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Benzothiophene estrogen receptor modulators to treat medical disorders

A kind of pharmacy and halogen technology, applied in the field of benzothiophene compounds and compositions thereof

Pending Publication Date: 2021-05-25
G1 THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Aqueous insolubility of fulvestrant poses challenges to achieving and maintaining effective serum concentrations

Method used

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  • Benzothiophene estrogen receptor modulators to treat medical disorders
  • Benzothiophene estrogen receptor modulators to treat medical disorders
  • Benzothiophene estrogen receptor modulators to treat medical disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0243] In one embodiment, n1 is 2.

[0244] In one embodiment, n1 is 3.

[0245] In one embodiment, n1 is 4.

[0246] In one embodiment, n1 is 5.

[0247] In one embodiment, n1 is 6.

[0248] In one embodiment, the compound of formula I is

[0249] In one embodiment, the compound of formula I is

[0250] In one embodiment, the compound of formula I is

[0251] In one embodiment, the compound of formula I is

[0252] In one embodiment, the compound of formula I is

[0253] In one embodiment, the compound of formula I is

[0254] In one embodiment, the compound of formula I is

[0255] In one embodiment, the compound of formula I is

[0256] In one embodiment, the compound of formula I is

[0257] In one embodiment, the compound of formula I is

[0258] In one embodiment, the compound of formula II is

[0259] In one embodiment, the compound of formula II is

[0260] In one embodiment, the compound of formula II is

[0261] In one embodime...

Embodiment 1

[0667] Example 1: Representative Compounds of the Invention

[0668] Table 1 provides non-limiting examples of compounds of the invention that may be prepared according to the methods described above or in Example 2. Those of ordinary skill in the art will be able to use these methods, or routine variations thereof, to prepare the compounds described herein.

[0669] Table 1.

[0670]

[0671]

[0672]

[0673]

[0674]

[0675] Table 1B.

[0676]

[0677]

[0678] Table 2 provides representative examples of compounds of formula I:

[0679] Table 2. Non-limiting examples of compounds of formula I

[0680]

[0681]

[0682]

[0683]

[0684] Table 3 provides representative examples of compounds of formula II:

[0685] Table 3. Non-limiting examples of compounds of formula II

[0686]

[0687]

[0688]

[0689]

[0690] Table 4 provides representative examples of compounds of formula III:

[0691] Table 4. Non-limiting examples of...

Embodiment 2

[0766] Example 2. Representative Synthetic Methods

[0767] Synthesis of compound 100: ((S)-(4-fluoro-2,6-dimethylphenyl)(3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl) Oxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)methanone)

[0768]

[0769] Option 8

[0770]In Step 1, 100 g of compound 32 was dissolved in thionyl chloride and pyridine. Methanol was added to this solution to afford compound 33. Compound 33 was recrystallized to obtain 50 g of pure product. H-NMR is clean. In step 2, 25 g of compound 33 were subjected to 1.3 equivalents of n-butyllithium and compound 34. After column purification, 9.8 g of pure compound 35 were isolated. H-NMR is clean. In step 3, 50 g of compound 35 was mixed with BBr 3 The reaction yielded 48 g of compound 36 after work-up and purification. H-NMR is clean. In Step 4, 43.8 g of compound 36 were reacted with sodium hydride and benzyl bromide to yield 61.6 g of compound 37. In step 5, compound 37 is then mixed with compound 38 and cesiu...

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Abstract

This invention is a benzothiophene estrogen receptor modulator or its pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof or a pharmaceutically acceptable composition thereof to treat an estrogen-related medical disorder. The invention also includes a combination thereof with another active agent such as a CDK inhibitor, including a CDK4 / 6 inhibitor, to treat a disorder mediated by the estrogen receptor, as described in more detail herein.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Application No. 62 / 764,757, filed August 16, 2018, which is incorporated herein by reference for all purposes. technical field [0003] The present invention relates to benzothiophene compounds and compositions thereof for treating estrogen-related diseases. Background technique [0004] Estrogen regulates a range of metabolic processes in humans, notably reproduction, cardiovascular health, skeletal integrity, cognition and behavior. Estrogen also plays a key role in many human diseases, including various types of cancer (such as breast, ovarian, colorectal, prostate, kidney and endometrial cancer), osteoporosis, neurodegeneration disease, cardiovascular disease, insulin resistance, lupus, endometriosis and obesity. In many of these diseases, estrogen mediates the disease through the estrogen receptor. Deroo, et al., Estrogen Receptors and Human Disease, J. C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/381A61P35/00C07D333/52
CPCA61P35/00A61K31/381C07D409/12C07D333/64C07D333/68A61K45/06A61K31/4025A61K31/67A61K31/675A61K31/519A61K31/5377A61K2300/00C07F9/655354C07F9/65586
Inventor J·C·斯特鲁姆
Owner G1 THERAPEUTICS INC
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