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Long-acting Rasagiline prodrug as well as preparation method and application thereof

A prodrug and long-acting technology, applied in the field of long-acting rasagiline prodrug and its preparation, can solve the problems of forgetfulness, easy fusion of solid particles, and difficulty in controlling the drug release rate in the body, etc.

Active Publication Date: 2019-03-05
GUANGZHOU HENOVCOM BIOSCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the main target of Parkinson's disease is the elderly, and the elderly have the characteristics of poor memory and easy forgetting, there will be a huge market for the development of long-acting Parkinson's disease drugs. Public reports of effective drugs
[0009] WO 2013088255 and US 20150210712 reported a series of prodrugs of rasagiline, we found in the test that the melting point of the compound reported in the patent is lower than room temperature (25°C), which cannot meet the ideal physical and chemical properties of long-acting suspension drugs Requirements, such low melting point compounds are easy to fuse solid particles during long-term storage or after entering the body, and it is difficult to control the release rate of the drug in the body, so it is not suitable for long-acting drugs

Method used

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  • Long-acting Rasagiline prodrug as well as preparation method and application thereof
  • Long-acting Rasagiline prodrug as well as preparation method and application thereof
  • Long-acting Rasagiline prodrug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1 (Preparation of ((rasagiline-N-formyl)oxy)-methyl palmitate (see International Patent Application WO2013088255)

[0087]

[0088] Dissolve 1.0 g of rasagiline-N-carbonyl chloride methyl ester and 0.3 g of TBAI in THF / DMF (5+4 mL), add 1.5 g of potassium palmitate, and heat overnight at an external temperature of 57°C under argon protection. Stop the reaction, spin off THF, add isopropyl ether 30mL and stir for 10min, filter, and wash the filtrate with water (15mL filtrate) successively, saturated NaHCO 3 Washed, dried over anhydrous sodium sulfate, concentrated, and the concentrate was subjected to silica gel column chromatography (PE / EA=20:1-10:1) to obtain 0.76 g of a viscous product, yield: 41.53%.

[0089] 1 H-NMR (CDCl 3 ,400MHz)δ7.26(m,2H),7.19(m,2H),5.87(m,2.5H),5.78(m,0.5H),4.17(d,J=14.0Hz,0.5H),4.02( d,J=14.0Hz,0.5H),3.62(d,J=14.0Hz,0.5H),3.52(d,J=14.0Hz,0.5H),3.06(m,1H),2.86(m,1H) ,2.47(m,1H),2.36(m,2H),2.24(m,1H),2.21(s,0.5H),2.15(s,0.5H),1.6...

Embodiment 2

[0091] The preparation of embodiment 2 ((rasagiline-N-formyl) oxygen group)-naphthalene acetate methyl ester

[0092]

[0093] Dissolve 0.9 g of rasagiline-N-carbonyl chloride methyl ester and 0.25 g of TBAI in 15 mL of acetonitrile, add 0.92 g of potassium naphthalene acetate, and heat for 5 h at an external temperature of 60°C under the protection of argon. The reaction was stopped, the solvent was evaporated by rotary evaporation, 20 mL of ethyl acetate was added to dissolve, and saturated NaHCO 3 Wash (10mL×3), wash with saturated NaCl (10mL), anhydrous NaCl 2 SO 4 Dried, filtered, and spin-dried to obtain 1.38 g of crude product as light brown syrup. The crude product was recrystallized from methanol to obtain 0.65 g of pure rasagiline-N-carbomethyl naphthalene acetate as a white solid powder.

[0094] 1 HNMR (CDCl 3,400MHz)δ8.01(dd,J=14.8,8.4Hz,1H),7.84(m,2H),7.5(m,4H),7.22(m,3H),7.09(m,1H),5.90(m ,1.5H),5.82(dd,J=14.8,6.0Hz1H),5.54(t,J=8.0Hz,0.5H),4.16(s,1.07H)...

Embodiment 3

[0096] Example 3 (Preparation of ((rasagiline-N-formyl)oxy)-methyl stearate (see International Patent Application WO2013088255)

[0097]

[0098] Dissolve 2.0 g of rasagiline methyl carbochloride and 0.56 g of TBAI in 40 mL of DMF, add 3.2 g of potassium stearate, and heat the reaction overnight at an external temperature of 65° C. under the protection of argon. Stop the reaction, add 80mL of water, add 80mL of isopropyl ether for extraction, then use saturated NaHCO 3 Wash (30mL×2), saturated NaCl wash (30mL), anhydrous NaCl 2 SO 4 Dry, filter and spin dry to obtain 4.32g of crude product. The crude product was subjected to silica gel column chromatography (PE / EA=10:1) to obtain 3 g of the product as light yellow syrup with a yield of 51.55%.

[0099] 1 HNMR (CDCl 3 ,400MHz)δ7.25(m,2H),7.19(m,2H),5.87(m,2.5H),5.66(m,0.5H),4.12(d,J=17.6Hz,0.5H),3.98( d,J=17.6Hz,0.5H),3.57(d,J=17.6Hz,0.5H),3.47(d,J=17.6Hz,0.5H),3.06(m,1H),2.85(m,1H) ,2.46(m,1H),2.37(m,2H),2.24(m,1H),2...

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Abstract

The invention relates to a long-acting Rasagiline prodrug as well as a preparation method and application thereof. The structure of the long-acting Rasagiline prodrug is as shown in formula I: (shownin the description), wherein T is selected from (shown in the description) or none; R1 and R2 are respectively independently selected from hydrogen, deuterium and methyl; W is selected from (CH2)N ornone, and n is selected from an integer of 1 to 15; X is selected from (CH2)m or none, and m is selected from an integer of 1 to 10; Y is selected from -C(=O)NH-, -NHC(=O) or none; and R3 is selectedfrom substituted or unsubstituted alkyl of C1 to C30, substituted or unsubstituted C2 to C3 alkenyl, substituted or unsubstituted C2 to C30 alkynyl, substituted or unsubstituted C3 to C30 naphthenic base, cholanic aliphatic chain, -R<3a>-C(=O)O-R<3b>, -R<3a>-OC(=O)-R<3b>, -R<3a>-C(=O)NH-R<3b>, -R<3a>-NHC(=O)-R<3b>, or -R<3a>-S(=O)1-2O-R<3b> and -R<3a>-OS(=O)1-2-R<3b>. The Rasagiline prodrug of theinvention is high in melting point, low in solubility, capable of forming a drug library by virtue of injection administration in a body, capable of increasing the release time of the drug in the body, and capable of playing the lasting-acting treatment.

Description

[0001] Cross References to Related Applications [0002] This application claims the priority of Chinese patent application CN201710742461.X submitted on August 25, 2017, and its entire content is hereby incorporated herein by reference. technical field [0003] The invention belongs to the field of medicinal chemistry, in particular to a long-acting rasagiline prodrug and its preparation method and application. Background technique [0004] Parkinson's disease (PD), also known as Parkinson's paralysis, is a common neurodegenerative disease characterized by progressive, multiple, and insidious onset. Resting tremor and postural instability. The incidence of PD is rare in people before the age of 50, and the incidence rises rapidly after the age of 60. It is estimated that there are more than 2 million PD patients in China, and the incidence rate of people over 65 years old is about 1.7%. As China gradually enters the aging process, this number has an upward trend. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/24C07C269/06C07J41/00A61K31/325A61K31/575A61P25/16A61P25/28
CPCA61P25/16A61P25/28C07C271/24C07J41/0033C07C2602/08C07B2200/07A61K31/325A61K31/575C07C9/00C07C211/42C07C269/06C07C271/16C07J41/0055A61K31/27A61K31/4188
Inventor 张健存李德耀周溢谦吴毅武
Owner GUANGZHOU HENOVCOM BIOSCI CO LTD
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