CN1415619A - Compound for adjusting functional activity of vascular endothelial cell, its preparation method as well as usage - Google Patents

Compound for adjusting functional activity of vascular endothelial cell, its preparation method as well as usage Download PDF

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CN1415619A
CN1415619A CN 01137268 CN01137268A CN1415619A CN 1415619 A CN1415619 A CN 1415619A CN 01137268 CN01137268 CN 01137268 CN 01137268 A CN01137268 A CN 01137268A CN 1415619 A CN1415619 A CN 1415619A
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hydrocarbyl
phosphono
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CN100500679C (en
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杨日芳
汪海
赵如胜
慕邵峰
恽榴红
张雁芳
赵利枝
陈冬梅
费改顺
陈凯
龙超良
山丽梅
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

A compound for regulating the function and activity of vascular endothelial cells, its isomer, racemate or optical isomer, medical salt and solvated substance, its preparing process, and its application in preparing the medicines for preventing and treating the cardiovascular diseases, such as hypertension, diabetes, etc are disclosed.

Description

Compound with function activity of regulating vascular endothelial cells and preparation method and application thereof
The present invention relates to substituted alpha-amino nitrile, alpha-amino carboxylic acid and alpha-amino phosphonic acid with the function regulating activity of vascular endothelial cell, their derivative, their stereo isomer, medicinal salt and solvate, their preparation process, and their application in preventing and treating vascular endothelial cell dysfunction related cardiac vascular diseases, such as hypertension, congestive heart failure, venous intima inflammation, microcirculation disturbance, etc. and diabetes, senility and ischemia, etc. or as tool medicine for researching vascular endothelial cell function or its dysfunction related cardiac vascular diseases, and the medicine composition containing these compounds.
Cardiovascular diseases are serious diseases that seriously endanger human health and are an important cause of death and disability in the population worldwide. Vascular endothelial cells are one of the largest, secretory organs in the body. It can secrete and metabolize various vasoactive substances, and has irreplaceable effects in regulating vascular tension, maintaining blood balance and the like. The presence of acetylcholine (ACh) activated protein (EPA) on vascular endothelial cells. Vascular endothelial cell dysfunction characterized by EPA-mediated reduction in endothelial-dependent vasodilatory reactivity is present in disease states such as hypertension, coronary heart disease, congestive heart failure, aging, ischemia, and chronic smoking. The development of the protective medicine of the vascular endothelial cells to maintain the normal physiological function and correct abnormal pathological changes provides a new prevention and treatment measure for the cardiovascular and cerebrovascular diseases.
EPA is a new potential drug action target, and the physiological action of EPA is to adjust blood tension and maintain blood balance under the action of endogenous and endothelial cell autocrine ACh. In diseases caused by endothelial cell dysfunction, EPA is the earliest changing indicator and has important pathophysiological effects.
EPA reports have been studied as a new subtype of muscarinic (M) receptors, and research tools have been limited to classical M receptor agonists and antagonists. EPA is used as a new potential drug action target, and no research report is found in the pharmaceutical chemistry.
At present, no drug reports which specifically acts on vascular endothelial cells exist, but some statins, fibrates and other hypolipidemic drugs and glitazones hypoglycemic drugs have the effect of regulating the endothelial cell function.
The application of the compound of the general formula I and the derivative thereof in the aspects of regulating the function of endothelial cells, preventing or treating cardiovascular diseases such as hypertension, congestive heart failure and the like is not reported.
The invention aims to find and develop a novel medicine which has the function of regulating endothelial cells and can prevent or treat cardiovascular diseases related to dysfunction of vascular endothelial cells, in particular to prevent or treat cardiovascular diseases such as hypertension, congestive heart failure, endophlebitis, microcirculatory disturbance and the like, diabetes, aging, ischemia and the like.
The present inventors have extensively studied and found that a compound represented by formula I or formula Ia having an excellent effect of regulating the function of vascular endothelial cells can be used for preventing or treating cardiovascular diseases associated with dysfunction of vascular endothelial cells, such as hypertension, congestive heart failure, endophlebitis, microcirculatory disturbance, etc., and diseases such as diabetes, aging, ischemia, etc. The research shows that the compound shown in the formula I or the formula Ia has the function of regulating the function of vascular endothelial cells. Further synthesis and research show that the derivative provided by the invention and a proper inorganic acid or organic acid or a medicinal salt formed by the derivative and an inorganic base or an organic base also have the function of regulating the function of vascular endothelial cells. The present invention has been completed based on the above finding.
The invention relates to the 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 diseases related to vascular endothelial cell dysfunction, such as hypertension, congestive heart failure, endophlebitis, microcirculation disturbance and the like, diabetes, aging, ischemia and other diseases or as a tool medicament for researching vascular endothelial cell function or cardiovascular and cerebrovascular diseases related to vascular endothelial cell dysfunction,
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, C4-10Aryloxycarbonyl, 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-C1-6An alkyl group, an amino group,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 related to the dysfunction of vascular endothelial cells, such as hypertension, congestive heart failure, endometritis, microcirculation disturbance and the like, and diseases such as diabetes, aging, ischemia and the likeaThe new compound, the derivative, the isomer, the racemate or the optical isomer, the medicinal salt or the solvate thereof,
Figure A0113726800181
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-hydroxyRadical 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 acidBase, 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 groupsBase, (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 yet another aspect, the invention relates to methods for preventing or treating disorders associated with vascular endothelial cell dysfunction, such as hypertension, congestive heart failure, endophlebitis, microcirculatory disturbance, and the likeCardiovascular diseases, diabetes, aging, ischemia, and other diseases, its derivatives, isomers, racemates or optical isomers, pharmaceutical salts or solvates thereof,
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-C4-14Aromatic 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, C4-10Aryloxycarbonyl, substituted C4-10Aryloxycarbonyl, carbamoyl, C1-10Alkylamino carbonyl, C3-10Heterocyclic aminocarbonyl, substituted C3-10Heterocyclic aminocarbonyl group, C4-10Arylaminocarbonyl groups,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)6-10Arylamine group) (substituted C)3-10Heterocyclyloxy) 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 the prevention or treatment of cardiovascular diseases associated with dysfunction of vascular endothelial cells, in particular the prevention or treatment of cardiovascular diseases such as hypertension, congestive heart failure, endophlebitis, microcirculatory disturbance, and diabetes, aging, ischemiaA method for treating cardiovascular and cerebrovascular diseases with vascular endothelial cell dysfunction, such as hypertension, heart failure and the like, which comprises administering a prophylactically or therapeutically effective amount of formula I or formula IaA 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 A0113726800231
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 A0113726800241
or
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 A0113726800243
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.
According to the present invention, the term "diseases associated with dysfunction of vascular endothelial cells" used in the present invention refers to cardiovascular diseases associated with dysfunction of vascular endothelial cells, such as hypertension, congestive heart failure, endophlebitis, microcirculation disturbance, etc., and diseases of diabetes, ischemia and aging, etc.
According to the invention, compounds of the general formula I R1Or R2Preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 2-hydroxy respectivelyMethylethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2-propoxyethyl group, 2-isopropoxyethyl group, 2-butoxyethyl group, 2-isobutoxyethyl group, 2-tert-butoxyethyl group, 2-aminoethyl group, 2-methylaminoethyl group, 2-ethylaminoethyl group, 2-propylaminoethyl group, 2-isopropylaminoethyl group, 2-butylaminoethyl group, 2-isobutylaminoethyl group, 2-tert-butylaminoethyl group, 2- (dimethylamino) ethyl group, 2- (diethylamino) ethyl group, 2- (dipropylamino) ethyl group, 2- (dibutylamino) ethyl group, 2- (diisobutylamino) ethyl group, 2- (di-tert-butylamino) ethyl group, 2-morpholinoethyl group, 2-piperidinylethyl, 2-piperazinylethyl, 2- (4-methylpiperazinyl) 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, 3- (dibutylamino) propyl, 3- (dipropylamino) propyl, 3- (diisobutylamino) propyl group, 3- (di-tert-butylamino) propyl group, 3-morpholinopropyl group, 3-piperidinopropyl group, 3-piperazinopropyl group, 3- (4-methylpiperazino) propyl group; 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 two preferred embodiments of the invention, R is1R2N is 4- (2-pyridyl) piperazinyl, R3Is 3, 5-dimethoxy-4-hydroxyphenyl or 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 medicine for preventing or treating cardiovascular diseases related to the dysfunction of vascular endothelial cells, such as hypertension, congestive heart failure, phlebitis and the like, diabetes, aging, ischemia and the like, or used as a tool medicine for researching the diseases related to the function of the vascular endothelial cells or the dysfunction of the vascular endothelial cellsaThe new compound, the derivative, the isomer, the racemate or the optical isomer, the medicinal salt or the solvate thereof,
Figure A0113726800271
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 radicalBeta-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, C1-6Aryl radical, C1-6Alkoxy radical, C1-6Alkylthio, mono-, di-or trihaloGeneration 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 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.
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;
1- (cyanomethyl) -4-methylpiperazine;
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 an organic acid salt such as acetate, oxalate, citrate, gluconate, succinate, tartrate, p-toluenesulfonate, methanesulfonate, benzoate, lactate, maleate, nicotinate, cinnamate or 3-hydroxy-3-methylglutarate. 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-C4-14Aromatic 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 3-9-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 ringAn quinoline 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 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, C4-1Arylaminophosphonyl 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 the formula I and substituents thereof are the compound number R1R2N R3Y formula 1
Figure A0113726800301
PO(OEt)2 C22H32N3O6P2
Figure A0113726800302
PO(OEt)2 C21H30N3O5P3
Figure A0113726800303
PO(OEt)2 C20H28Cl2N3O4P4
Figure A0113726800311
PO(OEt)2 C20H28Br2N3O4P5 PO(OEt)2 C20H30N3O4P6
Figure A0113726800313
PO(OEt)2 C20H29N4O6P7 PO(OEt)2 C21H31N4O7P8
Figure A0113726800315
PO(OEt)2 C20H30N3O5P9 PO(OEt)2 C20H30N3O5P10 PO(OEt)2 C16H29N2O4P11 PO(OEt)2 C18H33N2O6P12 PO(OEt)2 C17H31N2O5P13
Figure A01137268003110
PO(OEt)2 C16H28N3O6P14 PO(OEt)2 C16H30N3O7P15
Figure A01137268003112
PO(OEt)2 C16H29N2O5P16
Figure A01137268003113
PO(OEt)2 C16H29N2O5P17 PO(OEt)2 C15H26NO5P18 PO(OEt)2 C17H30NO7P19 PO(OEt)2 C16H28NO6P20
Figure A01137268003117
PO(OEt)2 C15H25N2O7P21
Figure A01137268003118
PO(OEt)2 C15H27N3O8P22
Figure A01137268003119
PO(OEt)2 C15H26NO6P23 PO(OEt)2 C15H26NO6P24
Figure A0113726800321
PO(OEt)2 C21H31N4O6P25
Figure A0113726800322
PO(OEt)2 C20H29N4O5P26 PO(OEt)2 C19H27Cl2N4O4P27 PO(OEt)2 C19H27Br2N4O4P28 PO(OEt)2 C19H29N4O4P29 PO(OEt)2 C19H28N5O6P30
Figure A0113726800327
PO(OEt)2 C20H30N5O7P31
Figure A0113726800328
PO(OEt)2 C19H29N4O5P32 PO(OEt)2 C19H29N4O5P33 PO(OEt)2 C22H34N3O6P34 PO(OEt)2 C22H32N3O5P35
Figure A01137268003212
PO(OEt)2 C20H30Cl2N3O4P36
Figure A01137268003213
PO(OEt)2 C20H30Br2N3O4P37 PO(OEt)2 C20H32N3O4P38
Figure A01137268003215
PO(OEt)2 C20H31N4O6P39 PO(OEt)2 C21H33N4O7P40
Figure A01137268003217
PO(OEt)2 C20H32N3O5P41 PO(OEt)2 C20H32N3O5P42
Figure A01137268003219
PO(OEt)2 C27H44N4O6P43 PO(OEt)2 C27H42N4O5P44 PO(OEt)2 C25H40Cl2N4O4P45 PO(OEt)2 C25H40Br2N4O4P46
Figure A0113726800333
PO(OEt)2 C25H42N4O4P47
Figure A0113726800334
PO(OEt)2 C25H41N5O6P48
Figure A0113726800335
PO(OEt)2 C26H43N5O7P49
Figure A0113726800336
PO(OEt)2 C25H42N4O5P50
Figure A0113726800337
PO(OEt)2 C25H42N4O5P51 PO(OEt)2 C23H32FN2O6P52
Figure A0113726800339
PO(OEt)2 C22H30FN2O5P53 PO(OEt)2 C21H28Cl2FN2O4P54 PO(OEt)2 C21H28Br2FN2O4P55
Figure A01137268003312
PO(OEt)2 C21H30FN2O4P56
Figure A01137268003313
PO(OEt)2 C21H29FN3O6P57
Figure A01137268003314
PO(OEt)2 C22H31N3O7P58
Figure A01137268003315
PO(OEt)2 C21H30FN2O5P59 PO(OEt)2 C21H30FN2O5P60
Figure A01137268003317
PO(OEt)2 C23H32FN2O6P61
Figure A01137268003318
PO(OEt)2 C22H30FN2O5P62
Figure A01137268003319
PO(OEt)2 C21H28Cl2FN2O4P63
Figure A0113726800341
PO(OEt)2 C21H28Br2FN2O4P64 PO(OEt)2 C21H30FN2O4P65
Figure A0113726800343
PO(OEt)2 C21H29FN3O6P66
Figure A0113726800344
PO(OEt)2 C22H31N3O7P67
Figure A0113726800345
PO(OEt)2 C21H30FN2O5P68 PO(OEt)2 C21H30FN2O5P69
Figure A0113726800347
PO(OEt)2 C23H31Cl2N2O6P70
Figure A0113726800348
PO(OEt)2 C22H29Cl2N2O5P71
Figure A0113726800349
PO(OEt)2 C21H27Cl4N2O4P72
Figure A01137268003410
PO(OEt)2 C21H27Br2Cl2N2O4
P73
Figure A01137268003411
PO(OEt)2 C21H29Cl2N2O4P74 PO(OEt)2 C21H28Cl2N3O6P75 PO(OEt)2 C22H30Cl2N3O7P76
Figure A01137268003414
PO(OEt)2 C21H29Cl2N2O5P77
Figure A01137268003415
PO(OEt)2 C21H29Cl2N2O5P78
Figure A01137268003416
PO(OEt)2 C24H34ClN2O6P79 PO(OEt)2 C23H32ClN2O5P80
Figure A01137268003418
PO(OEt)2 C22H30Cl3N2O4P81
Figure A01137268003419
PO(OEt)2 C22H30Br2ClN2O4P82 PO(OEt)2 C22H32ClN2O4P83 PO(OEt)2 C22H31ClN3O6P84
Figure A0113726800352
PO(OEt)2 C23H33ClN3O7P85
Figure A0113726800353
PO(OEt)2 C22H32ClN2O5P86 PO(OEt)2 C22H31N2O7P87 PO(OEt)2 C24H33N2O8P88 PO(OEt)2 C23H31N2O7P89
Figure A0113726800357
PO(OEt)2 C22H29Cl2N2O6P90 PO(OEt)2 C22H29Br2N2O6P91
Figure A0113726800359
PO(OEt)2 C22H31N2O6P92 PO(OEt)2 C22H30N3O8P93
Figure A01137268003511
PO(OEt)2 C23H32N3O9P94
Figure A01137268003512
PO(OEt)2 C22H31N2O7P95
Figure A01137268003513
PO(OEt)2 C22H31N2O7P96 PO(OEt)2 C24H44N3O7P97
Figure A01137268003515
PO(OEt)2 C23H42N3O6P98 PO(OEt)2 C22H40Cl2N3O5P99 PO(OEt)2 C22H40Br2N3O5P100
Figure A01137268003518
PO(OEt)2 C22H42N3O5P101 PO(OEt)2 C22H41N4O7P102
Figure A01137268003520
PO(OEt)2 C23H43N4O8P103 PO(OEt)2 C22H42N3O6P104
Figure A0113726800362
PO(OEt)2 C22H42N3O6P105
Figure A0113726800363
PO(OEt)2 C22H34N5O8P106 PO(OEt)2 C21H32N5O7P107
Figure A0113726800365
PO(OEt)2 C20H30Cl2N5O6P108 PO(OEt)2 C20H30Br2N5O6P109
Figure A0113726800367
PO(OEt)2 C20H32N5O6P110
Figure A0113726800368
PO(OEt)2 C20H31N6O8P112
Figure A0113726800369
PO(OEt)2 C21H33N6O9P113 PO(OEt)2 C20H32N5O7P114 PO(OEt)2 C20H32N5O7P115 PO(OEt)2 C30H37F2N2O6P116 PO(OEt)2 C29H35F2N2O5P117
Figure A01137268003614
PO(OEt)2 C28H33Cl2F2N2O4P118
Figure A01137268003615
PO(OEt)2 C28H33Br2F2N2O4P119
Figure A01137268003616
PO(OEt)2 C28H35F2N2O4P120 PO(OEt)2 C28H34F2N3O6P121
Figure A0113726800371
PO(OEt)2 C29H36F2N3O7P122 PO(OEt)2 C28H35F2N2O5P123 PO(OEt)2 C28H35F2N2O5P124 PO(OEt)2 C21H31N4O6P125
Figure A0113726800375
PO(OEt)2 C21H29N4O5P126 PO(OEt)2 C19H27Cl2N4O4P127
Figure A0113726800377
PO(OEt)2 C19H27Br2N4O4P128
Figure A0113726800378
PO(OEt)2 C19H29N4O4P129 PO(OEt)2 C19H28N5O6P130 PO(OEt)2 C20H30N5O7P131
Figure A01137268003711
PO(OEt)2 C19H29N4O5P132
Figure A01137268003712
PO(OEt)2 C-19H29N4O5P when Y is cyano, preferred compounds of formula I and substituents thereof are shown in Table 1.
Table 2Y ═ CN, preferred compounds of formula I and their substituents compound No. R1R2N R3Y molecular formula 133 H CN C6H10N2O134 H CN C7H13N3135
Figure A01137268003715
CN C15H20N2O4136 CN C13H14N2O3137 CN C10H12N2O2128
Figure A01137268003718
CN C10H12N2OS139 CN C12H13ClN2O140
Figure A0113726800382
CN C12H13FN2O141
Figure A0113726800383
CN C12H13FN2O142
Figure A0113726800384
CN C12H13FN2O143
Figure A0113726800385
CN C12H12ClFN2O144 CN C12H12ClFN2O145 CN C13H16N2O146
Figure A0113726800388
CN C13H16N2O147 CN C13H16N2O148 CN C16H23N3O3149 CN C15H20N4O4150
Figure A01137268003812
CN C14H17N3O2151 CN C14H16ClN3O2152
Figure A01137268003814
CN C11H15N3O153
Figure A01137268003815
CN C11H15N3S154
Figure A01137268003816
CN C13H16ClN3155 CN C13H16FN3156 CN C13H16FN3157
Figure A01137268003819
CN C13H16FN3158
Figure A01137268003820
CN C13H15ClFN3159 CN C13H15ClFN3160 CN C13H19N3161 CN C13H19N3162
Figure A01137268003824
CN C13H19N3163 CN C16H14N2O2164 CN C13H12N2O165
Figure A01137268003827
CN C17H17N3O166 CN C17H19ClN4167
Figure A0113726800391
CN C19H24N4O3168 CN C19H24N4O3169 CN C18H22N4O3170 CN C17H20N4O2171
Figure A0113726800395
CN C16H17FN4172
Figure A0113726800396
CN C17H20N4173 CN C17H20N4174
Figure A0113726800398
CN C17H20N4175
Figure A0113726800399
CN C13H20ClN3176 CN C16H27N3O3177
Figure A01137268003911
CN C16H27N3O3178 CN C13H20FN3179 CN C14H23N3180
Figure A01137268003914
CN C14H23N3181
Figure A01137268003915
CN C14H23N3182 CN C19H21N3183
Figure A01137268003917
CN C9H12N2184 CN C15H14N2O
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 ═ in formula ICONH2Compound number R1R2N R3Y molecular formula 185 H CONH2 C6H12N2O2186 H CONH2 C7H15N3O187 CONH2 C15H22N2O5188
Figure A0113726800403
CONH2 C13H16N2O4189 CONH2 C10H14N2O3190
Figure A0113726800405
CONH2 C10H14N2O2S191 CONH2 C12H15ClN2O2192 CONH2 C12H15FN2O2193
Figure A0113726800408
CONH2 C12H15FN2O2194
Figure A0113726800409
CONH2 C12H15FN2O2195 CONH2 C12H14ClFN2O2196
Figure A01137268004011
CONH2 C12H14ClFN2O2197
Figure A01137268004012
CONH2 C13H18N2O2198 CONH2 C13H18N2O2199 CONH2 C13H18N2O2200 CONH2 C16H25N3O4201
Figure A01137268004016
CONH2 C15H22N4O5202 CONH2 C14H19N3O3203
Figure A01137268004018
CONH2 C14H18ClN3O3204 CONH2 C11H17N3O2205
Figure A01137268004020
CONH2 C11H17N3OS206
Figure A01137268004021
CONH2 C13H18ClN3O207 CONH2 C13H18FN3O208 CONH2 C13H18FN3O209
Figure A01137268004024
CONH2 C13H18FN3O210
Figure A01137268004025
CONH2 C13H17ClFN3O211 CONH2 C13H17ClFN3O212
Figure A01137268004027
CONH2 C13H21N3O213 CONH2 C13H21N3O214
Figure A0113726800411
CONH2 C13H21N3O215
Figure A0113726800412
CONH2 C16H18N2O3216
Figure A0113726800413
CONH2 C13H14N2O2217 CONH2 C17H19N3O2218
Figure A0113726800415
CONH2 C17H21ClN4O219
Figure A0113726800416
CONH2 C19H26N4O4220
Figure A0113726800417
CONH2 C19H26N4O4221
Figure A0113726800418
CONH2 C18H24N4O4222
Figure A0113726800419
CONH2 C17H22N4O3223 CONH2 C16H19FN4O224
Figure A01137268004111
CONH2 C17H22N4O225 CONH2 C17H22N4O226 CONH2 C17H22N4O227 CONH2 C13H22ClN3O228
Figure A01137268004115
CONH2 C16H29N3O4229
Figure A01137268004116
CONH2 C16H29N3O4230
Figure A01137268004117
CONH2 C13H22FN3O231
Figure A01137268004118
CONH2 C14H25N3O232
Figure A01137268004119
CONH2 C14H25N3O233 CONH2 C14H25N3O234
Figure A01137268004121
CONH2 C18H26ClN3O235
Figure A01137268004122
CONH2 C18H26ClN3O236 CONH2 C18H26ClN3O237
Figure A0113726800421
CONH2 C18H26FN3O238 CONH2 C18H26FN3O239 CONH2 C18H26FN3O240 CONH2 C19H29N3O241
Figure A0113726800425
CONH2 C19H29N3O242
Figure A0113726800426
CONH2 C19H29N3O243 CONH2 C19H29N3O2244
Figure A0113726800428
CONH2 C19H29N3O2245 CONH2 C19H29N3O2246 CONH2 C18H25ClFN3O247
Figure A01137268004211
CONH2 C18H25ClFN3O248 CONH2 C24H30F2N3O249
Figure A01137268004213
CONH2 C19H23N3O250 CONH2 C9H14N2O251 CONH2 C15H16N2O2When 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 Compound number R1R2N R3Y formula 252
Figure A0113726800432
H CO2H C6H11NO3253 H CO2H C7H14N2O2254
Figure A0113726800434
CO2H C15H21NO6255 CO2H C13H15NO5256 CO2H C10H13NO4257 CO2H C10H13NO3S258
Figure A0113726800438
CO2H C12H14ClNO3259
Figure A0113726800439
CO2H C12H14FNO3260
Figure A01137268004310
CO2H C12H14FNO3261
Figure A01137268004311
CO2H C12H14FNO3262
Figure A01137268004312
CO2H C12H13ClFNO3263
Figure A01137268004313
CO2H C12H13ClFNO3264 CO2H C13H17NO3265
Figure A01137268004315
CO2H C13H17NO3266 CO2H C13H17NO3267
Figure A01137268004317
CO2H C16H24N2O5268 CO2H C15H21N3O6269 CO2H C14H18N2O4270 CO2H C14H17ClN2O4271
Figure A01137268004321
CO2H C11H16N2O3272
Figure A01137268004322
CO2H C11H16N2O2S273 CO2H C13H17ClN2O2274
Figure A0113726800441
CO2H C13H17FN2O2275
Figure A0113726800442
CO2H C13H17FN2O2276
Figure A0113726800443
CO2H C13H17FN2O2277
Figure A0113726800444
CO2H C13H16ClFN2O2278
Figure A0113726800445
CO2H C13H16ClFN2O2279
Figure A0113726800446
CO2H C13H20N2O2280
Figure A0113726800447
CO2H C13H20N2O2281
Figure A0113726800448
CO2H C13H20N2O2282
Figure A0113726800449
CO2H C16H17NO4283 CO2H C13H13NO3284
Figure A01137268004411
CO2H C17H18N2O3285 CO2H C17H20ClN3O2286
Figure A01137268004413
CO2H C19H25N3O5287 CO2H C19H25N3O5288
Figure A01137268004415
CO2H C18H23N3O5289 CO2H C17H21N3O4290 CO2H C16H18FN5O2291 CO2H C17H21N3O2292 CO2H C17H21N3O2293
Figure A01137268004420
CO2H C17H21N3O2294 CO2H C13H21ClN2O2295 CO2H C16H28N2O5296
Figure A01137268004423
CO2H C16H28N2O5297 CO2H C13H21FN2O2298
Figure A01137268004425
CO2H C14H24N2O2299 CO2H C14H24N2O2300
Figure A0113726800451
CO2H C14H24N2O2301 CO2H C18H25ClN2O2302 CO2H C18H25ClN2O2303
Figure A0113726800454
CO2H C18H25ClN2O2304 CO2H C18H25FN2O2305 CO2H C18H25FN2O2306 CO2H C18H25FN2O2307
Figure A0113726800458
CO2H C19H28N2O2308 CO2H C19H28N2O2309
Figure A01137268004510
CO2H C19H28N2O2310 CO2H C19H28N2O3311 CO2H C19H28N2O3312
Figure A01137268004513
CO2H C19H28N2O3313
Figure A01137268004514
CO2H C18H24ClFN2O2314 CO2H C18H24ClFN2O2315
Figure A0113726800461
CO2H C24H29F2N2O2316
Figure A0113726800462
CO2H C19H22N2O2317 CO2H C9H13NO2318 CO2H C15H15NO3When 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 Compound number R1R2N R3Y formula 319 H CO2Me C7H13NO3320
Figure A0113726800466
H CO2Me C8H16N2O2321 CO2Me C16H23NO6322 CO2Me C14H17NO5323
Figure A0113726800469
CO2Me C11H15NO4324 CO2Me C11H15NO3S325 CO2Me C13H16ClNO3326
Figure A01137268004612
CO2Me C13H16FNO3327 CO2Me C13H16FNO3328
Figure A01137268004614
CO2Me C13H16FNO3329
Figure A01137268004615
CO2Me C13H15ClFNO3330 CO2Me C13H15ClFNO3331
Figure A01137268004617
CO2Me C14H19NO3332 CO2Me C14H19NO3333 CO2Me C14H19NO3334 CO2Me C17H26N2O5335 CO2Me C16H23N3O6336
Figure A0113726800472
CO2Me C15H20N2O4337 CO2Me C15H19ClN2O4338 CO2Me C12H18N2O3339
Figure A0113726800475
CO2Me C12H18N2O2S340 CO2Me C14H19ClN2O2341 CO2Me C14H19FN2O2342
Figure A0113726800478
CO2Me C14H19FN2O2343 CO2Me C14H19FN2O2344
Figure A01137268004710
CO2Me C14H18ClFN2O2345 CO2Me C14H18ClFN2O2346
Figure A01137268004712
CO2Me C14H22N2O2347 CO2Me C14H22N2O2348
Figure A01137268004714
CO2Me C14H22N2O2349
Figure A01137268004715
CO2Me C17H19NO4350
Figure A01137268004716
CO2Me C14H15NO3351 CO2Me C18H20N2O3352 CO2Me C19H22ClN3O2353
Figure A01137268004719
CO2Me C20H27N3O5354
Figure A01137268004720
CO2Me C20H27N3O5355
Figure A01137268004721
CO2Me C19H25N3O5356 CO2Me C18H23N3O4357
Figure A01137268004723
CO2Me C17H20FN5O2358
Figure A01137268004724
CO2Me C18H23N3O2359
Figure A01137268004725
CO2Me C18H23N3O2360
Figure A01137268004726
CO2Me C18H23N3O2361
Figure A01137268004727
CO2Me C14H23ClN2O2362 CO2Me C17H30N2O5363
Figure A0113726800482
CO2Me C17H30N2O5364
Figure A0113726800483
CO2Me C14H23FN2O2365 CO2Me C15H26N2O2366
Figure A0113726800485
CO2Me C15H26N2O2367 CO2Me C15H26N2O2368 CO2Me C19H27ClN2O2369
Figure A0113726800488
CO2Me C19H27ClN2O2370
Figure A0113726800489
CO2Me C19H27ClN2O2371
Figure A01137268004810
CO2Me C19H27FN2O2372 CO2Me C19H27FN2O2373
Figure A01137268004812
CO2Me C19H27FN2O2374 CO2Me C20H30N2O2375 CO2Me C20H30N2O2376 CO2Me C20H30N2O2377 CO2Me C20H30N2O3378
Figure A01137268004817
CO2Me C20H30N2O3379
Figure A0113726800491
CO2Me C20H30N2O3380 CO2Me C19H26ClFN2O2381
Figure A0113726800493
CO2Me C19H26ClFN2O2382
Figure A0113726800494
CO2Me C25H31F2N2O2383 CO2Me C20H24N2O2384 CO2Me C10H15NO2385
Figure A0113726800497
CO2Me C16H17NO3
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 OrgChem, 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 present invention, the compounds of formula I or Ia and stereoisomers thereof can modulate the function of vascular endothelial cells, induce vasodilatory responses, and show excellent effects in preventing or treating diseases associated with endothelial cell dysfunction, such as cardiovascular diseases, e.g., hypertension, congestive heart failure, endophlebitis, microcirculatory disturbance, etc., and diseases such as diabetes, aging, ischemia, etc. Therefore, the compound can be used as a medicament for preventing or treating diseases related to endothelial cell dysfunction, such as cardiovascular diseases including hypertension, congestive heart failure, endophlebitis, microcirculation disturbance and the like, and diseases including diabetes, aging, ischemia and the like, and the medicaments can be used for animals, preferably mammals, particularly human beings.
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. MedicineThe 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 such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; 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 unit into a pill, it can be used broadlyVarious carriers are used as is well known in the art. 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, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added.
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, weight and individual response of the patient or animal, the particular compound used, the route of administrationDiameter and number of administrations. 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 elution is carried out by chloroform-ethanol (4: 1), 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(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 is 135-136 ℃,1H-NMR(D2O，ppm)1.00-1.20(m，6H)，3.40-3.50(m，4H)，3.65-4.05(m，16H)，4.385 5.007(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, replacing 3, 5-dimethoxy-4-hydroxybenzaldehyde with vanillin and recrystallized from isopropanol-cyclohexane to give white granular crystals with a yield of 64.9% and mp130-132 ℃. 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)，3.940 3.978(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)，6.757 6.770(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: mp208-209 ℃,1H-NMR(D2O，ppm)1.00-1.25(m，6H)，3.38-3.50(m，4H)，3.65-4.05(m，13H)，4.405 5.004(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)，3.745 3.801(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)，6.830 6.849(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 4, substituting morpholine by N-methylpiperazine, 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 preparation of (3, 4-methylenedioxyphenyl) -2- (4-methylpiperazinyl) acetonitrile-Compound 150
Weighing 1.10g (0.0224mol) sodium cyanide, 2.21g (0.0213mol) sodium bisulfite and 3.10g (0.0206mol) piperonal, adding 20ml water, shaking, adding 2.10g (0.0210mol) N-methylpiperazine and 10ml ethanol, reacting at about 50 ℃ under stirring for 40 hours, cooling, adding water, extracting with diethyl ether for 3 times, drying with anhydrous magnesium sulfate, recovering solvent, and extracting with diethyl ether-petroleumEther crystallization gave 3.50g (65.8%) of white crystals, 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)，6.793 6.814(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-Et2Salifying O to obtain 2- (2-furyl) -2- (4-methylpiperazinyl) acetonitrile hydrochloride 2.05g (84.7%) and mp174-175 deg.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；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)，6.604 6.611(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-Et2Salifying O to obtain white solid, and carrying out mp181-184 ℃.
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 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, mp87-89 ℃.
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%), mp90-92 ℃. The following biological activity experiments are used to further illustrate the present invention.
Biological Effect experiment 1 Effect of representative Compounds of formula I of the invention on Ex vivo rat aortic ring endothelium dependent vasodilatory reactivity (EPA agonist Activity) and on Guinea pig ileum contractile response (M)3Agonistic activity)
TABLE 1 EPA agonistic activity of representative compounds of formula I of the invention with M3Agonistic activity
Compound No. EPA agonist activity M3Agonistic activity
1 +++ -
2 +++ -
3 +++ -
133 ++ -
134 ++ -
135 +++ -
136 ++ -
137 ++ -
148 +++ -
149 +++ -
150 ++ -
184 - -
250 + -
385 + -: "-" represents significant activity, "+" represents maximum relaxation rate < 20%, "+" represents maximum relaxation rate of 20-50%, "+ + + +" represents maximum relaxation rate > 50%. TABLE 2 reaction of the compounds of the invention of the formula I with isolated rat aortic ring vasodilation
Post-endothelialization 184.0 ± 25.3(14) 5.7 ± 5.8 × 8 (281.4 ± 19.3(12) 13.9 ± 6.7 × 7(7) 385.0 ± 18.4(9) 20.1 ± 10.4(3) 14860.4 ± 19.7(7) 6.9 ± 3.3 (3) 14971.7 ± 25.5(5) 3.7 ± 1.1(3) 15558.3 ± 26.2(5) 6.2 ± 4.0 (3) notes of maximal vasodilation (%) of the ringing endothelial-dependent compound when endothelium is intact: x + -SD, n is 3-14, P is less than 0.05, P is less than 0.01.
The above experimental results show that the inventionThe compounds of formula I are selective in activating EPA, but not M3The receptor had no significant effect; its vasodilatory effect is endothelium dependent.
One of the research methods of the biological effect experiment 1 is that Wistar rats are used for male and female parents and the body weight is 200-; the male and female guinea pigs are used as well as the male and female guinea pigs, and the weight of 300 +/-50 g guinea pigs is provided by the experimental animal center of military medical academy of sciences. The Wistar rat is killed by cutting off the head, the chest is opened rapidly, the thoracic and abdominal part of the aorta is taken out and placed in the Krebs-Ringer nutrient solution (NaCl 118, KCl 4.7, CaCl)2 11.0、KH2PO4 1.2、NaHCO325.0, 11.1 portions of glucose and EDTACA-Na2 0.026mmol.L-1PH7.4), cutting into artery rings with fixed length of 3-5mm, placing in a constant temperature bath at 37 deg.C containing 10ml of Krebs-Ringer nutrient solution, fixing the lower end, connecting the upper end to an automatic balance recorder via a tension transducer, recording tension change of the blood vessel rings, and continuously introducing 95% O2And 5% CO2The mixed gas of (1). The arterial ring preload was 1.5g, and after equilibration for 60min, the following experiment was carried out at 0.62. mu. mol.L-1NE pre-contracted blood vessels, after re-equilibration for 40min, at 0.62. mu. mol.L-1NE constricts blood vessels to the maximum extent of constriction and reaches the plateau value, 10 is added after stabilization-5mol.L-1The compounds were evaluated and the effect of the new structural compounds on vascular tone was observed. The ratio of the amplitude of the compound-induced vasodilation or contraction to the amplitude of the NE-induced maximum contraction is the rate of vasodilation or contraction of the blood vessel, with the NE-induced maximum contraction amplitude being 100%.
After gently scraping the endothelium with a cotton swab, at 0.62. mu. mol.L-1NE contracts blood vessels, after reaching the maximum contraction amplitude, 10 is added-6mol.L-1ACh, observing whether there is vasomotor reaction to determine whether the endothelium is completely removed, washing the specimen, balancing for 40min, and adding 0.62 μmol-1NE contracts blood vessels, after reaching the maximum contraction amplitude, 10 is added-5mol.L-1The compound is evaluated and screened, the change of the vascular tension is observed, and whether the vasodilatation effect is endothelium-dependent relaxation effect or not is preliminarily judged.
The experimental methods are detailed in the references: feletou M, Vanhoutte PM, endo-dependent hyperpolarization of cane sugar methyl music, Br J Pharmacol, 1988; 93: 515-524.
Second method of biological Effect experiment 1, guinea pig fasted 24 hours before the experiment, stunned, rapidly taken out the ileum 10-20cm from the cecum, cut into 1.5cm intestine, washed with Taiwan liquid, and placed in mixed O2And (4) saturated Taiwang liquid for standby. Ligating two ends of the intestinal canal with silk thread, placing in a constant temperature bath tank of 37 deg.C containing 10ml of Taiwanese liquid, and continuously introducing 95% O2And 5% CO2The mixed gas of (1). The lower end is fixed, and the upper end is connected with an automatic balance recorder through a tension transducer. The resting tension is 3.0g, the experiment is started after the specimen is stabilized for 20min and the base line is stabilized, and the ileum contraction curve is traced. At 10-6mol.L-1Arecoline is a positive control, and can cause rapid and strong contraction reaction lasting for more than 30 min. Test Compound concentration of 10-5mol.L-1Experimental data are expressed as the shrinkage of the ileum. The experimental methods are detailed in the references: bekemeier H, Hirschemmann R, Giessler AJ. Carrageenin-induced chromatography in rates and mice: a model for testing antithrombogicsubsistence Agents and Actions, 1985; 16(5): 446-451.
Biological effects experiment 2 effect of active candidate compounds on nitric oxide and prostacyclin production on isolated rat aortic rings. TABLE 3 antagonism of the vasodilatory Effect of Indometacin and L-NAME on Compound 1 and Compound 2
Maximum vasodilation (%) of anti-effect compound the control indomethacin group L-NAME group 184.0 ± 25.3(14) 14.2 ± 6.8 × (3) 26.2 ± 28.0 × (6) 281.4 ± 19.3(12) 23.8 ± 13.3: (7) 28.8 ± 22.5: (3): x + -SD, n is 3-14, P is less than 0.05, P is less than 0.01. Experimental data are expressed as X ± SD, and significance analysis is performed using a group t-test or self-paired t-test, using the SAS D2P8 program.
The experimental results show that the vasodilatation effect of the compound 1 and the compound 2 can be antagonized by L-NAME and indometacin, and the L-NAME is an NO synthetase inhibitor, specifically inhibits the synthesis of vascular endothelial cells, releases NO and antagonizes the vasodilatation effect; indomethacin is cyclooxygenase inhibitor in arachidonic acid metabolism, and can specifically inhibit PGI2Antagonize its vasodilatory effect;
taken together, the endothelial-dependent vasodilatory responses induced by compounds 1 and 2 were via PGI2And the two pathways of NO work together,
the experimental method of biological effect 2 adopts isolated rat aortic ring experiment with the dosage of 0.62 mu mol-1NE shrinkage specimens, after maximum shrinkage balance, 10 was added-6mol.L-1Indometacin and 10-4mol.L-1After the L-NAME pre-incubation of the specimen for 5min, 0.62 mu mol-1NE shrinkage specimens, after maximum shrinkage balance, 10 was added-5mol.L-1Compounds 1 and 2, observed for changes in the diastolic rate of the specimen. Biological effects experiment 3 the effect of the novel compound 1 on blood pressure and cardiac function in rats.TABLE 4 Compound 1(10mg/kg, iv) on anesthetized normal rats blood pressure and cardiac functionInfluence of index (b) change (%) of each index at different times (minutes) after administration of the index (b) 51015304560
Front MAP 10096.6 + -6.394.4 + -5.992.7 + -7.2* 86.8±9.8** 86.1±12* 87.5±15HR 100 99.9±2.4 99.1±2.7 96.1±2.7** 94.4±3.7** 96.0±4.2* 96.2±4.8LVSP 100 102.0±7.8 100.2±5.2 100.5±7.3 98.8±6.9 102.2±7.8 100.9±10.0+dp/dtmax 100 99.3±11.9 96.2±10.9 93.5±11.9 93.5±11.9 95.0±10.4 89.0±14.5T+dp/dtmax 100 101.1±12.5 104.3±12.1 104.7±15.4 101.7±2.9 106.4±14.9 98.3±3.0+dp/dtmax/I 100 99.4±6.0 93.6±11.9 93.4±9.2 90.9±11.4 89.8±14.1 85.1±14.6PVmax 100 102.0±10.4 91.0±23.4 88.0±19.8 73.0±24.8 75.0±18.3 72.0±20.2-dp/dtmax 100 93.7±6.7 93.5±9.3 90.5±9.0 84.510.9 89.8±7.24 86.0±9.2T-dp/dtmax100100.0 + -5.1101.6 + -6.5103.5 + -5.9104.6 + -6.8103.2 + -10.2103.8 + -8.7 notes: MAP is mean arterial pressure; HR is heart rate; cardiac contractile function indicators are: LVSP is left ventricular systolic pressure, + dp/dtmaxThe maximum rate of change of the left ventricular isovolumetric pressure, + dp/dtmaxthe/IP is the left chamber pressure logarithm, T + dp/dtmaxThe time of the high-section maximum change rate of the indoor pressure, and Vmax is the myocardial fiber shortening rate; diastolic function indices are: -dp/dtmaxThe maximum rate of change of the left ventricular isovolumetric pressure, T-dp/dtmaxThe time of the maximum change rate of the indoor pressure drop section. Data are presented as X ± SD, n is 8, p < 0.05, p < 0.01, compared to pre-dose, and data are statistically tested using paired t-tests.
The experimental results show that the compound 1 has obvious influence on blood pressure and cardiac function at 0.1-1.0mg/kg, and the high dose of 10mg/kg has the functions of slightly reducing mean arterial pressure and slightly reducing heart rate; has no obvious influence on the systolic function and the diastolic function of the heart.
The experimental method of the biological effect experiment 3 is that after a Wistar rat is anesthetized by pentobarbital sodium, the ventral side of the neck is deviated to the right, the right common carotid artery is separated, the distal end is ligated, the right common carotid artery is inserted into a tube, the tube is filled with 0.03% heparin normal saline and is connected with a pressure transducer and a recorder, and the change of the pressure waveform on an oscilloscope is observed; the signal is input into SMUP-PC biological information processing system, and can automatically record each index of mean arterial pressure and cardiac function. The operation steps are detailed in the literature: Aguilar-Bryan L, Nichols CG, Wechsler SW, et al, cloning of the β cell high-affinity sulfenylurea receptor: science (Wash DC) 1995; 268; 423-6.

Claims (21)

1. General formula IaThe compound, the derivative, the isomer, the racemate or the optical isomer, the medicinal acid addition salt, the medicinal salt or the solvate thereof,
Figure A0113726800021
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)4-5Aryl) 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) phosphono group,Single 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 groupBase, (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.
2. The compound of claim 1 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;
2- (4-hydroxy-3-methoxyphenyl) -2- (4-methylpiperazinyl) methylphosphonic acid diethyl ester;
1- (cyanomethyl) -4-methylpiperazine;
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.
3. The compound of claim 1 or 2, 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 compound of claim 1 or 2, 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. The novel compound of claim 1 and derivatives thereof wherein said compound is diethyl 2- (3, 5-dimethoxy-4-hydroxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonate hydrochloride.
6. The novel compound of claim 1 and derivatives thereof wherein said compound is diethyl 2- (4-hydroxy-3-methoxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonate hydrochloride.
7. A process for preparing a compound of the formula I as defined in claim 1aCompound (i.e. when R is3'HO-Ar, Y-PO (OR) OR'), which comprises reacting a phenol aldehyde, a secondary amine and a phosphite ester by heating to 40-300 ℃ and/OR pressurizing to 0.1-20MPa, wherein R is1’、R2' and R3'As defined above, R and R' are C0-10A hydrocarbyl group.
8. The method of claim 7, wherein the primary amine is reacted with R4The' X reaction is carried out in the presence of a catalyst, wherein the catalyst is an acid catalyst, and the acid catalyst is a Lewis acid comprising an organic acid or an inorganic acid.
9. The process of claim 8 wherein the catalyst is a base catalyst and the base catalyst is a lewis base comprises an organic base, a tertiary amine, and an inorganic base.
10. The method according to claim 7 or 8, wherein the organic solvent is methanol, ethanol, propanol, isopropanol, butanol, acetone, butanone, toluene, xylene, 1, 2-dichloroethane, methylfuran, 1, 4-dioxane, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide.
11. The application of the compound shown in the general formula I, the derivative, the isomer, the racemate or the optical isomer, the medicinal salt or the solvate thereof in the preparation of medicaments for preventing or treating cardiovascular diseases related to vascular endothelial cell dysfunction, such as hypertension, congestive heart failure, endophlebitis, microcirculation disturbance and the like, diabetes, aging, ischemia and other diseases or the application of the compound as a tool medicament for researching cardiovascular and cerebrovascular diseases related to vascular and cell functions or dysfunction thereof,
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 C4-10Aryl sulfideRadical 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, cyanoNitro group, 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.
12. The use of claim 11, wherein:
R1or R2Methyl, 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, 2- (diisobutylamino) ethyl, tert-butyl, 2-butylaminoethyl, 2-dimethylaminoethyl, 2- (dipropylamino) ethyl, 2- (diisobutylamino) ethyl, 2-, 2- (di-tert-butylamino) ethyl, 2-morpholinoethyl, 2-piperidinylethyl, 2-piperazinylethyl, 2- (4-methylpiperazinyl) 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-piperidinylethyl, 2-piperazinylethyl, 2- (4-methylpiperazinyl) ethyl, 3-hydroxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-isopropylaminopropyl, 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 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, 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;
R3represents a hydrogen atom, a 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 represents cyano, carboxy, 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.
13. The use of claim 11, wherein R is1R2N is 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-piperidinylmethyl-2-pyridyl) piperazinyl-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-fluorophenyl) piperazinyl, 4- (2-chlorophenyl) piperazinyl, 4- (3, 4-dichlorophenyl) piperazinyl, and the like, 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-piperidinylpiperidinyl.
14. The use of claim 11 or 12, wherein R is1R2N is 4- (2-pyridyl) piperazinyl and Y is diethoxyphosphonyl.
15. The use of claim 11, 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.
16. The use of claim 11, 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.
17. The use of claim 14, wherein said compound is diethyl 2- (3, 5-dimethoxy-4-hydroxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonate hydrochloride
18. The use of claim 14, wherein said compound is diethyl 2- (4-hydroxy-3-methoxyphenyl) -2- [4- (2-pyridyl) piperazinyl ] methylphosphonate hydrochloride.
19. The use as claimed in claim 11, wherein the use is in the preparation of a medicament for the prevention or treatment of cardiovascular diseases such as hypertension, hyperlipidemia, congestive heart failure, etc., and diseases such as diabetes, aging, ischemia, etc.
20. The compound shown in the general formula I, the derivative, the isomer, the racemate or the optical isomer, the medicinal salt or the solvate thereof, which is used for preventing or treating cardiovascular diseases related to the dysfunction of vascular endothelial cells, in particular the cardiovascular diseases such as hypertension, congestive heart failure, phlebitis, microcirculation disturbance and the like, diabetes, the diseases such as diabetes, aging, ischemia and the like,
Figure A0113726800101
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 radical、β-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 group、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.
21. Pharmaceutical composition containing at least one compound of formula I as claimed in any of claims 1 to 5 or 20aOr a compound of formula I, a derivative, an isomer, a racemate or an optical isomer thereof, a medicinal salt thereof, or a solvate thereof and a medicinal carrier or excipient.
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US3954761A (en) * 1968-10-17 1976-05-04 Petrolite Corporation Piperazine phosphonic acids
FR2750862B1 (en) * 1996-07-12 1998-10-16 Dupin Jean Pierre USE OF FUSED DIAZOTA HETEROCYCLES WITH AN AROMATIC OR HETEROAROMATIC SYSTEM FOR THE TREATMENT OF THROMBO-EMBOLIC DISEASES

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US7538114B2 (en) 2006-06-28 2009-05-26 Amgen Inc. Glycine transporter-1 inhibitors
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