolidine or pyrrolidine ring, each unsubstituted or substituted by lower alkyl; and Ar and R₂ have meaning as defined under (a);

(c) or wherein Ri and R₂ together with the carbon atom to which they are attached form a ring system selected from C₃-C -cycloalkane which is unsubstituted or substituted by lower alkyl; oxa-cyclohexane, thia-cyclohexane, indane, tetralin, piperidine or piperidine substituted on nitrogen by acyl, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, (carboxy, esterified or amidated carboxy)-lower alkyl or by lower alkylsulfonyl; and Ar and R have meaning as defined under (a); wherein the term "carbocyclic aryl" means phenyl; phenyl that is mono-, di- or tri-substituted by one, two or three radicals selected from lower alkyl, lower alkoxy, hydroxy, halogen, cyano, trifluoromethyl, lower alkylenedioxy and oxy-C₂-C₃- alkylene; or 1- or 2-naphthyl; wherein the term "heterocyclic aryl" means pyridyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted by lower alkyl or halogen; or a pharmaceutically acceptable salt thereof, 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, a mTOR inhibitor agent e.g. rapamycin derivatives, e.g. 40-O-(2-hydroxyethyl)-rapamycin, 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 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 or a telomerase inhibitior, a tyrosine kinase inhibitor, ■ 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, agents generically termed tyrphostins such as AG957 etc., an osteoclast activity inhibitor, e.g. Bisphosphonates e.g. pamidronate, aledronate etc.

In a further embodiment, according to the invention, a MMP inhibitor of formula II

(a) wherein

Ar is carbocyclic or heterocyclic aryl;

R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃-

C -cycloalkyl, C₃-C -cycloalkyl-lower alkyl, (oxa or thia)-C₃-C₆-cycloalkyl, [(oxa or thia)-C₃-

C₆-cycloalkyl] -lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl;;

RI is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃-

C₇-cycloalkyl, C -C -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, (carbocyclic or heterocyclic aryl)-lower alkoxy-lower alkyl, lower alkyl-

(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, (N-lower alkyl-piperazino or N-carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, (mo holino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylρiperidyl)-lower alkyl, acylamino-lower alkyl, piperidyl or N-lower alkylpiperidyl; R is hydrogen or lower alkyl;

(b) or wherein R and Ri together with the chain to which they are attached form a 1,2,3,4- tetrahydro-isoquinoline, piperidine, oxazolidine, thiazolidine or pyrrolidine ring, each unsubstituted or substituted by lower alkyl; and Ar and R₂ have meaning as defined under (a);

(c) or wherein Ri and R₂ together with the carbon atom to which they are attached form a ring system selected from C₃-C₇-cycloalkane which is unsubstituted or substituted by lower alkyl; oxa-cyclohexane, thia-cyclohexane, indane, tetralin, piperidine or piperidine substituted on nitrogen by acyl, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, (carboxy, esterified or amidated carboxy)-lower alkyl or by lower alkylsulfonyl; and Ar and R have meaning as defined under (a); pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti- inflammatory agent, a NS AID, or an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, an osteoclast activity inhibitor.

In a another embodiment, according to the invention, a MMP inhibitor of formula III

wherein

Ar is carbocyclic or heterocyclic aryl;

R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃- C -cycloalkyl, C₃-C₇-cycloaLtyl-lower alkyl, (oxa or thia)-C₃-C₆-cycloalkyl, [(oxa or thia)-C₃- C₆-cycloalkyl] -lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, suWmyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl; Ri is C₈-Cιo-cycloalkyl, (N-acyl-piperidyl)-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acyl or N-lower alkylpiperidyl)-(hydroxy or lower alkoxy)-lower alkyl, pyrrolidinyl, hexahydroazepinyl, N-lower alkyl-(hexahydroazepinyl or pyrrolidinyl), N-acyl-(hexahydroazepinyl, piperidyl or pyrrolidinyl), C₈-Cjo-oxacycloaLkyl, C₅-Cιo-thiacycloalkyl, (hydroxy or oxo)-C5-C₁₀-cycloalkyl, (hydroxy or oxo)-C₅-C₁₀- thiacycloalkyl, (hydroxy or oxo)-C₅-C₁₀-oxacycloalkyl, (amino, mono- or di-lower alkylamino or acylamino)-C5-Cι₀-cycloalkyl, 2-oxo-(pyrrolidinyl, piperidyl or hexahydroazepinyl); R₂ is hydrogen or lower alkyl; pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti-inflammatory agent, a NSAID, or an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, an osteoclast activity inhibitor.

In yet another embodiment, according to the invention, a MMP inhibitor of formula IN

(a) wherein

Ar is carbocyclic or heterocyclic aryl; R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic: aryl, heterocyclic aryl, ,. biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃- C₇-cycloalkyl, C₃-C -Cycloalkyl-lower alkyl, (oxa or thia)-C₃- C₆-cycloalkyl, [(oxa or thia)- C₃-C₆-cycloalkyl] -lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N- lower alkyl-piperazino or N-carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, or (morpholino, thiomorphohno, piperidino, pyrrolidino, piperidyl or N- lower alkylpiperidyl)-lower alkyl; Ri is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃- C -cycloalkyl, C₃-C -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, (carbocyclic or heterocyclic aryl)-lower alkoxy-lower alkyl, lower alkyl- (thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, (N-lower alkyl-piperazino or N- carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acyl or N-lower alkylpiperidyl)- lower alkyl, acylamino-lower alkyl, piperidyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acyl or N-lower alkylpiperidyl)-(hydroxy or lower alkoxy) lower alkyl, pyrrolidinyl, hexahydroazepinyl, N-lower alkyl or N- acyl(hexahydroazepinyl, piperidyl or pyrrolidinyl), C₅-C₁₀-oxacycloalkyl, C₅-C1₀- thiacycloalkyl, (hydroxy- or oxo-) C5-C₁₀-cycloalkyl, (hydroxy- or oxo-) C₅-C1Q- thiacycloalkyl, (hydroxy- or oxo-) C5-C10- oxacycloalkyl, (amino, mono- or dialkylamino or acylamino)-C₅-C₁₀- cycloalkyl, 2-oxo(pyrrolidinyl, piperidyl or hexahydroazepinyl), (carbocyclic or heterocyclic aryl)-(thio, sulfinyl or sulfonyl)-lower alkyl; R₂ is hydrogen or lower alkyl;

(b) or wherein R and Ri together with the chain to which they are attached form a 1,2,3,4- tetrahydro-isoquinoline, piperidine, oxazolidine, thiazolidine or pyrrolidine ring, each unsubstituted or substituted by lower alkyl; and Ar and R₂ have meaning as defined under (c) or wherein Ri and R₂ together with the carbon atom to which they are attached form a ring system selected from C₃-C₇-cycloalkane which is unsubstituted or substituted by lower alkyl; oxa-cyclohexane, thia-cyclohexane, indane, tetralin, piperidine or piperidine substituted on nitrogen by acyl, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, (carboxy, esterified or amidated carboxy)-lower alkyl or by lower alkylsulfonyl; and Ar and R have meaning as defined under (a);

pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti- inflammatory agent, aNSAID, or an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, an osteoclast activity inhibitor.

In even yet another embodiment, according to the invention, a MMP inhibitor of formula V

wherein

Ar represents carbocyclic aryl, heterocyclic aryl or biaryl;

Ri represents lower alkyl, cycloalkyl, (carbocyclic or heterocyclic aryl)-lower alkyl, lower alkoxy-lower alkyl, carbocyclic aryl, heterocyclic aryl, cycloalkyl-lower alkyl or halogen- lower alkyl;

R₂ represents hydrogen or lower alkyl;

R₃ and R₄ represent independently hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, acyloxy, lower alkoxy-lower alkoxy, trifluoromethyl or cyano; or R₃ and R together on adjacent carbon atoms represent lower alkylenedioxy; n represents an integer from 1 to 5; pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti- inflammatory agent, a NS ADD, an antiproliferative agent, a tyrosine kinase inhibitor, agents •generically termed tyrphostins, or an osteoclast activity inhibitor.

According to the invention in a second aspect, a MMP inhibitor of formula VI

wherein

RI is a substituent of Formula Q: A-(O-(CR₅H)n)m-O-CH2 Formula Q wherein n is 1, 2, 3 or 4, preferably 2; m is 0, l, 2or3; each R5 is independently H, Cl-10 (optionally hydroxy-, Cl-6 alkoxy-, amino-, Cl-6 alkylamino-, thiol-, Cl-6 alkylmercapto- or protected hydroxy, amino or thiol substituted) alkyl, C2-6 alkenyl, C6-14(optionally hydroxy-, Cl-6 alkoxy-, amino-, Cl-6 alkylamino-, halo- or cyano- substituted) aryl, or C6-14 (aryl) Cl-6 alkyl; preferably H, phenyl, benzyl or C 1-5 alkyl;

A is hydrogen, Cl-10 alkyl, C6-14 aryl, C6-14 aryl(Cl-6 alkyl), (C6-14 aryl)carbonyl, or (Cl- 10 alkyl)carbonyl; preferably hydrogen, Cl-6 alkyl (e.g., methyl or cyclohexyl), phenyl or benzyl; R2 is C2-12 alkyl, C3-12 alkenyl, C3-7(optionally hydroxy-, Cl-6 alkoxy-, amino-, or Cl-6 alkylamino- substituted) cycloalkyl, C5-14 aryl, or C5-14 aryl(CIx alkyl), wherein aryl groups are optionally substituted by hydroxy-, Cl-6 alkyl-, Cl-6 alkoxy-, amino-, halo or cyano-; preferably phenyl, 4-methylphenyl, 4-methoxyphenyl, cyclohexyl or isobutyl;

_R3 is Cl-10 (optionally hydroxy- or Cl-6 alkoxy- amino-, Cl-6 alkylamino-, thiol-, Cl-6 alkylmercapto- or protected hydroxy-, amino- or thiol- substituted) alkyl (e.g., t-butyl,

^" or cyclohexylmethyl), C6-14 (optionally hydroxy-, C6-14 aryloxy-, or Cl-10 alkoxy-, amino-, Cl-6 alkylamino-, halo-, or cyano- substituted) aryl (e.g., benzyl, p-methoxybenzyl, p benzyloxybenzyl), or indolylmethyl (e.g., 2-indolylmethyl); preferably benzyl or t butyl;

R4 is methyl, pyridyl, or a substituent of formula X-Y- wherein X is morpholino, pyridyl or aryl (preferably morpholino), and Y is C 1-12 alkylene in which up to four of the methylene (-CH2-) units are optionally replaced with -CO-, -NH-, -SO2- or -O-; for example methyl, 2-pyridyl, morphol inocarbonyl methyl, 5-(morpholino)pentyl, or 5 (morpholinocarbonyl)pentyl . or a pharmaceutically acceptable salt thereof, 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, a mTOR inhibitor agent e.g. rapamycin derivatives, e.g. 40-O-(2-hydroxyethyl)-rapamycin, 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 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 or a telomerase inhibitior, a tyrosine kinase inhibitor, 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, agents generically termed tyrphostins such as AG957 etc., an osteoclast activity inhibitor, e.g. Bisphosphonates e.g. pamidronate, aledronate etc.

In a further embodiment, according to the invention, a MMP inhibitor of formula VI'

in which

RI' is a substituent of Formula Q':

A'-(O-(CH2)n^,)m'-O-CH₂ Formula Q' such that n' is an integer one or two, preferably two; m' is an integer zero, one, two, or three;

A' is hydrogen, C_6-ι₄ aryl, CI.J_O alkyl, (C_6-14 aryl)carbonyl, or (CM_O alkyl)carbonyl,

(preferably C_1-6 alkyl, e.g., methyl or cyclohexyl);

R2' is C_2-6 alkyl, preferably isobutyl;

R3' is C _O (optionally hydroxy- or Cl-6 alkoxy-substituted) alkyl (e.g., t-butyl, or cyclohexylmethyl), C6-14 (optionally hydroxy-, C6-14 aryloxy-, or Cl-6 alkoxy-substituted) aryl (e.g., benzyl, p-methoxybenzyl, p-benzyloxybenzyl), or indolylmethyl (e.g., 2 indolylmethyl); preferably benzyl or t-butyl;

R4' is methyl, pyridyl, or a substituent of formula X-Y- wherein X is morpholino, pyridyl or aryl (preferably morpholino), and Y is C-12 alkylene in which up to four of the methylene (-CH2-) units are optionally replaced with -CO-, -ΝH-, -SO2- or -O-; for example methyl, 2-pyridyl, morpholinocarbonylmethyl, 5-(morpholino)pentyl, or 5

(morpholinocarbonyl)pentyl; pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti-inflammatory agent, a NS AID, or an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, an osteoclast activity inhibitor.

In a another embodiment, according to the invention, a MMP inhibitor of formula VI wherein: (i) RI is of formula Q or Q' (preferably formula Q') and A of formula Q is hydrogen, Cl-6 alkyl, e.g., methyl or cyclohexyl (e.g., so that R, of formula VI is for example hydroxymethyl, cyclohexyloxyethoxymethyl, methoxyethoxyethoxymethyl, or hydroxyethyloxymethyl) or (C_6-14 aryl)carbonyl, e.g. benzoyl (e.g. so that R, of formula VI is for example benzoyloxymethyl, benzoyloxyethoxyethyl or benzoyloxyethoxyethoxymethyl);

(ii) R2 of formula VI is cyclohexyl, phenyl, 4-methylphenyl, 4-methoxyphenyl or isobutyl;

(iii) R3 of formula VI is benzyl or t-butyl; and

(iv) R4 of formula VI is methyl or morpholinocarbonylfci -₆)alkyl and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti- inflammatory agent, a NS AID, or an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, an osteoclast activity inhibitor.

In yet another embodiment, according to the invention, a MMP inhibitor of formula Via

or Formula VIb

most preferably that of Formula Via, wherein RI, R2, R3 and R4 are as defined by the corresponding groups RI, R2, R3 and R4 with respect to formula VI; any Novel Compounds when in the form of mixtures of enantiomers, e.g. as racemic mixtures, though preferably when in pure or substantially pure enantiomeric form, e.g. in a form in which the Novel Compound content comprises at least 90%, preferably at least 95%, and especially at least 98%, of a single isomer (i.e. comprises less than 10%, preferably less than 5%, and especially less than 2%, of other Novel Compound isomers; pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti-inflammatory agent, a NS AID, or an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, an osteoclast activity inhibitor.

In a third aspect of the invention, a MMP inhibitor of formula VII

wherein

R represents hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, adamantyl, aryl, biaryl, or mono- or di-(cycloalkyl, aryl or biaryl)-lower alkyl, di-(lower alkyl or aryl-lower alkyl)-amino-lower alkyl, or (piperidino, morpholino, pyrrolidino)-lower alkyl; RI represents hydrogen, lower alkyl, cycloalkyl, aryl, biaryl, or (cycloalkyl, aryl or biaryl) - lower alkyl;

R2 represents hydrogen, lower alkyl, lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, amino, mono- or di-(lower alkyl or aryl-lower alkyl)-amino, acylarnino, or (lower alkyl or aryl-lower alkyl)-(thio, sulfinyl or sulfonyl); R3 represents hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl, cycloalkyl-lower alkyl, or C2-C7-alkyl interrupted by S, SO, SO2, O or N-R5; R4 represents hydrogen or acyl;

R5 represents hydrogen, lower alkyl, aryl-lower alkyl, acyl, or (lower alkyl, aryl or aryl-lower alkyl)-sulfonyl;

A together with the carbon to which it is attached forms a ring and represents a bivalent radical of the formula (CH2)p which may be interrupted by S, SO, SO2, O, or N-R5; n represents an integer from zero to four; p represents an integer from 2 to 6; any pharmaceutically acceptable salts thereof; and disulfides corresponding to said compounds of formula I wherein R4 is hydrogen, or a pharmaceutically acceptable salt thereof, 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, a mTOR inhibitor agent e.g. rapamycin derivatives, e.g. 40-O-(2-hydroxyethyl)-rapamycin, 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 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 or a telomerase inhibitior, a tyrosine kinase inhibitor, 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, agents generically termed tyrphostins such as AG957 etc., an osteoclast activity inhibitor, e.g. Bisphosphonates e.g. pamidronate, aledronate etc.

In a further embodiment, according to the invention, a MMP inhibitor of formula VIII

wherein R, R3, R4 and R5 have meaning as defined above with respect to formula VII, RI' represents cycloalkyl, aryl or biaryl; and Y represents CHR2, S, SO, SO2, O, or NR5. or pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti- inflammatory agent, a NSAID, or an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, an osteoclast activity inhibitor.

In a another embodiment, according to the invention, a MMP inhibitor of formula IX

wherein R' is carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl or lower alkyl; RI" is carbocyclic or heterocyclic aryl, or biaryl; R2' is hydrogen, lower alkyl or lower alkoxy; R3, is hydrogen, lower alkyl or carbocyclic aryl-lower alkyl; and R4' is hydrogen, lower alkanoyl, aryl-lower alkanoyl or aroyl. or pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti-inflammatory agent, a NSAID, or an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, an osteoclast activity inhibitor.

Preferred are said compound of formula IX wherein R2 is at the 4-position of the cyclohexane ring.

In yet another embodiment, according to the invention, a MMP inhibitor of formula X

wherein, R2 and the amide chain are cis to each other, and R, RI, R2, R3 and R4 have meaning as defined hereinabove with respect to formula VII, or pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti- inflammatory agent, a NSAID, or an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, an osteoclast activity inhibitor.

Preferred in turn are said compounds of formula X wherein R is monocyclic carbocyclic or heterocyclic aryl; R, is monocyclic carbocyclic aryl; R2 is lower alkoxy; R3 is hydrogen; and R4 is hydrogen or lower alkanoyl; or pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof; may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti -inflammatory agent, a NSAID, an antiproliferative agent, a tyrosine kinase inhibitor, agents generically termed tyrphostins, or an osteoclast activity inhibitor.

The present invention also provides the local administration or delivery of a MMP inhibitor of formula I, II, III, IV, V, VI, VT, Via, VIb, VII, VIII, IX or X in conjunction with a calcineurin inhibitor, e.g. as disclosed above, a mTOR inhibitor agent e.g. rapamycin derivatives, e.g. 40- O-(2-hydroxyethyι)-rapamycin, an EDG-Receptor agonist, e.g. as disclosed above, a microtubule stabilizing or destabilizing agent, e.g. as disclosed above, an osteoclast activity inhibitor, 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 compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, e.g. as disclosed above, an inhibitor of a modulator (i.e. antagonists or agonists) of kinases, 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 MMP inhibitor of formula I, II, III, IV, V, VI, VI', Via, VIb, VII, VIII, IX or X, optionally in conjunction with one or more other active ingredients, e.g. as disclosed above, or a therapeutically effective amount of a MMP inhibitor of formula I, II, III, IV, V, VI, VI', Via, VIb, VII, VIII, IX or X in conjunction with one or more other active ingredients as disclosed above.

2. A method for the stabilisation of vulnerable atherosclerotic plaques in a mammal in need thereof, comprising local administration of a therapeutically effective amount of a MMP inhibitor of formula I, II, III, IV, V, VI, VI', Via, VIb, VII, VIII, IX or X, optionally in conjunction with one or more other active ingredients, e.g. as disclosed above.

3. A method for the treatment of intimal thickening in vessel walls or stabilisation of vulnerable atherosclerotic plaques comprising the controlled delivery from any catheter- based device, intraluminal medical device or device applied to the external/ adventitial aspect of the vessel of a therapeutically effective amount of a MMP inhibitor of formula I, II, III, IN, N, VI, VI', Via, VIb, VII, VIII, IX or X, optionally in conjunction with one or more other active ingredients, e.g. as disclosed above.

Preferably the treatment of a) intimal thickening in vessel walls due to atherosclerosis, stenosis or restenosis, e.g. following revascularization, neovascularization or any other vascular procedure besides traditional revascularisation, and/or inflammation and/or thrombosis. b) Closure of A-V access e.g. the access used in renal dialysis patients c) Constrictive remodeling proximal and distal to the catheter-based device or intraluminal medical device d) Vulnerable atherosclerotic plaques

4. 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, intraluminal medical device or a device applied to the external/ adventitial aspect of the vessel, and b) a therapeutic dosage of a MMP inhibitor of formula I, II, III, IV, V, VI, VF, Via, VIb, VII, VIII, IX or X, 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, medical device or a device applied to the external/ adventitial aspect of the vessel.

Such a local delivery device or system can be used to reduce atherosclerosis, stenosis or restenosis as an adjunct to revascularization, bypass or grafting procedures or any other vascular procedure besides traditional revascularisation e.g. CABG, aneurysm repair, anastomic hyperplasia, 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 polytetrafluoroethylene grafting and with or without stenting, or in in conjunction with any other heart or transplantation procedures, or congenital vascular interventions. Use to reduce, constrictive remodeling proximal and distal to the drug delivery device or system, reduced flow after any other vascular procedure besides traditional revascularisation e.g. CABG, aneurysm repair, anastomic hyperplasia, local delivery to the adventitia accompanying revascularisation, ect, closure of A-V access e.g. the access used in renal dialysis patients. Such a local delivery device or system can also be used to stabilise vulnerable atherosclerotic plaques.

A MMP inhibitor of formula I, II, III, IV, V, VI, VI', Via, VIb, VII, VIII, IX or X or a pharmaceutically acceptable salt thereof will be referred to hereinafter as "drug". The other active ingredients which may be used in conjunction with a MMP inhibitor of formula I, II, III, IV, , V, VI, VF, Via, VIb, VII, VIII, IX or X as disclosed above, will be referred to hereinafter collectively as "adjunct". Drug(s) shall mean drug or drug+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, NJ. (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 or vessel 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 stenosed vessel or body passageway in order to 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; polyphosphazenes; 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 methylmethacrylate); 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 inhibit 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. Preferred combinations are those comprising a MMP inhibitor of formula I, II, III, IV or V in conjunction or association with a compound having antiproliferative properties, e.g. taxol, paclitaxel, docetaxel, an epothilone, a tyrosine kinase inhibitor, a VEGF receptor tyrosine kinase inliibitor, a VEGF receptor inhibitor, a compound binding to VEGF, a mTOR inhibitor agent e.g. rapamycin derivatives, e.g. 40-O-(2-hydroxyethyl)-rapamycin, a compound having anti-inflammatory properties, e.g. a steroid, a cyclooxygenase inhibitor, combination of a MMP inhibitor of formula I, II, III, IV or V with a compound having anti-inflammatory properties has particularly beneficial effects when used in the treatment or prevention of restenosis in diabetic patients.

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.

Al . 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 one of the following compounds: N-Hydroxy-2-[(4- methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3-methyl-butyramide, 2-[(4-Ethoxy- benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl-l -methylcarbamoyl-proρyl)-N-l -hydroxy-2-hydroxylmethyl-3-(4- methoxy-hexa-2,4-dienyl)-succinamide. 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 N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3- methyl-butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2- (4-ρropoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl-l-methylcarbamoyl-propyl)-N-l- hydroxy-2-h droxylmethyl-3 -(4-methoxy-hexa-2,4-dienyl)-succinamide significantly reduced neointimal lesion formation at 28 days following balloon injury when administered at a dose of from 0.2 to 3.5 mg preferably 0.5 to 2.0 mg/kg. For example N-Hydroxy-2-[(4-methoxy- benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3-methyl-butyramide administered at 0.5, 1.0, and 2.0 mg/kg , the percent inhibition is similar at all three doses: inhibition is 17% at the lowest dose (0.5 mg/kg) and 37% at the highest dose (2.0 mg kg). N-Hydroxy-2-[(4-methoxy- benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3-methyl-butyramide, 2-[(4-Ethoxy- benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy-cyclohexyl)-acetamide orN-4-(2,2-Dimethyl-l-methylcarbamoyl-propyl)-N-l-hydroxy-2-hydroxylmethyl-3-(4- methoxy-hexa-2,4-dienyl)-succinamide has the beneficial effect to inhibit lesions at 4 weeks • post-ballooning. 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. N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3-methyl- butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4- propoxy-cy clohexy I)-acetamide or N-4-(2,2-Dimethyl- 1 -methy lcarbamoy 1-propy 1)-N- 1 - hydroxy-2-hydroxylmethyl-3-(4-methoxy-hexa-2,4-dienyl)-succinamide is administered orally by gavage at 30 mg/kg once daily from 3 days prior to stenting until day 27 post-stenting. In this model, the treatment with the N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3- ylmethyl-amino]-3-methyl-butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl- - amino]-N-hydroxy-2-(4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl-l- methylcarbamoyl-propyl)-N- 1 -hydroxy-2-hydroxylmethyl-3 -(4-methoxy-hexa-2,4-dienyl)- succinamide results in a marked reduction in the extent of restenotic lesion formation compared with placebo treatment: for example, the treatment with zoledronic acid produces a significant reduction in average neointimal thickness (29% reduction; PO.0001), neointimal area (17% reduction P<.04), and percent arterial stenosis (17% reduction P<.0002). Treatment with N-Hydroxy-2- [(4-methoxy-benzenesulfonyl)-pyridin-3 -y lmethyl-amino] -3 -mefhy 1- butyramide did not result in differences in EEL area compared with control, indicating that treatment was not associated with either constrictive remodeling or aneurysmal-type arterial expansion. 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. In arterial segments from the animals treated with N- Hydroxy-2- [(4-methoxy-benzenesulfonyl)-pyridin-3 -y lmethyl-amino] -3 -methyl-butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy- cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 -methylcarbamoyl-propyl)-N- 1 -hydroxy-2- hydroxylmethyl-3-(4-methoxy-hexa-2,4-dienyl)-succinamide the intima is well healed, characterized by a compact neointima consisting of smooth muscle cells and endothelium fully covering the lumen surface both over stent struts and between struts. The following example is illustrative of the invention without limitating it. A stent is weighed and then mounted for coating. While the stent is rotating, a solution of polylactide glycolide, 0.70 mg/ml N-Hydroxy-2-[(4-methoxy-benzenesulfonyι)-pyridin-3- ylmethyl-amino]-3-methyl-butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl- amino]-N-hydroxy-2-(4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 - methylcarbamoyl-propyl)-N-l-hydroxy-2-hydroxylmethyl-3-(4-methoxy-hexa-2,4-dienyl)- succinamide 0.0015 mg/ml and 1 mg/ml tyrosine kinase inhibitor 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.3 N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3-methyl- butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4- propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl-l-methylcarbamoyl-propyl)-N-l- hy droxy-2-hy droxylmethy 1-3 -(4-methoxy-hexa-2,4-dienyl)-succinamide stability in pharmaceutically acceptable polymers at body temperature and -Hydroxy-2-[(4-methoxy- benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3-methyl-butyramide, 2-[(4-Ethoxy- benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 -methylcarbamoyl-propyl)-N- 1 -hy droxy-2-hy droxylmethy 1-3 -(4- methoxy-hexa-2,4-dienyl)-succinamide release from polymer coatings.

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 (PEGVwater 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 N-Hydroxy-2-[(4- methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3-methyl-butyramide, 2-[(4-Ethoxy- benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 -methylcarbamoyl-ρropyl)-N- 1 -hy droxy-2-hy droxylmethy 1-3 -(4- methoxy-hexa-2,4-dienyι)-succinamide concentrations. Such assays can show a stable N- Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3-methyl-butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy- cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 -methylcarbamoyl-propyl)-N- 1 -hydroxy-2- h droxylmethy 1-3 -(4-methoxy-hexa-2,4-dienyl)-succinamide release from coated stents for more than 45 days. By the term "stable N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin- 3 -y lmethyl-amino] -3 -methyl-butyramide, 2- [(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethy 1- amino]-N-hydroxy-2-(4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl-l - methylcarbamoyl-propyl)-N- 1 -hydroxy-2-hydroxylmethyl-3 -(4-mefhoxy-hexa-2,4-dienyl)- succinamide release" we mean less than 10% of variation of the drug release rate. Controlled release techniques used by the person skilled in the art allow an unexpected easy adaptation of the required N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3- methyl-butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2- (4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl-l -methylcarbamoyl-propyl)-N-l- hy droxy-2-hy droxylmethy 1-3 -(4-methoxy-hexa-2,4-dienyl)-succinarnide release rate. Thus, by selecting appropriate amounts of reactants in the coating mixture it is possible to easily control the bioeffectiveness of the N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3- y lmethyl-amino] -3 -methy 1-butyramide, 2- [(4-Ethoxy-benzenesulfonyl)-pyridin-4-y lmethyl- amino] -N-hydroxy-2-(4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 - methylcarbamoyl-propyl)-N-l-hydroxy-2-hydroxylmethyl-3-(4-methoxy-hexa-2,4-dienyl)- succinamide coated stents. Depending on the kind of coating technology used, the drug may be eluted from coating passively, actively or by light activation.

Release of N-Hy droxy-2- [(4-methoxy-benzenesulfony l)-pyridin-3 -y lmethyl-amino] -3 -methy 1- butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4- propoxy-cy clohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 -methy lcarbamoyl-propyl)-N- 1 - hydroxy-2-hydroxylmethyl-3-(4-methoxy-hexa-2,4-dienyl)-succinamide 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.), which is in lyophilized form and is 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. In a separate study, it was found that N-Hy droxy-2- [(4-methoxy- benzenesulfonyl)-pyridin-3-ylmethyl-amino] -3 -methy 1-butyramide, 2-[(4-Ethoxy- benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-proρoxy-cyclohexyl)-acetamide orN-4-(2,2-Dimethyl-l-methylcarbamoyl-propyl)-N-l-hydroxy-2-hydroxylmethyl-3-(4- rnethoxy-hexa-2,4-dienyl)-succinamide in human plasma was stable at 37° C. for 72 hours. PDGF-stimulated receptor tyrosine kinase assay is performed on the last piece of each sample to determine the N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3- methyl-butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2- (4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 -methylcarbamoyl-propyl)-N- 1 - hydroxy-2-hydroxylmethyl-3-(4-methoxy-hexa-2,4-dienyl)-succinamide activity. The inhibition of PDGF-stimulated receptor tyrosine kinase activity in vitro is 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). Such assays can show that the activity of N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3- ylmethyl-amino] -3 -methy 1-butyramide, 2- [(4-Ethoxy-benzenesulfony l)-pyridin-4-y lmethyl- amino] -N-hydroxy-2-(4-propoxy-cyclohexyl)-acetamide or N-4-(2,2-Dimethyl-l - methylcarbamoyl-propyl)-N- 1 -hydroxy-2-hy droxylmethy 1-3 -(4-methoxy-hexa-2,4-dienyl)- succinamide released from stent after 45 days is still 91% of that of the normal activity ofN- Hy droxy-2- [(4-methoxy-benzenesulfony l)-pyridin-3 -y lmethyl-amino] -3 -methy 1-butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy- cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 -methy lcarbamoyl-propy 1)-N- 1 -hydroxy-2- hydroxylmethyl-3-(4-methoxy-hexa-2,4-dienyl)-succinamide. In the same assay, freeN- Hydroxy-2-[(4-methoxy-benzenesulfonyl)-ρyridin-3-ylmethyl-amino]-3-methyl-butyr amide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy- cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 -methy lcarbamoyl-propy 1)-N- 1 -hydroxy-2- hydroxylmethyl-3-(4-methoxy-hexa-2,4-dienyl)-succinamide shows a strong decrease of its activity day after day. These assays can prove the unexpected high stability ofN-Hydroxy-2- [(4-methoxy-benzenesulfony l)-pyridin-3 -y lmethyl-amino] -3 -methy 1-butyramide, 2- [(4- Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy-cyclohexyl)- acetamide or N-4-(2,2 -Dimethyl- 1 -methylcarbamoyl-propyl)-N- 1 -hy droxy-2 -hy droxylmethy 1- 3-(4-methoxy-hexa-2,4-dienyl)-succinamide in polymer coatings.

A.4 Examples of synergic combinations. Further experiments similar to that of example Al revealed synergic combinations when N- Hydroxy-2-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-3-methyl-butyramide, 2-[(4-Ethoxy-benzenesulfonyl)-pyridin-4-ylmethyl-amino]-N-hydroxy-2-(4-propoxy- cyclohexyl)-acetamide or N-4-(2,2-Dimethyl- 1 -methy lcarbamoyl-propy 1)-N- 1 -hydroxy-2- hydroxylmethyl-3-(4-methoxy-hexa-2,4-dienyl)-succinamide is used in conjunction with several agents.

Data points just spanning the IC₅₀ of the agents alone or in combination are entered into the CalcuSyn program (CalcuSyn, Biosoft, Cambridge UK). This program calculates a nonexclusive combination index (CI), whose value is indicative of the interaction of the two compounds, where CI ~ 1 represents nearly additive effects; 0.85 - 0.9 indicates a slight synergism and a value below 0.85 indicates synergy.

A CI. of 0.3 + 0.03 was obtained for the combination of N-Hydroxy-2-[(4-methoxy- benzenesulfonyl)-pyridin-3 -y lmethyl-amino] -3 -methyl-butyramide, and Taxol^® and a CI. of 0.4 + 0.04 for the combination of N-Hy droxy-2- [(4-methoxy-benzenesulfonyl)-pyridin-3 - ylmethyl-amino] -3 -methyl-butyramide and doxorubicin. Slight synergism or synergy can be observed with Taxol, doxorubicin, Vinblastine and several other compounds as disclosed above.

The combinations especially show a synergistic therapeutic effect, e.g. with regard to slowing down, arresting or reversing arteriosclerosis, thrombosis, restenosis and/or inflammation diseases, but also in further surprising beneficial effects, e.g. allowing for less side-effects, an improved quality of life and a decreased mortality and morbidity, compared to a monotherapy applying only one of the pharmaceutically active ingredients used in the combination.

Claims

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 MMP inhibitor of formula I

wherein

Ar is carbocyclic or heterocyclic aryl;

R is hydrogen, lower alkyl, carbocyclic aryHower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly- halo-lower alkyl, C₃- C₇- cycloalkyl, C₃-C -cycloalkyl- lower alkyl, (oxa or thia)-C₃-C₆- cycloalkyl, [(oxa or thia)- C₃-C₆- cycloalkyl]-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl; Rx is hydrogen, lower alkyl, carbocyclic arytlower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃- Cio- cycloalkyl, C₃-C -cycloalkyl- lower alkyl, (lower alkyl, cycloalkyl, carbocyclic-lower alkyl, lower alkoxy-lower alkyl or halogen-lower alkyl and (4-OH or lower-alkoxy))- cyclohexyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, (carbocyclic or heterocyclic aryl)-lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, (N-lower alkyl-piperazino or N- carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl>lower alkyl, - acylamino-lower alkyl, piperidyl or N-lower alkylpiperidyl, (N-acyl-piperidyl)-lower alkyl, (morpholino, thiomo holino, piperidino, pyrrolidino, piperidyl, N-acyl or N-lower alkylpiperidyl)- (hydroxy or lower alkoxy lower alkyl, pyrrolidinyl, hexahydroazepinyl, N- lower alkyl-(hexahydroazepinyl or pyrrolidinyl), N-acyl- (hexahydroazepinyl, piperidyl or pyrrolidinyl), C₅- C₁₀-oxacycloalkyl, C₅-C₁₀-thiacycloalkyl, (hydroxy or oxo>C₅ -Cio- cycloalkyl, (hydroxy or oxo>C ₅-C₁₀-thiacycloalkyl, (hydroxy or oxo>C₅-C₁₀~oxacycloalkyl, (amino, mono- or di-lower alkylamino or acylamino)-C₅-Cio-cycloalkyl, 2-oxo-(pyrrolidinyl, piperidyl or hexahydroazepinyl), (carbocyclic or heterocyclic aryl (thio, sulfinyl or sulfonyl)- lower alkyl; R₂ is hydrogen or lower alkyl;

(c) or wherein Ri and R₂ together with the carbon atom to which they are attached form a ring system selected from C₃-C₇-cycloalkane which is unsubstituted or substituted by lower alkyl; oxa-cyclohexane, thia-cyclohexane, indane, tetralin, piperidine or piperidine substituted on nitrogen by acyl, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, (carboxy, esterified or amidated carboxy)-lower alkyl or by lower alkylsulfonyl; and Ar and R have meaning as defined under (a); wherein the term "carbocyclic aryl" means phenyl; phenyl that is mono-, di- or tri-substituted by one, two or three radicals selected from lower alkyl, lower alkoxy, hydroxy, halogen, cyano, trifluoromethyl, lower alkylenedioxy and oxy-C₂-C₃- alkylene; or 1- or 2-naphthyl; wherein the term "heterocyclic aryl" means pyridyl, quinolinyl, isaquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted by lower alkyl or halogen;

or a pharmaceutically acceptable salt thereof, optionally in conjunction with one or more other active ingredients.

2. 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 MMP inhibitor of formula VI

wherein

RI is a substituent of Formula Q: A-(O-(CR₅H)n)m-O-CH2 Formula Q wherein n is 1, 2, 3 or 4, preferably 2; m is O, 1, 2 or3; each R5 is independently H, Cl-10 (optionally hydroxy-, Cl-6 alkoxy-, amino-, Cl-6 alkylamino-, thiol-, Cl-6 alkylmercapto- or protected hydroxy, amino or thiol substituted) alkyl, C2-6 alkenyl, C6-14(optionally hydroxy-, Cl-6 alkoxy-, amino-, Cl-6 alkylamino-, halo- or cyano- substituted) aryl, or C6-14 (aryl) Cl-6alkyl; preferably H, phenyl, benzyl or Cl-5 alkyl;

A is hydrogen, Cl-10 alkyl, C6-14 aryl, C6-14 aryl(Cl-6 alkyl), (C6-14 aryl)carbonyl, or (Cl- 10 alkyl)carbonyl; preferably hydrogen, Cl-6 alkyl (e.g., methyl or cyclohexyl), phenyl α benzyl; R2 is C2-12 alkyl, C3-12 alkenyl, C3-7(optionally hydroxy-, Cl-6 alkoxy-, amino-, or Cl-6 alkylamino- substituted) cycloalkyl, C5-14 aryl, or C5-14 aryl(Cl-6 alkyl), wherein aryl groups are optionally substituted by hydroxy-, Cl-6 alkyl-, Cl-6 alkoxy-, amino-, halo or cyano-; preferably phenyl, 4-methylphenyl, 4-methoxyphenyl, cyclohexyl or isobutyl; R3 is Cl-10 (optionally hydroxy- or Cl-6 alkoxy- amino-, Cl-6 alkylamino-, thiol-, Cl-6 alkylmercapto- or protected hydroxy-, amino- or thiol- substituted) alkyl (e.g., t-butyl, or cyclohexylmethyl), C6-14 (optionally hydroxy-, C6-14aryloxy-, or Cl-6 alkoxy-, amino-, Cl-6 alkylamino-, halo-, or cyano- substituted) aryl (e.g., benzyl, p-methoxybenzyl, p benzyloxybenzyl), or indolylmethyl (e.g., 2-indolylmethyl); preferably benzyl or t butyl;

R4 is methyl, pyridyl, or a substituent of formula X-Y- wherein X is morpholino, pyridyl or aryl (preferably morpholino), and Y is Cl-12alkylene in which up to four of the methylene (-CH2-) units are optionally replaced with -CO-, -NH-, -SO2- or -O-; for example methyl, 2-pyridyl, morphol inocarbonyl methyl, 5-(morpholino)pentyl, or 5 (morpholinocarbonyl)pentyl

3. 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 MMP inhibitor of formula VII

wherein

R represents hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, alamantyl, aryl, biaryl, or mono- or di-(cycloalkyl, aryl or biaryiyiower alkyl, di-(lower alkyl or aryl-lower alkyl)-amino-lower alkyl, or (piperidino, morpholino, pyrrolidino)-lower alkyl; R, represents hydrogen, lower alkyl, cycloalkyl, aryl, biaryl, or(cycloalkyl, aryl or biaryl) - lower alkyl; R2 represents hydrogen, lower alkyl, lower alkoxy, aryHower alkyl, aryl-lower alkoxy, amino, mono- or di-(lower alkyl or aryl-lower alkyl)-amino, acylamino, or

(lower alkyl or aryl-lower alkyl)-(thio, sulfinyl or sulfonyl);

R3 represents hydrogen, lower alkyl, cycloalkyl, aryHower alkyl, cycloalkyl-lower alkyl, or C2-C7-alkyl interrupted by S, SO, SO2, O or N-R5;

R4 represents hydrogen or acyl;

A together with the carbon to which it is attached forms a ring and represents a bivalent radical of the formula (CH2)ρ which may be interrupted by S, SO, SO2,

O, or -R5; n represents an integer from zero to four; p represents an integer from 2 to 6; any pharmaceutically acceptable salts thereof; and disulfides corresponding to said compounds of formula VII wherein R4 is hydrogen, or a pharmaceutically acceptable salt thereof, may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti-inflammatory agent, a NSAID, or an antiproliferative agent, a telomerase inhibitior, a tyrosine kinase inhibitor, an osteoclast activity inhibitor.

4. A method for the stabilisation of vulnerable atherosclerotic plaques in a mammal in need thereof, comprising local administration of a therapeutically effective amount of a MMP inhibitor of formula I, VI or VII or a pharmaceutically acceptable salt thereof, optionally in conjunction with one or more other active ingredients.

5. A method for the treatment of intimal thickening in vessel walls or stabilisation of vulnerable atherosclerotic plaques comprising the controlled delivery from any catheter-based device, intraluminal medical device or device applied to the external/ adventitial aspect of the vessel of a therapeutically effective amount of a MMP inhibitor of formula I, VI or VII, or a pharmaceutically acceptable salt thereof, optionally in conjunction with one or more other active ingredients.

6. A method according to any one of claims 1-5 wherein a MMP inhibitor of formula I, VI or VII or a pharmaceutically acceptable salt thereof is administered or delivered in conjunction with one or more other active ingredients selected from a calcineurin inhibitor, an EDG-Receptor agonist, an anti-inflammatory agent, a mTOR inhibitor agent, an antiproliferative agent, a microtubule stabilizing or destabilizing agent, a tyrosine kinase inhibitor, a compound which inhibits osteoclast activity, a compound which inhibits the PDGF receptor tyrosine kinase or a compound or antibody or antibody which binds to PDGF or reduces expression of the PDGF receptor, 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, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound or antibody which binds to VEGF, a modulator of kinases.

7. A drug delivery device or system comprising a) a medical device adapted for local application or administration in hollow tubes, and b) a therapeutic dosage of a MMP inhibitor of formula I, VI or VII or a pharmaceutically acceptable salt thereof being releasably affixed to the medical device.

8. A device according to claim 7 comprising b) a therapeutic dosage of a MMP inhibitor of formula I, VI or VII or a pharmaceutically acceptable salt thereof in conjunction with a therapeutic dosage of one or more other active ingredients, each being releasably affixed to the medical device and the other active ingredient being selected from a calcineurin inhibitor, an EDG-Receptor agonist, an anti-inflammatory agent, a mTOR inhibitor agent, an antiproliferative agent, a microtubule stabilizing or destabilizing agent, a tyrosine kinase inhibitor, a compound which inhibits osteoclast activity, 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, 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, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, an inhibitor of a modulator of kinases.

9. A device according to claim 7 comprising b) a therapeutic dosage of a MMP inhibitor of formula I, VI or VII or a pharmaceutically acceptable salt thereof in conjunction with a therapeutic dosage of one or more other active ingredients, each being releasably affixed to the medical device and the other active ingredient being selected from a calcineurin inhibitor, a mTOR inhibitor agent, an EDG-Receptor agonist, an anti-inflammatory agent, a microtubule stabilizing or destabilizing agent, a compound which inhibits osteoclast activity, 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, 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, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, an inhibitor of a modulator of kinases.

10. A method according to claim 1 , 2 or 3 wherein the administration or delivery is intravascular, intranasal, intrabronchial, interperitoneal or eosophagal.

11. 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 MMP inhibitor of formula I, VI or VII or a pharmaceutically acceptable salt thereof in conjunction with a therapeutic dosage of one or more other active ingredients, each being releasably affixed to the medical device and the other active ingredient being selected from a calcineurin inhibitor, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti-inflammatory agent, a microtubule stabilizing or destabilizing agent, a compound which inhibits osteoclast activity, 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, 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, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, an inhibitor of a modulator of kinases.

12. 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 MMP inhibitor of formula I, VI or VII or a pharmaceutically acceptable salt thereof in conjunction with a therapeutic dosage of one or more other active ingredients, each being releasably affixed to the medical device and the other active ingredient being selected from a calcineurin inhibitor, an EDG-Receptor agonist, a mTOR inhibitor agent, an anti-inflammatory agent, a microtubule stabilizing or destabilizing agent, a compound which inhibits osteoclast activity, 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, 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, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, an inhibitor or a modulator of kinases.

13. A method according to any one of claims 1-5 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.

14. A method according to any one of claims 1-3 wherein the MMP inhibitor of formula I, VI, VII or a pharmaceutically acceptable salt thereof is administered from a stent or from a coating applied to a stent.

15. A method according to claim 4 or 5 wherein a MMP inliibitor of formula I, VI or VII or a pharmaceutically acceptable salt thereof is delivered from a stent or from a coating applied to a stent.

16. A method according to claim 1, 2, 3 or 11 for the treatment of atherosclerosis, stenosis, restenosis or inflammation or stabilisation of vulnerable plaque.

17. A method according to claim 4, 5 or 12 for the treatment of atherosclerosis, stenosis, restenosis or inflammation or stabilisation of vulnerable plaque.

18. A device according to claim 7 which is a catheter delivery system, a local injection device, an indwelling device, a stent, a stent-graft or a sleeve.

19. A device according to claim 7 which is a coated stent.

20. A device according to claim 8 or 9 which is a catheter delivery system, a local injection device, an indwelling device, a stent, a stent-graft or a sleeve.

21. A device according to claim 8 or 9 which is a coated stent.