WO2015184248A1 - Procédés de traitement de maladies fibrotiques - Google Patents

Procédés de traitement de maladies fibrotiques Download PDF

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WO2015184248A1
WO2015184248A1 PCT/US2015/033158 US2015033158W WO2015184248A1 WO 2015184248 A1 WO2015184248 A1 WO 2015184248A1 US 2015033158 W US2015033158 W US 2015033158W WO 2015184248 A1 WO2015184248 A1 WO 2015184248A1
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galectin
compound
day
inhibitor
deuterium
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Roger D. Tung
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Concert Pharmaceuticals Inc
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Concert Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/732—Pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • 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.
  • 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).
  • NASH nonalcoholic steatohepatitis
  • 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.
  • PF pulmonary fibrosis
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Kidney disease 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.
  • 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.
  • 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
  • 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.
  • kidney disease 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.
  • 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.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • Pulmonary fibrosis 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.
  • 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.
  • environmental and occupational pollutants such as in asbestosis, silicosis and exposure to certain gases
  • IPF interstitial lung diseases
  • IPF interstitial lung diseases
  • UIP interstitial pneumonia
  • An individual is classified as having pulmonary fibrosis if he or she has evidence of lung damage pathological abnormalities from biopsy or imaging tests.
  • 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 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.
  • galectin-3 inhibitor binds galectin-3 and may inhibit its anti- apoptotic activity.
  • the galectin- 3 inhibitor inhibits interaction of galectin-3 with an anti-apoptotic Bcl-2 protein, such as Bcl-2 or bcl-xL.
  • the inhibitor inhibits phosphorylation of galectin-3, e.g., inhibits
  • 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.
  • the galectin-3 inhibitor inhibits expression of galectin- 3.
  • 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.
  • the galectin-3 inhibitor may comprise galactose.
  • 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; ⁇ - ⁇ -LacNAc; Gal-P-l,4-GlcNAc-P-l,2-(Gal-P-l,4- GlcNAc-P-1,4)- Man-a- 1 ,3)-( ⁇ 1- ⁇ - 1 ,4-GlcNAc-P- 1 ,2-( ⁇ 1- ⁇ - 1 ,4-GlcNAc-P- 1 ,6)-
  • 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.
  • 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.
  • 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.
  • 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, ⁇ -Galp, ⁇ - ⁇ , ⁇ - Rha/?, a-Rha/?
  • 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
  • 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,
  • modified pectin polygalacturonic backbone with pendent side chains of rhamnose residues having decreased branching.
  • 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.
  • 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.
  • modified pectin has the structure of a pectic acid polymer with some of the pectic side chains still present.
  • 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.
  • GPC Gel Permeation Chromatography
  • MALLS Multi Angle Laser Light Scattering
  • Degree of esterification is another characteristic of modified pectins.
  • 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.
  • the modified pectin is composed entirely of a single type of saccharide subunit.
  • the modified pectin comprises at least two, preferably at least three, and most preferably at least four types of saccharide subunits.
  • the modified pectin may be composed entirely of galacturonic acid subunits.
  • the modified pectin may comprise a combination of galacturonic acid and rhamnose subunits.
  • the modified pectin may comprise a combination of galacturonic acid, rhamnose, and galactose subunits.
  • the modified pectin may comprise a combination of galacturonic acid, rhamnose, and arabinose subunits.
  • the modified pectin may comprise a combination of galacturonic acid, rhamnose, galactose, and arabinose subunits.
  • the galacturonic acid content of modified pectin is greater than 50%, preferably greater than 60% and most preferably greater than 80%.
  • 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%;
  • the arabinose content is less than 15%, preferably less than 10% and most preferably less than 5%.
  • 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.
  • linkages it is meant the sites at which the individual sugars in pectin are attached to one another.
  • the modified pectin comprises only a single type of linkage.
  • the modified pectin comprises at least two types of linkages, or at least 3 types of linkages.
  • the modified pectin may comprise only alpha- 1,4-linked galacturonic acid subunits.
  • the modified pectin may comprise alpha- 1,4-linked galacturonic acid subunits and alpha- 1,2-rhamnose subunits.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ -galactosides.
  • CCD carbohydrate-recognition-binding domain
  • GCS-lOO is as follows:
  • GCS-lOO is composed of several types of sugars arranged in a complex polymeric configuration with multiple side- branches.
  • GCS-lOO has multiple side-branches containing 4-linked sugar ⁇ - galactose subunits with 4,6 linked branched points, which are recognized by the carbohydrate binding domain of galectin-3.
  • 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.
  • 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.
  • GCS-lOO 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.
  • 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.
  • a pectin may comprise galactose, xylose, apiose, glucose, arabinose, rhamnose, uronic acid (e.g., galacturonic acid) and/or mannose residues.
  • a pectin may be a mixture of chemical species.
  • a pectin may comprise a molecular weight distribution of polysaccharide chains.
  • a pectin may comprise two or more polysaccharides of different chemical composition.
  • a pectin may be fragmented into two or more fragments.
  • a pectin may be fragmented by exposure to any suitable chemical condition to form a pectin fragment.
  • 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).
  • hydrolysis e.g., acid hydrolysis, alkaline hydrolysis, and/or catalytic hydrolysis
  • enzymatic digestion e.g., oxidative lysis, and/or radiative lysis
  • pectin fragment refers to a pectin having a molecular weight less than the parent pectin from which the pectin fragment is derived.
  • 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.
  • a pectin fragment may bind to galectin-3 more strongly than the parent pectin from which the pectin fragment was derived.
  • 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.
  • a pectin fragment may be purified with respect to molecular weight.
  • 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.
  • an antisense nucleic acid may be targeted to a region of the gene encoding galectin-3 in a cell.
  • 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
  • the invention relates to the use of RNA interference (RNAi) to effect knockdown of expression of the galectin-3 gene with siRNA.
  • RNAi RNA interference
  • 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.
  • an inhibitor of galectin-3 activity may include a glycoconjugate, such as a glycolipid, glycopeptide, or proteoglycan.
  • 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.
  • a disease e.g., a disease or disorder delineated herein
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • 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.
  • 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).
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a compound described herein e.g., compounds of structural formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof
  • variable incorporation at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • a variable may be referred to generally (e.g., "each Z") or may be referred to specifically (e.g., Z 3 , Z 4 , Z 5 , 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 Z 3 , Z 4 and Z 5 ).
  • each of R 1 and R 2 is independently selected from -CH 3 and -CD 3 ;
  • R 5 is hydrogen or deuterium
  • each Z is hydrogen or deuterium
  • each Z 4 is hydrogen or deuterium
  • each Z 5 is hydrogen or deuterium
  • Y 1 is hydrogen or deuterium.
  • each Z is hydrogen.
  • the compound of structural formula (I) is represented by the following structural formula:
  • the compound of structural formula (I) is represented by the following structural formula:
  • R 5 is deuterium, and the remainder of the variables are as defined in the 1 st , 2 nd or 3 rd specific embodiment.
  • R 5 is hydrogen, and the remainder of the variables are as defined in the 1 st , 2 nd or 3 rd specific embodiment.
  • R 1 is -CH 3 and R 2 is -CD 3 ; and the remainder of the variables are as defined in the 1 st , 2 nd , 3 rd , 4 th or 5 th specific embodiment.
  • R 1 is -CD 3 and R 2 is -CH 3 ; and the remainder of the variables are as defined in the 1 st , 2 nd , 3 rd , 4 th or 5 th specific embodiment.
  • R x and R 2 are both -CH 3 ; and the remainder of the variables are as defined in the 1 st , 2 nd , 3 rd , 4 th or 5 th specific embodiment.
  • R x and R 2 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.
  • Y 1 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.
  • Y 1 is hydrogen.
  • the compound is represented by the following structural formula:
  • 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.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable 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.
  • 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.
  • 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
  • the compounds described e.g., compounds of structural formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof
  • 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.
  • 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.
  • any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
  • patient as used herein includes human or a non-human patients, but is preferably a human.
  • the patient is administered an effective amount of a compound described 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 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.
  • the compound described herein e.g., compounds of formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof
  • 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.
  • any one of these dosages are administered once per day. Alternatively, any one of these dosages are administered twice per day.
  • 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.
  • the galectin-3 inhibitor e.g., GCS-
  • any one of these dosages are administered once per day.
  • any one of these dosages are administered twice per day.
  • the compound can be administered to the patient once a day, twice a day, or three times a day.
  • the galectin-3 inhibitor e.g., GCS-
  • 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.
  • GCS- lOO is administered at a dosage range of 0.05 mg/m", 0.1 mg/m 2 , 0.5 mg/m 2 , 1.0 mg/m 2 , 1.5 mg/m 2 , 2.0 mg/m 2 , 2.5 mg/m 2 , 3.0 mg/m 2 , 3.5 mg/m 2 or
  • any one of these dosages are administered once per day.
  • 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.
  • a compound described herein e.g., a compound of structural formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof
  • 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.
  • a disease or disorder described herein e.g., treating fibrotic disease
  • the galectin-3 inhibitor e.g., GCS- lOO
  • a compound described herein e.g., a compound of structural formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof
  • 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
  • the galectin-3 inhibitor e.g., GCS-lOO
  • both the compounds described herein and the galectin-3 inhibitor 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.
  • galectin-3 inhibitor e.g., GCS-lOO
  • GCS-lOO galectin-3 inhibitor
  • 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).
  • a compound described herein e.g., compounds of structural formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof
  • the galectin-3 inhibitor e.g., GCS- 100.
  • 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.
  • a compound described herein e.g., compounds of structural formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof
  • the galectin-3 inhibitor e.g., GCS- 100
  • the pharmaceutical composition is pyrogen-free.
  • 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.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphat
  • 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
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous,
  • 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
  • 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.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • 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.
  • 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.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • 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.

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Abstract

La présente invention concerne un nouveau procédé de traitement d'une maladie fibrotique chez un patient. Le procédé comprend l'administration au patient d'une quantité efficace des composés décrits dans la présente invention et d'un inhibiteur de la galectine-3. La présente invention concerne un procédé de traitement d'une maladie fibrotique chez un patient comprenant l'administration au patient d'une quantité efficace d'un composé représenté par la formule structurelle suivante :
PCT/US2015/033158 2014-05-30 2015-05-29 Procédés de traitement de maladies fibrotiques Ceased WO2015184248A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021195020A1 (fr) * 2020-03-23 2021-09-30 G3 Pharmaceuticals, Inc. Méthodes et compositions pour prévenir et traiter la fibrose résultant d'une infection à coronavirus

Citations (5)

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Publication number Priority date Publication date Assignee Title
US20110053961A1 (en) * 2009-02-27 2011-03-03 Concert Pharmaceuticals, Inc. Substituted xanthine derivatives
US20130029955A1 (en) * 2011-05-25 2013-01-31 Pieter Muntendam Inhibitors of galectin-3 and methods of use thereof
US20130095127A1 (en) * 2010-03-26 2013-04-18 La Jolla Institute For Allergy And Immunology METHODS OF INHIBITING INFLAMMATION AND INFLAMMATORY DISEASES USING Gal-3BP (BTBD17B, LGALS3BP, GALECTIN-3 BINDING PROTEIN, MAC-2 BINDING PROTEIN)
CA2856016A1 (fr) * 2011-11-18 2013-05-23 Tokiyoshi AYABE Agent de traitement de la fibrose intestinale
US20140213519A1 (en) * 2013-01-25 2014-07-31 Cardiorentis Ltd. Methods of treating cardiovascular indications

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110053961A1 (en) * 2009-02-27 2011-03-03 Concert Pharmaceuticals, Inc. Substituted xanthine derivatives
US20130095127A1 (en) * 2010-03-26 2013-04-18 La Jolla Institute For Allergy And Immunology METHODS OF INHIBITING INFLAMMATION AND INFLAMMATORY DISEASES USING Gal-3BP (BTBD17B, LGALS3BP, GALECTIN-3 BINDING PROTEIN, MAC-2 BINDING PROTEIN)
US20130029955A1 (en) * 2011-05-25 2013-01-31 Pieter Muntendam Inhibitors of galectin-3 and methods of use thereof
CA2856016A1 (fr) * 2011-11-18 2013-05-23 Tokiyoshi AYABE Agent de traitement de la fibrose intestinale
US20140213519A1 (en) * 2013-01-25 2014-07-31 Cardiorentis Ltd. Methods of treating cardiovascular indications

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021195020A1 (fr) * 2020-03-23 2021-09-30 G3 Pharmaceuticals, Inc. Méthodes et compositions pour prévenir et traiter la fibrose résultant d'une infection à coronavirus

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