Deuterated forms and derivatives of volinanserin

A technology of compounds and structural formulas, applied in the field of deuterated forms and derivatives of fliserin, which can solve problems such as reduced metabolic clearance rate

Pending Publication Date: 2021-12-03
TERRAN BIOSCIENCES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For some compounds, deuteration can lead to decreased metabolic clearance from the body

Method used

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  • Deuterated forms and derivatives of volinanserin
  • Deuterated forms and derivatives of volinanserin
  • Deuterated forms and derivatives of volinanserin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0085]

[0086]

[0087] In some embodiments, the compound is selected from any of the compounds described in Table 1 (above), wherein any atom not designated as deuterium is present in its natural isotopic abundance.

[0088] In some embodiments, the compound of structural formula (I) or structural formula (II) is selected from any of the compounds described in Table 2 (below), wherein X, when present, is -OH; Y 1a and Y 1b the same; Y 2a and Y 2b the same; Y 3a and Y 3b the same; and Y 4a , Y 4b , Y 5 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 each for hydrogen:

[0089] Table 2: Exemplary embodiments of structural formula (I)

[0090]

[0091]

[0092] In some embodiments, the compound is selected from any of the compounds described in Table 2 (above), wherein any atom not designated as deuterium is present in its natural isotopic abundance.

[0093] In some embodiments, the compound of structural formula (I) or structural formula (II) is selected from any ...

Embodiment 1

[0222] Example 1. Synthesis of (R)-(2,3-bis(methoxy-d 3 )phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol (Compound 147).

[0223] Scheme 6. Preparation of (R)-(2,3-bis(methoxy-d 3 )phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol (Compound 147).

[0224]

[0225] Step 1. 1,2-bis(methoxy-d 3 ) benzene (21b). To a solution of 1,2-dihydroxybenzene (20a) (30 g, 272.5 mmol) in anhydrous DMSO (250 mL) was added KOH (61.2 g, 1090 mmol) at room temperature, followed by methyl iodide-d 3 (42.4 mL, 681.1 mmol, Sigma Aldrich, >99.5% atomic D). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (800 mL), and washed with CH 2 Cl 2 (4 x 600 mL) extraction. The combined organic layers were washed with water (3×1 L), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was dried (vacuum oven) to afford 21b (36.4 g, 92%) as a yellow oil.

[0226] Step 2. 4-(2,3-bis(methoxy-d 3 ) Benzo...

Embodiment 2

[0235] Example 2. Synthesis of (R)-(1-(4-fluorophenethyl)piperidin-4-yl)(2-methoxy-3-(methoxy-d 3 ) phenyl) methanol (compound 115).

[0236] Scheme 7. Preparation of (R)-(1-(4-fluorophenethyl)piperidin-4-yl)(2-methoxy-3-(methoxy-d 3 ) phenyl) methanol (compound 115).

[0237]

[0238] Step 1. 2-((1-(4-fluorophenethyl)piperidin-4-yl)(hydroxy)methyl)-6-(methoxy-d 3 ) phenol (30b). To a solution of 6b (2.5 g, 7 mmol) in anhydrous THF (100 mL) was added a 1.0 M solution of lithium tri-sec-butylborohydride in THF (27 mL, 27 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 hours, then heated at 70°C overnight. The reaction mixture was cooled to 0 °C and quenched with water (150 mL). Separate the layers with Et 2 The aqueous layer was extracted with O (2 x 150 mL). The combined organic layers were washed with saturated saline solution and dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. Chromatography (Interchim automated chromatography s...

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Abstract

Deuterated forms of volinanserin according to structural formula (I), and their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and methods of treatment or prevention using these compounds or pharmaceutical compositions are described. The compounds are useful for treating or preventing a disease or condition selected from psychosis, schizophrenia, schizoaffective disorder, Parkinson's disease, Lewy body dementia, sleep disorder (including insomnia), agitation, mood disorder (including depression), thromboembolic disorder, autism, and attention deficit hyperactivity disorder.

Description

[0001] related application [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 784,056, filed December 21, 2018. The entire teaching of this application is incorporated herein by reference. Background technique [0003] Many existing drugs have poor absorption, distribution, metabolism and / or excretion (ADME) properties, which prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason why drug candidates fail in clinical trials. While formulation techniques and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME issues present in many drugs and drug candidates. One such problem is rapid metabolism, which causes many drugs to be cleared from the body too quickly that would otherwise be very effective in treating disease. A possible solution to rapid drug clearance is frequent or high dose dosing to ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61J1/00A61K38/22C07K14/575
CPCC07D211/22A61P25/00A61P7/02C07K14/70571A61P25/16A61P25/18A61P25/24A61P25/28A61J1/00A61K38/22C07K14/575C07B59/002C07D211/14A61K31/445C07B2200/05
Inventor S·温特劳布S·L·哈比森
Owner TERRAN BIOSCIENCES INC
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