Novel galactoside inhibitor of galectins

Abstract

The present invention relates to a high affinity galectin-3 inhibitor alpha-D-galactopyranose derivative of formula (I), a pharmaceutical salt or solvate thereof, for use in treatment of inflammation.

Description

[0001] NOVEL GALACTOSIDE INHIBITOR OF GALECTINS

[0002] Technical field

[0003] The present invention relates to a novel compound, the use of said compound 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 compound.

[0004] Background Art

[0005] Galectins are proteins with a characteristic carbohydrate recognition domain (CRD). This is a tightly folded P-sandwich of about 130 amino acids (about 15 kDa) with the two defining features 1) a P -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 P-galactose binding site. Galectins are synthesized as cytosolic proteins from where they can be targeted to the nucleus, specific cytososlic sites, or secreted to engage in mechanisms effecting physiological functions such as inflammation, immune responses, cell-migration and autophagy. (Johannes et. al 2018) There are now over 9319 publications on galectins in PubMed, with most, as mentioned above, about 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)

[0006] 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 P-D-galactopyranoside were recently reviewed and examplified in Blanchard et. al 2014 and Sethi et. al 2021. Summary of the invention

[0007] The compound of the present invention is a novel a-D-galactopyranose compound that unexpectedly have shown high affinity for galectin-3 and is considered a novel potent drug candidate.

[0008] The compound of formula (I) was first identified as a metabolite during clinical trials involving Selvigaltin (also termed GB1211), an orally available small molecule galectin-3 inhibitor, which was evaluated in a multiple part clinical trial to assess the effect of liver disease on pharmacokinetics (PK) and safety, in compliance with guideline requirements.

[0009] The compound of formula (I) was synthesized as shown in the experimental section and tested to have galectin 3 affinity similar to Selvigaltin.

[0010] In a broad aspect the present invention concerns a a-D-galactopyranose compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0011] In an embodiment the compound of formula (I) is the free form. In a further embodiment the compound of formula (I) is a solid form, such as a solid form of the free form.

[0012] In a still further embodiment the solid form is an amorphous form.

[0013] In a further aspect the present invention relates to a compound of formula (I) for use as a medicine.

[0014] In a still further aspect, the present invention relates to 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. In a further aspect the present invention relates to a compound of formula (I) 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. In a further embodiment the disease or disorder is selected from the group consisting of inflammation, such as acute post myocardial infarctions (MI), acute coronary syndrome, acute stent occlusion, acute myocardial reperfusion injury, acute pneumonitidies, acute lung injury (ALI), acute kidney injury (AKI), acute hepatitis, acute on chronic liver failure, acute alcohol hepatitis, acute pancreatitis, acute uveitis, acute pancreatitis related liponecrosis, acute retinitis, acute nephritis, acute myocarditis, chronic autoimmune diseases in all organs, (e.g. lung, liver, kidney, heart, skin, muscle, gut), chronic bacterial infections, chronic viral related inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart, acute post-surgical ocular fibrosis, acute transplantation rejection of the kidney, heart, lung, liver, and pancreas, acute post explosion / improvised explosive devices, acute post toxic dust (such as dust from terror attack known as 9 / 11), acute chemical exposure, chronic lung fibrosis, interstitial lung fibrosis (IPF), Interstitial Lung Disease (ILD), Childhood ILD (ChILD); chronic liver fibrosis, chronic alcohol fibrosis, chronic viral fibrosis, chronic diabetic fibrosis, diabetic nephropathy, chronic glomerulonephritis, renal artery stenosis, endometriosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancers, 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; coagulopathies, such as thrombosis proneness idiopathic (thrombophilia), autoimmune based thrombophilia, microthrombosis at multiorgan failure, COVID-19 related coagulopathy, thrombophilia in cancer disease; cardiovascular disorders, such as cardiac fibrosis, cardiac failure, left and right atrial fibrillation, atheromatosis, arterial inflammation, arterial calcification, aortic stenosis; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; endocrine disorders, such as Addison, autoimmune hypophysitis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; atrophic diseases in the brain, such as Alzheimer’s and Parkinson’s, atrophic diseases in the cerebellum, such as cerebellar atrophy, atrophic spinal diseases such as ALS; disorders related to transplantation in organs, such as anti -rejection prophylaxis, anti-acute rejection, anti-chronic rejection; acute burn; acute inflammatory reaction; chronic acute skin graft rejection; chronic scarring; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, pulmonary arterial hypertension, Rheumatoid disease associated interstitial lung disease RA-ILD, Systemic Sclerosis SSc-ILD, lung disease with fibrosis such as COPD (Chronic Obstructive Pulmonary Disease) and asthma; Otosclerosis, mesothelioma; post-surgery disorders, such as anti-keloid, anti-stricture, antiadhesion, anti-thrombosis, fibrosis / scar reduction following cosmetic procedures; toxin exposure disorders, such as toxic hepatitis, cholera toxin related, mushroom toxin based acute renal failure, pertussis toxin, aeromonas hydrophila enterotoxin, cadmium induced cardiac toxicity, helicobacter O-antigen related toxicity, LPS based toxicity, Streptozotocin toxicity, asbestos exposure, Nephrogenic Systemic Fibrosis (Post Contrast Agents); Tissue injury, such as Spinal cord injury, Peripheral nerve repair; congenital hepatic fibrosis; hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; liver disorders, such as nonalcoholic steatohepatitis (NASH) 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 (ALS), multiple sclerosis (MS), peripheral nephropathy.

[0015] In a still further aspect 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 (I) of the present invention is administered to a mammal in need of said treatment. In a further embodiment the disease or disorder is selected from the group consisting of inflammation, such as acute post myocardial infarctions (MI), acute coronary syndrome, acute stent occlusion, acute myocardial reperfusion injury, acute pneumonitidies, acute lung injury (ALI), acute kidney injury (AKI), acute hepatitis, acute on chronic liver failure, acute alcohol hepatitis, acute pancreatitis, acute uveitis, acute pancreatitis related liponecrosis, acute retinitis, acute nephritis, acute myocarditis, chronic autoimmune diseases in all organs, (e.g. lung, liver, kidney, heart, skin, muscle, gut), chronic bacterial infections, chronic viral related inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart, acute post-surgical ocular fibrosis, acute transplantation rejection of the kidney, heart, lung, liver, and pancreas, acute post explosion / improvised explosive devices, acute post toxic dust (such as dust from terror attack known as 9 / 11), acute chemical exposure, chronic lung fibrosis, interstitial lung fibrosis (IPF), Interstitial Lung Disease (ILD), Childhood ILD (ChILD); chronic liver fibrosis, chronic alcohol fibrosis, chronic viral fibrosis, chronic diabetic fibrosis, diabetic nephropathy, chronic glomerulonephritis, renal artery stenosis, endometriosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancers, 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; coagulopathies, such as thrombosis proneness idiopathic (thrombophilia), autoimmune based thrombophilia, microthrombosis at multiorgan failure, COVID-19 related coagulopathy, thrombophilia in cancer disease; cardiovascular disorders, such as cardiac fibrosis, cardiac failure, left and right atrial fibrillation, atheromatosis, arterial inflammation, arterial calcification, aortic stenosis; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; endocrine disorders, such as Addison, autoimmune hypophysitis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; atrophic diseases in the brain, such as Alzheimer’s and Parkinson’s, atrophic diseases in the cerebellum, such as cerebellar atrophy, atrophic spinal diseases such as ALS; disorders related to transplantation in organs, such as anti -rejection prophylaxis, anti-acute rejection, anti-chronic rejection; acute burn; acute inflammatory reaction; chronic acute skin graft rejection; chronic scarring; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, pulmonary arterial hypertension, Rheumatoid disease associated interstitial lung disease RA-ILD, Systemic Sclerosis SSc-ILD, lung disease with fibrosis such as COPD (Chronic Obstructive Pulmonary Disease) and asthma; Otosclerosis, mesothelioma; post-surgery disorders, such as anti-keloid, anti-stricture, antiadhesion, anti-thrombosis, fibrosis / scar reduction following cosmetic procedures; toxin exposure disorders, such as toxic hepatitis, cholera toxin related, mushroom toxin based acute renal failure, pertussis toxin, aeromonas hydrophila enterotoxin, cadmium induced cardiac toxicity, helicobacter O-antigen related toxicity, LPS based toxicity, Streptozotocin toxicity, asbestos exposure, Nephrogenic Systemic Fibrosis (Post Contrast Agents); Tissue injury, such as Spinal cord injury, Peripheral nerve repair; congenital hepatic fibrosis; hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; liver disorders, such as nonalcoholic steatohepatitis (NASH) 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 (ALS), multiple sclerosis (MS), peripheral nephropathy.

[0016] Another aspect of the present invention concerns combination therapy involving administering a compound of formula (I) of the present invention together with a therapeutically active compound different from the compound of formula (I) (interchangeable with “a different therapeutically active compound”). In one embodiment the present invention relates to a combination of a compound of formula (I) 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. In an embodiment of the present invention, a therapeutically effective amount of at least one compound of formula (I) of the present invention is administered to a mammal in need thereof in combination with a different therapeutically active compound. In a further embodiment, said combination of a compound of formula (I) 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 erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. 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.

[0017] A non-limiting group of cancers given as examples of cancers, including both solid and liquid cancers, that may be treated, managed and / or prevented by administration of a compound of formula (I) in combination with a different therapeutically active compound is selected from: colon carcinoma, breast cancer, head and neck cancer, testis cancer, urothelial 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 carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioblastomas, neuronomas, craniopharingiomas, schwannomas, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroama, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias and lymphomas, acute lymphocytic leukemia and acute myelocytic polycythemia vera, multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, rectum cancer, urinary cancers, uterine cancers, oral cancers, skin cancers, stomach cancer, brain tumors, liver cancer, laryngeal cancer, esophageal cancer, mammary tumors, childhood-null acute lymphoid leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytoid leukemia, acute megakaryocytoid leukemia, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T cell leukemia, small and large non-small cell lung carcinoma, acute granulocytic leukemia, germ cell tumors, endometrial cancer, gastric cancer, cancer of the head and neck, chronic lymphoid leukemia, hairy cell leukemia and thyroid cancer.

[0018] In some aspects of the present invention, the administration of at least one compound of formula (I) of the present invention and at least one additional therapeutic agent demonstrates therapeutic synergy. In some aspects of the methods of the present invention, a measurement of response to treatment observed after administering both at least one compound of formula (I) 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 (I) of the present invention or the additional therapeutic agent alone.

[0019] A further aspect of the present invention concerns combination therapy involving administering a compound of formula (I) of the present invention together with an anti-fibrotic compound different from the compound of formula (I) to a mammal in need thereof. In a further embodiment, such anti-fibrotic compound may be selected from the following non-limiting group of anti-fibrotic compounds: pirfenidone, nintedanib, simtuzumab (GS-6624, AB0024), BG00011 (STX100), PRM-151, PRM-167, PEG-FGF21, BMS-986020, FG-3019, MN-001, IW001, SAR156597, GSK2126458, PAT-1251 and PBL4050. A further aspect of the present invention concerns combination therapy involving administering a compound of formula (I) of the present invention together with an anti-cardiovascular compound different from the compound of formula (I) to a mammal in need thereof.

[0020] A still further aspect of the present invention concerns combination therapy involving administering a compound of formula (I) in combination with a further conventional cancer treatment such as chemotherapy and / or radiotherapy, and / or treatment with immunostimulating substances, and / or gene therapy, and / or treatment with antibodies and / or treatment using dendritic cells, to a mammal in need thereof.

[0021] In an embodiment the compound of formula (I) is administered together with at least one additional therapeutic agent selected from an antineoplastic chemotherapy agent. In a further embodiment, 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, Thioguanine, Valrubicin, Vinblastine, Vincristine, Vindesine and Vinorelbine. In one embodiment, 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.

[0022] In a further embodiment of the present invention, the further conventional cancer treatment includes radiation therapy. In some embodiments, radiation therapy includes localized radiation therapy delivered to the tumor. In some embodiments, radiation therapy includes total body irradiation.

[0023] In other embodiments of the present invention the further cancer treatment is selected from the group of immunostimulating substances e.g. cytokines and antibodies. Such 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 (the HECT, RING and U-box proteins) 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. Several 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.

[0024] In some embodiments of the present invention the compound of formula (I) is administered together with at least one additional therapeutic agent selected from a checkpoint inhibitor. In some embodiments of the invention, 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, CD160, VISTA, B7- H4, B7-2, CD155, CD226, TIGIT, CD96, LAG3, GITF, 0X40, CD137, CD40, IDO, and TDO. These are known targets and some of these targets are described in Melero et al., Nature Reviews Cancer (2015). Examples of check point inhibitors administered together with the compound of formula (I) are Anti-PD-1 : Nivolumab, Pembrolizumab, Cemiplimab. Anti-PD-Ll : 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 (I).

[0025] In some embodiments of the present invention the compound of formula (I) is administered together with at least one additional therapeutic agent selected from an inhibitor of indoleamine-2, 3 -dioxygenase (IDO).

[0026] In some embodiments of the present invention the compound of formula (I) is administered together with at least one additional therapeutic agent selected from one or more inhibitors of the CTLA4 pathway. In some embodiments, the inhibitor of the CTLA4 pathway is selected from one or more antibodies against CTLA4.

[0027] In some embodiments of the present invention the compound of formula (I) is administered together with at least one additional therapeutic agent selected from one or more inhibitors of the PD-l / PD-L pathway. In some embodiments, the one or more inhibitors of the PD-l / 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-PDl antibodies can be induced such as mRNA based introduction of genetic material which sets forth in-body production of anti-PDl or anti-PDLl antibodies or fragments of such antibodies.

[0028] Detailed Description of the invention

[0029] During clinical trials selvigaltin (also termed GB1211), an orally available small molecule galectin-3 inhibitor, was evaluated in a multiple part clinical trial to assess the effect of liver disease on pharmacokinetics (PK) and safety, in compliance with guideline requirements.

[0030] The trial was a phase Ib / IIa three-part study. Parts 1 and 3 had single-dose, open-label designs assessing PK (plasma [total and unbound] and urine), safety, and tolerability of an effective amount of oral selvigaltin, e.g. lOOmg, in participants with Child-Pugh B (moderate cirrhosis, Part 1) and Child-Pugh C (severe cirrhosis, Part 3), compared with healthy-matched participants.

[0031] All participants received selvigaltin and completed the study. No adverse events were reported. Selvigaltin absorption was timely, with median time to reach maximum total plasma concentration following drug administration of 3.49 and 4.00 h post-dose for Child-Pugh B and C participants, respectively; comparable with controls. Total plasma selvigaltin exposure was higher for participants with cirrhosis compared with controls. Whilst maximum plasma drug concentration (Cmax) was unaffected in Child-Pugh B participants, area under the plasma concentration-time curve from time zero to infinity (AUCco) increased by ~ 1.7-fold compared with controls, and half-life was prolonged (geometric mean 28.15 vs. 16.38 h). In Child- Pugh C participants, Cmax increased by ~ 1.3-fold, AUCco increased by ~ 1.5-fold, and half-life was prolonged (21.05 vs. 16.14 h). Unbound fractions of selvigaltin were unaffected in both groups. No trend was observed in urinary excretion of unchanged selvigaltin in either group.

[0032] Selvigaltin and a metabolite identified as the compound of formula (I) was detected in the AUC(0-72h) pooled plasma samples from treated participants across the groups.

[0033] In one part (Part 1), following single oral administration of selvigaltin, unchanged selvigaltin was the most abundant component in plasma in both healthy and Child-Pugh B participants. A metabolite (the compound of formula (I)) was the most abundant metabolite in the samples from both groups.

[0034] In a second part (Part 3), parent selvigaltin was also the most abundant component in the plasma profiles of both healthy and Child-Pugh C participants. The proportion of selvigaltin was somewhat lower in the AUC(0-72h) pooled plasma samples taken from Child-Pugh C participants than in corresponding healthy participants. Unlike in first part, the metabolite was not detected in either of the groups in Part 3.

[0035] The skilled person will understand that it may be necessary to adjust or change the order of steps in the processes for making the compound of formula (I), and such change of order is encompassed by the aspects of the process as described above and accompanying description of the process steps.

[0036] Furthermore, the skilled person will understand that the processes described above and hereinafter the functional groups of intermediate compounds may need to be protected by protecting groups.

[0037] 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(trimethyl silyl), PMB (p-methoxybensyl), and tetrahydropyranyl. Suitable proteting groups for carboxylic acid include (Ci-e)-alkyl or benzyl esters. Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for S include S- C(=N)NH2, TIPS.

[0038] The protection and deprotection of functional groups may take place before or after any reaction in the above-mentioned processes.

[0039] Furthermore the skilled person will appreciate, that, in order to obtain compounds of the invention in an alternative, and on some occasions more convenient manner, the individual process steps mentioned hereinbefore may be performed in different order, and / or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and / or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups.

[0040] In a still further embodiment the compound (I) is on free form. “On free form” as used herein means a compound of formula (I), 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. In one embodiment the free form is an anhydrate. In another embodiment the free form is a solvate, such as a hydrate.

[0041] In a further embodiment the compound of formula (I) is a solid amorphous form.

[0042] Whenever a “compound of formula (I)” is used herein it means the compound of formula (I) in any form incl the free form or as a salt thereof, such as a pharmaceutically acceptable salt thereof, unless otherwise indicated herein or clearly contradicted by context.

[0043] The term “treatment” and “treating” as used herein 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.

[0044] The term "a therapeutically effective amount" of a compound of formula (I) 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.

[0045] In a still further aspect, the present invention relates to a pharmaceutical composition comprising the compound of formula (I) and optionally a pharmaceutically acceptable additive, such as a carrier or an excipient.

[0046] As used herein “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.

[0047] 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 (I) 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.

[0048] As mentioned above, the 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. In some embodiments, the pharmaceutical compositions comprise from 0.01 to 99.99 % by weight of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier and from 0.01 to 99.99 % by weight of a compound of formula (I) 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.

[0049] The 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.

[0050] Further embodiments of the process are described in the experimental section herein, and each individual process as well as each starting material constitutes embodiments that may form part of embodiments.

[0051] The above embodiments should be seen as referring to any one of the aspects (such as ‘method for treatment’, ‘pharmaceutical composition’, ‘compound for use as a medicament’, or ‘compound for use in a method’) described herein as well as any one of the embodiments described herein unless it is specified that an embodiment relates to a certain aspect or aspects of the present invention.

[0052] All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0053] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0054] Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0055] The terms “a” and “an” and “the” and similar referents as used in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. In particular, the terms “a” and “an” and “the” can be exchanged with “at least one” or “one or more” and has such meaning unless clearly contradicted by context.

[0056] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also pro-vide a corresponding approximate measurement, modified by "about," where appropriate).

[0057] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated.

[0058] The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and / or enforceability of such patent documents.

[0059] The term “and / or” as used herein is intended to mean both alternatives as well as each of the alternatives individually. For instance, the expression “xxx and / or yyy” means “xxx and yyy”; “xxx”; or “yyy”, all three alternatives are subject to individual embodiments.

[0060] The description herein of any aspect or embodiment of the invention using terms such as “comprising”, “having”, “including” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that “consists of’, “consists essentially of’, or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context e.g., a composition described herein as comprising a particular element should be understood as alsodescribing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

[0061] The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention indiverse forms thereof.

[0062] Experimental procedures (Evaluation of Kd values)

[0063] The affinity of the compound of formula (I) for galectins were determined by an assay where the compound was used as an inhibitor of galectin 3 binding according to Galectin-3 -Binding Glycomimetics that Strongly Reduce Bleomycin- Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition. Chembiochem 2016, 17 (18), 1759-1770 by Delaine, T.; Collins, P.; MacKinnon, A.; Sharma, G.; Stegmayr, J.; Rajput, V. K.; Mandal, S.; Cumpstey, I.; Larumbe, A.; Salameh, B. A.; et al.

[0064] Scheme 1. Synthesis of the N-oxide.

[0065] Experimental section

[0066] Chemistry

[0067] General procedures

[0068] Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker Avance II 400 MHz spectrometer, 400 MHz Varian or a 500 MHz Bruker AVANCE III 500 instrument or a 500 MHz Bruker Avance Neo 500 instrument, at ambient temperature. Chemical shifts are reported in ppm (5) using the residual solvent as internal standard. Peak multiplicities are expressed as follow: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplet; q, quartet; m, multiplet; br s, broad singlet. HRMS was determined by direct infusion on a Waters XEVO-G2 QTOF mass spectrometer using electrospray ionization (ESI). LC-MS were acquired on an Agilent 1100 or Agilent 1200 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Columns: Waters symmetry 2.1 x 30 mm C18, Chromolith RP-18 2 x 50 mm or XBridge C18 (4.6 x 50 mm, 3.5 m) or SunFire C18 (4.6 x 50 mm, 3.5 pm). Solvent A water + 0.1% TFA and solvent B Acetonitrile + 0.1% TFA. Wavelength: 254 nM. Preparative HPLC was performed on a Gilson system. A) Flow: 10 ml / min Column: kromasil 100-5-C18 column. Wavelength: 254 nM. Solvent A water + 0.1% TFA and solvent B Acetonitrile + 0.1% TFA. B) on a Gilson 215. Flow: 25 ml / min Column: XBrige prep C18 10 pm OBD (19 x 250 mm) column. Wavelength: 254 nM. Solvent A water (10 mM Ammonium hydrogen carbonate) and solvent B Acetonitrile. Flash chromatography was performed on a Biotage SP1 automated system, using Biotage Snap KP-Sil 25 g or 50 g cartridges. Compounds 5 and 6 were of >95% purity according to HPLC- (Agilent series 1100 system, column Eclipse XDB-C18, 0.8 ml / min EEO-MeCN gradient 5-95% 13 min with 0.1% trifluoroacetic acid). l,2,4,6-Tetra-O-acetyl-3-azido-3-deoxy-l-thio-a-D-galactopyranoside 2

[0069] A solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-P-D-galactopyranosyl chloride 1 [Zetterberg et al, 2018] (4.0 g, 11.4 mmol) and potassium thioacetate (2.02 g, 17.1 mmol) in DMF (25 mL) was stirred 1 h at 40 °C. The mixture was partitioned between EtOAc and saturated aq NaHCCh.Tthe organic phase was dried, evaporated, and purified by column chromatography (PEZEtOAc) to afford compound 2 (2.90 g, 52 %). 'H NMR (CDC13, 400 MHz) 5 6.25 (d, J = 5.3 Hz, 1H, H-l), 5.43 (d, J = 2.9 Hz, 1H, H-4), 5.40 (dd, J = 11.0, 5.3 Hz, 1H, H-2), 4.16 - 3.97 (m, 3H, H-5 and H-6), 3.71 (dd, J = 10.9, 3.3 Hz, 1H, H-3), 2.43 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.04 (s, 3H, CH3). ESI-MS m / z calculated for [Ci4Hi9N3O8SNa]+: 412.1; found: 411.9.

[0070] 5-Bromopyridin-l-oxide-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-l-thio-a-D- galactopyranoside 3

[0071] To a cooled (0 °C) solution of compound 2 (495 mg, 1.27 mmol) in DMF (6.0 mL) 3- bromo-5-fluoropyridine-l -oxide (366 mg, 1.91 mmol) and diethylamine (186 mg, 2.54 mmol) were added and the mixture was stirred overnight at rt. The mixture was poured into water (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with brine, dried, evaporated, and purified by column chromatography (PEZEtOAc) to afford compound 3 (362 mg, 55 %). 'H NMR (CDC13, 400 MHz) 5 8.19 - 8.15 (m, 2H, Ph), 7.42 - 8.15 (m, 1H, Ph), 5.98 (d, J= 5.6 Hz, 1H, H-l), 5.42 (d, J= 2.4 Hz, 1H, H-4), 5.23 - 5.19 (m, 1H, H-2), 4.50 - 4.47 (m, 1H, H-5), 4.10 - 4.07 (m, 1H, H-6), 3.99 - 3.94 (m, 1H, H-6'), 3.84 (dd, J = 11.2, 3.2 Hz, 1H, H-3), 2.12 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.03 (s, 3H, CH3). ESI-MS m / z calculated for [Ci?H2oBrN408S]+: 519.0; found: 519.1.

[0072] 5-Bromopyridin-l-oxide-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5- trifluorophenyl)-LH-l ,2,3-triazol-l -yl]-l-thio-a-D-galactopyranoside 4

[0073] To a solution of compound 3 (362 mg, 0.70 mmol) and l,2,3-trifluoro-5-[2- (trimethylsilyl)ethynyl]benzene (191 mg, 0.84 mmol) in DMF (4.0 mL) (+)-sodium L-ascorbate (138 mg, 0.70 mmol) and copper(II) sulfate pentahydrate (174 mg, 0.70 mmol) were added and the mixture was stirred 3 h at rt. The mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried, evaporated, and purified by column chromatography (PEZEtOAc) to afford compound 4 (341 mg, 72 %). 'H NMR (CD3OD, 400 MHz) 5 8.54 (s, 1H, Ph), 8.51 (d, J= 1.2 Hz, 2H, Ph), 7.96 (d, J= 1.2 Hz, 1H, Ph), 7.65 - 7.60 (m, 2H, Ph), 6.45 (d, J= 5.6 Hz, 1H, H-l), 6.18 - 6.14 (m, 1H), 5.65 (d, J = 2.0 Hz, 1H, H-4), 5.53 (dd, J= 11.6, 2.8 Hz, 1H, H-3), 4.17 - 4.13 (m, 3H, H-5 and H-6), 2.04 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.94 (s, 3H, CH3). ESIMS m / z calculated for [C25H23BrF3N4OsS]+: 675.0; found: 674.5.

[0074] 5-Bromopyridin-l-oxide-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-lH-l ,2,3- triazol-l-yl]-l-thio-a-D-galactopyranoside 5 = Mia (as an amorphous form of the compound of formula (I))

[0075] A solution of compound 4 (341 mg, 0.51 mmol) in MeOH / Et3N / water (6.0 mL, 3:2:1) was stirred overnight at rt. The mixture was concentrated and purified by preparative HPLC to afford compound 5 (128 mg, 46 %). 'H NMR (CD3OD, 400 MHz) 5 8.57 (s, 1H, Ph), 8.53 (t, J= 1.5 Hz, 1H, Ph), 8.45 (t, J= 1.5 Hz, 1H, Ph), 8.01 (t, J= 1.4 Hz, 1H, Ph), 7.71 - 7.61 (m, 2H, Ph), 6.12 (d, J= 4.8 Hz, 1H, H-l), 5.02 (dd, J= 11.3, 2.5 Hz, 1H, H-3), 4.97 (dd, J= 11.4, 4.9 Hz, 1H, H-2), 4.42 - 4.35 (m, 1H, H-4), 4.21 - 4.16 (m, 1H, H-5), 3.75 (dd, J= 11.7, 7.1 Hz, 1H, H-6), 3.70 (dd, J= 11.7, 4.9 Hz, 1H, H-6').13C NMR (CD3OD, 101 MHz) 5 152.9, 145.6, 140.5, 140.1, 139.8, 138.1, 135.0, 128.9, 122.9, 121.3, 110.7, 90.1, 74.4, 69.5, 66.4, 65.4, 62.3. HRMS calculated for [Ci9Hi7BrF3N4O5S]+: 549.0050; found: 549.0073.

Claims

We Claim:

1. An a-D-galactopyranose compound of formula (I)or a pharmaceutically acceptaoie san or solvate thereof.

2. The compound of claim 1 as the free form.

3. The compound of claim 1 or 2 as a solid form.

4. The compound of any one of claims 1-3 on amorphous form.

5. The compound of any one of claims 1-4 for use as a medicine.

6. A pharmaceutical composition comprising the compound of any one of the previous claims and optionally a pharmaceutically acceptable additive.

7. The compound of any one of the claims 1-6 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.

8. The compound for use according to claim 7, wherein said disorder is selected from the group consisting of inflammation, such as acute post myocardial infarctions (MI), acute coronary syndrome, acute stent occlusion, acute myocardial reperfusion injury, acute pneumonitidies, acute lung injury (ALI), acute kidney injury (AKI), acute hepatitis, acute on chronic liver failure, acute alcohol hepatitis, acute pancreatitis, acute uveitis, acute pancreatitis related liponecrosis, acute retinitis, acute nephritis, acute myocarditis, chronic autoimmune diseases in all organs, (e.g. lung,liver, kidney, heart, skin, muscle, gut), chronic bacterial infections, chronic viral related inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart, acute post- surgical ocular fibrosis, acute transplantation rejection of the kidney, heart, lung, liver, and pancreas, acute post explosion / improvised explosive devices, acute post toxic dust (such as dust from terror attack known as 9 / 11), acute chemical exposure, chronic lung fibrosis, interstitial lung fibrosis (IPF), Interstitial Lung Disease (ILD), Childhood ILD (ChILD); chronic liver fibrosis, chronic alcohol fibrosis, chronic viral fibrosis, chronic diabetic fibrosis, diabetic nephropathy, chronic glomerulonephritis, renal artery stenosis, endometriosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancers, 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; coagulopathies, such as thrombosis proneness idiopathic (thrombophilia), autoimmune based thrombophilia, microthrombosis at multiorgan failure, COVID-19 related coagulopathy, thrombophilia in cancer disease; cardiovascular disorders, such as cardiac fibrosis, cardiac failure, left and right atrial fibrillation, atheromatosis, arterial inflammation, arterial calcification, aortic stenosis; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; endocrine disorders, such as Addison, autoimmune hypophysitis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; atrophic diseases in the brain, such as Alzheimer’s and Parkinson’s, atrophic diseases in the cerebellum, such as cerebellar atrophy, atrophic spinal diseases such as ALS; disorders related to transplantation in organs, such as anti -rejection prophylaxis, anti-acute rejection, anti-chronic rejection; acute burn; acute inflammatory reaction; chronic acute skin graft rejection; chronic scarring; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, pulmonary arterial hypertension, Rheumatoid disease associated interstitial lung disease RA-ILD, Systemic Sclerosis SSc-ILD, lung disease with fibrosis such as COPD (Chronic Obstructive Pulmonary Disease) and asthma; Otosclerosis,mesothelioma; post-surgery disorders, such as anti-keloid, anti-stricture, antiadhesion, anti-thrombosis, fibrosis / scar reduction following cosmetic procedures; toxin exposure disorders, such as toxic hepatitis, cholera toxin related, mushroom toxin based acute renal failure, pertussis toxin, aeromonas hydrophila enterotoxin, cadmium induced cardiac toxicity, helicobacter O-antigen related toxicity, LPS based toxicity, Streptozotocin toxicity, asbestos exposure, Nephrogenic Systemic Fibrosis (Post Contrast Agents); Tissue injury, such as Spinal cord injury, Peripheral nerve repair; congenital hepatic fibrosis; hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; liver disorders, such as nonalcoholic steatohepatitis (NASH) 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 (ALS), multiple sclerosis (MS), peripheral nephropathy.

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