Molecular design synthesis for inhibiting kallikrein activity

Abstract

The present application relates to the preparation of new physiological and pharmaceutically active molecules, and belongs to the field of pharmaceutical synthesis chemistry, and relates to the design and preparation of a class of molecules capable of inhibiting the activity of human kallikrein. Firstly, fluoroacrylic acid and alcohol compounds are used as raw materials to obtain a class of fluoroallyl alcohol compounds; then the fluoroallyl alcohol is condensed with carboxylic acid compounds to obtain fluoroallyl carboxylic acid ester compounds with general formula (I) capable of inhibiting the activity of human kallikrein. The compounds are considered to be useful for treating diabetic complications, eye diseases and edema-related diseases. In addition, they have potential applications in the diagnosis and treatment of some cancers.

Description

Technical Field

[0001] This invention relates to the preparation of novel physiologically and pharmaceutically active molecules, belonging to the field of pharmaceutical synthetic chemistry, specifically to the design and preparation of a class of molecules that inhibit human kallikrein activity. Background Technology

[0002] Kallikrein (KLK) is a serine protease found in various tissues and biological fluids. It is an enzyme that catalyzes the release of bioactive peptides from macromolecular precursors (kininogen). It has multiple physiological functions, participating in the regulation of brain development, physiological adaptation, and other metabolic processes. Kallikrein is involved in many disease responses, including inflammation, hypotension, nephritis, diabetic nephropathy, and skin diseases. In the central nervous system, kallikrein is significantly associated with the pathogenesis of epilepsy and Alzheimer's disease. Recent studies have confirmed that synthetically produced kallikrein inhibitors can effectively inhibit the invasion of breast, prostate, and ovarian cancer cells, demonstrating significant potential value in cancer treatment and prevention.

[0003] This invention addresses the impact of kallikrein activity on the development of various diseases and its potential applications in the diagnosis, prevention, and treatment of cancer. This patented invention designs and synthesizes a new class of organic compounds with significant potential for inhibiting kallikrein activity. Therefore, the novel compounds synthesized in this invention are considered to have substantial potential applications in the diagnosis and treatment of diabetic complications, eye diseases, edema-related diseases, and breast, prostate, and ovarian cancers. Summary of the Invention

[0004] This invention employs the following technical solution: a molecular design and synthesis for inhibiting kallikrein activity, characterized in that: firstly, fluoroacrylic acid and alcohol compounds are used as raw materials, tris(2-phenylpyridine)iridium is used as a catalyst, triethylenediamine is used as a base, tert-butyl peroxide is used as an initiator, and acetonitrile is used as a solvent, and the reaction is carried out according to the following reaction formula to obtain a class of fluoroallyl alcohol compounds; then, the fluoroallyl alcohol is condensed with a carboxylic acid compound to obtain a fluoroallyl alcohol carboxylic acid ester structure compound with general formula (I) that can inhibit kallikrein activity:

[0005]

[0006] This invention designs a class of fluoroallyl carboxylic acid ester compounds, which are considered useful for treating diabetic complications, eye diseases, and edema-related conditions. Furthermore, they have potential value in the diagnosis and treatment of some cancers. Detailed Implementation

[0007] The technical solution of the present invention will be further described below through specific embodiments:

[0008] Example 1, the reaction formula of this example is as follows:

[0009]

[0010] Step 1: Under air, tris(2-phenylpyridine)iridium (1 mol%), triethylenediamine (1 equiv), and 2-fluoro-3-p-fluorophenylacrylic acid (1 mmol) were added to a sealed reaction tube with a side arm and a magnetic inlet. The reaction tube was purged with argon three times. Under argon protection, 2.5 mL of acetonitrile and 2.5 mL of ethanol were added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 36 hours.

[0011] Step 2: The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by adding 10 mL of dichloromethane and 1.1 equivalents of cyclopentylformic acid. 1.1 equivalents of N,N′-dicyclohexylcarbodiimide were added under stirring at room temperature, and the reaction was carried out for 4 hours. The product was separated, with a total yield of 70% and a product purity of 100%.

[0012] Example 2

[0013] The reaction formula for this embodiment is as follows:

[0014]

[0015] Step 1: Under air, tris(2-phenylpyridine)iridium (1 mol%), triethylenediamine (1 equiv), and 2-fluoro-3-p-bromophenylacrylic acid (1 mmol) were added to a sealed reaction tube with a side arm and a magnetic inlet. The reaction tube was purged with argon three times. Under argon protection, 2.5 mL of acetonitrile and 2.5 mL of ethanol were added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 36 hours.

[0016] Step 2: The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by adding 10 mL of dichloromethane and 1.1 equivalents of cyclopentylformic acid. 1.1 equivalents of N,N′-dicyclohexylcarbodiimide were added under stirring at room temperature, and the reaction was carried out for 4 hours. The product was separated, with a total yield of 68% and a product purity of 100%.

[0017] Example 3

[0018] The reaction formula for this embodiment is as follows:

[0019]

[0020] Step 1: Under air, tris(2-phenylpyridine)iridium (1 mol%), triethylenediamine (1 equiv), and 2-fluoro-3-p-fluorophenylacrylic acid (1 mmol) were added to a sealed reaction tube with a side arm and a magnetic inlet. The reaction tube was purged with argon three times. Under argon protection, 2.5 mL of acetonitrile and 2.5 mL of ethanol were added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 36 hours.

[0021] Step 2: The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by adding 10 mL of dichloromethane and 1.1 equivalents of p-chlorophenylacetic acid. 1.1 equivalents of N,N′-dicyclohexylcarbodiimide were added under stirring at room temperature, and the reaction was carried out for 4 hours. The product was separated, with a total yield of 72% and a product purity of 100%.

[0022] Example 4

[0023] The reaction formula for this embodiment is as follows:

[0024]

[0025] Step 1: Under air, tris(2-phenylpyridine)iridium (1 mol%), triethylenediamine (1 equiv), and 2-fluoro-3-p-fluorophenylacrylic acid (1 mmol) were added to a sealed reaction tube with a side arm and a magnetic inlet. The reaction tube was purged with argon three times. Under argon protection, 2.5 mL of acetonitrile and 2.5 mL of 3-hydroxypropionitrile were added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 36 hours.

[0026] Step 2: The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by adding 10 mL of dichloromethane and 1.1 equivalents of cyclopentylformic acid. 1.1 equivalents of N,N′-dicyclohexylcarbodiimide were added under stirring at room temperature, and the reaction was carried out for 4 hours. The product was separated, with a total yield of 50% and a product purity of 100%.

[0027] Example 5

[0028] The reaction formula for this embodiment is as follows:

[0029]

[0030] Step 1: Under air, tris(2-phenylpyridine)iridium (1 mol%), triethylenediamine (1 equiv), and 2-fluoro-3-phenylacrylic acid (1 mmol) were added to a sealed reaction tube with a side arm and a magnetic inlet. The reaction tube was purged with argon three times. Under argon protection, 2.5 mL of acetonitrile and 2.5 mL of methyl 3-hydroxypropionate were added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 36 hours.

[0031] Step 2: The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by adding 10 mL of dichloromethane and 1.1 equivalents of p-chlorophenylacetic acid. 1.1 equivalents of N,N′-dicyclohexylcarbodiimide were added under stirring at room temperature, and the reaction was carried out for 4 hours. The product was separated, with a total yield of 48% and a product purity of 100%.

[0032] The amounts of each substance used and the reaction conditions were experimentally extended to the examples to demonstrate that the technical solution of the present invention has good functional group compatibility.

[0033] The present invention has been described in detail above. The above description is only an embodiment of the present invention and should not be construed as limiting the scope of this application. All equivalent changes and modifications made within the scope of this application should still fall within the scope of the present invention.

[0034] Attached Figure Description

[0035] Figure 1 The proton NMR spectrum of product 3 prepared in this invention;

[0036] Figure 2 The nuclear magnetic resonance fluorine spectrum of product 3 prepared in this invention;

[0037] Figure 3 The nuclear magnetic resonance carbon spectrum of product 3 prepared in this invention.

Claims

1. The design and synthesis of a class of molecules that inhibit kallikrein activity, characterized by: First, using fluorinated acrylic acid and alcohols as raw materials, tris(2-phenylpyridine)iridium as a catalyst, triethylenediamine as a base, tert-butyl peroxide as an initiator, and acetonitrile as a solvent, the reaction was carried out under illumination at a wavelength of 465 nm according to the following reaction formula to obtain a class of fluorinated allyl alcohols; then, fluorinated allyl alcohols react with carboxylic acid compounds... Condensation with N,N′-dicyclohexylcarbodiimide as the condensing agent yields fluoroallyl carboxylic acid ester compounds with the general formula (I) that can inhibit kallikrein activity: R1 represents hydrogen, fluorine, or bromine; R2 represents hydrogen or methyl; R3 represents methyl, ethyl, or cyano; and R4 and R5 represent methyl, cyclopentyl, or phenylethyl.

2. The molecular design and synthesis of a type of inhibitory kallikrein activity according to claim 1, characterized in that: In the first step, the amount of catalyst is 1% of the amount of fluoroacrylic acid, and the amount of triethylenediamine as a base is 1 times the amount of fluoroacrylic acid.

3. The molecular design and synthesis of a type of inhibitory kallikrein activity according to claim 1, characterized in that: The amount of condensing agent mentioned in the second step is 1.1 times the amount of fluoroallyl alcohol, and the amount of carboxylic acid is 1.1 times the amount of fluoroallyl alcohol.

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