Compound containing naphthoquinone oxime structure and medical application of compound as bombesin receptor subtype 3 agonist

A technology of a compound, naphthoquinone oxime, applied in the field of medicinal chemistry, can solve problems such as poor selectivity and defects, and achieve the effects of simple preparation method, strong agonist activity, and high yield

Pending Publication Date: 2022-03-15
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Existing bombesin receptor subtype-3 agonists, however, have deficiencies
For example, the structurally modified small peptide (dY-Bombesin) of bombesin has poor selectivity for bombesin receptor subtype-3

Method used

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  • Compound containing naphthoquinone oxime structure and medical application of compound as bombesin receptor subtype 3 agonist
  • Compound containing naphthoquinone oxime structure and medical application of compound as bombesin receptor subtype 3 agonist
  • Compound containing naphthoquinone oxime structure and medical application of compound as bombesin receptor subtype 3 agonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] This embodiment relates to a kind of 6-(4-hydroxyl-3,3-dimethyl-1-enebutyl)-5,8-dimethoxy-1,4-naphthalene with structural formula (Ⅲ-1) Synthesis of diketodioxime furan-2-carboxylate, the synthetic route is attached figure 1 As shown, it specifically includes the following steps:

[0062] Step 1. Synthesis of intermediate 2-(4-hydroxyl-3,3-dimethyl-1-enyl)-1,4,5,8-tetramethoxynaphthalene with structural formula (X):

[0063]

[0064] Specifically include the following steps:

[0065] Zinc powder (10 equivalents) and bromoisoamylene (5 equivalents) were added to 1,4,5,8-tetramethoxy-2-naphthaldehyde (1.38 g, figure 1 Formula (XVII) shown in, the molar ratio of formula (XVII) and bromoisoamylene is 1:5) in tetrahydrofuran solution (20mL), then slowly add saturated aqueous ammonium chloride solution (10mL) at 0°C , TLC monitored the reaction. After Compound IX disappeared, the zinc powder was removed by filtration, and ethyl acetate (50 mL) and 2.0 N HCl (25 mL) wer...

Embodiment 2

[0079]

[0080] This embodiment relates to a kind of 6-(4-hydroxyl-3,3-dimethyl-1-enebutyl)-5,8-dimethoxy-1,4-naphthalene with structural formula (IV-1) The synthesis of diketodioxime tetrahydrofuran-2-formate, the synthetic route is attached figure 1 As shown, the specific steps are basically the same as in Example 1, except that in Step 2, this example uses tetrahydrofuran-2-carboxylic acid instead of furan-2-carboxylic acid.

[0081] The obtained product was light yellow powder with a total yield of 36.1%. 1 H NMR (400MHz, DMSO-d 6 ):δ12.13(s,1H),12.08(s,1H),7.39(dd,J=1.3Hz,2H),6.87(d,J=3.1Hz,1H),6.05–5.92(m,2H) ,5.04(dt,J=10.8,1.3Hz,1H),4.95(dd,J=17.6,1.4Hz,1H),4.59–4.48(m,1H),3.84(td,J=6.7,2.4Hz,2H ),3.75(s,2H),3.67(s,3H),2.33–2.17(m,1H),2.02–1.79(m,3H),1.05(d,J=3.1Hz,3H),1.00(s, 3H).

Embodiment 3

[0083]

[0084]

[0085] This embodiment relates to a kind of 6-(4-hydroxyl-3,3-dimethyl-1-enebutyl)-5,8-dimethoxy-1,4-naphthalene with structural formula (V-1) The synthesis of diketodioxime pyridine-2-carboxylate, the synthetic route is attached figure 1 As shown, the specific steps are basically the same as in Example 1, except that in Step 2, this example uses pyridine-2-carboxylic acid instead of furan-2-carboxylic acid.

[0086] The obtained product was a light yellow powder with a total yield of 37.2%. 1 H NMR (400MHz, DMSO-d 6 )δ12.17(s,1H),12.09(s,1H),8.78(d,J=4.8Hz,1H),8.18(d,J=7.8Hz,1H),8.04(td,J=7.8,1.8 Hz,1H),7.67(dd,J=7.6,4.8Hz,1H),7.39(s,2H),7.03(s,1H),6.25(s,1H),6.13(dd,J=17.5,10.8Hz ,1H),5.06(d,J=10.8Hz,1H),4.99(d,J=17.5Hz,1H),3.75(s,3H),3.68(s,3H),1.12(d,J=16.9Hz ,7H).

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Abstract

The invention relates to a compound containing a naphthoquinone oxime structure, which is characterized in that the structure of the compound is as shown in the following formula (I) or (II): wherein G1 represents alkyl, a benzene ring or a heterocyclic ring; the heterocyclic ring comprises substituent-containing pyridine, furan, tetrahydrofuran and physiologically acceptable salts thereof; and G2 represents alkyl alcohol containing hydroxyl at the tail end and having 1-6 carbon atoms. The compound containing the naphthoquinone oxime structure is novel in structure and good in stability. And the preparation method is simple and convenient, the reaction condition is mild, and the yield is higher. In-vitro experiments show that the compound has frombesin receptor subtype 3 agonist activity and has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a compound containing a naphthoquinone oxime structure and its medical use as a bombesin receptor subtype-3 agonist, in particular to a 6-(4-hydroxy- 3,3-Dimethyl-1-butenyl)-5,8-dimethoxy-1,4-naphthalenedione dioxime carboxylate derivatives and their role as bombesin receptor subtype-3 Medicinal uses of agonists. Background technique [0002] So far, the bombesin receptor family has three receptor members, which are gastrin-releasing peptide receptor (GRPR), neuromedin B receptor (NMBR), bombesin receptor subtype-3 (BRS- 3). Bombesin receptor subtype-3 is widely distributed in the human body, mainly in the central nervous system, gastrointestinal tract, pancreatic islets, developing lung tissue and lung cancer tissue. [0003] After research, bombesin receptor subtype-3 knockout mice exhibited symptoms of obesity and impaired glucose homeostasis, indica...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/68C07D307/24C07D213/79C07D213/803C07D213/80C07C251/46C07C271/22C07C249/08C07C269/06A61K31/341A61K31/4406A61K31/44A61K31/4402A61K31/4409A61K31/27A61K31/235A61K31/222A61K31/15A61P3/04A61P3/10A61P35/00A61P25/00A61P37/02A61P5/50
CPCC07D307/68C07D307/24C07D213/79C07D213/803C07D213/80C07C251/46C07C271/22A61P3/04A61P3/10A61P35/00A61P25/00A61P37/02A61P5/50C07C2602/10
Inventor 张岩吴乐昊崔家华李绍顺肖华
Owner SHANGHAI JIAO TONG UNIV
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