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Amide linked ep4 agonist-bisphosphonate compounds and uses thereof

A compound, the technology of sodium hydrogen phosphonate, applied in the compound of elements of Group 5/15 of the periodic table, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc.

Active Publication Date: 2020-12-15
SIMON FRASER UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many EP4 agonists are associated with systemic side effects

Method used

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  • Amide linked ep4 agonist-bisphosphonate compounds and uses thereof
  • Amide linked ep4 agonist-bisphosphonate compounds and uses thereof
  • Amide linked ep4 agonist-bisphosphonate compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment Construction

[0171] Synthesis of C3-conjugated compound 1

[0172]

[0173] a) 4-(carboxymethyl)benzoic acid (1.6 equiv), DCC (1.5 equiv), DMAP (0.02 equiv), pyridine (2.4 equiv), CH 2 Cl 2 , room temperature, 2h; b) N-hydroxysuccinimide (2.7 equivalents), EDCl (2.7 equivalents), DMF, room temperature, 7h, the yield after the completion of the two-step reaction was 80%; c) alendronic acid (4 equivalents), triethylamine (11.3 equivalents), DMF / H 2 O(v / v)2:1, room temperature, 10min, 80%.

[0174] 2,5-Dioxypyrrolidinyl-1-yl 4-(2-(((R,E)-4-((R)-1-(7-ethoxy-7-oxoheptyl)- 5-oxopyrrolidinyl-2-yl)-1,1-difluoro-1-phenylbut-3-en-2-yl)oxy)-2-oxoethyl)benzoate ( 9)(2,5-Dioxopyrrolidin-1-yl4-(2-(((R,E)-4-((R)-1-(7-ethoxy-7-oxoheptyl)-5-oxopyrrolidin-2-yl )-1,1-difluoro-1-phenylbut-3-en-2-yl)oxy)-2-oxoethyl)benzoate(9))

[0175] EP4-ester 7 (0.200g, 0.47mmol, 1 equiv) dissolved in dry CH 2 Cl 2 (2.4mL), then 4-(carboxymethyl)benzoic acid (0.134g, 0.75mmol, 1.6eq), DMAP (0.001g, 0.01mmol, 0....

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Abstract

The present invention relates to EP4 agonist-bisphosphonate conjugated compounds or related compounds and uses thereof. The conjugated compounds or related compounds can be used to deliver EP4 agonists or related compounds to a desired site of action, such as bone. Bisphosphonate moieties linked to EP4 agonists via an amide linker are associated with inhibition of bone resorption and bone localization.

Description

technical field [0001] The present invention relates to conjugated compounds and methods for their preparation and use. Background technique [0002] Prostaglandins are a subclass of eicosanoids found in most tissues of the body, which are involved in a variety of physiological functions in animals, including smooth muscle contraction, reproduction, autoimmunity, inflammation, reduction of intraocular pressure, etc. prostaglandin E 2 (PGE 2 ) are associated with various physiological and / or pathological conditions, such as stimulation of bone formation, increased bone mass, arthritis, pain, inflammation, cancer, multiple sclerosis, inflammatory bowel disease, etc. [0003] PGE 2 Binds to four receptors (EP1, EP2, EP3 and EP4). The EP4 receptor is associated with intracellular cyclic adenosine monophosphate (cAMP) production and is distributed in various types of tissues, suggesting that its role in PGE 2 It plays an important role in biological events mediated by smooth...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/572C07F9/38A61K31/675A61K31/663A61P19/08A61P19/10A61K47/54
CPCC07F9/3873C07F9/572A61K47/548A61P19/08
Inventor 马里恩·戴维南罗本特·N·扬陈刚
Owner SIMON FRASER UNIVERSITY