WO2022189459A2 - Nouvel inhibiteur de galectines à base de galactoside - Google Patents

Nouvel inhibiteur de galectines à base de galactoside Download PDF

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WO2022189459A2
WO2022189459A2 PCT/EP2022/055945 EP2022055945W WO2022189459A2 WO 2022189459 A2 WO2022189459 A2 WO 2022189459A2 EP 2022055945 W EP2022055945 W EP 2022055945W WO 2022189459 A2 WO2022189459 A2 WO 2022189459A2
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optionally substituted
alkyl
halogen
cycloalkyl
substituted
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WO2022189459A3 (fr
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Kristoffer Peterson
Fredrik Zetterberg
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Galecto Biotech AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel compounds, the use of said compounds as medicament and for the manufacture of a medicament for the treatment of diseases or disorders such as but not limited to cancers; fibrosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; pathological angiogenesis; eye diseases; HIV-1 diseases; inflammation or transplant rejection in mammals.
  • the invention also relates to pharmaceutical compositions comprising said novel compounds.
  • Galectins are proteins with a characteristic carbohydrate recognition domain (CRD). This is a tightly folded ⁇ -sandwich of about 130 amino acids (about 15 kDa) with the two defining features 1) a ⁇ - galactose binding site and 2) sufficient similarity in a sequence motif of about seven amino acids, most of which (about six residues) make up the ⁇ -galactose binding site.
  • CCD carbohydrate recognition domain
  • galectins-1 >1989) and -3 (>4791).
  • Evidence from literature suggests roles for galectins in e.g. fibrosis, inflammation and cancer (Dings et al., Dube-Delarosbil et al.2017)
  • Galectin-1 is widely expressed in many cell types and tissues (www.proteinatlas.org) being involved in mechanisms such as apoptosis, adhesion and migration, cell transformation, invasion and metastasis immune escape and angiogenesis. Upregulation of galectin 1 has also been associated with cancer (Dings et al. 2018), inflammation (Sundblad et al., 2017) fibrotic disease (Kathiriya et al. 2017, Wu et al. 2019 and Bennet et al.2019) and diabetes (Drake et al. 2022).
  • Example of small molecule ligands including ⁇ -D-galactopyranoside were recently reviewed and examplified in Blanchard et al.2016 and Sethi et al.2021).
  • Galectin-3 is widely expressed in many cell types and tissues (www.proteinatlas.org) being involved in mechanisms such as apoptosis, adhesion and migration, cell transformation, invasion and metastasis immune escape and angiogenesis. Upregulation of galectin 3 has also been associated with cancer, inflammation, neurodegenerative disease, fibrotic disease and diabetes (Dings et al. 2018, Slack et al. 2020, Li et al. 2016) Example of small molecule ligands including ⁇ -D-galactopyranoside were recently reviewed and examplified in Blanchard et al. 2014 and Sethi et al.2021.
  • the compounds of the present invention are novel ⁇ -D-galactopyranose compounds that unexpectedly have shown high affinity for galectin-1 and/or galectin- 3 and are considered novel potent drug candidates.
  • the present invention concerns a ⁇ -D-galactopyranose compound of formula (1) wherein the pyranose ring is ⁇ -D-galactopyranose,
  • a 1 is (R 1 ) n -Z 1a , wherein Z 1a is a five membered heterocycle having at least one heteroatom selected from O, S, and N, except 1,2,3-triazole and is attached to the ⁇ -D-galactopyranose; n is 1 or 2; each R 1 is independently selected from a) C 1-6 alkyl optionally substituted with a halogen; C 1-6 alkyl substituted with a OH; halogen; CN; C 2 -alkynyl; OH; OC 1-6 alkyl optionally substituted with a halogen;C 3-6 cycloalkyl optionally substituted with a halogen; SH; SC 1-6 alkyl optionally substituted with a halogen; NR 2 R 3 , wherein R 2 and R 3 are independently selected from H, C 1-6 alkyl optionally substituted with a halogen, C 3-6 cycloalkyl optionally substituted with a halogen, C
  • Z 2 is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2, 2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazoly
  • B 1 is a) wherein the asterix on the X is linked to D-galactopyranose and is in the beta anomeric conformation
  • R 36 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl optionally substituted with a C 1-3 alkyl or 5- or 6-membered heteroaryl optionally substituted with a C 1-3 alkyl, C 1-6 alkyl substituted with a phenyl optionally substituted with a C 1-3 alkyl or 5- or 6-membered heteroaryl optionally substituted with a C 1-3 alkyl;
  • R 37 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl optionally substituted with a C 1-3 alkyl or 5- or 6-membered heteroaryl optionally substituted with a C 1-3 alkyl, C 1-6 alkyl substituted with a phenyl optionally substituted with a C 1-3 alkyl or 5- or 6-membered heteroaryl optionally substituted with a C 1-3 alkyl; or R 36 and R 37 together with the carbon atom to which they are attached form a non-aromatic 3 -6-membered ring optionally containing 1 or 2 nitrogen, 1 or 2 oxygen and/or 1 or 2 sulphur, optionally substituted with a group selected from one or more halogen, hydroxy, CN, C 1-6 alkyl optionally substituted with a C 3-6 cycloalkyl, C 3-6 cycloalkyl, SO 2 -C 1-6 alkyl optionally substituted with a C 3-6 cyclo
  • R 38 is selected from i) aryl optionally substituted with a group selected from C 1-6 alkyl, C 1-6 alkyl substituted with a halogen, OH, C 1-6 alkyl substituted with a hydroxy, C 1-6 alkoxy substituted with a halogen, C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with a group selected from halogen or C1- 3 alkyl, (CH 2 ) 0-1 -C 3 - 6 cycloalkyl optionally substituted with a group selected from halogen or C 1- 3 alkyl, C 4-6 cyclic ether, CH 2 -C 4-6 cyclic ether, CH 2 CH 2 - C 4-6 cyclic ether, CH 2 -CH 2 -NR 42 R 43 , wherein R 42 and R 43 together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl such as selected from azetidine-1-yl,
  • X 1 is selected from C 1-6 alkyl or X 1 is absent and R 39 is linked to N;
  • R 39 is attached to N or X 1 and is selected from aryl or heteroaryl optionally substituted with one or more halogen, hydroxy, CN, C 1-6 alkyl, SO 2 C 1-3 alkyl, C 1-6 alkyl substituted with a halogen, C 1-6 alkyl substituted with a hydroxy, C 1-6 alkoxy substituted with a halogen, C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with a group selected from halogen or C 1-3 alkyl, amino, ethynyl, heterocycloalkyl;
  • R 50 is selected from the group consisting of a) H, b) OH, c) OC 1-6 alkyl optionally substituted with one or more halogen, phenyl, phenyl substituted with one or more groups selected from OH and halogen, CN, OR 49 , NR 51 R 52 , CONH 2 , and CONR 53 R 54 , wherein R 53 andR 54 are independently selected from H, C 1-3 alkyl, and cyclopropyl, or R 53 andR 54 together with the nitrogen may form a heterocycloalkyl optionally substituted with a group selected from OH, wherein R 49 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH 3 optionally substituted with a F, OCH 2 CH 3 optionally substituted with a F, OH, and R 55 -CONH- wherein R 55 is selected from C 1-3 alkyl and cyclopropyl, R 51 is selected from the
  • Z 1a is selected from 1,2,4-triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxolyl, dithiolyl, thiazolyl, isothiazolyl, furanyl, thiophen, pyrrolyl, imidazolyl, or pyrazolyl.
  • Z 1a is a pyrazolyl.
  • Z 1a is a pyrazolyl
  • C 1 and C 2 are independently selected from R 1 (when one of C 1 and C 2 is a hydrogen then n is 1 in (R 1 ) n -Z 1a , and when n is 2 then none of C 1 and C 2 is a hydrogen) wherein the asterix * indicates the nitrogen atom of the pyrazole ring that is covalently attached to the galactopyranose.
  • n is i and C 1 is selected from R 1 and C 2 is hydrogen.
  • C 1 is selected from a phenyl optionally substituted with one, two or three substitutents selected from the group consisting of a halogen, a CN, cyclopropyl optionally substituted with a F, isopropyl optionally substituted with a F, OC 1-3 alkyl optionally substituted with a F, O-cyclopropyl optionally substituted with a F, O-isopropyl optionally substituted with a F, and a C 1-3 alkyl optionally substituted with a F; and C 2 is hydrogen.
  • C 1 is selected from a phenyl substituted with one, two or three substitutents selected from the group consisting of Cl, F, Br and 1, such as three F.
  • C 1 is selected from a phenyl substituted with three substitutents selected from the group consisting of Cl and F, such as one Cl and two F.
  • substituents are connected to the ortho, meta and para positions of the phenyl.
  • meta and para positions of the phenyl Typically, meta and para positions of the phenyl.
  • the three substitunets are connected to the ortho, meta and para positions of the phenyl.
  • C 1 is selected from a thiazolyl optionally substituted with one, two or three substitutents selected from the group consisting of a halogen, a CN, cyclopropyl optionally substituted with a F, isopropyl optionally substituted with a F, O C 1-3 alkyl optionally substituted with a F, O-cyclopropyl optionally substituted with a F, O-isopropyl optionally substituted with a F, and a C 1-3 alkyl optionally substituted with a F; and C 2 is hydrogen.
  • C 1 is selected from a thiazol substituted with a halogen, such as one halogen, e.g., one Cl.
  • B 1 is wherein the asterix on the X is linked to D-galactopyranose and is in the beta anomeric conformation, and X, R 36 , R 37 , and R 38 are as defined in above under the compound of formula (1).
  • X is S.
  • R 36 and R 37 together with the carbon atom to which they are attached form a non-aromatic 5-6-membered ring optionally containing 1 nitrogen and/or 1 oxygen, optionally substituted with a group selected from one or more halogen, hydroxy, CN, C 1-6 alkyl optionally substituted with a C 3-6 cycloalkyl, C 3-6 cycloalkyl, SO 2 -C 1-6 alkyl optionally substituted with a C 3-6 cycloalkyl, SO 2 -C 3-6 cycloalkyl, CO-C 1-6 alkyl optionally substituted with a C 3-6 cycloalkyl, CO-C 3-6 cycloalkyl, COO-C 1-6 alkyl optionally substituted with a C 3-6 cycloalkyl, COO-C 3-6 cycloalkyl, CONH-C 1-6 alkyl optionally substituted with a C 3-6 cycloalkyl, CONH-C 3-6 cycloalky
  • R 36 and R 37 together with the carbon atom to which they are attached form a non-aromatic 5-6-membered ring optionally containing 1 nitrogen and/or 1 oxygen, optionally substituted with a group selected from halogen, C 1-6 alkyl and SO 2 -C 1-6 alkyl, such as two F, one methyl or one SO 2 CH 3 .
  • R 38 is heteroaryl optionally substituted with a group selected from C 1-6 alkyl, C 1-6 alkyl substituted with a halogen, C 1-6 alkyl substituted with a hydroxy, C 1-6 alkoxy substituted with a halogen, C 3-6 cycloalkyl, C 3 - 6 cycloalkyl substituted with a group selected from halogen or C 1-3 alkyl, (CH 2 ) 0-1 -C 3-6 cycloalkyl optionally substituted with a group selected from halogen or C 1-3 alkyl, C 4 - 6 cyclic ether, CH 2 -C 4-6 cyclic ether, CH 2 CH 2 -C 4-6 cyclic ether, CH 2 -CH 2 -NR 44 R 45 , wherein R 44 and R 45 together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl such as selected from azetidine-1-yl, pyrrol
  • R 38 is pyridinyl substituted with a group selected from C 1-6 alkyl substituted with a halogen and C 3-6 cycloalkyl, such as one CF 3 or one cyclopropyl.
  • R 38 is pyridinyl substituted with a C 1-6 alkyl, such as a methyl, typically one methyl.
  • R 38 is pyridinyl substituted with a halogen, such as a Cl, typically one Cl.
  • X 1 is selected from C 1-6 alkyl and R 39 is selected from aryl or heteroaryl optionally substituted with one or more halogen, hydroxy, CN, C 1-6 alkyl, SO 2 C 1-3 alkyl, C 1-6 alkyl substituted with a halogen, C 1-6 alkyl substituted with a hydroxy, C 1-6 alkoxy substituted with a halogen, C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with a group selected from halogen or C 1-3 alkyl, amino, ethynyl, heterocycloalkyl.
  • X 1 is absent and R 39 is linked to N and is selected from phenyl substituted with one or more halogen and CN.
  • R 39 is phenyl substituted with one or two selected from Cl and CN.
  • R 50 is selected from H, OH, OC 1 -4 alkyl, such as O-methyl, O-ethyl, or O-isopropyl, or OC 1 -4 alkyl substituted with one CONR 53 R 54 , wherein R 53 andR 54 are independently selected from H, C 1-3 alkyl, and cyclopropyl, or R 53 andR 54 together with the nitrogen form a heterocycloalkyl optionally substituted with a group selected from OH.
  • R 50 is selected from OH.
  • R 50 is selected from OC 1 -4 alkyl such as O-methyl, substituted with one CONR 53 R 54 , wherein R 53 andR 54 together with the nitrogen form a heterocycloalkyl optionally substituted with a group selected from OH.
  • the present invention concerns a ⁇ -D-galactopyranose compound of formula (1) selected from any one of the group consisting of:
  • the present invention relates to a compound of formula (1) for use as a medicine.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of any one of the previous claims and optionally a pharmaceutically acceptable additive, such as a carrier and/or excipient.
  • the present invention relates to a compound of formula (1) of the present invention for use in a method for treating a disorder relating to the binding of a galectin-3 to a ligand in a mammal, such as a human.
  • the disease or disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, intestinal fibrosis, ankylosing spondylitis,
  • neovascularization related to cancer and eye diseases, such as age- related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Hermansky- Pudlak syndrome, pulmonary arterial hypertension, RA-ILD, SSc-ILD, Lung disease with fibrosis such as COPD and asthma.
  • Otosclerosis mesothelioma
  • liver disorders such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease
  • Liver cirrhosis of various origins such as alcoholic and non-alcoholic, autoimmune cirrhosis such as primary biliary cirrhosis and sclerosing cholangitis, virally induced cirrhosis, cirrhosis induced by genetic disease.
  • Liver cancer cholangiocarcinoma, biliary tract cancer
  • neurodegenerative disorders such as Parkinsons disease, Alzheimers disease, cognitive impairment, cerebrovascular diseases such as stroke, traumatic brain injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, peripheral nephropathy.
  • the present invention relates to a method for treatment of a disease or disorder relating to the binding of a galectin-3 to a ligand in a mammal, such as a human, wherein a therapeutically effective amount of at least one compound of formula (1) of the present invention is administered to a mammal in need of said treatment.
  • the disease or disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, intestinal fibrosis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular
  • neovascularization related to cancer and eye diseases, such as age- related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Hermansky- Pudlak syndrome, pulmonary arterial hypertension, RA-ILD, SSc-ILD, Lung disease with fibrosis such as COPD and asthma.
  • Otosclerosis mesothelioma
  • liver disorders such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease
  • Liver cirrhosis of various origins such as alcoholic and non-alcoholic, autoimmune cirrhosis such as primary biliary cirrhosis and sclerosing cholangitis, virally induced cirrhosis, cirrhosis induced by genetic disease.
  • Another aspect of the present invention concerns combination therapy involving administering a compound of formula (1) of the present invention together with a therapeutically active compound different from the compound of formula (1) (interchangeable with “a different therapeutically active compound”).
  • the present invention relates to a combination of a compound of formula (1) and a different therapeutically active compound for use in treatment of a disorder relating to the binding of a galectin-3 to a ligand in a mammal.
  • Such disorders are disclosed below.
  • a therapeutically effective amount of at least one compound of formula (1) of the present invention is administered to a mammal in need thereof in combination with a different therapeutically active compound.
  • said combination of a compound of formula (1) together with a different therapeutically active compound is administered to a mammal suffering from a disorder selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, systemic lupus
  • neovascularization related to cancer and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistens; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Hermansky- Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.
  • a non-limiting group of cancers given as examples of cancers that may be treated, managed and/or prevented by administration of a compound of formula (1) in combination with a different therapeutically active compound is selected from: colon carcinoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangeosarcoma, lymphangeoendothelia sarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystandeocarcinoma, medullary
  • the administration of at least one compound of formula (1) of the present invention and at least one additional therapeutic agent demonstrates therapeutic synergy.
  • a measurement of response to treatment observed after administering both at least one compound of formula (1) of the present invention and the additional therapeutic agent is improved over the same measurement of response to treatment observed after administering either the at least one compound of formula (1) of the present invention or the additional therapeutic agent alone.
  • a further aspect of the present invention concerns combination therapy involving administering a compound of formula (1) of the present invention together with an anti-fibrotic compound different form the compound of formula (1) to a mammal in need thereof.
  • such anti-fibrotic compound may be selected from the following non-limiting group of anti-fibrotic compounds: pirfenidone, nintedanib, pumpuzumab (GS-6624, AB0024), BG00011 (STX100), PRM-151, PRM-167, PEG-FGF21, BMS-986020, FG-3019, MN-001, IW001, SAR156597, GSK2126458, PAT-1251 and PBI-4050.
  • a still further aspect of the present invention concerns combination therapy involving administering a compound of formula (1) in combination with a further conventional cancer treatment such as chemotherapy or radiotherapy, or treatment with immunostimulating substances, gene therapy, treatment with antibodies and treatment using dendritic cells, to a mammal in need thereof.
  • a further conventional cancer treatment such as chemotherapy or radiotherapy, or treatment with immunostimulating substances, gene therapy, treatment with antibodies and treatment using dendritic cells
  • the compound of formula (1) is administered together with at least one additional therapeutic agent selected from an antineoplastic chemotherapy agent.
  • the antineoplastic chemotherapeutic agent is selected from: all-trans retinoic acid, Actimide, Azacitidine, Azathioprine, Bleomycin, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Irinotecan, Lenalidomide, Leucovorin, Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Revlimid, Temozolomide, Teniposide, Thi
  • a chemotherapeutic agent for use in the combination of the present agent may, itself, be a combination of different chemotherapeutic agents.
  • Suitable combinations include FOLFOX and IFL.
  • FOLFOX is a combination which includes 5 -fluorouracil (5-FU), leucovorin, and oxaliplatin.
  • IFL treatment includes irinotecan, 5-FU, and leucovorin.
  • the further conventional cancer treatment includes radiation therapy.
  • radiation therapy includes localized radiation therapy delivered to the tumor.
  • radiation therapy includes total body irradiation.
  • the further cancer treatment is selected from the group of immunostimulating substances e.g. cytokines and antibodies.
  • immunostimulating substances e.g. cytokines and antibodies.
  • cytokines may be selected from the group consisting of, but not limited to: GM-CSF, type I IFN, interleukin 21, interleukin 2, interleukin 12 and interleukin 15.
  • the antibody is preferably an immunostimulating antibody such as anti-CD40 or anti-CTLA-4 antibodies.
  • the immunostimulatory substance may also be a substance capable of depletion of immune inhibitory cells (e.g. regulatory T-cells) or factors, said substance may for example be E3 ubiquitin ligases.
  • E3 ubiquitin ligases have emerged as key molecular regulators of immune cell function, and each may be involved in the regulation of immune responses during infection by targeting specific inhibitory molecules for proteolytic destruction.
  • HECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation.
  • the compound of formula (1) is administered together with at least one additional therapeutic agent selected from a checkpoint inhibitor.
  • the checkpoint inhibitor is acting on one or more of the following, non-limiting group of targets: CEACAM1, galectin-9, TIM3, CD80, CTLA4, PD-1, PD-L1, HVEM, BTLA, CD 160, VISTA, B7- H4, B7-2, CD155, CD226, TIGIT, CD96, LAG3, GITF, 0X40, CD137, CD40, IDO, and TDO.
  • targets are known targets and some of these targets are described in Melero et al., Nature Reviews Cancer (2015).
  • check point inhibitors administered together with the compound of formula (1) are Anti-PD-1 : Nivolumab, Pembrolizumab, Cemiplimab. Anti-PD-1 : Atezolizumab, Avelumab, Durvalumab and one Anti-CTLA-4: Ipilimumab. Each one of these check point inhibitors can be made the subject of an embodiment in combination with any one of the compounds of formula (1).
  • the compound of formula (1) is administered together with at least one additional therapeutic agent selected from an inhibitor of indoleamine-2, 3-dioxygenase (IDO).
  • additional therapeutic agent selected from an inhibitor of indoleamine-2, 3-dioxygenase (IDO).
  • the compound of formula (1) is administered together with at least one additional therapeutic agent selected from one or more inhibitors of the CTLA4 pathway.
  • the inhibitor of the CTLA4 pathway is selected from one or more antibodies against CTLA4.
  • the compound of formula (1) is administered together with at least one additional therapeutic agent selected from one or more inhibitors of the PD-1/PD-L pathway.
  • the one or more inhibitors of the PD-1/PD-L pathway are selected from one or more antibodies or antibody fragments against PD-1, PD-L1, and/or PD-L2, or other ways by which an anti -PD 1 antibodies can be induced such as mRNA based introduction of genetic material which sets forth in-body production of anti -PD 1 or anti-PDLl antibodies or fragments of such antibodies.
  • the present invention relates to a process of preparing a compound of formula II or a pharmaceutically acceptable salt or solvate thereof comprising the step al where C 1 , C 2 , X, R 36 , R 37 , R 38 and R 50 are defined as above under formula 1; al) Reacting a compound of formula I wherein Z 1 is a halide such as bromine or iodine with a compound of formula C 1 -Y 1 , wherein Y 1 is defined as a boronic acid, borinatester, tinalkyl or zincalkyl suitable for cross-coupling reactions such as Suzuki, Stille or Negishi couplings in the presence of a catalyst such as palladium tetrakis or Pd(dppf)Cl 2 in a suitable solvent such as 1,4-dioxane/water or acetonitrile optionally in the presence of a base such as K 2 CO 3, optionally in the presence of a cupper salt such as Cul, optional
  • the present invention relates to a process of preparing a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof comprising the step a2 where C 1 , C 2 , X 1 , R 39 and R 50 are defined as above under formula 1; a2) Reacting a compound of formula III wherein Z 2 is a halide such as bromine or iodine with a compound of formula C 1 -Y 3 , wherein Y 3 is defined as a boronic acid, borinatester, tinalkyl or zincalkyl suitable for cross-coupling reactions such as Suzuki, Stille or Negishi couplings in the presence of a catalyst such as palladium tetrakis or Pd(dppf)Cl 2 in a suitable solvent such as 1,4-dioxane/water optionally in the presence of a base such as K 2 CO 3, optionally at elevated temperatures to give a compound of formula IV; alternatively, reacting a compound of formula III wherein
  • the present invention relates to a process of preparing a compound of formula XI or a pharmaceutically acceptable salt or solvate thereof comprising the steps a3-a8 where C 2 , X, R 36 , R 37 and R 38 are defined as above under formula 1;
  • B 1 is defined as above under formula 1, such as , in the presence of a base such as CS 2 CO 3 in an inert solvent such as DMF to give a compound of formula X. a8) Reacting a compound of formula X with a base such as sodium methoxide in a solvent such as methanol to give a compound of formula XI.
  • the present invention relates to a process of preparing a compound of formula XIII or a pharmaceutically acceptable salt or solvate thereof comprising the step a9 where X, R 36 , R 37 and R 38 are defined as above under formula i; a9) Reacting a compound of formula XII wherein Y 5 is a protecting group such as quinoline with a carbonyl compound such as in the presence of a strong base such as LDA or BuLi in a suitable solvent such as THF to give an intermediate where the protective group Y 5 is cleaved, in the case of quinoline, by reacting it with sodium cyanoborohydride in acetic acid to give a compound of formula XIII.
  • the present invention relates to a process of preparing a compound of formula XII or a pharmaceutically acceptable salt or solvate thereof comprising the step a10 where X and R 38 are defined as above under formula 1; alO) Reacting a compound of formula XIV wherein Z 4 is a halide such as bromine with a compound of formula X-Y 5 wherein Y 5 is a protective group such as quinoline in the presence of a base such as Cs 2 CO 3 in a suitable solvent such as DMF to give a compound of formula XII.
  • the present invention relates to a process of preparing a compound of formula XX or a pharmaceutically acceptable salt or solvate thereof comprising the steps a11-a15 where C 2 , X 1 , R 39 and R 50 are defined as above under formula 1; Y 6 and Y 7 together form a protective group such as benzylidene, Y 8 is a protective group such as a boc-group, Z 5 is defined as a halogen such as iodine or bromine and Z 6 is defined as a boronic acid or a borinate.
  • the present invention relates to a process of preparing a compound of formula XXV or a pharmaceutically acceptable salt or solvate thereof comprising the steps a16-a19 where X 1 and R 39 are defined as above under formula 1; al6) Reacting a compound of formula XXI wherein Y 9 -Y 12 is a protective group such as acetate, with a cyanide reagent such as trimethyl silyl cyanide in the presence of a reagent such as boron trifluoride diethyl etherate in an inert solvent such as nitromethane at 0 °C to give a compound of the formula XXII.
  • the compound of formula XXIII, wherein Y 9 and Y 10 together form a protective group such as benzylidene and Y 11 is a hydrogen could be reacted with a reagent of formula Z 7 -Y 11 wherein Z 7 is a halide such as iodine or bromine in the presence of a base such as Cs 2 CO 3 in a solvent such as DMF to give another compound of formula XXIII wherein Y 9 and Y 10 together form a protective group such as benzylidene and Y 11 is selected from c), d) or e) under R 50 under formula 1.
  • the present invention relates to a process of preparing a compound of formula XXVII or a pharmaceutically acceptable salt or solvate thereof comprising the step a20 where X 1 and R 39 are defined as above under formula 1; a20) Reacting a compound of formula XXVI with (1S,2S)-trans-2-aminocyclohexanol in the presence of a reducing agent such as sodium cyanoborohydride in a suitable solvent such as DMF to give a compound of formula XXVII.
  • a reducing agent such as sodium cyanoborohydride
  • the present invention relates to a process of preparing a compound of formula XXX or a pharmaceutically acceptable salt or solvate thereof comprising the steps a21-a23 where C 2 , R 36 , R 37 and R 38 are defined as above under formula 1; a21) Reacting a compound of formula XXVIII wherein Z 8 is a halide such as iodine with hydrogen bromide in acetic acid, in a suitable solvent such as DCM to give an intermediate, which is reacted with 4-methylbenzenethiol in the presence of a base such as K 2 CO 3 in a suitable solvent such as DMF to give a compound of formula XXIX.
  • a suitable solvent such as DCM
  • the present invention relates to a process of preparing a compound of formula XXXII or a pharmaceutically acceptable salt or solvate thereof comprising the step a24 where R 36 , R 37 and R 38 are defined as above under formula 1; a24) Reacting a compound of formula XXXIII with a base such as lithium diisopropylamide in a suitable solvent such as THF at -78 °C followed by treatment with a compound of the formula to give a compound of formula XXXII.
  • the present invention relates to a process of preparing a compound of formula XXXV or a pharmaceutically acceptable salt or solvate thereof comprising the step a25 where C 1 , C 2 , R 36 , R 37 and R 38 are defined as above under formula 1 and Y 12 is selected from c), d) or e) under R 50 under formula 1; a25) Reacting a compound of formula XXXIV with benzaldehyde dimethylacetal in the presence of an acid, such as p-toluenesulfonic acid, in a suitable solvent such as acetonitrile to give an intermediate, which is reacted with a reagent of formula Z 9 -Y 12 wherein Z 9 is a halide in the presence of a base, such as lithium tert-butoxide, in a suitable solvent such as DMF to give an intermediate, which is reacted with TFA in water to give a compound of formula XXXV.
  • the present invention relates to a process of preparing a compound of formula XXXVII or a pharmaceutically acceptable salt or solvate thereof comprising the step a26 where C 2 , R 36 , R 37 and R 38 are defined as above under formula 1 and Y 13 is selected from c), d) or e) under R 50 under formula 1; a26) Reacting a compound of formula XXXVI wherein Z 10 is a halide such as iodine with benzaldehyde dimethylacetal in the presence of an acid, such as p- toluenesulfonic acid, in a suitable solvent such as acetonitrile to give an intermediate, which is reacted with a reagent of formula Z 11 -Y 13 wherein Z 11 is a halide in the presence of a base, such as lithium tert-but oxide, in a suitable solvent such as DMF to give an intermediate, which is reacted with TFA in water to give a
  • the present invention concerns a ⁇ -D-galactopyranose compound of formula (1) selected from any one of the exemplified compounds of examples 1-11 or a pharmaceutically acceptable salt thereof.
  • the present invention concerns a ⁇ -D-galactopyranose compound of formula (1) selected from any one of the exemplified compounds of examples 12-20 or a pharmaceutically acceptable salt thereof.
  • Functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid.
  • Suitable protecting groups for hydroxy include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert-butyl), trialkyl silyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldipheylsilyl or trimethyl silyl), AcO(acetoxy), TBS(t-butyldimethylsilyl), TMS(trimethylsilyl), PMB (p-methoxybenzyl), and tetrahydropyranyl.
  • alkyl groups e.g. methyl, allyl, benzyl or tert-butyl
  • trialkyl silyl or diarylalkylsilyl groups e.g. t-butyldimethylsilyl, t-butyldipheylsilyl or
  • Suitable proteting groups for carboxylic acid include (C 1-6 )-alkyl or benzyl esters.
  • Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy -methyl or 2-trimethylsilylethoxycarbonyl (Teoc).
  • the protection and deprotection of functional groups may take place before or after any reaction in the above-mentioned processes.
  • the compound (1) is on free form.
  • “On free form” as used herein means a compound of formula (1), either an acid form or base form, or as a neutral compound, depending on the substitutents. The free form does not have any acid salt or base salt in addition.
  • the free form is an anhydrate.
  • the free form is a solvate, such as a hydrate.
  • the compound of formula (1) is a crystalline form.
  • a therapeutically effective amount of at least one compound is administered to a mammal in need of said treatment.
  • C 1-x alkyl as used herein means a straight or branched alkyl group containing 1-x carbon atoms, e.g. C 1-5 or C 1-6 , such as methyl, ethyl, isopropyl, propyl, butyl, pentyl or hexyl.
  • branched C 3-x alkyl as used herein means a branched alkyl group containing 3-x carbon atoms e.g. C 3-5 or C 3-6 , such as isopropyl, isobutyl, tert-butyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2- dimethylbutyl, 2,3 -dimethylbutyl .
  • OC 1-x alkyl as used herein means an alkoxy group containing 1-x carbon atoms, e.g. C 1-5 or C 1-6 , such as methoxy, ethoxy, propoxy, butyloxy, pentyloxy or hexyloxy.
  • SC 1-x alkyl as used herein means an alkylthio group containing 1-x carbon atoms, e.g. C 1-5 or C 1-6 , such as thiomethyl or thioethyl.
  • C 3-x cycloalkyl as used herein means a cyclic alkyl group containing 3-x carbon atoms, e.g. C 3-6 or C 3-7, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1 -methyl cyclopropyl.
  • OC 3-x cycloalkyl as used herein means a cyclic alkoxy group containing 3-x carbon atoms, e.g. C 3-6 or C 3-7, such as cyclopropoxy, cyclobutoxy, and cyclopentyloxy.
  • C(O)C 1-6 alkyl as used herein means a carbonyl group whereto is attached a C 1-6 alkyl.
  • C(O)C 3-6 cycloalkyl as used herein means a carbonyl group whereto is attached a C 3-6 cycloalkyl.
  • C(O)OC 1-6 alkyl as used herein means a carbonyl group whereto is attached a C 1-6 alkoxy.
  • C(O)OC 3-6 cycloalkyl as used herein means a carbonyl group whereto is attached a C 3-6 cycloalkoxy.
  • S(O 2 )C 3-6 cycloalkyl as used herein means a sulphonyl group whereto is attached a C 3-6 cycloalkyl.
  • S(O 2 )C 1-6 alkyl as used herein means a sulphonyl group whereto is attached a C 1-6 alkyl.
  • C 2-6 alkenyl as used herein means a straight or branched hydrocarbon chain containing one double bond.
  • C 5-7 cycloalkyl as used herein means a cyclic alkyl group containing 5-7 carbon atoms, such as cyclopentyl, cyclohexyl, or cycloheptyl.
  • CN as used herein means a cyano group
  • halogen as used herein means Cl, F, Br or I.
  • C 1-6 alkoxy as used herein means an oxygen linked to a C 1-6 alkyl, such as methoxy or ethoxy.
  • C 1-6 alkylthio as used herein means a sulphur linked to a C 1-6 alkyl, such as thiomethoxy or thioethoxy.
  • C 2 -alkynyl as used herein means C(triple bond)CH.
  • a five or six membered heteroaromatic ring as used herein means one five membered heteroaromatic ring or one six membered heteroaromatic ring.
  • the five membered heteroaromatic ring contains 5 ring atoms of which one to four are heteroatoms selected from N, O, and S.
  • the six membered heteroaromatic ring contains 6 ring atoms of which one to five are heteroatoms selected from N, O and S. Examples include thiophene, furan, pyran, pyrrole, imidazole, pyrazole, isothiazole, isooxazole, pyridine, pyrazine, pyrimidine and pyridazine.
  • heteroaromatic rings When such heteroaromatic rings are substituents they are termed thiophenyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl. Also included are oxazoyl, thiazoyl, thiadiazoly, oxadiazoyl, and pyridonyl.
  • an aryl as used herein means an aromatic ring having at least 6 carbonatoms and includes phenyl and naphthyl.
  • heterocycle such as heteroaryl or heterocycloalkyl
  • a heterocycle consisting of one or more 3-7 membered ring systems containing one or more heteroatoms and wherein such ring systems may optionally be aromatic.
  • a heteroaryl as used herein means a mono or bicyclic aromatic ringsystem containing one or more heteroatoms, such as 1-10, e.g.
  • 1-6 selected from O, S, and N, including but not limited to oxazolyl, oxadiazolyl, thiophenyl, thiadiazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidonyl, quinolinyl, azaquionolyl, isoquinolinyl, azaisoquinolyl, quinazolinyl, azaquinazolinyl, bensozazoyl, azabensoxazoyl, bensothiazoyl, or azabensothiazoyl.
  • a heterocycloalkyl as used herein means a mono or bicyclic 3-7 membered alifatic heterocycle containing one or more heteroatoms, such as 1-7, e.g. 1-5, selected from O, S, and N, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothipyranyl, or piperidonyl.
  • a spiro heterocycle as used herein means a two-ring system connected by a common carbon atom, and containing from 5 to 12 ring members wherein from 2 to 11 are carbon atoms and at least one is a heteroatom, such as a hetero atom selected from one or more N, S, O; one example is N-(2-oxa)-6- azaspiro [3.3] heptanyl.
  • treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications.
  • the treatment may either be performed in an acute or in a chronic way.
  • the patient to be treated is preferably a mammal; in particular, a human being, but it may also include animals, such as dogs, cats, cows, sheep and pigs.
  • a therapeutically effective amount of a compound of formula (1) of the present invention as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (1) and optionally a pharmaceutically acceptable additive, such as a carrier or an excipient.
  • pharmaceutically acceptable additive is intended without limitation to include carriers, excipients, diluents, adjuvant, colorings, aroma, preservatives etc. that the skilled person would consider using when formulating a compound of the present invention in order to make a pharmaceutical composition.
  • the adjuvants, diluents, excipients and/or carriers that may be used in the composition of the invention must be pharmaceutically acceptable in the sense of being compatible with the compound of formula (1) and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof. It is preferred that the compositions shall not contain any material that may cause an adverse reaction, such as an allergic reaction.
  • the adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person skilled within the art.
  • compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier.
  • the pharmaceutical compositions comprise from 1 to 99 % by weight of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99 % by weight of a compound as herein disclosed.
  • the combined amount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier may not constitute more than 100% by weight of the composition, particularly the pharmaceutical composition.
  • only one compound as herein disclosed is used for the purposes discussed above.
  • two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.
  • composition particularly pharmaceutical composition comprising a compound set forth herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous substances, solutions, transdermal patches or suppositories.
  • Example 1-20 The affinity of Example 1-20 for galectins were determined by a fluorescence anisotropy assay where the compound was used as an inhibitor of the interaction between galectin and a fluorescein tagged saccharide probe as described Sorme, P., Kahl-Knutsson, B., Huflejt, M., Nilsson, U. J, and Leffler H. (2004) Fluorescence polarization as an analytical tool to evaluate galectin-ligand interactions. Anal. Biochem.
  • Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400 MHz Bruker AVANCE III 500 instrument or a Varian instrument at 400 MHz, at 25 °C.
  • LC-MS were acquired on an Agilent 1200 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Column: XBridge C18 (4.6 x 50 mm, 3.5 ⁇ m) or SunFire C18 (4.6 x 50 mm, 3.5 ⁇ m).
  • LC-MS were acquired on an Agilent 1100 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Column: Waters symmetry 2.1 x 30 mm C18 or Chromolith RP-18 2 x 50 mm. Solvent A water + 0.1% TFA and solvent B Acetonitrile + 0.1% TFA. Wavelength 254 nm.
  • Preparative HPLC was performed on a Gilson 215. Flow: 25 mL/min Column: XBrige prep C18 10 ⁇ m OBD (19 x 250 mm) column. Wavelength: 254 nM. Solvent A water (10 mM Ammonium hydrogen carbonate) and solvent B Acetonitrile. Alternatively, preparative HPLC were acquired on a Gilson system. Flow: 15 ml/min Column: kromasil 100-5-C18 column. Wavelength: 220 nm. Solvent A water + 0.1% TFA and solvent B Acetonitrile + 0.1% TFA. The following abbreviations are used aq: aqueous
  • DIPEA Diisopropylethylamine
  • MeOD Deuterated methanol mm: millimeter mM: millimolar
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium(0)
  • PE petroleum ether pH: acidity
  • TFA trifluoroacetic acid
  • THF Tetrahydrofuran
  • TMS Trimethyl silyl UV: Ultraviolet ⁇ : ⁇ ngstrom
  • Example 1 is made, starting from 1,2:5,6-di-O-isopropylidene- ⁇ -D-gulofuranose, by following the processes a1 and a3-10 described above.
  • Example 2 is made, starting from 1,2:5,6-di-O-isopropylidene- ⁇ -D-gulofuranose, by following the processes al and a3-10 described above.
  • Example 3 is made, starting from 1,2:5,6-di-O-isopropylidene- ⁇ -D-gulofuranose, by following the processes al and a3-10 described above.
  • Example 4 is made, starting from 1,2:5,6-di-O-isopropylidene- ⁇ -D-gulofuranose, by following the processes al and a3-10 described above.
  • Example 5 is made, starting from 1,2:5,6-di-O-isopropylidene- ⁇ -D-gulofuranose, by following the processes a1, a3-10 and a25 described above.
  • Example 6 is made, starting from 1,2:5,6-di-O-isopropylidene- ⁇ -D-gulofuranose, by following the processes al, a3-5 and a21-24 described above.
  • Example 7 is made, starting from 1,2:5,6-di-O-isopropylidene- ⁇ -D-gulofuranose, by following the processes al, a3-5 and a21-24 described above.
  • Example 8 2,6-Anhydro-N-(3-chloro-5-cyanophenyl)-4-deoxy-4-[4-(3,4,5-trifluorophenyl)- 1H-1,2-pyrazol-1-yl]-N- [(1 S,2S)-2-hydroxycyclohexyl]-3-O-methyl-D-glycero-L- manno-heptonamide
  • Example 8 is made, starting from 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy- ⁇ -D- galactopyranoside, by following the processes a2 and all-20 described above. In process al7 the optional step is performed using iodomethane.
  • Example 9 is made, starting from 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy- ⁇ -D- galactopyranoside, by following the processes a2 and all-20 described above.
  • the optional step is performed using iodomethane.
  • Example 10 is made, starting from 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy- ⁇ -D- galactopyranoside, by following the processes a2 and all-20 described above.
  • the optional step is performed using 4-(bromoacetyl)morphiline.
  • Example 11 2,6-Anhydro-N-(3,5-dichlorophenyl)-4-deoxy-4-[4-(3,4,5-trifluorophenyl)-1H-1,2- pyrazol-1-yl]-N-[(1S,2S)-2-hydroxycyclohexyl]-3-O- ⁇ 2-[(S)-3-hydroxypyrrolidin- 1-yl]-2-oxoethyl ⁇ -D-glycero-L-manno-heptonamide
  • Example 11 is made, starting from 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy- ⁇ -D- galactopyranoside, by following the processes a2 and a11-20 described above.
  • Tributyl-(4-chlorothiazol-2-yl)stannane To a cooled (-78 °C) solution of 2-bromo-4-chloro-thiazole (200 mg, 1.0 mmol) in diethyl ether (3.3 mL) n-butyl lithium (443 ⁇ L, 2.5 M in hexanes, 1.11 mmol) was added and the mixture was stirred 25 min at -78 °C. Tributyltin chloride (364 ⁇ L, 1.21 mmol) was added and the mixture was slowly allowed to reach rt. The reaction was quenched with water (3 mL) and the organic phase was separated.
  • Li P.; Liu, S.; Lu, M.; Bandyopadhyay, G.; Oh, D.; Imamura, T.; Johnson, A. M. F.; Sears, D.; Shen, Z.; Cui, B.; Kong, L.; Hou, S.; Liang, X.; Iovino, S.; Watkins, S. M.; Ying, W.; Osborn, O.; Wollam, J.; Brenner, M.; Olefsky, J. M. Hematopoietic- Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance. Cell 2016, 167 (4), 973-984. el2. https://doi.Org/10.1016/j.cell.2016.10.025.

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Abstract

La présente invention concerne un composé bêta D-galactopyranose de formule (I). Le cycle pyranose est le β-D-galactopyranose, et ces composés sont des inhibiteurs de galectine-3 à haute affinité destinés à être utilisés dans le traitement d'une inflammation ; d'une fibrose, telle qu'une fibrose pulmonaire, une fibrose hépatique, une fibrose rénale, une fibrose ophtalmologique et une fibrose de la peau et du cœur ; de la cicatrisation ; de la formation de chéloïde ; de la formation de cicatrices aberrantes ; d'adhésions chirurgicales ; de la sclérodermie ; de la sclérose systémique ; d'un choc septique ; d'un cancer tels que les carcinomes, les sarcomes, les leucémies et les lymphomes, tels que les lymphomes à lymphocytes T ; de la formation de métastases de cancers ; de maladies auto-immunes telles que le psoriasis, la polyarthrite rhumatoïde, la maladie de Crohn, la colite ulcéreuse, la fibrose intestinale, la spondylarthrite ankylosante, le lupus érythémateux disséminé ; de troubles métaboliques ; d'une cardiopathie ; d'une insuffisance cardiaque ; d'une sténose aortique ; d'une athérosclérose, d'une angiogenèse pathologique, telle que l'angiogenèse oculaire ou une maladie ou un état associé à l'angiogenèse oculaire, par exemple une néovascularisation associée à un cancer ; et de maladies oculaires, telles que la dégénérescence maculaire liée à l'âge et la néovascularisation cornéenne ; d'une athérosclérose ; de maladies métaboliques telles que le diabète ; le diabète de type 2 ; la résistance à l'insuline ; l'obésité ; l'insuffisance cardiaque diastolique ; l'asthme et d'autres maladies pulmonaires interstitielles, y compris le syndrome de Hermansky-Pudlak, l'hypertension artérielle pulmonaire, la RA-ILD, la SSc-ILD, d'une maladie pulmonaire à fibrose telle que la BPCO et l'asthme. Ces composés peuvent en outre être utilisés dans le traitement d'une otosclérose, d'un mésothéliome ; de troubles hépatiques, tels que la stéatohépatite non alcoolique ou la stéatose hépatique non alcoolique, la cirrhose du foie de diverses origines, telles que la cirrhose auto-immune alcoolique ou non alcoolique comme la cirrhose biliaire primitive et la cholangite sclérosante, une cirrhose induite par un virus, une cirrhose induite par une maladie génétique. Ces composés peuvent par ailleurs être utilisés dans le traitement d'un cancer du foie, d'un cholangiocarcinome, d'un cancer des voies biliaires ; de troubles neurodégénératifs tels que la maladie de Parkinson, la maladie d'Alzheimer, d'une déficience cognitive, de maladies cérébrovasculaires telles qu'un accident vasculaire cérébral, un traumatisme crânien, la maladie de Huntington, la sclérose latérale amyotrophique, la sclérose en plaques, la néphropathie périphérique.
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