WO2005061448A1 - Compositions et methodes de traitement d'affections vasculaires - Google Patents

Compositions et methodes de traitement d'affections vasculaires Download PDF

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WO2005061448A1
WO2005061448A1 PCT/AU2004/001829 AU2004001829W WO2005061448A1 WO 2005061448 A1 WO2005061448 A1 WO 2005061448A1 AU 2004001829 W AU2004001829 W AU 2004001829W WO 2005061448 A1 WO2005061448 A1 WO 2005061448A1
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alkyl
substituted
aryl
group
aneurysm
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PCT/AU2004/001829
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Anthony E Dear
Robert Widdop
Tracey Gaspari
Antony Vinh
David Martin
Lovisha F. Dousha
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Monash University
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Publication of WO2005061448A1 publication Critical patent/WO2005061448A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/61—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/12—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to other hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to the field of vascular disease. More specifically the present invention relates to the treatment and prevention of aneurysm and neointimal hyperplasia using novel and known compounds.
  • An aneurysm is an abnormal dilation of a blood vessel that poses a risk to health from the potential for rupture, clotting, or dissecting. Rupture of an aneurysm in the brain causes stroke, and rupture of an aneurysm in the abdomen causes shock.
  • the abdominal aortic aneurysm (AAA) is the most common type of aneurysm.
  • AAA's cause many deaths as they are usually silent until a medical emergency occurs. If the patient is thin and has a moderately large AAA, it may be palpable below the rib cage. Many aneurysms are incidentally discovered as a result of medical imaging for other conditions, by ultrasound exams, CAT scans, MRI's, or even by X-ray of the abdomen. Few patients survive the rupture of an aneurysm. The best predictor of risk of rupture is the size of the aneurysm. The diameter of a normal aorta is about 2 centimeters. Once a AAA has reached 5-6 centimeters in diameter, the risk of rupture is substantial, probably about 50/50 over the next few years.
  • TAA thoracic aortic aneurysm
  • a TAA is a localized expansion of the wall of the aorta within the chest cavity, and is often caused by atherosclerosis, hypertension, congenital disorders such as Marfan's syndrome, trauma, or less commonly, syphilis. Atherosclerosis is by far the most common cause.
  • TAA patients have no symptoms until the aneurysm begins to leak or expand.
  • Most non-leaking thoracic aortic aneurysms are detected by chest X- ray or a chest CT scan conducted for other reasons. Chest or back pain may indicate acute expansion or leakage of the aneurysm.
  • a chest CT scan identifies the diameter of the aorta and the exact location of the aneurysm.
  • An aortogram (a special set of X-ray images made during injection of dye into the aorta) may also identify the location and extent of the aneurysm and identify any branch arteries of the aorta that are also involved.
  • TAA The treatment of TAA depends on the location of the aneurysm.
  • surgery to replace the aorta is recommended if the diameter of the aorta measures greater than 5-6 cm.
  • the aorta is replaced with a fabric substitute in an operation that uses a heart-lung machine.
  • a specialized technique called "circulatory arrest" (a period without blood circulation while on life support) may be necessary. Of course, this is a procedure with inherent risk.
  • aorta For patients with aneurysms of the descending thoracic aorta, two options are available. For patients with aneurysms that are larger than 6 cm, an operation for replacement of the aorta with a fabric substitute can be done, or the aorta can be stented.
  • Stenting involves the use of a tube placed inside the vessel and can be performed without a chest incision, with specialized catheters that are introduced through arteries at the groin. Not all patients with descending thoracic aneurysms are candidates for stenting, however.
  • the long-term prognosis for patients with TAA is determined by other medical problems such as heart disease and diabetes, which may have caused or contributed to the condition.
  • Serious complications after aortic surgery can include heart attack, irregular pulse, bleeding, stroke, paralysis, graft infection, and kidney damage. Death early after the operation may occur in 5-10% of patients.
  • Aneurysms can also occur in the brain.
  • An intracerebral aneurysm is a small, thin walled dilatation of one of the large blood vessels that supply the brain. These aneurysms pose a risk to health from the potential for rupture and subsequent bleeding into the brain and/or the fluid-filled spaces that surround the brain (the subarachnoid space). These so-called saccular or "berry” aneurysms occur at the bifurcation of the large blood vessels at the base of the brain.
  • Intracerebral aneurysms can result from trauma, infection, or neoplastic disease. Most aneurysms, however, result from a developmental abnormality of the inside lining or intima of an artery with abnormal thinning of the vessel at the site of origin. It appears there may be a genetic predisposition to the development of intracerebral aneurysms; the existence in some families runs as high as 10%, approximately 10 times higher than that found in the general population. There are several other causes of intracerebral aneurys, such as infected embolic material from a bacterial infection on one of the heart valves being deposited on one of the arteries in the brain (mycotic aneurym).
  • Cerebral aneurysmal rupture leads to subarachnoid. hemorrhage (SAH) and occurs most often in patients between 40 and 60 years of age with approximately equal sex distribution. Cigarette smoking and excess alcohol use have been shown to increase the risk of rupture. Likewise, the existence of intracerebral aneurysms is associated with other diseases such as polycystic kidney disease, coarctation of the aorta, and fibromuscular hyperplasia. Other factors such as high blood pressure seem to be less important since aneurysms often occur in persons with normal blood pressure.
  • cerebral aneurysms are usually asymptomatic prior to rupture.
  • an expanding aneurysm can have a "mass" effect causing problems with double vision, loss of vision, numbness in the face, an enlarged pupil size, or a drooping eyelid.
  • patients who have an aneurysm rupture experience sudden onset of a severe headache, frequently accompanied by transient loss of consciousness and sometimes vomiting.
  • a stiff neck often follows.
  • Rupture of an aneurysm usually occur while the person is active rather than during sleep.
  • patients experience a warning or "sentinel” headache which is attributed to a smaller leakage of blood usually preceding a major bleed by several hours to days later.
  • These milder headaches are often associated with nausea and vomiting and are often mistaken for migraine headaches.
  • Carotid and vertebral angiography is the only definitive means of demonstrating an intracerebral aneurysm, while a CT scan of the head will confirm the presence of blood within the brain or subarachnoid space if an aneurysm has ruptured. Lumbar puncture is sometimes used to evaluate for the presence of blood in the cerebrospinal fluid if the results of the CT scan are equivocal. More recently, non-invasive studies using magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) have shown promise in detection of aneurysms. However, the intracerebral angiogram remains the test of choice.
  • MRI magnetic resonance imaging
  • MRA magnetic resonance angiography
  • a guide to prognosis is provided by the neurologic grade (Hunt and Hess Grades l-V) of the patient determined by his/her level of consciousness and neurologic deficits when first examined upon arrival to the hospital.
  • Cerebral vasospasm after aneurysmal subarachnoid hemorrhage usually occur within the first 14 days of rupture and is a major cause of morbidity and mortality in survivors of the bleed. Its incidence has varied in different studies between approximately 20 to 80% of all patients with SAH and its occurrence is related to the amount of subarachnoid blood in the brain. Other complications including re-bleeding from an aneurysm and hydrocephalus also contribute to the overall morbidity and mortality. In addition, dangerous cardiac arrhythmias may develop in the acute period following a bleed.
  • Neointimal hyperplasia is the pathological process that underlies graft atherosclerosis, stenosis, and the majority of vascular graft occlusion. It is a condition that is commonly seen after various forms of vascular injury and a major component of a vein graft's response to harvest and surgical implantation into high-pressure arterial circulation. Smooth muscle cells in the middle layer (i.e. media layer) of the vessel wall become activated, divide, proliferate and migrate into the inner layer (i.e. intima layer).
  • the resulting abnormal neointimal cells express pro- inflammatory molecules, including cytokines, chemokines and adhesion molecules that further trigger a cascade of events that lead to occlusive neointimal disease and eventually graft failure.
  • pro-inflammatory molecules including cytokines, chemokines and adhesion molecules that further trigger a cascade of events that lead to occlusive neointimal disease and eventually graft failure.
  • Taxol, rapamycin, and radiation have achieved some success in preliminary trials in suppressing intimal hyperplasia, in part because the drugs and radiation are particularly effective when they are delivered or released into the injured artery. This form of delivery targets the vascular bed at risk and prevents systemic toxicity.
  • none of the aforementioned compounds is specific for the vascular smooth muscle cell, the cell responsible for the intimal lesion, and it is possible that failure of endothelial regeneration may leave the reconstructed vessel vulnerable to late thrombosis as has been shown in irradiated and stented coronary arteries.
  • the inventors have alleviated a problem of the prior art by providing novel compounds useful in the treatment or prevention of aneurysm and neointimal hyperplasia. Also provided for is the use of certain known compounds that have been found to have efficacy in the treatment or prevention of aneurysm and neointimal hyperplasia.
  • Fig. 1 shows the results of an in vitro smooth muscle cell migration assay.
  • Cells were treated with varying concentrations of MCT-1 , oxamflatin, or vehicle.
  • Fig. 2A shows an example of Northern Blot analysis performed on WSR rat VSMC following treatment with Oxamflatin and/or Metacept-1 for 16 hours. mRNA loading was examined under UV illumination.
  • Fig. 3A shows a membrane probed with a monoclonal antibody to MMP-2 to detect presence of the protein.
  • the lower panel shows the same western blot following staining with coomassie blue dye to demonstrate that loading of conditioned media was balanced.
  • Fig. 4A shows a membrane probed with a monoclonal antibody to MMP-2.
  • the lower panel shows the same western blot following staining with coomassie blue dye to demonstrate that loading of conditioned media was even.
  • Fig. 5A shows a membrane probed with a monoclonal antibody to MMP-2.
  • the lower panel shows the same western blot following staining with coomassie blue dye to demonstrate that loading of conditioned media was even.
  • Fig. 6A shows a representative Gelatin zymography - white bands indicate proteolysis of gelatin present in SDS-PAGE gel.
  • Fig. 7A shows a gelatin Zymogram - white bands indicate sites of proteolytic activity on a gelatin SDS-PAGE gel.
  • Fig. 8A is a gelatin zymogram showing white bands of proteolytic cleavage on a gelatin SDS-PAGE gel.
  • Fig. 10 shows the incidence of aneurysm in a mouse model after treatment with oxamflatin or MCT-1.
  • Fig 11 shows the effects of oxamflatin and MCT-1 on incidence of AAA in a murine model.
  • Panel A shows percentage incidence taking into account deceased animals, while Panel B excludes deceased animals. Bars correspond to the legend on the right of the histogram (ie, from left to right in Panel A, the first bar is placebo, the second bar is vehicle, the third bar is oxamflatin 1 ⁇ M etc). Doxycycline is a positive control.
  • Fig. 12 shows the effect of MCT-1 on neointimal development in a murine model by reference to vessel wall thickness as measured by diameter in ⁇ m (Panel A) and % of luminal diameter (Panel B). Placebo animals were not treated with Ang II. Doxycycline is a positive control.
  • Fig 13 shows neointimal development in a murine model. Transverse sections of the ascending aorta of 12-week old mice treated for 2 weeks were stained with haematoxylin and eosin under 40x magnification. Scale bar represents 20 ⁇ m.
  • Vehicle treated wild type (2) Vehicle treated ApoE "7" .
  • the histogram represents intimal and medial growth in a proximal section of ascending aorta in 12-week old wild type mice and 12-week old ApoE "7" mice treated for 2 weeks with vehicle.
  • Fig 14 shows neointimal development in a murine model. Transverse sections of the ascending aorta of 30-week old mice treated for 2 weeks were stained with haematoxylin and eosin under 40x magnification. Scale bar represents 20 ⁇ m.
  • Vehicle treated wild type (2) Vehicle treated ApoE "7" . The histogram represents intimal and medial growth in a proximal section of ascending aorta in 30-week old wild type mice and 30-week old ApoE "7" mice treated for 2 weeks with vehicle.
  • Fig 15 shows neointimal development in a murine model.
  • Transverse sections of carotid arteries from 12-week old ApoE "7" mice treated for 2 weeks were stained with haematoxylin and eosin under 20x magnification. Scale bar represents 20 ⁇ m.
  • the histogram represents wall growth in a section of common carotid artery in 12-week old ApoE "7” mice subjected to cuff placement or not (contralateral) treated for 2 weeks with Ang II (1000ng/kg/min).
  • the present invention provides compounds of the formula o II R-l— S- N- L-A li I O R 2
  • Ri is selected from the group consisting of H, CrC ⁇ 2 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C12 alkenyl, C3-C-12 cycloalkyl, substituted C3 - C12 cycloalkyl, C2-C12 althyryl, substituted C2-C12 althyryl, bicycloalkyl, substituted bicycloalkyl, tricycloalkyl, substituted tricycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl cycloalkyl, substituted alkyl cycloalkyl, cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, alkyl aryl, substituted alkyl aryl, substituted alkyl aryl, aryl alkyl, substituted alkyl heteroaryl, substituted al
  • R2 is selected from the group consisting of H, Ci-C-i 2 alkyl, substituted C1-C12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C ⁇ 2 alkenyl, C 3 -C-12 cycloalkyl, substituted C3 - C12 cycloalkyl, C2-C12 althyryl, substituted C2-C12 althyryl, bicycloalkyl, substituted bicycloalkyl, tricycloalkyl, substituted tricycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl cycloalkyl, substituted alkyl cycloalkyl, cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, alkyl aryl, substituted alkyl aryl,
  • L is a linking group
  • A is selected from the group consisting of
  • R3 is selected from the group consisting of H, C1-C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C2-C12 alkenyl, C 3 -C12 cycloalkyl, substituted C3 - C12 cycloalkyl, C2-C12 althyryl, substituted C2-C12 althyryl, bicycloalkyl, substituted bicycloalkyl, tricycloalkyl, substituted tricycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl cycloalkyl, substituted alkyl cycloalkyl, cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, alkyl aryl, substituted alkyl aryl, substituted alkyl aryl, aryl alkyl
  • the linking group is such that there are from 4-12 bonds in the shortest direct chain through the linker joining the nitrogen moiety of the sulfonamide with the group A.
  • Suitable linking groups are selected from the group consisting of: (1)
  • each R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • n is an integer from 0 to 3
  • each R 5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • n is an integer from 0 to 3
  • each R 6 is independently selected from the growth consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio , alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • O is an integer from 0 to 4.
  • R 7 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxcy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • X is O or S
  • Each Rs is independently selected from the group consisting of
  • Rg is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • Rio is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • Z is O or CH 2 (4)
  • Ru each Ru is independently selected from the group consisting of q is an integer from 0 to 4
  • R12 is independently selected fro the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • R is an integer from 0 to 4.
  • Each R 13 is independently selected from the graph consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • S is an integer from 0 to 4.
  • Ru is selected from the graph consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • linker is of the formula selected from the following:
  • the compound has the following structural formula
  • Metacept-1 The above compound is referred to herein as Metacept-1 or MCT-1.
  • the present invention provides pharmaceutical compositions including the compounds of the present invention.
  • the present invention provides the use of a compound described herein in the preparation of a medicament for the treatment or prevention of aneurysm or neointimal hyperplasia.
  • the present invention provides a method for treating or preventing aneurysm or neointimal hyperplasia comprising administering to a subject in need thereof a therapeutic amount of a compound or composition as described herein.
  • the present invention provides compounds of the formula
  • Ri is selected from the group consisting of H, C1-C 12 alkyl, substituted C1-C12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, substituted C3 - C12 cycloalkyl, C2-C12 althyryl, substituted C2-C12 althyryl, bicycloalkyl, substituted bicycloalkyl, tricycloalkyl, substituted tricycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl cycloalkyl, substituted alkyl cycloalkyl, cycloalkyl alkyl, substituted cycloalkyl alkyl, alkyl aryl, substituted alkyl aryl, substituted alkyl aryl, aryl alkyl, substituted alkyl heteroaryl, substituted alkyl heteroaryl, heteroaryl alky
  • R2 is selected from the group consisting of H, C- 1 -C 1 2 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C2-C 1 2 alkenyl, C 3 -C12 cycloalkyl, substituted C3 - C12 cycloalkyl, C2-C12 althyryl, substituted C2-C12 althyryl, bicycloalkyl, substituted bicycloalkyl, tricycloalkyl, substituted tricycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl cycloalkyl, substituted alkyl cycloalkyl, cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, alkyl aryl, substituted alkyl aryl, substituted alkyl aryl, substituted
  • L is a linking group
  • A is selected from the group consisting of
  • R3 is selected from the group consisting of H, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C2-C12 alkenyl, C 3 -C12 cycloalkyl , substituted C3 - C12 cycloalkyl, C2-C12 althyryl, substituted C2-C12 althyryl, bicycloalkyl, substituted bicycloalkyl, tricycloalkyl, substituted tricycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl cycloalkyl, substituted alkyl cycloalkyl, cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, substituted cycloalkyl alkyl, alkyl aryl, substituted alkyl aryl, substituted alkyl aryl, substituted alky
  • the linking group is such that there are from 4-12 bonds in the shortest direct chain through the linker joining the nitrogen moiety of the sulfonamide with the group A.
  • Suitable linking groups are selected from the group consisting of: (1)
  • each R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • n is an integer from 0 to 3
  • each R 5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro ' , acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • n is an integer from 0 to 3
  • each R 6 is independently selected from the growth consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • O is an integer from 0 to 4.
  • R 7 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • X is O or S
  • Each R 8 is independently selected from the group consisting of
  • Rg is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • Rio is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • Z is O or CH 2
  • R 11 each Ru is independently selected from the group consisting of q is an integer from 0 to 4
  • R12 is independently selected fro the group consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • R is an integer from 0 to 4
  • Each R ⁇ 3 is independently selected from the graph consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • S is an integer from 0 to 4.
  • R ⁇ is selected from the graph consisting of alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.
  • linker is of the formula selected from the following:
  • the compound has the structure selected from the group consisting of
  • Applicants have shown that compounds as described herein (and especially compound K as shown above (referred to herein as metacept-1 or MCT-1) have efficacy in the treatment and/or prevention of aneurysm or neointimal hyperplasia. Also included in the present invention are derivatives of the compounds detailed above. The skilled person will understand that various modifications may be made to the structures of the compounds defined herein without materially affecting their biological activities.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary ammonium compounds
  • wetting agents such as sodium citrate or dicalcium phosphate
  • fillers or extenders as for example
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3 -butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, so
  • composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • salts refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like See, for example, Berge S. M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
  • the present invention provides a method for treating or preventing aneurysm or neointimal hyperplasia comprising administering to a subject in need thereof a therapeutic amount of a compound or composition as described above.
  • the present invention further provides a method for treating or preventing aneurysm or neointimal hyperplasia comprising administering to a subject in need thereof of a therapeutic amount of amiloride or oxamflatin or a derivative thereof.
  • Amiloride hydrochloride is sold under a number of trade names including Kaluril (Alphapharm Pty Ltd; Australia) and Midamore (Merck Sharp and Dohme Pty Ltd).
  • compositions containing amiloride have been known in the art for many years, although have only been approved for clinical use in diuresis.
  • the drug has a known potassium conserving role leading to weak natriuretic, diuretic and antihypertensive activities.
  • the main indication for use is to conserve potassium in patients receiving strong diuretics in whom excessive potassium loss is expected.
  • amiloride and compounds described herein are proposed to have activity in the treatment and prevention of aneurysm or neointimal hyperplasia.
  • the present invention also includes the use of other known derivatives of amiloride such as phenamil, benzamil, dichlorobenzamil, ethylisopropyl amiloride, and 5-(N,N-dimethyl) amiloride for the treatment of aneurysm or neointimal hyperplasia.
  • amiloride such as phenamil, benzamil, dichlorobenzamil, ethylisopropyl amiloride, and 5-(N,N-dimethyl) amiloride for the treatment of aneurysm or neointimal hyperplasia.
  • oxamflatin and other derivatives have activity in the treatment and prevention of aneurysm or neointimal hyperplasia.
  • Oxamflatin ((2E)-5-[3-(phenylsulfonylamino)phenyl]pent-2-ene-4-ynohydroxamic acid), has the following formula:
  • This compound has been found in US 5534654 to possess activity against the growth of vascular endothelial cells and the expression of lymphocyte adhesive factors, detransforming activity of cells transformed by ras gene, inhibition of cell growth and have effect on inflammation and on tumors. It has previously been shown to reduce primary tumour growth but has not been indicated to have any benefit in the inhibition of metastatic disease spread. Cell growth inhibition as demonstrated by this compound is quite different to cellular spread that requires an element of mobility not present in cell growth. However, the Applicants have been the first to propose a new use for this compound and its known derivatives for the treatment of aneurysm or neointimal hyperplasia.
  • treatment does not necessarily imply that a subject is treated until total recovery. Similarly, “prevention” does not necessarily mean that the subject will not eventually contract a disease condition. Accordingly, treatment and prevention include amelioration of the symptoms of a particular condition or preventing or otherwise reducing the risk of developing a particular condition.
  • prevention may be considered as reducing the severity of onset of a particular condition. “Treatment' may also reduce the severity of an existing condition or simply inhibit the further progression of the condition.
  • the term "therapeutic amount” means an amount necessary to at least partly attain the desired response.
  • the term "subject” is intended to include humans, primates, livestock animals ' (eg horses, cattle, sheep, pigs and donkeys), laboratory test animals (eg mice, rats, rabbits, guinea pigs), companion animals (eg dogs, cats) captive wild animals (eg kangaroos, deer, foxes), poultry birds (eg chickens, ducks, bantams, pheasants) reptiles and fish.
  • the subject is a human or a laboratory test animal. In a highly preferred form the subject is a human.
  • the present invention is relevant to the treatment of a broad range of aneurysms.
  • the aneurysm is selected from the group consisting of abdominal aortic aneurysm, thoracic aortic aneurysm and cerebral aneurysm. More preferably, the aneurysm is abdominal aortic aneurysm.
  • the compound is administered at a rate of 0.5 to 30 mg per day for a human subject. Extrapolation of the dosages used for the in vivo studies described herein translates to around 0.5mg to 2.0mg per day for the average human.
  • the compound of the pharmaceutical composition is contemplated to exhibit therapeutic activity when administered in an amount which depends on the particular case. The variation depends, for example, on the human or animal and the compound chosen. A broad range of doses may be applicable. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, weekly, monthly or other suitable time intervals or the dose may be proportionally reduced as indicated by the exigencies of the situation.
  • the aneurysm is selected from the group including abdominal aortic aneurysm, thoracic aortic aneurysm and cerebral aneurysm. More preferably, the aneurysm is abdominal aortic aneurysm.
  • the compounds and compositions described herein may be administered by any suitable route including either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray. In a preferred form of the invention the compound is administered orally or intravenously.
  • the compound is administered at a rate of 5 to 30 mg per day. Even more preferably the compound is administered at a rate of 20 mg per day.
  • the present invention provides the use of a compound described herein in the preparation of a medicament for the treatment or prevention of aneurysm or neointimal hyperplasia.
  • the aneurysm is selected from the group including abdominal aortic aneurysm, thoracic aortic aneurysm and cerebral aneurysm. More preferably, the aneurysm is abdominal aortic aneurysm.
  • the medicament is formulated for administration orally or intravenously. More preferably the medicament is formulated to allow administration at a rate of 0.5 to 30 mg per day.
  • a subject may be treated with a combination of any of the compounds described herein, or with any other compound.
  • the invention further provides the use of a compound described herein in the preparation of a medicament for the treatment or prevention of neointimal hyperplasia.
  • the present invention provides a method of modulating the migration of a vascular smooth muscle cell, said method comprising exposing the cell to an effective amount of a compound or composition as described herein.
  • Yet a further aspect provides a method of modulating the expression of a matrix metalloproteinase in a vascular smooth muscle cell, said method comprising exposing the cell to an effective amount of a compound or composition as described herein.
  • the matrix metalloproteinase is matrix metalloproteinase 2 or matrix metalloproteinase 9.
  • a further aspect of the present invention provides a method of inhibiting proteolytic activity in a vascular smooth muscle cell, said method comprising exposing the cell to an effective amount of a compound or a composition described herein.
  • the present invention provides a method of remodelling the wall of a blood vessel, said method comprising exposing the blood vessel wall to an effective amount of a compound or a composition as described herein.
  • Rat smooth muscle cells were placed into 3D-culture (collagen, +/- 10nM FGF- 9) and place into migration chambers containing a fibronectin coated membrane.
  • the lower chamber contained PDGF-BB as the chemotactic agent. Migration was then allowed to occur over the next 24 hours. Then SMCs and collagen were removed from the top chamber and SMCs that had migrated completely through the membrane were stained with crystal violet and counted. Ten microscope fields were counted for each agent/concentration and then averaged (mean +/- SEM). Raw data has been graphed and presented in Fig 1. Overall, it can be seen that MCT-1 inhibits the migration of SMCs from a collagen/growth factor-rich matrix towards a chemotactic factor.
  • Human vascular smooth muscle cells, Wistar rat aortic vascular smooth muscle cells, and human HT-1080 fibrosarcoma cells were cultured in 90x14mm Nunclon tissue culture dishes containing 5ml of Dulbecco's Modified Eagles Medium (DMEM) supplemented with 10% (w/v) heat inactivated foetal calf serum, 50units/ml penicillin with 50 ⁇ g/ml streptomycin and 2mM glutamine. Cell cultures were grown in a 37°C incubator with 5% (w/v) C0 2 with 95% (w/v) air mixture.
  • DMEM Dulbecco's Modified Eagles Medium
  • the medium in each dish was aspirated, the cells washed with PBS, and trypsinised at 37°C, then a haemocytmeter was used to assess cell numbers. 1x 10 6 cells were seeded onto 60x15mm Nunclon tissue culture dishes containing 3ml DMEM containing serum and incubated at 37°C for approximately 48 hours until confluent.
  • a confluent 90x14mm dish of cells had the media aspirated and washed with 3ml PBS, and incubated with 3ml of warmed trypsin at 37°C for approximately 5 minutes.
  • Cells were collected, placed in 50ml falcon tube with 10ml of fresh DMEM and centrifuged at 2000rpm for five minutes.
  • the media was aspirated from the cell pellet, which was resuspended in 1 ml of freezing solution for each aliquot into cryotubes. Vials were placed on ice for 15 minutes, dry ice for 15 minutes, and finally in liquid nitrogen for long - term storage.
  • the media was aspirated from a confluent 60x15mm dish of cells and replaced with 2ml of serum-free, DMEM and 1 ⁇ l of a stock solution of Oxamflatin or Metacept-1 to give final concentrations of 50nM, 500nM and 5 ⁇ M.
  • the cells were stimulated at 37°C for either 16 hours or 24 hours before harvesting.
  • a 100 ⁇ l aliquot of competent E.coli DH5 cells was thawed from -80°C stock and transformed with the MCHC6-MMP-2 expression vector (see Appendix I). Immediately thereafter, they were kept on ice for 30 minutes, heat shocked at 42°C for 2 minutes and incubated on ice for 2 minutes. 500 ⁇ l of LB broth was added to the cells and incubated on a shaker for one hour at 37°C and 225rpm. The culture was streaked onto a Petri dish containing LB agar supplemented with 50ng/ml Ampicillin and incubated overnight at 37°C.
  • Single colonies of Ampicillin resistant colonies expressing the transformed MMP-2 plasmid DNA were selected using a toothpick and amplified in 3ml LB broth containing 3 ⁇ l of Ampicillin overnight on a shaker at 37°C and 225rpm. The entire 3ml culture was then amplified in a 200ml LB broth containing 10 ⁇ g/ml Ampicillin overnight at 37°C and 225rpm.
  • the 200ml culture was centrifuged for 15 minutes at 4°C and 4000rpm. The supernatant was discarded and the bacterial pellet resuspended in 20ml STE buffer , transferred to a 50ml falcon tube and centrifuged at 4000 rpm for 15 minutes at 4°C. The supernatant was discarded and the pellet resuspended in 9ml of Solution I , then 1 ml of lysozyme in 10mM TRIS (pH 8.0) . The solution was left at room temperature for 5 minutes then thoroughly mixed with 20ml of freshly prepared Solution II .
  • the solution was incubated at room temperature for 10 minutes, and 15ml of ice-cold Solution III was added, accompanied by vigorous shaking, stored on ice for 10 minutes, then centrifuged for 15 minutes at 4°C and 4000 rpm.
  • the supernatant was filtered through four-layered cheesecloth and cold isopropanol at 0.6 x the volume was added, mixed thoroughly and left at room temperature for one hour.
  • the mixture was centrifuged for fifteen minutes at room temperature and 5000 rpm, the supernatant discarded, the pellet rinsed with 70% ethanol then dissolved in 3ml of TE buffer (pH 8.0).
  • the solution was extracted once with equal volume phenol, once with phenol/chloroform and once with chloroform.
  • the upper layer was mixed with 10% of the volume of 3M sodium Acetate (pH5.5) and 2.5x the volume of 100% ethanol.
  • the DNA was precipitated at -80°C for 1 hour, centrifuged again for 10 minutes at 4°C and 13,500, the supernatant removed and the pellet dissolved in 500 ⁇ l TE buffer (pH 8.0).
  • optical density (O.D) of a 1 :100 dilution (in water) of the sample was assessed using a spectrometer at 260nm (1 O.D. unit at 260nm is equal to 50 ⁇ g DNA/ml).
  • the restriction enzyme digestion reaction consisted of the following: 1. Plasmid DNA of required volume 2. 2 ⁇ i of 10X BSA 3. 2 ⁇ l of 10X buffer 4. Xhol added to a final concentration of 1 U of restriction enzyme per 1 ⁇ g of DNA 5. Remainder of volume consisted of water (usually this reaction volume was 20 ⁇ l).
  • the reaction mixture was incubated at 37°C for two hours, 6X DNA loading buffer was added to each sample which were loaded onto a 1% (w/v) agarose gel together with 10 ⁇ l of lambda standard digested with Hindlll and EcoRI to identify the fragment sizes.
  • the gel was electrophoresed for 2 hours at 100V using 1 X TBE buffer, and the bands visualized under UV. The required DNA fragments were excised out of the gel and purified using QIAquick Gel Extraction Kit according to the manufacturer's instructions.
  • RNA Extraction This was performed following the protocol of Chromczynski and Sacchi (Chromczynski and Sacchi, 1987). Each confluent dish of cells were rinsed with 2ml of PBS, 500 ⁇ l of Solution D was added, and the mixtures were transferred to separate eppendorf tubes and stored at -20°C until required.
  • 1g of agarose was mixed with 70ml milli-Q water and 10ml 10X MOPS and heated until the agarose had dissolved.
  • 1 I ethidium bromide and 20ml formaldehyde were added in the fume hood and the mixture poured into a prepared gel tray, with a comb 1cm from the edge of the tray, and left to set.
  • RNA extract 10 ⁇ g was mixed with approximately 20 ⁇ l of RNA loading buffer , heated at 65°C for 5 minutes, iced for 5 minutes, and loaded onto the gel, with 1X MOPS as the running buffer.
  • the gel was electrophoresed at 70V and 100mA for 2-3 hours until the dye front had moved approximately 8cm.
  • the gel was de-stained overnight in milli-Q water to remove excess ethidium bromide.
  • RNA bands were visualised on a UV trans-illuminator to assess loading, and transferred onto a nitrocellulose membrane via capillary action for a minimum of 6 hours.
  • the membrane was exposed to UV light for 30 seconds to cross-link the RNA, then baked at 80°C for 2 hours to fix RNA to the membrane. Then the membrane was incubated in 10ml of 50% formamide pre-hybridization buffer containing 200 ⁇ g/ml salmon sperm DNA for 2 hours at 42°C.
  • the MMP-2 probe used in the northern blots was a 2Kb fragment cDNA fragment excised from plasmid DNA, specifically, the pCHC6 vector, using Xho I (Kindly donated by Professor Rik Thompson, St Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Australia)
  • the probe was labelled using the Prime-a-gene® Labelling system following the manufacturer's instructions. The solution was incubated for one hour at 37°C. A G-50 sephadex column suspended in STE buffer was pre-washed with STE buffer, then the probe was added. The labelled cDNA probe is larger than the unlabelled probe, so it moves around the G-50 beads more quickly than the unlabelled probe (which must move through the beads) and is eluted sooner from the column. Increments of 3 or 4 drops were collected into approximately 25 eppendorf tubes, and the 3-4 tubes containing the highest counts (as assessed by a Geiger counter) were pooled to form the hybridisation probe.
  • the probe was strand separated at 100°C for 5 minutes, placed on ice, pulse centrifuged then added directly to the pre-hybridisation buffer of the membrane and incubated overnight at 42°C. The following day, the membrane was rinsed twice with 2 x SSC; twice for 15-20 minutes at 55°C in 2 x SSC/0.1% (w/v) SDS, and finally washed with 0.1 SSC/0.1% (w/v) SDS until the background radioactivity was at a satisfactory level (tested crudely via Geiger counter). The membrane was blotted dry, wrapped in plastic covering and exposed to autoradiographic film at -80°C using an intensifying screen.
  • the membrane was blotted in blot solution for 2 hours at room temperature or overnight at 4°C.
  • the membrane was washed (rinsed twice with 1 x TBS with 0.1 % Tween, followed by a fifteen minute wash (with shaking) and two five minute washes (with shaking)).
  • the primary antibody was diluted in blot solution (1 :1000 dilution for MMP-2 mAb, 1 :3000 dilution for TIMP-2 mAb), and the membrane was incubated in the diluted antibody overnight at 4°C.
  • the membrane was washed as previously, then the membrane was incubated (1 ⁇ l anti-mouse monoclonal antibody in 5ml blot solution) in diluted secondary antibody for one hour at room temperature. Following a third wash, the membrane was incubated in ECL solution for 60 seconds, blotted dry on paper towel, wrapped in plastic and placed against exposure film for 30 seconds to 15 minutes.
  • Gelatin Zymography 10 ⁇ l of Laemmeli sample buffer was added to 40 ⁇ l of conditioned medium and loaded onto a non-reducing SDS-PAGE gel containing 0.15%(w/v) gelatin. The gel was electrophoresed at 140V in gelatin zymography running buffer for approximately 90 minutes. The stacking gel was removed and the gel washed twice for 30 minutes in 2.5% (v/v) Triton X-100 solution to remove SDS, then placed in Zymography developing buffer and incubated overnight at 37°C.
  • Results were analysed using Prism Software by analysis of variance (ANOVA), using the unpaired t-test.
  • Controls in each experiment were considered 100%, with treated samples calculated as a percentage of the control so as to allow comparison between experiments. Results were considered statistically significant if p ⁇ 0.05.
  • Optical density values were obtained using a microplate reader at 450nm. If more than one of each sample had been tested, the average was deemed to be the result. As the readings were inverse to the activity (i.e. the higher the value, the lower the activity), the values were re-calculated as in the following table.
  • Control sample i.e. MMP-2 diluted with DMEM
  • CM samples were taken as a percentage.
  • EXAMPLE 3 Oxamflatin and Metacept-1 Treatment Modulates MMP-2 mRNA Expression in VSMC WSR rat vascular smooth muscle cells were treated with 5 ⁇ M of Oxamflatin, Metacept-1 and Oxamflatin and Metacept-1 combined for 16 hours. Treatment with 5 ⁇ M of Oxamflatin alone resulted in approximately 45% inhibition of mRNA expression, as determined by Northern blotting (p ⁇ 0.0005). Blotting also showed that combined treatment of Oxamflatin and Metacept-1 inhibited mRNA expression by approximately 55% (p ⁇ 0.005). Treatment with Metacept-1 alone did not produce any statistically significant inhibition (Fig. 2).
  • EXAMPLE 4 Treatment with Oxamflatin and Metacept-1 Modulates MMP-2 Protein Expression in VSMC
  • Oxamflatin treatment was the most effective, showing statistically significant inhibition of over 75% of the expression seen in untreated cells (p ⁇ .001).
  • Metacept-1 treatment produced a statistically significant (p ⁇ 0.05) inhibition that was not as great as that associated with Oxamflatin, while treatment with both drugs resulted in statistically significant inhibition by more than 50% (p>0.001).
  • MCT-1 Metacept-1
  • the MMP-2 expression of human vascular smooth muscle cells is greatly reduced by treatment with MCT-1 for 24 hours, particularly at 5 ⁇ M concentration, which reduces expression to less than 20% of untreated cells (p ⁇ 0.0001 ).
  • EXAMPLE 5 Oxamflatin and Metacept-1 Treatment Modulates MMP-2 Mediated Proteolytic activity in VSMC.
  • Panel B shows that treatment with 5 ⁇ M of Oxamflatin and 5 ⁇ M Metacept-1 together for 16 hours resulted in statistically significant (p ⁇ 0.05) reduction in MMP-2 proteolytic activity to approximately 65% of the proteolytic activity shown by untreated cells.
  • the zymogram in Fig. 6A shows a relatively high expression of MMP-2, and little or no MMP-9 expression, a result that was seen in all zymograms performed on rat aortic smooth muscle cells.
  • Fig. 7A suggests a small amount of MMP-9 production by hVSMC, due to the band of gelatinolytic activity that corresponds to a protein length of roughly 92kDa, the size of the MMP-9 protein. A band at this position was only occasionally distinguishable on zymograms performed on hVSMC, and the effects of drug treatment could not be determined.
  • MCT-1 Metacept-1
  • EXAMPLE 6 Effect of Conditioned Media (CM) from Human Vascular Smooth Muscle Cells on the Proteolytic Activity of Recombinant MMP-2.
  • Serum-free DMEM conditioned by human vascular smooth muscle cells for 16 hours was used to dilute recombinant MMP-2 and the activity was assessed using a commercial assay (Chemicon).
  • the human, AMPA-activated MMP-2 was included with the kit.
  • the conditioned media was tested undiluted and diluted 1 :5 with serum-free DMEM, in addition to serum-free DMEM alone, which acted as a control. Each sample was used to dilute recombinant MMP-2 and the activity tested using the assay kit.
  • angiotensin II Ang II
  • AAA angiotensin II
  • aneurysms characterized by complex tissue remodeling in the adventitia similar to human disease.
  • the aneurysmal tissue also showed exacerbated vascular inflammation, such as monocyte/macrophage infiltration in the vascular wall.
  • mice Animal preparation and test compounds At approximately 6 months of age, Alzet osmotic mini-pumps (Model 2004) were subcutaneously implanted into the subscapular space of apoE deficient mice.
  • mice received treatment with either: saline (vehicle or placebo group), Ang II alone (at 1.44mg/kg/day), Ang II co-treated with either 1 ⁇ M or 5 ⁇ M oxamflatin, or Ang II co-treated with either 1 ⁇ M or 5 ⁇ M MCT-1.
  • mice were sacrificed and the heart and aorta removed, and connective tissue around the aorta was carefully removed by dissection.
  • the diameter of the abdominal aorta was grossly imaged and calculated using a Moticam-480P Digital Camera (and appropriate Motic Images Plus 2.0 software). The aortic diameter at the location of aneurysm formation was further validated postmortem by direct measurement of cross sections of the suprarenal aorta (See Histopathological Examination). Additional groups of mice will be used to test dose-response relationships of test compounds, as well as the ability of test compounds to regress existing aneurysms.
  • Systolic blood pressure measurements were taken prior to and at the end of the treatment. On the day of blood pressure determination, mice are placed under a 100 watt lamp for 20 minutes before being placed in a restrainer. Systolic blood pressure is then measured repeatedly using a noninvasive tail cuff device and recorded on a data acquisition system (PowerLab; AD Instruments, Australia). Systolic blood pressure was averaged from five consecutive measurements.
  • aortae dissected from all placebo and treatment groups are immersion fixed in Carnoy's fixative (60% alcohol, 30% chloroform, 10% glacial acetic acid).
  • Cross-sections of aorta (2.5 mm in thickness) are made between the superior mesenteric and right renal arteries. A small portion of the right renal artery is left attached to the samples to facilitate orientation of the specimen.
  • These tissues are dehydrated through a graded ethanol series, cleared with xylene, infiltrated with warm paraffin, embedded in paraffin blocks, cut at 5- ⁇ m thickness, and stained with hematoxylin and eosin.
  • Direct measurements of aneurysms from the suprarenal aorta are made after tissue sections have been prepared for histological examination.
  • the lumen and adventitial circumferences at the maximal expended portion of the suprarenal aorta are quantified by image analysis (MCID system) that is then used to calculate the luminal and outer diameters of the vessel.
  • the wall thickness will be calculated from the difference between the luminal and outer diameters.
  • Quantification of the degree of atherosclerosis exhibited in all treatment groups will be performed on the aortic arch and thoracic aorta.
  • the abdominal aorta will be excluded due to aneurysm formation.
  • the aortic arch and trunk will be cut open for en face staining with Oil Red O. Imaging will be performed using the Moticam-480P Digital Camera and quantitated using appropriate software (Motic Images Plus 2.0). Lesion area will be measured and expressed as a percentage of the total area of the vessel.
  • Panel A of Fig 11 demonstrates the efficacy of oxamflatin and MCT-1 in lowering the incidence of AAA. Control animals demonstrated an incidence of 81 %, with all treated animals showing incidences of 60% or less. It is notable that MCT-1 was able to lower AAA incidence to levels lower than treatment with doxycycline which is the "gold standard" for treatment of AAA in animal models.
  • Figure 12 shows the efficacy of MCT-1 with reference to wall thickness, and again shows the superiority of this compound to doxycycline and likely decrease in AAA progression.
  • EXAMPLE 8 Validation of animal model. - This Example demonstrates that the murine model used to generate experimental data in this application is valid for abdominal aortic aneurysm.
  • mice with a >99% C57BL/6J background were obtained from Animal Resources Centre (WA) and male C57BL/J6 mice were obtained from Central Animal Services (Monash University). All mice were obtained at 5 weeks of age and weighed between 25-35g at the time of experiments. These animals were housed in standard mouse cages located in the Pharmacology Animal House, Monash University, Clayton, at 21 ⁇ 5°C with a 12 hour light/dark cycle. Standard food and water was provided ad libitum until
  • Osmotic mini-pumps were prepared prior to the surgery. All drugs were dissolved in saline and using a syringe, injected into the pump. The mice were anaesthetised via isoflurane inhalation. The throat area of the mice was shaved and a small incision ( ⁇ 1cm) was made along this region. The common carotid artery was isolated from surrounding tissue using curved forceps. A 3 mm long piece of polyethylene tubing, with an internal diameter of 0.28mm (Tyco Electronics, USA), was cut longitudinally and placed around the common carotid artery and secured in place by a double knot of 6-0 Dysilk (Dynek Pty Ltd, Australia).
  • the incision was closed with sutures using 4-0 Dysilk. Following this, a small area in the scapular region of the neck was shaved and an incision made between the scapulae, allowing enough room for the osmotic mini-pumps to be inserted. Again, the incision was closed with sutures using 4-0 Dysilk. Antibiotic powder (Cicatrin, Pfizer) was placed on both incision areas.
  • Systolic blood pressure of all mice were measured using the non-invasive tail- cuff apparatus (ADInstruments, Sydney). Prior to taking the systolic blood pressure measurement, the mice were heated under an external light source for 20 minutes. Following this period, the mice were placed in a perspex mouse restrainer, leaving the tail accessible. An inflatable cuff, through which pressure was applied, was placed around the proximal end of the tail with a piezoelectric transducer around the tail distal to the cuff, to detect a pulsing flow signal from the caudal artery. Pressure was measured by a Maclab-8 data acquisition system, via a pressure transducer connected to a Maclab bridge amplifier (ADInstruments, Sydney).
  • Aortic rings were cut transversely from the abdominal aorta in order to carry out in vitro organ bath studies.
  • Four aortic rings were obtained ( ⁇ 3mm long) from the abdominal aorta.
  • Two stainless steel wires were threaded through the lumen of the aorta with the tissues then being mounted and suspended in vertical 10 ml organ baths containing Krebs' bicarbonate solution at 37°C and bubbled with carbogen (95% 0 2 and 5% CO 2 ).
  • Tension in the aortic rings was set to 0.5g. Isometric tension was measured continuously via a force transducer (Grass FT03) and displayed on a Macintosh using a Maclab data acquisition system (ADInstruments, Sydney). Tissues were allowed to equilibrate for 90 minutes, with the Krebs' bicarbonate solution being changed every 15 minutes.
  • Carotid artery was dissected and fixed in Carnoy's fixative (60% ethanol, 30% chloroform, 10% glacial acetic acid) until used. The tissue was then transferred to 70% ethanol. After 24 hours in 70% ethanol solution, the tissue was put into a biopsy pad encased in a cassette. Tissues in the cassettes were then processed through a series of graded alcohol washes using the automated paraffin processor in the Histology Central Facility (Monash University, Clayton), to dehydrate tissues before being embedded in paraffin blocks. 5 ⁇ m cross- sections of the tissues were then obtained using a microtome and placed on a microscope slide. Slides were dried overnight in a 40°C oven.
  • slides Prior to staining, slides were heated in a 60°C oven for 20 minutes to melt excess wax. The slides then underwent washing through a series of xylene clearing solutions and dehydrated with alcohol. Tap water was then used to wash the slides for 2 minutes followed by immersion in haematoxylin for 5 minutes. Again, the tissues were washed with tap water for 3 minutes and immersed in Scott's tap water for 1 minute. Slides were then placed in aqueous eosin for 3 minutes and dehydrated with alcohol and placed again in a xylene clearing solution. Coverslips were then mounted onto the microscope slides with polystyrene (DPX).
  • DPX polystyrene
  • WLR wall : lumen ratio
  • SBP Systolic blood pressure
  • IMR intima : media ratio
  • Wall : lumen ratios were obtained to measure neointimal formation. WLR was obtained by dividing vessel wall area by lumen area. All values are expressed as mean ⁇ standard error of the mean (SEM). Statistical significance was acknowledged where p ⁇ 0.05.
  • FIGS 13 and 14 show neointimal growth in the wall of the aorta in 12 and 30 week APOE knock out mice respectively, whilst FIG 15 shows neointimal formation in the cuffed and uncuffed carotid ateries in 12 week old animals treated with ATM for 2 weeks. Cuffing the artery induces neointimal hyperplasia. As can be seen from the data the cuffed artery demonstrates neointimal hyperplasia.
  • EXAMPLE 9 Assessment of efficacy of compounds for the treatment of aneurysm in humans.
  • the following experimental protocol is provided to illustrate how the present invention may be tested on humans in a clinical trial.
  • the protocol illustrates the evaluation of compounds and compositions of the present invention for efficacy in the treatment and prevention of aneurysm.
  • subjects will cease any existing therapy 2 weeks before commencement of the study. After the 2 week "washout" period, all subjects will then be subjected to a chest CT scan to create a baseline measurement.

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Abstract

L'invention concerne des méthodes de traitement de maladies vasculaires telles que l'anévrisme (en particulier l'anévrisme de l'aorte abdominale) et l'hyperplasie néo-intimale. Ces traitements comprennent l'utilisation de composés connus tels que l'amiloride et l'oxamflatine, et de nouveaux dérivés de l'acide hydroxamique.
PCT/AU2004/001829 2003-12-24 2004-12-24 Compositions et methodes de traitement d'affections vasculaires WO2005061448A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2020142809A1 (fr) * 2019-01-08 2020-07-16 Monash University Méthode de traitement et dispositif

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