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Preparation method and application of 4-imidazolyl-containing glutaminyl cyclase inhibitor

A glutaminyl cyclase and imidazole-based technology, which is applied in the field of preparation of glutaminyl cyclase inhibitors, can solve the problems of cumbersome synthesis steps, single key pharmacophore structure, and limited molecular activity, and achieve High yield, simple and feasible process route, high activity effect

Active Publication Date: 2019-02-05
SHENZHEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a preparation method and application of a glutaminyl cyclase inhibitor containing 4-imidazolyl, aiming at solving the problem of existing glutaminyl cyclase inhibition. However, there are problems such as cumbersome synthesis steps, single key pharmacophore structure, and limited molecular activity.

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  • Preparation method and application of 4-imidazolyl-containing glutaminyl cyclase inhibitor
  • Preparation method and application of 4-imidazolyl-containing glutaminyl cyclase inhibitor
  • Preparation method and application of 4-imidazolyl-containing glutaminyl cyclase inhibitor

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preparation example Construction

[0026] Wherein, the preparation method of the glutaminyl cyclase inhibitor containing 4-imidazolyl comprises steps:

[0027] with bromo substituents and R 1 The B unit raw material and with boronic acid group and R 2 Starting from the C unit raw material, the biphenyl intermediate of the B unit and the C unit coupling is prepared through the Suzuki coupling reaction;

[0028] Using the biphenyl intermediate coupled with the B unit and the C unit and 2-(1H-imidazol-4-yl)ethylamine as raw materials, the SN 2 The reaction prepares the glutaminyl cyclase inhibitor containing 4-imidazolyl;

[0029] The linked positions of the A unit and the C unit in the B unit are adjacent positions.

[0030] Specifically, since the existing chemical structural formula is The free N-H on the 1-imidazolyl pharmacophore on the glutaminyl cyclase inhibitor is difficult to form hydrogen bonds with the Asp248 amino acid residue in the active center of glutaminyl cyclase, which can only reduce the ...

Embodiment 1

[0044] The synthesis of N-([1,1'-biphenyl]-2-methyl)-2-(1H-imidazol-4-yl)ethyl-1-amine, its synthetic route is as follows:

[0045]

[0046] 1), the preparation of 2-(bromomethyl)-1,1'-biphenyl:

[0047] 2-Bromomethylbromobenzene (7.53 mmol, 1 equiv), phenylboronic acid (9.04 mmol, 1.2 equiv) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Dichloromethane complex (0.45mmol, 0.06 equivalent) was placed in a 50ml round bottom flask, and 10ml of dioxane and 10ml of 2mol / L K 2 CO 3 Solution, 100 ° C, reflux for 3h. Add saturated NaCl solution to quench the reaction, cool to room temperature, extract three times with ethyl acetate, wash once with saturated NaCl solution after combining, anhydrous NaCl 2 SO4 dried, and the product was collected by silica gel column chromatography with a yield of 79%.

[0048] 2), the preparation of N-([1,1'-biphenyl]-2-methyl)-2-(1H-imidazol-4-yl)ethyl-1-amine:

[0049] Dissolve 2-(bromomethyl)-1,1'-biphenyl (1.35mmol, 1 e...

Embodiment 2

[0051] N-(3',4,4',5'-tetramethoxy-[1,1'-biphenyl]-2-methyl)-2-(1H-imidazol-4-yl)ethyl-1 -The synthesis of amine, its synthetic route is as follows:

[0052]

[0053] 1), the preparation of 2-(bromomethyl)-3',4,4',5'-tetramethoxy-1,1'-biphenyl:

[0054] 2-Bromomethyl-4-methoxybromobenzene (6.49mmol, 1 equivalent), 3,4,5-trimethoxyphenylboronic acid (7.78mmol, 1.2 equivalents) and [1,1'-bis(di Phenylphosphine) ferrocene] dichloropalladium (II) dichloromethane complex (0.39mmol, 0.06 equivalents) is placed in a 50ml round bottom flask, and 10ml of dioxane and 10ml of 2mol / L K 2 CO 3 Solution, 100 ° C, reflux for 3h. Add saturated NaCl solution to quench the reaction, cool to room temperature, extract three times with ethyl acetate, wash once with saturated NaCl solution after combining, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 63%.

[0055] 2), N-(3',4,4',5'-tetramethoxy-[1,1'-biphenyl]-2-methyl)-2-...

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Abstract

The invention discloses a preparation method and application of a 4-imidazolyl-containing glutaminyl cyclase inhibitor. The preparation method comprises the following steps that a B unit raw materialwith a bromine substituent group and R1 and a C unit raw material with a boric acid group and R2 are firstly subjected to Suzuki coupling reaction so as to prepare a B unit and C unit coupled biphenylintermediate; and the B unit and C unit coupled biphenyl intermediate and a 2-(1H-imidazole-4-yl)ethylamine serve as raw materials and are subjected to SN2 reaction so as to prepare a compound basedon 4-imidazolyl pharmacophore. According to the preparation method, preparation can be completed only through the two steps of Suzuki coupling reaction and SN2 reaction, the process route is simple and feasible, the yield is high, and the method is more suitable for large-scale preparation; and the 4-imidazolyl-containing glutaminyl cyclase inhibitor prepared through the preparation method has higher activity and can be widely applied to development of new drugs such as high-efficiency QC inhibitor, development of drugs for AD, tumor, rheumatoid arthritis and other QC specificity high-expression related diseases and early diagnosis and diagnosis kits, and the like.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method and application of a 4-imidazolyl-containing glutaminyl cyclase inhibitor. Background technique [0002] Glutaminyl cyclase (Glutaminyl cyclase, QC, EC2.3.2.5) is an enzyme that catalyzes the intramolecular cyclization reaction of N-terminal glutamine such as polypeptides and proteins to generate pyroglutamic acid (pGlu). In 1963, QC was first discovered in the latex of tropical plant papaya (Carica papaya), and later studies confirmed that QC is distributed in plants, animals, and microorganisms. In plants, the physiological function of QC is not very clear, and it may play a certain role in the process of plant defense against pathogenic microorganisms. QC in animals has important biological functions such as changing the N-terminal chemical structure of proteins, regulating activity, and enhancing stability. [0003] Recent studies have confirmed that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64A61P1/16G01N33/573
CPCA61P1/16A61P17/06A61P19/02A61P25/28A61P35/00A61P37/02G01N33/573C07D233/64C07D405/12
Inventor 吴海强李玥贺震旦刘志刚余熙邹永东郑易之刘立忠吴序栎
Owner SHENZHEN UNIV
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