CN100486981C - Compound possessing function for preventing and curing atherosclerosis and its application in biologic pharmacological science - Google Patents

Abstract

The present invention provides the compound represented by general formula I with the function of preventing and treating atherosclerosis, its derivatives, its isomers, racemates or optical isomers, pharmaceutically acceptable salts or solvates thereof, containing them The pharmaceutical composition, its preparation method, and the application of the compound in the preparation of drugs for the prevention or treatment of atherosclerosis, hyperlipidemia, coronary heart disease, stroke and other cardiovascular and cerebrovascular diseases, or as a tool medicine It is used in the study of cardiovascular and cerebrovascular diseases such as atherosclerosis.

Description

Compounds capable of preventing and treating atherosclerosis and their applications in biomedicine

The present invention relates to novel substituted α-aminonitriles, α-aminocarboxylic acids, α-aminophosphonic acids, their derivatives, their stereoisomers, their pharmaceutically acceptable salts or their solvates, and their preparation methods, Its application in the prevention or treatment of cardiovascular and cerebrovascular diseases such as atherosclerosis, hyperlipidemia, coronary heart disease and stroke, and the pharmaceutical composition containing these compounds.

Atherosclerosis is the pathological basis of cardiovascular and cerebrovascular diseases such as coronary heart disease, myocardial infarction, and stroke, with high mortality and disability. Coronary heart disease accounts for half of the 1 million deaths from cardiovascular and cerebrovascular diseases in the United States every year, and it is the only important disease in Western countries. In my country in 1995, the results of pathological examination of accidental deaths aged 19-35 in Beijing showed that the detection rate of coronary heart disease was 71%, and those with advanced disease were as high as 23%. With the improvement of social and economic level, the incidence rate showed an increasing trend . Two-thirds of patients with acute myocardial infarction can survive, but two-thirds of them cannot fully recover. In the United States alone, the resulting medical and wage losses amount to $50-100 billion a year.

Epidemiological studies have revealed several major environmental and genetic predisposition factors associated with atherosclerosis. Its pathogenesis is quite complicated, and many growth factors, cytokines and vascular regulatory molecules are involved in its process. For example, various factors (hyperlipidemia, smoking and blood rheological changes during hypertension) can activate endothelial cells to change their functions (such as expressing a large number of adhesion molecules, chemokines, and inflammatory factors; metabolism of vasoactive substances). disorders; increased endothelial permeability and changes in the antithrombotic properties of the surface, etc.). As a result, monocytes adhere to the endothelium to increase and pass through the endothelial gap to localize under the endothelium and transform into macrophages; the low-density lipoprotein entering the endothelium increases, and excessive superoxide anion is produced locally in the damaged endothelium After being oxidized to oxidized low-density lipoprotein, macrophages phagocytize a large number of oxidized low-density lipoproteins to become foam cells, forming the lipid streak changes in the early stage of atherosclerosis. Due to the gradual increase of cell accumulation in the lesion area, some lipid-phagocytic macrophages re-enter the blood stream, so thrombus forms at the branch and bifurcation site of irregular blood flow such as eddy current and backflow. Platelets in thrombus can release a variety of growth regulators, which can act together with a variety of regulators released by activated macrophages in the blood vessel wall to smooth muscle cells, stimulate smooth muscle cell migration and proliferation, and form new connective tissue, leading to atherosclerosis Sclerotic lesions develop into progressive complex lesions. Elimination of any influencing factors that lead to the occurrence and development of lesions can prevent the occurrence or development of atherosclerosis and make the lesions subside. Such as regulating blood lipids; preventing low-density lipoprotein oxidation; improving endothelial function; preventing monocyte adhesion; preventing platelet adhesion and thrombosis, and inhibiting smooth muscle cell migration and proliferation. The compound of the general formula I and its derivatives of the present application play the role of preventing and treating cardiovascular and cerebrovascular diseases such as atherosclerosis, hyperlipidemia, coronary heart disease and stroke through two links of regulating blood lipid and preventing low-density lipoprotein oxidation.

The types of drugs currently clinically used to prevent and treat cardiovascular and cerebrovascular diseases such as atherosclerosis, hyperlipidemia, coronary heart disease, and stroke include: blood lipid-regulating drugs, antioxidant drugs, antiplatelet drugs, and antithrombotic drugs. The efficacy, safety and specificity of the above-mentioned drugs in anti-atherosclerosis are not certain. In recent years, with the in-depth understanding of the mechanism of atherosclerosis, anti-oxidation and anti-cell adhesion (such as GPIIb/IIIa antagonists) anti-atherosclerotic drugs have become a research hotspot in the international pharmaceutical industry, but no curative effect has been seen yet. The exact drug is listed.

The use of the compound of general formula I of the present invention and its derivatives in the prevention and treatment of cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia and stroke has not been reported yet.

The purpose of the present invention is to find and develop new drugs for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia and stroke.

After extensive and in-depth research, the present inventors have now found a novel compound represented by formula I or formula Ia with definite anti-atherosclerosis, blood lipid-regulating, and anti-oxidation effects, and this type of compound can be used to prevent or treat atherosclerosis , coronary heart disease, hyperlipidemia, stroke and other cardiovascular and cerebrovascular diseases. Studies have shown that the compound represented by formula I or formula Ia has the functions of anti-atherosclerosis, regulating blood fat and anti-oxidation. Further synthesis and research have shown that the pharmaceutically acceptable salts formed by the derivatives included in the present invention with appropriate inorganic acids or organic acids or with inorganic bases or organic bases also have the same effect on atherosclerosis, coronary heart disease, hyperlipidemia, and stroke. effects of cardiovascular and cerebrovascular diseases. The present invention has been accomplished based on the above findings.

The first aspect of the present invention relates to compounds represented by general formula I, derivatives thereof, isomers, racemates or optical isomers, pharmaceutically acceptable salts thereof, or solvates thereof, which can be used for preventing or treating arteriosclerosis Use in the medicine of cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, stroke, etc. or as a tool drug for cardiovascular diseases such as atherosclerosis,

in:

R ₁ , R ₂ , and R ₃ represent hydrogen atom, C _1-20 saturated or unsaturated linear or branched aliphatic hydrocarbon, C _3-20 cycloalkane group, substituted C _3-20 cycloalkane group, C _4-20 aromatic hydrocarbon group, substituted C _5-20 aromatic hydrocarbon group, C _3-20 heterocyclic hydrocarbon group, substituted C _3-20 heterocyclic hydrocarbon group, β-hydroxyl C _2-20 hydrocarbon group, β-C _{1 -10} alkyloxy C _2-10 alkyl, β-C _5-14 arylcarbonyloxy C _2-10 alkyl, β-substituted C _5-14 arylcarbonyloxy C _2-10 alkyl, β-C _1-10 alkoxy C _{2 -10} hydrocarbyl, β-C _4-10 aryloxy C _2-10 hydrocarbyl, β-substituted C _4-10 aryloxy C _2-10 hydrocarbyl, β-mercapto C _2-20 hydrocarbyl, β-C _1-10 Alkylthio C _2-10 hydrocarbon group, β-C _4-10 arylthio C _2-10 hydrocarbon group, β-substituted C _4-10 arylthio C _2-10 hydrocarbon group, β-amino C _2-20 hydrocarbon group, β -C _1-10 alkylamino C _2-10 hydrocarbyl, β-C _4-14 arylamino C _2-10 hydrocarbyl, β-substituted C _4-14 arylamino C _2-10 hydrocarbyl, β-C _{1- 10} alkamide C _2-10 hydrocarbon group, β-C _5-14 arylamide C _2-10 hydrocarbon group, β-substituted C _5-14 arylamide C _1-10 hydrocarbon group, γ-hydroxyl C _2-20 hydrocarbon group, γ-C _1-10 alkylcarbonyloxy C _2-10 hydrocarbon group, γ-C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group, γ-substituted C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group, γ- C _1-10 aryloxy C _2-10 hydrocarbon group, γ-substituted C _5-10 aryloxy C _2-10 hydrocarbon group, γ-mercapto C _2-20 hydrocarbon group, γ-C _1-10 alkylthio C _{2- 10} hydrocarbon group, γ-C _4-10 arylthio C _2-10 hydrocarbon group, γ-substituted C _5-10 arylthio C _2-10 hydrocarbon group, γ-amino C _2-20 hydrocarbon group, γ-C _1-10 alkane Amino C _2-10 hydrocarbon group, γ-C _4-14 arylamino C _2-10 hydrocarbon group, γ-substituted C _4-14 arylamino C _2-10 hydrocarbon group, γ-C _1-10 alkamide C _{2 -10} hydrocarbon group, γ-C _5-14 aramide C _2-10 hydrocarbon group, γ-substituted C _5-14 aramide C _2-10 hydrocarbon group; or

R ₁ and R ₂ or R ₃ form a 3-9 membered ring structure, especially morpholine ring, piperazine ring, piperidine ring, pyrroline ring, imidazoline ring, pyrazoline ring, thiazoline ring, homomorphic ring Phenyl ring, homopiperazine ring, homopiperidine ring, substituted piperazine ring, N-(substituted C _4-6 aryl) piperazine ring, substituted piperidine ring, substituted pyrroline ring, substituted imidazole Oline ring, N-(substituted C _4-6 aryl) imidazoline ring, substituted pyrazoline ring, N-(substituted C _4-6 aryl) pyrazoline ring, substituted thiazoline ring, substituted Homomorpholine ring, substituted homopiperazine ring, N-(substituted C _4-6 aromatic hydrocarbon group) homopiperazine ring, substituted homopiperidine ring, wherein, the substitution of each substituent group The group is selected from: halogen, hydroxyl, cyano, nitro, C _1-10 hydrocarbon group, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-6 alkylthio group, one, two or three halo C _1-6 alkyl, amino, C _1-10 hydrocarbon amino, C _1-10 alkoxyl, C _6-10 aroyloxy or C _1-10 hydrocarbon amide;

Y stands for cyano, carboxyl, phosphonic acid, C _1-10 alkoxycarbonyl, C _3-10 heterocyclic oxycarbonyl, substituted C _3-10 heterocyclic oxycarbonyl, C _4-10 aryloxycarbonyl , Substituted C _4-10 aryloxycarbonyl, carbamoyl, C _1-10 alkylaminocarbonyl, C _3-10 heterocyclic aminocarbonyl, substituted C _3-10 heterocyclic aminocarbonyl, C _{4- 10} arylaminocarbonyl, substituted C _4-10 arylaminocarbonyl, mono-C _1-10 alkoxyphosphono, mono-C _3-10 heterocyclyl phosphono, mono(substituted C _3-10 heterooxy Base) phosphono, mono C _4-10 aryloxy phosphono, mono (substituted C _4-10 aryloxy) phosphono, bis (C _1-10 alkoxy) phosphono, bis (C _3-10 Heteroepoxy) phosphono, bis(substituted C _3-10 heteroepoxy) phosphono, bis(C _4-10 aryloxy) phosphono, bis(substituted C _4-10 aryloxy) phosphine Acyl, mono C _1-10 alkylamino phosphono, mono C _4-10 heterocyclic amino phosphono, mono (substituted C _4-10 heterocyclic amino) phosphono, mono C _4-10 aryl amino phosphine Acyl, mono(substituted C _5-10 arylamino) phosphono, bis(C _1-10 alkylamino) phosphono, bis(C _{4 -10} heterocyclic amino) phosphono, bis(substituted C _{4 -10} heterocyclic amino) phosphono, two (C _4-10 arylamino) phosphono, two (substituted C _5-10 arylamino) phosphono, (C _1-10 alkylamino) (C _{1 -10} alkoxy) phosphono, (C _4-10 heterocyclic amino) (C _1-10 alkoxy) phosphono, (substituted C _4-10 heterocyclic amino) (C _{1 -10} alkoxy Base) phosphono, (C _4-10 arylamino) (C _1-10 alkoxy) phosphono, (substituted C _5-10 arylamino) (C _1-10 alkoxy) phosphono, ( C _1-10 alkylamino) (C _3-10 heterocyclyl) phosphono, (C _{4 -10} heterocyclic amino) (C _3-10 heterocyclyl) phosphono, (substituted C _{4- 10} heterocyclic amino) (C _3-10 heterocyclic oxy) phosphono, (C _4-10 arylamino) (C _3-10 heterocyclic oxy) phosphono, (substituted C _5-10 arylamine Base) (C _3-10 heterocyclic oxy) phosphono, (C _1-10 alkylamino) (substituted C _3-10 heterocyclic oxy) phosphono, (C _4-10 heterocyclic amine) ( Substituted C _3-10 heterocyclic oxy) phosphono, (substituted C _4-10 heterocyclic amine) (substituted C _3-10 heterocyclic oxy) phosphono, (C _4-10 arylamino) (Substituted C _3-10 Heteroepoxy) Phosphono, (Substituted C _5-10 Arylamino) (Substituted C _3-10 Heteroepoxy) Phosphono, (C _1-10 Alkylamino) (C _4-10 aryloxy) phosphono, (C _4-10 heterocyclic amino) (C _4-10 aryloxy) phosphono, (substituted C _4-10 heterocyclic Amino) (C _4-10 aryloxy) phosphono, (C _4-10 arylamino) (C _4-10 aryloxy) phosphono, (substituted C _5-10 arylamino) (C _{4 -10} aryloxy) phosphono, (C _1-10 alkylamino) (substituted C _4-10 aryloxy) phosphono, (C _4-10 heterocyclic amino) (substituted C _4-10 aryl Oxygen) phosphono, (substituted C _4-10 heterocyclic amino) (substituted C _4-10 aryloxy) phosphono, (C _4-10 arylamino) (substituted C _4-10 aryloxy Base) phosphono, (substituted C _5-10 arylamino) (substituted C _4-10 aryloxy) phosphono, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl , thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the substituents in the "disubstituted phosphono" can be the same or different, and the heterocycle refers to a 1- 3 mono or fused heterocyclic rings selected from N, O or S heteroatoms, the substituents of each substituent group selected from: halogen, hydroxyl, cyano, nitro, C _1-6 hydrocarbyl, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-5 alkylthio group, one, two or trihalogenated C _1-6 alkyl group, amino group, C _1-10 hydrocarbon amino group, C _{1- 10} hydrocarbon acyloxy, C _6-10 aroyloxy or C _1-10 hydrocarbon amido.

The second aspect of the present invention relates to the new compound represented by the general formula _Ia , its derivatives, its isomers, and its derivatives for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, and stroke. Rotary or optical isomers, pharmaceutically acceptable salts or solvates thereof,

in:

R ₁ ', R ₂ ', R ₃ ' respectively represent hydrogen atom, C _1-20 saturated or unsaturated straight chain or branched aliphatic hydrocarbon, C _3-20 cycloalkane group, substituted C _3-20 cycloalkane C _4-20 aromatic hydrocarbon group, substituted C _5-20 aromatic hydrocarbon group, C _3-20 heterocyclic hydrocarbon group, substituted C _3-20 heterocyclic hydrocarbon group, β-hydroxyl C _2-20 hydrocarbon group, β _- C _1-10 Alkylcarbonyloxy C _2-10 alkyl, β-C _5-14 arylcarbonyloxy C _2-10 alkyl, β-substituted C _5-14 arylcarbonyloxy C _2-10 alkyl, β-C _1-10 alkoxy C _2-10 hydrocarbon group, β-C _4-10 aryloxy C _2-10 hydrocarbon group, β-substituted C _4-10 aryloxy C _2-10 hydrocarbon group, β-mercapto C _2-20 hydrocarbon group, β-C _1-10 Alkylthio C _2-10 Hydrocarbyl, β-C _4-10 Arylthio C _2-10 Hydrocarbyl, β-Substituted C _4-10 Arylthio C _2-10 Hydrocarbyl, β-Amino C _2-20 Hydrocarbyl, β-C _1-10 alkylamino C _2-10 hydrocarbyl, β-C _4-14 arylamino C _2-10 hydrocarbyl, β-substituted C _4-14 arylamino C _2-10 hydrocarbyl, β- C _1-10 alkamido C _2-10 hydrocarbyl, β-C _5-14 aramido C _2-10 hydrocarbyl, β-substituted C _5-14 aramido C _1-10 hydrocarbyl, γ-hydroxyl C _{2- 20} hydrocarbon group, γ-C _1-10 alkylcarbonyloxy C _2-10 hydrocarbon group, γ-C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group, γ-substituted C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group , γ-C _1-10 aryloxy C _2-10 alkyl, γ-substituted C _5-10 aryloxy C _2-10 alkyl, γ-mercapto C _2-20 alkyl, γ-C _1-10 alkylthio C _2-10 hydrocarbyl, γ-C _4-10 arylthio C _2-10 hydrocarbyl, γ-substituted C _5-10 arylthio C _2-10 hydrocarbyl, γ-amino C _2-20 hydrocarbyl, γ-C _{1 -10} alkylamino C _2-10 hydrocarbon group, γ-C _4-14 arylamino C _2-10 hydrocarbon group, γ-substituted C _4-14 arylamino C _2-10 hydrocarbon group, γ-C _1-10 alkamide C _2-10 hydrocarbon group, γ-C _5-14 arylamide C _2-10 hydrocarbon group, γ-substituted C _5-14 arylamide C _2-10 hydrocarbon group; or

R ₁ ' and R ₂ ' or R ₃ ' form a 3-9-membered ring structure, especially a morpholine ring, piperazine ring, piperidine ring, pyrroline ring, imidazoline ring, pyrazoline ring, thiazoline ring , homomorpholine ring, homopiperazine ring, homopiperidine ring, substituted piperazine ring, N-(substituted C _4-6 aromatic hydrocarbon group) piperazine ring, substituted piperidine ring, substituted pyrroline ring, Substituted imidazoline ring, N-(substituted C _4-6 aryl) imidazoline ring, substituted pyrazoline ring, N-(substituted C _4-6 aryl) pyrazoline ring, substituted thiazoline Ring, substituted homomorpholine ring, substituted homopiperazine ring, N-(substituted C _4-6 aromatic hydrocarbon group) homopiperazine ring, substituted homopiperidine ring, wherein each group with a substituent The substituent of the group is selected from: halogen, hydroxyl, cyano, nitro, C _1-10 hydrocarbon group, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-6 alkylthio group, one, two or Trihalogenated C _1-6 alkyl, amino, C _1-10 hydrocarbon amino, C _1-10 acyloxy, C _6-10 aroyloxy or C _1-10 hydrocarbon amide;

Y stands for cyano, carboxyl, phosphonic acid, C _1-10 alkoxycarbonyl, C _3-10 heterocyclic oxycarbonyl, substituted C _3-10 heterocyclic oxycarbonyl, C _4-10 aryloxycarbonyl , Substituted C _4-10 aryloxycarbonyl, carbamoyl, C _1-10 alkylaminocarbonyl, C _3-10 heterocyclic aminocarbonyl, substituted C _3-10 heterocyclic aminocarbonyl, C _{4- 10} arylaminocarbonyl, substituted C _4-10 arylaminocarbonyl, mono-C _1-10 alkoxyphosphono, mono-C _3-10 heterocyclyl phosphono, mono(substituted C _3-10 heterooxy Base) phosphono, mono C _4-10 aryloxy phosphono, mono (substituted C _4-10 aryloxy) phosphono, bis (C _1-10 alkoxy) phosphono, bis (C _3-10 Heteroepoxy) phosphono, bis(substituted C _3-10 heteroepoxy) phosphono, bis(C _4-10 aryloxy) phosphono, bis(substituted C _4-10 aryloxy) phosphine Acyl, mono C _1-10 alkylamino phosphono, mono C _4-10 heterocyclic amino phosphono, mono (substituted C _4-10 heterocyclic amino) phosphono, mono C _4-10 aryl amino phosphine Acyl, mono(substituted C _5-10 arylamino) phosphono, bis(C _1-10 alkylamino) phosphono, bis(C _{4 -10} heterocyclic amino) phosphono, bis(substituted C _{4 -10} heterocyclic amino) phosphono, two (C _4-10 arylamino) phosphono, two (substituted C _5-10 arylamino) phosphono, (C _1-10 alkylamino) (C _{1 -10} alkoxy) phosphono, (C _4-10 heterocyclic amino) (C _1-10 alkoxy) phosphono, (substituted C _4-10 heterocyclic amino) (C _{1 -10} alkoxy Base) phosphono, (C _4-10 arylamino) (C _1-10 alkoxy) phosphono, (substituted C _5-10 arylamino) (C _1-10 alkoxy) phosphono, ( C _1-10 alkylamino) (C _3-10 heterocyclyl) phosphono, (C _{4 -10} heterocyclic amino) (C _3-10 heterocyclyl) phosphono, (substituted C _{4- 10} heterocyclic amino) (C _3-10 heterocyclic oxy) phosphono, (C _4-10 arylamino) (C _3-10 heterocyclic oxy) phosphono, (substituted C _5-10 arylamine Base) (C _3-10 heterocyclic oxy) phosphono, (C _1-10 alkylamino) (substituted C _3-10 heterocyclic oxy) phosphono, (C _4-10 heterocyclic amine) ( Substituted C _3-10 heterocyclic oxy) phosphono, (substituted C _4-10 heterocyclic amine) (substituted C _3-10 heterocyclic oxy) phosphono, (C _4-10 arylamino) (Substituted C _3-10 Heteroepoxy) Phosphono, (Substituted C _5-10 Arylamino) (Substituted C _3-10 Heteroepoxy) Phosphono, (C _1-10 Alkylamino) (C _4-10 aryloxy) phosphono, (C _4-10 heterocyclic amino) (C _4-10 aryloxy) phosphono, (substituted C _4-10 heterocyclic Amino) (C _4-10 aryloxy) phosphono, (C _4-10 arylamino) (C _4-10 aryloxy) phosphono, (substituted C _5-10 arylamino) (C _{4 -10} aryloxy) phosphono, (C _1-10 alkylamino) (substituted C _4-10 aryloxy) phosphono, (C _4-10 heterocyclic amino) (substituted C _4-10 aryl Oxygen) phosphono, (substituted C _4-10 heterocyclic amino) (substituted C _4-10 aryloxy) phosphono, (C _4-10 arylamino) (substituted C _4-10 aryloxy Base) phosphono, (substituted C _5-10 arylamino) (substituted C _4-10 aryloxy) phosphono, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl , thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the substituents in the "disubstituted phosphono" can be the same or different, and the heterocycle refers to a 1- 3 mono or fused heterocyclic rings selected from N, O or S heteroatoms, the substituents of each substituent group selected from: halogen, hydroxyl, cyano, nitro, C _1-6 hydrocarbyl, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-6 alkylthio group, one, two or trihalogenated C _1-6 alkyl group, amino group, C _1-10 hydrocarbon amino group, C _{1- 10} hydrocarbon acyloxy, C _6-10 aroyloxy or C _1-10 hydrocarbon amido.

Another aspect of the present invention relates to compounds represented by general formula I, derivatives thereof, isomers and racemates thereof for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia and stroke Or optical isomers, pharmaceutically acceptable salts or solvates thereof,

in:

R ₁ , R ₂ , and R ₃ represent hydrogen atom, C _1-20 saturated or unsaturated linear or branched aliphatic hydrocarbon, C _3-20 cycloalkane group, substituted C _3-20 cycloalkane group, C _4-20 aromatic hydrocarbon group, substituted C _5-20 aromatic hydrocarbon group, C _3-20 heterocyclic hydrocarbon group, substituted C _3-20 heterocyclic hydrocarbon group, β-hydroxyl C _2-20 hydrocarbon group, β-C _{1 -10} alkyloxy C _2-10 alkyl, β-C _5-14 arylcarbonyloxy C _2-10 alkyl, β-substituted C _5-14 arylcarbonyloxy C _2-10 alkyl, β-C _1-10 alkoxy C _{2 -10} hydrocarbyl, β-C _4-10 aryloxy C _2-10 hydrocarbyl, β-substituted C _4-10 aryloxy C _2-10 hydrocarbyl, β-mercapto C _2-20 hydrocarbyl, β-C _1-10 Alkylthio C _2-10 hydrocarbon group, β-C _4-10 arylthio C _2-10 hydrocarbon group, β-substituted C _4-10 arylthio C _2-10 hydrocarbon group, β-amino C _2-20 hydrocarbon group, β -C _1-10 alkylamino C _2-10 hydrocarbyl, β-C _4-14 arylamino C _2-10 hydrocarbyl, β-substituted C _4-14 arylamino C _2-10 hydrocarbyl, β-C _{1- 10} alkamide C _2-10 hydrocarbon group, β-C _5-14 arylamide C _2-10 hydrocarbon group, β-substituted C _5-14 arylamide C _1-10 hydrocarbon group, γ-hydroxyl C _2-20 hydrocarbon group, γ-C _1-10 alkylcarbonyloxy C _2-10 hydrocarbon group, γ-C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group, γ-substituted C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group, γ- C _1-10 aryloxy C _2-10 hydrocarbon group, γ-substituted C _5-10 aryloxy C _2-10 hydrocarbon group, γ-mercapto C _2-20 hydrocarbon group, γ-C _1-10 alkylthio C _{2- 10} hydrocarbon group, γ-C _4-10 arylthio C _2-10 hydrocarbon group, γ-substituted C _5-10 arylthio C _2-10 hydrocarbon group, γ-amino C _2-20 hydrocarbon group, γ-C _1-10 alkane Amino C _2-10 hydrocarbon group, γ-C _4-14 arylamino C _2-10 hydrocarbon group, γ-substituted C _4-14 arylamino C _2-10 hydrocarbon group, γ-C _1-10 alkamide C _{2 -10} hydrocarbon group, γ-C _5-14 aramide C _2-10 hydrocarbon group, γ-substituted C _5-14 aramide C _2-10 hydrocarbon group; or

R ₁ and R ₂ or R ₃ form a 3-9 membered ring structure, especially morpholine ring, piperazine ring, piperidine ring, pyrroline ring, imidazoline ring, pyrazoline ring, thiazoline ring, homomorphic ring Phenyl ring, homopiperazine ring, homopiperidine ring, substituted piperazine ring, N-(substituted C _4-6 aryl) piperazine ring, substituted piperidine ring, substituted pyrroline ring, substituted imidazole Oline ring, N-(substituted C _4-6 aryl) imidazoline ring, substituted pyrazoline ring, N-(substituted C _4-6 aryl) pyrazoline ring, substituted thiazoline ring, substituted Homomorpholine ring, substituted homopiperazine ring, N-(substituted C _4-6 aromatic hydrocarbon group) homopiperazine ring, substituted homopiperidine ring, wherein, the substitution of each substituent group The group is selected from: halogen, hydroxyl, cyano, nitro, C _1-10 hydrocarbon group, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-6 alkylthio group, one, two or three halo C _1-6 alkyl, amino, C _1-10 hydrocarbon amino, C _1-10 alkoxyl, C _6-10 aroyloxy or C _1-10 hydrocarbon amide;

Y stands for cyano, carboxyl, phosphonic acid, C _1-10 alkoxycarbonyl, C _3-10 heterocyclic oxycarbonyl, substituted C _3-10 heterocyclic oxycarbonyl, C _4-10 aryloxycarbonyl , Substituted C _4-10 aryloxycarbonyl, carbamoyl, C _1-10 alkylaminocarbonyl, C _3-10 heterocyclic aminocarbonyl, substituted C _3-10 heterocyclic aminocarbonyl, C _{4- 10} arylaminocarbonyl, substituted C _4-10 arylaminocarbonyl, mono-C _1-10 alkoxyphosphono, mono-C _3-10 heterocyclyl phosphono, mono(substituted C _3-10 heterooxy Base) phosphono, mono C _4-10 aryloxy phosphono, mono (substituted C _4-10 aryloxy) phosphono, bis (C _1-10 alkoxy) phosphono, bis (C _3-10 Heteroepoxy) phosphono, bis(substituted C _3-10 heteroepoxy) phosphono, bis(C _4-10 aryloxy) phosphono, bis(substituted C _4-10 aryloxy) phosphine Acyl, mono C _1-10 alkylamino phosphono, mono C _4-10 heterocyclic amino phosphono, mono (substituted C _4-10 heterocyclic amino) phosphono, mono C _4-10 aryl amino phosphine Acyl, mono(substituted C _5-10 arylamino) phosphono, bis(C _1-10 alkylamino) phosphono, bis(C _{4 -10} heterocyclic amino) phosphono, bis(substituted C _{4 -10} heterocyclic amino) phosphono, two (C _4-10 arylamino) phosphono, two (substituted C _5-10 arylamino) phosphono, (C _1-10 alkylamino) (C _{1 -10} alkoxy) phosphono, (C _4-10 heterocyclic amino) (C _1-10 alkoxy) phosphono, (substituted C _4-10 heterocyclic amino) (C _{1 -10} alkoxy Base) phosphono, (C _4-10 arylamino) (C _1-10 alkoxy) phosphono, (substituted C _5-10 arylamino) (C _1-10 alkoxy) phosphono, ( C _1-10 alkylamino) (C _3-10 heterocyclyl) phosphono, (C _{4 -10} heterocyclic amino) (C _3-10 heterocyclyl) phosphono, (substituted C _{4- 10} heterocyclic amino) (C _3-10 heterocyclic oxy) phosphono, (C _4-10 arylamino) (C _3-10 heterocyclic oxy) phosphono, (substituted C _5-10 arylamine Base) (C _3-10 heterocyclic oxy) phosphono, (C _1-10 alkylamino) (substituted C _3-10 heterocyclic oxy) phosphono, (C _4-10 heterocyclic amine) ( Substituted C _3-10 heterocyclic oxy) phosphono, (substituted C _4-10 heterocyclic amine) (substituted C _3-10 heterocyclic oxy) phosphono, (C _4-10 arylamino) (Substituted C _3-10 Heteroepoxy) Phosphono, (Substituted C _5-10 Arylamino) (Substituted C _3-10 Heteroepoxy) Phosphono, (C _1-10 Alkylamino) (C _4-10 aryloxy) phosphono, (C _4-10 heterocyclic amino) (C _4-10 aryloxy) phosphono, (substituted C _4-10 heterocyclic Amino) (C _4-10 aryloxy) phosphono, (C _4-10 arylamino) (C _4-10 aryloxy) phosphono, (substituted C _5-10 arylamino) (C _{4 -10} aryloxy) phosphono, (C _1-10 alkylamino) (substituted C _4-10 aryloxy) phosphono, (C _4-10 heterocyclic amino) (substituted C _4-10 aryl Oxygen) phosphono, (substituted C _4-10 heterocyclic amino) (substituted C _4-10 aryloxy) phosphono, (C _4-10 arylamino) (substituted C _4-10 aryloxy Base) phosphono, (substituted C _5-10 arylamino) (substituted C _4-10 aryloxy) phosphono, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl , thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the substituents in the "disubstituted phosphono" can be the same or different, and the heterocycle refers to a 1- 3 mono or fused heterocyclic rings selected from N, O or S heteroatoms, the substituents of each substituent group selected from: halogen, hydroxyl, cyano, nitro, C _1-6 hydrocarbyl, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-6 alkylthio group, one, two or trihalogenated C _1-6 alkyl group, amino group, C _1-10 hydrocarbon amino group, C _{1- 10} hydrocarbon acyloxy, C _6-10 aroyloxy or C _1-10 hydrocarbon amido.

Another aspect of the present invention relates to a pharmaceutical composition, which contains at least one compound represented by formula _Ia or formula I, its derivatives, its isomers, racemates or optical isomers, its pharmaceutically acceptable salts or Solvates, and pharmaceutically acceptable carriers or excipients.

The present invention also relates to a method for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, and stroke, which comprises administering a preventive or therapeutically effective dose of the formula I or a compound of formula I _a , derivatives thereof, isomers, racemates or optical isomers thereof, pharmaceutically acceptable salts or solvates thereof.

The present invention also relates to a method for preparing the compound of formula _Ia above: first, the inventors have discovered a novel Mannich-like reaction, that is, when R ₃ '=HO-Ar, Y=PO(OR)OR',

Phenolic, secondary amine and phosphite are prepared by heating to 40-300°C and/or pressurizing to 0.1-20Mpa in the presence/absence of organic solvents and presence/absence of catalysts, wherein R ₁ ', R ₂ ' and R ₃ ' are as defined above, R and R' are C _0-10 hydrocarbon groups; the organic solvents are methanol, ethanol, propanol, isopropanol, butanol, acetone, butanone, toluene, xylene, 1,2-dichloroethane, methylhydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N -Methylpyrrolidone, dimethyl sulfoxide; the catalyst is acid or/and base catalyst, the acid catalyst is Lewis acid including organic acid or inorganic acid, and the base catalyst is Lewis base including organic base tertiary amine and inorganic base. The discovery and application of this reaction enabled the inventors to prepare a large amount of highly active novel α-aminophosphonic acid and its derivatives.

Its amide can be obtained by preparing an acid halide from the corresponding acid and condensing it with the corresponding amine according to methods known in the art, or it can be prepared by reacting the corresponding acid and the corresponding amine in the presence of a condensing agent.

Secondly, when Y=CN, the following ternary Mannich reaction can be applied,

或

or

When Y=COOH, it can be prepared by hydrolysis of the corresponding nitrile, and its hydrolysis method is acid hydrolysis, alkali hydrolysis or hydrogen peroxide oxidative hydrolysis known in the art; or it can be prepared by hydrolysis of the corresponding amide, and its hydrolysis method is based on Acid hydrolysis or base hydrolysis known in the art.

When Y=COOR, CONHR or CONRR', it can be prepared from the corresponding carboxylic acid by esterification and amidation methods known in the art.

Again, it can also be prepared by alkylation of the corresponding amine with the corresponding halogenated hydrocarbon or sulfonate,

或

or

The above method also includes the step of making the product obtained by the reaction into isomers or optical isomers through asymmetric reaction or further resolution; it also includes reacting the product obtained by the reaction with an inorganic acid or an organic acid , forming pharmaceutically acceptable salts, i.e. salts of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid; or organic acid salts, i.e. acetic acid, oxalic acid, citric acid, gluconic acid, succinic acid, tartaric acid, p-toluenesulfonic acid , methanesulfonic acid, benzoic acid, lactic acid and maleic acid salts; also include the pharmaceutically acceptable salts formed by reacting the reaction product with an inorganic base or an organic base, that is, alkali metals such as Li, Na and K; and alkaline earth metals Such as Ca and Mg; with organic bases such as diethanolamine, choline, etc.; or with chiral bases such as alkylphenylamine to form pharmaceutically acceptable salts.

Description of drawings

Fig. 1 shows the effect of the compound of formula I or formula Ia on TBARS of the present invention A: the drug concentration is 25 μmol.L ^-1 ; B: the drug concentration is 250 μmol.L ^-1 .

According to the present invention, diseases related to atherosclerosis refer to diseases related to the formation of atherosclerosis, such as cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, and stroke.

According to the compound of general formula I of the present invention, R ₁ or R ₂ are preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 2-hydroxyethyl, 2-methyl Oxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 2-isobutoxyethyl, 2-tert Butoxyethyl, 2-aminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl, 2-propylaminoethyl, 2-isopropylaminoethyl, 2-butylaminoethyl , 2-isobutylaminoethyl, 2-tert-butylaminoethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 2-(dipropylamino)ethyl, 2 -(dipropylamino)ethyl, 2-(dibutylamino)ethyl, 2-(diisobutylamino)ethyl, 2-(di-tert-butylamino)ethyl, 2-morpholinoethyl, 2-piperidinylethyl, 2-piperazinylethyl, 2-(4-methylpiperazinyl)ethyl, 3-hydroxypropyl, 3-methoxypropyl, 3-ethoxypropyl Base, 3-propoxypropyl, 3-isopropoxypropyl, 3-butoxypropyl, 3-isobutoxypropyl, 3-tert-butoxypropyl, 3-aminopropyl , 3-methylaminopropyl, 3-ethylaminopropyl, 3-propylaminopropyl, 3-isopropylaminopropyl, 3-butylaminopropyl, 3-isobutylaminopropyl, 3 -tert-butylaminopropyl, 3-(dimethylamino)propyl, 3-(dipropylamino)propyl, 3-(dipropylamino)propyl, 3-(dipropylamino)propyl, 3-( Dibutylamino)propyl, 3-(diisobutylamino)propyl, 3-(di-tert-butylamino)propyl, 3-morpholinopropyl, 3-piperidylpropyl, 3-piperazine propyl, 3-(4-methylpiperazinyl)propyl,; or,

R ₁ R ₂ N is preferably morpholinyl, piperazinyl, 4-methylpiperazinyl, 4-(2-pyridyl)piperazinyl, 4-(4-methyl-2-pyridyl)piperazine Base, 4-(4-piperidinyl-2-pyridyl)piperazinyl, 4-(3-pyridyl)piperazinyl, 4-(4-pyridyl)piperazinyl, 4-(2- Pyrimidinyl)piperazinyl, 4-(4-pyrimidinyl)piperazinyl, 4-(5-pyrimidinyl)piperazinyl, 4-(6-pyrimidinyl)piperazinyl, 4-(2-pyridazine Base) piperazinyl, 4-(4,6-dimethoxy-2-triazinyl)piperazinyl, 4-(2-chlorophenyl)piperazinyl, 4-(3-chlorophenyl) Piperazinyl, 4-(4-chlorophenyl)piperazinyl, 4-(2-fluorophenyl)piperazinyl, 4-(3-fluorophenyl)piperazinyl, 4-(4-fluorobenzene Base) piperazinyl, 4-(2-chlorophenyl)piperazinyl, 4-(3,4-dichlorophenyl)piperazinyl, 4-(5-chloro-2-methylphenyl)piperazinyl Azinyl, 4-(2-methoxyphenyl)piperazinyl, 4-(3-methoxyphenyl)piperazinyl, 4-(4-methoxyphenyl)piperazinyl, 4- Bis(4-fluorophenyl)methylpiperazinyl, 4-carbamoyl-4-piperidinylpiperidinyl;

_R3 is preferably a hydrogen atom, a methyl group, a C _2-12 hydrocarbon group, a C _3-8 cycloalkyl group, a C _6-12 aromatic hydrocarbon group, a substituted C _6-12 aromatic hydrocarbon group, a C _4-12 heterocyclic aromatic hydrocarbon group, a substituted C _4-12 heterocyclic aromatic hydrocarbon groups, wherein, the substituents of each substituent group are selected from: halogen, hydroxyl, cyano, nitro, C _1-6 hydrocarbon groups, C _4-6 aromatic hydrocarbon groups, C _1-6 alkoxy, C _1-6 alkylthio, one, two or trihalogenated C _1-6 alkyl, amino, C _1-10 hydrocarbon amino, C _1-10 acyloxy, C _6-10 aroyloxy group or C _1-10 hydrocarbon amido group, one, two, three or four substituents can be the same or different;

Y is preferably cyano, carboxyl, C _1-10 alkoxycarbonyl, carbamoyl, C _1-10 alkylaminocarbonyl, phosphonic acid, one C _1-10 alkoxyphosphono, two C _1-10 Hydrocarbyloxyphosphono, C _1-10 hydrocarbyloxy C _1-10 hydrocarbylaminophosphono, one C _1-10 hydrocarbylaminophosphono, two C _1-10 hydrocarbylaminophosphono, imidazolyl, pyrazole Base, triazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl.

In a preferred embodiment of the present invention, said R ₁ R ₂ N is 4-(2-pyridyl)piperazinyl, R ₃ is 4-hydroxy-3-methoxyphenyl, Y is diethyl Oxyphosphono.

According to the invention, acid addition salts of compounds of formula I or formula Ia are for example inorganic acid salts such as hydrochloride, sulfate, phosphate, hydrobromide; or organic acid salts such as acetate, oxalate, Citrate, gluconate, succinate, tartrate, p-toluenesulfonate, methanesulfonate, benzoate, lactate and maleate; compounds of formula I form salts with bases, for example bases Metal salts such as lithium, sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; organic base salts such as diethanolamine salts and choline salts, etc.; or chiral base salts such as alkylphenylamine salts.

Solvates of the compounds of the present invention may be hydrates or contain other solvents of crystallization such as alcohols.

The present invention further relates to a new general formula _I a used for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, and stroke, or as a tool drug for researching diseases related to atherosclerosis The indicated novel compounds, derivatives thereof, isomers, racemates or optical isomers, pharmaceutically acceptable salts or solvates thereof,

in:

R ₁ ', R ₂ ', R ₃ ' respectively represent hydrogen atom, C _1-20 saturated or unsaturated straight chain or branched aliphatic hydrocarbon, C _3-20 cycloalkane group, substituted C _3-20 cycloalkane C _4-20 aromatic hydrocarbon group, substituted C _5-20 aromatic hydrocarbon group, C _3-20 heterocyclic hydrocarbon group, substituted C _3-20 heterocyclic hydrocarbon group, β-hydroxyl C _2-20 hydrocarbon group, β _- C _1-10 Alkylcarbonyloxy C _2-10 alkyl, β-C _5-14 arylcarbonyloxy C _2-10 alkyl, β-substituted C _5-14 arylcarbonyloxy C _2-10 alkyl, β-C _1-10 alkoxy C _2-10 hydrocarbon group, β-C _4-10 aryloxy C _2-10 hydrocarbon group, β-substituted C _4-10 aryloxy C _2-10 hydrocarbon group, β-mercapto C _2-20 hydrocarbon group, β-C _1-10 Alkylthio C _2-10 Hydrocarbyl, β-C _4-10 Arylthio C _2-10 Hydrocarbyl, β-Substituted C _4-10 Arylthio C _2-10 Hydrocarbyl, β-Amino C _2-20 Hydrocarbyl, β-C _1-10 alkylamino C _2-10 hydrocarbyl, β-C _4-14 arylamino C _2-10 hydrocarbyl, β-substituted C _4-14 arylamino C _2-10 hydrocarbyl, β- C _1-10 alkamido C _2-10 hydrocarbyl, β-C _5-14 aramido C _2-10 hydrocarbyl, β-substituted C _5-14 aramido C _1-10 hydrocarbyl, γ-hydroxyl C _{2- 20} hydrocarbon group, γ-C _1-10 alkylcarbonyloxy C _2-10 hydrocarbon group, γ-C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group, γ-substituted C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group , γ-C _1-10 aryloxy C _2-10 alkyl, γ-substituted C _5-10 aryloxy C _2-10 alkyl, γ-mercapto C _2-20 alkyl, γ-C _1-10 alkylthio C _2-10 hydrocarbyl, γ-C _4-10 arylthio C _2-10 hydrocarbyl, γ-substituted C _5-10 arylthio C _2-10 hydrocarbyl, γ-amino C _2-20 hydrocarbyl, γ-C _{1 -10} alkylamino C _2-10 hydrocarbon group, γ-C _4-14 arylamino C _2-10 hydrocarbon group, γ-substituted C _4-14 arylamino C _2-10 hydrocarbon group, γ-C _1-10 alkamide C _2-10 hydrocarbon group, γ-C _5-14 arylamide C _2-10 hydrocarbon group, γ-substituted C _5-14 arylamide C _2-10 hydrocarbon group; or

R ₁ ' and R ₂ ' or R ₃ ' form a 3-9-membered ring structure, especially a morpholine ring, piperazine ring, piperidine ring, pyrroline ring, imidazoline ring, pyrazoline ring, thiazoline ring , homomorpholine ring, homopiperazine ring, homopiperidine ring, substituted piperazine ring, N-(substituted C _4-6 aromatic hydrocarbon group) piperazine ring, substituted piperidine ring, substituted pyrroline ring, Substituted imidazoline ring, N-(substituted C _4-6 aryl) imidazoline ring, substituted pyrazoline ring, N-(substituted C _4-6 aryl) pyrazoline ring, substituted thiazoline Ring, substituted homomorpholine ring, substituted homopiperazine ring, N-(substituted C _4-6 aromatic hydrocarbon group) homopiperazine ring, substituted homopiperidine ring, wherein each group with a substituent The substituent of the group is selected from: halogen, hydroxyl, cyano, nitro, C _1-10 hydrocarbon group, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-6 alkylthio group, one, two or Trihalogenated C _1-6 alkyl, amino, C _1-10 hydrocarbon amino, C _1-10 acyloxy, C _6-10 aroyloxy or C _1-10 hydrocarbon amide;

Y stands for cyano, carboxyl, phosphonic acid, C _1-10 alkoxycarbonyl, C _3-10 heterocyclic oxycarbonyl, C _4-10 aryloxycarbonyl, substituted C _4-10 aryloxycarbonyl, ammonia Formyl, C _1-10 alkylaminocarbonyl, C _3-10 heterocyclic aminocarbonyl, C _4-10 arylaminocarbonyl, substituted C _4-10 arylaminocarbonyl, C _1-10 alkoxyphosphonyl , C _3-10 heterocyclyl phosphono, C _4-10 aryloxy phosphono, substituted C _4-10 aryloxy phosphono, C _1-10 alkylamino phosphono, C _4-10 heterocyclic amine Phosphonoyl, C _4-10 arylaminophosphono, substituted C _5-10 arylaminophosphono, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazole Linyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the heterocyclic ring refers to a single or condensed heterocyclic ring containing 1-3 heteroatoms selected from N, O or S, each with a substitution _The substituent of the radical group is selected from: halogen, hydroxyl, cyano, nitro, C _1-6 hydrocarbon group, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-6 alkylthio group, a , Di- or trihalogenated C _1-6 alkyl group, amino group, C _1-10 hydrocarbon amino group, C _1-10 hydrocarbon acyloxy group, C _6-10 aroyloxy group or C _1-10 hydrocarbon amido group.

Preferably, the compound of formula Ia of the present invention can be selected from any one of the following compounds:

Diethyl 2-(3,5-dimethoxy-4-hydroxyphenyl)-2-[4-(2-pyridyl)piperazinyl]methylphosphonate;

Diethyl 2-(4-hydroxy-3-methoxyphenyl)-2-[4-(2-pyridyl)piperazinyl]methylphosphonate;

Diethyl 2-(4-hydroxy-3-methoxyphenyl)-2-(4-methylpiperazinyl)methylphosphonate;

2-(3,4-methylenedioxyphenyl)-2-(4-methylpiperazinyl)acetonitrile;

2-(2-furyl)-2-(4-methylpiperazinyl)acetonitrile;

2-cyano-1,4-dibenzylpiperazine

2-cyano-1-methyl-1-azabicyclo[3,2,1]-2-heptene (2-cyano-2-tropine)

8-benzyl-6β-cyano-8-azabicyclo[3,2,1]oct-3-en-2-one; and

2-morpholino-2-(3,4,5-trimethoxyphenyl)acetic acid.

According to the present invention, the amine derivatives represented by formula _Ia , their isomers, racemates or optical isomers, pharmaceutically acceptable salts or solvates also have the function of preventing or treating regulating the function of vascular endothelial cells. Wherein the acid addition salt of the amine derivative of formula _Ia is for example inorganic acid salt such as hydrochloride, sulfate, phosphate, hydrobromide; Or organic acid salt such as acetate, oxalate, citrate, Gluconate, succinate, tartrate, p-toluenesulfonate, mesylate, benzoate, lactate, maleate, nicotinate, cinnamate, or 3-hydroxy-3- Methyl glutarate. Preference is given to _the hydrochloride, maleate, p-toluenesulfonate, cinnamate and 3-hydroxy-3-methylglutarate salts of the amine derivatives of formula Ia. Furthermore, salts of the compounds of formula Ia with bases and solvates thereof are as defined above for compounds of formula I.

More specifically, in the derivatives of general formula I of the present invention, R ₁ , R ₂ , and R ₃ may be the same or different, and represent hydrogen atoms, C _1-20 saturated or unsaturated straight-chain or branched aliphatic hydrocarbons, C _3-20 cycloalkane group, substituted C _3-20 cycloalkane group, C _4-20 aromatic hydrocarbon group, substituted C _5-20 aromatic hydrocarbon group, C _3-20 heterocyclic hydrocarbon group, substituted C _3-20 heterocyclic hydrocarbon group, β-Hydroxy C _2-20 Hydrocarbyl, β-C _1-10 Alkylcarbonyloxy C _2-10 Hydrocarbyl, β-C _5-14 Arylcarbonyloxy C _2-10 Hydrocarbyl, β-Substituted C _5-14 Arylcarbonyloxy C _2-10 hydrocarbon group, β-C _1-10 alkoxy C _2-10 hydrocarbon group, β-C _4-10 aryloxy C _2-10 hydrocarbon group, β-substituted C _4-10 aryloxy C _{2- 10} hydrocarbon group, β-mercapto C _2-20 hydrocarbon group, β-C _1-10 alkylthio C _2-10 hydrocarbon group, β-C _4-10 arylthio C _2-10 hydrocarbon group, β-substituted C _4-10 aromatic Sulfuryl C _2-10 hydrocarbon group, β-amino C _2-20 hydrocarbon group, β-C _1-10 alkylamino C _2-10 hydrocarbon group, β-C _4-14 arylamino C _2-10 hydrocarbon group, β-substituted C _4-14 arylamino C _2-10 hydrocarbyl, β-C _1-10 alkamido C _2-10 hydrocarbyl, β-C _5-14 arylamide C _2-10 hydrocarbyl, β-substituted C _5-14 Aramide group C _1-10 hydrocarbon group, γ-hydroxyl C _2-20 hydrocarbon group, γ-C _1-10 alkylcarbonyloxy C _2-10 hydrocarbon group, γ-C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group, γ -Substituted C _5-14 arylcarbonyloxy C _2-10 hydrocarbon group, γ-C _1-10 aryloxy C _2-10 hydrocarbon group, γ-substituted C _5-10 aryloxy C _2-10 hydrocarbon group, γ-mercapto C _2-20 hydrocarbon group, γ-C _1-10 alkylthio C _2-10 hydrocarbon group, γ-C _4-10 arylthio C _2-10 hydrocarbon group, γ-substituted C _5-10 arylthio C _2-10 Hydrocarbyl, γ-amino C _2-20 hydrocarbyl, γ-C _1-10 alkylamino C _2-10 hydrocarbyl, γ-C _4-14 arylamino C _2-10 hydrocarbyl, γ-substituted C _4-14 arylamine C _2-10 hydrocarbon group, γ-C _1-10 alkamide C _2-10 hydrocarbon group, γ-C _5-14 arylamide C _2-10 hydrocarbon group, γ-substituted C _5-14 arylamide C _{2- 10} hydrocarbyl; or

R ₁ and R ₂ or R ₃ form a 3-9 membered ring structure, especially morpholine ring, piperazine ring, piperidine ring, pyrroline ring, imidazoline ring, pyrazoline ring, thiazoline ring, homomorphic ring Phenyl ring, homopiperazine ring, homopiperidine ring, substituted piperazine ring, N-(substituted C _4-6 aryl) piperazine ring, substituted piperidine ring, substituted pyrroline ring, substituted imidazole Oline ring, N-(substituted C _4-6 aryl) imidazoline ring, substituted pyrazoline ring, N-(substituted C _4-6 aryl) pyrazoline ring, substituted thiazoline ring, substituted Homomorpholine ring, substituted homopiperazine ring, N-(substituted C _4-6 aromatic hydrocarbon group) homopiperazine ring, substituted homopiperidine ring, wherein, the substitution of each substituent group The group is selected from: halogen, hydroxyl, cyano, nitro, C _1-10 hydrocarbon group, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-6 alkylthio group, one, two or three halo C _1-6 alkyl, amino, C _1-10 hydrocarbon amino, C _1-10 alkoxy, C _5-10 aroyloxy or C _1-10 hydrocarbon amide;

Y stands for cyano, carboxyl, phosphonic acid, C _1-10 alkoxycarbonyl, C _3-10 heterocyclic oxycarbonyl, C _4-10 aryloxycarbonyl, substituted C _4-10 aryloxycarbonyl, ammonia Formyl, C _1-10 alkylaminocarbonyl, C _3-10 heterocyclic aminocarbonyl, C _4-10 arylaminocarbonyl, substituted C _4-10 arylaminocarbonyl, C _1-10 alkoxyphosphonyl , C _3-10 heterocyclyl phosphono, C _4-10 aryloxy phosphono, substituted C _4-10 aryloxy phosphono, C _1-10 alkylamino phosphono, C _4-10 heterocyclic amine Phosphonoyl, C _4-10 arylaminophosphono, substituted C _5-10 arylaminophosphono, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazole Linyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the heterocyclic ring refers to a single or condensed heterocyclic ring containing 1-3 heteroatoms selected from N, O or S, each with a substitution The substituent of the radical group is selected from: halogen, hydroxyl, cyano, nitro, _{C 1-6} hydrocarbon group, C _4-6 aromatic hydrocarbon group, C _1-6 alkoxy group, C _1-6 alkylthio group, a , Di- or trihalogenated C _1-6 alkyl, amino, C _1-10 hydrocarbon amino, C _1-10 acyloxy, C _6-10 aroyloxy or C _1-10 hydrocarbon amide;

See Table 1 for preferred compounds of formula I when Y=PO(OEt) ₂ .

Table 1 When Y=PO(OEt) ₂ , preferred formula I compounds and their substituents

When Y is cyano, preferred compounds of formula I and their substituents are shown in Table 1.

When table 2 Y=CN, preferred formula I compound and its substituent

When Y=CONH ₂ , the preferred compounds and substituents are shown in Table 3

Table 3 Preferred compounds of formula I, wherein Y=CONH ₂ in formula I

When Y=CO ₂ H, the preferred compounds and substituents are shown in Table 4

Table 4 Preferred compounds of formula I, wherein Y=CO ₂ H in formula I

When Y=CO ₂ Me, the preferred compounds and substituents are shown in Table 5

Table 5 Preferred compounds of formula I, wherein Y=CO ₂ Me in formula I

Furthermore, if the compound of formula Ia has _a modifiable group, it can also be reacted with an appropriate derivatization reagent to prepare the corresponding derivative. Such as alkylation of phenolic hydroxyl group (such as methylation, carboxymethylation and alkoxycarbonyl methylation), esterification, ester hydrolysis, etc.

According to the present invention, when Y=PO(OR')OR" in the compound of formula I _a , the general preparation method is a novel Mannich-like reaction discovered by the inventor, and its general conditions are generally: phenolic aldehyde, secondary amine and phosphite It is prepared by heating reaction with or without the presence of organic solvents. Unlike previous reactions, this reaction does not require acid chloride as a catalyst.

According to the present invention, when Y=CN in the compound represented by general formula I, general methods can be prepared according to methods known in the art, see Houben-Weyl. Meth Org Chem, 1952, 8: 282-283.

When Y=CONH in the compound represented by general formula I ₂ , the general method can be prepared by hydrolysis of the corresponding nitrile according to methods known in the art, referring to Houben-Weyl.Meth Org Chem, 1952, 8:661-663; J Am Chem Soc, 1960, 82:4642-4644.

When Y=COOH in the compound represented by general formula I, the general method can be prepared by hydrolysis of the corresponding nitrile according to methods known in the art, referring to Houben-Weyl.Meth Org Chem, 1952, 8: 428-431; or Prepared from the corresponding amides, see Houben-Weyl. Meth Org Chem, 1952, 8:432.

When Y=COOR' in the compound represented by general formula I, the general method can be prepared from the corresponding nitrile according to methods known in the art, referring to Houben-Weyl.Meth Org Chem, 1952, 8:536-537; or Prepared from the corresponding acids, see Houben-Weyl. Meth Org Chem, 1952, 8:542-547.

Compounds represented by general formula I can also be prepared by alkylation methods known in the art, i.e. from corresponding secondary amines or phenols with appropriate halides or sulfonates, see Org Synth, 1955, Coll Vol 3: 256-258.

According to the invention, the compounds of formula I or formula _Ia may exist in stereoisomeric forms. Asymmetric centers present in compounds of formula (I) may have either the R-configuration or the S-configuration. The present invention includes all possible stereoisomers such as enantiomers or diastereomers, as well as mixtures of two or more stereoisomers, for example in any desired ratio of enantiomers and/or diastereomers mixture. Accordingly, the present invention relates to enantiomers, eg the le- and dex-enantiomers in enantiomerically pure form, and mixtures or racemates of the two enantiomers in different proportions. If cis/trans isomers exist, the invention relates to both the cis and trans forms and mixtures of these forms. Single stereoisomers can be prepared, if desired, by resolution of mixtures according to conventional methods, or by, for example, stereoselective synthesis. The present invention also relates to the tautomeric forms of the compounds of formula I, if a mobile hydrogen atom is present.

According to the present invention, the compound of formula I or I _a and its stereoisomers have anti-atherosclerosis, anti-oxidation, and blood-lipid-regulating effects. It can be used to prevent or treat cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia and stroke. Therefore, it can be used as a drug for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, and stroke. This type of drug can be used for animals, preferably for mammals, especially for humans.

The present invention therefore also relates to pharmaceutical compositions containing as active ingredient an effective dose of at least one compound of formula I or formula _Ia , or a pharmaceutically acceptable salt thereof and/or stereoisomers thereof, as well as conventional pharmaceutical excipients or adjuvants . In general, the pharmaceutical compositions according to the invention contain 0.1-90% by weight of compounds of the formula I or formula _Ia and/or their physiologically acceptable salts. Pharmaceutical compositions can be prepared according to methods known in the art. When used for this purpose, if desired, the compound of formula I or _formula Ia and/or stereoisomers can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to make it available as human appropriate administration form or dosage form.

The compound of formula I or formula I a of the present invention or _the pharmaceutical composition containing it can be administered in unit dose form, and the route of administration can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum etc. Dosage forms such as tablets, capsules, drop pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, lyophilized powder injections wait. It can be common preparations, sustained-release preparations, controlled-release preparations and various microparticle drug delivery systems. Various carriers known in the art can be widely used for tableting unit dosage forms. Examples of carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid Aluminum, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, acacia mucilage, gelatin paste, sodium carboxymethylcellulose , shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbate Sugar alcohol fatty acid esters, sodium lauryl sulfonate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption enhancers , such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets. In order to formulate a dosage unit into a pellet, various carriers known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin , ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecylsulfonate, methylcellulose, ethylcellulose, etc. In order to formulate the administration unit into a suppository, various carriers known in the art can be widely used. Examples of carriers are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like. In order to make the administration unit into capsules, the active ingredient formula I or the compound of formula I _a or its stereoisomers are mixed with the above-mentioned various carriers, and the resulting mixture is placed in hard capsules or soft capsules. The active ingredient formula I or _the compound of formula Ia or its stereoisomers can also be made into microcapsules, suspended in an aqueous medium to form a suspension, and can also be packed into hard capsules or made into injections for application. In order to prepare the dosage unit into injection preparations, such as solutions, emulsions, lyophilized powder injections and suspensions, all diluents commonly used in this field can be used, for example, water, ethanol, polyethylene glycol, 1,3 - Propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In addition, in order to prepare isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin can be added to the preparation for injection, and in addition, conventional solubilizers, buffers, pH regulators, etc. can also be added.

In addition, colorants, preservatives, fragrances, correctives, sweeteners or other materials can also be added to the pharmaceutical preparations, if necessary.

The dosage of the compound of formula I or formula I _{a of} the present invention, or its pharmaceutically acceptable salt or its stereoisomer depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, age, and degree of the patient or animal. Body weight and individual response, specific compound used, route of administration and frequency of administration, etc. The above dose can be administered in a single dose or divided into several, eg two, three or four doses.

Example

The present invention can be further illustrated by the following examples, but these examples do not imply any limitation to the present invention.

Example 1 2-(3,5-dimethoxy-4-hydroxyphenyl)-2-[4-(2-pyridyl)piperazinyl]methylphosphonic acid diethyl ester—compound 1

Weigh 26.60g (0.146mol) 3,5-dimethoxy-4-hydroxybenzaldehyde, 23.20g (0.141mol) 1-(2-pyridyl) piperazine and 21.10g (0.153mol) diethyl phosphite Add 50ml of absolute ethanol to dissolve the ester, stir at a bath temperature of about 60°C for 3.5 days, evaporate the solvent, perform silica gel column chromatography, first wash off excess raw materials with chloroform, and then elute with chloroform-ethanol (4:1) , recovered the solvent, and then crystallized with isopropanol-1,4-dioxane to obtain 46.8 g of colorless crystals, with a yield of 71.3%, and mp 125-127°C. Elemental Analysis Calcd. C ₂₂ H ₃₂ N ₃ O ₆ P (%) C 56.76, H 6.93, N 9.02, Found C 56.80, H 6.92, N 8.88. ¹ H-NMR (CDCl ₃ , ppm) 1.05-1.12 (t, J=7.04Hz, 3H), 1.35-1.38 (t, J=7.04Hz, 3H), 2.60-2.70 (m, 2H), 2.90-3.00 (m, 2H), 3.45-3.75(m, 4H), 3.7853.821(d, J=20.33Hz, 1H), 3.902(s, 6H), 3.90-4.00(m, 2H), 4.20-4.30(m , 2H), 5.542 (s, 1H), 6.60-6.70 (m, 2H), 6.739 (s, 2H), 7.50-7.60 (m, 1H), 8.15-8.17 (dd, 1H). MS (FAB ⁺ , m/z) 466.2 (M+1), 328.1 (B, M-PO(OEt) ₂ ). Dissolve compound 1 in isopropanol, then form a salt with HCl-Et ₂ O to obtain hydrochloride: mp 135-136°C, ¹ H-NMR (D ₂ O, ppm) 1.00-1.20 (m, 6H), 3.40-3.50(m, 4H), 3.65-4.05(m, 16H), 4.3855.007(dd, J=11-15Hz, 1H), 6.726(d, J=2.20Hz, 1H), 6.874(s, 1H ), 7.021(t, J=6.59Hz, 1H), 7.23-7.28(m, 1H), 8.013(d, J=2.20Hz, 1H), 8.025(m→d, J=2.20Hz, 1H). MS (FAB ⁺ , m/z) 466.2 (M+1), 328.1 (B, M-PO(OEt) ₂ ).

Example 2 2-(4-hydroxyl-3-methoxyphenyl)-2-[4-(2-pyridyl)piperazinyl]methylphosphonic acid diethyl ester—compound 2

According to the method of Example 1, it was prepared by replacing 3,5-dimethoxy-4-hydroxybenzaldehyde with vanillin, and recrystallized with isopropanol-cyclohexane to obtain white granular crystals with a yield of 64.9%, mp 130 -132°C. Elemental analysis C ₂₁ H ₃₀ N ₃ O ₅ P (%) Calculated value C 57.92, H 6.94, N 9.65; found value C 57.86, H 7.01, N 9.48; ¹ H-NMR (CO(CD ₃ ) ₂ , ppm) 0.97-1.00(t, J=7.17Hz, 3H), 1.27-1.30(t, J=7.02Hz, 3H), 2.48-2.53(m, 2H), 2.88-2.92(m, 2H), 3.071(s, 1H), 3.45-3.49(t, J=5.04Hz, 2H), 3.66-3.74(m, 1H), 3.785(s, 3H), 3.81-3.92(m, 1H), 3.9403.978(d, J= 23.19Hz, 1H), 4.15-4.26(m, 2H), 6.50-6.52(m, 1H), 6.6686.683(d, J=8.85Hz, 1H), 6.7576.770(d, J=7.94Hz, 1H ), 6.90-6.93 (d, J=7.94Hz, 1H), 7.138 (s, 1H), 7.39-7.43 (m, 1H), 8.00-8.02 (dd, 1H). MS (EI, m/z) 435.1 (M ⁺ ), 298.1 (B, M-PO(OEt) ₂ ). Hydrochloride: mp 208-209°C, ¹ H-NMR (D ₂ O, ppm) 1.00-1.25 (m, 6H), 3.38-3.50 (m, 4H), 3.65-4.05 (m, 13H), 4.4055. 004(dd, J=11-14Hz, 1H), 6.84-6.92(m, 1H), 6.96-7.04(m, 2H), 7.10-7.30(m, 2H), 7.774(m→s, J=2.20Hz , 1H), 8.025 (m, 1H). MS (FAB ⁺ , m/z) 436.2 (M+1), 298.1 (B, M-PO(OEt) ₂ ).

Example 3 2-(4-hydroxyl-3-methoxyphenyl)-2-(4-methylpiperazinyl)methylphosphonic acid diethyl ester—the preparation of compound 11

According to the method of Example 1, it was prepared by reaction of N-methylpiperazine, crystallized from ether-ethanol, the yield was 94.1%, ¹ H-NMR (CDCl ₃ , ppm) 1.05-1.09 (t, J=7.08Hz, 3H ), 1.34-1.38(t, J=7.08Hz, 3H), 2.25(s, 3H), 2.38-2.53(m, 4H), 2.80-2.94(m, 2H), 3.62-3.74(m, 2H), 3.7453.801(d, J=22.46Hz, 1H), 3.862(s, 3H), 3.80-3.98(m, 2H), 4.08-4.32(m, 2H), 6.7656.786(d, J=8.30Hz, 1H), 6.8306.849(d, J=7.81Hz, 1H), 7.034(s, 1H).MS(EI ⁺ , m/z) 372.2(M ⁺ ), 274.1(M-MP) ⁺ , 235.1(B , M-PO(OEt) ₂ ).

Embodiment 4 N-(cyanomethyl) morpholine—preparation of compound 133

Weigh 8.30g (0.11mol) of chloroacetonitrile, add 50ml of anhydrous diethyl ether, stir and cool with ice water, add dropwise 17.50g (0.20mol) of morpholine and 20ml of anhydrous diethyl ether, after the dripping is complete, let it stand overnight, and filter it the next day , washed thoroughly with anhydrous ether, combined ether solutions, and rotary evaporating off the low boiling point to obtain 12.20 g (96.8%) of a light red liquid, that is, compound 1. Take 2.60g (0.020mol) of the liquid, dissolve it in 20ml of anhydrous ether, and form a salt with HCl-Et ₂ O to obtain 3.20g (95.4%) of a white solid, namely N-(cyanoethyl)morpholine hydrochloride, mp , Elemental analysis C ₆ H ₁₁ ClN ₂ O (%) theoretical value C44.32, H6.82, N17.23; measured value C44.36, H6.83, N17.31. ¹ H-NMR (D ₂ O, ppm) 3.37-3.46 (m, 4H), 3.95-4.02 (t, J=4.58Hz, 4H), 4.37-4.43 (m, 2H).

Example 5 1-(cyanomethyl)-4-methylpiperazine—preparation of compound 134

According to the method of Example 1, N-methylpiperazine was used instead of morpholine, and the yield of compound 2 was 98.1%; the yield of salt formation was 97.2%. ¹ H-NMR (D ₂ O, ppm) 2.70-2.80 (m, 2H), 2.92-2.93 (d, J=1.10Hz, 3H), 3.12-3.24 (m, 4H), 3.55-3.64 (m, 2H ), 3.82-3.84 (d, J=1.10Hz, 2H).

Example 6 2-(3,4-methylenedioxyphenyl)-2-(4-methylpiperazinyl)acetonitrile—preparation of compound 150

Weigh 1.10g (0.0224mol) sodium cyanide, 2.21g (0.0213mol) sodium bisulfite and 3.10g (0.0206mol) piperonal, add 20ml water, shake well, then add 2.10g (0.0210mol) N-formazan Basepiperazine and 10ml ethanol were reacted at a bath temperature of about 50°C with stirring for 40 hours, cooled, added water, extracted three times with diethyl ether, dried over anhydrous magnesium sulfate, recovered the solvent, and crystallized with diethyl ether-petroleum ether to obtain a white crystal 3.50 g (65.8%), mp 87-88°C. Elemental analysis C ₁₄ H ₁₇ N ₃ O ₂ (%) Theoretical C 64.85, H 6.61, N 16.20; found C 64.88, H 6.59, N 16.27. ¹ _H ^_ s, 3H), 2.40-2.55(m, 4H), 2.55-2.64(m, 4H), 4.721(s, 1H), 5.993(s, 2H), 6.7936.814(d, J=8.30Hz, 1H) , 6.994(s, 1H), 7.0057.025(d, J=8.30Hz, 1H); MS(FAB ⁺ , m/z) 260.2(M+1) ⁺ , 259.2(M ⁺ ), 258.2(M-1 ) ⁺ , 233.2(M-CN) ⁺ , 160.0(B, (M-MP) ⁺ ).

Example 7 2-(2-furyl)-2-(4-methylpiperazinyl)acetonitrile—preparation of compound 152

Weigh 1.40g (0.0103mol) of N-methylpiperazine hydrochloride, 1.01g (0.0105mol) of furfuraldehyde and 0.52g (0.0106mol) of sodium cyanide, dissolve in 10ml of water and 20ml of ethanol, and bathe at about 55°C Stir the reaction in warm for about 6 hours, cool, add 50ml of water, then extract with ethyl acetate (70ml×2), dry over anhydrous sodium sulfate, recover the solvent, the residue is compound 2, and use EtOH-AcOEt-Et ₂ O Dissolve, and form HCl-Et ₂ O into a salt to obtain 2.05 g (84.7%) of 2-(2-furyl)-2-(4-methylpiperazinyl)acetonitrile hydrochloride, mp 174-175°C. IR (KBr pellet, cm ^-1 ) 3435.79 (br), 2800-2400 (m), 1460.65, 1184.56, 1143.60, 1111.70, 1015.64, 983.75, 878.48, 752.43; ¹ H-NMR (CDCl ₃ , ppm) 2.826 2.837 (d, J=4.39Hz, 3H), 2.90-3.05(m, 4H), 3.06-3.24(m, 2H), 3.50-3.62(m, 2H), 4.945(s, 1H), 6.42-6.44(m , 1H), 6.6046.611(d, J=2.93Hz, 1H), 7.483(s, 1H), 12.925(br, 1H); MS (FAB ⁺ , m/z) 447.2(2M-Cl ^-1 ) ⁺ , 206.1 (M-Cl ⁻¹ ) ⁺ , 179.1 (B, (B-CN) ⁺ ).

Example 8 2-cyano-1,4-dibenzylpiperazine—preparation of compound 182

Weigh 10.65g (0.050mol) of 2,3-dibromopropionitrile, add 40ml of dry benzene, and drop in 10.20g (0.101mol) of triethylamine and 12.05g (0.050mol) of N at 40°C under stirring, 20ml of N'-dibenzylethylenediamine solution in dry benzene, dropwise, reflux for 3 hours, cool, filter, wash the solid with benzene, combine the benzene liquid, recover benzene, silica gel column chromatography, to obtain a light yellow thick liquid, That is, the compound; take 1.0 g of the product, dissolve it with 20 ml of diethyl ether, form a salt with diethyl ether hydrochloride, separate out a thick solid, discard the solvent, and crystallize with isopropanol-diethyl ether to obtain 0.90 g (80.0%) of hydrochloride, mp170-171 ℃.

Example 9 2-cyano-1-methyl-1-azabicyclo[3,2,1]-2-heptene (2-cyano-2-tropene)—the preparation of compound 183

Weigh 30.20g (0.258mol) of 2,4,6-cycloheptatrienenitrile, put it into a reaction kettle, add 200ml of methylamino alcohol solution, place it in an oil bath at 85-90°C and heat it for 28 hours, cool, and open kettle, rotary evaporated to remove the low boiling point part, and then distilled under reduced pressure to obtain 33.80g (88.5%) of light yellow liquid, bp95-98℃/2-3mmHg. Salted by HCl-Et ₂ O, a white solid was obtained, mp 181- 184°C.

Example 10 8-benzyl-6β-cyano-8-azabicyclo[3,2,1]oct-3-en-2-one—preparation of compound 184

Weigh 11.20g (0.050mol) of N-benzyl-3-hydroxypyridine chloride and 0.10g of hydroquinone, add 25ml of acrylonitrile, 10ml of triethylamine and 65ml of tetrahydrofuran, reflux and stir overnight. The next day, filter, remove the solvent by rotary evaporation, add 100ml of diethyl ether, filter, recover the solvent, and recrystallize the residue with ethanol to obtain 6.35g (53.4%) of yellow crystals, mp 87-89°C.

Example 11 2-carbamoyl-1-methyl-1-azabicyclo[3,2,1]-2-heptene (anhydroecgonine amide)—the preparation of compound 250

Take 3.05g (0.0206mol) of 2-cyano-2-tropene, dissolve it in 20ml of concentrated hydrochloric acid, reflux for 6 hours, evaporate the water under reduced pressure, and crystallize with absolute ethanol to obtain 3.46g (82.5%) of a white solid , mp218-221°C.

Example 12 Preparation of 2-morpholino-2-(3,4,5-trimethoxyphenyl)acetic acid—compound 254

With reference to the method of Example 11, take 1.80 g (6.46 mmol) of 2-morpholino-2-(3,4,5-trimethoxyphenyl) acetonitrile hydrochloride, dissolve it in 25 ml of concentrated hydrochloric acid and 15 ml of water, and reflux Reaction overnight, the next day, rotary evaporated to dryness, the residue was dissolved in absolute ethanol, added ether to precipitate, filtered, the solid was washed with ether, and then recrystallized in absolute ethanol.

Example 13 8-benzyl-6β-methoxycarbonyl-8-azabicyclo[3,2,1]oct-3-en-2-one—preparation of compound 385

According to the method of Example 10, methyl acrylate was used instead of acrylonitrile to obtain 6.50 g (48.0%), mp 90-92 ° C.

The following biological activity experiments further illustrate the present invention.

Experimental example of biological activity 1. Experiment of the antioxidative effect of the new compound The general formula I compound of the present invention is to Cu ²⁺ inducing the end product thiobarbituric acid reactive substances (TBARS) of normal human low-density lipoprotein (LDL) oxidation in vitro Generated inhibitory effects.

As shown in Figure 1, incubation of normal human low-density lipoprotein with Cu ²⁺ can induce LDL oxidative modification, and its oxidative end product, thiobarbituric acid reactive substance, significantly increases. The compound concentration of the new structure compound was 25 μmol.L ^-1 . When the compound was incubated with LDL for 5 hours in the LDL oxidation reaction system, the inhibition rates of TBARS formation were compound 2 (50.72%), compound 4 (33.75%), VitE (27.67 %), Compound 135 (20.08%), Compound 149 (17.74%), Compound 155 (17.67%), Compound 148 (13.87%), Compound 134 (6.21%). When the concentration was 250 μmol.L ^-1 , when incubated with LDL for 5 hours in the LDL oxidation reaction system, the inhibition rates of TBARS production were compound 149 (82.06%), compound 2 (74.32%), compound 155 (70.88%), Compound 133 (65.66%), Compound 1 (48.65%), Compound 135 (44.31%), Compound 4 (30.71%), Compound 148 (24.50%), Compound 134 (15.04%), Compound 5 (8.97%), Compound 136 (8.90%).

Biological Effect Experimental Example 1. Experiments on the antioxidant effect of new compounds suggest that the compound of general formula I of the present invention has a significant antioxidant effect, and its representative compounds 2 and 4 have stronger antioxidant effects than VitE. Studies have shown that drugs with antioxidant effects, such as probucol, can not only block the development of atherosclerotic lesions, but also have the effect of promoting the regression of lesions (see Document 1). The strong antioxidant effect of compound 2 is expected to be used in the treatment of atherosclerotic diseases and free radical-related diseases.

Literature 1 Nagano Y, Naramura T, Matsuzawa Y, et al. Probucol andatherosclerosis in the WHHR lonely term anti atherosclerotic effect and effects on established plaques. Atherosclerosis, 1992; 92: 131.

Biological Effect Experimental Example 1. The experimental research method of the antioxidative effect of the new compound: get a certain amount of LDL dialyzed through EDTA-free phosphate buffered saline (PBS), and the concentration of heregulin is 2.0mg L ^-1 , add successively Equal volumes of PBS (blank control), Vit E (positive control) and different concentrations of samples to be tested (final concentrations of 250 and 25 μmol.L ^-1 ), and then adding Cu ²⁺ , incubated at 37°C to induce LDL oxidation, each Samples were taken every 1 hour for testing. Add a certain amount of thiobarbituric acid to the sample to be tested to make it react, and measure the amount of oxidation products generated by colorimetry. Observe the antioxidant effect of the drug.

Biological Effect Experimental Example 2 The influence of the representative compound 2 of formula 2 of the present invention on the inhibitory effect of high cholesterol-induced blood lipid elevation.

As shown in Table 1, the big-eared white rabbits were fed with high cholesterol, and at the same time, 210 mg/kg of the compound was orally administered to the big-eared white rabbits, and the effect of the drug on hyperlipidemia induced by high-cholesterol feeding was observed. Compound 2 can significantly reduce the increase of plasma total cholesterol and low-density lipoprotein cholesterol induced by high-cholesterol feeding, and has a tendency to inhibit the increase of TG. After a month of high-fat diet, the levels of TC, LDL-C, and TG in rabbits were significantly increased. Compared with the normal diet group, the increase rates were 53 times, 95 times, and 1.5 times, respectively. The corresponding TC, LDL-C levels of the compound 2 administration group The increase ranges were 14.52 and 27.47 times respectively, and there was no difference between TG and normal diet group. It is suggested that compound 2 can significantly reduce the increase of TC and LDL-C induced by high cholesterol (P<0.01 compared with the high-fat diet group), and has a tendency to inhibit the increase of TG.

Table 1. Effect of compound 2 on blood lipids of rabbits fed with high cholesterol for 1 month

Note: The blood lipid concentration is mmol.L ^-1 . The data are expressed as x±s, compared with the normal diet group: ^* P<0.05, ^** P<0.01. Compared with the high-fat diet group: #P<0.05, ##P <0.01. Data processing application SAS software D2P8 program.

Biological Effect Experiment Example 2 suggests that compound 2 has a significant effect on blood lipid regulation. In recent years, several large series of clinical studies have confirmed that lowering plasma TC, especially LDL, can reduce the risk of coronary heart disease, and lowering serum LDL in high-risk groups is expected to reduce the morbidity and mortality of CHD by one-third in the 21st century One (see literature 2, 3, 4). Compound 2 has a significant blood lipid regulating effect, showing good prospects for preventing and treating coronary heart disease.

Literature 2 Scandinavian Simvastatin survival study Group. Rnadomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the scandinavian simvastatin suvvivalstudy (4s) [J]. Lancet, 1994; 344: 1383-389.

Literature 3 Shepherd J, Cbbesm, Ford L, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia west of scotland coronary prevention study group[J]. N Engl J Med; 1995, 333: 1301-307.

Literature 4 Scott MG. Cholesterol and coronary heart disease-the21th century[J]. Arch Intern Med; 1997, 157: 1177-184

Biological Effect Experimental Example 3 Effect of representative compound 2 of the present invention on atherosclerosis induced by elevated blood lipids in rabbits fed with high cholesterol.

Feed the big-eared white rabbits with high cholesterol, and at the same time give the compound 210mg/kg orally to the big-eared white rabbits, and observe the effect of the drugs on the formation of aortic plaques in the rabbits. In the high cholesterol feeding group, the arterial wall was significantly thickened, and the milky yellow plaque raised on the intima surface fused into a sheet, covering the entire surface of the thoracic aorta and abdominal aorta. In the compound 2 administration group, the arterial wall was slightly thickened, and the lesions were more serious in the aortic root and arch, involving the entire thoracic aorta, and a small amount involved the abdominal aorta, and the plaques were not fused into sheets. It is suggested that compound 2 can inhibit atherosclerosis caused by hyperlipidemia induced by high cholesterol feeding.

Biological Effect Experiment Example 3 suggests that feeding with high cholesterol can induce hyperlipidemia and lead to atherosclerosis, and compound 2 can inhibit the formation of atherosclerosis caused by hyperlipidemia.

Biological effect experiment Example 2, the research method of example 3: big-eared white rabbit, ♂, body weight about 2kg. Each rat was given a high-fat feed of 120g.d ^-1 (containing 1.2 grams of cholesterol), and the normal diet group was given a basic feed of 120g.d ^-1 . The administration group took the compound orally at 210 mg/kg.d. At one month of the experiment, blood samples from rabbit ear veins were collected, serum was separated, and plasma total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured. To observe the effect of the drug on the increase in blood lipids induced by high cholesterol. At 1.5 months of the experiment, the animals were sacrificed, the aorta was routinely processed, and the effect of the drug on the general distribution of atherosclerotic plaque formation induced by hypercholesterolemia and hyperlipidemia in rabbits was observed with the naked eye.

For the experimental method, please refer to the references: Chen Kai, Zhang Yanfang, Wang Qian, et al. Characteristics of hyperlipidemia and atherosclerosis induced by feeding rabbits, quails and rats with high cholesterol; Chinese Journal of Pharmaceutical Sciences of PLA, 17(3):117-124

Claims (7)

1. The application of the compound shown in general formula I or its pharmaceutically acceptable salt in the preparation of the medicine that can be used to prevent or treat cardiovascular and cerebrovascular diseases, or as the purposes of the tool medicine for researching these diseases in: R ₁ R ₂ N is piperazinyl, 4-methylpiperazinyl, 4-(2-pyridyl)piperazinyl, 4-(4-methyl-2-pyridyl)piperazinyl, 4-( 4-piperidinyl-2-pyridyl)piperazinyl, 4-(3-pyridyl)piperazinyl, 4-(4-pyridyl)piperazinyl, 4-(2-pyrimidinyl)piperazinyl Base, 4-(4-pyrimidinyl)piperazinyl, 4-(5-pyrimidinyl)piperazinyl, 4-(6-pyrimidinyl)piperazinyl, 4-(2-pyridazinyl)piperazinyl , 4-(4,6-dimethoxy-2-triazinyl)piperazinyl, 4-(2-chlorophenyl)piperazinyl, 4-(3-chlorophenyl)piperazinyl, 4 -(4-chlorophenyl)piperazinyl, 4-(2-fluorophenyl)piperazinyl, 4-(3-fluorophenyl)piperazinyl, 4-(4-fluorophenyl)piperazinyl , 4-(2-chlorophenyl)piperazinyl, 4-(3,4-dichlorophenyl)piperazinyl, 4-(5-chloro-2-methylphenyl)piperazinyl, 4- (2-methoxyphenyl)piperazinyl, 4-(3-methoxyphenyl)piperazinyl, 4-(4-methoxyphenyl)piperazinyl, 4-bis(4-fluoro Phenyl)methylpiperazinyl; R ₃ represents C _6-12 aromatic hydrocarbon group, substituted C _6-12 aromatic hydrocarbon group, wherein, the substituent of each substituent group is selected from: halogen, hydroxyl, cyano, nitro, C _1-6 Hydrocarbyl, C _4-6 aromatic hydrocarbon, C _1-6 alkoxy, C _1-6 alkylthio, one, two or trihalogenated C _1-6 alkyl, amino, C _1-10 hydrocarbon amino, C _1-10 hydrocarbon acyloxy, C _6-10 aroyloxy or C _1-10 hydrocarbon amido, one, two, three or four substituents can be the same or different; Y represents a phosphonic acid group, a C _1-10 alkoxy phosphono group, a _{C 1-10} alkoxy phosphono group, a C _1-10 alkoxy C _1-10 alkyl amino phosphono group, a C _{1-10 alkoxy} phosphono group Hydrocarbylaminophosphono, diC _1-10 hydrocarbylaminophosphono. 2. The use according to claim 1, wherein said R ₁ R ₂ N is 4-(2-pyridyl)piperazinyl, and Y is diethoxyphosphono. 3. application as claimed in claim 1, wherein, described medicinal salt is the salt of medicinal acid addition, is selected from hydrochloride, sulfate, phosphate, hydrobromide; Or acetate, oxalate salt, citrate, gluconate, succinate, tartrate, p-toluenesulfonate, methanesulfonate, benzoate, lactate or maleate. 4. The application of claim 1, wherein said pharmaceutically acceptable salt is a salt formed with a base, selected from alkali metal salts, alkaline earth metal salts, salts formed with organic bases or salts formed with chiral bases. 5. the application of claim 1 or 2, wherein the compound of formula I is selected from Diethyl 2-(3,5-dimethoxy-4-hydroxyphenyl)-2-[4-(2-pyridyl)piperazinyl]methylphosphonate; Diethyl 2-(4-hydroxy-3-methoxyphenyl)-2-[4-(2-pyridyl)piperazinyl]methylphosphonate; Diethyl 2-(4-hydroxy-3-methoxyphenyl)-2-(4-methylpiperazinyl)methylphosphonate. 6. as the arbitrary application of claim 1-3, wherein, described compound is 2-(4-hydroxyl-3-methoxyphenyl)-2-[4-(2-pyridyl) piperazinyl ] Diethyl methylphosphonate hydrochloride. 7. The application according to claim 6, wherein said application refers to the use in the preparation of cardiovascular and cerebrovascular disease drugs for the prevention or treatment of atherosclerosis, hyperlipidemia, coronary heart disease, and stroke.

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