WO2015184248A1 - Methods of treating fibrotic diseases - Google Patents

Abstract

The present invention relates to a novel method of treating fibrotic disease in a patient. The method comprises administering to the patient an effective amount of compounds described herein and a galectin-3 inhibitor. This invention relates to a method of treating a fibrotic disease in a patient comprising administering to the patient an effective amount of a compound represented by the structural formula (I) or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are optionally replaced with deuterium, and an effective amount of a galectin-3 inhibitor.

Description

METHODS OF TREATING FIBROTIC DISEASES

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. Provisional Patent

Application No. 62/005,320, filed May 30, 2014, the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Fibrosis refers to the excessive and persistent formation of scar tissue, which is responsible for morbidity and mortality associated with organ failure in a variety of chronic diseases affecting the kidneys, liver, lungs, skin, and heart. For example, fibrosis is a final common pathway in chronic kidney disease (CKD) that leads to disease progression and ultimately organ failure. Liver fibrosis can cause the liver to become seriously scarred, hardened, and unable to function normally in patients with nonalcoholic steatohepatitis (NASH). The formation or development of excess fibrous connective tissue in the lung is the hallmark of pulmonary fibrosis (PF). Radiation, especially over time, can cause the abnormal production of fibrin, which accumulates in and damages the irradiated tissue. Progressive heart failure can occur in part because of the deposition of fibrous tissue in the heart muscle. Thus, fibrotic disease is a major health problem in today's society and available treatments are either not available or only partially effective. There is a great need for new medicines to treat fibrotic disease.

SUMMARY OF THE INVENTION

This invention relates to a method of treating a fibrotic disease in a patient comprising administering to the patient an effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof and an effective amount of a galectin-3 inhibitor. One or more hydrogen atoms in the compound of formula (I) are optionally replaced with deuterium. DETAILED DESCRIPTION OF THE INVENTION

The invention provides a method of treating fibrotic disease in a patient comprising administering to the patient an effective amount of a compound of structural formula (I) or a pharmaceutically acceptable salt thereof and an effective amount of a galectin-3 inhibitor. These compounds have anti-fibrotic effects that are believed to be largely responsible for their ability to protect tissue and organ function.

"Fibrotic disease" refers to a disease or condition characterized by a pathological process leading from tissue injury through its encapsulation by extracellular matrix, and the result of the process, which is a pathological formation of scar tissue. Examples include any tissue disorder, including, but not limited to, cirrhosis, kidney fibrosis, liver fibrosis, ovarian fibrosis, lung fibrosis, gastrointestinal or stomach fibrosis, heart fibrosis, dermal fibrosis and fibroids. Specific examples of fibrotic diseases include chronic kidney disease, non-alcoholic steatohepatitis, pulmonary fibrosis, post-radiation dermal and tissue fibrosis, cardiac fibrosis, primary biliary cirrhosis, scleroderma (a.k.a. progressive systemic sclerosis), sarcoidosis, diabetic retinopathy, retroperitoneal fibrosis, and uterine fibrosis post pelvic inflammatory disease.

Chronic kidney disease (CKD) is a condition characterized by a gradual loss of kidney function over time. Kidney disease may eventually lead to kidney failure, which requires dialysis or a kidney transplant to maintain life. According to the National Kidney Foundation, 26 million Americans have CKD and millions of others are at increased risk. The two main causes of chronic kidney disease are diabetes and high blood pressure, which are responsible for up to two-thirds of the cases. Other conditions that affect the kidneys include glomerulonephritis, a group of diseases that cause inflammation and damage to the kidney's filtering units; inherited diseases, such as polycystic kidney disease, which causes large cysts to form in the kidneys and damage the surrounding tissue; malformations that occur as a in utero; lupus and other diseases that affect the body's immune system; obstructions caused by problems like kidney stones, tumors or an enlarged prostate gland in men; poisonous agents or medications that if taken in doses or over chronic durations that exceed safety parameters, or are taken concomitantly with other medications that are contraindicated due to safety risks; environmental exposure; physical trauma, for example, direct and forceful blow to the kidneys and repeated urinary infections.

Kidney function is best estimated by glomerular filtration rate (GFR) and usually expressed as estimated GFR or eGFR. This is typically calculated by measuring levels of serum creatinine (measured in mg/dL), a waste product in the blood, and then applying a mathematical formula that accounts for additional variables, including age, race and gender. If the filtration in the kidney is deficient, serum creatinine levels are higher than normal; increasing serum creatinine indicates a worsening of kidney function. GFR and eGFR are measured in units of milliliters per minute per 1.73 meters squared, which is a typical adult body surface area. Chromic kidney disease is defined as significant loss of kidney function as measured by an eGFR of <60 for three months or evidence of kidney damage such as persistent proteinuria or pathological abnormalities from biopsy or imaging tests. Chronic kidney disease is categorized by stages to guide clinical practice. Stage 1 is an eGFR of > 90 considered normal or increased eGFR with evidence of kidney damage; Stage 2 is eGFR 60 to 89 with evidence of kidney damage known as mild or early stage kidney disease, Stage 3 is 30 to 59 or moderate or mid-stage kidney disease, Stage 4 is 15 to 29 or severe or advanced kidney disease and Stage 5 is below 15 which indicates kidney failure and if sustained or worsens, requires dialysis or kidney transplantation to avoid death.

While various biological processes contribute to kidney disease such as inflammation and reactive oxygen species, fibrosis is a final common pathway for kidney failure. An individual is classified as having chronic kidney disease if he or she has a GFR of less than 60 mL/min/1.73 m for at least three months or evidence of kidney damage such as persistent proteinuria or pathological abnormalities from biopsy or imaging tests.

Current standard of care for chronic kidney disease is aimed at renoprotective effects, such as proteinuria reduction and decreased rate of GFR decline, by using treatment with angiotensin modulators, particularly the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor blockers (ARBs). These are antihypertensive agents that also have the effect of reducing albuminuria and slowing the decline of renal function. However, despite treatment with these drugs, many chronic kidney disease patients continue to experience loss in renal function at a rate that is significantly faster than normal age-related decline. No new disease modifying treatments for chronic kidney disease have been approved by the FDA in the last decade.

Nonalcoholic steatohepatitis or NASH affects 2 to 5 percent of Americans and is becoming more common, possibly because of the greater number of Americans with obesity. NASH resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. The major feature in NASH is fat in the liver, along with inflammation and damage. People with NASH often feel well and are unaware that they have a liver problem. Nevertheless, NASH can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to work properly.

Symptoms of NASH include elevations in liver tests that are included in routine blood test panels, such as alanine aminotransferase (ALT) or aspartate aminotransferase (AST). After excluding alternative reasons for elevations (such as medications, viral hepatitis, or excessive use of alcohol) and if an X-ray or an imaging study of the liver show fat, NASH is suspected. Actual diagnosis of NASH is when examination of the liver tissue shows fat along with inflammation and damage to liver cells. This liver biopsy also determines whether scar tissue has developed in the liver. An individual is classified as having non-alcoholic steatohepatitis if he or she has evidence of liver damage such as fat in the liver, along with inflammation or pathological abnormalities from biopsy or imaging tests.

Currently, there are no specific therapies for NASH. Instead, those diagnosed with NASH are advised to reduce their weight (if obese or overweight), follow a balanced and healthy diet, increase physical activity, avoid alcohol, and avoid unnecessary medications.

Pulmonary fibrosis (PF) is the formation or development of excess fibrous connective tissue in the lungs. The lung of a person with PF becomes thickened, stiff, and scarred, reducing the ability of the lungs to transfer oxygen into the bloodstream. As a result, the brain, heart, and other organs do not get the oxygen they need to function properly.

PF may be a secondary effect of other diseases, such as interstitial lung diseases (for example, autoimmune disorders, viral infections or other microscopic injuries to the lung). Diseases and conditions that may cause pulmonary fibrosis as a secondary effect include: inhalation of environmental and occupational pollutants (such as in asbestosis, silicosis and exposure to certain gases); hypersensitivity pneumonitis (most often resulting from inhaling dust contaminated with bacterial, fungal, or animal products); cigarette smoking; connective tissue diseases (such as rheumatoid arthritis, SLE and scleroderma); other diseases that involve connective tissue (such as sarcoidosis and Wegener's granulomatosis); infections; medications, (for example, amiodarone, bleomycin (pingyangmycin), busulfan, methotrexate, apomorphine, and nitrofurantoin); and radiation therapy to the chest.

PF can also appear without any known cause, and is then referred to as "idiopathic pulmonary fibrosis" or "IPF". IPF belongs to a large group of more than 200 lung diseases known as interstitial lung diseases (ILD), in which the interstitium, the tissue between the air sacs in the lung, is the primary site of injury, but also the airspaces, peripheral airways, and vessels can be damaged as well. Lung tissue from people with IPF shows a characteristic histopathologic pattern known as usual interstitial pneumonia (UIP). UIP is therefore the pathologic counterpart of IPF.

An individual is classified as having pulmonary fibrosis if he or she has evidence of lung damage pathological abnormalities from biopsy or imaging tests.

Treatment options for pulmonary fibrosis are very limited and are focused on slowing down the progression of the disease. Though research trials are ongoing, there is no evidence that any medications can significantly help this condition. Lung transplantation is the only therapeutic option available in severe cases.

Post-radiation dermal and tissue fibrosis is a common complication of radiation treatment. Any tissue within the radiation field can be affected including nerves, muscles, blood vessels, bones, tendons, ligaments, heart or lungs. The clinical manifestations that result from radiation fibrosis (RF) are called radiation fibrosis syndrome (RFS). RF can occur a few weeks or months after radiation treatment and continues for the duration of a patient's life. An individual is classified as having post-radiation dermal and tissue fibrosis if he or she has evidence of dermal or tissue damage pathological abnormalities from biopsy or imaging tests. There is no way to stop the progressive RF that results from radiation treatment.

Cardiac fibrosis (CF) is a hallmark of heart disease and is associated with increased deposition of matrix proteins in the myocardium. Under normal conditions, specialized cells known as fibroblasts deposit layers of collagen protein to form a scar and thereby enable wounds to heal. However, in abnormal circumstances excessive production of matrix proteins, such as collagen, results in pathological scarring, or fibrosis. In the heart, the buildup of matrix leaves the organ stiff and inflexible, unable to properly relax and function. Progressive heart failure can result in reduced contractility of the heart, dilation of the heart chambers, reduced cardiac output with multiple resultant symptoms including edema, shortness of breath, reduced kidney function, mental confusion, and others. An individual is classified as having cardiac fibrosis if he or she has evidence of heart damage pathological abnormalities from biopsy or imaging tests.

As used herein a "galectin-3 inhibitor" binds galectin-3 and may inhibit its anti- apoptotic activity. In certain embodiments, the galectin- 3 inhibitor inhibits interaction of galectin-3 with an anti-apoptotic Bcl-2 protein, such as Bcl-2 or bcl-xL. In certain

embodiments, the inhibitor inhibits phosphorylation of galectin-3, e.g., inhibits

phosphorylation of galectin-3 at Ser-6. In certain embodiments, the galectin-3 inhibitor inhibits translocation of galectin-3 between the nucleus and cytoplasm or inhibits galectin-3 translocation to the perinuclear membranes and inhibits cytochrome C release from mitochondria. In certain embodiments, the galectin-3 inhibitor inhibits expression of galectin- 3. For instance, the galectin-3 inhibitor can be an antisense or RNAi construct having a sequence corresponding to a portion of the mRNA sequence transcribed from the galectin-3 gene.

A galectin-3 inhibitor may be a carbohydrate, a protein (e.g., an antibody or antibody fragment), peptides or polypeptides, a nucleic acid (e.g., an aptamer), or a small molecule. A carbohydrate galectin-3 inhibitor may be a polysaccharide, a disaccharide, a monosaccharide, a pectin, a naturally- occurring carbohydrate, a synthetic carbohydrate, and the like. Any suitable carbohydrate may be used. In some embodiments, the galectin-3 inhibitor may comprise galactose. In some embodiments, the galectin-3 inhibitor may comprise glucose, galactose, fucose, arabinose, arabitol, allose, altrose, gulose,

galactosamine, hammelose, lyxose, mannose, mannitol, mannosamine, ribose, rhamnose, threose, talose, xylose, uronic acids thereof, and combinations thereof. Non-limiting examples of carbohydrates include lactose; LacNAc; Gal-P-l,4-GlcNAc-P-l,3-Gal-pi,4-Glc; Gal-P-1,3- GlcNAc-P-l,3-Gal-P-l,4-Glc; Gal-P-l,4-GlcNAc-P-l,3-Gal; Gal-P-l,4-GlcNAc-P- l,2-(Gal-P- l,4-GlcNAc-P-l,6)-Man; Με-β-LacNAc; Gal-P-l,4-GlcNAc-P-l,2-(Gal-P-l,4- GlcNAc-P-1,4)- Man-a- 1 ,3)-(ϋα1-β- 1 ,4-GlcNAc-P- 1 ,2-(ϋα1-β- 1 ,4-GlcNAc-P- 1 ,6)- Man-a- 1 ,6)-Man; Gal-β- 1 ,4- Fru; Gal-P-l,4-ManNAc; Gal-a-l,6-Gal; Με-β-Gal; GlcNAc- P-1,3-Gal; GlcNAc-P-1,4- GlcNAc; Glc-P-1,4-Glc; and GlcNAc; where Gal is galactosyl, Glc is glucosyl, Man is mannosyl, Fru is fructosyl, NAc is N-acetyl, and Me is methyl.

In some embodiments, a galectin-3 inhibitor is a carbohydrate-derived polymer containing an active galectin binding sugar site, but having somewhat higher molecular weights than simple sugars so that such molecules are capable of sustained blocking, activating, suppressing, or otherwise interacting with other portions of the galectin protein. One class of therapeutic materials comprises oligomeric or polymeric species of natural or synthetic origin, rich in galactose or arabinose. Such materials will preferably have a molecular weight in the range of up to 500,000 daltons and, more preferably, in the range of up to 100,000 daltons. For example, certain galectin-3 inhibitors comprise a polymeric backbone having side chains dependent therefrom. The side chains are terminated by a galactose, rhamnose, xylose, or arabinose unit. This material may be synthetic, natural, or semi- synthetic. In one particular embodiment, the galectin-3 inhibitor comprises a substantially demethoxylated polygalacturonic acid backbone which may be interrupted with rhamnose residues with galactose terminated side chains pendent therefrom. Another particular material comprises a homogalacturonan backbone with or without side chains pendent therefrom. One group of materials falling within this general class comprises a substantially demethoxylated polygalacturonic acid backbone having rhamnose, galactose, arabinose or other sugar residues pendent therefrom.

Materials of this general type are described by formulas I and II below, and it is to be understood that yet other variants of this general compound may be prepared and utilized in accord with the principles of the present invention. Homogalacturonan

- [α-GalpA- (1→4)- -Gal/?A]_n- (I)

Rhamnogalacturonan Ym

I

- [ [a-Galjt?A]_n-X- [a-Gal/?A]₀] _p -

(Π)

In the formulae above, m is > 0, n, o and p are >1, X is a-Rha/?; and Y_m represents a linear or branched chain of sugars (each Y in the chain Y_m can independently represent a different sugar within the chain). The sugar Y maybe, but is not limited to, any of the following: a-Galp, β-Galp, β-Αρί , β- Rha/?, a-Rha/? , a-Fuc/?, β-Glc/jA, a-GalpA, β-GalpA, β-Dha/jA, Kdo/?, β- Ace/, a-Ara , β-Ara , and -Χγΐρ. Abbreviated monomer names used herein are defined as follows: GalA: galacturonic acid, Rha: rhamnose, Gal: galactose, Api: erythro-apiose, Fuc: fucose, GlcA: glucuronic acid, DhaA: 3-deoxy-D- fyjcoheptulosaric acid, Kdo: 3-deoxy-D-ma/mc>-2-octulosonic acid, Ace: aceric acid (3-C-carboxy- 5-deoxy-L- lyxose), Ara: arabinose. Italicized p stands for pyranose and italicized/ stands for furanose.)

Such compounds may be prepared from naturally occurring pectin, and are referred to as partially depolymerized pectin or modified pectin. An exemplary polymer of this type is modified pectin, preferably water soluble pH modified citrus pectin. Suitable polymers of this type are disclosed in, for example U.S. Patents 5,834,442, 5,895,784, 6,274,566 and

6,500,807, and PCT Publication WO 03/000118. It will be understood that natural pectin does not possess a strictly regular repeating structure, and that additional random variations are likely to be introduced by partial hydrolysis of the pectin, so that the identity of Ym and the values of n and o may vary from one iteration to the next of the p repeating units represented by formula II above.

Pectins are polysaccharides found in the cell walls of terrestrial plants. Pectin is a complex carbohydrate having a highly branched structure comprised of a polygalacturonic backbone with numerous branching side chains dependent therefrom. The branching creates regions which are characterized as being "smooth" and "hairy." It has been found that pectin can be modified by various chemical, enzymatic or physical treatments to break the molecule into smaller portions having a more linearized, substantially demethoxylated,

polygalacturonic backbone with pendent side chains of rhamnose residues having decreased branching. The resulting partially depolymerized pectin is known in the art as modified pectin, U.S. Patent 5,895,784, the disclosure of which is incorporated herein by reference, describes modified pectin materials, and techniques for their preparation. The material of the 784 patent is described as being prepared by a pH based modification procedure in which the pectin is put into solution and exposed to a series of programmed changes in pH which results in the breakdown of the molecule to yield therapeutically effective modified pectin. The material in the 784 patent is most preferably prepared from citrus pectin; although, it is to be understood that modified pectins may be prepared from pectin from other sources, such as apple pectin. Also, modification may be done by enzymatic treatment of the pectin, or by physical processes such as heating. Further disclosure of modified pectins and techniques for their preparation and use are also found in U.S. Patent 5,834,442 and U.S. Patent Application Serial No. 08/024,487, the disclosures of which are incorporated herein by reference.

Modified pectins of this type generally have molecular weights in the range of less than 100 kilodalton. A group of such materials has an average molecular weight of less than 3 kilodalton. Another group has an average molecular weight in the range of 1-15 kilodalton, with a specific group of materials having a molecular weight of about 10 kilodalton. In one embodiment, modified pectin has the structure of a pectic acid polymer with some of the pectic side chains still present. In preferred embodiments, the modified pectin is a copolymer of homogalacturonic acid and rhamnogalacturonan I in which some of the galactose- and arabinose-containing sidechains are still attached. The modified pectin may have a molecular weight of 1 to 500 kilodaltons (kD), preferably 10 to 250 kD, more preferably 50-200 kD, 70- 150 kD, and most preferably 80 to 100 kD as measured by Gel Permeation Chromatography (GPC) with Multi Angle Laser Light Scattering (MALLS) detection.

Degree of esterification is another characteristic of modified pectins. In certain embodiments, the degree of esterification may be between 0 and 80%, preferably 0 to 50%, more preferably 0 to 25% and most preferably less than 10%.

Saccharide content is another characteristic of modified pectins. In certain

embodiments, the modified pectin is composed entirely of a single type of saccharide subunit. Hi other embodiments, the modified pectin comprises at least two, preferably at least three, and most preferably at least four types of saccharide subunits. For example, the modified pectin may be composed entirely of galacturonic acid subunits. Alternatively, the modified pectin may comprise a combination of galacturonic acid and rhamnose subunits. In yet another example, the modified pectin may comprise a combination of galacturonic acid, rhamnose, and galactose subunits. In yet another example, the modified pectin may comprise a combination of galacturonic acid, rhamnose, and arabinose subunits. In still yet another example, the modified pectin may comprise a combination of galacturonic acid, rhamnose, galactose, and arabinose subunits. In some embodiments, the galacturonic acid content of modified pectin is greater than 50%, preferably greater than 60% and most preferably greater than 80%. In some embodiments, the rhamnose content is less than 25%, preferably less than 15% and most preferably less than 10%; the galactose content is less than 50%, preferably less than 40% and most preferably less than 30%; and the arabinose content is less than 15%, preferably less than 10% and most preferably less than 5%. In certain embodiments, the modified pectin may contain other uronic acids, xylose, ribose, lyxose, glucose, allose, altrose, idose, talose, gluose, mannose, fructose, psicose, sorbose or talalose in addition to the saccharide units mentioned above.

Modified pectin suitable for use in the subject methods may also have any of a variety of linkages or a combination thereof. By linkages it is meant the sites at which the individual sugars in pectin are attached to one another. Hi some embodiments, the modified pectin comprises only a single type of linkage. In certain embodiments, the modified pectin comprises at least two types of linkages, or at least 3 types of linkages. For example, the modified pectin may comprise only alpha- 1,4-linked galacturonic acid subunits.

Alternatively, the modified pectin may comprise alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits. In another example, the modified pectin may be composed of alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2- rhamnose subunits linked through the 4 position to arabinose subunits. In another example, the modified pectin may comprise alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to arabinose subunits with additional 3-linked arabinose subunits. In another example, the modified pectin may comprise alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to arabinose subunits with additional 5-linked arabinose units. In another example, the modified pectin may comprise alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to arabinose subunits with additional 3-linked and 5- linked arabinose subunits. In another example, the modified pectin may comprise alpha- 1,4- linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to arabinose subunits with additional 3-linked and 5-linked arabinose subunits with 3,5-linked arabinose branch points. In another example, the modified pectin may comprise alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to galactose subunits. In another example, the modified pectin may comprise alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to galactose subunits with additional 3-linked galactose subunits. In another example, the modified pectin may comprise alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to galactose subunits with additional 4-linked galactose subunits. In another example, the modified pectin may comprise alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to galactose subunits with additional 3-linked galactose subunits with 3,6- linked branch points. In another example, the modified pectin may comprise alpha- 1,4- linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to galactose subunits with additional 4-linked galactose subunits with 4,6-linked branch points. In certain embodiments, the side chains of the modified pectin may comprise uronic acids, galacturonic acid, glucuronic acid, rhamnose, xylose, ribose, lyxose, glucose, allose, altrose, idose, talose, gluose, mannose, fructose, psicose, sorbose or talalose in addition to the saccharide units described above.

In certain embodiments, the galectin-3 inhibitor is GCS-lOO. GCS-lOO is modified pectin, and has the ability to bind to and block the effects of galectin-3, an approximately 30 kDa protein containing a carbohydrate-recognition-binding domain (CRD) of about 130 amino acids that enable the specific binding of β-galactosides. Specifically, the structure of

GCS-lOO is as follows:

can be seen, GCS-lOO is composed of several types of sugars arranged in a complex polymeric configuration with multiple side- branches. In particular, GCS-lOO has multiple side-branches containing 4-linked sugar β- galactose subunits with 4,6 linked branched points, which are recognized by the carbohydrate binding domain of galectin-3. In addition, GCS-lOO comprises alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits linked through the 4 position to the side branched galactose subunits. Thus GCS-lOO is able to bind to and sequester multiple molecules of extracellular galectin-3. GCS-lOO is further described in US 8128966, US 8187642, WO 2006017356, WO 2005095463, and WO 2004091634, the teachings of each are all incorporated herein by reference.

The ability of GCS-lOO, to bind and sequester galectin-3 makes it useful in preventing and treating diseases in which galectin-3 plays a role, such as fibrosis. Additionally, because of its high average molecular weight (-1000 kD), GCS-100 resides in the body for an extended period, increasing the time to interact with and sequester circulating galectin-3.

In some embodiments, a pectin may be a full-length pectin, e.g., a pectin that has not been subjected to fragmentation. In other embodiments, the pectin may be a pectin fragment. In some instances, a pectin may be linear. In other instances, a pectin may be branched. In some embodiments, the pectin may be a homogalacturonan, a substituted galacturonan, or a rhamnogalacturonan. In some embodiments, a pectin may comprise galactose, xylose, apiose, glucose, arabinose, rhamnose, uronic acid (e.g., galacturonic acid) and/or mannose residues. In some embodiments, a pectin may be a mixture of chemical species. For example, a pectin may comprise a molecular weight distribution of polysaccharide chains. In some instances, a pectin may comprise two or more polysaccharides of different chemical composition.

In some embodiments, a pectin may be fragmented into two or more fragments. For example, a pectin may be fragmented by exposure to any suitable chemical condition to form a pectin fragment. For example, in some cases, a pectin may be fragmented by hydrolysis (e.g., acid hydrolysis, alkaline hydrolysis, and/or catalytic hydrolysis), enzymatic digestion, oxidative lysis, and/or radiative lysis (i.e., by x-rays or gamma rays). Generally, "pectin fragment" refers to a pectin having a molecular weight less than the parent pectin from which the pectin fragment is derived. However, it should be understood that a pectin fragment may be subjected to modification that may alter the molecular weight.

Pectin fragments of interest are capable of binding to galectin-3. In some instances, a pectin fragment may bind to galectin-3 more strongly than the parent pectin from which the pectin fragment was derived. In some embodiments, it may be advantageous to purify a pectin fragment. For example, a mixture of pectin fragments may contain fragments that bind to galectin-3 and fragments that do not bind to galectin-3. Purifying the mixture such that it contains a higher proportion of fragments that bind galectin-3 may, in some embodiments, result in such advantageous properties as increased efficacy and/or reduced side effects upon administration to a subject. A pectin fragment may be purified by any suitable method. For example, in some embodiments, a pectin fragment may be purified with respect to molecular weight. In another example, a pectin fragment may be purified by affinity chromatography.

Additional inhibitors of galectin-3 include nucleic acids, such as antisense nucleic acids, oligonucleotides, and small interfering RNAs (siRNAs) and nucleic acid aptamers. Antisense nucleic acids refers to a polynucleotide or peptide nucleic acid capable of binding to a specific DNA or RNA sequence and inhibiting galectin-3 expression. An antisense nucleic acid can be delivered, for example, as an expression plasmid which, when transcribed in the cell, produces RNA which is complementary to at least a unique portion of the cellular mRNA which encodes galectin-3. In some embodiments, an antisense nucleic acid may be targeted to a region of the gene encoding galectin-3 in a cell. Alternatively, the construct is an oligonucleotide which is generated ex vivo and which, when introduced into the cell causes inhibition of expression by hybridizing with the mRNA and/or genomic sequences encoding galectin-3. Such oligonucleotides are optionally modified oligonucleotides which are resistant to endogenous nucleases, e.g., exonucleases and/or endonucleases, and is therefore stable in vivo. Exemplary nucleic acid molecules for use as antisense oligonucleotides are

phosphoramidate, phosphothioate and methylphosphonate analogs of DNA (see also U.S. Patent Nos. 5,176,996; 5,264,564; and 5,256,775). Additionally, general approaches to constructing oligomers useful in nucleic acid therapy have been reviewed, for example, by van der Krol et al, (1988) Biotechniques 6:958-976; and Stein et al, 1988, Cancer Res.

48:2659-2668. In another embodiment, the invention relates to the use of RNA interference (RNAi) to effect knockdown of expression of the galectin-3 gene with siRNA.

An exemplary protein therapeutic is described in PCT publication WO 02/100343, which discloses certain N-Terminally truncated galectin-3 proteins that inhibit the binding of intact galectin-3 to carbohydrate ligands and thereby also inhibit the multimerization and cross-linking activities of galectin-3 that may be required for its anti-apoptotic activity. In some embodiments, a galectin-3 antibody may be used as an inhibitor of galectin-3. In some cases, the antibody may be selective for an epitope present in galectin-3. Galectin-3 antibodies include human, humanized, and chimeric antibodies.

Exemplary small molecule inhibitors of galectin-3 include thiodigalactoside (such as described in Leffler et al, 1986, J. Biol. Chem. 261: 10119) and agents described in PCT publication WO 02/057284.

In some cases, an inhibitor of galectin-3 activity may include a glycoconjugate, such as a glycolipid, glycopeptide, or proteoglycan.

The term "treat" means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

"Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

The term "compound," when referring to a compound used in the disclosed methods, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The term "isotopologue" refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound. In the compounds of this invention unless otherwise specified any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or

"hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).

It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada, E et al., Seikagaku, 1994, 66: 15;

Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

In yet another embodiment, a compound described herein (e.g., compounds of structural formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof) has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium

incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Throughout this specification, a variable may be referred to generally (e.g., "each Z") or may be referred to specifically (e.g., Z³, Z⁴, Z⁵, etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable (for example, "Z includes Z³, Z⁴ and Z⁵).

In a 1^st specific embodiment, for the methods described above, the compound of structural formula (I) is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

each of R 1 and R 2 is independently selected from -CH₃ and -CD₃;

R⁵ is hydrogen or deuterium;

each Z is hydrogen or deuterium;

each Z⁴ is hydrogen or deuterium;

each Z⁵ is hydrogen or deuterium; and

Y¹ is hydrogen or deuterium.

In one embodiment, for compound of structural formula (II), each Z is hydrogen. In a 2^nd specific embodiment, for methods described above, the compound of structural formula (I) is represented by the following structural formula:

), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above for structural formula (II). In a 3 rd specific embodiment, for methods described in the first and second

embodiments, the compound of structural formula (I) is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above for structural formula (II).

In a 4^th specific embodiment, for compounds of structural formula (II), (III) or (IV), R⁵ is deuterium, and the remainder of the variables are as defined in the 1^st, 2^nd or 3^rd specific embodiment.

In a 5^th specific embodiment, for compounds of structural formula (II), (III) or (IV), R⁵ is hydrogen, and the remainder of the variables are as defined in the 1^st, 2^nd or 3^rd specific embodiment.

In a 6^th specific embodiment, for compounds of structural formula (II), (III) or (IV), R¹ is -CH₃ and R² is -CD₃; and the remainder of the variables are as defined in the 1^st, 2^nd, 3^rd, 4^th or 5^th specific embodiment.

In a 7^th specific embodiment, for compounds of structural formula (II), (III) or (IV), R¹ is -CD₃ and R² is -CH₃; and the remainder of the variables are as defined in the 1^st, 2^nd, 3^rd, 4^th or 5^th specific embodiment.

In a 8^th specific embodiment, for compounds of structural formula (II), (III) or (IV), R^x and R² are both -CH₃; and the remainder of the variables are as defined in the 1^st, 2^nd, 3^rd, 4^th or 5^th specific embodiment.

In a 9^th specific embodiment, for compounds of structural formula (II), (III) or (IV), R^x and R² are both -CD ; and the remainder of the variables are as defined in the 1^st, 2^nd, 3^rd, 4^th or 5^th specific embodiment.

In a 10^th specific embodiment, for compounds of structural formula (II), (III) or (IV), Y¹ is deuterium; and the remainder of the variables are as defined in the 1^st, 2^nd, 3^rd, 4^th, 5^th, 6^th, 7^th, 8^th or 9^th specific embodiment. Alternatively, Y¹ is hydrogen. In an 11 specific embodiment, for methods described herein, the compound is represented by the following structural formula:

(V) or a pharmaceutically acceptable salt thereof.

The invention also provides the use of salts of the compounds described herein.

A salt of a compound of described herein is formed between an acid and a basic group of the compound, such as an amino functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,

monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

The compounds described (e.g., compounds of structural formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof), contain an asymmetric carbon atom. As such, compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers. Accordingly, a compound used in the disclosed methods may exist as either a racemic mixture or a scalemic mixture, or as individual respective enantiomer that are substantially free from another possible enantiomer. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the

stereochemistry, it is understood to represent either a racemic mixture or a scalemic mixture, or each individual enantiomer substantially free from the other enantiomer.

When a particular enantiomer of a compound used in the disclosed methods is depicted by name or structure, the enantiomeric purity of the compounds is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Enantiomeric purity" means the weight percent of the desired enantiomer relative to the combined weight of both enantiomers.

In another embodiment, any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.

The compounds used in the disclosed methods can be prepared by methods disclosed in U.S. Patent No.8,263,601 and U.S. Published Application No. 20090239886, the entire teachings of which are incorporated herein by reference.

The term "patient" as used herein includes human or a non-human patients, but is preferably a human.

In another embodiment, for methods described herein, the patient is administered an effective amount of a compound described herein. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to therapeutically treat the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, slow the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the therapeutic effect(s) of another therapy. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al., Cancer Chemother. Rep, 1966, 50: 219. Body surface area may be determined approximately from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.

Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for pentoxifylline.

In one embodiment, for methods described herein, the compound described herein (e.g., compounds of formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof) is administered to the patient at a dosage range of 300 mg/day to 2400 mg/day, 400 mg/day to 2400 mg/day, 600 mg/day to 2400 mg/day, 600 mg/day to 1800 mg/day, 600 mg/day to 1200 mg/day, 900 mg/day to 2400 mg/day or 900 mg/day to 1800 mg/day. In one embodiment, the patient is administered with the compound at a dosage of 300 mg/day, 400 mg/day, 600 mg/day, 900 mg/day, 1200 mg/day, 1500 mg/day or 1800 mg/day. In one embodiment, any one of these dosages are administered once per day. Alternatively, any one of these dosages are administered twice per day.

In another embodiment, the compound can be administered to the patient once a day, twice a day, or three times a day. In another embodiment, the 600 mg of compound is administered to the patient twice daily.

In one embodiment, for methods described herein, the galectin-3 inhibitor (e.g., GCS-

2 2 2

100) is administered to the patient at a dosage range of 0.05 mg/m" to 4.0 mg/m", 0.05 mg/m"

2 2 2 2 2 2 2 to 3.0 mg/m , 0.1 mg/m to 2.5 mg/m , 0.5 mg/m to 2.0 mg/m , or 1.0 mg/m to 1.5 mg/m , 0.05 mg/m² to 1.5 mg/m², 0.05 mg/m² to 1.0 mg/m², 0.5 mg/m² to 2.0 mg/m², 1.0 mg/m² to

2 2 2 2 2

3.0 mg/m , 1.5 mg/m to 3.0 mg/m , or 1.0 mg/m to 2.5 mg/m . In one embodiment, the

2 2 2 patient is administered with the compound at a dosage of 0.05 mg/m , 0.1 mg/m , 0.5 mg/m ,

2 2 2 2 2 2 2

1.0 mg/m , 1.5 mg/m , 2.0 mg/m , 2.5 mg/m , 3.0 mg/m , 3.5 mg/m or 4.0 mg/m . In one embodiment, any one of these dosages are administered once per day. Alternatively, any one of these dosages are administered twice per day. In another embodiment, the compound can be administered to the patient once a day, twice a day, or three times a day.

In one embodiment, for methods described herein, the galectin-3 inhibitor (e.g., GCS-

2 2 2

100) is administered at a dosage range of 0.05 mg/m" to 4.0 mg/m", 0.05 mg/m" to 3.0

2 2 2 2 2 2 2 mg/m , 0.1 mg/m to 2.5 mg/m , 0.5 mg/m to 2.0 mg/m , or 1.0 mg/m to 1.5 mg/m , 0.05 mg/m² to 1.5 mg/m², 0.05 mg/m² to 1.0 mg/m², 0.5 mg/m² to 2.0 mg/m², 1.0 mg/m² to 3.0

2 2 2 2 2

mg/m , 1.5 mg/m to 3.0 mg/m , or 1.0 mg/m to 2.5 mg/m and the compound of structural formula (I) is administered at a dosage range of 300 mg/day to 2400 mg/day, 400 mg/day to 2400 mg/day, 600 mg/day to 2400 mg/day, 600 mg/day to 1800 mg/day, 600 mg/day to 1200 mg/day, 900 mg/day to 2400 mg/day or 900 mg/day to 1800 mg/day. In one embodiment, for methods described herein, GCS- lOO is administered at a dosage range of 0.05 mg/m", 0.1 mg/m², 0.5 mg/m², 1.0 mg/m², 1.5 mg/m², 2.0 mg/m², 2.5 mg/m², 3.0 mg/m², 3.5 mg/m² or

4.0 mg/m and the compound of structural formula (I) is administered at a dosage range of 300 mg/day, 400 mg/day, 600 mg/day, 900 mg/day, 1200 mg/day, 1500 mg/day or 1800 mg/day. In one embodiment, any one of these dosages are administered once per day.

Alternatively, any one of these dosages are administered twice per day.

The present invention also provides a use of a compound described herein (e.g., a compound of structural formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a disease or disorder described herein (e.g., treating fibrotic disease) in a patient.

Another aspect of the invention is a compound described herein (e.g., a compound of structural formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof) for use in the treatment of a disease or disorder described herein (e.g., treating fibrotic disease) in a patient.

The term "administered" or "co-administered" as used herein means that the the galectin-3 inhibitor (e.g., GCS- lOO) may be administered together with a compound described herein (e.g., a compound of structural formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof) as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the galectin-3 inhibitor (e.g., GCS-lOO) may be administered prior to, consecutively with, or following the administration of a compound described herein. In such combination therapy treatment, both the compounds described herein and the galectin-3 inhibitor (e.g., GCS- lOO) are administered by conventional methods. The administration of a combination used in the disclosed methods , comprising both a compound disclosed herein and the galectin-3 inhibitor (e.g., GCS-lOO), to a patient does not preclude the separate administration of a compounds disclosed herein or the galectin-3 inhibitor (e.g., GCS-lOO) to said patient at another time during a course of treatment.

Effective amounts of the galectin-3 inhibitor (e.g., GCS-lOO) are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective- amount range.

In one embodiment, for methods described herein, a composition comprising an effective amount of a compound described herein (e.g., compounds of structural formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof) can be used and the galectin-3 inhibitor (e.g., GCS- 100). In one embodiment, the composition is a

pharmaceutical compositions comprising an effective amount of a compound described herein (e.g., compounds of structural formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof) and the galectin-3 inhibitor (e.g., GCS- 100) and an acceptable carrier.

In one embodiment, the pharmaceutical composition is pyrogen-free. Preferably, a composition of this invention is formulated for pharmaceutical use ("a pharmaceutical composition"), wherein the carrier is a pharmaceutically acceptable carrier. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds described herein in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of an amorphous form of a compound described herein optionally formulated with a poloxamer, such as

LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.

The pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous,

intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's

Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

Claims

We claim:

A method of treating fibrotic disease in a patient, comprising administering to the patient an effective amount of a compound represented by structural formula (I):

or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are optionally replaced with deuterium, and an effective amount of a galectin-3 inhibitor.

2. The method of claim 1, wherein the fibrotic disease is selected from chronic kidney disease, non-alcoholic steatohepatitis, pulmonary fibrosis, post-radiation dermal and tissue fibrosis, cardiac fibrosis, primary biliary cirrhosis, scleroderma, sarcoidosis, diabetic retinopathy, retroperitoneal fibrosis, and uterine fibrosis post pelvic inflammatory disease.

3. The method of claim 1, wherein the fibrotic disease is selected from chronic kidney disease.

4. The method of claim 1, wherein the galectin-3 inhibitor is a carbohydrate.

5. The method of claim 1, wherein the galectin-3 inhibitor is a modified pectin.

6. The method of claim 1, wherein the galectin-3 inhibitor is GCS-100.

7. The method of any one of claims 1-6, wherein the galectin-3 inhibitor is administered at a dosage range of 0.05 mg/m 2 to 3.0 mg/m 2.

8. The method of any one of claims 1-6, wherein the galectin-3 inhibitor is administered at a dosage range of 0.1 mg/m 2 to 2.0 mg/m 2.

9. The method of any one of claims 1-8, wherein the compound of structural formula (I) is administered at a dosage range of 600 mg/day to 2400 mg/day.

10. The method of any one of claims 1-8, wherein the compound structural formula (I) is administered at a dosage range of 600 mg/day to 1800 mg/day.

11. The method of any one of claims 1-6, wherein the galectin-3 inhibitor is administered at a dosage range of 0.05 mg/m 2 to 3.0 mg/m 2 and the compound of structural formula (I) is administered at a dosage range of 600 mg/day to 2400 mg/day. The method of any one of claims 1-6, wherein the galectin-3 inhibitor is administered at a dosage range of 0.1 mg/m 2 to 2.0 mg/m 2 and the compound of structural formula

(I) is administered at a dosage range of 600 mg/day to 1800 mg/day.

13. The method of any one of claims 1-12, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

each of R 1 and R 2 is independently selected from -CH₃ and -CD ;

R⁵ is hydrogen or deuterium;

each Z is hydrogen or deuterium;

each Z⁴ is hydrogen or deuterium;

each Z⁵ is hydrogen or deuterium; and

Y¹ is hydrogen or deuterium.

14. The method of claim 13, wherein each Z is hydrogen.

15. The method of claim 13, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

16. The method of claim 13, wherein the compound is

(V) or a pharmaceutically acceptable salt thereof.

17. The method of claim 15 or 16, wherein the optical purity of the compound is at least 95%.

18. The method of any one of claims 1-17, wherein any hydrogen atom not designated as deuterium is present at its natural isotopic abundance.

19. The method of any one of claims 1-18, wherein the isotopic enrichment factor for each designated deuterium atom is at least 6000.

20. The method of any one of claims 1-18, wherein the isotopic enrichment factor for each designated deuterium atom is at least 6600.