WO2008131481A1

WO2008131481A1 - Treatment of mesangioproliferative diseases

Info

Publication number: WO2008131481A1
Application number: PCT/AU2008/000576
Authority: WO
Inventors: Darren James Kelly; Richard Ernest Gilbert
Original assignee: University of Melbourne; Fibrotech Therapeutics Pty Ltd
Current assignee: University of Melbourne; Fibrotech Therapeutics Pty Ltd
Priority date: 2007-04-26
Filing date: 2008-04-24
Publication date: 2008-11-06
Anticipated expiration: 2009-10-26

Abstract

Pharmaceutical compositions and methods including tranilast-type compounds are disclosed for treating and/or preventing mesangioproliferative diseases. In aspects of the invention, tranilast-type compounds or pharmaceutical compositions including tranilast-type compounds are used in the treatment and/or prevention of IgA nephropathy.

Description

TREATMENT OF M ES ANGIOPROLI FERATIVE DISEASES

Field of invention

The invention relates to methods and compositions for treatment of a mesangioproliferative disease, including IgA deposition diseases, in particular IgA nephropathy.

Background of invention

Mesangial proliferative glomerulonephritis is a kidney disorder characterised clinically by nephrotic syndrome (protein loss in the urine and swelling of the body). It may be present as acute, chronic, or rapidly progressive glomerulonephritis, and may progress to chronic renal failure. It is seen more commonly in lupus patients who develop glomerulonephritis, and in patients who have Immunoglobulin A (IgA) nephropathy.

IgA nephropathy is the commonest primary glomerulonephritis in the world. While initially viewed as a relatively benign disease, recent studies have highlighted the poor prognosis in some with end-stage renal disease developing in 15- 40% of patients [Donadio and Grande, N Engl J Med. 2002 Sep 5; 347(10):738-48 2002] despite the widespread use of ACE inhibitors. Histopathologically, IgA nephropathy is characterised by increased mesangial cell number and glomerular matrix accumulation implicating growth factors with proproliferative and pro-fibrotic activity as pathogenetic factors. Indeed, these actions are consistent with those of platelet-derived growth factor (PDGF) with overexpression of both ligand and receptor demonstrated in renal biopsies taken from patients with IgA nephropathy. Moreover, the amelioration of injury by blocking PDGF and/or its receptor in the Thy1 model of mesangial proliferative glomerulonephritis have led to the speculation that strategies that antagonize PDGF may be useful in the treatment of IgA nephropathy.

The deposition of Immunoglobulin A (IgA) in human tissues and organs is a characteristic of many human diseases including IgA nephropathy, Dermatitis herpetiformis (DH), and Henoch-Schonlein purpura (HS). Deposition of IgA is responsible for a variety of clinical manifestations such as renal failure, skin blistering, rash, arthritis, gastrointestinal bleeding and abdominal pain.

While several potential therapies have been shown to attenuate mesangial proliferation and extracellular matrix deposition in order to treat mesangial proliferative glomerulonephritis, far fewer therapies have been shown to also reduce the magnitude of proteinurea. Accordingly, there is a need for further therapies for treating mesangial proliferative diseases, including IgA nephropathy, by reducing both structural and functional manifestations of such diseases.

Summary of invention

The present invention relates to methods for treating a mesangioproliferative disease, in particular IgA nephropathy, in a subject suffering from the disease. The methods include administering to the subject a therapeutically effective amount of at least one tranilast- type compound, or a pharmaceutically acceptable salt or solvate thereof. Treating a mesangioproliferative disease includes inhibiting the progression of the mesangioproliferative disease, preventing the mesangioproliferative disease, and/or ameliorating a symptom of the mesangioproliferative disease.

The invention relates to a method for treating a mesangioproliferative disease, in a subject comprising administering to the subject a therapeutically effective amount of a tranilast-type compound, or a pharmaceutically acceptable salt or solvate thereof, or a medicament comprising a tranilast-type compound and a pharmaceutically acceptable carrier, excipient, or vehicle, which results in beneficial effects following treatment. In an aspect, the invention relates to a method of treatment comprising administering a therapeutically effective amount of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof, which upon administration to a subject with symptoms of a mesangioproliferative disease, produces beneficial effects, in particular sustained beneficial effects.

The mesangioproliferative disease may be an IgA deposition disease. In a preferred embodiment, the mesangioproliferative disease is IgA nephropathy. In certain embodiments, the method of treatment includes administering a therapeutically effective amount of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof, which upon administration to a subject with symptoms of a mesangioproliferative disease produces a beneficial effect, in particular a sustained beneficial effect. In certain embodiments, the beneficial effect is evidenced by one or more of: reduction or inhibition of PDGF activity, reduction or inhibition of TGF-β activity, reduction or inhibition of PDGF-induced mesangial cell proliferation, reduction or inhibition of mesangial cell numbers, reduction or inhibition of glomerular matrix accumulation, reduction or elimination of IgA deposition in the glomerular mesangium, reduction or elimination of macroscopic hematuria, reduction or elimination of proteinuria, and reduction or elimination of hypertension.

In a further aspect, the invention provides a method involving administering to a subject a therapeutically effective amount of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof, which inhibits or reduces IgA deposition or which causes dissolution and/or disruption of pre-existing IgA aggregates.

In a further aspect the present invention provides a method of preventing or reducing proteinuria in a subject including administering to the subject a therapeutically effective amount of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the present invention provides a method of reversing or reducing IgA deposition in glomerular mesangium after the onset of symptoms of IgA nephropathy in a subject including administering to the subject a therapeutically effective amount for reversing or reducing IgA deposition in glomerular mesangium after the onset of symptoms of IgA nephropathy, of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the invention provides a method for amelioriating a symptom of an IgA deposition disease, in particular IgA nephropathy, comprising administering a therapeutically effective amount for amelioriating a symptom of an IgA deposition disease, in particular IgA nephropathy, of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the invention provides a method for ameiioriating progression of an IgA deposition disease, in particular IgA nephropathy, comprising administering a therapeutically effective amount for ameiioriating progression of an IgA deposition disease, in particular IgA nephropathy, of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the invention relates to a method of delaying the progression of an IgA deposition disease, in particular IgA nephropathy, comprising administering a therapeutically effective amount for delaying the progression of IgA nephropathy of at least one tranilast-type compound, a pharmaceutically acceptable salt or solvate thereof.

In a further aspect the present invention relates to a method of increasing survival or improving the lifespan of a subject suffering from a mesangioproliferative disease, in particular IgA nephropathy, including administering a therapeutically effective amount for increasing survival or improving a lifespan of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof.

In the methods of the present invention, the tranilast-type compound may be administered as a pharmaceutical composition as described herein.

In a further aspect, the present invention provides a pharmaceutical composition for treating a mesangioproliferative disease, in particular IgA nephropathy, including a therapeutically effective amount of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof.

Preferably, the tranilast-type compound is a compound of formula I

Formula

wherein R-i and R₂, which may be the same or different, are selected from the group consisting of a Ci to C-io alkyl, C₃ to Cio cycloalkyl, C₃ to Ci₀ cycloalkylmethyl, C₃ to do alkene, C₃ to C₁₀ alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

Xi and X₂ are the same or different and are selected from the group consisting of a bond, O, N and S;

T is a single or double bond;

R₃ is selected from the group consisting of H, C₃ to do alkene, C₃ to do alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

R₄ is selected from the group consisting of H, OH, OR₆, NHR₆ and NR₆Rz;

R5 is selected from the group consisting of H, NHR₆, NR₆R₇, ORs, halogen, C₃ to do alkene, C₃ to do alkyne and a chain consisting of a heterocyclic or fused ring, any of which may be optionally substituted;

R₆ and R₇, which may be the same or different, are selected from the group consisting of H, C₁ to Ci₀ alkyl, C₃ to do cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀ alkyne, aryl, C₅ to C₂₀ alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; Rs is selected from the group consisting of H, Ci to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, C₃ to Cio cycloalkylmethyl, C₃ to C-io alkene, C₃ to C₁₀ alkyne, aryl, C₅ to C₂o alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; and

n is an integer between 0 and 4.

or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, preferably R₁ and R₂ are the same or different and are selected from the group consisting of optionally substituted Ci to Ci₀ alkyl, optionally substituted C₂ to do alkynyl and a chain including an optionally substituted triazole. In a further embodiment, preferably R₃ and R₄ are the same or different and are selected from the group consisting of OH, hydrogen, halogen, optionally substituted Ci to Cio alkyl and optionally substituted C₂ to Cio alkynyl. In yet a further embodiment, preferably one of Ri and R₂ is methyl and the other of Ri and R₂ is propargyl or a chain containing a 1 ,4- disubstituted 1 ,2,3-triazole.

In a further embodiment, the compound of formula I can not be tranilast (N-[3,4- dimethoxycinnamoyl]anthranilic acid).

In particular embodiments, the present invention provides a pharmaceutical composition in a form adapted for administration to a subject to provide beneficial effects in the treatment of a mesangioproliferative disease, in particular IgA nephropathy.

In another aspect the present invention provides a pharmaceutical composition for treating a mesangioproliferative disease, in particular IgA nephropathy, including a therapeutically effective amount of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, excipient or vehicle.

In an aspect, the present invention provides a pharmaceutical composition including at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof in a therapeutically effective amount for reducing and/or eliminating proteinuria in a subject suffering from IgA nephropathy. The pharmaceutical composition may include a pharmaceutically acceptable carrier, excipient, or vehicle.

In yet a further aspect the present invention provides the use of at least one tranilast- type compound or a pharmaceutically acceptable salt or solvate thereof for the preparation of a pharmaceutical composition for treating a mesangioproliferative disease, in particular IgA nephropathy.

The present invention additionally provides a method of preparing a stable pharmaceutical composition including at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof in a therapeutically effective amount for treating a mesangioproliferative disease, in particular IgA nephropathy.

In another aspect, the present invention provides a kit for treating a mesangioproliferative disease, in particular IgA nephropathy, including:

• at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof; and

• instructions for administering the tranilast-type compound to a subject in order to treat an IgA deposition disease.

These and other aspects, features, and advantages of the present invention should be apparent to those skilled in the art from the following detailed description.

Figures

Figure 1

Effects of tranilast on platelet-derived growth factor (PDGF)-stimulated proliferation and collagen synthesis, as assessed by ³H-thymidine and ³H-proline incorporation, respectively. Data are expressed as mean ± SEM.* p <0.05 versus PDGF (50 ng/ml) alone; f P <0.01 versus tranilast 10, 30 μU. Figure 2

Effect of tranilast on PDGF-induced phosphorylation of PDGFR-/?. PDGFR-/? was phosphorylated by PDGF and inhibited by tranilast in a dose-dependent manner. Tranilast did not affect PDGFR-/? protein levels. Data are expressed as mean ±SEM. *P<0.01 versus untreated.

Figure 3

Photomicrograph of PAS-stained kidney section from control animals (A), rats with experimental mesangial proliferative glomerulonephritis receiving either vehicle (B) or tranilast (C). Magnification ^χ400. Compared with control animals, untreated rats show marked glomerular hypercellularity and mesangial matrix expansion. Tranilast-treated rats show near-normal glomerular histology.

Figure 4

Glomerular cellularity as assessed by the number of nuclei per glomerular cross-section (GCS) in 50 hilar glomeruli per animal. Glomerular hypercellularity was increased in Thy-1 nephritis and attenuated by tranilast. Data are expressed as mean ± SEM. *P<0.05 versus control; tP<0.05 versus Thy-1.

Figure 5

Representative photomicrographs showing glomerular macrophage infiltration (ED-1 immunolabelling) in control, Thy1 and tranilast-treated Thy1 animals (Magnification, ^χ400) and quantification as assessed by the number of ED-1+cells per glomerular cross-section (GCS) in 50 hilar glomeruli per animal. Data are expressed as mean + SEM. *P<0.01 versus control ; fP<0.01 versus Thy-1.

Figure 6

lmmunostaining for α-smooth muscle actin (left panel) and type IV collagen (right panel) in photomicrograph of kidney section from control (A), untreated (B), and tranilast- treated rats (C) with experimental mesangial proliferative glomerulonephritis. Magnification, *400.

Figure 7

Activated mesangial cells (A) and type IV collagen deposition (B) as assessed by the proportional area immunostained with σ-smooth muscle actin and type IV collagen antibodies, respectively. Data are expressed as (mean ± SEM) per glomerular cross- section (gcs) in 50 hilar glomeruli per animal from untreated and tranilast-treated rats. *P<0.05 versus control; tP<0.01 versus Thy-1.

Figure 8

Glomerular cellularity as assessed by the number of nuclei per glomerular cross-section (gcs) in 50 hilar glomeruli per animal in H & E stained sections. Glomerular hypercellularity was significantly attenuated by FT011. Data are expressed as mean + SEM. *P<0.05 versus controls; ^#P<0.05 versus untreated.

Figure 9

Glomerular mesangial expansion was significantly increased in Anti-Thy-1 rats and attenuated by FT011. Data are expressed as mean ± SEM. *P<0.05 versus controls; ^#P<0.05 versus untreated.

Figure 10

Photomicrograph of H & E (I) and PAS (II) stained kidneys from control (A) and control + FT011 (B), anti-thy-1 experimental mesangial proliferative glomerulonephritis (C) or anti-thy-1 experimental mesangial proliferative glomerulonephritis treated with FT011 (C). Compared with control animals, untreated rats with mesangial proliferative glomerulonephritis have marked glomerular hypercellularity and mesangial matrix expansion that is significantly attenuated by FT011 treatment. Magnification χ400.

Figure 11

Activated mesangial cells. Data are expressed as the proportional area of α-smooth muscle actin immunostaining (mean ± SEM) per glomerular cross-section (gcs) in 50 hilar glomeruli per animal from untreated and FT011-treated rats. ^*P<0.01 versus control; *P<0.05 versus untreated.

Figure 12

Immunostaining for α-smooth muscle actin in kidneys from control (A), control + FT011 (B), anti-Thy-1 (C) and anti-Thy-1 treated with FT011 (D) Magnification χ400.

Figure 13

Type IV collagen deposition. Data are expressed as proportional area (mean ± SEM) of collagen IV immunostaining per glomerular cross-section (gcs) in 50 hilar glomeruli per animal from untreated and FT011 -treated rats. *P<0.01 versus control; ^#P<0.05 versus untreated.

Figure 14

Immunostaining for type IV collagen in kidney sections from controls (A), control + FT011 (B), anti-Thy-1 (C), and anti-Thy-1 rats treated with FT011 (D) Magnification

Figure 15

Quantitation of macrophage number (ED-1). The number of ED-1 positive cells per glomerular cross-section (gcs) in 50 hilar glomeruli per animal; Data are expressed as mean ± SEM. ^*P<0.01 versus control, ^#P<0.05 versus untreated.

Figure 16

Representative photomicrograph of ED-1 stained sections from control (A), control + FT011 (B), anti-Thy-1 (C) and anti-Thy-1 rats treated with FT011 (D). In control (A) and control treated with FT011 (B) rats, only an occasional macrophage was observed, while anti-Thy-1 rats (C) were associated with numerous macrophage. Treatment of anti-Thy-1 rats with FT011 (D) was associated with a reduction in glomerular macrophage number. Magnification x400.

Detailed description of embodiments

The recitation of numerical ranges by endpoints herein includes all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1 , 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is to be understood that all numbers and fractions thereof are presumed to be modified by the term "about." The term "about" means plus or minus 0.1 to 50%, 5-50%, or 10-40%, preferably 10-20%, more preferably 10% or 15%, of the number to which reference is being made. Further, it is to be understood that "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a compound" includes a mixture of two or more compounds.

A "beneficial effect" refers to an effect of a tranilast-type compound or pharmaceutical composition thereof, including favorable pharmacological and/or therapeutic effects, and improved biological activity. In aspects of the invention, the beneficial effects may include one or more of the following: reduction or inhibition of PDGF activity, reduction or inhibition of TGF-β activity, reduction or inhibition of PDGF-induced mesangial cell proliferation, reduction or inhibition of mesangial cell numbers, reduction or inhibition of glomerular matrix accumulation, reduction or elimination of IgA deposition in the glomerular mesangium, reduction or elimination of macroscopic hematuria, reduction or elimination of proteinuria, and/or reduction or elimination of hypertension.

In aspects of the invention, the beneficial effect is a "sustained beneficial effect" where the beneficial effect is sustained for a prolonged period of time after termination of treatment. A treatment can be sustained over several years thereby having a major beneficial impact on the severity of the disease and its complications. A beneficial effect may be sustained for a prolonged period of at least about 2 to 4 weeks, 2 to 5 weeks, 3 to 5 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 14 weeks, 2 to 16 weeks, 2 to 20 weeks, 2 to 24 weeks, 2 weeks to 12 months, 2 weeks to 18 months, 2 weeks to 24 months, or several years following treatment. The period of time a beneficial effect is sustained may correlate with the duration and timing of the treatment. A subject may be treated continuously for about or at least about 2 to 4 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 14 weeks, 2 to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, or several years, periodically or continuously.

The beneficial effect may be a statistically significant effect in terms of statistical analysis of an effect of a tranilast-type compound, versus the effects without such a compound. "Statistically significant" or "significantly different" effects or levels may represent levels that are higher or lower than a standard. In embodiments of the invention, the difference may be 1.5, 2, 3, 4, 5, or 6 times higher or lower compared with the effect obtained without a tranilast-type compound.

The term "pharmaceutically acceptable carrier, excipient, or vehicle" refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered. A carrier, excipient, or vehicle may include diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous material such as absorbents that may be needed in order to prepare a particular pharmaceutical composition. Examples of carriers etc. include but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for an active substance is well known in the art.

"Therapeutically effective amount" relates to the amount or dose of a tranilast-type compound or pharmaceutical composition thereof, that will lead to one or more desired effects, in particular, one or more beneficial effects. A therapeutically effective amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the substance to elicit a desired response in the subject. A dosage regimen may be adjusted to provide the optimum therapeutic response (e.g. sustained beneficial effects). For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A therapeutically effective amount includes a prophyiactically effective amount.

"Mesangioproliferative Disease", "Mesangial proliferative glomerulonephritis (MPGN)" or "Mesangioproliferative glomerulonephritis" refer to any disease or condition involving proliferation of mesangial cells and are used interchangeably herein. Characteristic light microscopic findings of this disease are expansion of the mesangium with little or no involvement of the capillary lumina. Mesangial cell proliferation may be accompanied by an increase in mesangial matrix and in advanced cases by mesangial sclerosis, lmmunohistochemistry studies may reveal deposits of IgA (IgA nephropathy) or, IgG, IgM, C3 and C1q in the glomerular capillary wall or mesangium. However, the presence of deposits is not an obligate finding to making the diagnosis of MPGN. Mesangioproliferative glomerulonephritis can be divided into two main groups: primary and secondary. Primary Mesangioproliferative glomerulonephritis includes IgA nephropathy, non-lgA mesangial proliferative glomerulonephritis, IgM mesangial proliferative glomerulonephritis, and Henoch-Schoenlein purpura (i.e., a skin and kidney disease characterized by deposition of IgAI in skin tissue and kidney). The secondary forms accompany a wide range of diseases, such as systemic lupus erythematosus, glomerulonephritis with hepatitis and vasculitis, multiple sclerosis, and rheumatoid arthritis.

"IgA deposition disease" refers to any disease characterised by the deposition of immunoglobulin A (IgA) in tissue or organs. Such diseases include, but are not limited to, IgA neuropathy, dermatitis herpetiformis and Henoch-Schonlein purpura. In an IgA deposition disease, IgA may be deposited in immune complexes in tissue, such as the skin and kidney.

"IgA nephropathy" refers to a kidney disease characterized by IgAI deposits within the kidney.

A "tranilast-type compound" includes tranilast (N-(3,4-dimethoxycinnamoyl)anthranilic acid) and derivatives thereof, may include those disclosed in US patent no 3,940,422.

Examples of further suitable tranilast-type compounds are provided in International patent application number WO 2008/003141 , the entire contents of which is incorporated herein by reference. In particular, the tranilast-type compound is a compound of the formula I

Formula I

wherein R₁ and R₂, which may be the same or different, are selected from the group consisting of a Ci to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, C₃ to do cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to do alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

T is a single or double bond;

R₃ is selected from the group consisting of H, C₃ to do alkene, C₃ to C₁₀ alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

R₄ is selected from the group consisting of H, OH, OR₆, NHRe and NR₆R₇;

R₅ is selected from the group consisting of H, NHR₆, NR₆R₇, ORs, halogen, C₃ to do alkene, C₃ to C₁₀ alkyne and a chain consisting of a heterocyclic or fused ring, any of which may be optionally substituted;

Re and R₇, which may be the same or different, are selected from the group consisting of H, C₁ to C-io alkyl, C₃ to do cycloalkyl, C₃ to do cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to do alkyne, aryl, C₅ to C₂₀ alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; Rs is selected from the group consisting of H, Ci to Ct₀ alkyl, C₃ to C₁₀ cycloalkyl, C₃ to C1₀ cycloalkylmethyl, C₃ to C-₁₀ alkene, C₃ to Ci₀ alkyne, aryl, C₅ to C2₀ alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; and

n is an integer between 0 and 4.

In certain embodiments, when Xi and X₂ are both O or a bond, and one of Ri or R₂ is a Ci to C₄ alkyl, the other of Ri or R₂ is a C₄ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C_1O alkyne, or a chain containing a heterocyclic fused ring.

In further embodiments the compound of Formula excludes tranilast (3,4- dimethoxycinnamoyl)anthranilic acid.

In further embodiments of the invention, the tranilast-type compound is a compound of the Formula Il

Formula Il

wherein Rg or R₄₀. which may be the same or different, are selected from the group consisting of H, C-i to C₁₀ alkyl, C₃ to Cs terminal or non-terminal alkyne or a cyclopentyl, cyclohexyl, cyclohexylmethyl or cyclopentylmethyl group.

In certain embodiments, when one of Ri or R₂ of Formula Il is a Ci to C₄ alkyl, the other of R₁ or R₂ is a C4 to C₁₀ alkyl, C₃ to C₁O cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkyne or a chain containing a heterocyclic or fused ring, any of which are optionally substituted.

In further embodiments, the compound of Formula Il excludes tranilast (3,4- dimethoxycinnamoyl)anthranilic acid.

In further embodiments of the invention, the tranilast-type compound is a compound of the Formula III or Formula IV

Formula Formula IV

wherein G is a cyclopentyl ring, a cyclohexyl ring or a 1 ,4-disubstituted 1 ,2,3-triazole ring; and

q is an integer between O and 6.

In further embodiments of the invention, the tranilast-type compound is a compound of the formula V

Formula V

wherein R₅ is optionally substituted methyl, ethyl, propyl, hydroxyl or halogen; and R₆ is an optionally substituted alkynyl, in particular a C₂ to C₁O alkynyl or a chain containing an optionally substituted triazole. In a more particular embodiment, Re is propargyl or a 1 ,4-disubstituted 1 ,2,3-triazole. In a preferred embodiment, R₅ is methyl and R₆ is propargyl.

In a further embodiment, the compound of Formula V excludes tranilast (3,4- dimethoxycinnamoyl)anthranilic acid .

In a further embodiment, the tranilast-type compound has the formula Vl

Formula Vl

wherein n is an integer between 1 and 10, preferably 1 and 6; and R is hydrogen or Ci to do alkyl.

In a further embodiment, the tranilast-type compound has the formula VII

Formula VII

wherein n is an integer between 1 and 10, preferably 1 and 6; and R is hydrogen or optionally substituted Ci to C-io alkyl.

In a further embodiment, the tranilast-type compound has the formula VIII

Formula VIlI wherein n is an integer between 1 and 10, preferably 1 and 6; and R is hydrogen or any one of the following optionally substituted groups, alkyl, in particular Ci to Ci₀ alkyl, aryl, arylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, alkylamido, aminoalkyl, acylamino and arylamido.

In a further embodiment, the tranilast-type compound has the formula IX

Formula IX

wherein n is an integer between 1 and 10, preferably 1 and 6; and R is hydrogen, or any one of the following optionally substituted groups, alkyl, in particular Ci to Ci₀ alkyl, aryl, arylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, alkylamido, aminoalkyl, acylamino and arylamido.

In further preferred embodiments, the tranilast-type compound is selected from Group A, consisting of

Group A:

10

In further preferred embodiments, the tranilast-type compound is selected from Group B, consisting of

Group B:

In a preferred embodiment, the tranilast-type compound a the compound of the formula X

Formula X

The compound of the formula X is also referred to as FT011.

A tranilast-type compound also includes a prodrug of the compounds described above. As used herein, the term "prodrug" refers to a tranilast-type compound including structural modifications thereto, such that in vivo the prodrug is converted, for example, by hydrolytic, oxidative, reductive, or enzymatic cleavage into a parent compound (e.g., active compound or active derivative or analogue thereof). The term includes bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. Examples of barriers include, without limitation, solubility, permeability, stability, presystemic metabolism and targeting limitations (J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004). Prodrugs may be, for example, metabolically labile mono- or di-ester derivatives of a parent compound having a carboxylic acid group.

A tranilast-type compound also includes a derivative or analogue of the compounds described above. "Derivatives" include functional derivatives, chemical derivatives, or variants. A "functional derivative" refers to a compound that possesses an activity (either functional or structural) that is substantially similar to the activity of a described tranilast-type compound. The term "chemical derivative" describes a molecule that contains additional chemical moieties which are not normally a part of the base molecule. The term "variant" is meant to refer to a molecule substantially similar in structure and/or biological activity to a compound or parts thereof. The term "analogue" includes a compound substantially similar in function to a compound described above. An "analogue" can include a chemical compound that is structurally similar to another but differs slightly in composition. Differences include without limitation the replacement of an atom or functional group with an atom or functional group of a different element.

Further, a tranilast-type compound encompasses all possible enantiomers, stereoisomers including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures and tautomers of the compounds described above.

A tranilast-type compound also includes an isotopically labelled compound described above, for example, a compound incorporating at least one ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, or ¹⁷O, atom.

The present invention also encompasses the use of a pharmaceutically acceptable salt or solvate of a tranilast-type compound. Suitable salts include salts that may be formed where acidic protons in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with alkali metals, e.g. sodium and potassium, magnesium, calcium, and aluminium. Suitable organic salts include those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Suitable salts include acid addition salts formed with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g. acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benezenesulfonic acid). When there are two acidic groups present, a pharmaceutically acceptable salt may be a mono-acid-mono-salt or a di-salt; and similarly where there are more than two acidic groups present, some or all of such groups can be salified. Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

As used herein "alkyl", either alone or within other terms such as "arylalkyl", means a monovalent, saturated hydrocarbon radical which may be a straight chain (i.e. linear) or a branched chain. In certain aspects of the invention, an alkyl radical includes from about 1 to 24 or 1 to 20 carbon atoms, preferably from about 1 to 10, 1 to 8, 3 to 8, 1 to 6, or 1 to 3 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, sec-butyl, tert-butyl, tert- pentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, n-dodecyl, n-tetradecyl, pentadecyl, n-hexadecyl, heptadecyl, n-octadecyl, nonadecyl, eicosyl, dosyl, n-tetracosyl, and the like, along with branched variations thereof.

In certain embodiments of the invention an alkyl radical is a CrCβ lower alkyl including or selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl, isopropyl, isobutyl, isopentyl, amyl, tributyl, sec-butyl, tert-butyl, tert-pentyl, and n- hexyl. Where an alkyl radical is defined as being optionally substituted, the alkyl radical may be substituted with substituents at positions that do not significantly interfere with the preparation of tranilast-type compounds and that do not significantly reduce the efficacy of the compounds. The alkyl radicals may be substituted with one to five substituents including halo, lower alkoxy, hydroxyl, cyano, nitro, thio, alkenyl, alkynyl, amino, substituted amino, carboxyl, sulfonyl, sulfenyl, sulfinyl, sulfate, sulfoxide, substituted carboxyl, halogenated lower alkyl (e.g. CF₃), halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, aryl (e.g., phenylmethyl), heteroaryl (e.g., pyridyl), heterocyclyl (e.g., piperidinyl, morpholinyl) and by groups as described below.

The term "alkenyl" refers to an unsaturated, acyclic branched or straight-chain hydrocarbon radical including at least one double bond. Alkenyl radicals may contain from about 2 to 24 or 2 to 10 carbon atoms, preferably from about 3 to 8 carbon atoms and more preferably about 3 to 6 or 2 to 6 carbon atoms. Examples of suitable alkenyl radicals include ethenyl, propenyl such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1 -yl (allyl), prop-2-en-2-yl, buten-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but~2-en-2-yl, buta-1,3-dien-1-yl, buta-1 ,3-dien-2-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like. Where an alkenyl radical is defined as being optionally substituted, the alkenyl radical may be substituted with those substituents listed above in relation to the term alkyl or by groups as described below.

The term "alkynyl" refers to an unsaturated, branched or straight-chain hydrocarbon radical including one or more triple bonds. Alkynyl radicals may contain about 1 to 20, 1 to 15, or 2 to 10 carbon atoms, preferably about 3 to 8 carbon atoms and more preferably about 3 to 6 carbon atoms. Examples of suitable alkynyl radicals include ethynyl, such as prop-1-yn-1-yl, prop-2-yn-1 -yl (propargyl), butynyls such as but-1-yn-1- yl, but-1-yn-3-yl, but-3-yn-1-yl, pentynyls such as pentyn-1-yl, pentyn-2-yl, 4- methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexynyls such as hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, and 3,3-dimethylbutyn-1-yl radicals and the like. Where an alkynyl radical is defined as being optionally substituted, the alkynyl radical may be substituted with those substituents listed above in relation to the term alkyl or by groups as described below. The term "cycloalkynyl" refers to cyclic alkynyl groups.

The term "alkoxy" refers to a linear or branched oxy-containing radical having an alkyl portion of one to about ten carbon atoms, such as a methoxy radical. Particular alkoxy radicals are "lower alkoxy" radicals having about 1 to 6, 1 to 4 or 1 to 3 carbon atoms. An alkoxy having about 1-6 carbon atoms includes a CrCβ alkyl-O- radical wherein Cr Cβ alkyl has the meaning set out herein. Illustrative examples of alkoxy radicals include without limitation methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy. When defined as being optionally substituted, an "alkoxy" radical may be further substituted with one or more substituents including alkyl atoms (in particular lower alkyl) to provide "alkylalkoxy" radicals; halo, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals (e.g. fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy) and "haloalkoxyalkyl" radicals (e.g. fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl).

The term "acyl", alone or in combination, means a carbonyl or thiocarbonyl group bonded to a radical selected from, for example, optionally substituted, hydrido, alkyl (e.g. haloalkyl), alkenyl, alkynyl, alkoxy ("acyloxy" including acetyloxy, butyryloxy, iso- valeryloxy, phenylacetyloxy, benzoyloxy, p-methoxybenzoyloxy, and substituted acyloxy such as alkoxyalkyl and haloalkoxy), aryl, halo, heterocyclyl, heteroaryl, sulfinyl (e.g. alkylsulfinylalkyl), sulfonyl (e.g. alkylsulfonylalkyl), cycloalkyl, cycloalkenyl, thioalkyl, thioaryl, amino (e.g alkylamino or dialkylamino), and aralkoxy. Illustrative examples of "acyl" radicals are formyl, acetyl, 2-chloroacetyl, 2-bromacetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.

The term "cycloalkyl" refers to radicals having from about 3 to 16 or 3 to 15 carbon atoms and containing one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantyl, and the like. In certain aspects of the invention the cycloalkyl radicals are "lower cycloalkyl" radicals having from about 3 to 10, 3 to 8, 3 to 6, or 3 to 4 carbon atoms, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "cycloalkyl" also embraces radicals where cycloalkyl radicals are fused with aryl radicals or heterocyclyl radicals. Where a cycloalkyl radical is defined as being optionally substituted, the cycloalkyl radical may be substituted with groups as described below.

The term "cycloalkenyl" refers to a radical including about 2 to 16, 4 to 16, 2 to 15, 2 to 10, 4 to 10, 3 to 8, 3 to 6, or 4 to 6 carbon atoms, one or more carbon-carbon double bonds, and one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused. In certain aspects of the invention the cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms, in particular cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Where a cycloalkenyl radical is defined as being optionally substituted, the cycloalkyl radical may be substituted with groups as described below. The term "aryl", alone or in combination, refers to a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The term "fused" means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common or shared with the first ring. In aspects of the invention an aryl radical has 4 to 24 carbon atoms, in particular 4 to 10, 4 to 8, or 4 to 6 carbon atoms. The term "aryl" includes without limitation aromatic radicals such as phenyl, naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, azulenyl, tetrahydronaphthyl, indanyl, biphenyl, acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl, preferably phenyl. An aryl radical may be optionally substituted with groups as disclosed herein, in particular hydroxyl, alkyl, carbonyl, carboxyl, thiol, amino, and/or halo.

The term "aralkyl" used herein refers to an alkyl group with an aryl substituent, the term "aralkenyl" used herein refers to an alkenyl group with an aryl substituent, and the term "aralkynyl" used herein refers to an alkynyl group with an aryl substituent. Examples of substituted aryl radicals include benzyl, chlorobenyzl, and amino benzyl.

The term "heteroatom" refers to an atom other than carbon, e.g., a nitrogen, oxygen, sulfur or phosphorus atom. A heteroatom-containing radical refers to a molecule or molecular fragment in which one or more carbon atoms is replaced with a heteroatom. Accordingly, the term "heteroalkyl" refers to an alkyl substituent that is heteroatom- containing, the term "heterocyclic" refers to a cyclic substituent that is heteroatom- containing (see below), the term "heteroaryl" refers to an aryl substituent that is heteroatom-containing (see below), and the like.

The term "heteroaryl" refers to fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 3 to 15, 3 to 10, 5 to 15, 5 to 10, or 5 to 8 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. A heteroaryl radical may contain one, two or three rings and the rings may be attached in a pendant manner or may be fused. Examples of "heteroaryl" radicals, include without limitation, an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl and the like; an unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, in particular, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl and the like; an unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, in particular, 2-furyl, 3-furyl, and the like; an unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, in particular, 2-thienyl, 3-thienyl, and the like; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, in particular, oxazolyl, isoxazolyl, and oxadiazolyl; an unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, in particular benzoxazolyl, benzoxadiazolyl and the like; an unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl and the like; an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as benzothiazolyl, benzothiadiazolyl and the like. The term also includes radicals where heterocyclic radicals are fused with aryl radicals, in particular bicyclic radicals such as benzofuran, benzothiophene, and the like. When defined as being optionally substituted, a heteroaryl radical may be optionally substituted with groups as described below.

The term "heterocyclic" refers to saturated and partially saturated heteroatom- containing ring-shaped radicals having from about 3 to 15, 3 to 10, 5 to 15, 5 to 10, or 3 to 8 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. A heterocylic radical may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include without limitation a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl]; a saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; and, a saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl] etc. Examples of partially saturated heterocyclyl radicals include without limitation dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Illustrative heterocyclic radicals include without limitation 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1 ,3-dioxolanyI, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, and the like. When defined as being optionally substituted, a heterocyclic radical may be optionally substituted with groups as described below.

As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo and iodo, especially fluoro or chloro. The terms "haloalkyl," "haloalkenyl" or "haloalkynyl" refer to an alkyl, alkenyl, or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.

The term "amino", alone or in combination, refers to a radical where a nitrogen atom (N) is bonded to three substituents being any combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or silyl with the general chemical formula -NR₁₀Rn where Ri₀ and Rn can be any combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, silyl, heteroaryl, or heterocyclic which may or may not be substituted. Optionally one substituent on the nitrogen atom may be a hydroxyl group (- OH) to provide an amine known as a hydroxylamine. Illustrative examples of amino groups are amino (-NH₂), alkylamino, acylamino, cycloamino, acycloalkylamino, arylamino, arylalkylamino, and lower alkylsilylamino, in particular methylamino, ethylamino, dimethylamino, 2-propylamino, butylamino, isobutylamino, cyclopropylamino, benzylamino, aliylamino, hydroxylamino, cyclohexylamino, piperidine, benzylamino, diphenylmethylamino, tritylamino, trimethylsilylamino, and dimethyl-tert- butylsilylamino.

"Amido" refers to a functional group containing a carbon atom double-bonded to an oxygen atom and additionally singly bonded to a nitrogen atom [-C(O)-N]. The term includes a primary amide i.e., an unsubstituted amide group [-C(O)-NH₂]; a secondary amide and a tertiary amide, i.e., amides in which nitrogen is substituted with one and two non-hydrogen groups respectively.

When a radical in a tranilast-type compound may be optionally substituted, one or more substituents apparent to a person skilled in the art may be used, including without limitation alkyl, alkenyl, alkynyl, alkanoyl, alkylene, alkenylene, hydroxyalkyl, haloalkyl, haloalkylene, haloalkenyl, alkoxy, alkenyloxy, alkenyloxyalkyl, alkoxyalkyl, aryl, alkylaryl, haloalkoxy, haloalkenyloxy, heterocyclic, heteroaryl, sulfonyl, sulfenyl, alkylsulfonyl, sulfinyl, alkylsulfinyl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, amino, oxy, halo, azido, thio, cyano, hydroxyl, phosphonato, phosphinato, thioalkyl, alkylamino, arylamino, arylsulfonyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino, heteroaryloxy, heteroaryloxylalkyl, arylacetamidoyl, aryloxy, aroyl, aralkanoyl, aralkoxy, aryloxyalkyl, haloaryloxyalkyl, heteroaroyl, heteroaralkanoyl, heteroaralkoxy, hetθroaralkoxyalkyl, thioaryl, arylthioalkyl, alkoxyalkyl, and acyl groups.

A tranilast-type compound may be prepared using reactions and methods generally known to the person of ordinary skill in the art, having regard to that knowledge and the disclosure of this application. For example, tranilast-type compounds have been synthesized and tested within the context of the treatment of allergies, as described in US 3,940,422. Reactions for producing tranilast-type compounds are generally performed in a solvent appropriate to the reagents and materials used and suitable for the reactions being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the compounds should be consistent with the proposed reaction steps. This will sometimes require modification of the order of the synthetic steps or selection of one particular process scheme over another in order to obtain a desired tranilast-type compound. It will be recognized that another major consideration in the development of a synthetic route is the selection of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the skilled artisan is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

The starting materials and reagents used in preparing tranilast-type compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or Lancaster Synthesis Inc. (Windham, N. H.) or are prepared by methods well known to a person of ordinary skill in the art, following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991 ; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, N.Y., 1991 ; March J.: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, N. Y.; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

The starting materials, intermediates, and tranilast-type compounds may be isolated and purified using conventional techniques, such as precipitation, filtration, distillation, crystallization, chromatography, and the like. Tranilast-type compounds may be characterized using conventional methods, including physical constants and spectroscopic methods, in particular HPLC.

Tranilast-type compounds which are basic in nature can form a wide variety of different salts with various inorganic and organic acids. In practice is it desirable to first isolate a tranilast-type compound from the reaction mixture as a pharmaceutically unacceptable salt and then convert the latter to the free base compound by treatment with an alkaline reagent and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of base tranilast-type compounds are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.

Tranilast-type compounds which are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. These salts may be prepared by conventional techniques by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are typically employed to ensure completeness of reaction and maximum product yields. Pharmaceutical compositions

The invention provides a pharmaceutical composition including a therapeutically effective amount of a tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof, for treating a mesangioproliferative disease, in particular IgA nephropathy, for treating symptoms caused by a mesangioproliferative disease, in particular IgA nephropathy, and/or for suppressing the progression thereof. In aspects of the invention a pharmaceutical composition is in a form suitable for oral, topical, rectal, nasal, or parenteral administration. The pharmaceutical composition may be in the form of a liquid solution, syrup, elixir, aqueous or oily suspension, emulsion, tablet, pill, capsule, lozenge, troche, powder, granule, emulsion, sustained release formulation, or powder.

Pharmaceutical compositions of the present invention or fractions thereof for pharmaceutical or veterinary use may include suitable pharmaceutically acceptable carriers, excipients, and vehicles selected based on the intended form of administration, and consistent with conventional pharmaceutical practices. Suitable pharmaceutical carriers, excipients, and vehicles are described in the standard text, Remington: The Science and Practice of Pharmacy (21^st Edition. University of the Sciences in Philadelphia (Editor), Mack Publishing Company).

For example, for oral administration in the form of a capsule or tablet, the active components can be combined with oral, non-toxic pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol, sorbital, and the like. For oral administration in a liquid form, the tranilast-type compounds may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Suitable binders (e.g. gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums, and waxes), lubricants (e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride), disintegrating agents (e.g. starch, methyl cellulose, agar, bentonite, and xanthan gum), flavoring agents, and coloring agents may also be combined in the pharmaceutical composition or components thereof. Pharmaceutical compositions as described herein can further include wetting or emulsifying agents, or pH buffering agents.

As a further example, pharmaceutical compositions for parenteral administration may include sterile aqueous or non-aqueous solvents, syrups, emulsions with edible oil, or other solvents conveniently used for parenteral administration of therapeutically active agents. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Examples of aqueous solvents include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline, isotonic glucose solution, and buffered media. A pharmaceutical composition intended for parenteral administration may also include conventional additives such as dispersing or suspending agents, stabilizers, buffers, or preservatives, e.g. antioxidants such as methylhydroxybenzoate or similar additives. Dispersing or suspending agents that can be used for aqueous suspensions include synthetic or natural gums, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, and polyvinylpyrrolidone.

A pharmaceutical composition including a tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof may also be in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions include those adapted for:

(a) oral administration, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;

(b) parenteral administration, for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat;

(c) topical applications, e.g. as a cream, ointment or spray applied to the skin; or (d) intravaginally, e.g. as a pessary, cream or foam.

A pharmaceutical composition of the invention may be sterilized by, for example, filtration through a bacteria retaining filter, addition of sterilizing agents to the pharmaceutical composition, irradiation of the pharmaceutical composition, or heating the pharmaceutical composition. Alternatively, the compounds or compositions of the present invention may be provided as sterile solid preparations e.g. lyophilized powder, which are readily dissolved in sterile solvent immediately prior to use.

After pharmaceutical compositions have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a pharmaceutical composition of the invention, such labeling would include amount, frequency, and method of administration.

According to the invention, a kit is provided. In an aspect, the kit includes a tranilast- type compound or a pharmaceutical composition according to the present invention in kit form. The kit can be a package which houses a container which contains a pharmaceutical composition according to the present invention and also houses instructions for administering the pharmaceutical composition to a subject.

In embodiments of the invention, a pharmaceutical pack or kit is provided including one or more containers filled with one or more of the ingredients of a pharmaceutical composition according to the present invention to provide a beneficial effect, in particular a sustained beneficial effect. Associated with such containers) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the labeling, manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.

Applications

The invention contemplates the use of a tranilast-type compound or pharmaceutical composition including a tranilast-type compound for treating a mesangioproliferative disease, in particular preventing, and/or ameliorating disease severity, disease symptoms, and/or periodicity of recurrence of IgA nephropathy. The invention contemplates treating in a mammal a mesangioproliferative disease, in particular IgA nephropathy using the pharmaceutical composition or treatments of the invention. Preferably, the mammal is a human.

In an aspect of the invention a compound of the formula I to X or any one of Group A or Group B, preferably formula I, is utilized in the treatment of a mesangioproliferative disease, in particular IgA nephropathy. Thus, a mesangioproliferative disease, in particular IgA nephropathy, may be treated by administering a therapeutically effective amount of a compound of the formula I to X or any one of Group A or Group B. Such treatment may be effective for retarding the effects of a mesangioproliferative disease, in particular IgA nephropathy, including specifically, but not exclusively, mesangial proliferation, matrix accumulation, macrophage infiltration, and proteinuria.

In an embodiment, beneficial effects of a pharmaceutical composition or treatment of the invention for a mesangioproliferative disease, in particular IgA nephropathy, can manifest as one or more or all of the following:

a) A reduction, slowing or prevention of an increase in, or an absence of symptoms of a mesangioproliferative disease, in particular IgA nephropathy, including without limitation proteinuria, hematuria, fatigue, malaise, myalgia, and/or hypertension, after administration to a subject with symptoms of IgA nephropathy.

b) A reduction, slowing or prevention of an increase in accumulation of IgA deposition in the glomerular mesangium relative to the levels measured in the absence of a compound disclosed herein in subjects with symptoms of IgA nephropathy. In aspects of the invention, the compound induces at least about a

2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in IgA deposition in the glomerular mesangium.

c) A reduction in the kinetics of assembly of IgA deposition in the glomerular mesangium, in particular a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction in the kinetics of IgA deposition in the glomerular mesangium of subjects with IgA nephropathy.

d) A reduction, slowing or prevention of PDGF-induced mesangial cell proliferation, relative to the amount measured in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy. In aspects of the invention, the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in PDGF-induced mesangial cell proliferation.

e) A reduction or inhibition of mesangial cell numbers relative to the numbers measured in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy. In aspects of the invention, the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in mesangial cell numbers.

f) A reduction, slowing or prevention of glomerular matrix accumulation relative to the amount of accumulation in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy. In aspects of the invention, the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in glomerular matrix accumulation.

g) A reduction or inhibition of PDGF activity relative to the amount measured in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy. In aspects of the invention, the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%,

40%, 50%, 60%, 70%, 80%, or 90% reduction or inhibition of PDGF activity.

h) A reduction or inhibition of TGF-β activity relative to the amount measured in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy. In aspects of the invention, the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction or inhibition of TGF-β activity.

i) A reduction or inhibition of collagen synthesis relative to the amount measured in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy. In aspects of the invention, the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%,

40%, 50%, 60%, 70%, 80%, or 90% reduction or inhibition of collagen synthesis.

j) A reduction or elimination of hematuria, in particular macroscopic hematuria relative to the amount in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy. In aspects of the invention, the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction of hematuria, in particular macroscopic hematuria.

k) A reduction or elimination of proteinuria relative to the amount in the absence of a compound disclosed herein in subjects with symptoms of a mesangioproliferative disease, in particular IgA nephropathy. In aspects of the invention, the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction of proteinuria.

I) A reduction or elimination of hypertension relative to the amount in the absence of a compound disclosed herein in subjects with symptoms of a mMesangioproliferative disease, in particular IgA nephropathy. In aspects of the invention, the compound induces at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction of hypertension.

m) A reduction or slowing of the rate of disease progression in a subject with an IgA deposition disease, in particular IgA nephropathy.

n) A reduction in mortality. o) An increase in survival or longevity in a subject with symptoms of an IgA deposition disease, in particular IgA nephropathy.

In aspects of the invention beneficial effects of a pharmaceutical composition or treatment of the invention can manifest as (a) and (b); (a), (b) and (c); (a), (b), (c) and (d); (a), (b), (C), (d), (e) and (f); (a), (b), (c), (d), (e), (f) and (g); (a) to (h); (a) to (i); (a) to G), (a) to (k), (a) to (I), (a) to (m), (a) to (n), or (a) to (o).

Compounds, compositions and methods of the invention can be selected that have sustained beneficial effects, preferably statistically significant sustained beneficial effects. In an embodiment, a pharmaceutical composition with statistically significant sustained beneficial effects is provided including a therapeutically effective amount of a compound of the invention.

Greater efficacy and potency of a treatment of the invention in some aspects may improve the therapeutic ratio of treatment, reducing untoward side effects and toxicity. Selected methods of the invention may also improve long-standing disease even when treatment is begun long after the appearance of symptoms. Prolonged efficacious treatment can be achieved in accordance with the invention following administration of a tranilast-type compound, in particular a compound of the formula I to X or any one of Group A or Group B, preferably formula I, or pharmaceutical composition including same.

In an aspect, the invention provides a method for reducing proteinuria in a subject including administering to the subject a tranilast-type compound.

In a further aspect, the invention provides a method for treating IgA nephropathy in a patient in need thereof which includes administering to the individual a pharmaceutical composition that provides a tranilast-type compound of the invention in a dose sufficient to reduce proteinuria in the patient. In another aspect, the invention provides a method for treating IgA nephropathy including administering, preferably orally or systemically, an amount of a tranilast-type compound of the invention to a mammal, to reduce proteinuria, in particular for a prolonged period following administration. The invention in an embodiment provides a method for treating a mesangioproliferative disease, in particular IgA nephropathy, the method including administering to a mammal in need thereof a pharmaceutical composition including a tranilast-type compound of the invention in an amount sufficient to reduce mesangial proliferation, matrix expansion and/or macrophage infiltration, preferably for a prolonged period following administration, thereby treating the mesangioproliferative disease, in particular IgA nephropathy.

In another aspect, the invention provides a method for treating an IgA nephropathy by providing a pharmaceutical composition including a tranilast-type compound of the invention in an amount sufficient to disrupt IgA deposition in a subject, in particular for a prolonged period following administration. In an embodiment the method additionally includes determining the amount of IgA deposits. The amount of IgA deposits may be measured using an antibody specific for IgA labeled with a detectable substance.

In a further aspect, the invention provides a method for preventing and/or treating IgA nephropathy, the method including administering to a mammal in need thereof a pharmaceutical composition including a tranilast-type compound of the invention in an amount sufficient to disrupt IgA deposits, reduce mesangial proliferation, matrix expansion, proteinuria and/or macrophage infiltration preferably for a prolonged period following administration thereby treating the IgA nephropathy.

The present invention also includes methods and compositions of the invention in combination with one or more additional agents. For example, methods and pharmaceutical compositions for treating mesangioproliferative disease, in particular IgA nephropathy, may include without limitation, ACE inhibitors, angiotensin Il receptor blockers, immuno-suppressive drugs such as azathioprine, prednisone, cyclophosphamide (e.g., Cytoxan), fish oil (omega-3 fatty acids), and mycophenolate mofetil, agents that are used for the treatment of complications resulting from or associated with a mesangioproliferative disease, or general medications that treat or prevent side effects. It is intended to include any chemically compatible combination of pharmaceutically-active agents, as long as the combination does not eliminate the activity of the tranilast compound. It will be appreciated that a tranilast-type compound and the other agent(s) may be administered separately, sequentially or simultaneously.

The invention contemplates the use of at least one tranilast-type compound for the preparation of a pharmaceutical composition for treating a mesangioproliferative disease, in particular IgA nephropathy. The invention additionally provides uses of a tranilast-type compound in the preparation of pharmaceutical compositions for the prevention and/or treatment of a mesangioproliferative disease, in particular IgA nephropathy. In an embodiment, the invention relates to the use of a therapeutically effective amount of at least one compound of the formula I to X or at least one compound of Group A and/or Group B for preparation of a pharmaceutical composition for providing therapeutic effects, in particular beneficial effects, preferably sustained beneficial effects, in treating a mesangioproliferative disease, in particular an IgA nephropathy. In a still further embodiment the invention provides the use of a tranilast- type compound for the preparation of a pharmaceutical composition for prolonged or sustained treatment of a mesangioproliferative disease, in particular IgA nephropathy.

Therapeutic efficacy and toxicity of pharmaceutical compositions and methods of the invention may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals such as by calculating a statistical parameter such as the ED₅₀ (the dose that is therapeutically effective in 50% of the population) or LD_5O (the dose lethal to 50% of the population) statistics. The therapeutic index is the dose ratio of therapeutic to toxic effects and it can be expressed as the ED₅o/LD_5O ratio. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. By way of example, one or more of the therapeutic effects, in particular beneficial effects disclosed herein, can be demonstrated in a subject or disease model, for example, Wister Kyoto rats with induced anti-Thy-1 nephritis as illustrated in the Example.

Administration

Compounds and pharmaceutical compositions of the present invention can be administered by any means that produce contact of the active agent(s) with the agent's sites of action in the body of a subject or patient to produce a therapeutic effect, in particular a beneficial effect, in particular a sustained beneficial effect. The active ingredients can be administered simultaneously or sequentially and in any order at different points in time to provide the desired beneficial effects. The tranilast-type compound or pharmaceutical composition according to the invention can be formulated for sustained release, for delivery locally or systemically. It lies within the capability of a skilled physician or veterinarian to select a form and route of administration that optimizes the effects of the pharmaceutical compositions and treatments of the present invention to provide therapeutic effects, in particular beneficial effects, more particularly sustained beneficial effects.

A tranilast-type compound or pharmaceutical composition may be suitable for oral, topical (including buccal and sublingual), ocular (including tear film, anterior chamber, posterior chamber or subretinal administration), rectal, nasal, vaginal or parenteral administration. The term "parenteral" as used herein includes subcutaneous injections, aerosol for administration to lungs or nasal cavity, intravenous, intramuscular, intrathecal, intracranial, injection or infusion techniques.

In an aspect of the invention, a tranilast-type compound or pharmaceutical composition may be administered in an oral dosage form such as a tablet, capsule (each of which includes sustained release or timed release formulations), pill, powder, granule, elixir, tincture, suspension, syrup, and emulsion.

A tranilast-type compound or pharmaceutical composition may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular forms, all utilizing dosage forms well known to those of ordinary skill in the pharmaceutical arts.

The pharmaceutical compositions of the invention may be administered by intranasal route via topical use of suitable intranasal vehicles, or via a transdermal route, for example using conventional transdermal skin patches. A dosage protocol for administration using a transdermal delivery system may be continuous rather than intermittent throughout the dosage regimen. ,

In one contemplated method a compound of Formula I to X or any one of Group A or Group B for in vivo application, can be administered parenterally by injection or by gradual perfusion over time. Administration may be intravenously, intra-arterially, intraperitoneally, intramuscularly, subcutaneously, intracavity, transdermally or infusion by, for example, osmotic pump.

The dosage regimen of the invention will vary depending upon known factors such as the pharmacodynamic characteristics of the tranilast-type compound or pharmaceutical composition and their mode and route of administration; the species, age, sex, health, medical condition, and weight of the patient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, the route of administration, the renal and hepatic function of the patient, and the desired effect.

An amount of a therapeutic of the invention which will be effective in the treatment of a mesangioproliferative disease, in particular an IgA nephropathy, to provide therapeutic effects, in particular beneficial effects, more particularly sustained beneficial effects, can be determined by standard clinical techniques. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease, and should be decided according to the judgment of the practitioner and each patient's circumstances.

Suitable dosage ranges for administration are particularly selected to provide therapeutic effects, in particular beneficial effects, more particularly sustained beneficial effects. A dosage range is generally effective for triggering the desired biological responses. The pharmacokinetics of orally administered tranilast have been studied in humans (Charng, etal., (2002) Journal of Food and Drug Analysis 10:135-138), and this information can be utilized by the skilled addressee in determining the dosage regimen of a traniiast-type compound.

A pharmaceutical composition or treatment of the invention may include a unit dosage of at least one tranilast-type compound. A "unit dosage" or "dosage unit" refers to a unitary i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose including either the active agents as such or a mixture with one or more solid or liquid pharmaceutical excipients, carriers, or vehicles. Dosage ranges for tranilast-type compounds are generally about 0.1 mg to about 2 g per kilogram body weight (assuming a 70 kg subject) per day. In aspects of the invention the dosage range may be about 1 mg to about 200 mg per kg per day about 1 mg to about 200 mg per kg per day, about 1 mg to about 100 mg per kg per day, about 5 to 100 mg per kg per day, about 1 mg to about 50 mg per kg per day, about 2 to about 50 mg per kg per day, about 2 mg to about 40 mg per kg, about 2 mg to 30 mg per kg per day, about 2 to 20 mg per kg per day, about 2 to about 25 mg per kg per day, about 2 to 20 mg per kg per day, about 3 to 25 mg per kg per day, about 3 to 20 mg per kg per day, or about 3 to 15 mg per kg per day.

In aspects of the invention, a pharmaceutical composition may include about 1 mg to about 1000 mg, about 50 mg to about 1000 mg, about 50 mg to about 900 mg, about 75 mg to about 900 mg, about 100 mg to about 900 mg, about 200 mg to about 900 mg, about 300 mg to about 900 mg, or about 100 mg to about 500 mg, about 100 mg to about 400 mg, or about 100 mg to about 300 mg, of a tranilast-type compound.

In an aspect of the invention a dosage level of a tranilast-type compound, in particular a compound of the formula I to X or any one of Group A or Group B is of the order of about 4 mg to about 13 mg per kilogram body weight (assuming a 70 kg subject) per day. The amount of the compound of Formula I to X or any one of Group A or Group B which may be combined with the carrier materials to produce a single dosage will vary, depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain about 300 mg to 900mg of the compound with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition. Unit dosages will generally contain between from about 100 mg to 300 mg of the compound of I to X or any one of Group A or Group B.

In aspects of the invention, the daily doses of a tranilast-type compound may be from about 0.01 mg/kg per day to 1000 mg/kg per day. Small doses (0.01-1 mg) may be administered initially, followed by increasing doses up to about 1000 mg/kg per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localised delivery route) may be employed to the extent patient tolerance permits. A subject may be treated with a compound of the formula I to X or any one of Group A or Group B or pharmaceutical composition or formulation thereof on substantially any desired schedule. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds. For example, a daily dose may be administered in one, two, three or four doses per day. Thus, a pharmaceutical composition of the invention may be administered one or more times per day, in particular 1 or 2 times per day, once per week, once a month or continuously. However, a subject may be treated less frequently, such as every other day or once a week, or more frequently. A compound, pharmaceutical composition or formulation of the invention may be administered to a subject for about or at least about 1 week, 2 weeks to 4 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, or 2 weeks to 24 months, periodically or continuously.

In aspects of the invention, the dosage ranges of a tranilast-type compound may be administered once twice, three times or more daily, especially once or twice daily. In a particular aspect, a tranilast-type compound of the formula I to X or any one of Group A or Group B is administered in a divided dose schedule, such that there are at least two administrations in total in the schedule. Administrations are given preferably at least every two hours for up to four hours or longer; for example the compound may be administered every hour or every half hour. In an embodiment, the divided-dose regimen includes a second administration of the compound after an interval from the first administration sufficiently long that the level of the compound in the blood has decreased to approximately 5-30% of the maximum plasma level reached after the first administration, so as to maintain an effective content of the compound in the blood. Optionally one or more subsequent administrations may be given at a corresponding interval from each preceding administration, preferably when the plasma level has decreased to approximately 10-50% of the immediately-preceding maximum.

In an aspect, the required dose of a compound disclosed herein, administered twice daily is about 1 to 50 mg/kg/day, 1 to 40 mg/kg/day, 3 to 40 mg/kg/day, 3 to 30 mg/kg/day, 3 to 25 mg/kg/day, most preferably 3 to 20 mg/kg/day. Dosages of a tranilast-type compound, and related dosage regimes, that are particularly suitable for use in treating mesangioproliferative diseases include:

• a daily dose of approximately 300mg of a tranilast-type compound, which may be administered in a dosage regime of 100mg of a tranilast-type compound three times daily; and

• a daily dose of 600 to 900mg of a tranilast-type compound, which may be administered in a dosage regime of 300 to 450mg of a tranilast-type compound twice daily.

The invention will be described in greater detail by way of the following examples. These examples are offered for illustrative purposes, and is not intended to limit the invention in any manner.

EXAMPLE 1

The following methods were used in the study described in Example 1.

Antibodies

Monoclonal OX-7, anti-rat Thy-1.1 antibody was used for the induction of mesangial proliferative glomerulonephritis. Macrophages were detected using ED1 , anti-rat CD68 and myofibroblasts were identified by labeling with 1A4, anti-human α-smooth muscle actin (Sigma Immunochemicals , St. Louis, MO, USA). A polyclonal goat anti- bovine/anti-human type IV collagen antibody (Southern Biotechnology, Birmingham, AL, USA) was used to examine extracellular matrix.

Mesangial cell culture

For in vitro studies, tranilast was prepared in dimethyl sulfoxide as 1000-fold stock solutions (DMSO). This stock solution was then diluted in cell culture medium to the required final concentration of 0 to 100 μmol/L. A well-characterized cloned mesangial cell line (1097) isolated from Sprague-Dawley rats was used between passages 20 and 40. For these experiments, cells were cultured in Dulbecco's Modified Eagle's Medium (DME, Invitrogen, Grand Island, NY, USA) with heat-inactivated fetal calf serum (FCS), 100 U/mL penicillin, and 100 μg/mL streptomycin in humidified 5% CO₂ atmosphere at 37°C. Mesangial cells were plated out in 24-well plates in DME/5% FCS and allowed to adhere overnight. The subconfluent cells were then starved overnight in DME/0.5% FCS prior to commencement of studies.

Proliferation

To determine the effects of tranilast on mesangial cell proliferation cells were treated with 0 to 100 μmol/L tranilast for 4 hours prior to the addition of recombinant PDGF-BB 50 ng/mL (Sigma, St Louis, MO). Cells were incubated for a further 20 hours and ³H thymidine (1 μCi/well, Amersham Bioscience, Little Chalfont, Buckinghamshire, UK) was added for the last 4 hours of culture. Cells were washed twice in ice cold phosphate buffered saline (PBS), incubated in ice cold 10% TCA for 30 minutes, followed by a final

wash in ice cold 10% TCA. The cells were then dissolved in 1 M sodium hydroxide. This solution was then neutralized with hydrochloric acid, and scintillation counting was performed. Replicates of three wells were used. Cell viability was assessed by trypan blue exclusion.

Collagen synthesis

³H-proline incorporation was used as an index of collagen production. Mesangial cells were plated, cultured, and starved as for thymidine incorporation except that 150 μM

Lascorbic acid was incubated in the starve medium for 4 hours. Cells were pretreated with 0-100 μM tranilast for 4 hours prior to the addition of PDGF-BB (50 ng/mL) and

1μCi/well L-[ 2, 3, 4, 5-3H] proline (Amersham). Cells were cultured for a further 44 hours and washed and counted as for thymidine incorporation. Replicates of three wells were used.

PDGF receptor phosphorylation

To examine the effects of tranilast on PDGF receptor (PDGFR) activation, cells were plated into 6-weII culture dishes in DMEM/10%FBS at low density and allowed to adhere overnight. The subconfluent cells were then starved overnight in DMEM/0.5%FBS, prior to pre-treatment with 0 to 100 μmol/L tranilast or without tranilast for 4 hours, followed by stimulation with PDGF-BB (50ng/mL). At the end of the incubation, cells were immediately placed on ice, washed once with ice-cold PBS, and lysed in 100 μ\ of lysis buffer of 50 mM Tris, pH 7.4, 150 mM NaCl, 1mM EDTA, 1 mM EGTA, 0.5% Triton X-100, 0.5% lgepal CA-630, 0.1% SDS₁ 1 mM Na vanadate, 50 mM NaF, 25 mM β glycerophosphate, 1OmM Na pyrophosphate, 10 μg/mL aprotinin, 10 μg/mL leupeptin, and 1 mM AEBSF. Cell lysates were passed through a 21 G needle five times to aid solubilisation. Lysates were placed on ice for 30 minutes before centrifuging at 13,000 rpm at 4°C to remove cell debris, and protein concentration determined using the Bio-Rad Protein Assay (Bio-Rad Laboratories, Hercules, CA). Lysates were subjected to western blot analysis. In brief, samples with equal concentrations of protein were separated on 10% SDS-polyacrylamide gels transferred onto PVDF membranes (Roche Pharmaceuticals, Australia). Membranes were blocked with 5% nonfat milk in TBST (Tris buffered saline, 0.1% Tween 20) before overnight incubation at 4⁰C with 1 :1000 rabbit anti-phosphorylated PDGFR-β (p-PDGFR-β; Cell Signaling, Beverly, MA) in 5% bovine serum albumin (BSA). After extensive washes in TBST, membranes were incubated with horseradish peroxidase-conjugated anti-rabbit IgG (DAKO, Denmark) for 1 hour at room temperature. Signal was detected with enhanced chemiluminescent reagent and exposure to Hyperfilm (Amersham, Little Chalfont, UK). After detection of phosphorylated-PDGFR (p-PDGFR)-^, the membranes were stripped and probed with anti-PDGFR-β antibody (1 :300 in 2% fat free milk, Santa Cms). Bands were quantified densitometrically as previously described as ratios of the densities of p-PDGFR-/? to total PDGFR-β.

Rat anti-Thy-1 nephritis

Twenty-four male Wister Kyoto rats that weighed 200 to 250 g were randomized to three groups of 8 animals each. Anti-Thy-1 nephritis was induced in two groups of eight rats by an intravenous injection of 5 mg/kg OX-7 IgG. Starting one day after OX-7 IgG administration, animals received daily gavage with either tranilast (400 mg/kg per day; Pharm Chemical, Shanghai Lansheng Corporation, Shanghai, China) or vehicle control until killed on day 6, the peak of mesangial proliferation in this model. The administration of tranilast was commenced 24 hours after OX-7 administration as mesangiolysis is complete by this time.

Proteinuria and renal function assessment

Twenty-four hour urine collections and blood samples were taken at baseline, 3 days prior to OX-7 administration, and at day 6 post OX-7. Urinary protein concentration was measured by the benzethonium chloride method. Serum and urine creatinine levels were measured using the Jaffe rate reaction.

Histology and lmmunohistochemistry

Tissues were fixed in 10% neutral-buffered formalin and embedded in paraffin. Kidney sections (4 μm) were stained with periodic acid-Schiffs reagent (PAS). Nuclei were counted in 50 hilar glomeruli in each animal.

Type IV collagen.

In brief, immunostaining for type IV collagen was performed by the following method. Kidney sections were rehydrated and treated with 1% H₂O₂/methanol followed by incubation in Protein Blocking Agent (Lipshaw-lmmunon, Pittsburgh, PA, USA) for 20 minutes at room temperature. Sections were then incubated with type IV collagen antibody for 60 minutes at room temperature, washed in PBS, and incubated with biotinylated goat anti-rabbit immunoglobulin (Dako, Carpinteria, CA, USA) followed by incubation with avidin-biotin peroxidase complex (ABC; Vector, Burlingham, CA, USA). Peroxidase conjugates were subsequently localized using diaminobenzidine tetrahydrochloride (DAB) as a chromogen. Sections were then counterstained with Mayer's hematoxylin.

α-Smooth muscle actin

Immunostaining for α-smooth muscle actin was performed in formalin fixed tissue sections using a microwave-based technique to prevent antibody cross-reactivity. In brief, sections were microwave treated for 10 minutes in 0.01 mol/L sodium citrate buffer, pH 6.0, and then labeled with α-smooth muscle actin antibody using a three- layer peroxidase-antiperoxidase method and developed with 3,3- DAB (Sigma) to produce a brown color.

Negative controls.

Sections incubated with protein blocking agent instead of primary antisera served as negative controls. Tissues were also incubated with irrelevant isotype control antibodies. Tissues treated in this manner showed no positive staining.

Quantitation of immunohistochemistry

Sections stained with ED1 antibody were scored manually counting immunolabelled cells in fifty hilar glomeruli in cross section under high power (x400) with the observer masked to the study group. The magnitude of immunostaining for α-smooth muscle actin or type IV collagen was quantitated using computer-assisted image analysis. In brief, for each tissue section, images from three nonoverlapping, randomly selected fields were examined by light microscopy (Olympus BX-50; Olympus Optical, Tokyo, Japan) and digitized using a high-resolution camera (Fujix HC-2000; Fujifilm, Tokyo, Japan). All images were obtained using a 20 objective lens. Digitized images were then captured on a Power Macintosh G3 computer (Apple Computer Inc., Cupertino, CA, USA) equipped with an in-built graphic board and opened using analytical software (Analytical Imaging Software, Ontario, Canada). The area of brown on an immunoperoxidase-stained section was selected for its colour range, and the proportional area of tissue with this range of colour was then quantitated on 50 hilar glomeruli per animal such that the magnitude of immunolabeling was expressed as the proportional area of the tissue section that stained brown.

Statistics

All data are shown as mean ± SEM unless otherwise specified. Data were analyzed by analysis of variance (ANOVA) using the StatView IV program (Brainpower, Calabasas, CA, USA) on a Macintosh G4. Comparisons between group means were performed by Fisher's least significant difference method. A P value of less than 0.05 was considered statistically significant.

Results

In vitro studies

PDGF-induced ³H-thymidine incorporation and ³H-proline incorporation in mesangial cells were each inhibited by treatment of cells with tranilast in a dose-dependent fashion (Fig. 1). PDGF-induced phosphorylation of PDGFR-/? was also inhibited by tranilast without affecting total PDGFR-/? (Figure 2). Mesangial cells remained viable, as evidenced by trypan blue exclusion and the maintenance of normal mesangial cell appearance, including nuclear morphology.

Animal characteristics

The administration of OX-7 IgG both with and without tranilast was well tolerated by all experimental animals with no weight loss or evidence of distress. Proteinuria was increased in animals that received OX-7 IgG compared with control rats and was improved by tranilast treatment (Table 1 ).

Table 1. Animal characteristics in control and experimental mesangial proliferative glomerulonephritis with or without tranilast treatment.

Data are expressed as mean ± SEM.

^* p < 0.05 versus control, ^f p < 0.05 versus Thy-1

Glomerular histopathology

In PAS-stained sections, mesangial hypercellularity and increased mesangial matrix were noted in glomeruli of untreated rats. These pathological changes were substantially attenuated in rats that had received tranilast (Fig. 3). Similarly, when assessed by the nuclear counting of PAS-stained sections, animals with anti-Thy-1 nephritis displayed moderate glomerular hypercellularity when compared with control animals that was also reduced by tranilast (Fig. 4). The number of macrophages (ED- 1+) was increased 5-fold compared with control rats and reduced by treatment with tranilast (Fig. 5). The proportional area of glomeruli immunostained for α-smooth muscle actin indicating activated mesangial cells was also increased in untreated rats with anti- Thy-1 nephritis and reduced by treatment with tranilast (Figures. 6 and 7). Marked accumulation of immunostainable type IV collagen was present in untreated rats with antiThy-1 nephritis and was significantly reduced by treatment with tranilast (Figures. 6 and 7).

Discussion

Mesangial proliferation, matrix expansion and macrophage infiltration are hallmarks of glomerulonephritis. Using a widely studied model that simulates mesangial proliferative disease, this experiment shows that tranilast, attenuates both the extent of histological injury and the magnitude of proteinuria. In particular, this experiment shows that, in addition to ameliorating structural injury in the in vivo context, tranilast also abrogates

PDGF-induced mesangial cell proliferation, collagen synthesis and PDGFR-/? phosphorylation in mesangial cell culture. However, the mechanism of action of tranilast that contributes to the beneficial effects of this compound on kidney structure and function, that are demonstrated in this experiment are uncertain.

In summary, this experiment, in which tranilast reduced both the structural and functional manifestations of experimental mesangial proliferative glomerulonephritis, suggests that despite the unanswered questions regarding its mechanism of action tranilast is suitable as a potential therapy for mesangial proliferative glomerulonephritis including IgA nephropathy, particularly in the context of its efficacy and apparent safety in studies of human diabetic nephropathy. EXAMPLE 2

FT011 Attenuates Acute Experimental Mesangial Proliferative Glomerulonephritis

Methods

Antibodies

Anti-rat Thy-1.1 antibody (Monoclonal OX-7 IgG, gift from Dr. Nikolic-Paterson) was used for the induction of mesangial proliferative glomerulonephritis [1], macrophages were detected using ED1 , mouse anti-rat CD68 antibody (Serotec, Oxford, UK) [2]. Mouse anti-human α-smooth muscle actin (clone 1A4) antibody (DAKO, Denmark) was used to identify myofibroblasts. A polyclonal goat anti-human type IV collagen antibody (Southern Biotechnology, Birmingham, AL, USA) was also used to examine extracellular matrix.

Rat anti-Thy-1 nephritis

Male Wister rats (western Australia) weighed 200 to 250 gram were randomised to control and anti-thy-1 nephritis groups of 16 animals each. Anti-Thy-1 nephritis was induced by an intravenous injection of 5 mg/kg OX-7 IgG, as previously described [3]. Starting one day after OX-7 IgG or vehicle (0.9 % saline) administration, animals were further divided to receive either FT011 (100 mg/kg bid gavage; Fibrotech Therapeutics Pty Ltd, Melbourne) or vehicle control until culled on day 6, the peak of mesangial proliferation in this model [3]. The administration of FT011 was commenced 24 hours after OX-7 IgG administration as mesangiolysis is completed by this time [3].

Histology

Tissues were fixed in 10% neutral-buffered formalin and were embedded in paraffin. Kidney sections (4 μm) were stained with Haematoxylin and eosin (H & E) and periodic acid-Schiff s reagent (PAS). Quantitation of glomerular nuclei and mesangial expansion were performed by examining 50 hilar glomeruli per animal with light microscope.

lmmunohistochemistry

Type IV collagen

lmmunostaining for type IV collagen was performed as previously described [4]. In brief, kidney sections were rehydrated and treated with 3% H₂O₂ followed by incubation in Protein Blocking Agent (Lipshaw-lmmunon, Pittsburgh, PA, USA) for 20 minutes at room temperature. Sections were then incubated with type IV collagen antibody (diluted 1 in 40 with PBS) for 60 minutes at room temperature, washed in PBS, and incubated with biotinylated rabbit anti-goat immunoglobulin (Dako, Carpinteria, CA, USA) followed by incubation with avidin-biotin peroxidase complex (ABC; Vector, Burlingham, CA, USA). Peroxidase conjugates were subsequently localized using diaminobenzidine tetrahydrochloride (DAB) as a chromogen. Sections were then counterstained with Mayer's hematoxylin.

α-Smooth muscle actin

lmmunostaining for α-smooth muscle actin was performed in formalin fixed tissue sections using a microwave-based pre-treatment technique, as previously described [5]. In brief, sections were microwave treated for 10 minutes in 0.01mol/L sodium citrate buffer, pH 6.0, and then labeled with α-smooth muscle actin antibody (diluted 1 in 50 with PBS) using a three-layer peroxidase-antiperoxidase method and developed with 3,3-DAB (Sigma) to produce a brown color.

Macrophages

lmmunostaining for macrophages was performed in formalin fixed tissue sections, as previously described [6]. In brief, sections were microwave treated for 10 minutes in 0.01mol/L sodium citrate buffer, pH 6.0, and then labeled with mouse anti-rat CD68 (diluted 1 in 300 with PBS) using a three-layer peroxidase-antiperoxidase method and developed with 3,3-DAB (Sigma) to produce a brown colour. Quantitation of mesangial expansion and immunohistochemistry

The magnitude of mesangial expansion with PAS and immunostaining for α-smooth muscle actin or type IV collagen was quantitated using computer-assisted image analysis as previously described [7,8]. In brief, images from 50 hilar glomeruli per animal were examined by light microscopy (Olympus BX-50; Olympus Optical, Tokyo, Japan) and digitized using a high-resolution camera (Fujix HC-2000; Fujifilm, Tokyo, Japan). All images were obtained using x40 objective lens. Digitized images were then captured on a Power Macintosh G5 computer (Apple Computer Inc., Cupertino, CA, USA) equipped with an in-built graphic board and opened using analytical software (Analytical Imaging Software, Ontario, Canada). The area of magenta on a PAS stained or brown on an immunoperoxidase-stained section was selected for its colour range, and the proportional area of tissue with this range of colour was then quantitated on 50 hilar glomeruli per animal such that the magnitude of mesangial expansion and immunolabeling were expressed as the proportional area of the tissue section that stained magenta and brown, respectively.

Statistics

All data are shown as mean ± SEM unless otherwise specified. Data were analyzed by analysis of variance (ANOVA) using the StatView IV program (Brainpower, Calabasas, CA, USA) on a Macintosh G3. Comparisons between group means were performed by Fisher's least significant difference method. A P value of less than 0.05 was considered statistically significant.

RESULTS

Clinical characteristics

The administration of FT011 was well tolerated by experimental animals with no weight loss or change in blood pressure (Table 2). Table 2. Animal characteristics in control and experimental mesangial proliferative glomerulonephritis (Anti-Thy-1).

Data are expressed as mean ± SEM

Glomerular hypercellularity and mesangial proliferation

In H & E and PAS-stained sections, glomerular hypercellularity and mesangial expansion was evident in untreated rats following anti-Thy-1 nephritis when compared with control rats (Figures 8 to 10). These pathological changes were significantly attenuated with FT011 treatment (Figures 8 to 10).

Mesangial cell activation

The proportional area of glomeruli immunostained for α-smooth muscle actin (indicating activation of mesangial cells) was increased with anti-Thy-1 and significantly reduced by treatment with FT011 (Figures 11 and 12).

Glomerular matrix accumulation

Marked accumulation of immunostainable type IV collagen was present in untreated rats with anti-Thy-1 nephritis and was significantly reduced by treatment with FT011 (Figures 13 and 14). Glomerular macrophage infiltration

Increased macrophage infiltration was evident in anti-Thy-1 nephritic rats when compared to control rats (Figures 15 and 16), while treatment with FT011 was associated with a significant reduction in glomerular macrophages (Figures 15 and 16).

REFERENCES

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2. Van den Berg TK, Dopp EA, Breve JJ, et al.: The heterogeneity of the reticulum of rat peripheral lymphoid organs identified by monoclonal antibodies. Eur J

Immunol 19:1747-1756, 1989

3. Gilbert RE, Kelly DJ, McKay T, et al.: PDGF signal transduction inhibition ameliorates experimental mesangial proliferative glomerulonephritis. Kidney lnt 59:1324-1332, 2001

4. Rumble JR, Cooper ME, Soulis T, et al.: Vascular hypertrophy in experimental diabetes. Role of advanced glycation end products. J Clin Invest 99:1016-1027, 1997

5. Tesch GH, Lan HY, Atkins RC, et al.: Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol 151 :141-150, 1997

6. Wu LL, Cox A, Roe CJ, et al.: Transforming growth factor beta 1 and renal injury following subtotal nephrectomy in the rat: role of the renin-angiotensin system. Kidney lnt 51 :1553-1567, 1997

7. Lehr HA, van der Loos CM, Teeling P, et al.: Complete chromogen separation and analysis in double immunohistochemical stains using photoshop-based image analysis. J Histochem Cytochem 47:119-126, 1999

8. Lehr HA, Mankoff DA, Corwin D, et al.: Application of photoshop-based image analysis to quantification of hormone receptor expression in breast cancer. J Histochem Cytochem 45:1559-1565, 1997 The present invention is not to be limited in scope by the specific embodiments described herein, since such embodiments are intended as but single illustrations of one aspect of the invention and any functionally equivalent embodiments are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

All publications, patents and patent applications referred to herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. All publications, patents and patent applications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the methods etc. which are reported therein which might be used in connection with the invention.

Claims

1. A pharmaceutical composition for treating a mesangioproliferative disease including a therapeutically effective amount of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier, excipient or vehicle.

2. A pharmaceutical composition according to claim 1 wherein the tranilast-type compound is a compound of formula I

Formula I

wherein Ri and R₂, which may be the same or different, are selected from the group consisting of a Ci to C₁₀ alkyl, C3 to C₁₀ cycloalkyl, C3 to C10 cycloalkylmethyl, C₃ to Ci₀ alkene, C₃ to C10 alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

T is a single or double bond;

R₃ is selected from the group consisting of H, C₃ to C-10 alkene, C₃ to C₁₀ alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

R₄ is selected from the group consisting of H, OH, OR₆, NHR₆ and NR₆R₇; R₅ is selected from the group consisting of H, NHR₆, NR₆R₇, ORs, halogen, C₃ to C-io alkene, C₃ to C₁₀ alkyne and a chain consisting of a heterocyclic or fused ring, any of which may be optionally substituted;

R₆ and R₇, which may be the same or different, are selected from the group consisting of H, Ci to do alkyl, C₃ to do cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀ alkyne, aryl, C₅ to C₂o alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

R₈ is selected from the group consisting of H, Ci to do alkyl, C₃ to Ci₀ cycloalkyl, C₃ to do cycloalkylmethyl, C₃ to Ci₀ alkene, C₃ to Ci₀ alkyne, aryl, C₅ to C20 alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; and

n is an integer between 0 and 4,

or a pharmaceutically acceptable salt or solvate thereof.

A pharmaceutical composition according to claim 1 , wherein the tranilast-type compound is a compound of the Formula Il

Formula Il

wherein Rg or R-io, which may be the same or different, are selected from the group consisting of H, C₁ to C₁₀ alkyl, C₃ to C₈ terminal or non-terminal alkyne or a cyclopentyl, cyclohexyl, cyclohexylmethyl or cyclopentylmethyl group, or a pharmaceutically acceptable salt or solvate thereof.

4. A pharmaceutical composition according to claim 1 , wherein the tranilast-type compound is a compound of the Formula III or Formula IV

Formula III Formula IV

wherein G is a cyclopentyl ring, a cyclohexyl ring or a 1 ,4-disubstituted 1 ,2,3- triazole ring; and

q is an integer between 0 and 6,

or a pharmaceutically acceptable salt or solvate thereof.

5. A pharmaceutical composition according to claim 1 , wherein the tranilast-type compound is a compound of the formula V

Formula V

wherein R₅ is optionally substituted methyl, ethyl, propyl, hydroxyl or halogen; and R₆ is an optionally substituted alkynyl, in particular a C₂ to Ci₀ alkynyl or a chain containing an optionally substituted triazole. In a more particular embodiment, R₆ is propargyl or a 1 ,4-disubstituted 1 ,2,3-triazole. In a preferred embodiment, R₅ is methyl and R₆ is propargyl, or a pharmaceutically acceptable salt or solvate thereof.

6. A pharmaceutical composition according to claim 1 , wherein the tranilast-type compound is selected from the group consisting of the following:

or a pharmaceutically acceptable salt or solvate thereof.

7. A pharmaceutical composition according to claim 1 , wherein the tranilast-type compound is selected from the group consisting of

10

or a pharmaceutically acceptable salt or solvate thereof.

8. A pharmaceutical composition according to claim 1 , wherein the trani last-type compound is a the compound of the formula X

Formula X

or a pharmaceutically acceptable salt or solvate thereof.

9. Use of at least one tranilast-type compound, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of a mesangioproliferative disease.

10. A use according to claim 9, wherein treating the mesangioproliferative disease includes inhibiting the progression of the mesangioproliferative disease, preventing the mesangioproliferative disease, and/or ameliorating a symptom of the mesangioproliferative disease.

11. A use according to claim 9 wherein the mesangioproliferative disease is IgA nephropathy.

12. A use according to claim 9 wherein the tranilast-type compound is a compound of formula I

Formula

wherein R₁ and R₂, which may be the same or different, are selected from the group consisting of a C₁ to C_1O alkyl, C₃ to C₁₀ cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀ alkene, C₃ to C₁₀ alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

X₁ and X₂ are the same or different and are selected from the group consisting of a bond, O, N and S;

T is a single or double bond;

R₃ is selected from the group consisting of H, C₃ to C_1O alkene, C₃ to C₁₀ alkyne and a chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

R₄ is selected from the group consisting of H, OH, OR₆, NHR₆ and NR₆R₇;

R₅ is selected from the group consisting of H, NHR₆, NR₆R₇, OR₈, halogen, C₃ to C_1O alkene, C₃ to C₁₀ alkyne and a chain consisting of a heterocyclic or fused ring, any of which may be optionally substituted;

R₆ and R₇, which may be the same or different, are selected from the group consisting of H, C₁ to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, C₃ to Ci₀ cycloalkylmethyl, C₃ to C₁O alkene, C₃ to C₁O alkyne, aryl, C₅ to C₂o alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; R₈ is selected from the group consisting of H, Ci to do alkyl, C₃ to do cycloalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C10 alkene, C₃ to C₁₀ alkyne, aryl, C5 to C₂o alkaryl, and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; and

n is an integer between 0 and 4,

or a pharmaceutically acceptable salt or solvate thereof.

13. A use according to claim 9, wherein the tranilast-type compound is a compound of the Formula Il

Formula Il

wherein R₉ or R-io, which may be the same or different, are selected from the group consisting of H, Ci to do alkyl, C₃ to C₈ terminal or non-terminal alkyne or a cyclopentyl, cyclohexyl, cyclohexylmethyl or cyclopentylmethyl group,

or a pharmaceutically acceptable salt or solvate thereof.

14. A use according to claim 9, wherein the tranilast-type compound is a compound of the Formula III or Formula IV

Formula Formula IV

q is an integer between O and 6,

or a pharmaceutically acceptable salt or solvate thereof.

15. A use according to claim 9, wherein the tranilast-type compound is selected from the group consisting of

10

or a pharmaceutically acceptable salt or solvate thereof.

16. A use according to claim 9, wherein the tranilast-type compound is selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

17. A use according to claim 9, wherein the tranilast-type compound is a compound of the formula X

Formula X

or a pharmaceutically acceptable salt or solvate thereof.

18. A use according to claim 9 wherein the tranilast-type compound is administered as a pharmaceutical composition according to claim 1.

19. Use of at least one tranilast-type compound or a pharmaceutically acceptable salt or solvate thereof for the preparation of a pharmaceutical composition for treating a mesangioproliferative disease.

20. A kit for treating a mesangioproliferative disease including:

• instructions for administering the tranilast-type compound to a subject in order to treat a mesangioproliferative disease.