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Preparation method of small molecular compound SPAM1

A small molecule compound, compound technology, applied in medical preparations containing active ingredients, drug combinations, organic chemistry, etc., can solve the problems of limitation, poor in vivo stability of PACAP, limited function of crossing biological barriers, etc. The effect of low molecular weight

Pending Publication Date: 2022-07-29
余榕捷 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although PACAP has potential anti-aging pharmaceutical development value, in view of the extremely poor stability of PACAP in vivo, for example, the half-life of PACAP38 in vivo is less than 2min, and its function of crossing biological barriers is limited, so it is extremely difficult to directly develop PACAP into a drug limits

Method used

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  • Preparation method of small molecular compound SPAM1
  • Preparation method of small molecular compound SPAM1
  • Preparation method of small molecular compound SPAM1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: Pilot-scale synthesis technique of SPAM1 (two-step method)

[0038] according tofigure 1 shown, a two-step synthesis was used. Step 1: In a 150 mL flask equipped with a condenser, benzamide A (5.45 g, 40.0 mmol, 1.0, etc.) and succinic hydride B (4.00 g, 40.0 mmol, 1.0, etc.) were mixed in 50 mL of toluene middle. The suspension was vigorously refluxed for 3 hours and then cooled to room temperature. The resulting product C was filtered as a white solid, washed with Et2O and dried (8.833 g, 88.3% yield). Product NMR detection such as figure 2 shown.

[0039] Step 2: Synthesize according to the following feeding ratios:

[0040]

[0041]

[0042] At room temperature, C and D were sequentially added to the 500 mL reaction flask, followed by the solvent DCM and F, and stirred. Continue to clarify the system with the addition of the shrinking agent EDCI in batches, the color is dark brown. E was added to the reaction system, and the reaction was ...

Embodiment 2

[0043] Example 2: SPAM1 effectively up-regulates the level of PACAP in the body

[0044] Thirty BALb / c mice, SPF grade, 8-10 weeks old, body weight 22-27g, half male and half male, were randomly divided into 3 groups, 10 mice in each group: 1) SPAM1 low-dose group, intraperitoneal injection of 10umol / kg 2) SPAM1 high-dose group, intraperitoneal injection of 100umol / kg; 3) Normal control group, intraperitoneal injection of normal saline; 30 min after injection, orbital blood was collected, and serum was detected by ELISA kit for PACAP. The result is as Figure 4 As shown, SPAM1 effectively up-regulated the content of PACAP in serum, and the up-regulation was concentration-dependent.

Embodiment 3

[0045] Example 3: SPAM1 effectively up-regulates the expression of PACAP-specific receptor PAC1-R

[0046] The mouse neural cells Neuro2a naturally expressing PAC1-R were cultured to a confluence rate of more than 80%, 1uM-100uM SPAM1 was added, and the cells were disrupted after 1 h of incubation; the supernatant of the whole cell lysate was subjected to SDS-PAGE and anti-PAC1- The antibody against the C-terminus of R was detected by western blot. The result is as Figure 5 As shown, 1 uM, 10 uM and 100 uM of SPAM1 up-regulated the expression of PAC1-R in neural cells in a concentration-dependent manner.

[0047] Human neuronal cells SHSY-5Y naturally expressing PAC1-R were cultured to a confluence rate of more than 80%. After incubation with 100uM SPAM1 for 1 h, immunofluorescence confocal observation was performed: DAPI staining in the nucleus was violet-blue, while that targeting PAC1-R was red The fluorescent signal was significantly up-regulated by SPAM1 ( Image 6 )....

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Abstract

The invention discloses a preparation method of a small molecular compound SPAM1, the structure of the small molecular compound SPAM1 is shown as a formula (I), and R is null or H2O or HCl; the SPAM1 disclosed by the invention is small in molecular weight, and can efficiently pass through biological barriers including a blood brain barrier, a blood testis barrier and the like; according to the SPAM1 disclosed by the invention, the expression of a neurotransmitter / tempering PACAP secreted by hypothalamus-pituitary and a specific receptor PAC1-R thereof is up-regulated through positive feedback, and the SPAM1 acts on downstream glands of a gonad axis and an adrenal axis, so that the regulation effect is comprehensive; the SPAM1 specifically targets PAC1-R1, only acts on cells and tissues naturally expressing a PAC1-R nervous system and an endocrine system, and has small side effects. Therefore, the SPAM1 will become a novel small molecule compound medicine for effectively treating and preventing aging and disorder of functions of a nervous system, an endocrine system and an immune system, which are closely related to the neuropeptide PACAP.

Description

technical field [0001] The present invention relates to the field of chemistry and biochemistry, in particular, to a small molecule compound SPAM1 that effectively upregulates the expression of neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) and its specific receptor PAC1-R : 4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyryl)methylbenzoic acid and derivatives thereof, efficient preparation method of SPAM1 and its application in prevention and treatment The application of PACAP and its specific receptor PAC1-R in the nervous system, endocrine system, and physiological and pathological diseases and functional decline of the immune system. Background technique [0002] The neuropeptide PACAP, originally isolated from bovine hypothalamus-pituitary, belongs to the vasoactive intestinal peptide / secretin / ghrelin / glucagon superfamily; PACAP is an extremely conserved active peptide during evolution, frog and Human PACAP differs by only one amino acid [1]. PACA...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/90A61P25/00A61P5/00A61P37/02
CPCA61P25/00A61P37/02C07D239/90A61P5/00
Inventor 余榕捷
Owner 余榕捷
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