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Novel galactoside inhibitors of galectin

A technology of galactopyranose and halogen, applied in the field of new compounds

Pending Publication Date: 2022-05-17
GALECTO BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite exhibiting higher affinity for galectins, 3,3'-derivatized thiodigalactosides in their multistep synthesis involving double inversion reactions to obtain 3-N-derivatized galactose building blocks has some disadvantages

Method used

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  • Novel galactoside inhibitors of galectin
  • Novel galactoside inhibitors of galectin
  • Novel galactoside inhibitors of galectin

Examples

Experimental program
Comparison scheme
Effect test

example 35

[0477] In vivo mouse pharmacokinetics of Example 35

[0478] Example 35 Intravenous (IV) administration of 1 mg / kg and oral (PO) administration of 10 mg / kg resulted in excellent systemic bioavailability, Figure 1 . Furthermore, good exposure was observed in the brain, Figure 2. After oral administration, the ratio of the exposure in the brain of Example 35 to the exposure in the plasma was determined as the AUC 脑 / AUC 血浆 = 0.19. (AUC = area under the curve)

[0479] Figure 1: Mean plasma levels after intravenous and oral administration

[0480]

[0481] Figure 2: Mean Brain Tissue Concentrations Following IV and Oral Administration

[0482]

[0483] Synthesis of Example Compounds and Intermediates

[0484] General experiment:

[0485] Nuclear magnetic resonance (NMR) spectra were recorded on a 400 MHz Varian instrument or on a 500 MHz Bruker Avance Neo 500 instrument at 25°C.

[0486] Chemical shifts are reported in ppm(d) using residual solvent as internal stand...

example 1

[0528] 3-Chlorophenyl-3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyran Glycoside

[0529]

[0530]3-Chlorophenyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (30mg, 0.069 mmol), (3-fluorophenyl)boronic acid (19mg, 0.14mmol), K 2 CO 3 (38mg, 0.28mmol) and Pd(dppf)Cl 2 (7.6 mg, 0.010 mmol) in dioxane / water (1 mL, 2:1) was stirred at 60°C for 3 hours. The mixture was concentrated and analyzed by preparative HPLC (C 18 ,H 2 O / MeCN / 0.1% TFA) to give the title compound (5 mg, 16%). [C 21 h 20 ClFN 2 o 4 S][M+H] + ESI-MS m / z calculated for: 451.1; found: 450.7. 1 H NMR (400Mhz, methanol-d 4 )δ8.17(s,1H),7.92(s,1H),7.64(s,1H),7.55–7.51(m,1H),7.42–7.27(m,5H),6.93(t,J=7.8Hz ,1H),5.81(d,J=5.4Hz,1H),4.89–4.86(m,1H),4.57(dd,J=11.4,2.7Hz,1H),4.47(t,J=6.1Hz,1H) , 4.21 (d, J=1.9Hz, 1H), 3.75 (dd, J=11.4, 5.8Hz, 1H), 3.65 (dd, J=11.4, 6.6Hz, 1H).

example 2

[0532] 5-Chloropyridin-3-yl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-sulfur Di-alpha-D-galactopyranoside

[0533]

[0534] 5-chloropyridin-3-yl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside ( 49mg, 0.11mmol), (4-chloro-3,5-difluorophenyl) boric acid (43mg, 0.22mmol), K 2 CO 3 (78mg, 0.56mg) and Pd(dppf)Cl 2 (12mg, 0.017mmol) solution was dissolved in 1,4-dioxane / water (1mL, 2:1) and stirred at 90°C for 4 hours. The mixture was partitioned between EtOAc and water, the organic phase was dried and concentrated. The residue was passed through preparative HPLC (C 18 ,H 2 O / MeCN / 0.1% TFA) to give the title compound (5 mg, 9%). [C 20 h 17 Cl 2 f 2 N 3 o 4 S][M+H] + ESI-MS m / z calculated: 504.0; found: 503.8. 1 H NMR (400Mhz, methanol-d 4 )δ8.64(d, J=1.7Hz, 1H), 8.47(d, J=2.1Hz, 1H), 8.24(s, 1H), 8.20(t, J=2.0Hz, 1H), 7.97(s, 1H), 7.38(d, J=8.3Hz, 2H), 5.91(d, J=5.4Hz, 1H), 4.91–4.86(m, 1H), 4.61(dd, J=11.3, 2.7Hz, 1H...

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Abstract

The present invention relates to D-galactopyranose compounds of formula (1) wherein the pyranose ring is beta-D-galactopyranose, these compounds are high affinity galectin-3 inhibitors for use in the treatment of inflammation; thrombosis caused by inflammation; specific dermatitis; acute coronary syndrome; fibrosis, such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ocular fibrosis, and fibrosis of the skin and heart; local fibrosis, such as Duput's foot disease and Petroleum disease; fibrosis complications of other therapies such as coronary artery stents, bile duct stents, cerebral artery stents and ureteral stents; scleroderma; scars; scar tumor formation; new coronal pneumonia-19; acute lung injury; an ARDS; viral pneumonia; abnormal scar formation; surgical adhesion; infectious shock; cancers such as colorectal cancer, other gastrointestinal cancers such as pancreatic cancer, gastric cancer, biliary tract cancer, lung cancer, mesothelioma, female cancers such as breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, brain cancers such as myeloblastoma, glioma, meningioma, skeletal and muscle sarcoma and other sarcoma, leukemia and lymphoma such as T cell lymphoma; transplant rejection; metastatic cancers; aging; dementia; alzheimer's disease; bone diseases driven by TGF-beta, such as osteogenesis imperfection; pulmonary arterial hypertension; autoimmune diseases, such as psoriasis, rheumatoid arthritis, rheumatoid lung disease; , Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; viral infections such as influenza virus, HIV, herpes virus, coronavirus, hepatitis C; metabolic disorders; heart diseases; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, such as neovascularization associated with cancer; and ocular diseases such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases; diabetes; type I diabetes; type 2 diabetes; insulin resistance; obesity; marfan's syndrome; a Royal's syndrome; kidney disease; diastolic heart failure; fibrotic pulmonary complications of aPD1 and other CPI therapies; asthma and other interstitial lung diseases, including Hermanski-Priderac syndrome, liver diseases, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease; uterine diseases, such as uterine fibroids and uterine or cervical fibrosis.

Description

technical field [0001] The present invention relates to novel compounds, their use as medicaments and for their production in the treatment of cancer in mammals; fibrosis; scarring; keloid formation; abnormal scarring; surgical adhesions; pathological angiogenesis; eye diseases; HIV- 1 Disease; use of a drug for inflammation or transplant rejection. In addition, some compounds may cross the blood-brain barrier and may be useful in the treatment of central nervous system (CNS) disorders. In addition, some compounds are suitable as oral medicines. The invention also relates to pharmaceutical compositions comprising said novel compounds. Background technique [0002] Galectins are proteins with a characteristic carbohydrate recognition domain (CRD) (Leffler et al., 2004). It is a tightly folded β-sandwich structure of approximately 130 amino acids (approximately 15 kDa) with two defining features: 1) a β-galactose binding site and 2) a sequence motif of approximately 7 amino...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/14C07H19/24A61K31/7056A61K31/706A61P1/08A61P1/16A61P3/00A61P3/04A61P3/10A61P7/02A61P9/00A61P9/04A61P9/10A61P11/00A61P13/12A61P15/08A61P17/00A61P25/28A61P27/02A61P29/00A61P31/12A61P31/14A61P31/18A61P31/22A61P35/00A61P35/02A61P37/06A61P39/06A61P41/00
CPCC07H19/14C07H19/24A61P29/00A61P17/00A61P7/02A61P1/16A61P13/12A61P27/02A61P11/00A61P9/00A61P31/14A61P31/12A61P41/00A61P1/08A61P35/00A61P35/02A61P37/06A61P25/28A61P31/18A61P31/22A61P9/04A61P3/00A61P9/10A61P3/10A61P3/04A61P15/08A61P39/06C07H19/04C07H19/052
Inventor F·塞特贝里K·彼得松
Owner GALECTO BIOTECH
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