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Paliperidone amino acid derivatives and their applications

An alkyl and methyl technology, applied in the field of paliperidone amino acid derivatives and its application, can solve problems such as weight gain

Active Publication Date: 2016-12-28
NHWA PHARMA CORPORATION +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, at the same time paliperidone has an effect on the histamine receptor H 1 and adrenergic alpha 1 The receptor also has high affinity, so it is easy to cause side effects of weight gain, high prolactin and orthostatic hypotension in application

Method used

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  • Paliperidone amino acid derivatives and their applications
  • Paliperidone amino acid derivatives and their applications
  • Paliperidone amino acid derivatives and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1, 3-(2-(4-(6-fluoro-benzisoxazole)-3-piperidinyl)-ethyl)-2-methyl-4-oxygen-6,7,8, 9‐tetrahydro‐4H‐pyrido[1,2‐a]9‐pyrimidinyl‐4‐aminobutyrate hydrochloride

[0057] (1) Take 4-aminobutyric acid (10.3g, 100mmol) and add it to the reaction flask, add 50ml water, and 100ml acetone, add triethylamine (110mmol), stir at room temperature until completely dissolved, add Boc in batches Acid anhydride (26.2g, 120mmol), reacted at room temperature for 4h. Stop the reaction, evaporate acetone under reduced pressure, extract with ether 50ml×2, discard several layers, adjust the pH of the aqueous layer to 4‐5 with 10% dilute hydrochloric acid, extract with ethyl acetate 200ml×3, combine several layers , dried with anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain 18.5 g of a colorless oil, with a yield of 91.1%. MS(ESI)m / z204.2([M+H] + ).

[0058] (2) Take 2.0g (10mmol) of the first step product, add 50ml of dichloromethane, add 3.4g (9mmol...

Embodiment 2

[0060] Example 2, 3-(2-(4-(6-fluoro-benzisoxazole)-3-piperidinyl)-ethyl)-2-methyl-4-oxygen-6,7,8, 9‐tetrahydro‐4H‐pyrido[1,2‐a]9‐pyrimidinyl‐3‐(aminomethyl)‐5‐methyl‐hexanoate hydrochloride

[0061] Using 3-aminomethyl-5-methylhexanoic acid instead of 4-aminobutyric acid, the target compound 2 was prepared according to the method of Example 1.

[0062] The structural formula of the target compound 2 is shown in Table 1, and its melting point is 185-187°C. 1 H NMR(DMSO)δ11.15(s,1H),8.19‐8.23(m,1H),7.69‐7.73(m,1H),7.30‐7.35(m,1H),5.68(t,J=8Hz,2H ),3.95‐3.98(m,1H),3.71‐3.76(m,3H),3.45‐3.51(m,4H),3.11‐3.18(m,4H),2.92‐2.96(m,1H),2.51‐2.56 (m,4H),2.51(s,2H),2.38‐2.40(m,2H),2.31(s,3H),2.23‐2.27(m,2H),1.72‐1.99(m,7H),1.02(d , J=6.6Hz, 6H). MS(ESI)m / z568.3([M+H] + ).

Embodiment 3

[0063] Example 3, 3-(2-(4-(6-fluoro-benzisoxazole)-3-piperidinyl)-ethyl)-2-methyl-4-oxygen-6,7,8, 9‐tetrahydro‐4H‐pyrido[1,2‐a]9‐pyrimidinyl‐4‐amino‐2‐methylbutyrate hydrochloride

[0064] Using 4-amino-2-methylbutyric acid instead of 4-aminobutyric acid, the target compound 3 was prepared according to the method of Example 1.

[0065] The structural formula of the target compound 3 is shown in Table 1, and its melting point is 188-189°C. 1H NMR(DMSO)δ11.20(s,1H),8.17‐8.20(m,1H),7.70‐7.76(m,1H),7.29‐7.33(m,1H),5.70(t,J=8Hz,2H ),3.89‐3.92(m,1H),3.72‐3.77(m,3H),3.45‐3.51(m,4H),3.14‐3.18(m,4H),2.95‐2.99(m,1H),2.51‐2.57 (m,4H),2.38‐2.41(m,2H),2.99(s,3H),2.23‐2.27(m,3H),1.92‐1.99(m,5H),1.43(d,J=6Hz,2H) . MS(ESI)m / z526.3([M+H] + ).

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Abstract

The present invention belongs to pharmaceutical chemistry field. Paliperidone amino acids derivates and use thereof are disclosed After experiment, it is found that the compounds can be used for preparing medicant for treating mental diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to paliperidone amino acid derivatives and applications thereof. Background technique [0002] Schizophrenia is the most serious and harmful disease among all mental diseases, with a global incidence of about 1‐2%. Patients with schizophrenia have a lifetime prevalence of 0.7-0.8%, with no apparent relationship to sex, race, or social boundaries, and a mortality rate 2-3 times higher than in the general population. The latest research shows that the social burden of mental illness ranks first among diseases in China, surpassing diseases such as cardiovascular and cerebrovascular diseases, respiratory system and malignant tumors. [0003] There are two main categories of existing schizophrenic drugs: typical anti-schizophrenic drugs and atypical anti-schizophrenic drugs. Typical antipsychotics (eg, chlorpromazine and haloperidol) block dopamine D 2 receptor, and has ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/519A61P25/18A61P25/22A61P25/24
CPCC07D471/04A61P25/18A61P25/22A61P25/24
Inventor 张桂森陈寅孙家权徐祥清于民权刘欣刘笔锋
Owner NHWA PHARMA CORPORATION
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