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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4192—1,2,3-Triazoles
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

• Galectin-3 (Gal-3) is a b-galactoside binding lectin of about 30 KDa (Cell 76: 597- 598), that is involved in the regulation of inflammatory and fibrotic processes.
• Gal-3 promotes fibroblast proliferation and transformation and mediates collagen production (Circulation 110:3121-3128).
• Gal-3 is localyzed in many cellular location such as cytoplasm, nucleus, and cell surface. Gal-3 is also secreted by various cell types, mainly macrophages and monocytes into the blood stream (J Pharmacol Exp Ther 351 :336-343). There are multiple lines of evidence in the literature supporting the involment of Gal-3 in the development of fibrotic process in multiple organs such as lung (Am J. Respir. Crit. Care Med. 185: 537-546), liver (PNAS 103:5060-5065) and kidney (Am. J. Pathol. 172:288-298). Gal-3 has also been identified as a biomarker for heart failure indicating that modulation of Gal-3 has potential uses in the treatment of heart failure (Curr. Heart Fail.
• Gal-3 Human Lectin for Treatment of Cancer. ACS Symposium Series, Vol.
• Gal-3 inhibitors have proven to have positive effects when used in combination immunotherapy (Galectin Therapeutics. Press Release, February 7, 2017).
• the present disclosure relates to compounds of the present invention, which inhibit Gal-3, and include pharmaceutically acceptable salts, compositions comprising such compounds, and methods using and making such compounds and compositions.
• the present invention provides, inter alia , a compound of Formula
• X is independently selected from -C(O)-, -CH 2 -, and -CH 2 C(0)-;
• Ar 1 is independently phenyl or naphthyl; and wherein each ring moiety is substituted with 1 to 5 substituents selected from cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
• R 1 is independently selected from H, C 1-4 alkyl, and C 1-4 haloalkyl
• R 2 is independently H or C 1-4 alkyl
• R 3 is independently selected from Ar 2 , -(CH 2 )i-2Ar 2 , and -CH 2 CH 2 NR 4 Ar 2 ;
• Ar 2 is independently selected from phenyl, , and heteroaryl including from 5 to 10 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(R 5 ), O, and S; and wherein each ring moiety is substituted with 0 to 4 substituents selected from OH, cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, N(CI-4 alkyl)2, -S02(C 1-4 alkyl), -OPh, -OBn, C3-6 cycloalkyl, and phenyl substituted with 0 to 1 substituent selected from cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4
• R 4 is independently H or C 1-4 alkyl
• R 5 is independently H or C 1-4 alkyl.
• Ar 1 is independently phenyl or naphthyl; and wherein each ring moiety is substituted with 1 to 3 substituents selected from cyano, halogen, C 1-4 alkyl, and C 1-4 alkoxy;
• R 1 is independently H or C 1-4 alkyl
• Ar 2 is independently selected from phenyl, , pyridinyl, benzothiophenyl, benzothiazolyl, N-( C 1-4 alkyl)-indazolyl, and quinolinyl; and wherein each ring moiety is substituted with 0 to 4 substituents selected from OH, cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, N(CI-4 alkyl)2, -S02(C 1-4 alkyl), -OPh, and -OBn.
• Ar 1 is independently selected from:
• R 3 is independently selected from Ar 2 , -(CH 2 ) 1-2 Ar 2 , and -CH 2 CH 2 NR 4 Ar 2 ;
• R 1 is independently H or CH3;
• R 2 is independently selected from: H, CH3, -CH 2 CH3, and -CH(CH 3 )2; and R 4 is independently H or CH3.
• the invention provides a compound selected from the exemplified examples or a pharmaceutically acceptable salt thereof.
• the invention provides a compound selected from the
• the invention provides a compound selected from the
• the invention provides a compound selected from the
• Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons.
• Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
• Terms with a hydrocarbon moiety include straight and branched isomers for the hydrocarbon portion which are composed of 1 to 6 carbons.
• Halo includes fluoro, chloro, bromo, and iodo.
• Haloalkyl and“haloalkoxy” include all halogenated isomers from monohalo to perhalo.
• Aryl means a monocyclic or bicyclic aromatic ring system having 5 to 12 carbon atoms wherein one or both of the rings are aromatic.
• Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
• Heteroaryl means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art.
• the invention includes all pharmaceutically acceptable salt forms of the compounds.
• Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents.
• Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
• Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine,
• the invention includes all stereoisomeric forms of the compounds including enantiomers and diastereomers. Methods of making and separating stereoisomers are known in the art.
• the invention includes all tautomeric forms of the compounds.
• the invention includes atropisomers and rotational isomers.
• the invention is intended to include all isotopes of atoms occurring in the present compounds.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• Isotopes of carbon include 13 C and 14 C.
• Isotopically- labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
• ASSAY BUFFER Composition 25 mM HEPES, 100 mM NaCl, 0.005% Tween 20, 0.05% BSA prepared in sterile water (all reagents from Sigma).
• Negative Control 100% DMSO (1 ⁇ L) + His-tagged hGal-3(20 ⁇ L) +Anti His Terbium Antibody (5 ⁇ L) + Strep d2 Aantibody (5 ⁇ L) STOCKS PREPARATION:
• PROTOCOL The Gal-3 assays were performed in 384 white Opti plates in three replicates at room temperature with gentle shaking at 250-300 rpmFrom the original stocks, 2.525X working stock concentrations of His- tagged recombinant human Gal-3 (hGal-3) and that of B-ASF were prepared. From the working stock, 20 ⁇ L of hGal-3 (15 nM) and 20 ⁇ L B-ASF (15 nM) were added to the plates. In Negative Control, only hGal- 3 was added. A concentration range of 50x working stocks were prepared for the compounds in 100% DMSO.
• the Solution was prepared by dissolving the PBS packets procured from Sigma Aldrich (Catalogue No.: P3813-5xl0Pak) - 1 Pack in ILiter of Milli-Q water.
• Biotin-tagged hGalectin-3 A 0.82mg/mL stock solution (28.6 kDa, 28.6713 pM) of biotin tagged hGal-3 in-house synthesized by the proteomic group was used for the titration.
• TD-139 EXT-001109-01-001: A small molecule synthesized in-house, used as an internal standard for the small molecule screening in hGalectin-3 neutralization binding assay.
• the plates were later blocked with 10% FBS and incubated for lh at room temperature. Later the plate was washed with 300 ⁇ L of wash buffer (PBS with 0.05% Tween-20) for 3 times.
• wash buffer PBS with 0.05% Tween-20
• test compounds After spin drying the plates from previous washing, lOO ⁇ L of test compounds, at various concentrations as specified in the plate-map (pre-incubated with the hGalectin-3 or mGalectin-3 at concentration 15nM for lh at Room Temperature-RT) were added onto the plate as per the plate map. The plates were run in duplicates for data duplication and reproducibility.
• the ICso values of the program compounds were as presented in the report (attached in excel format from Curve master compilation).
• the Plate control TD-139 had an IC50 value of 10.3 nM and 108.12 nM for human and mouse Galectin-3 respectively. The same was plotted on the semi-log graph.
• Another aspect of the invention is a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• Another aspect of the invention is a method for treating a patient afflicted with a disease or condition selected from fibrosis of organs (including liver, kidney, lung, heart and skin), liver diseases and conditions (including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, and hepatic blood flow disorder), cell proliferative diseases, cancers, and conditions (including solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)) and invasive metastasis of cancer cell),
• a disease or condition selected from fibrosis of organs (including liver, kidney, lung, heart and skin), liver diseases and conditions (including acute hepatitis, chronic hepatitis, liver fibrosis,
• inflammatory diseases and conditions including psoriasis, nephropathy, and pneumonia
• gastrointestinal tract diseases and conditions including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion
• renal diseases and conditions including urinary tract-associated diseases and conditions (including benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, and symptoms derived from diabetes), lower urinary tract diseases and conditions (including obstruction of lower urinary tract), inflammatory diseases and conditions of lower urinary tract (including dysuria and frequent urination), pancreatic diseases and conditions, abnormal
• angiogenesis-associated diseases and conditions including arterial obstruction, scleroderma, brain-associated diseases and conditions (including cerebral infarction and cerebral hemorrhage), neuropathic pain and peripheral neuropathy, ocular diseases and conditions (including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring) with a compound of the present invention.
• AMD age-related macular degeneration
• PVR proliferative vitreoretinopathy
• cicatricial pemphigoid glaucoma filtration surgery scarring
• Another aspect of the invention is a method of treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis and systemic sclerosis comprising administering to a compound of the present invention to a patient.
• Another aspect of the invention is a method for treating fibrosis of organs
• Another aspect of the invention is a method for treating liver diseases and conditions (including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, and hepatic blood flow disorder) comprising administering to a compound of the present invention to a patient.
• liver diseases and conditions including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, and hepatic blood flow disorder
• Another aspect of the invention is a method for treating cell proliferative diseases, cancers, and conditions (including solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)) and invasive metastasis of cancer cell) comprising administering to a compound of the present invention to a patient.
• cell proliferative diseases, cancers, and conditions including solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)
• CLL chronic lymphocytic leukemia
• Another aspect of the invention is a method for treating inflammatory diseases and conditions (including psoriasis, nephropathy, and pneumonia) comprising administering to a compound of the present invention to a patient.
• inflammatory diseases and conditions including psoriasis, nephropathy, and pneumonia
• Another aspect of the invention is a method for treating gastrointestinal tract diseases and conditions (including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion) comprising administering to a compound of the present invention to a patient.
• IBS irritable bowel syndrome
• IBD inflammatory bowel disease
• pancreatic secretion a method for treating gastrointestinal tract diseases and conditions comprising administering to a compound of the present invention to a patient.
• Another aspect of the invention is a method for treating renal diseases and conditions comprising administering to a compound of the present invention to a patient.
• Another aspect of the invention is a method for treating urinary tract-associated diseases and conditions (including benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, and symptoms derived from diabetes) comprising administering to a compound of the present invention to a patient.
• urinary tract-associated diseases and conditions including benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, and symptoms derived from diabetes
• Another aspect of the invention is a method for treating lower urinary tract diseases and conditions (including obstruction of lower urinary tract), inflammatory diseases and conditions of lower urinary tract (including dysuria and frequent urination) comprising administering to a compound of the present invention to a patient.
• Another aspect of the invention is a method for treating pancreatic diseases and conditions comprising administering to a compound of the present invention to a patient.
• Another aspect of the invention is a method for treating abnormal angiogenesis- associated diseases and conditions (including arterial obstruction) comprising
• Another aspect of the invention is a method for treating brain-associated diseases and conditions (including cerebral infarction and cerebral hemorrhage) comprising administering to a compound of the present invention to a patient.
• brain-associated diseases and conditions including cerebral infarction and cerebral hemorrhage
• Another aspect of the invention is a method for treating neuropathic pain and peripheral neuropathy comprising administering to a compound of the present invention to a patient.
• Another aspect of the invention is a method for treating ocular diseases and conditions (including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring) comprising administering to a compound of the present invention to a patient.
• ocular diseases and conditions including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring
• the compounds of the invention may be used in the treatment and/or prophylaxis of conditions in which Gal-3 plays a role.
• the compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of a condition in which inhibition of the physiological activity of Gal-3 is useful, such as diseases in which a Gal-3 receptor participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.
• the compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).
• “Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of pain.
• Patient means a person afflicted with pain and suitable for therapy as understood by practitioners in the field.
• compositions comprised of a therapeutically effective amount of a compound of the present invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients.
• a therapeutically effective amount is that which is needed to provide a meaningful patient benefit.
• Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
• Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and
• Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg.
• antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.
• Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
• the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
• the dosing regimen will be similar to other agents used clinically.
• the daily dose will be 1-100 mg/kg body weight daily.
• more compound is required orally and less parenterally.
• the specific dosing regime will be determined by a physician using sound medical judgement.
• reaction mixture was degassed and then heated at 85 °C for 1.5 h.
• the reaction mixture was poured into ice and filtered.
• the filter cake was washed with water (50 ml) and DCM (30 ml), and dried under vacuum to provide methyl (4aR,6R,7R,8S,8aR)-7-acetoxy-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-lH- l,2,3-triazol-l-yl)hexahydropyrano[3,2-d][l,3]dioxine-6-carboxylate (3.4 g, 6.05 mmol, 99 % yield) as a light yellow solid.
• LCMS (M + H) + 534.0.
• the mixture was stirred at rt for 30 min and then quenched with AcOH (0.5 mL).
• the mixture was diluted with acetic acid (0.5 mL) and injected to prep HPLC.
• the correct fraction was concentrated under vacuum, basified with saturated NaHCO 3 solution, and extracted with dichloromethane (3 x 20 mL). The combined extract was dried over anhydrous Na2SCh.
• hGal-3 (HTRF) IC 50 0.087 mM.
• iodomethane (2 N in t-butyl ethyl ether) (0.085 mL, 0.169 mmol) at 0 °C was added sodium hydride (60% oil dispersion) (9.01 mg, 0.225 mmol) in one portion.
• the mixture was stirred at rt for 30 min and then quenched with AcOH (0.5 mL).
• the mixture was diluted with ethyl acetate (50 mL), washed with water (2 x 15 mL) and brine (15 mL), and dried over anhydrous NaiSCri.
• the mixture was stirred at rt for 6 h and then at 50 °C for 10 h. It was re-cooled at 0 °C before additional iodomethane (0.175 mL, 2.80 mmol) and sodium hydride (60% oil dispersion) (140 mg, 2.31 mmol) were added. The mixture was heated at 50 °C for another 4 h. The mixture was cooled to 0 °C and quenched with acetic acid (1 mL, 17.47 mmol), diluted with water (150 mL), and adjusted its pH value to 7. The insoluble material was collected by suction filtration, followed by flash chromatography
• the mixture was stirred at rt for 30 min, and then quenched with AcOH (0.5 mL).
• the mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO 3 solution (15 mL), water (2 x 15 mL), an brine (15 mL).
• the reaction mixture was degassed and heated at 85 °C for 1.5 h.
• the reaction was poured into ice.
• the resulting insoluble material was collected by suction filtration and dried under vacuum.
• the crude product was further purified with flash chromatography (24 g silica gel, solid loading, 0- 50% ethyl acetate/dichloromethane) to provide methyl (4aR,6R,7R,8S,8aR)-7-acetoxy-8- (4-(4-chloro-3,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-2-phenylhexahydropyrano[3,2- d][l,3]dioxine-6-carboxylate (286 mg, 0.520 mmol, 98 % yield) as a white solid.
• Step 4 (4aR,6R,7R,8R,8aR)-N-(Benzo[d]thiazol-6-yl)-8-(4-(4-chloro-3,5- difluorophenyl)- 1H- 1 ,2,3 -triazol- 1 -yl)-7-hydroxy-2-phenylhexahydropyrano[3 ,2- d] [ 1 ,3 ]dioxine-6-carboxamide
• dichloromethane (5 mL) was added N,N-diisopropylethylamine (0.153 mL, 0.875 mmol), followed by 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in EtOAc) (557 mg, 0.875 mmol). The resulting solution was stirred at rt for 1 h and then concentrated under vacuum.
• reaction mixture was stirred at rt overnight, diluted with water (30 mL), acidified to pH 3-4 with 1M HC1 aq solution, and extracted with EtOAc (2 x 50 mL). The combined extract was dried over MgSO 4 , filtered and concentrated under vacuum.
• Step 2 (4aR,6R,7R,8S,8aR)-6-((5-Chloro-2-(trifluoromethyl)phenyl)carbamoyl)-8-(4-(4- chloro-3,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-2-phenylhexahydropyrano[3,2- d][l,3]dioxin-7-yl acetate
• Step 3 (4aR,6R,7R,8R,8aR)-N-(5-Chloro-2-(trifluoromethyl)phenyl)-8-(4-(4-chloro-3,5- difluorophenyl)- 1H- 1 ,2,3 -triazol- 1 -yl)-7-hydroxy-N-methyl-2- phenylhexahydropyrano[3,2-d][l,3]dioxine-6-carboxamide
• Step 1 (4aR,6R,7R,8R,8aR)-N-(Benzo[b]thiophen-6-yl)-7-hydroxy-2-phenyl-8-(4-(3,4,5- trifluorophenyl)- 1H- 1 ,2,3 -triazol- 1 -yl)hexahydropyrano[3 ,2-d] [1,3 ]dioxine-6- carboxamide
• hGal-3 (HTRF) IC 5 o 0.166 mM.
• hGal-3 (HTRF) ICso 0.102 mM.

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• 2020
  • 2020-04-08 EP EP20722856.0A patent/EP3953349A1/en active Pending
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