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

Compound possessing function for preventing and curing atherosclerosis and its application in biologic pharmacological science Download PDF

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CN100486981C
CN100486981C CNB011372737A CN01137273A CN100486981C CN 100486981 C CN100486981 C CN 100486981C CN B011372737 A CNB011372737 A CN B011372737A CN 01137273 A CN01137273 A CN 01137273A CN 100486981 C CN100486981 C CN 100486981C
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piperazinyl
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hydrocarbyl
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CN1415617A (en
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汪海
杨日芳
山丽梅
赵如胜
陈凯
恽榴红
王倩
赵利枝
龙超良
慕邵峰
张雁芳
费改顺
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

A compound for preventing and treating atherosclerosis, its derivative, isomer, racemate or optical isomer, medical salt and solvated substance, the medical composition containing them, its preparing process, and its application in preparing medicines for treating atherosclerosis, hyperlipomia, coronary heart disease, etc are disclosed.

Description

Compound with function of preventing and treating atherosclerosis and application thereof in biological medicine
The present invention relates to novel substituted alpha-amino nitriles, alpha-amino carboxylic acids, alpha-amino phosphonic acids, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof or solvates thereof, a preparation method thereof, applications thereof in preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, hyperlipidemia, coronary heart disease, cerebral apoplexy, etc., and a pharmaceutical composition containing the compounds.
Atherosclerosis is the pathological basis of cardiovascular and cerebrovascular diseases such as coronary heart disease, myocardial infarction, cerebral apoplexy and the like, and has high mortality rate and high disability rate. Coronary heart disease accounts for half of 100 million deaths in the United states annually due to cardiovascular and cerebrovascular disease, and is the only important disease in Western countries. The pathological examination result of the 19-35 year old accidental death patient in Beijing area in 1995 shows that the detection rate of coronary heart disease is 71%, the later-stage lesion patient is up to 23%, and the incidence rate is on the increasing trend along with the improvement of the social and economic levels. 2/3 survived in acute myocardial infarction patients, but 2/3 failed to recover completely. The medical and payroll losses incurred in the united states alone are up to 500-.
Epidemiological studies have revealed that several major environmental factors and genetic predisposition factors are associated with atherosclerosis. Its pathogenesis is rather complex, and numerous growth factors, cytokines and vascular regulatory molecules are involved in its process. For example, various factors (changes in hemorheology in hyperlipidemia, smoking and hypertension) can activate endothelial cells to alter their function (e.g., expression of a number of adhesion molecules, chemokines, inflammatory factors, metabolic disorders of vasoactive substances, increased endothelial permeability, and changes in surface antithrombotic properties). As a result, monocyte adhesion to endothelium increases and localizes across the endothelial space to endothelial down-conversion to macrophages; the low density lipoprotein entering under the endothelium is increased and oxidized into oxidized low density lipoprotein under the action of excessive superoxide anion locally generated by damaged endothelium, and macrophages engulf the oxidized low density lipoprotein to become foam cells in a large quantity, so that lipid stripe change in the early stage of atherosclerosis is formed. As the accumulation of cells in the lesion area gradually increases, some macrophages which engulf lipids re-enter the blood stream, and then thrombus is formed at the branch and bifurcation parts of irregular blood flow such as vortex, reflux and the like. Platelets in the thrombus release various growth regulating factors, and the growth regulating factors and various regulating factors released by activated macrophages in the blood vessel wall act on smooth muscle cells together to stimulate the migration and proliferation of the smooth muscle cells and form new connective tissues, so that the atherosclerotic lesion is developed into a progressive complex lesion. The elimination of any influencing factor leading to the development and development of the lesion can prevent the development and development of atherosclerosis and can make the lesion regress. Such as regulating blood lipid; preventing oxidation of low density lipoprotein; 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 the derivative thereof play roles in preventing and treating cardiovascular and cerebrovascular diseases such as atherosclerosis, hyperlipidemia, coronary heart disease, cerebral apoplexy and the like through two links of regulating blood fat and preventing low-density lipoprotein oxidation.
The types of drugs clinically used for preventing and treating cardiovascular and cerebrovascular diseases such as atherosclerosis, hyperlipidemia, coronary heart disease, cerebral apoplexy and the like at present comprise: lipid regulating drugs, antioxidant drugs, antiplatelet drugs, antithrombotic drugs, etc. The medicines are not certain in the aspects of curative effect, safety and specificity of resisting atherosclerosis. In recent years, with the deep understanding of the mechanism of atherosclerosis, anti-atherosclerosis drugs such as anti-oxidation and anti-cell adhesion (such as GPIIb/IIIa antagonists) become hot spots of research in the international pharmaceutical industry, but no drug with definite curative effect is available on the market.
The application of the compound of the general formula I and the derivative thereof in preventing and treating atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and other cardiovascular and cerebrovascular diseases is not reported.
The invention aims to find and develop a new medicine for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and the like.
The inventor of the invention has extensively and deeply researched, and has found that the novel compound shown in the formula I or the formula Ia has exact anti-atherosclerosis, blood fat regulation and antioxidation effects, and the compound can be used for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and the like. Research shows that the compound shown in the formula I or the formula Ia has the functions of resisting atherosclerosis, regulating blood fat and resisting oxidation. Further synthesis and research show that the derivative and proper inorganic acid or organic acid or medicinal salt formed by the derivative and inorganic base or organic base also have the effects of treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and the like. The present invention has been completed based on the above finding.
The invention relates to application of a compound shown in a general formula I, a derivative, an isomer, a racemate or an optical isomer, a medicinal salt or a solvate thereof in preparing a medicament for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and the like or as a tool medicament for researching cardiovascular and cerebrovascular diseases such as atherosclerosis and the like,
Figure C01137273D00061
wherein:
R1、R2、R3each represents a hydrogen atom, C1-20Saturated or unsaturated, linear or branched aliphatic hydrocarbons, C3-20Cycloalkyl, substituted C3-20Cycloalkyl radical, C4-20Aromatic hydrocarbon group of (1), substituted C5-20Aromatic hydrocarbon group, C3-20Heterocycloalkyl, substituted C3-20Heterocyclic hydrocarbon radicals, beta-hydroxy C2-20Hydrocarbyl, beta-C1 -10Alkylcarbonyloxy C2-10Hydrocarbyl, beta-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-C1-10Alkoxy radical C2-10Hydrocarbyl, beta-C4-10Aryloxy radical C2-10Hydrocarbyl, beta-substituted C4-10Aryloxy radical C2-10Hydrocarbyl, beta-mercapto C2-20Hydrocarbyl, beta-C1-10Alkylthio group C2-10Hydrocarbyl, beta-C4-10Arylthio radical C2-10Hydrocarbyl, beta-substituted C4-10Arylthio radical C2-10Hydrocarbyl, beta-amino C2-20Hydrocarbyl, beta-C1-10Alkylamino radical C2-10Hydrocarbyl, beta-C4-14Arylamino group C2-10Hydrocarbyl, beta-substituted C4-14Arylamino group C2-10Hydrocarbyl, beta-C1-10Alkylamido C2-10Hydrocarbyl, beta-C5-14Aromatic amide radical C2-10Hydrocarbyl, beta-substituted C5-14Aromatic amide radical C1-10Hydrocarbyl, gamma-hydroxy C2-20Hydrocarbyl, gamma-C1-10Alkylcarbonyloxy C2-10Hydrocarbyl, gamma-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-C1-10Aryloxy radical C2-10Hydrocarbyl, gamma-substituted C5-10Aryloxy radical C2-10Hydrocarbyl, gamma-mercapto C2-20Hydrocarbyl, gamma-C1-10Alkylthio group C2-10Hydrocarbyl, gamma-C4-10Arylthio radical C2-10Hydrocarbyl, gamma-substituted C5-10Arylthio radical C2-10Hydrocarbyl, gamma-amino C2-20Hydrocarbyl, gamma-C1-10Alkylamino radical C2-10Hydrocarbyl, gamma-C4-14Arylamino group C2-10Hydrocarbyl, gamma-substituted C4-14Arylamino group C2-10Hydrocarbyl, gamma-C1-10Alkylamido C2-10Hydrocarbyl, gamma-C5-14Aromatic amide radical C2-10Hydrocarbyl, gamma-substituted C5-14Aromatic amide radical C2-10A hydrocarbyl group; or
R1And R2Or R3Generating a 3-to 9-membered cyclic structure, in particular a morpholine ring, a piperazine ring, a piperidine ring, a pyrroline ring, an imidazoline ring, a pyrazoline ring, a thiazoline ring, a homomorpholine ring, a homopiperazine ring, a homopiperidine ring, a substituted piperazine ring, an N- (substituted C)4-6Aryl) piperazine ring, substituted piperidine ring, substituted pyrroline ring, substituted imidazoline ring, N- (substituted C)4-6Aralkyl) imidazoline ring, substituted pyrazoline ring, N- (substituted C)4-6Aryl group) pyrazoline ring, substituted thiazoline ring, substituted homomorpholine ring, substituted homopiperazine ring, N- (substituted C)4-6Aryl) homopiperazine rings, substituted homopiperidine rings, in which each group bears a substituentThe substituents are selected from: halogen, hydroxy, cyano, nitro, C1-10Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Hydrocarbylamino, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarbon amide group;
y represents cyano, carboxy, phosphonic acid, C1-10Alkoxycarbonyl group, C3-10Heterocyclyloxycarbonyl, substituted C3-10Heterocyclyloxycarbonyl radical, C4-10Aryloxycarbonyl, substituted C4-10Aryloxycarbonyl, carbamoyl, C1-10Alkylamino carbonyl, C3-10Heterocyclic aminocarbonyl, substituted C3-10Heterocyclic aminocarbonyl group, C4-10Arylaminocarbonyl, substituted C4-10Arylaminocarbonyl, mono C1-10Alkoxyphosphono, mono C3-10Heterocyclyloxyphosphono, mono (substituted C)3-10Heterocyclyloxy) phosphono, mono C4-10Aryloxyphosphonyl, mono (substituted C)4-10Aryloxy) phosphono, di (C)1-10Alkoxy) phosphono, di (C)3-10Heterocyclyloxy) phosphono, di (substituted C)3-10Heterocyclyloxy) phosphono, di (C)4-10Aryloxy) phosphono, di (substituted C)4-10Aryloxy) phosphono, mono C1-10Alkylamino phosphono, mono C4-10Heterocyclic aminophosphonyl, mono (substituted C)4-10Heterocyclic amino) phosphonyl, mono C4-10Arylaminophosphonyl, mono (substituted C)5-10Arylamino) phosphonyl, di (C)1-10Alkylamino) phosphono, di (C)4 -10Heterocyclic amino) phosphono, di (substituted C)4-10Heterocyclic amino) phosphono, di (C)4-10Arylamino) phosphonyl, di (substituted C)5-10Arylamino) phosphonyl, (C)1-10Alkylamino) (C1-10Alkoxy) phosphonyl, (C)4-10Heterocyclic amino) (C1-10Alkoxy) phosphonyl, (substituted C)4-10Heterocyclic amino) (C1 -10Alkoxy) phosphonyl, (C)4-10Arylamino) (C)1-10Alkoxy) phosphonoRadical (substituted C)5-10Arylamino) (C)1-10Alkoxy) phosphonyl, (C)1-10Alkylamino) (C3-10Heterocyclyloxy) phosphono, (C)4 -10Heterocyclic amino) (C3-10Heterocyclyloxy) phosphono, (substituted C)4-10Heterocyclic amino) (C3-10Heterocyclyloxy) phosphono, (C)4-10Arylamino) (C)3-10Heterocyclyloxy) phosphono, (substituted C)5-10Arylamino) (C)3-10Heterocyclyloxy) phosphono, (C)1-10Alkylamino) (substituted C3-10Heterocyclyloxy) phosphono, (C)4-10Heterocyclic amino) (substituted C3-10Heterocyclyloxy) phosphono, (substituted C)4-10Heterocyclic amino) (substituted C3-10Heterocyclyloxy) phosphono, (C)4-10Arylamino) (substituted C3-10Heterocyclyloxy) phosphono, (substituted C)5-10Arylamino) (substituted C3-10Heterocyclyloxy) phosphono, (C)1-10Alkylamino) (C4-10Aryloxy) phosphono group, (C)4-10Heterocyclic amino) (C4-10Aryloxy) phosphono, (substituted C)4-10Heterocyclic amino) (C4-10Aryloxy) phosphono group, (C)4-10Arylamino) (C)4-10Aryloxy) phosphono, (substituted C)5-10Arylamino) (C)4-10Aryloxy) phosphono group, (C)1-10Alkylamino) (substituted C4-10Aryloxy) phosphono group, (C)4-10Heterocyclic amino) (substituted C4-10Aryloxy) phosphono, (substituted C)4-10Heterocyclic amino) (substituted C4-10Aryloxy) phosphono group, (C)4-10Arylamino) (substituted C4-10Aryloxy) phosphono, (substituted C)5-10Arylamino) (substituted C4-10Aryloxy) phosphono, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the substituents in said "disubstituted phosphono" may be the same or different, and the heterocycle refers to a mono-or fused heterocycle containing 1 to 3 heteroatoms selected from N, O or S, and the substituents of each substituent-bearing group are selected from: halogen, hydroxy, cyano, nitro, C1-6Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-5Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Alkylamino radical, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarbon amide group.
The second aspect of the invention relates to the general formula I for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and the likeaThe new compound, the derivative, the isomer, the racemate or the optical isomer, the medicinal salt or the solvate thereof,
Figure C01137273D00081
wherein:
R1’、R2’、R3' independently represent a hydrogen atom, C1-20Saturated or unsaturated, linear or branched aliphatic hydrocarbons, C3-20Cycloalkyl, substituted C3-20Cycloalkyl radical, C4-20Aromatic hydrocarbon group of (1), substituted C5- 20Aromatic hydrocarbon group, C3-20Heterocycloalkyl, substituted C3-20Heterocyclic hydrocarbon radicals, beta-hydroxy C2-20Hydrocarbyl, beta-C1-10Alkylcarbonyloxy C2-10Hydrocarbyl, beta-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-C1-10Alkoxy radical C2-10Hydrocarbyl, beta-C4-10Aryloxy radical C2-10Hydrocarbyl, beta-substituted C4-10Aryloxy radical C2-10Hydrocarbyl, beta-mercapto C2-20Hydrocarbyl, beta-C1-10Alkylthio group C2-10Hydrocarbyl, beta-C4-10Arylthio radical C2-10Hydrocarbyl, beta-substituted C4-10Arylthio radical C2-10Hydrocarbyl, beta-amino C2-20Hydrocarbyl, beta-C1-10Alkylamino radical C2-10Hydrocarbyl, beta-C4-14Arylamino group C2-10Hydrocarbyl, beta-substituted C4-14Arylamino group C2-10Hydrocarbyl, beta-C1-10Alkylamido C2-10Hydrocarbyl, beta-C5-14Aromatic amide radical C2-10Hydrocarbyl, beta-substituted C5-14Aromatic amide radical C1-10Hydrocarbyl, gamma-hydroxy C2-20Hydrocarbyl, gamma-C1-10Alkylcarbonyloxy C2-10Hydrocarbyl, gamma-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-C1-10Aryloxy radical C2-10Hydrocarbyl, gamma-substituted C5-10Aryloxy radical C2-10Hydrocarbyl, gamma-mercapto C2-20Hydrocarbyl, gamma-C1-10Alkylthio group C2-10Hydrocarbyl, gamma-C4-10Arylthio radical C2-10Hydrocarbyl, gamma-substituted C5-10Arylthio radical C2-10Hydrocarbyl, gamma-amino C2-20Hydrocarbyl, gamma-C1-10Alkylamino radical C2-10Hydrocarbyl, gamma-C4-14Arylamino group C2-10Hydrocarbyl, gamma-substituted C4-14Arylamino group C2-10Hydrocarbyl, gamma-C1-10Alkylamido C2-10Hydrocarbyl, gamma-C5-14Aromatic amide radical C2-10Hydrocarbyl, gamma-substituted C5-14Aromatic amide radical C2-10A hydrocarbyl group; or
R1' and R2' or R3' Generation of 3-to 9-membered cyclic structures, in particular morpholine, piperazine, piperidine, pyrroline, imidazoline, pyrazoline, thiazoline, homomorpholine, homopiperazine, homopiperidine, substituted piperazine, N- (substituted C)4-6Aryl) piperazine ring, substituted piperidine ring, substituted pyrroline ring, substituted imidazoline ring, N- (substituted C)4-6Aralkyl) imidazoline ring, substituted pyrazoline ring, N- (substituted C)4-6Aryl group) pyrazoline ring, substituted thiazoline ring, substituted homomorpholine ring, substituted homopiperazine ring, N- (substituted C)4-6Aryl) homopiperazine rings, substituted homopiperidine rings, wherein the substituents for each substituent-bearing group are selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-10Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Hydrocarbylamino, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarbon amide group;
y represents cyano, carboxy, phosphonic acid, C1-10Alkoxycarbonyl group, C3-10Heterocyclyloxycarbonyl, substituted C3-10Heterocyclyloxycarbonyl radical, C4-10Aryloxycarbonyl, substituted C4-10Aryloxycarbonyl, carbamoyl, C1-10Alkylamino carbonyl, C3-10Heterocyclic aminocarbonyl, substituted C3-10Heterocyclic aminocarbonyl group, C4-10Arylaminocarbonyl, substituted C4-10Arylaminocarbonyl, mono C1-10Alkoxyphosphono, mono C3-10Heterocyclyloxyphosphono, mono (substituted C)3-10Heterocyclyloxy) phosphono, mono C4-10Aryloxyphosphonyl, mono (substituted C)4-10Aryloxy) phosphono, di (C)1-10Alkoxy) phosphono, di (C)3-10Heterocyclyloxy) phosphono, di (substituted C)3-10Heterocyclyloxy) phosphono, di (C)4-10Aryloxy) phosphono, di (substituted C)4-10Aryloxy) phosphono, mono C1-10Alkylamino phosphono, mono C4-10Heterocyclic aminophosphonyl, mono (substituted C)4-10Heterocyclic amino) phosphonyl, mono C4-10Arylaminophosphonyl, mono (substituted C)5-10Arylamino) phosphonyl, di (C)1-10Alkylamino) phosphono, di (C)4 -10Heterocyclic amino) phosphono, di (substituted C)4-10Heterocyclic amino) phosphono, di (C)4-10Arylamino) phosphonyl, di (substituted C)5-10Arylamino) phosphonyl, (C)1-10Alkylamino) (C1-10Alkoxy) phosphonyl, (C)4-10Heterocyclic amino) (C1-10Alkoxy) phosphonyl, (substituted C)4-10Heterocyclic amino) (C1 -10Alkoxy) phosphonyl, (C)4-10Arylamino) (C)1-10Alkoxy) phosphonyl, (substituted C)5-10Arylamino) (C)1-10Alkoxy) phosphonyl, (C)1-10Alkylamino) (C3-10Heterocyclyloxy) phosphono, (C)4 -10Heterocyclic amino) (C3-10Heterocyclyloxy) phosphono, (substituted C)4-10Heterocyclic amino) (C3-10Heterocyclyloxy) phosphono, (C)4-10Arylamino) (C)3-10Heterocyclyloxy) phosphono, (substituted C)5-10Arylamino) (C)3-10Heterocyclyloxy) phosphono, (C)1-10Alkylamino) (substituted C3-10Heterocyclyloxy) phosphono, (C)4-10Heterocyclic amino) (substituted C3-10Heterocyclyloxy) phosphono, (substituted C)4-10Heterocyclic amino) (substituted C3-10Heterocyclyloxy) phosphono, (C)4-10Arylamino) (substituted C3-10Heterocyclyloxy) phosphono, (substituted C)5-10Arylamino) (substituted C3-10Heterocyclyloxy) phosphono, (C)1-10Alkylamino) (C4-10Aryloxy) phosphono group, (C)4-10Heterocyclic amino) (C4-10Aryloxy) phosphono, (substituted C)4-10Heterocyclic amino) (C4-10Aryloxy) phosphono group, (C)4-10Arylamino) (C)4-10Aryloxy) phosphono, (substituted C)5-10Arylamino) (C)4-10Aryloxy) phosphono group, (C)1-10Alkylamino) (substituted C4-10Aryloxy) phosphono group, (C)4-10Heterocyclic amino) (substituted C4-10Aryloxy) phosphono, (substituted C)4-10Heterocyclic amino) (substituted C4-10Aryloxy) phosphono group, (C)4-10Arylamino) (substituted C4-10Aryloxy) phosphono, (substituted C)5-10Arylamino) (substituted C4-10Aryloxy) phosphono, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the substituents in said "disubstituted phosphono" may be the same or different, and the heterocycle refers to a mono-or fused heterocycle containing 1 to 3 heteroatoms selected from N, O or S, and the substituents of each substituent-bearing group are selected from: halogen, hydroxy, cyano, nitro, C1-6Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Alkylamino radical, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarbon amide group.
The invention also relates to a compound shown in the general formula I, a derivative, an isomer, a racemate or an optical isomer, a medicinal salt or a solvate thereof for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and the like,
wherein:
R1、R2、R3each represents a hydrogen atom, C1-20Saturated or unsaturated, linear or branched aliphatic hydrocarbons, C3-20Cycloalkyl, substituted C3-20Cycloalkyl radical, C4-20Aromatic hydrocarbon group of (1), substituted C5-20Aromatic hydrocarbon group, C3-20Heterocycloalkyl, substituted C3-20Heterocyclic hydrocarbon radicals, beta-hydroxy C2-20Hydrocarbyl, beta-C1 -10Alkylcarbonyloxy C2-10Hydrocarbyl, beta-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-C1-10Alkoxy radical C2-10Hydrocarbyl, beta-C4-10Aryloxy radical C2-10Hydrocarbyl, beta-substituted C4-10Aryloxy radical C2-10Hydrocarbyl, beta-mercapto C2-20Hydrocarbyl, beta-C1-10Alkylthio group C2-10Hydrocarbyl, beta-C4-10Arylthio radical C2-10Hydrocarbyl, beta-substituted C4-10Arylthio radical C2-10Hydrocarbyl, beta-amino C2-20Hydrocarbyl, beta-C1-10Alkylamino radical C2-10Hydrocarbyl, beta-C4-14Arylamino group C2-10Hydrocarbyl, beta-substituted C4-14Arylamino group C2-10Hydrocarbyl, beta-C1-10Alkylamido C2-10Hydrocarbyl, beta-C5-14Aromatic amide radical C2-10Hydrocarbyl, beta-substituted C5-14Aromatic amide radical C1-10Hydrocarbyl, gamma-hydroxy C2-20Hydrocarbyl, gamma-C1-10Alkylcarbonyloxy C2-10Hydrocarbyl, gamma-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-C1-10Aryloxy radical C2-10Hydrocarbyl, gamma-substituted C5-10Aryloxy radical C2-10Hydrocarbyl, gamma-mercapto C2-20Hydrocarbyl, gamma-C1-10Alkylthio group C2-10Hydrocarbyl, gamma-C4-10Arylthio radical C2-10Hydrocarbyl, gamma-substituted C5-10Arylthio radical C2-10Hydrocarbyl, gamma-amino C2-20Hydrocarbyl, gamma-C1-10Alkylamino radical C2-10Hydrocarbyl, gamma-C4-14Arylamino group C2-10Hydrocarbyl, gamma-substituted C4-14Arylamino group C2-10Hydrocarbyl, gamma-C1-10Alkylamido C2-10Hydrocarbyl, gamma-C5-14Aromatic amide radical C2-10Hydrocarbyl, gamma-substituted C5-14Aromatic amide radical C2-10A hydrocarbyl group; or
R1And R2Or R3Generating a 3-to 9-membered cyclic structure, in particular a morpholine ring, a piperazine ring, a piperidine ring, a pyrroline ring, an imidazoline ring, a pyrazoline ring, a thiazoline ring, a homomorpholine ring, a homopiperazine ring, a homopiperidine ring, a substituted piperazine ring, an N- (substituted C)4-6Aryl) piperazine ring, substituted piperidine ring, substituted pyrroline ring, substituted imidazoline ring, N- (substituted C)4-6Aralkyl) imidazoline ring, substituted pyrazoline ring, N- (substituted C)4-6Aryl group) pyrazoline ring, substituted thiazoline ring, substituted homomorpholine ring, substituted homopiperazine ring, N- (substituted C)4-6Aryl) homopiperazine rings, substituted homopiperidine rings, wherein the substituents for each substituent-bearing group are selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-10Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Hydrocarbylamino, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarbon amide group;
y represents cyano, carboxy, phosphonic acid, C1-10Alkoxycarbonyl group, C3-10Heterocyclyloxycarbonyl, substituted C3-10Heterocyclyloxycarbonyl radical, C4-10An aryloxycarbonyl group,Substituted C4-10Aryloxycarbonyl, carbamoyl, C1-10Alkylamino carbonyl, C3-10Heterocyclic aminocarbonyl, substituted C3-10Heterocyclic aminocarbonyl group, C4-10Arylaminocarbonyl, substituted C4-10Arylaminocarbonyl, mono C1-10Alkoxyphosphono, mono C3-10Heterocyclyloxyphosphono, mono (substituted C)3-10Heterocyclyloxy) phosphono, mono C4-10Aryloxyphosphonyl, mono (substituted C)4-10Aryloxy) phosphono, di (C)1-10Alkoxy) phosphono, di (C)3-10Heterocyclyloxy) phosphono, di (substituted C)3-10Heterocyclyloxy) phosphono, di (C)4-10Aryloxy) phosphono, di (substituted C)4-10Aryloxy) phosphono, mono C1-10Alkylamino phosphono, mono C4-10Heterocyclic aminophosphonyl, mono (substituted C)4-10Heterocyclic amino) phosphonyl, mono C4-10Arylaminophosphonyl, mono (substituted C)5-10Arylamino) phosphonyl, di (C)1-10Alkylamino) phosphono, di (C)4 -10Heterocyclic amino) phosphono, di (substituted C)4-10Heterocyclic amino) phosphono, di (C)4-10Arylamino) phosphonyl, di (substituted C)5-10Arylamino) phosphonyl, (C)1-10Alkylamino) (C1-10Alkoxy) phosphonyl, (C)4-10Heterocyclic amino) (C1-10Alkoxy) phosphonyl, (substituted C)4-10Heterocyclic amino) (C1 -10Alkoxy) phosphonyl, (C)4-10Arylamino) (C)1-10Alkoxy) phosphonyl, (substituted C)5-10Arylamino) (C)1-10Alkoxy) phosphonyl, (C)1-10Alkylamino) (C3-10Heterocyclyloxy) phosphono, (C)4 -10Heterocyclic amino) (C3-10Heterocyclyloxy) phosphono, (substituted C)4-10Heterocyclic amino) (C3-10Heterocyclyloxy) phosphono, (C)4-10Arylamino) (C)3-10Heterocyclyloxy) phosphono, (substituted C)5-10Arylamino) (C)3-10Heterocyclyloxy) phosphono, (C)1-10Alkylamino) (substituted C3-10Heterocyclyloxy) phosphono, (C)4-10Heterocyclic amino) (substituted C3-10Heterocyclyloxy) phosphono, (substituted C)4-10Heterocyclic amino) (substituted C3-10Heterocyclyloxy) phosphono, (C)4-10Arylamino) (substituted C3-10Heterocyclyloxy) phosphono, (substituted C)5-10Arylamino) (substituted C3-10Heterocyclyloxy) phosphono, (C)1-10Alkylamino) (C4-10Aryloxy) phosphono group, (C)4-10Heterocyclic amino) (C4-10Aryloxy) phosphono, (substituted C)4-10Heterocyclic amino) (C4-10Aryloxy) phosphono group, (C)4-10Arylamino) (C)4-10Aryloxy) phosphono, (substituted C)5-10Arylamino) (C)4-10Aryloxy) phosphono group, (C)1-10Alkylamino) (substituted C4-10Aryloxy) phosphono group, (C)4-10Heterocyclic amino) (substituted C4-10Aryloxy) phosphono, (substituted C)4-10Heterocyclic amino) (substituted C4-10Aryloxy) phosphono group, (C)4-10Arylamino) (substituted C4-10Aryloxy) phosphono, (substituted C)5-10Arylamino) (substituted C4-10Aryloxy) phosphono, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the substituents in said "disubstituted phosphono" may be the same or different, and the heterocycle refers to a mono-or fused heterocycle containing 1 to 3 heteroatoms selected from N, O or S, and the substituents of each substituent-bearing group are selected from: halogen, hydroxy, cyano, nitro, C1-6Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Alkylamino radical, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarbon amide group.
In a further aspect, the invention relates to pharmaceutical compositions comprising at least one compound of formula IaOr a compound shown in the formula I, a derivative, an isomer, a racemate or an optical isomer, a medicinal salt or a solvate thereof, and a medicinal carrier or excipient.
The invention also relates to a method for preventing or treating atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and other cardiovascular and cerebrovascular diseases, which comprises the step of administering a preventive or therapeutic effective amount of a compound shown in formula I or formula I to a patient suffering from the cardiovascular and cerebrovascular diseasesaA derivative, isomer, racemate or optical isomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
The invention also relates to the preparation of the above formula IaMethods of Compounds: first, the present inventors have discovered a novel class of Mannich-like reactions, i.e., when R is involved3When HO-Ar, Y-PO (OR) OR',
Figure C01137273D00131
the phenolic aldehyde, the secondary amine and the phosphite ester are reacted by heating to 40-300 ℃ and/or pressurizing to 0.1-20Mpa in the presence/absence of an organic solvent and a catalyst, wherein R1’、R2' and R3'As defined above, R and R' are C0-10A hydrocarbyl group; the organic solvent is methanol, ethanol, propanol, isopropanol, butanol, acetone, butanone, toluene, xylene, 1, 2-dichloroethane, methyl hydrogen furan, 1, 4-dioxane, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; the catalyst is acid or/and alkali catalyst, the acid catalyst is Lewis acid comprising organic acid or inorganic acid, and the alkali catalyst is Lewis base comprising organic alkali tertiary amine and inorganic alkali. The discovery and application of this reaction have enabled the present inventors to prepare novel α -aminophosphonic acids and derivatives thereof with high activity in large quantities.
The amides may be prepared by preparing the acid halides from the corresponding acids and condensing with the corresponding amines, or by reacting the corresponding acids with the corresponding amines in the presence of condensing agents, as is well known in the art.
Secondly, when Y ═ CN, the following ternary Mannich reaction can be applied,
Figure C01137273D00132
or
Figure C01137273D00141
When Y ═ COOH, it can be prepared by hydrolysis of the corresponding nitrile by acid hydrolysis, base hydrolysis or hydrogen peroxide hydrolysis methods well known in the art; or by hydrolysis of the corresponding amide by acid or base hydrolysis methods well known in the art.
When Y ═ COOR, CONHR or CONRR', they can be prepared from the corresponding carboxylic acids by esterification and amidation methods well known in the art.
And, again, also from the corresponding amines with the corresponding halohydrocarbons or sulfonates by alkylation,
Figure C01137273D00142
or
The method also comprises the step of preparing an isomer or an optical isomer from a product obtained by the reaction through asymmetric reaction or further resolution; further comprising reacting the product obtained by the reaction with an inorganic or organic acid to form a pharmaceutically acceptable salt, i.e., a salt of an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; or organic acid salts, i.e., salts of acetic acid, oxalic acid, citric acid, gluconic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, lactic acid, and maleic acid; also included are pharmaceutically acceptable salts formed by reacting the product of the reaction with an inorganic or organic base, i.e., an alkali metal such as Li, Na and K; with alkaline earth metals such as Ca and Mg; with organic bases such as diethanolamine, choline and the like; or with chiral bases such as alkylphenylamine and the like.
Drawings
FIG. 1 shows the effect of the invention on TBARS of a compound of formula I or formula Ia: the drug concentration is 25 mu mol-1(ii) a B: the drug concentration is 250 mu mol-1。
According to the invention, atherosclerosis-related diseases refer to diseases related to atherosclerosis formation, such as atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and other cardiovascular and cerebrovascular diseases.
According to the invention, compounds of the general formula I R1Or R2Preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, 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- (dibutylamino) ethyl, tert-butyl, 2-hydroxyethylamino, 2-dimethylaminoethyl, 2- (dipropylamino) ethyl, 2- (diisobutylamino) ethyl, 2- (di-tert-butylamino) ethyl, 2-morpholinoethyl, 2-piperidinylethyl, 2-piperazinylethyl, 2- (4-methylpiperazino) ethyl, 3-hydroxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 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, 2- (di-tert-butylamino) propyl, 2-morpholinoethyl, 2-piperidinylethyl, 2-piperazinylethyl, 2-piperazinylpropyl, 3- (dipropylamino) propyl, 3- (dibutylamino) propyl, 3- (diisobutylamino) propyl, 3-, (Di-tert-butylamino) propyl, 3-morpholinopropyl, 3-piperidinopropyl, 3-piperazinopropyl, 3- (4-methylpiperazino) propyl; or,
R1R2n is preferably morpholinyl, piperazinyl, 4-methylpiperazinyl, 4- (2-pyridyl) piperazinyl, 4- (4-methyl-2-pyridyl) piperazinyl, 4- (4-piperidinylmethyl-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-pyridazinyl) piperazinyl, 4- (4, 6-dimethoxy-2-triazinyl) piperazinyl, 4- (2-chlorophenyl) piperazinyl, 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-fluorophenyl) methylpiperazinyl, 4-carbamoyl-4-piperidinyl;
R3preferably a hydrogen atom, methyl group, C2-12A hydrocarbon group of3-8Cycloalkyl radical, C6-12Aryl, substituted C6-12Aryl radical, C4-12Heterocyclic aromatic hydrocarbon radicals, substituted C4-12A heterocyclic aromatic hydrocarbon group, wherein the substituent of each substituent-bearing group is selected from: halogen, hydroxy, cyano, nitro, C1-6Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Alkylamino radical, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarboxamide group, the substituent can have one, two, three or four, and can be the same or different;
y is preferably cyano, carboxyl, C1-10Alkoxycarbonyl, carbamoyl, C1-10Hydrocarbyl aminocarbonyl, phosphonic acid, mono C1-10Hydrocarbyloxyphosphonyl, di-C1-10Hydrocarbyloxyphosphonyl radical, C1-10Hydrocarbyloxy group C1-10Hydrocarbylaminophosphonyl radical, C1-10Hydrocarbylaminophosphonyl, di-C1-10Hydrocarbylaminophosphonyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl.
In a preferred embodiment of the present invention, said R is1R2N is 4- (2-pyridyl) piperazinyl, R3Is 4-hydroxy-3-methoxyphenyl and Y is diethoxyphosphonyl.
According to the invention, acid addition salts of the compounds of formula I or formula Ia are illustrated by 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; salts of compounds of formula I with bases are illustrated by alkali 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, choline salts and the like; or chiral base salts such as alkylphenylamine salts.
Solvates of the compounds of the invention may be hydrates or contain other crystallization solvents such as alcohols.
The invention further relates to a novel general formula I for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipidemia, cerebral apoplexy and the like or used as a tool medicine for researching diseases related to atherosclerosisaThe new compound, the derivative, the isomer, the racemate or the optical isomer, the medicinal salt or the solvate thereof,
Figure C01137273D00161
wherein:
R1’、R2’、R3' independently represent a hydrogen atom, C1-20Saturated or unsaturated straight chain ofOr branched aliphatic hydrocarbons, C3-20Cycloalkyl, substituted C3-20Cycloalkyl radical, C4-20Aromatic hydrocarbon group of (1), substituted C5- 20Aromatic hydrocarbon group, C3-20Heterocycloalkyl, substituted C3-20Heterocyclic hydrocarbon radicals, beta-hydroxy C2-20Hydrocarbyl, beta-C1-10Alkylcarbonyloxy C2-10Hydrocarbyl, beta-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-C1-10Alkoxy radical C2-10Hydrocarbyl, beta-C4-10Aryloxy radical C2-10Hydrocarbyl, beta-substituted C4-10Aryloxy radical C2-10Hydrocarbyl, beta-mercapto C2-20Hydrocarbyl, beta-C1-10Alkylthio group C2-10Hydrocarbyl, beta-C4-10Arylthio radical C2-10Hydrocarbyl, beta-substituted C4-10Arylthio radical C2-10Hydrocarbyl, beta-amino C2-20Hydrocarbyl, beta-C1-10Alkylamino radical C2-10Hydrocarbyl, beta-C4-14Arylamino group C2-10Hydrocarbyl, beta-substituted C4-14Arylamino group C2-10Hydrocarbyl, beta-C1-10Alkylamido C2-10Hydrocarbyl, beta-C5-14Aromatic amide radical C2-10Hydrocarbyl, beta-substituted C5-14Aromatic amide radical C1-10Hydrocarbyl, gamma-hydroxy C2-20Hydrocarbyl, gamma-C1-10Alkylcarbonyloxy C2-10Hydrocarbyl, gamma-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-C1-10Aryloxy radical C2-10Hydrocarbyl, gamma-substituted C5-10Aryloxy radical C2-10Hydrocarbyl, gamma-mercapto C2-20Hydrocarbyl, gamma-C1-10Alkylthio group C2-10Hydrocarbyl, gamma-C4-10Arylthio radical C2-10Hydrocarbyl, gamma-substituted C5-10Arylthio radical C2-10Hydrocarbyl, gamma-amino C2-20Hydrocarbyl, gamma-C1-10Alkylamino radical C2-10Hydrocarbyl, gamma-C4-14Arylamino group C2-10Hydrocarbyl, gamma-substituted C4-14Arylamino group C2-10Hydrocarbyl, gamma-C1-10Alkylamido C2-10Hydrocarbyl, gamma-C5-14Aromatic amide radical C2-10Hydrocarbyl, gamma-substituted C5-14Aromatic amide groupC2-10A hydrocarbyl group; or
R1' and R2' or R3' Generation of 3-to 9-membered cyclic structures, in particular morpholine, piperazine, piperidine, pyrroline, imidazoline, pyrazoline, thiazoline, homomorpholine, homopiperazine, homopiperidine, substituted piperazine, N- (substituted C)4-6Aryl) piperazine ring, substituted piperidine ring, substituted pyrroline ring, substituted imidazoline ring, N- (substituted C)4-6Aralkyl) imidazoline ring, substituted pyrazoline ring, N- (substituted C)4-6Aryl group) pyrazoline ring, substituted thiazoline ring, substituted homomorpholine ring, substituted homopiperazine ring, N- (substituted C)4-6Aryl) homopiperazine rings, substituted homopiperidine rings, wherein the substituents for each substituent-bearing group are selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-10Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Hydrocarbylamino, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarbon amide group;
y represents cyano, carboxy, phosphonic acid, C1-10Alkoxycarbonyl group, C3-10Heterocyclyloxycarbonyl radical, C4-10Aryloxycarbonyl, substituted C4-10Aryloxycarbonyl, carbamoyl, C1-10Alkylamino carbonyl, C3-10Heterocyclic aminocarbonyl group, C4-10Arylaminocarbonyl, substituted C4-10Arylaminocarbonyl group, C1-10Alkoxyphosphono group, C3-10Heterocycleoxyphosphonyl radical, C4-10Aryloxyphosphonyl, substituted C4-10Aryloxy phosphono group, C1-10Alkylamino phosphono group, C4-10Heterocyclic aminophosphonyl radical, C4-10Arylaminophosphonyl group, substituted C5-10Arylaminophosphonyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the heterocycle means a mono-or fused heterocycle containing 1 to 3 heteroatoms selected from N, O or S, each withSubstituents of the group of substituents are selected from: halogen, hydroxy, cyano, nitro, C1-6Hydrocarbyl radical, C4-6Aryl radical, C1 -6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Alkylamino radical, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarbon amide group.
Preferably, the compound of formula Ia of the present invention may be selected from any one of the group consisting of:
2- (3, 5-dimethoxy-4-hydroxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonic acid diethyl ester;
2- (4-hydroxy-3-methoxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonic acid diethyl ester;
2- (4-hydroxy-3-methoxyphenyl) -2- (4-methylpiperazinyl) methylphosphonic acid diethyl ester;
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-tropene)
8-benzyl-6 β -cyano-8-azabicyclo [3, 2, 1] oct-3-en-2-one; and
2-morpholinyl-2- (3, 4, 5-trimethoxyphenyl) acetic acid.
According to the invention, formula IaThe amine derivative, isomer, racemate or optical isomer, medicinal salt or solvate thereof also has the function of preventing or treating and regulating the function of vascular endothelial cells. Wherein formula IaAcid addition salts of amine derivatives are exemplified by inorganic acid salts such as hydrochloride, sulfate, phosphate, hydrobromide; or organic acid salt such as acetate, oxalate, citrate, and grapeA sugar acid salt, a succinate salt, a tartrate salt, a p-toluenesulfonate salt, a methanesulfonate salt, a benzoate salt, a lactate salt, a maleate salt, a nicotinate salt, a cinnamate salt or a 3-hydroxy-3-methylglutarate salt. Preference is given to formula IaHydrochloride, maleate, p-toluenesulfonate, cinnamate and 3-hydroxy-3-methylglutarate of the amine derivative. Furthermore, salts of compounds of formula Ia with bases and solvates thereof are as defined above for compounds of formula I.
More specifically, in the derivatives of the general formula I of the present invention, R1、R2、R3May be the same or different and each represents a hydrogen atom, C1-20Saturated or unsaturated, linear or branched aliphatic hydrocarbons, C3-20Cycloalkyl, substituted C3-20Cycloalkyl radical, C4-20Aromatic hydrocarbon group of (1), substituted C5-20Aromatic hydrocarbon group, C3-20Heterocycloalkyl, substituted C3-20Heterocyclic hydrocarbon radicals, beta-hydroxy C2-20Hydrocarbyl, beta-C1-10Alkylcarbonyloxy C2-10Hydrocarbyl, beta-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, beta-C1-10Alkoxy radical C2-10Hydrocarbyl, beta-C4-10Aryloxy radical C2-10Hydrocarbyl, beta-substituted C4-10Aryloxy radical C2-10Hydrocarbyl, beta-mercapto C2-20Hydrocarbyl, beta-C1-10Alkylthio group C2-10Hydrocarbyl, beta-C4-10Arylthio radical C2-10Hydrocarbyl, beta-substituted C4-10Arylthio radical C2-10Hydrocarbyl, beta-amino C2-20Hydrocarbyl, beta-C1-10Alkylamino radical C2-10Hydrocarbyl, beta-C4-14Arylamino group C2-10Hydrocarbyl, beta-substituted C4-14Arylamino group C2-10Hydrocarbyl, beta-C1-10Alkylamido C2-10Hydrocarbyl, beta-C5-14Aromatic amide radical C2-10Hydrocarbyl, beta-substituted C5-14Aromatic amide radical C1-10Hydrocarbyl, gamma-hydroxy C2-20Hydrocarbyl, gamma-C1-10Alkylcarbonyloxy C2-10Hydrocarbyl, gamma-C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-substituted C5-14Aryl carbonyloxy C2-10Hydrocarbyl, gamma-C1-10Aryloxy radicalC2-10Hydrocarbyl, gamma-substituted C5-10Aryloxy radical C2-10Hydrocarbyl, gamma-mercapto C2-20Hydrocarbyl, gamma-C1-10Alkylthio group C2-10Hydrocarbyl, gamma-C4-10Arylthio radical C2-10Hydrocarbyl, gamma-substituted C5-10Arylthio radical C2-10Hydrocarbyl, gamma-amino C2-20Hydrocarbyl, gamma-C1-10Alkylamino radical C2-10Hydrocarbyl, gamma-C4-14Arylamino group C2-10Hydrocarbyl, gamma-substituted C4-14Arylamino group C2-10Hydrocarbyl, gamma-C1-10Alkylamido C2-10Hydrocarbyl, gamma-C5-14Aromatic amide radical C2-10Hydrocarbyl, gamma-substituted C5-14Aromatic amide radical C2-10A hydrocarbyl group; or
R1And R2Or R3Generating a 3-to 9-membered cyclic structure, in particular a morpholine ring, a piperazine ring, a piperidine ring, a pyrroline ring, an imidazoline ring, a pyrazoline ring, a thiazoline ring, a homomorpholine ring, a homopiperazine ring, a homopiperidine ring, a substituted piperazine ring, an N- (substituted C)4-6Aryl) piperazine ring, substituted piperidine ring, substituted pyrroline ring, substituted imidazoline ring, N- (substituted C)4-6Aralkyl) imidazoline ring, substituted pyrazoline ring, N- (substituted C)4-6Aryl group) pyrazoline ring, substituted thiazoline ring, substituted homomorpholine ring, substituted homopiperazine ring, N- (substituted C)4-6Aryl) homopiperazine rings, substituted homopiperidine rings, wherein the substituents for each substituent-bearing group are selected from the group consisting of: halogen, hydroxy, cyano, nitro, C1-10Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Hydrocarbylamino, C1-10Hydrocarbon acyloxy, C5-10Aroyloxy radical or C1-10A hydrocarbon amide group;
y represents cyano, carboxy, phosphonic acid, C1-10Alkoxycarbonyl group, C3-10Heterocyclyloxycarbonyl radical, C4-10Aryloxycarbonyl, substituted C4-10Aryloxycarbonyl, carbamoyl, C1-10Alkylamino carbonyl, C3-10Heterocyclic aminocarbonylsBase, C4-10Arylaminocarbonyl, substituted C4-10Arylaminocarbonyl group, C1-10Alkoxyphosphono group, C3-10Heterocycleoxyphosphonyl radical, C4-10Aryloxyphosphonyl, substituted C4-10Aryloxy phosphono group, C1-10Alkylamino phosphono group, C4-10Heterocyclic aminophosphonyl radical, C4-10Arylaminophosphonyl group, substituted C5-10Arylaminophosphonyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, wherein the heterocycle refers to a mono-or fused heterocycle containing 1 to 3 heteroatoms selected from N, O or S, and the substituent of each substituent-bearing group is selected from: halogen, hydroxy, cyano, nitro, C1-6Hydrocarbyl radical, C4-6Aryl radical, C1 -6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Alkylamino radical, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarbon amide group;
when Y is PO (OEt)2Preferred compounds of formula I are shown in Table 1.
TABLE 1Y ═ PO (OEt)2Preferred compounds of formula I and substituents thereof
Figure C01137273D00201
Figure C01137273D00211
Figure C01137273D00221
Figure C01137273D00251
Figure C01137273D00261
When Y is cyano, preferred compounds of formula I and substituents thereof are shown in Table 1.
Table 2 preferred compounds of formula I and substituents thereof when Y ═ CN
Figure C01137273D00272
Figure C01137273D00281
Figure C01137273D00291
When Y is CONH2Preferred compounds and substituents are shown in Table 3
Table 3 preference is given to compounds of the formula I, where Y ═ CONH in formula I2
Figure C01137273D00292
Figure C01137273D00301
Figure C01137273D00311
Figure C01137273D00321
When Y is CO2H, preferred compounds and substituents are shown in Table 4
Table 4 preference is given to compounds of the formula I in which Y ═ CO2H
Figure C01137273D00322
Figure C01137273D00331
Figure C01137273D00351
Figure C01137273D00361
When Y is CO2Me, preferred compounds and substituents are shown in Table 5
Table 5 preference is given to compounds of the formula I in which Y ═ CO2Me
Figure C01137273D00362
Figure C01137273D00371
Figure C01137273D00381
Figure C01137273D00391
Further, formula IaIf the compound has a modifiable group, the compound can be reacted with a proper derivatization reagent to prepare a corresponding derivative. Such as alkylation of phenolic hydroxyl groups (e.g., methylation, carboxymethylation, and alkoxycarbonylmethylation), esterification, ester hydrolysis, and the like.
According to the invention, formula IaWhen Y ═ PO (OR') OR "in the compound, the general preparation method is a new type of Mannich reaction found by the present inventors, and the general conditions are as follows: phenolic aldehyde, secondary amine and phosphite ester are heated and reacted in the presence/absence of an organic solvent, and unlike the previous reaction, the reaction does not need acyl chloride as a catalyst.
When Y ═ CN in the compounds represented by general formula I according to the present invention, the general procedure can be prepared according to methods known in the art, see Houben-weyl. 282-283.
When Y ═ CONH in the compounds represented by formula I2General procedures can be prepared from the corresponding nitrile by hydrolysis according to methods known in the art, see Houben-weyl. 661-; j Am Chem Soc, 1960, 82: 4642-4644.
When Y ═ COOH in the compounds represented by formula I, the general procedure can be prepared from the corresponding nitrile by hydrolysis according to methods known in the art, see Houben-weyl. 428-431; or from the corresponding amides, see Houben-weyl. meth Org Chem, 1952, 8: 432.
when Y ═ COOR' in the compounds represented by formula I, the general procedure can be prepared from the corresponding nitriles according to methods known in the art, see Houben-weyl. 536-; or from the corresponding acids, see Houben-weyl. meth Org Chem, 1952, 8: 542-547.
The compounds represented by formula I can also be prepared via alkylation methods well known in the art, i.e. from the corresponding secondary amines or phenols with appropriate halides or sulfonates, see Org Synth, 1955, col Vol 3: 256-258.
According to the invention, formula I or formula IaThe compounds may exist in stereoisomeric forms. The asymmetric centers present in the compounds of formula (I) may have 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 mixtures of enantiomers and/or diastereomers, in any desired ratio. The invention therefore relates to enantiomers, for example the levo-and dextro-enantiomers in enantiomerically pure form, and mixtures or racemates of the two enantiomers in different ratios. If cis/trans isomers are present, the present invention relates to the cis form and the trans form as well as mixtures of these forms. If desired, the single stereoisomers may be prepared by resolution of a mixture according to conventional methods, or by, for example, stereoselective synthesis. The invention also relates to tautomeric forms of the compounds of the formula I, if motorized hydrogen atoms are present.
According to the invention, formula I or IaThe compound and its stereoisomer have effects of resisting atherosclerosis, resisting oxidation, and regulating blood lipid. Can be used for preventing or treating cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hyperlipemia, and apoplexy. Therefore, can be used for preventing or treating atherosclerosis, coronary heart disease, and hypertensionBlood lipid, cerebral apoplexy, etc., and can be used in animals, preferably mammals, especially human.
The invention therefore also relates to pharmaceutical compositions containing, as active ingredient, an effective amount of at least one compound of formula I or of formula IaPharmaceutical compositions of the compounds, or pharmaceutically acceptable salts and/or stereoisomers thereof, and conventional pharmaceutical excipients or adjuvants. Typically, the pharmaceutical compositions of the present invention comprise 0.1 to 90% by weight of formula I or formula IaA compound and/or a physiologically acceptable salt thereof. The pharmaceutical compositions may be prepared according to methods known in the art. For this purpose, if desired, formula I or formula IaThe compounds and/or stereoisomers are combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants and formulated into a suitable administration form or dosage form for human use.
The invention is of formula I or formula IaThe compound or pharmaceutical composition containing it can be administered in unit dosage form, and the administration route can be intestinal or parenteral, such as oral, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum. The administration dosage forms include tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized powder for injection, etc. Can be common preparation, sustained release preparation, controlled release preparation and various microparticle drug delivery systems. In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents, e.g. dried starch, alginates, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol esterFatty acid esters, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, and the like; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. For making the administration units into pills, a wide variety of carriers well known in the art can be used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc. For making the administration unit into a suppository, various carriers well known in the art can be widely used. As examples of the carrier, there may be mentioned, for example, polyethylene glycol, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like. For the encapsulation of the administration units, the active ingredient is of the formula I or of the formula IaThe compound or its stereoisomer is mixed with the above-mentioned various carriers, and the mixture thus obtained is placed in hard gelatin capsules or soft capsules. The effective component can also be represented by formula I or formula IaThe compound or the stereoisomer thereof is prepared into microcapsules, is suspended in an aqueous medium to form a suspension, and can also be filled into hard capsules or prepared into injections for application. For preparing the administration unit into preparations for injection, such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in the art can be used, for example, water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, and the like. In addition, for the preparation of isotonic injection, can be added to the preparation for injection of appropriate amount of sodium chloride, glucose or glycerol, in addition, can also be added with conventional cosolvent, buffer, pH adjustmentAgents, and the like.
In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired.
The invention is represented by formula I or formula IaThe dosage of the compound, or a pharmaceutically acceptable salt or stereoisomer thereof, to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight and individual response of the patient or animal, the particular compound used, the route of administration and the number of administrations, etc. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g. two, three or four dosage forms.
Examples
The invention is further illustrated by the following examples, which are not intended to be limiting in any way.
EXAMPLE 12 preparation of diethyl (3, 5-dimethoxy-4-hydroxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonate, Compound 1
26.60g (0.146mol) of 3, 5-dimethoxy-4-hydroxybenzaldehyde, 23.20g (0.141mol) of 1- (2-pyridyl) piperazine and 21.10g (0.153mol) of diethyl phosphite are weighed, 50ml of absolute ethyl alcohol is added for dissolution, the mixture is stirred for 3.5 days at the bath temperature of about 60 ℃, a solvent is evaporated, silica gel column chromatography is carried out, excessive raw materials are washed away by chloroform, then the chloroform-ethanol (4:1) is used for elution, the solvent is recovered, and then isopropanol-1, 4-dioxane is used for crystallization, thus obtaining 46.8g of colorless crystals, the yield is 71.3 percent, and the mp is 125-127 ℃. Elemental analysis C22H32N3O6P (%) calcd for C56.76, H6.93, N9.02, found C56.80, H6.92, N8.88.1H-NMR(CDCl3，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). Dissolving Compound 1 in isopropanol, and adding HCl-Et2And O, salifying to obtain hydrochloride: mp 135-136 deg.c,1H-NMR(D2O，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 22 preparation of diethyl- (4-hydroxy-3-methoxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonate Compound 2
Prepared according to the method of example 1, vanillin instead of 3, 5-dimethoxy-4-hydroxybenzaldehyde, and recrystallized from isopropanol-cyclohexane to obtain white granular crystals with a yield of 64.9% and mp 130-. Elemental analysis C21H30N3O5P (%) calcd for C57.92, H6.94, N9.65; found C57.86, H7.01, N9.48;1H-NMR(CO(CD3)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 salt: mp 208 and 209,1H-NMR(D2O，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 32 preparation of diethyl (4-hydroxy-3-methoxyphenyl) -2- (4-methylpiperazinyl) methylphosphonate Compound 11
Prepared by the method of example 1, by reaction of N-methylpiperazine, crystallization from ether-ethanol, yield 94.1%,1H-NMR(CDCl3，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)。
EXAMPLE 4 preparation of N- (cyanomethyl) morpholine-compound 133
Weighing 8.30g (0.11mol) of chloroacetonitrile, adding 50ml of anhydrous ether, stirring, cooling with ice water, dropwise adding 17.50g (0.20mol) of morpholine and 20ml of anhydrous ether, standing overnight after dropwise adding, filtering the mixture, fully washing with the anhydrous ether, combining ether solutions, and rotationally evaporating a low-boiling-point part to obtain 12.20g (96.8%) of light red liquid, namely the compound 1. 2.60g (0.020mol) of the liquid are taken, dissolved in 20ml of anhydrous ether and added with HCl-Et2O salt formation to give 3.20g (95.4%) of a white solid, i.e.N- (cyanoethyl) morpholine hydrochloride, mp, elemental analysis C6H11ClN2Theoretical values of O (%) C44.32, H6.82, N17.23; found C44.36, H6.83, N17.31.1H-NMR(D2O，ppm)3.37-3.46(m，4H)，3.95-4.02(t，J＝4.58Hz，4H)，4.37-4.43(m，2H).
EXAMPLE 51 preparation of- (cyanomethyl) -4-methylpiperazine-Compound 134
Prepared according to the method of example 1, substituting N-methylpiperazine for morpholine, compound 2 yield 98.1%; the salt formation yield is 97.2%.1H-NMR(D2O，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 62- (3, 4-methylenedioxyphenyl) -2- (4-methylpiperazinyl) acetonitrile-preparation of Compound 150
Weighing 1.10g (0.0224mol) of sodium cyanide, 2.21g (0.0213mol) of sodium bisulfite and 3.10g (0.0206mol) of piperonal, adding 20ml of water, shaking up, adding 2.10g (0.0210mol) of N-methylpiperazine and 10ml of ethanol, reacting for 40 hours at about 50 ℃ while stirring, cooling, adding water, extracting for 3 times with diethyl ether, drying with anhydrous magnesium sulfate, recovering the solvent, crystallizing with diethyl ether-petroleum ether to obtain 3.50g (65.8%) of white crystals, and mp87-88 ℃. Elemental analysis C14H17N3O2(%) theoretical C64.85, H6.61, N16.20; found C64.88, H6.59, N16.27. IR (KBr pellet, cm)-1)3457.92，2905.61，2244.99，2220.27，2187.02，1504.49，1504.49，1496.79，1460.03，1452.37，1258.70，1113.09，932.23，825.46；1H-NMR(CDCl3，ppm)2.293(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 72 preparation of- (2-furyl) -2- (4-methylpiperazinyl) acetonitrile-Compound 152
Weighing 1.40g (0.0103mol) of N-methylpiperazine hydrochloride, 1.01g (0.0105mol) of furaldehyde and 0.52g (0.0106mol) of sodium cyanide, dissolving in 10ml of water and 20ml of ethanol, stirring at about 55 ℃ for reaction for about 6 hours, cooling, adding 50ml of water, extracting with ethyl acetate (70ml × 2), drying with anhydrous sodium sulfate, recovering solvent to obtain a residue, namely compound 2, and extracting with EtOH-AcOEt-Et2O dissolution, HCl-Et2O salification to obtain 2- (2-furyl) -2- (4-methylpiperazinyl) acetonitrile hydrochloride 2.05g (84.7%), mp 174 and 175 ℃. 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；1H-NMR(CDCl3，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 82 preparation of cyano-1, 4-dibenzylpiperazine-compound 182
Weighing 10.65g (0.050mol) of 2, 3-dibromopropionitrile, adding 40ml of dry benzene, dripping 20ml of dry benzene solution in which 10.20g (0.101mol) of triethylamine and 12.05g (0.050mol) of N, N' -dibenzylethylenediamine are dissolved at 40 ℃ under stirring, refluxing for 3 hours after dripping, cooling, filtering, washing solids with benzene, combining benzene liquid, recovering benzene, and performing silica gel column chromatography to obtain light yellow thick liquid, namely a compound; dissolving 1.0g product in 20ml diethyl ether, salifying with hydrochloric ether, precipitating to obtain thick solid, discarding solvent, crystallizing with isopropanol-diethyl ether to obtain hydrochloride 0.90g (80.0%), mp170-171 deg.C.
EXAMPLE 92 preparation of cyano-1-methyl-1-azabicyclo [3, 2, 1] -2-heptene (2-cyano-2-tropene) -Compound 183
Weighing 30.20g (0.258mol) of 2, 4, 6-cycloheptatrienenitrile, putting the weighed 2, 4, 6-cycloheptatrienenitrile into a reaction kettle, adding 200ml of methylamine alcohol solution, putting the mixture into an oil bath at 85-90 ℃, heating for reaction for 28 hours, cooling, opening the kettle, performing rotary evaporation to remove a low boiling point part, and then performing reduced pressure distillation to obtain 33.80g (88.5%) of light yellow liquid, bp95-98 ℃/2-3mmHg, and using HCl-Et2O salifying to obtain a white solid, and carrying out mp 181-184 ℃.
EXAMPLE 108 preparation of benzyl-6 β -cyano-8-azabicyclo [3, 2, 1] oct-3-en-2-one-Compound 184
11.20g (0.050mol) of N-benzyl-3-hydroxypyridine chloride and 0.10g of hydroquinone were weighed, and 25ml of acrylonitrile, 10ml of triethylamine and 65ml of tetrahydrofuran were added thereto, and the mixture was stirred under reflux overnight. The next day, filtration was carried out, the solvent was evaporated off by rotary evaporation, 100ml of diethyl ether was added, filtration was carried out, the solvent was recovered, and the residue was recrystallized from ethanol to give 6.35g (53.4%) of yellow crystals, mp 87-89 ℃.
EXAMPLE 112 preparation of carbamoyl-1-methyl-1-azabicyclo [3, 2, 1] -2-heptene (anhydroecgonine amide) -Compound 250
3.05g (0.0206mol) of 2-cyano-2-tropine is taken and dissolved in 20ml of concentrated hydrochloric acid, reflux reaction is carried out for 6 hours, water is evaporated under reduced pressure, and anhydrous ethanol is used for crystallization to obtain 3.46g (82.5%) of white solid, and mp218-221 ℃ is carried out.
Example 122 preparation of morpholinyl-2- (3, 4, 5-trimethoxyphenyl) acetic acid-compound 254
Referring to the method of example 11, 2-morpholinyl-2- (3, 4, 5-trimethoxyphenyl) acetonitrile hydrochloride 1.80g (6.46mmol) is dissolved in 25ml concentrated hydrochloric acid and 15ml water, the reflux reaction is carried out overnight, the next day, the rotary evaporation is carried out, the residue is dissolved in absolute ethyl alcohol, ether is added for precipitation, the filtration is carried out, the solid is washed by ether, and the recrystallization is carried out by absolute ethyl alcohol.
EXAMPLE 138 preparation of benzyl-6 β -methoxycarbonyl-8-azabicyclo [3, 2, 1] oct-3-en-2-one-compound 385
Prepared according to the method of example 10, substituting acrylonitrile with methyl acrylate to give 6.50g (48.0%), mp 90-92 ℃.
The following biological activity experiments further illustrate the present invention.
Biological Activity test example 1 test of antioxidant Effect of novel Compounds of the general formula I of the present invention on Cu in vitro2+The effect of inhibition of the production of thiobarbituric acid reactive substance (TBARS), the final product that induces the oxidation of normal human low-density lipoprotein (LDL).
Normal human low density lipoprotein and Cu as shown in FIG. 12+Incubation can induce LDL oxidation modification, and oxidation end product thereof is thiobarbituric acidThe reaction mass is increased significantly. The concentration of the new structure compound is 25 mu mol-1When incubated with LDL for 5h in an LDL oxidation reaction system, the inhibition rates for TBARS production 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%), and compound 134 (6.21%), respectively. The concentration is 250 mu mol.L-1When incubated with LDL for 5h in an LDL oxidation reaction system, the inhibition rates for TBARS production were 149 (82.06%), 2 (74.32%), 155 (70.88%), 133 (65.66%), 1 (48.65%), 135 (44.31%), 4 (30.71%), 148 (24.50%), 134 (15.04%), 5 (8.97%), and 136 (8.90%), respectively.
Biological Effect Experimental example 1. experiment of antioxidant effect of the novel Compounds suggests that the compounds of formula I of the present invention have significant antioxidant effect, and that representative compounds 2 and 4 have a stronger antioxidant effect than VitE. Studies have shown that drugs having an antioxidant action, such as probucol, can both block the development of atherosclerotic lesions and have an effect of promoting regression of the lesions (see document 1). The strong antioxidation effect of the compound 2 is hopeful to be used for treating atherosclerotic diseases and diseases related to free radicals.
Reference 1Nagano Y, Naramura T, Matsuzawa Y, et al Probucol and thermalserosis in the WHHR lane term anti atheroscerotic effect and artifacts on anaerobic substrates et al atheroscerosis, 1992; 92: 131.
biological Effect test example 1. method for investigating the antioxidant Effect of novel Compounds: dialyzing with Phosphate Buffer Solution (PBS) without EDTA to adjust protein concentration to 2.0 mg.L-1Adding equal volume of PBS (blank control), Vit E (positive control) and different concentrations of the sample to be tested (final concentration is 250 and 25 mu mol. L) in turn-1) Then adding Cu respectively2+LDL oxidation was induced by incubation at 37 ℃ and samples were taken every 1 h. Adding a certain amount of sulfur to the sample to be testedBarbituric acid is reacted and the amount of the oxidation product produced is determined colorimetrically. The antioxidant effect of the drug was observed.
Biological effects experiment example 2 effect of compound 2 representative of the formula of the present invention on inhibition of high cholesterol-induced blood lipid elevation.
As shown in Table 1, the effect of the drug on hyperlipidemia induced by high cholesterol feeding was observed by feeding the white rabbits with high cholesterol while orally administering 210mg/kg of the compound to the white rabbits with high cholesterol. The compound 2 can remarkably reduce the increase of plasma total cholesterol and low-density lipoprotein cholesterol induced by high cholesterol feeding, and has the tendency of inhibiting the increase of TG. The TC and LDL-C, TG levels of the rabbits are obviously increased by one month after high-fat diet, compared with the normal diet group, the increase ranges are respectively 53 times, 95 times and 1.5 times, the corresponding increase ranges of the TC and the LDL-C of the compound 2 administration group are respectively 14.52 times and 27.47 times, and TG is not different from the 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 high fat diet group), and has the tendency of inhibiting TG increase.
TABLE 1 Effect of Compound 2 on blood lipids in rabbits raised at 1 month with high cholesterol
Figure C01137273D00481
Note: blood lipid concentration is mmol.L-1Data expressed in x ± s, compared to normal diet group:*P<0.05，**P<0.01. comparison with the group of high fat diets: # P<0.05，##P<0.01. The data processing application is a SAS software D2P8 program.
Biological effect experiment example 2 suggests that compound 2 has significant effect in regulating blood lipid. In recent years, several large series of clinical studies have demonstrated that lowering plasma TC, especially LDL, reduces the risk of coronary heart disease, and that lowering serum LDL in high risk populations promises to reduce the incidence and mortality of CHD in the21 st century by one third (see documents 2, 3, 4). The compound 2 has obvious blood fat regulating effect and shows good prospect of preventing and treating coronary heart disease.
Document 2 Scandinavian Simvastatin Survival study group, Rnadirected formulated tertiary of cholestrol lower in 4444 patents with a cardio heart disease: the scandinavian simvastatin sumivavalstudy (4s) [ J ]. Lancet, 1994; 344: 1383-389.
Document 3 Shepherd J, Cbbesm, Ford L, et al, prediction of coronary disease with pravastatin in men with hypercholestrolememawest of scotland coronary prediction study group [ J ]. N Engl J Med; 1995, 333: 1301-307.
Document 4 Scott MG. Cholesterol and coronary heart disease-the21th center [ J ]. Arch Intern Med; 1997, 157: 1177-184
Biological Effect experiment example 3 Effect of compound 2 representative of the formula of the present invention on atherosclerosis induced by elevated blood lipids in hypercholesterolemic rabbits.
The effect of the drug on the formation of aortic plaques in rabbits was observed by feeding the white rabbits with high cholesterol while orally administering 210mg/kg of the compound to the white rabbits. The arterial wall of the hypercholesterolemic feeding group was significantly thickened, and the raised cream yellow plaque on the intimal surface was fused into a sheet covering the entire thoracic and abdominal aortic surfaces. The arterial wall of the group administered with compound 2 was slightly thickened, the lesion was heavier at the root and arch of the aorta, spread to the entire thoracic aorta, spread to the abdominal aorta in a small amount, and the plaque was not fused into a piece. Suggesting that the compound 2 can inhibit atherosclerosis caused by hyperlipemia induced by high cholesterol feeding.
Biological effect experiment example 3 suggests that high cholesterol feeding can induce hyperlipidemia and cause atherosclerosis, and that compound 2 can inhibit atherosclerosis formation caused by hyperlipidemia.
Biological effect experiment the study methods of example 2 and example 3: the big ear white rabbits are kept for the whole male, and the body weight is about 2 kg. Each dosing was given high fat diet 120g.d-1(containing 1.2 g of bile)Sterol), basal diet 120g.d was given to the normal diet group-1. The administration group orally administered compound 210 mg/kg.d. At 1 month of experiment, rabbit ear vein blood specimen is collected, serum is separated, and total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride in blood plasma are measured. The effect of the drug on high cholesterol-induced elevation of blood lipids was observed. At 1.5 months of the experiment, animals were sacrificed, the aorta was treated routinely, and the effect of the drug on the general distribution of atherosclerotic plaque formation caused by hypercholesterolemia induced rabbit hyperlipidemia was visually observed.
The experimental methods are detailed in the references: chenkai, Zhang Yan Fang, Wanqian, etc. Hyperlipidemia and atherosclerosis induced by high cholesterol raising of rabbits, quails and rats; free military pharmacology, 17 (3): 117-124

Claims (7)

1. Application of compound shown in general formula I or medicinal salt thereof in preparing medicine for preventing or treating cardiovascular and cerebrovascular diseases or application of compound shown in general formula I or medicinal salt thereof as tool medicine for researching the diseases
Wherein:
R1R2n is piperazinyl, 4-methylpiperazinyl, 4- (2-pyridyl) piperazinyl, 4- (4-methyl-2-pyridyl) piperazinyl, 4- (4)-piperidinylmethyl-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-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-pyridyl) piperazinyl, and the like, 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-fluorophenyl) methylpiperazinyl;
R3represents C6-12Aryl, substituted C6-12An aromatic hydrocarbon group, wherein the substituent of each substituent-bearing group is selected from: halogen, hydroxy, cyano, nitro, C1-6Hydrocarbyl radical, C4-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihalo-C1-6Alkyl, amino, C1-10Alkylamino radical, C1-10Hydrocarbon acyloxy, C6-10Aroyloxy radical or C1-10A hydrocarboxamide group, the substituent can have one, two, three or four, and can be the same or different;
y represents phosphonic acid group, C1-10Hydrocarbyloxyphosphonyl, di-C1-10Hydrocarbyloxyphosphonyl radical, C1 -10Hydrocarbyloxy group C1-10Hydrocarbylaminophosphonyl radical, C1-10Hydrocarbylaminophosphonyl, di-C1-10A hydrocarbyl aminophosphonyl group.
2. The use of claim 1, wherein R is1R2N is 4- (2-pyridyl) piperazinyl and Y is diethoxyphosphonyl.
3. The use of claim 1, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt selected from the group consisting of hydrochloride, sulfate, phosphate, hydrobromide; or an acetate, oxalate, citrate, gluconate, succinate, tartrate, p-toluenesulfonate, methanesulfonate, benzoate, lactate or maleate salt.
4. The use according to claim 1, wherein the pharmaceutically acceptable salt is a salt with a base selected from an alkali metal salt, an alkaline earth metal salt, a salt with an organic base or a salt with a chiral base.
5. Use according to claim 1 or 2, wherein the compound of formula I is selected from
2- (3, 5-dimethoxy-4-hydroxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonic acid diethyl ester;
2- (4-hydroxy-3-methoxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonic acid diethyl ester;
diethyl 2- (4-hydroxy-3-methoxyphenyl) -2- (4-methylpiperazinyl) methylphosphonate.
6. The use according to any one of claims 1 to 3, wherein the compound is diethyl 2- (4-hydroxy-3-methoxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonate hydrochloride.
7. The use of claim 6, wherein the use is in the preparation of a medicament for preventing or treating atherosclerosis, hyperlipidemia, coronary heart disease, and stroke.
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US3925245A (en) * 1971-06-26 1975-12-09 Ciba Geigy Corp Corrosion inhibiting composition containing an aminoalkyl-phosphonic acid and an inorganic nitrite
US3954761A (en) * 1968-10-17 1976-05-04 Petrolite Corporation Piperazine phosphonic acids

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US3954761A (en) * 1968-10-17 1976-05-04 Petrolite Corporation Piperazine phosphonic acids
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