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Analogs of deutetrabenazine, their preparation and use

A technology of deuterated tetrabenazine and compounds, applied in the field of analogs of deuterated tetrabenazine, its preparation and application

Pending Publication Date: 2020-01-17
AUSPEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the desirable and beneficial effects of deuterated tetrabenazine, there remains a continuing need for superior compositions for the treatment of the aforementioned conditions

Method used

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  • Analogs of deutetrabenazine, their preparation and use
  • Analogs of deutetrabenazine, their preparation and use
  • Analogs of deutetrabenazine, their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0174] Example 1 prepares compound 1

[0175]

[0176] The crude material (10 g) obtained from the mother liquor of deuterated tetrabenazine was purified by recrystallization from EtOH (2 x 3V) to obtain 2.5 g of compound 1 as an off-white solid.

[0177] NMR Consistency Analysis of Compound 1

[0178] Compound 1:

[0179] Use 300MHz NMR instrument, use compound 1 in CDCl 3 (99.9% D atoms) to determine the following data in Table 2. See Figure 2 and Figure 3.

[0180] Table 2: 1 H NMR and 13 C NMR a,c distribution of

[0181]

[0182] Location 1 H chemical shift (split mode, coupling constant)

Location 1 H chemical shift (split mode, coupling constant)

1 2.61(m,1H),2.84(m,1H), 11 6.61(s,1H) 2 N / A 11b 3.42(d,J=10.8Hz,1H) 3 2.53(m,1H) 12 1.54(m,1H),1.80(m,1H) 4 2.71(m,1H),2.98(m,1H) 13 1.55(m,1H) 5 N / A 14 0.92(m,6H) 6 2.53(m,2H),3.02(m,2H) 15 N / A 7 3.14(m,1H),2.65(m,1H) 16 N / A ...

example 2

[0186] Example 2 prepares compound 2

[0187]

[0188] To deutetrabenazine (31.7 g, 10.0 mmol) and chloranil (26 g, 10.5 mmol) was added toluene (300 mL), and the mixture was heated at reflux for 2.5 h. Add toluene (500mL) to the dark solution, and wash with 300mL of 2N NaOH and H 2 O wash mixture. The toluene solution was dried (Na 2 SO 4 ), filtered and evaporated to dryness. The residue was crystallized from ethyl acetate to obtain 21 g (66%) of compound 2 as an off-white crystalline solid.

[0189] NMR Consistency Analysis of Compound 2

[0190] Compound 2:

[0191] Use 300MHz NMR instrument to use compound 2 in CDCl 3 (99.9% D atoms) to determine the following data in Table 3.

[0192] table 3: 1 H NMR and 13 C NMR a,b distribution of

[0193]

[0194]

[0195]

[0196]

[0197] a Assignments are based on the coupling mode, coupling constant, and chemical shift of the signal.

[0198] b Spectra were calibrated with reference to NMR solvent pe...

example 3

[0200] Example 3-preparation of crude deuterated tetrabenazine

[0201] step 1 : 2-acetyl-N,N,N,4-tetramethyl-1-pentanyl ammonium iodide: 3-[(dimethylamino)methyl]-5-methyl-hexan-2-one (90 g, 0.526 mol, 1.00 eq) was charged with methyl tert-butyl ether (1.35 L, 15.0 vol) and cooled at 0-10 °C. Iodomethane (171 g, 1.209 mol, 2.3 eq) was slowly added to the reaction mixture and stirred at 25-35°C for 15 hours. The reaction was warmed to 35-40°C for 2 hours. The precipitated solid was filtered under nitrogen and washed with methyl tert-butyl ether (900 mL, 10.0 vol). The crude product was further purified by slurrying in ethyl acetate (1.46 L, 10 vol) and filtered to obtain 2-acetyl-N,N,N,4-tetramethyl-1-iodide as a white solid Ammonium pentane (146 g).

[0202] step 2 : will contain d 6 The suspension of -6,7-dimethoxy-3,4-dihydroisoquinoline (hydrochloride or free base, 1.00eq) and solvent was charged with iodide 2-acetyl-N,N,N, 4-Tetramethyl-1-pentanmonium. (if usin...

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Abstract

The disclosure is directed to deutetrabenazine analogs, compositions comprising same and methods of detecting same in compositions comprising deutetrabenazine.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 471,484, filed March 15, 2017, the entire contents of which are incorporated herein by reference. Background technique [0003] Tetrabenazine (NITOMAN TM 、XENAZINE TM , Ro 1-9569) (1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinone phenoline) is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Tetrabenazine is commonly prescribed by physicians for the treatment of Huntington's disease (Savani et al., Neurology 2007, 68(10), 797; and Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1), 7 -17). [0004] [0005] Tetrabenazine [0006] d 6 - Tetrabenazine (d 6 -Tetrabenazine) (USAN and INN: deuterated tetrabenazine) is a deuterated analogue of tetrabenazine, which is traded under the trade name Tetrabenazine in the United States marketing. It has improved pharmacokinetic properties when compared t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4375A61P25/00
CPCA61K31/473A61K31/4745A61P25/14A61P25/28C07D471/04A61K9/20
Inventor C·张吉姆·克尔
Owner AUSPEX PHARMA INC
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