Growth hormone secretagogue derivative and preparation method thereof

A technology of drugs and compounds, applied in the field of medicine, can solve problems such as short half-life

Pending Publication Date: 2022-07-08
TUOJIE BIOTECH (SHANGHAI) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the compound suffers from a short half-life

Method used

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  • Growth hormone secretagogue derivative and preparation method thereof
  • Growth hormone secretagogue derivative and preparation method thereof
  • Growth hormone secretagogue derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] (R)-2-Amino-N-(1-(5-fluoro-1-(methylsulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-carbonyl -3-((Phenyl-d5)methoxy-d2)propan-2-yl)-2-methylpropanamide (1)

[0117]

[0118] The synthesis of intermediate BB-1 is as follows:

[0119]

[0120] first step:

[0121] Lithium bromide (754 mg, 8.68 mmol) was suspended in dry acetonitrile (10 mL), trimethylsilyl chloride (1.18 g, 10.85 mmol) was added, and finally benzyl alcohol-d7 (500 mg, 4.34 mmol) was added, and the reaction was heated under reflux. After monitoring the completion of the reaction by TLC, it was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to crude product BB (700 mg, yield 91%). ).

[0122] Step 2:

[0123] Sodium hydride (60%, 354 mg, 14.74 mmol) was suspended in dry DMF (6 mL), cooled to 0°C, and a solution of tert-...

Embodiment 2

[0150] (R)-2-Amino-N-(1-(1-(cyclopropylsulfonyl)-5-fluorospiro[indoline-3,4'-piperidin]-1'-yl)-1 -Carbonyl-3-((phenyl-d5)methoxy-d2)propan-2-yl)-2-methylpropionamidecarboxylate (2)

[0151]

[0152] Step 1: Benzyl 1-(Cyclopropylsulfonyl)-5-fluorospiro[indoline-3,4'-piperidine]-1'-carboxylate (2a)

[0153] 1a (1.50 g, 4.41 mmol) was dissolved in dichloromethane (10 mL), triethylamine (1.53 mL, 11.0 mmol) and 4-dimethylaminopyridine (53.8 mg, 441.0 umol) were added, and cooled to 0°C. Cyclopropanesulfonyl chloride (718 μL, 7.05 mmol) was added, and the temperature was raised to 40° C. to react. After the completion of the reaction monitored by TLC, water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to a crude product, which was subjected to flash column chromatography to obtain 2a (1.5 g , the yield is 77%).

[0...

Embodiment 3

[0165] (R)-2-Amino-N-(1-(5,6-difluoro-1-(methylsulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)- 1-Carbonyl-3-((phenyl-d5)methoxy-d2)propan-2-yl)-2-methylpropionamidecarboxylate (3)

[0166]

[0167] According to the synthetic method of Example 1, the starting material 4-fluorophenylhydrazine was replaced with 3,4-difluorophenylhydrazine, and the title compound 3 was obtained as the final product by formic acid system.

[0168] MS(ESI): m / z=572.1[M+H] +

[0169] 1 H NMR (400MHz, CD 3 OD)δ8.54(s,1H),7.36-6.58(m,2H),5.23-5.06(m,1H),4.60-4.45(m,1H),4.20-4.02(m,1H),3.96(s) ,2H),3.80–3.68(m,2H),3.28–3.13(m,1H),3.07–2.97(m,3H),2.92–2.75(m,1H),2.02–1.58(m,4H),1.56 –1.45(m,6H).

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PUM

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Abstract

The invention relates to a growth hormone secretagogue derivative and a preparation method thereof. Specifically, the invention relates to a growth hormone secretagogue derivative as shown in a formula I. The growth hormone secretagogue derivative can be used for treating and / or preventing a condition or disorder mediated by a growth hormone releasing peptide receptor.

Description

technical field [0001] The present disclosure belongs to the field of medicine, and in particular relates to a growth hormone secretagogue derivative and a preparation method thereof. Background technique [0002] Growth hormone secreted by the pituitary gland stimulates the growth of various tissues in the body that are able to grow. Various pathways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and hypoglycemia-inducing insulin, and activities such as sleep and exercise , by acting on the hypothalamus in some way, perhaps reducing the secretion of growth hormone-releasing inhibitors, perhaps increasing known secretory-stimulating growth hormone-releasing factors (GRFs) or hormones that release unknown endogenous growth hormones, or all of these hormones secretion, thereby indirectly releasing growth hormone from the pituitary gland. [0003] Ibutamoren (MK-677) is a specific or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K5/065A61K38/05A61P35/00
CPCC07K5/06034C07K5/0606C07K5/06078A61P35/00A61K38/00
Inventor 李云飞谭亮张芳
Owner TUOJIE BIOTECH (SHANGHAI) CO LTD
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