WO2016082786A1 - 一类三肽化合物及其制备方法与应用 - Google Patents

一类三肽化合物及其制备方法与应用 Download PDF

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WO2016082786A1
WO2016082786A1 PCT/CN2015/095758 CN2015095758W WO2016082786A1 WO 2016082786 A1 WO2016082786 A1 WO 2016082786A1 CN 2015095758 W CN2015095758 W CN 2015095758W WO 2016082786 A1 WO2016082786 A1 WO 2016082786A1
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acid
group
alkyl
carbon
compound
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French (fr)
Inventor
郑晓辉
白亚军
秦方刚
刘佩
方佳成
何希瑞
王笑笑
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Northwest University
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Northwest University
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Priority to JP2017527865A priority Critical patent/JP6689848B2/ja
Priority to DK15863217.4T priority patent/DK3225627T5/da
Priority to HK18102948.9A priority patent/HK1243437B/zh
Priority to KR1020177017351A priority patent/KR102098783B1/ko
Priority to ES15863217T priority patent/ES2897916T3/es
Priority to MYPI2017701895A priority patent/MY193996A/en
Priority to PL15863217T priority patent/PL3225627T3/pl
Priority to SG11201704235SA priority patent/SG11201704235SA/en
Priority to RU2017121590A priority patent/RU2685709C2/ru
Priority to AU2015353118A priority patent/AU2015353118B2/en
Priority to NZ732301A priority patent/NZ732301A/en
Priority to US15/529,633 priority patent/US11358985B2/en
Application filed by Northwest University filed Critical Northwest University
Priority to EP15863217.4A priority patent/EP3225627B9/en
Priority to SI201531768T priority patent/SI3225627T1/sl
Priority to CA2968595A priority patent/CA2968595C/en
Publication of WO2016082786A1 publication Critical patent/WO2016082786A1/zh
Priority to IL252448A priority patent/IL252448B/en
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Priority to CY20211100983T priority patent/CY1125043T1/el
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Definitions

  • This invention relates to a novel class of compounds of formula (I) and the corresponding pharmaceutically acceptable salts.
  • the invention also relates to a process for the preparation of such compounds or their corresponding salts or intermediates thereof.
  • the invention also relates to pharmaceutical compositions of the compounds. These compounds have an effect of inhibiting the biological activity of angiotensin converting enzyme, itself and its pharmaceutical composition for the prevention and treatment of hypertension and other cardiovascular and cerebrovascular diseases.
  • Hypertension is the biggest risk factor for heart disease, stroke, kidney disease and diabetes mellitus and death. 2 million deaths per year are associated with high blood pressure, and hypertension has become an important public health problem. (October 10, 2012 16:26 Source: China News Network) Hypertension and its complications have brought huge economic burdens to the society and the family. So far, people have made great progress in the treatment of hypertension and its complications, but still can not completely solve the pain of patients with hypertension. At the same time, the widespread harm of hypertension and its complications has led to the rapid development of the antihypertensive drug market.
  • hypertension has been treated with drugs, and has gradually formed diuretics, ⁇ -blockers, ⁇ -blockers, calcium antagonists (CCB), angiotensin-converting enzyme inhibitors.
  • ⁇ -blockers ⁇ -blockers
  • CB calcium antagonists
  • angiotensin-converting enzyme inhibitors ACEI and angiotensin receptor blockers (ARB)
  • ACEI angiotensin receptor blockers
  • angiotensin converting enzyme inhibitor since the advent of captopril in 1981, the proline as the mother nucleus against angiotensin converting enzyme (ACE) is a a zinc ion-containing exopeptidase)
  • ACEI angiotensin converting enzyme inhibitor
  • the drug design of the target has been a research hotspot in the field of antihypertensive, and successfully designed ACEI drugs and lead compounds containing key functional groups such as thiol, carboxylic acid and phosphoric acid such as dipeptide and tripeptide.
  • ACEI drugs at least 17 ACEI drugs have become the first line of clinical treatment for hypertension.
  • antihypertensive drugs also have different focuses, especially ARB antihypertensive drugs have become an important part of antihypertensive drugs with their long-acting and low side effects.
  • hypertensive patients are often accompanied by other cardiovascular and cerebrovascular diseases such as diabetes and kidney disease.
  • the use of only one antihypertensive drug often fails to achieve a good therapeutic effect, so the combination of two or more antihypertensive drugs has become a trend of clinical antihypertensive drugs. Therefore, it is imperative to develop multi-effect, multi-indication, and more effective antihypertensive drugs.
  • the present invention provides a class of tripeptide compounds having the structural formula (I) as follows:
  • R is represented by the general formula (II):
  • R 1 is selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, acyl, aroyl, aryl, aralkyl, heteroaryl or heteroarylalkyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, acyl, aroyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkane sulfide Base, aralkylthio, arylthio, F, Cl, Br, I, NO 2 or CN;
  • R 1 and R 2 are the same or different
  • n 0,1,2,3,4,5; when n ⁇ 2, a plurality of R 1 are the same or different;
  • n 0,1,2,3,4,5; when m ⁇ 2, a plurality of R 2 are the same or different;
  • W is selected from or among them or The left side is attached to the benzene ring; wherein: Z is selected from oxygen or nitrogen; and R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, Heteroaryl or heteroarylalkyl;
  • X is selected from oxygen or hydrogen
  • R' is a residue of an L-form or a D-form amino acid residue or an amino acid derivative, as shown in the formula (III), or R' is absent:
  • R' is an L-form or a D-form amino acid residue or a residue of an amino acid derivative, C-end and N-terminal connection, N-terminal with C-terminal connection;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; R 4 Same or different from R 5 ;
  • R" is represented by the general formula (IV):
  • Y is selected from the group consisting of oxygen, nitrogen or sulfur, and:
  • Y is oxygen, R "" is R 9, R "is -OR 9;
  • R"" is R 10 and R" is -SR 10 ;
  • R 7 , R 8 , R 9 and R 10 may be the same or different and are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclic, alkenyl, alkynyl, aryl, aralkyl. Base, heteroaryl or heteroarylalkyl;
  • R"' is selected from hydrogen or an alkyl group
  • L is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
  • K is selected from a carbon number of 2 to 8 alkyl groups, a heteroalkyl group, a carbon number of 3 to 8 alkenyl groups, or a combination of K and B and D.
  • K is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, hydroxy, alkoxy, aryloxy, aryl Base, aralkyl, heteroaryl or heteroarylalkyl;
  • B is carbon and K is hydrogen
  • alkyl, cycloalkyl, heteroalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups can each be unsubstituted or optionally independently Or a plurality of substituents selected from the group consisting of hydroxyl, alkoxy, aryloxy, thio, thioalkyl, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, Arylsulfonyl, sulfinylamino, alkyl, aryl, heteroaryl, alkylsulfinamide, arylsulfinamido, keto, carboxy, alkoxycarbonyl, carboxamide, alkoxycarbonyl Amino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano or nitro.
  • R 9 is a group selected from the group consisting of:
  • R" is a group selected from the group consisting of:
  • R" is a group selected from the group consisting of:
  • the above-mentioned tripeptide compound is selected from the compounds of the following structures:
  • the present invention also provides a hydrolysis product of the compound in the above compound wherein Y is oxygen.
  • the invention also provides enantiomers, tautomers, stereoisomers, rotamers, diastereomers or racemates of the above compounds.
  • the present invention also provides a pharmaceutically acceptable salt and a pharmaceutically acceptable ester of the above compound, the pharmaceutically acceptable salt comprising a pharmaceutically acceptable acid salt and a pharmaceutically acceptable basic salt
  • the pharmaceutically acceptable acid salt includes a salt formed by one of the following acids: sulfuric acid, hydrogen sulfate, hydrochloric acid, hydrobromine Acid, phosphoric acid, nitric acid, carbonic acid, boric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, butyric acid, pyruvic acid, maleic acid, malic acid, tartaric acid, citric acid, Ascorbic acid, benzoic acid, camphoric acid, fumaric acid, oxalic acid, succinic acid, camphorsulfonic acid, maleic acid, salicylic acid or alpha-lactic acid;
  • the pharmaceutically acceptable basic salt includes the following bases One of the formed salt
  • the present invention also provides a solvating mixture of the above compounds in one or a combination of two or more of water, methanol, ethanol, isopropanol, butanol, ethyl acetate and DMSO.
  • Another aspect of the present invention provides the use of the above compound for the preparation of a medicament for preventing, treating or delaying hypertension and its complications, including: coronary heart disease, angina pectoris, acute heart failure, chronic congestive heart failure, myocardial infarction And its sequelae, congestive heart disease, myocardial ischemia, myocarditis, myocardial fibrosis, cardiac hypertrophy, atherosclerosis, benign small arteriosclerosis, malignant arteriosclerosis, abnormal vascular growth and remodeling, angiogenesis Related diseases (such as neovascular macular degeneration), hyperaldosteronism, arrhythmia, kidney disease, diabetes, stroke, thrombosis, renal failure (eg, diabetic nephropathy), hyperlipidemia, obesity, hyperglycemia, retinal arteriosclerosis One or more of the disease, hypertensive fundus lesions.
  • coronary heart disease angina pectoris, acute heart failure, chronic congestive heart failure, myocardial infarction And
  • a pharmaceutical composition comprising: the compound described above, the pharmaceutically acceptable salt of the compound according to any one of claims 1-8, the pharmaceutically acceptable compound Accepted carriers, excipients, diluents.
  • Another aspect of the present invention provides the use of the above pharmaceutical composition for the preparation of a medicament for preventing, treating or delaying hypertension and its complications, including coronary heart disease, angina pectoris, heart failure (acute or chronic congestive heart) Failure), myocardial infarction and its sequelae, congestive heart disease, myocardial ischemia, myocarditis, myocardial fibrosis, cardiac hypertrophy, atherosclerosis, benign small arteriosclerosis, malignant arteriosclerosis, abnormal vascular growth Remodeling, angiogenesis-related diseases (such as neovascular macular degeneration), hyperaldosteronism, arrhythmia, kidney disease, diabetes, stroke, thrombosis, renal failure (eg, diabetic nephropathy), hyperlipidemia, obesity, high One or more of blood glucose, retinal arteriosclerosis, and hypertensive fundus lesions.
  • coronary heart disease angina pectoris, heart failure (acute or chronic congestive heart) Failure)
  • the present invention relates to a class of compounds which have the effect of inhibiting the biological activity of angiotensin converting enzyme, itself and its pharmaceutical composition for the prevention and treatment of hypertension and other cardiovascular and cerebrovascular diseases.
  • Figure 1 is a quadratic curve fit of the concentration of angiotensin converting enzyme and OD450nm;
  • Figure 2 shows the change of arterial systolic pressure in 221S-1a for 6 hours in SHR rats;
  • Figure 3 shows the systolic blood pressure of 221S-1a (1#, 3#, 5#) administered by SHR rats for 6 hours. Changes;
  • Figure 4 shows the changes of systolic blood pressure within 14 days after SDS rats were administered with 221S-1a for 7 days;
  • Figure 5 shows the changes of arterial systolic pressure in different doses of 221S-1a (2#, 4#, 6#) in SHR rats.
  • Salvia miltiorrhiza (Lan name: Salvia miltiorrhiza Bunge) has been used as a traditional Chinese medicine component and has been used as a treatment for cardiovascular and cerebrovascular diseases. Recently, in the treatment of hypertension, there have been many reports on the synergistic effect of Salvia miltiorrhiza. (Biological & Pharmaceutical Bulletin, 2011, 34(10), 1596-1601.; Phytotherapy Research, 2010, 24(5), 769-774.; American Journal of Physiology, 2007, 292 (5, Pt.
  • Danshensu is the main component of the water-soluble extract of Salvia miltiorrhiza. Its catechol and lactic acid structure make it uniquely anti-oxidant, protect cardiovascular and cerebrovascular, promote vasodilation, lower blood pressure and other functions. (Characterization of the Radical Scavenging And Antioxidant Activities of Danshensu and Salvianolic Acid B. Food and Chemical Toxicology, 2008, 46(1), 73-81; Protective effects and mechanism of Danshensu on endothelial vasoactivity in rats with isoproterenol-induced injury. Chinese herbal medicine, 2013, 1:59-64). It has been found that polyphenolic natural products have an inhibitory effect on angiotensin converting enzyme.
  • the present invention refers to the preliminary research results (CN 1868998A, ⁇ -(3,4-dihydroxyphenyl)- ⁇ -hydroxypropionic acid borneol Ester, its synthesis method and use), the Danshensu group and other phenolic acid groups are introduced into the traditional ACEI drug skeleton molecule, and combined with the design concept of "Jun-Guo-Pharma" and prodrugs, simultaneously introduce borneol, Groups such as menthol have designed a new class of drug precursors that potentially have angiotensin converting enzyme inhibitor properties.
  • the present invention is directed to the chemical structures of the disclosed angiotensin converting enzyme inhibitors, such as: captopril, enalapril, lisinopril, perindopril, alapril, delaipril, quinine Napoli, ramipril, cilazapril, benazepril, fosinopril, zofenopril, trandolapril, midazolam, temocapril, sulpiride and mohi Puli.
  • the present invention also refers to published patent documents relating to angiotensin converting enzyme inhibitors, such as: Antihypertensive mercaptoacylamino acid derivatives and their use, (1980, EP 9898 A1), Preparation of converting enzyme inhibitor 5, 6-dihydro [1 , 4]thiazino[4,3-a]quinoline-1(2H),4(4aH)-dione, (1981, US 4273927 A), [4R]-3-( ⁇ -Aroylpropionyl)-4-thiazolidinecarboxylic acids and Esters, (1983, US 4374249 A).
  • angiotensin converting enzyme inhibitors such as: Antihypertensive mercaptoacylamino acid derivatives and their use, (1980, EP 9898 A1), Preparation of converting enzyme inhibitor 5, 6-dihydro [1 , 4]thiazino[4,3-a]quinoline-1(2H),4(4aH)-dione, (1981
  • WO 9302679 A1 Method of treating premenstrual syndrome by administration of an angiotensin-converting enzyme inhibitor, which discloses the following compounds:
  • alkyl means a straight or branched aliphatic hydrocarbon group containing from 1 to 15 carbon atoms, and a preferred alkyl group contains from 1 to 6 carbon atoms. Including, but not limited to, methyl, ethyl, propyl, isopropyl,
  • substituted alkyl means that the alkyl group is substituted by one or more substituents, which may or may not be the same, and each substituent may be independently selected from the group consisting of alkyl, cycloalkyl, aryl, cyanide. a 1-3 amino group substituted with a 1,3-nitro group, a halogen, an alkoxy group, an amino group, an alkyl group, or a cycloalkyl group, a hydroxy group, a hydroxy group, a decyl group, an alkylthio group, an alkyl ketone group, or a carboxyl group.
  • substituted alkenyl means that the alkenyl group may be substituted by one or more substituents, which may or may not be the same, and each substituent may be independently selected from alkyl, cycloalkyl, aryl. , cyano, nitro, halogen, alkoxy, amino, alkyl substituted 1-3 amino or cycloalkyl substituted 1-3 amino, hydroxy, decyl, alkylthio, alkyl ketone, carboxyl .
  • alkynyl means an aliphatic hydrocarbon group containing at least one C ⁇ C triple bond, which may be straight or branched or A chain containing 2 to 15 carbon atoms. Preferred alkynyl containing hydrocarbon chains have from 2 to 8 carbon atoms.
  • substituted alkynyl means that the alkenyl group may be substituted by one or more substituents, which may or may not be the same, and each substituent may be independently selected from alkyl, cycloalkyl, aryl. , cyano, nitro, halogen, alkoxy, amino, alkyl substituted 1-3 amino or cycloalkyl substituted 1-3 amino, hydroxy, decyl, alkylthio, alkyl ketone, carboxyl .
  • aryl means an aromatic monocyclic or polycyclic structure containing from 6 to 14 carbon atoms, preferably from 6 to 12 carbon atoms.
  • substituted aryl means that the aryl group may be substituted by one or more substituents, which may or may not be the same, and each substituent may be independently selected from alkyl, cycloalkyl, aryl. , cyano, nitro, halogen, alkoxy, amino, alkyl substituted 1-3 amino or cycloalkyl substituted 1-3 amino, hydroxy, decyl, alkylthio, alkyl ketone, carboxyl .
  • heteroaryl means an aromatic monocyclic or polycyclic structure in which a carbon atom on one or more of the rings is replaced by another element, including but not limited to nitrogen, oxygen, sulfur, including 5-14 A carbon atom, preferably 5 to 12 carbon atoms.
  • Preferred heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, fluorenyl, quinolyl, isoquinolinyl, pyrazolyl, furyl, thienyl, thiazolyl, Oxazolyl, pyrrolyl, benzofuranyl, benzothienyl,
  • substituted heteroaryl means that the heteroaryl group may be substituted by one or more substituents, which may or may not be the same, and each substituent may be independently selected from alkyl, cycloalkyl, Aryl, cyano, nitro, halogen, alkoxy, amino, alkyl substituted 1-3 amino or cycloalkyl substituted 1-3 amino, hydroxy, decyl, alkylthio, alkyl ketone ,carboxyl.
  • Preferred substituted aralkyl groups include, but are not limited to, ligustrazine alcohol groups.
  • aralkyl means an aryl-alkyl group.
  • Aryl, Alkyl As described above, preferred aralkyl groups include, but are not limited to, benzyl, phenethyl.
  • substituted aralkyl means that the aralkyl group may be substituted by one or more substituents, which may or may not be the same, and each substituent may be independently selected from alkyl, cycloalkyl, Aryl, cyano, Nitro, halogen, alkoxy, amino, alkyl substituted 1-3 amino or cycloalkyl substituted 1-3 amino, hydroxy, decyl, alkylthio, alkyl ketone, carboxyl.
  • Preferred substituted aralkyl groups include, but are not limited to, p-methylbenzyl, isooctyl.
  • cycloalkyl means a non-aromatic monocyclic or polycyclic structure, typically containing from 3 to 10 carbon atoms.
  • Preferred cycloalkyl groups contain a ring structure of from 3 to 7 carbon atoms but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • substituted cycloalkyl means that the cycloalkyl group may be substituted by one or more substituents, which may or may not be the same, and each substituent may be independently selected from alkyl, aryl, cyanide. a 1-3 amino group substituted with a 1,3-nitro group, a halogen, an alkoxy group, an amino group, an alkyl group, or a cycloalkyl group, a hydroxy group, a hydroxy group, a decyl group, an alkylthio group, an alkyl ketone group, or a carboxyl group.
  • Preferred substituted cycloalkyl groups contain a ring structure of from 3 to 7 carbon atoms but are not limited to: dextrorotyl ketone, levomenthol, and norbornyl.
  • halogen means fluoro, chloro, bromo, iodo. Preferred halogens include fluorine, chlorine, and bromine.
  • heterocyclyl means a non-aromatic saturated monocyclic or polycyclic ring system, the ring system atoms are generally within 10 atoms, preferably 4 to 10 atoms, wherein one or more non-carbons are included in addition to the carbon atoms. Carbon atoms, such as nitrogen, oxygen, and sulfur atoms, may exist alone or in combination. Therein, no adjacent oxygen-oxygen, oxygen-sulfur or sulfur-sulfur groups are present in the ring system.
  • Preferred heterocyclic groups include, but are not limited to, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolyl and the like.
  • heterocyclyl means that the heterocyclyl group may be substituted by one or more substituents, which may or may not be the same, and each substituent may be independently selected from alkyl, aryl, cyanide. a 1-3 amino group substituted with a 1,3-nitro group, a halogen, an alkoxy group, an amino group, an alkyl group, or a cycloalkyl group, a hydroxy group, a hydroxy group, a decyl group, an alkylthio group, an alkyl ketone group, or a carboxyl group.
  • Preferred substituted heterocyclic groups include, but are not limited to, N-methylpiperazinyl, 3-fluoropiperidinyl, 2,6-dimethylmorpholinyl, 2-methylpyrrolyl and the like.
  • heteroarylalkyl means a heteroarylalkyl group, and the heteroaryl and alkyl are as described above.
  • Preferred heteroarylalkyl groups include, but are not limited to, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl.
  • acyl means alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkane Base-C(O)-, heterocyclyl-C(O)-.
  • acyl groups include, but are not limited to, acetyl, propionyl, cyclobutanoyl.
  • acyl means aryl-C(O)-, substituted aryl-C(O)-.
  • acyl groups include, but are not limited to, benzoyl, p-methylbenzoyl.
  • alkoxy means alkyl-O-, substituted alkyl-O-. Each group is as described above. Preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropyl, dextrorotyloxy, L-mentholoxy, 2,3,4-trimethoxybenzene-2'-alkenyl Propoxy (asalyloxy), ligustrazineoxy.
  • aralkoxy means aralkyl-O-, substituted arylalkyl-O-. Each group is as described above. Preferred aralkyloxy groups include, but are not limited to, benzyloxy, 2,3,4-trimethoxybenzene-2'-alkenyloxy (asalyloxy).
  • aryloxy means aryl-O-, substituted aryl-O-. Each group is as described above. Preferred aryloxy groups include, but are not limited to, phenoxy, p-methylphenoxy.
  • alkylthio means an alkyl-sulfan- group in which the alkyl moiety is as described above.
  • Preferred alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio.
  • aralkylthio means an aralkyl-sulfan- group in which the aralkyl group is as described above.
  • Preferred aralkylthio groups include, but are not limited to, benzylthio, phenethylthio.
  • arylthio means an aryl-sulfan- group in which the aryl group is as described above.
  • Preferred arylthio groups include, but are not limited to, phenylthio groups.
  • alkylsulfonyl means an alkyl-S(O 2 )- group.
  • the alkyl group is as described above.
  • Preferred alkylsulfonyl groups include, but are not limited to, methylsulfonyl, ethylsulfonyl.
  • arylsulfonyl means an aryl-S(O 2 )- group.
  • the aryl group is as described above.
  • Preferred arylsulfonyl groups include, but are not limited to, phenylsulfonyl, naphthylsulfonyl.
  • substituted refers to a group selected from a group that replaces one or more hydrogens at a specified atom and conforms to the normal valence of the specified atom, and the resulting compound is stable.
  • tripeptides and analogs thereof designed by the present invention also include “prodrugs”, “solvates”, “salts” (including: “acid salts”, “basic salts” and inner salts) and “esters”. .
  • “Prodrugs”, “solvates” and “salts” of these tripeptide compounds are within the scope of the invention. Wherein “solvate” and “salt” are equivalent to the free form of the corresponding compound.
  • prodrug means a compound of a prodrug which can be chemically or chemically converted into a compound of the formula (I) or a salt thereof or a solvate thereof or an ester thereof.
  • solvate means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves various degrees of ionic and covalent bonding, including hydrogen bonding, van der Waals forces, and the like. Among them, the "solvate” consists of two parts: a solution phase and a separable solvate. Suitable solvates include, but are not limited to, hydrates, methanolates, ethanol, DMSO, ethyl acetate complexes.
  • the acid forming the acid salt includes, but is not limited to, the following acids:
  • base forming the basic salt includes, but is not limited to, the following bases:
  • Alkali metals such as lithium, sodium and potassium, magnesium, calcium, and other alkaline earth metals, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, butyl lithium, ammonium, triethylamine, diisopropyl
  • a basic amino acid such as a base amine, ornithine, arginine, lysine or histidine.
  • the pharmaceutically acceptable ester formed by the tripeptide compound of the present invention means a hydroxyl group or a phenolic hydroxyl group and a carboxylic acid in the compound (including but not limited to: an alkyl carboxylic acid, a substituted alkyl carboxylic acid, an aryl carboxy group)
  • An acid, a substituted aryl carboxylic acid, an aralkyl carboxylic acid, a substituted aralkyl carboxylic acid, a cycloalkyl carboxylic acid, a substituted cycloalkyl carboxylic acid, a heterocyclic carboxylic acid, a heteroaryl alkyl carboxylic acid for example: a carboxylic acid ester formed by an acid ester, a propionate, a benzoate or a nicotinate; further comprising a hydroxyl group or a phenolic hydroxyl group and a sulfonic acid in the compound (including but not limited to: an alkyls,
  • tripeptide compounds of the present invention and their pharmaceutically acceptable (non-toxic, physiologically acceptable) “solvates”, “salts” (including: “acid salts”, “basic salts” and internal salts) , “ester”, and related “prodrugs”, the enantiomers, stereoisomers, rotamers, tautomers, positional isomers and racemates involved in the present invention within the scope.
  • protecting groups of sensitive cargo reactivity on the molecule of interest may be protected during the synthesis.
  • Representative protecting groups are described in T. W. Greene and P. G. M. Wuts "Protective Groups in Organic Synthesis” John Wiley & Sons, Inc., New York, 1999, the entire disclosure of which is incorporated herein by reference.
  • the corresponding protecting groups can be added or removed using methods well known in the art.
  • composition is intended to encompass a product that comprises a particular amount of a particular ingredient, as well as any product that is formed directly or indirectly from a particular combination of the specified ingredients.
  • “Mammal” means humans and other mammals.
  • Patient includes both humans and animals.
  • angiotensin converting enzyme By “effective amount” is meant that the amount of a compound or pharmaceutical composition of the invention is effective in inhibiting angiotensin converting enzyme and thereby producing the desired prophylactic, therapeutic, ameliorating or inhibiting effect.
  • “Pharmaceutically acceptable carrier” means a compound and composition having sufficient purity and quality for formulating the compositions of the present invention, which, when suitably administered to an animal or a human, does not produce an adverse reaction and is useful as a carrier for the drug.
  • “Pharmaceutically acceptable diluent” means a compound and composition having sufficient purity and quality for formulating the compositions of the present invention, which, when suitably administered to an animal or human, does not produce an adverse reaction, is used as a diluent for the drug. .
  • compositions generally comprise at least one compound of the invention and one or more pharmaceutically acceptable carriers.
  • the solid dosage form may comprise: a filler (such as starch, microcrystalline cellulose, sucrose, glucose, lactose, sorbitol, mannitol, etc.), a binder (gelatin, carboxymethylcellulose, alginate, arabic) Gum), humectant (glycerin), disintegrant (calcium carbonate, starch, agar, alginic acid), dissolution retarder (paraffin), absorption enhancer (quaternary ammonium salt compound), wetting agent (cetyl alcohol, single hard) Glycerol), adsorbent (kaolin, bentonite), lubricant (talc, solid polyethylene glycol, potassium stearate, calcium or magnesium salt, sodium lauryl sulfate, wherein the water-soluble lubricant includes: chlorination Sodium, sodium acetate, sodium benzoate oleate, colorants (clay, a
  • the compounds of the present invention can be formulated into suitable dosage forms such as tablets and capsules according to conventional pharmaceutical procedures.
  • the compound (I) of the present invention and pharmaceutically acceptable (non-toxic, physiologically acceptable) salts, esters, and pharmaceutical compositions thereof are suitable for preventing, treating or delaying cardiovascular and cerebrovascular diseases, particularly hypertension complication.
  • the conditions and diseases include: hypertension, coronary heart disease, angina pectoris, heart failure (acute or chronic congestive heart failure), myocardial infarction and its sequelae, congestive heart disease, myocardial ischemia, myocarditis, heart Muscle fibrosis, cardiac hypertrophy, atherosclerosis, benign small arteriosclerosis, malignant arteriosclerosis, abnormal vascular growth and remodeling, angiogenesis-related diseases (such as neovascular macular degeneration), hyperaldosteronism, One or more of arrhythmia, kidney disease, diabetes, stroke, thrombosis, renal failure (eg, diabetic nephropathy), hyperlipidemia, obesity, hyperglycemia, retinal arteriosclerosis, hypertensive fundus lesions.
  • R 1 is selected from a linear or branched alkyl group of C 1 -C 5 ;
  • Step (1) is to carry out the reaction of compound VI with a fatty alcohol in xylene, toluene or benzene for 3-12 hours, further optional for 4-10 hours, after cooling to room temperature, adding 2,4,5-trimethoxy
  • the benzaldehyde (compound V) and the catalyst are further refluxed for 5-24 hours, and further optionally for 8-14 hours to obtain the compound VII;
  • the fatty alcohol used in the step (1) is methanol, ethanol, propanol and isopropanol.
  • the catalyst used is pyridine, 2,4,6-trimethylpyridine, 2,6-dimethyl
  • the molar ratio of benzaldehyde is 0.1:1 to 2:1.
  • the reducing agent used in the step (2) is sodium borohydride, sodium dihydrobis(2-methoxyethoxy)aluminate, lithium aluminum hydride or diisobutylaluminum hydride; the ratio of the reducing agent to the compound VII is 1:1.
  • the solvent used is tetrahydrofuran, 1,4 dioxane, dimethyl ether, toluene, benzene, xylene, diethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, One or a combination of chloroform, tetrachloromethane and n-hexane; the reaction temperature is -78 ° C to 25 ° C; and the reaction time is between 0.5 and 24 hours.
  • the coupling reagent used in the synthesis of 221S-2a and 221S-144a is The coupling reagent used in the synthesis of 7a is HATU, the base used is DIPEA; the coupling reagent used in the synthesis of 221S-119a is PyBOP; the coupling reagent used in the synthesis of 221S-11a, 221S-12a is DCC.
  • amine-containing compounds can be prepared in the same manner as the hydrochloride salt.
  • other acid salts can be similarly added in a solvent containing an amine compound, and the corresponding acid is slowly added, and stirred at a low temperature (2-4 ° C) or room temperature for 2-10 hours to obtain the corresponding acid salt.
  • step 2 is carried out.
  • N-Boc valine (21.5 g, 0.1 mol), DCC (20.6 g, 0.1 mol), DMAP (1.22 g, 0.01 mmol) was added sequentially to 150 mL of DMF.
  • the reaction was stirred at room temperature for 10 minutes and then cooled to 0 °C.
  • Ethyl mercaptan (6.82 g, 0.11 mol) was further added dropwise and allowed to react overnight.
  • the reaction was quenched by adding 200 mL of water to the reaction system. After filtration, the filter cake was washed with ethyl acetate and taken out of the DCU. The combined organic layers were washed with aq. EtOAc EtOAc. Purification by low pressure chromatography chromatography gave product 221S-177a-118.4 g, yield 71%.
  • 221S-177a-1 (2.59 g, 10 mmol) was dissolved in EtOAc (25 mL). After stirring, HCl gas was passed at room temperature for 30 min. The remaining HCl gas was again purged with nitrogen, and the mixture was evaporated to dryness vacuo.
  • N-Boc valine (2.15 g, 10 mmol) was dissolved in dry THF (40 mL) and then 2,2'-dithiopyridine (2.20 g, 10 mmol), triphenylphosphine (3.14 g, 12 mmol). Stir at room temperature for 3 hours. It was extracted by extraction with an ethyl acetate/water system. Organic phase, washed with water, saturated aqueous sodium chloride solution, anhydrous sulfuric acid Magnesium is dried, filtered and concentrated. Purification by low pressure chromatography chromatography gave product 221S-181a-1 2.46 g, yield 80%.
  • step 6 0.28 g of 221S-181a-4 was obtained, and 221S-181 0.22 g was obtained. The rate is 48%. MS ESI+ve m/z: 460.0.
  • the present invention relates to novel angiotensin converting enzyme inhibitors. Its biological activity is further described by the following in vivo and in vitro assays.
  • High performance liquid chromatography determination Refer to Cushman et al. (Biochemical Pharmacology, 1971, 20(7): 1637-1648.; Journal of Dairy Science, 1995, 78(4): 777-783.), and reported methods
  • the compounds of the invention are assayed for angiotensin converting enzyme activity. This method is based on the content of hippuric acid (Hip), a hydrolysate of the mimicuryl-histyl-leucine (HHL), which is suitable for continuous monitoring of ACE activity.
  • Hip hippuric acid
  • HHL mimicuryl-histyl-leucine
  • the ACE inhibitory activity was obtained by measuring the change in the ultraviolet absorbance of hippuric acid generated before and after the addition of the inhibitor at 228 nm.
  • the ACE content was determined by double antibody sandwich ELISA: coated on an ELISA plate with an anti-mouse ACE antibody, and the mouse ACE in the sample or standard was bound to the coated antibody during the experiment, and the free component was washed away.
  • Biotinylated anti-mouse ACE antibody and horseradish peroxidase-labeled avidin were sequentially added.
  • the anti-mouse ACE antibody binds to the mouse ACE bound to the coated antibody, biotin binds to avidin to form an immune complex, and the free component is washed away.
  • Adding a chromogenic substrate (TMB) TMB appears blue under the catalysis of horseradish peroxidase and turns yellow after addition of stop solution.
  • the OD value was measured at a wavelength of 450 nm by a microplate reader, and the ACE concentration was in a quadratic nonlinear relationship with the OD450 value.
  • the concentration of ACE in the sample was calculated by drawing a
  • mice weighing (bw, 20 ⁇ 2 g), were randomly divided into 18 groups, 6 in each group.
  • the control group was the normal control group, the positive control drug captopril group, and the compound 221S group.
  • the stomach was administered once a day, and the stomach was administered at a dose of 0.05 mmol/kg (volume 10 ml/kg) for 7 days. 2 hours after the last intragastric administration, The neck was sacrificed and the heart, liver, brain, lung, kidney and blood were taken. The kidney was used for the test in this experiment, and other tissue samples were used for additional experimental tests. The kidneys were diluted 10 times with PBS, homogenized, centrifuged, and the supernatant was taken for measurement or stored at -20 ° C until use.
  • step (e) Discard the liquid in the well, dry and wash the plate 5 times, in the same manner as in step (c).
  • the experimental results show that the compound of the present invention can reduce the plasma ACE enzyme content in rats, and the decrease rate is larger than that of the positive drug captopril, and the compound 221S-1a has the most significant decrease effect.
  • the systolic blood pressure of the experimental rats was measured by the tail pulse indirect pressure measurement method.
  • SHR rats were intragastrically administered.
  • the sample and the control substance (captopril) were dissolved in distilled water containing 1% Tween 80, and the blank control group was given the same volume of distilled water containing 1% Tween 80.
  • the blood pressure was measured at 0.05 mmol/kg (volume 10 ml/kg), and the blood pressure was measured at 1 h, 2 h, 3 h, 4 h, and 6 h after gavage.
  • the awake rats were placed in a fixed box of a blood pressure meter, and a heating plate at 30 ° C was placed on the bottom of the fixed box, and preheated for 10 minutes to expand the local blood vessels.
  • the inflatable tubular tail cannula surrounds the root of the SHR, and the pressure electronic pulse detector is placed at the base of the rat tail.
  • the computer screen generates a signal, and the blood pressure is measured after stabilization, and the blood pressure is recorded. 5 readings of less than 10 mmHg, recording values separated by 10 seconds. The mean value was taken as the systolic blood pressure of the rat.

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Abstract

提供一类三肽化合物及其制备方法与应用。所涉及的化合物结构通式如式（I）所示。提供的化合物具有抑制血管紧张素转化酶的生物活性，其本身及其药物组合物具有对高血压以及其他心脑血管系统疾病的预防与治疗方面的作用。

Description

一类三肽化合物及其制备方法与应用 技术领域
本发明涉及一类新的化合物式(I)及相应的药学上可以接受的盐。本发明还涉及该类化合物或其相应盐或其中间体的制备方法。本发明还涉及到所述化合物的药物组合物。这些化合物具有抑制血管紧张素转化酶的生物活性，其本身及其药物组合物对高血压以及其他心脑血管系统疾病的预防与治疗方面的作用。
背景技术
2013年世界卫生日的主题就是控制高血压。据世界卫生组织(WHO)公布的调查数据可知，高血压及其相关并发症疾病已成为威胁人类生命健康的主要疾病之一，其发病率和死亡率已超过肿瘤性疾病跃居第一。世界范围内约有10亿高血压患者，每年导致710万例心血管死亡，如不控制，2025年其患病人数将增至15.6亿。中国疾病预防控制中心慢性非传染疾病预防控制中心最新的研究结果公布——2010年中国成年人中高血压患病率高达33.5％，据此估计患病总人数已突破3.3亿。高血压是心脏病、脑卒中、肾脏病和糖尿病发病和死亡的最大的危险因素，每年200万人死亡与高血压有关，高血压已成为重要公共卫生问题。(2012年10月10日16:26来源：中国新闻网)高血压疾病及其并发症给社会和家庭带来了巨大的疫病经济负担。迄今为止，人们对于高血压及其并发症的治疗研究已取得了巨大进展，但是仍然无法完全解决高血压患者的痛苦。与此同时，高血压及其并发症的广泛危害性引起了抗高血压药物市场的快速发展。近30年以来，高血压治疗以药物为主，并逐渐形成了包含利尿剂、β-受体阻滞剂、α-受体阻滞剂、钙拮抗剂(CCB)、血管紧张素转换酶抑制剂(ACEI)、血管紧张素受体拮抗剂(ARB)在内的六大类降压药物及其不同组合。
其中，血管紧张素转换酶抑制剂(angiotension converting enzyme inhibition,ACEI)，自1981年卡托普利问世以来，以脯氨酸为母核针对血管紧张素转换酶(angiotension converting enzyme，ACE，是一种含有锌离子的外肽酶)为 靶点的药物设计一直是降压领域的研究热点，并成功设计出二肽、三肽等含有巯基、羧酸、磷酸等关键官能团的ACEI药物及前导化合物。到目前为止，已有至少17种ACEI类药物成为临床上治疗高血压的一线药物。其他降压药也各有不同的侧重，特别是ARB类降压药以其缓和长效、低副作用逐渐成为降压药的重要组成部分。然而，临床病例中，高血压患者常伴有糖尿病、肾脏病等其他心脑血管疾病。仅用一种降压药往往不能达到较好的疗效，故两种或多种降压药联合应用已经成为临床降压用药的趋势。因此，开发多效、多适应症、更为优效的降压药物势在必行。
发明内容
本发明提供了一类三肽化合物，该化合物结构通式(I)如下：
Figure PCTCN2015095758-appb-000001
通式(I)中：
R为通式(II)所示：
Figure PCTCN2015095758-appb-000002
通式(II)中：
R1选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、酰基、芳酰基、芳基、芳烷基、杂芳基或杂芳烷基；
R2选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、酰基、芳酰基、芳基、芳烷基、杂芳基、杂芳烷基、烷硫基、芳烷硫基、芳硫基、F、Cl、Br、I、NO2或CN；
R1和R2相同或不同；
n＝0,1,2,3,4,5；n≥2时,多个R1之间相同或不同；
m＝0,1,2,3,4,5；m≥2时,多个R2之间相同或不同；
W选自
Figure PCTCN2015095758-appb-000003
或
Figure PCTCN2015095758-appb-000004
其中
Figure PCTCN2015095758-appb-000005
或
Figure PCTCN2015095758-appb-000006
左侧与苯环相连；其中：Z选自氧或氮；R6选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、芳基、芳烷基、杂芳基或杂芳烷基；
X选自氧或氢；
通式(I)中：
R'为L型或D型氨基酸残基或氨基酸衍生物的残基，如通式(III)所示，或者，R'不存在：
Figure PCTCN2015095758-appb-000007
R'为L型或D型氨基酸残基或氨基酸衍生物的残基时，
Figure PCTCN2015095758-appb-000008
的C端与
Figure PCTCN2015095758-appb-000009
的N端连接，N端与
Figure PCTCN2015095758-appb-000010
的C端连接；
R'不存在时，
Figure PCTCN2015095758-appb-000011
与
Figure PCTCN2015095758-appb-000012
以酰胺键或C-N键链接；
R4与R5各自独立选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、芳基、芳烷基、杂芳基和杂芳烷基；R4与R5相同或不同；
通式(I)中：
R"为通式(IV)所示：
Figure PCTCN2015095758-appb-000013
其中：
Y选自氧、氮或硫，并且：
Y为氮时，R””为R7和R8，R”为
Figure PCTCN2015095758-appb-000014
Y为氧时，R””为R9，R”为-OR9；
Y为硫时，R””为R10，R”为-SR10；
其中：R7、R8、R9、R10可以相同或不同，各自独立选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、芳基、芳烷基、杂芳基或杂芳烷基；
通式(I)中：
R”'选自氢或烷基；
A＝碳；
L选自氢、烷基、取代烷基、芳基或取代芳基；
D为碳或不存在，t＝0,1,2,3；并且：
当D为碳，B为碳时：A与B之间为碳碳双键或碳碳单键，K与B、D之间为环系 关系；或者，A与B之间为碳碳双键或碳碳单键，K与B连接且K与D不相连；
当K与B、D之间为环系关系时，K选自碳数为2到8烷基、杂烷基、碳数为3到8烯基，或者，K与B、D之间共同形成芳基、取代芳基、杂芳基或取代杂芳基；
当K与B连接且K与D不相连时，K选自氢、烷基、杂烷基、环烷基、杂环基、烯基、炔基、羟基、烷氧基、芳氧基、芳基、芳烷基、杂芳基或杂芳烷基；
当D为碳，B为硫时：则A与B之间为碳硫单键，K不存在；
当D不存时：B为碳，K为氢；
所述烷基、环烷基、杂烷基、杂环基、烯基、炔基、芳基、芳烷基、杂芳基和杂芳烷基各自可为未取代或任选独立的被一或多个选自以以下部分的取代基：羟基、烷氧基、芳氧基、硫代、硫代烷基、芳硫基、氨基、酰胺基、烷氨基、芳氨基、烷基磺酰基、芳基磺酰基、亚磺酰基氨基、烷基、芳基、杂芳基、烷基亚磺酰胺基、芳基亚磺酰胺基、酮基、羧基、烷氧羰基、羧酰胺基、烷氧羰基氨基、烷氧羰基氧基、烷基脲基、芳基脲基、卤代、氰基或硝基。
可选的，所述R基团
Figure PCTCN2015095758-appb-000015
选自下列结构：
Figure PCTCN2015095758-appb-000016
Figure PCTCN2015095758-appb-000017
可选的，所述R'基团
Figure PCTCN2015095758-appb-000018
选自下列结构：
Figure PCTCN2015095758-appb-000019
Figure PCTCN2015095758-appb-000020
Figure PCTCN2015095758-appb-000021
其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
可选的，当Y为氧时，R9为选自下列的基团：
甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、环丙基、环丁基、环戊基、环己基、环庚基或下列结构：
Figure PCTCN2015095758-appb-000022
Figure PCTCN2015095758-appb-000023
可选的，当Y为氮时，R"为选自下列的基团：
Figure PCTCN2015095758-appb-000024
Figure PCTCN2015095758-appb-000025
其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
可选的，当Y为硫时，R"为选自下列的基团：
Figure PCTCN2015095758-appb-000026
其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
可选的，上述通式(I)选自下列通式结构：
Figure PCTCN2015095758-appb-000027
其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
可选的，上述的三肽化合物选自下列结构的化合物：
Figure PCTCN2015095758-appb-000028
Figure PCTCN2015095758-appb-000029
Figure PCTCN2015095758-appb-000030
Figure PCTCN2015095758-appb-000031
Figure PCTCN2015095758-appb-000032
Figure PCTCN2015095758-appb-000033
Figure PCTCN2015095758-appb-000034
Figure PCTCN2015095758-appb-000035
Figure PCTCN2015095758-appb-000036
Figure PCTCN2015095758-appb-000037
Figure PCTCN2015095758-appb-000038
Figure PCTCN2015095758-appb-000039
Figure PCTCN2015095758-appb-000040
Figure PCTCN2015095758-appb-000041
Figure PCTCN2015095758-appb-000042
Figure PCTCN2015095758-appb-000043
Figure PCTCN2015095758-appb-000044
其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
本发明还提供了上述化合物中Y为氧时的化合物的水解产物。
本发明同时还提供了上述化合物的对映体、互变异构体、立体异构体、旋转异构体、非对映异构体或外消旋体。
本发明同时又提供了上述化合物药学上可接受的盐和药学上可接受的酯，所述药学上可接受的盐包括药学上可接受的酸式盐和药学上可接受的碱式盐，所述药学上可以接受的酸式盐包括下列酸中其中之一所形成的盐：硫酸、硫酸氢、盐酸、氢溴 酸、磷酸、硝酸、碳酸、硼酸、甲磺酸、苯磺酸、对甲基苯磺酸、甲酸、乙酸、丙酸、丁酸、丙酮酸、马来酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、苯甲酸、樟脑酸、富马酸、草酸、琥珀酸、樟脑磺酸、顺丁烯二酸、水杨酸或α-乳酸；所述药学上可以接受的碱式盐包括下列碱中其中之一所形成的盐：锂、钠、钾等碱金属，镁、钙、等碱土金属，氢氧化锂、氢氧化钠、氢氧化钾、氢化锂、氢化钠、丁基锂、铵、三乙胺、二异丙基乙基胺、鸟氨酸、精氨酸、赖氨酸或组氨酸；所述药学上可接受的酯包括化合物中羟基或酚羟基与酸形成的酯。
本发明同时又提供了上述化合物的溶剂化混合物，所述溶剂为水、甲醇、乙醇、异丙醇、丁醇、乙酸乙酯和DMSO中的一种或两种以上的组合。
Figure PCTCN2015095758-appb-000045
Figure PCTCN2015095758-appb-000046
Figure PCTCN2015095758-appb-000047
本发明另一方面提供了上述化合物用于制备预防、治疗或延缓高血压及其并发症药物的应用，所述并发症包括：冠心病、心绞痛、急性心力衰竭、慢性充血性心力衰竭、心肌梗塞及其后遗症、充血性心脏病、心肌缺血、心肌炎、心肌纤维化、心肌肥大、动脉粥样硬化、良性小动脉肾硬化症、恶性小动脉肾硬化症、血管生长异常和重塑、血管发生相关的疾病(如新血管黄斑变性)、醛固酮过多症、心律失常、肾病、糖尿病、脑卒中、血栓症、肾衰竭(如：糖尿病肾病)、高血脂、肥胖症、高血糖、视网膜动脉硬化症、高血压眼底病变中的一种或几种。
本发明另一方面又提供了一种药物组合物，该药物组合物包括：上述的化合物、权利要求1-8中任何一项所述的化合物药学上可接受的盐、上述的化合物药学上可接受的载体、赋形剂、稀释剂。
本发明另一方面还提供了上述药物组合物用于制备预防、治疗或延缓高血压及其并发症药物的应用，所述并发症包括：冠心病、心绞痛、心力衰竭(急性或慢性充血性心力衰竭)、心肌梗塞及其后遗症、充血性心脏病、心肌缺血、心肌炎、心肌纤维化、心肌肥大、动脉粥样硬化、良性小动脉肾硬化症、恶性小动脉肾硬化症、血管生长异常和重塑、血管发生相关的疾病(如新血管黄斑变性)、醛固酮过多症、心律失常、肾病、糖尿病、脑卒中、血栓症、肾衰竭(如：糖尿病肾病)、高血脂、肥胖症、高血糖、视网膜动脉硬化症、高血压眼底病变中的一种或几种。
本发明涉及的一类化合物具有抑制血管紧张素转化酶的生物活性，其本身及其药物组合物对高血压以及其他心脑血管系统疾病的预防与治疗方面的作用。
附图说明
图1为血管紧张素转化酶的浓度与OD450nm值得二次曲线拟合图；
图2为SHR大鼠灌胃221S-1a 6小时动脉收缩压变化情况；
图3为SHR大鼠灌胃不同剂量的221S-1a(1#,3#,5#)6小时内动脉收缩压的 变化情况；
图4为SHR大鼠灌胃221S-1a 7天后14天内收缩压变化情况；
图5为SHR大鼠灌胃不同剂量的221S-1a(2#,4#,6#)14天内动脉收缩压的变化情况。
具体实施方式
丹参(拉丁学名：Salvia miltiorrhiza Bunge)作为传统中药的中药组成部分，一直被用作治疗心脑血管类的疾病。近期，在治疗高血压方面，关于丹参的协同增效作用，已有多篇文献报道。(Biological&Pharmaceutical Bulletin，2011,34(10),1596-1601.；Phytotherapy Research，2010,24(5),769-774.；American Journal of Physiology，2007,292(5,Pt.2),H2131-H2137.；中国临床康复，2006,10(23),73-75；Medicinal and Aromatic Plants--Industrial Profiles，2000,14(Sage),193-205.)其中丹参类药物在联合普利类、沙坦类降压药，临床效果明显，特别是对高血压伴随糖尿病的患者作用显著。
丹参素是丹参水溶性提取物的主要成分，其邻苯二酚、乳酸结构，使其具有独特的抗氧化、保护心脑血管、促进血管舒张、降低血压等多种作用(Characterization of the Radical Scavenging and Antioxidant Activities of Danshensu and Salvianolic Acid B.Food and Chemical Toxicology,2008,46(1),73-81；丹参素对异丙肾上腺素损伤大鼠内皮血管活性的保护作用及机制研究.中草药，2013，1：59-64)。现已发现多酚类天然产物具有血管紧张素转化酶抑制的作用。(Angiotensin-Converting Enzyme Inhibitory Effects by Plant Phenolic Compounds:A Study of Structure Activity Relationships.J.Agric.Food Chem.2013,61,11832-11839.；Inhibition of Angiotesin-Converting Enzyme by Quercetin Alters the Vascular Response  to Brandykinin and Angiotensin I.Pharmacology，2002,65,182-186.；Ferulic Acid Improves Cardiovascular and Kidney Structure and Function in Hypertensive Rats.J.Cardiovasc.Pharmacol.2013,61,240-249.；Tannic Acid,an Inhibitor for Renal Angiotensin Type 1Receptor and Hypertension in Spontaneously Hypertensive Rats.Endocr.Rev.2012,33,SAT-248.)本发明参考前期研究成果(CN 1868998A，β-(3,4-二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途)，将丹参素基团及其他酚酸类基团引入传统ACEI类药物骨架分子中，并结合“君-使药对”及前药的设计思想，同时引入冰片、薄荷醇等基团，设计出一类新的潜在具有血管紧张素转化酶抑制剂性能的药物前导物。
本发明参考了已公开的血管紧张素转化酶抑制剂的化学结构，如：卡托普利、依那普利、赖诺普利、培哚普利、阿拉普利、地拉普利、喹那普利、雷米普利、西拉普利、贝那普利、福辛普利、佐芬普利、群多普利、咪达普利、替莫普利、螺普利及莫希普利。
本发明还参考了已公开的关于血管紧张素转化酶抑制剂的专利文献，如：Antihypertensive mercaptoacylamino acid derivatives and their use，(1980，EP 9898 A1)，Preparation of converting enzyme inhibitor 5,6-dihydro[1,4]thiazino[4,3-a]quinoline-1(2H),4(4aH)-dione，(1981，US 4273927 A)，[4R]-3-(ω-Aroylpropionyl)-4-thiazolidinecarboxylic acids and esters，(1983，US 4374249 A)。
也参考了，1993年，WO 9302679 A1，Method of treating premenstrual syndrome by administration of an angiotensin-converting enzyme inhibitor，其公开了下面的化合物：
Figure PCTCN2015095758-appb-000048
也参考了，2007年，US 20070032661 A1，Process for the preparation of intermediates of perindopril，其公开了下面的化合物：
Figure PCTCN2015095758-appb-000049
在本发明全文中，除非另外说明，以下名称或术语的定义适用于本发明的所有内容：
术语“烷基”意指为直链或支链脂肪烃基，包含1-15个碳原子，优选的烷基含有1-6个碳原子。包括，但不限于，甲基、乙基、丙基、异丙基、
术语“取代烷基”意指烷基基团被一个或多个取代基取代，取代基团可以相同，也可以不相同，各取代基可独立选自烷基、环烷基、芳基、氰基、硝基、卤素、烷氧基、氨基、烷基取代的1-3级氨基或环烷基取代的1-3级氨基、羟基、巯基、烷硫基、烷基酮基、羧基。
术语“烯基”意指含有至少一个C＝C双键的脂肪烃基，可为直链或支链或环链，包含2至15个碳原子。优选的含有烯基的烃链具有2-8个碳原子。
术语“取代烯基”意指该烯基基团可以被一个或多个取代基取代，取代基团可以相同，也可以不相同，各取代基可独立选自烷基、环烷基、芳基、氰基、硝基、卤素、烷氧基、氨基、烷基取代的1-3级氨基或环烷基取代的1-3级氨基、羟基、巯基、烷硫基、烷基酮基、羧基。
术语“炔基”意指含有至少一个C≡C三键的脂肪烃基，可为直链或支链或 环链，包含2至15个碳原子。优选的含有炔基的烃链具有2-8个碳原子。
术语“取代炔基”意指该烯基基团可以被一个或多个取代基取代，取代基团可以相同，也可以不相同，各取代基可独立选自烷基、环烷基、芳基、氰基、硝基、卤素、烷氧基、氨基、烷基取代的1-3级氨基或环烷基取代的1-3级氨基、羟基、巯基、烷硫基、烷基酮基、羧基。
术语“芳基”意指芳香族单环或多环结构，包含6-14的碳原子，优选6-12个碳原子。
术语“取代芳基”意指该芳基基团可以被一个或多个取代基取代，取代基团可以相同，也可以不相同，各取代基可独立选自烷基、环烷基、芳基、氰基、硝基、卤素、烷氧基、氨基、烷基取代的1-3级氨基或环烷基取代的1-3级氨基、羟基、巯基、烷硫基、烷基酮基、羧基。
术语“杂芳基”意指芳香族单环或多环结构，其中一个或多个环上的碳原子被其他元素取代，该其他元素包含但不限于氮、氧、硫，包含5-14的碳原子，优选5-12个碳原子。优选的杂芳基包含但不限于：吡啶基、嘧啶基、吡嗪基、哒嗪基、吲哚基、喹啉基、异喹啉基、吡唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡咯基、苯并呋喃基、苯并噻吩基、
术语“取代杂芳基”意指该杂芳基基团可以被一个或多个取代基取代，取代基团可以相同，也可以不相同，各取代基可独立选自烷基、环烷基、芳基、氰基、硝基、卤素、烷氧基、氨基、烷基取代的1-3级氨基或环烷基取代的1-3级氨基、羟基、巯基、烷硫基、烷基酮基、羧基。优选的取代芳烷基包含但不限于：川芎嗪醇基。
术语“芳烷基”意指芳基-烷基基团。芳基、烷基如上文所述，优选的芳烷基包含但不限于：苄基、苯乙基。
术语“取代芳烷基”意指该芳烷基基团可以被一个或多个取代基取代，取代基团可以相同，也可以不相同，各取代基可独立选自烷基、环烷基、芳基、氰基、 硝基、卤素、烷氧基、氨基、烷基取代的1-3级氨基或环烷基取代的1-3级氨基、羟基、巯基、烷硫基、烷基酮基、羧基。优选的取代芳烷基包含但不限于：对甲基苄基、细辛醇基。
术语“环烷基”意指非芳香族单环或多环结构，一般包含3至10个碳原子。优选的环烷基包含3-7个碳原子环结构但不限于：环丙基、环丁基、环戊基、环己基、环庚基。
术语“取代环烷基”意指该环烷基基团可以被一个或多个取代基取代，取代基团可以相同，也可以不相同，各取代基可独立选自烷基、芳基、氰基、硝基、卤素、烷氧基、氨基、烷基取代的1-3级氨基或环烷基取代的1-3级氨基、羟基、巯基、烷硫基、烷基酮基、羧基。优选的取代环烷基包含3-7个碳原子环结构但不限于：右旋冰片基、左旋薄荷醇基、降冰片基。
术语“卤素”意指氟、氯、溴、碘。优选的卤素包含氟、氯、溴。
术语“杂环基”意指非芳香族的饱和单环或多环系统，环系原子一般在10个原子以内，优选4-10个还原子，其中除碳原子外还含有一个或多个非碳原子，如氮、氧、硫原子，他们可以单独或组合存在。其中，在环系统中不存在相邻的氧-氧、氧-硫或硫-硫基团。优选的杂环基包含但不限于：哌嗪基、吗啉基、硫吗啉基、哌啶基、吡咯基等。
术语取代“杂环基”意指该杂环基基团可以被一个或多个取代基取代，取代基团可以相同，也可以不相同，各取代基可独立选自烷基、芳基、氰基、硝基、卤素、烷氧基、氨基、烷基取代的1-3级氨基或环烷基取代的1-3级氨基、羟基、巯基、烷硫基、烷基酮基、羧基。优选的取代杂环基包含但不限于：N-甲基哌嗪基、3-氟哌啶基、2，6-二甲基吗啉基、2-甲基吡咯基等。
术语“杂芳烷基”意指杂芳基烷基基团，杂芳基与烷基如上所述。优选的杂芳基烷基包含但不限于：2-吡啶甲基，3-吡啶甲基，4-吡啶甲基。
术语“酰基”意指烷基-C(O)-、取代烷基-C(O)-、环烷基-C(O)-、取代环烷 基-C(O)-、杂环基-C(O)-。各基团如上文所述，优选的酰基包含但不限于：乙酰基、丙酰基、环丁酰基。
术语“芳酰基”意指芳基-C(O)-、取代芳基-C(O)-。各基团如上文所述，优选的酰基包含但不限于：苯甲酰基、对甲基苯甲酰基。
术语“烷氧基”意指烷基-O-、取代烷基-O-。各基团如上文所述。优选的烷氧基包含但不限于：甲氧基、乙氧基、异丙基、右旋冰片氧基、左旋薄荷醇氧基、2,3,4-三甲氧基苯-2'-烯基丙氧基(细辛醇氧基)、川芎嗪氧基。
术语“芳烷氧基”意指芳烷基-O-、取代芳烷基-O-。各基团如上文所述。优选的芳烷氧基包含但不限于：苯甲氧基、2,3,4-三甲氧基苯-2'-烯基丙氧基(细辛醇氧基)。
术语“芳氧基”意指芳基-O-、取代芳基-O-。各基团如上文所述。优选的芳氧基包含但不限于：苯氧基、对甲基苯氧基。
术语“烷硫基”意指烷基-硫-基团，其中烷基部分如上所述。优选的烷硫基包含但不限于：甲硫基、乙硫基、丙硫基。
术语“芳烷硫基”意指芳烷基-硫-基团，其中芳烷基基团如上所述。优选的芳烷硫基包含但不限于：苯甲硫基、苯乙硫基。
术语“芳硫基”意指芳基-硫-基团，其中芳基基团如上所述。优选的芳硫基包含但不限于：苯硫基。
术语“烷基磺酰基”意指烷基-S(O2)-基团。烷基如上文所述。优选的烷基磺酰基包含但不限于：甲基磺酰基、乙基磺酰基。
术语“芳基磺酰基”意指芳基-S(O2)-基团。芳基如上文所述。优选的芳基磺酰基包含但不限于：苯磺酰基、萘磺酰基。
术语“至少一种”意指一种或多种。
术语“取代的”指选自指定的基团代替在指定的原子上的一个或多个氢，并符合指定原子的正常价态，且产生的化合物稳定。
术语“任意取代的”指根据需要，在满足取代的条件下，选用指定的基团、原子团或部分取代。
3.盐、溶剂化合物
本发明所设计的三肽及其类似物还包含其“前药”、“溶剂合物”、“盐”(包括：“酸式盐”、“碱式盐”和内盐)和“酯”。这些三肽类化合物的“前药”、“溶剂合物”和“盐”均在本发明范围内。其中，“溶剂合物”和“盐”等同于相应化合物的游离形式。
其中，术语“前药”意指药物前体的化合物，可通过代谢或体内化学转化成为通式(I)的化合物或其盐或其溶剂合物或其酯。
其中，术语“溶剂合物”意指本发明化合物与一种或多种溶剂分子的物理缔合。该物理缔合涉及各种程度的离子和共价键结合，包括氢键、范德华力等作用。其中，“溶剂合物”由两部分组成：溶液相和可分离溶剂合物两者。适当的溶剂合物包含但不限于：水合物、甲醇合物、乙醇、DMSO、乙酸乙酯合物。
术语“盐”包括酸式盐、碱式盐和内盐。意指本发明中设计的三肽类化合物(通式(I))与无机酸或有机酸所形成的酸式盐，与无机碱或有机碱所形成的碱式盐，以及三肽类化合物(通式(I))中含有的碱性基团(如氨基、胍基、咪唑基、吲哚基等)与酸性基团(如羧酸、烷基磺酸、磷酸等)所形成的内盐。
其中，形成酸式盐的酸包含但不限于以下酸：
硫酸、硫酸氢、盐酸、氢溴酸、磷酸、硝酸、碳酸、硼酸、甲磺酸、苯磺酸、对甲基苯磺酸、甲酸、乙酸、丙酸、丁酸、丙酮酸、马来酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、苯甲酸、樟脑酸、富马酸、草酸、琥珀酸、樟脑磺酸、顺丁烯二酸、水杨酸和α-乳酸。此外，由P.Stahl,Camille G.编辑的《Handbook of Pharmaceutical Salts.Properties,Selection and Use》,2002,Zurich:Wiley-VCH中介绍的药学上可以接受的形成盐的酸也可引用结合到本发明专利中。
其中，形成碱式盐的碱包含但不限于以下碱：
锂、钠、钾等碱金属，镁、钙、等碱土金属，氢氧化锂、氢氧化钠、氢氧化钾、氢化锂、氢化钠、丁基锂、铵、三乙胺、二异丙基乙基胺、鸟氨酸、精氨酸、赖氨酸、组氨酸等碱性氨基酸。
另外，本发明三肽类化合物所形成的药学上可以接受的酯，意指化合物中的羟基或酚羟基与羧酸(包含但不限于：烷基羧酸、取代烷基羧酸、芳基羧酸、取代芳基羧酸、芳烷基羧酸、取代芳烷基羧酸、环烷基羧酸、取代环烷基羧酸、杂环基羧酸、杂芳烷基羧酸，例如：乙酸酯、丙酸酯、苯甲酸酯、烟酸酯)形成的羧酸酯；还包括，化合物中的羟基或酚羟基与磺酸(包含但不限于：烷基磺酸、芳基磺酸、取代芳基磺酸酯，例如：甲磺酸酯、苯磺酸酯、对甲基苯磺酸酯)形成的磺酸酯；还包括，化合物中的羟基或酚羟基与氨基酸(包含但不限于：α-氨基酸、β-氨基酸、ω-氨基酸，例如丙氨酸酯、谷氨酸酯)形成的酯；还包括，化合物中的羟基或酚羟基与磷酸、单烷基磷酸、二烷基磷酸、亚磷酸(例如亚磷酸二乙酯)形成的磷酸酯。
另外，本发明三肽化合物及其药学上可接受的(无毒性、生理学上课接受的)“溶剂合物”、“盐”(包括：“酸式盐”、“碱式盐”和内盐)、“酯”，还有相关的“前药”，所涉及的对映体、立体异构体、旋转异构体、互变异构体、位置异构体和外消旋体均在本发明范围之内。
另外，在合成过程中可能保护所关注分子上的敏感货反应性的基团。代表性的保护基在T.W.Greene和P.G.M.Wuts“Protective Groups in Organic Synthesis”John Wiley&Sons,Inc.,New York,1999中叙述，其全部内容引入本发明作为参考。可以利用本领域公知的方法添加或去除相应的保护基。
4.药物组合物
术语“组合物”意指涵盖包含特定量的特定成分的产品，以及由特定量的特定成分的组合二直接或间接形成的任何产品。
“哺乳动物”意指人及其他哺乳动物。
“患者”包括人和动物。
“有效量”意指本发明所述的化合物或药物组合物的量在抑制血管紧张素转化酶上是有效的，并因此产生所需的预防、治疗、改善或抑制的效果。
“药学上可以接受的载体”意指具有用于配制本发明组合物的足够纯度和质量的化合物和组合物，在适当地给动物或人时，不产生不良反应，用作药物的载体。
“药学上可以接受的稀释剂”意指具有用于配制本发明组合物的足够纯度和质量的化合物和组合物，在适当地给动物或人时，不产生不良反应，用作药物的稀释剂。
药用组合物一般至少包括一种本发明化合物和一种或一种以上的药学上可接受的载体。其中，固体剂型可包含：填充剂(如淀粉、微晶纤维素、蔗糖、葡萄糖、乳糖、山梨醇、甘露糖醇等)、粘合剂(明胶、羧甲基纤维素、海藻酸盐、阿拉伯胶)、保湿剂(甘油)、崩解剂(碳酸钙、淀粉、琼脂、海藻酸)、溶解延迟剂(石蜡)、吸收促进剂(季铵盐化合物)、湿润剂(十六醇、单硬脂酸甘油酯)、吸附剂(高岭土、膨润土)、润滑剂(滑石粉、固体聚乙二醇、硬脂酸钾、钙或镁盐、月桂基硫酸钠，其中水溶性润滑剂包括：氯化钠、乙酸钠、苯甲酸钠油酸钠)、着色剂(粘土、氧化铝)及缓冲剂。
本发明的化合物可按照常规制药工艺制成合适的剂型，如片剂、胶囊。
5.病症和疾病
本发明的化合物(I)及其药学上可接受的(无毒性、生理学上课接受的)盐、酯、药物组合物适用于预防、治疗或延缓以下心脑血管疾病特别是与高血压相关及其并发症。
所述病症和疾病包括：高血压、冠心病、心绞痛、心力衰竭(急性或慢性充血性心力衰竭)、心肌梗塞及其后遗症、充血性心脏病、心肌缺血、心肌炎、心 肌纤维化、心肌肥大、动脉粥样硬化、良性小动脉肾硬化症、恶性小动脉肾硬化症、血管生长异常和重塑、血管发生相关的疾病(如新血管黄斑变性)、醛固酮过多症、心律失常、肾病、糖尿病、脑卒中、血栓症、肾衰竭(如：糖尿病肾病)、高血脂、肥胖症、高血糖、视网膜动脉硬化症、高血压眼底病变中的一种或几种。
6.本发明中所涉及的细辛醇制备方法包括：
(1)化合物V与化合物VI在脂肪醇的存在下经催化剂催化反应得到化合物VII：
Figure PCTCN2015095758-appb-000050
其中R1选自C1-C5的直链或支链烷基；
(2)还原化合物VII得到化合物VIII：
Figure PCTCN2015095758-appb-000051
步骤(1)是将化合物VI与脂肪醇先在二甲苯、甲苯或苯中回流反应3-12小时，进一步可选4-10个小时，冷却至室温后，加入2,4,5-三甲氧基苯甲醛(化合物V)与催化剂，再回流反应5-24小时，进一步可选8-14小时，得到化合物VII；步骤(1)中所使用的脂肪醇为甲醇、乙醇、丙醇、异丙醇、丁醇、异丁醇、正戊醇和异戊醇中的一种或其中任意组合，进一步可选甲醇和乙醇；中的一种或其中任意组合脂肪醇与化合物VI的摩尔比率在1:1～1:10，进一步可选脂肪醇与化合物VI的摩尔比率为1:1～1:4；所用的催化剂为吡啶、2,4,6-三甲基吡啶、2,6-二甲基吡啶、2,6-二叔丁基-4-甲基吡啶、4-二甲氨基吡啶、哌啶和四氢吡咯中的一种或其中任意组合；催化剂与2,4,5-三甲氧基苯甲醛的摩尔比率在 0.1:1～2:1。
步骤(2)所用还原剂为硼氢化钠、二氢双(2-甲氧乙氧基)铝酸钠、氢化铝锂或二异丁基氢化铝；还原剂与化合物VII的比率为1:1～10:1；所用溶剂为四氢呋喃、1,4二氧六环、二甲基乙二醚、甲苯、苯、二甲苯、乙醚、甲基叔丁基醚、二氯甲烷、二氯乙烷、三氯甲烷、四氯甲烷和正己烷中的一种或其中任意组合；反应温度在-78℃～25℃；反应时间在0.5～24小时之间。
缩写：
EDCI 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐
DCC 二环己基碳二亚胺
Alloc 烯丙氧甲酰基
Fmoc 芴甲氧羰基
Bn 苄基三苯甲基
Tr 三苯甲基
Figure PCTCN2015095758-appb-000052
 1-丙基磷酸酐
HOBt 1-羟基苯并三氮唑
THF 四氢呋喃
EtOAc 乙酸乙酯
MeOH 甲醇
EtOH 乙醇
TFA 三氟乙酸
DCM 二氯甲烷
DIPEA 二异丙基乙胺
DMF N,N-二甲基乙酰胺
DMSO 二甲基亚砜
DMAP 4-N,N-二甲基吡啶
HATU 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
PyBOP 1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐
Boc 叔丁氧羰基
Cbz 苄氧羰基
NMR 核磁共振
MS 质谱
以下提供制备和实例加以说明本发明的具体实施例。除非特别说明，否则这些具体实施例并不打算以任何方式限制本发明的范围，其实施例中使用的各种原料、方法完全在本领域技术人员的知识范围内。
实施例1：
Figure PCTCN2015095758-appb-000053
步骤一：
Figure PCTCN2015095758-appb-000054
1000毫升三口烧瓶，带温度计，分别加入L-脯氨酸(115.1g，1.0mol)、1,4-二氧六环(300mL)、2mol/L氢氧化钠水溶液(400mL)，冷却至0℃，搅拌10分钟，再滴加二碳酸二叔丁酯(283.8g，1.3mol)(60分钟内滴完)，缓慢升温，室温下搅拌6小时或过夜。反应液用4mol/L稀盐酸调节pH＝4，用乙酸乙酯/水体系萃取、洗涤3次，合并有机相，无水硫酸钠干燥，得221S-1a-1白色固体189.2克，产率88％。
步骤二：
Figure PCTCN2015095758-appb-000055
500毫升三口烧瓶，带温度计，分别加入221S-1a-1(2.15g，10mmol)、四氢呋喃(35mL)、D-冰片(1.39g，9mmol)、DMAP(0.12g，1mmol)，冷却至0℃，搅拌5分钟，分步加入EDCI(2.30g，12mmol)(15分钟内加完)，缓慢升温，室温下24小时。反应液用乙酸乙酯/水体系萃取、洗涤3次，合并有机相，无水硫酸钠干燥，抽滤，所得固体经硅胶色谱柱分离得到2.28克221S-1a-2，产率60％。
步骤三：
Figure PCTCN2015095758-appb-000056
500毫升单口烧瓶，分别加入221S-1a-2(3.51g，10mmol)、三氟乙酸(8mL)、二氯甲烷(16mL)，氮气保护下，室温搅拌5小时，减压浓缩后，加入乙酸乙酯(50mL)，水(50mL)，饱和碳酸氢钠水溶液(50mL)，萃取分离3次，合并有机相，无水硫酸钠干燥，抽滤，减压浓缩，得到浅黄色油状物或半固体221S-1a-3 2.2克，产率88％。产品无须进一步纯化，直接进入下一步反应。
步骤四：
Figure PCTCN2015095758-appb-000057
250毫升单口烧瓶，分别加入221S-1a-3(2.51g，10mmol)、N-Boc-Ala(2.08g，11mmol)、二氯甲烷(50mL)，HOBT(1.49g，11mmol)，EDCI(2.30g，12mmol)，氮气保护下，室温搅拌过夜，减压浓缩后，加入乙酸乙酯(50mL)，水(50mL)， 饱和碳酸氢钠水溶液(50mL)，萃取分离3次，合并有机相，无水硫酸钠干燥，抽滤，减压浓缩，所得粗品经硅胶色谱柱分离得到浅黄色油状物221S-1a-4 3.85克，产率91.2％。
MS m/z＝[M+1]423.2900
1H NMR(600MHz,CDCl3)δ5.39(d,J＝8.0Hz,1H),4.96(d,J＝9.7Hz,1H),4.56(dd,J＝8.4,3.9Hz,1H),4.52–4.44(m,1H),3.65–3.58(m,1H),2.38–2.30(m,1H),2.27–2.20(m,1H),2.09–1.97(m,3H),1.90–1.84(m,1H),1.77–1.72(m,1H),1.70–1.67(m,1H),1.43(s,9H),1.36(d,J＝6.9Hz,3H),1.33–1.21(m,3H),1.03(dd,J＝13.8,3.3Hz,1H),0.89(s,3H),0.86(s,3H),0.80(s,3H).
步骤五：
Figure PCTCN2015095758-appb-000058
按照实施例1步骤三，投4.22g 221S-1a-4得到浅黄色或类白色固体221S-1a-5 2.93g克，产率91％。产品无须进一步纯化，直接进入下一步反应。
MS m/z＝[M+1]323.2386
1H NMR(600MHz,cdcl3)δ4.94(d,J＝9.7Hz,1H),4.54(dd,J＝8.6,4.4Hz,1H),4.34(d,J＝6.7Hz,1H),3.69–3.63(m,1H),3.59–3.54(m,1H),2.36–2.27(m,2H),2.13–2.00(m,4H),1.83–1.74(m,2H),1.72–1.68(m,1H),1.56(d,J＝7.0Hz,3H),1.51(d,J＝6.9Hz,1H),1.34–1.27(m,1H),1.26–1.20(m,1H),0.97(dd,J＝13.8,3.2Hz,1H),0.89(s,3H),0.87(s,3H),0.78(s,3H).
步骤六：
Figure PCTCN2015095758-appb-000059
100毫升单口烧瓶，分别加入221S-1a-5(0.322g，1.0mmol)、D-丹参素(0.22g，1.1mmol)、N,N-二甲基甲酰胺(5mL)/六甲基磷酰胺(5mL)，HOBT(0.15g，1.1mmol)，EDCI(0.18g，1.3mmol)，氮气保护下，室温搅拌36小时，加入乙酸乙酯(50mL)，水(50mL)，饱和碳酸氢钠水溶液(50mL)，萃取分离3次，合并有机相，无水硫酸钠干燥，抽滤，减压浓缩，所得粗品经硅胶色谱柱分离得到类白色或浅白色泡沫状固体221S-1a 0.28克，产率56％。
MS m/z＝[M+1]：503.0
1H NMR(600MHz,CDCl3)δ8.16(s,1H),7.42(d,J＝8.1Hz,1H),6.81(d,J＝8.0Hz,1H),6.71(s,1H),6.65(d,J＝9.8Hz,1H),5.85(s,1H),4.93(d,J＝9.0Hz,1H),4.81–4.73(m,1H),4.31–4.26(m,1H),4.23(dd,J＝8.6,4.3Hz,1H),3.81(dd,J＝17.0,7.3Hz,1H),3.68–3.59(m,1H),3.34(d,J＝4.6Hz,1H),3.10(dd,J＝14.1,3.9Hz,1H),2.96(dd,J＝14.1,8.1Hz,1H),2.37–2.31(m,1H),2.25–2.17(m,1H),2.12–2.01(m,2H),1.98–1.92(m,1H),1.90–1.84(m,1H),1.79–1.73(m,1H),1.68(t,J＝4.4Hz,1H),1.40(d,J＝7.0Hz,3H),1.35–1.20(m,3H),1.02(dd,J＝13.8,3.4Hz,1H),0.88(s,3H),0.86(s,3H),0.80(s,3H).
13C NMR(600MHz,CDCl3)δ173.49(s),171.96(s),171.74(s),144.03(s),143.97(s),128.27(s),121.54(s),116.89(s),115.15(s),81.17(s),72.79(s),59.51(s),49.08(s),48.10(s),47.32(s),46.48(s),44.95 (s),39.81(s),36.64(s),29.30(s),28.14(s),27.29(s),24.94(s),19.82(s),18.94(s),17.71(s),13.70(s),0.15(s).
步骤七：
Figure PCTCN2015095758-appb-000060
100毫升单口烧瓶，分别加入221S-1a(0.251g，0.5mmol)、氢氧化锂(0.05g，2.0mmol)、水：甲醇：四氢呋喃＝3:1:1(10mL)，氮气保护下，室温搅拌16小时，加入乙酸乙酯(30mL)，水(30mL)，萃取分离3次，合并有机相，无水硫酸钠干燥，抽滤，减压浓缩，所得粗品经硅胶色谱柱分离得到类白色或浅白色泡沫状固体221S-1a-6 0.14克，产率76％。MS m/z＝[M+1]：366.9
根据上述实施例1中所描述的程序，替换适当的起始原料和试剂制备出通式(I)的下列化合物实施例2-28：
Figure PCTCN2015095758-appb-000061
表1
Figure PCTCN2015095758-appb-000062
Figure PCTCN2015095758-appb-000063
Figure PCTCN2015095758-appb-000064
Figure PCTCN2015095758-appb-000065
Figure PCTCN2015095758-appb-000066
其中，221S-2a、221S-144a合成过程中所用偶联试剂为
Figure PCTCN2015095758-appb-000067
7a合成过程中所用偶联试剂为HATU，所用碱为DIPEA；221S-119a合成过程中所用偶联试剂为 PyBOP；221S-11a，221S-12a合成过程中所用偶联试剂为DCC。
其中，关键中间体左旋丹参素的合成参考文献(CN 103288630)，川芎嗪醇的合成参考文献(Journal of Natural Products,2012,75(9),1589-1594.)，环己烷并脯氨酸的合成参考文献(Org.Biomol.Chem.,2012,10,2840-2846)，细辛醇的合成路线如下：
Figure PCTCN2015095758-appb-000068
i：(1)甲醇、甲苯，110℃，4小时；(2)吡啶，六氢吡啶，回流18小时；j：LiAlH4，THF，冰，AlCl3，0℃，30分钟
实施例29：
Figure PCTCN2015095758-appb-000069
步骤一：
Figure PCTCN2015095758-appb-000070
500毫升三口烧瓶，带温度计，分别加入N-Cbz脯氨酸(2.49g，10mmol)、DCM(50mL)、1-甲基哌嗪(1.10g，11mmol)、DMAP(0.12g，1.0mmol)，冷却至0℃，搅拌5分钟，分步加入EDCI(2.30g，12mmol)(15分钟内加完)，缓慢升温，室温下24小时。反应液用乙酸乙酯/水体系萃取、洗涤3次，合并有机相，无水硫酸钠干燥，抽滤，所得固体经硅胶色谱柱分离得到221S-151a-1 2.91克， 产率88％。
步骤二：
Figure PCTCN2015095758-appb-000071
500毫升三口烧瓶，分别加入221S-151a-1(1.66g，5mmol)、钯碳(0.16g)、甲醇(25mL)，通入氢气，常压，室温搅拌24小时。过滤除掉钯碳，减压旋蒸，所得油状物经硅胶色谱柱分离得到221S-151a-2 0.89克，产率90％。
步骤三：
Figure PCTCN2015095758-appb-000072
500毫升三口烧瓶，带温度计，分别加入221S-151a-2(1.97g，10mmol)、DCM(50mL)、N-Cbz丙氨酸(2.45g，11mmol)、DMAP(0.12g，1.0mmol)，冷却至0℃，搅拌5分钟，分步加入EDCI(2.30g，12mmol)(15分钟内加完)，缓慢升温，室温下24小时。反应液用乙酸乙酯/水体系萃取、洗涤3次，合并有机相，无水硫酸钠干燥，抽滤，所得固体经硅胶色谱柱分离得到221S-151a-3 3.26克，产率81％。
步骤四：
Figure PCTCN2015095758-appb-000073
同实施例29步骤二，投221S-151a-34.02克，得到221S-151a-4 2.01克，产率 75％。
步骤五：
Figure PCTCN2015095758-appb-000074
同实施例1步骤六，投221S 151a-4 0.27克得到221S 151a 0.27克，产率61％。
步骤六：
Figure PCTCN2015095758-appb-000075
500毫升三口烧瓶，分别加入221S-151a(0.45mg，1mmol)、甲醇(25mL)，冷却至0℃，搅拌5分钟，缓慢通入盐酸气体，2-4℃搅拌4小时。抽滤，所得白色固体为221S-151a-5 0.40克，产率83％。
其他含有胺类的化合物，可用同样的方法制成盐酸盐。此外其他酸式盐，也可用类似的方法，在含有胺类化合物的溶剂中，缓慢加入相应的酸，低温(2-4℃)或室温搅拌2-10小时得到相应的酸式盐。
实施例30-35：
根据上述实施例29中所描述的方法，替换适当的起始原料和试剂制备出通式(I)的下列化合物：
表2
Figure PCTCN2015095758-appb-000076
Figure PCTCN2015095758-appb-000077
其中，221S-153a合成过程中脯氨酸、丙氨酸均用Boc保护，脱Boc反应均按照
实施例1，步骤二进行。
实施例36：
Figure PCTCN2015095758-appb-000078
步骤一：
Figure PCTCN2015095758-appb-000079
N-Boc脯氨酸(21.5g，0.1mol)，DCC(20.6g，0.1mol)，DMAP(1.22g，0.01mmol)依次加入含有150mL的DMF中。该反应体系在室温搅拌10分钟后，冷至0℃。再滴加乙硫醇(6.82g，0.11mol)，反应过夜。向反应体系中加200mL水淬灭反应。过滤，滤饼用乙酸乙酯洗涤，出去DCU。合并有机相，依次用饱和碳酸钠水溶液(20mL×3)、水、饱和氯化钠水溶液洗涤，无水硫酸镁干燥，过滤，浓缩。低压色谱柱层析纯化得产品221S-177a-118.4g，产率71％。
步骤二：
Figure PCTCN2015095758-appb-000080
221S-177a-1(2.59g，10mmol)溶于EtOAc(25mL)，搅拌均匀后，于室温下通入HCl气体30分钟。再用氮气吹出剩余的HCl气体，减压旋蒸，真空干燥的白色固体221S-177a-21.66g，产率85％。
步骤三：
Figure PCTCN2015095758-appb-000081
250毫升单口烧瓶，分别加入221S-177a-2(1.95g，10mmol)、N-Boc-丙氨酸(2.08g，11mmol)、DCM(30mL)，HOBT(1.49g，11mmol)，EDCI(2.30g，12mmol)，氮气保护下，室温搅拌过夜，减压浓缩后，加入乙酸乙酯(50mL)，水(50mL)，饱和碳酸氢钠水溶液(50mL)，萃取分离3次，合并有机相，无水硫酸钠干燥，抽滤，减压浓缩，所得粗品经硅胶色谱柱分离得到浅黄色油状物221S-177a-3 2.51克，产率76％。
步骤四：
Figure PCTCN2015095758-appb-000082
同实施例1，步骤五，投3.3g 221S-177a-3，得到类白色固体221S-177a-4 1.66克，产率74％。产品无须进一步纯化，直接进入下一步反应。MS ESI+ve m/z:231.9。
步骤五：
Figure PCTCN2015095758-appb-000083
同实施例1，步骤六，投0.23g 221S-177a-4，得到221S-177a 0.22克，产率51％。MS ESI+ve m/z:411.2。
实施例37：
Figure PCTCN2015095758-appb-000084
步骤一：
Figure PCTCN2015095758-appb-000085
N-Boc脯氨酸(2.15g，10mmol)溶于干燥的THF(40mL)，再加入2,2'-二硫吡啶(2.20g，10mmol)，三苯基膦(3.14g，12mmol)。室温搅拌3小时。用乙酸乙酯/水体系萃取分离。有机相，再用水、饱和氯化钠水溶液洗涤，无水硫酸 镁干燥，过滤，浓缩。低压色谱柱层析纯化得产品221S-181a-1 2.46克，产率80％。
步骤二：
Figure PCTCN2015095758-appb-000086
同实施例1，步骤三，投3.08g 221S-181a-1，得到221S-181a-2 1.62克，产率78％。MS ESI+ve m/z:209.0。
步骤三：
Figure PCTCN2015095758-appb-000087
同实施例1，步骤四，投2.08g 221S-181a-2，得到221S-181a-3 3.31克，产率87％。MS ESI+ve m/z:379.9。
步骤四：
Figure PCTCN2015095758-appb-000088
同实施例1，步骤三，投3.80g 221S-181a-3，得到221S-181a-4 2.0克，产率73％。MS ESI+ve m/z:279.9。
步骤五：
Figure PCTCN2015095758-appb-000089
同实施例1，步骤六，投0.28g 221S-181a-4，得到221S-181 0.22克，产 率48％。MS ESI+ve m/z:460.0。
实施例37：
步骤一：
Figure PCTCN2015095758-appb-000090
250毫升单口烧瓶，分别加入221S-1a-5(0.32g，1.0mmol)、原儿茶醛(0.166g，1.2mmol)、二氯乙烷(25mL)，氰基硼氢化钠(0.10g，1.5mmol)，醋酸2滴，氮气保护下，室温6小时，减压浓缩后，加入乙酸乙酯(50mL)，水(50mL)，饱和碳酸氢钠水溶液(50mL)，萃取分离3次，合并有机相，无水硫酸钠干燥，抽滤，减压浓缩，所得粗品经硅胶色谱柱分离得到浅黄色油状物221S-211 0.15克，产率34％。
步骤二：
Figure PCTCN2015095758-appb-000091
同实施例1，步骤七，投0.44g 221S-211，得到221S-211-1 0.16克，产率52％。MS ESI+ve m/z:309.2。
本发明中所描述的具体实施例仅为对本发明精神举例说明。本发明所属技术领域的技术人员可以对所描述的具体实施例做各种各样的修改或补充或采用类似的方式代替，但并不偏离本发明的精神或超越所附权利要求书所定义的范围。
本发明LC-MS测试方法：
LC-QTOF MS&MS/MS条件:HPLC设备:Agilent 1200 Infinity LC；色谱 柱:Agilent HC-C184.6×250mm，5μm；流速:0.6mL/min.；柱温:30℃；流动相:A-H2O,0.1％乙酸/B-甲醇,A:B＝20:80；MS设备:Agilent 6520 QTOF；离子源:Dual ESI；离子模式:正；离子喷雾电压:3500V；干气温度:350℃；干气流速:10.0L/min.(N2)；喷雾器压力:45psi(N2)；碎裂器电压:130V；碰撞能量:分别为10，25，40eV。
本发明涉及新的血管紧张素转化酶抑制剂。其生物学活性通过下列体内、体外测定进一步描述。
血管紧张素转化酶(ACE)活性的测定
体外测定ACE活性
高效液相色谱法测定：参照Cushman等(Biochemical Pharmacology,1971,20(7):1637-1648.；Journal of Dairy Science,1995,78(4):777-783.)方法，并在报道的方法对本发明的化合物进行血管紧张素转化酶活性的测定。该法以适合连续监视ACE活性的Ang I的模拟物马尿酰-组氨酰-亮氨酸(HHL)的水解产物马尿酸(Hip)的含量为基础。当加入ACE抑制剂时，可抑制反应的进行，从而减少马尿酸的生成。因此，通过测定加入抑制剂前后所生成的马尿酸在228nm处紫外吸光度的变化得出ACE抑制活性。
材料和方法：
(1)材料：
实验仪器：
表3体外活性实验仪器
Figure PCTCN2015095758-appb-000092
Figure PCTCN2015095758-appb-000093
实验试剂：
表4体外活性实验试剂
Figure PCTCN2015095758-appb-000094
(2)实验方法
取25μL样品溶液(溶于pH＝8.3的50mM的HEPES盐酸缓冲液，其中含300mM的NaCl，样品量为50μmol)和200μL 0.3％底物HHL(溶于相同的缓冲液中)于37℃保温6min，加入50μL ACE(0.5U溶于1.5mL相同缓冲液中)，37℃下反应15min后，加入250μL，l mol/L的盐酸终止反应，混匀，放置5min后，加入2mL乙酸乙酯，强力振荡60s，1000×g离心l0min。上清液置沸水浴15min，加入3mL去离子水，混匀，静置。取20μL反应物进样，通过反相高效液相色谱检测马尿酸。以马尿酸的生成量判断样品对ACE的抑制作用，同时用缓冲液代替样品溶液做空白对照。样品对ACE抑制率(％)＝(对照品马尿酸峰值－样品马尿酸峰值)/对照品马尿酸峰值×100％。
色谱条件：
紫外检测器；检测波长：228nm；色谱柱：Agilent HC-C18 4.6×250mm，5μm；流速：l.0mL/min；进样量：20μL；柱温：30℃；流动相：乙睛-水(80/20)。结果如表5所示：
表5
Figure PCTCN2015095758-appb-000095
Figure PCTCN2015095758-appb-000096
Figure PCTCN2015095758-appb-000097
体内测定ACE含量
材料和方法：
实验仪器：
表6体内活性测试实验仪器
Figure PCTCN2015095758-appb-000098
实验材料：
表7体内活性实验材料及试剂
Figure PCTCN2015095758-appb-000099
实验原理:
双抗体夹心ELISA法测定ACE含量：用抗小鼠ACE抗体包被于酶标板上，实验时样品或标准品中的小鼠ACE会与包被抗体结合，游离的成分被洗去。依次加入生物素化的抗小鼠ACE抗体和辣根过氧化物酶标记的亲和素。抗小鼠ACE抗体与结合在包被抗体上的小鼠ACE结合、生物素与亲和素特异性结合而形成免疫复合物，游离的成分被洗去。加入显色底物(TMB)，TMB在辣根过氧化物酶的催化下呈现蓝色，加终止液后变成黄色。用酶标仪在450nm波长处测OD值，ACE浓度与OD450值之间呈二次非线性关系，通过绘制标准曲线计算出样品中ACE的浓度。
实验方法:
(1)实验动物处理方法：
取雄性昆明小鼠108只，体重(bw，20士2g)，随机分为18组，每组6只。分别为正常对照组，阳性对照药卡托普利组，化合物221S组。每天灌胃一次，按0.05mmol/kg灌胃(体积10ml/kg)，连续给药7天。末次灌胃给药2h后， 断颈处死，取心、肝、脑、肺、肾、血，其中肾用于本实验检测，其他组织样品用于另外实验检测。将肾脏用PBS稀释10倍，匀浆，离心，取上清用于测定或存于-20℃备用。
(2)ELISA操作方法：
采用ELISA检测小鼠肾脏组织中ACE的含量，所有步骤均严格按照说明书进行，主要步骤如下：
(a)加样：分别设空白孔(空白对照孔不加样品及酶标试剂，其余各步操作相同)、标准孔、待测样品孔。余孔分别加不同浓度的标准溶液或待测样品100μL，注意不要有气泡，轻轻混匀。酶标板加上盖，37℃反应90min。
(b)弃去液体，甩干，不用洗涤。每个孔中加入生物素化抗体工作液100μL(在使用前15分钟内配制)，酶标板加上覆膜，37℃温育1小时。
(c)弃去孔内液体，甩干，洗板3次，每次浸泡1-2分钟，大约350μL/每孔，甩干并在吸水纸上轻拍将孔内液体拍干。
(d)每孔加酶结合物工作液(临用前15分钟内配制)100μL，加上覆膜，37℃温育30分钟。
(e)弃去孔内液体，甩干，洗板5次，方法同步骤(c)。
(f)每孔加底物溶液(TMB)90μL，酶标板加上覆膜37℃避光孵育15分钟左右(根据实际显色情况酌情缩短或延长，但不可超过30分钟。当标准孔出现明显梯度时，即可终止)。
(g)每孔加终止液50μL，终止反应，此时蓝色立转黄色。终止液的加入顺序应尽量与底物溶液的加入顺序相同。
(h)立即用酶标仪在450nm波长测量各孔的光密度(OD值)。应提前打开酶标仪电源，预热仪器，设置好检测程序。
以上实验数据均用
Figure PCTCN2015095758-appb-000100
表示(SPSS19.0统计软件，t检验方法进行统计学处理)。
实验结果如图1所示，公式：y＝ax2+bx+c；其中，a：-0.0052；b：0.2556；c：-0.0233；R2：0.9968。
体内活性(ELISA法)结果如表8所示：
表8
Figure PCTCN2015095758-appb-000101
实验结果表明，本发明化合物能够降低大鼠血浆ACE酶的含量，且降低幅度均大于阳性药卡托普利，其中化合物221S-1a降低作用最为显著。
自发性高血压大鼠(SHR)血压的测定
实验仪器与试剂
实验仪器：
表9体内活性测试实验仪器
Figure PCTCN2015095758-appb-000102
实验材料：
表10体内活性实验材料及试剂
Figure PCTCN2015095758-appb-000103
实验方法：
SPF级雄性自发性高血压模型大鼠(SHR)，雄性，12周龄，体重200g±20g。分为三组：空白组、对照组和样品组，每组6只。饲养于西北大学生命科学院陕西省生物医药动物实验室，温度22℃，湿度50％，12小时光照/黑暗交替，自由 摄食进水。SHR大鼠适应环境5天后，开始训练大鼠以适应血压测量。给药前，测定各组SHR大鼠基础血压，收缩压在190±5mmHg之间。
(1)一次给药SHR大鼠血压的测定：
实验大鼠收缩压的测定采用尾脉搏间接测压法。
对SHR大鼠实施灌胃，样品与对照品(卡托普利)均溶于含1％吐温80的蒸馏水中，空白对照组灌胃同体积含1％吐温80的蒸馏水。按0.05mmol/kg灌胃(体积10ml/kg)，灌胃后分别于1h、2h、3h、4h、6h各测一次血压。
具体测量步骤：将清醒的大鼠放入血压仪的固定盒中，固定盒底部置30℃的加热板，预热10min，以扩张局部血管。待大鼠处于安静状态后，将可充气管状尾套管环绕SHR的鼠尾根部，并将压力电子脉搏检测器置于大鼠尾根部，电脑屏幕产生信号，稳定后测定血压值，记录血压变化小于10mmHg的5次读数，记录数值间隔10秒。取其均值作为该大鼠的收缩压。
(a)SHR大鼠灌胃221S-1a 6小时动脉收缩压变化情况如图2所示。
(b)SHR大鼠灌胃不同剂量的221S-1a 6小时内动脉收缩压的变化情况如图3所示。
结果显示，化合物221S-1a对SHR大鼠表现出较好的降压效果，具有较好的剂量依赖性，降压效果要好于卡托普利。
(2)多次给药SHR大鼠血压的测定：
按上述方法与剂量，连续灌胃7天，每天1次，给药2小时后测量血压。停药后，继续测量血压7天，每天1次，记录血压变化。
(a)SHR大鼠灌胃221S-1a 7天后14天内收缩压变化情况如图4所示。
(b)SHR大鼠灌胃不同剂量的221S-1a 14天内动脉收缩压的变化情况如图5所 示。
长期对SHR大鼠口服给化合物221S-1a 7天后，停止给药，记录14天内血压变化，结果显示：化合物221S-1a具有明显的降压效果，降压效果好于卡托普利。不同剂量的221S-1a对SHR大鼠的动脉收缩压的影响有明显的剂量依赖性。
以上实验数据均用
Figure PCTCN2015095758-appb-000104
表示(SPSS19.0统计软件，t检验方法进行统计学处理)。

Claims (16)

  1. 一类三肽化合物，其特征在于，该化合物结构通式(I)如下：
    Figure PCTCN2015095758-appb-100001
    通式(I)中：
    R为通式(II)所示：
    Figure PCTCN2015095758-appb-100002
    通式(II)中：
    R1选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、酰基、芳酰基、芳基、芳烷基、杂芳基或杂芳烷基；
    R2选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、酰基、芳酰基、芳基、芳烷基、杂芳基、杂芳烷基、烷硫基、芳烷硫基、芳硫基、F、Cl、Br、I、NO2或CN；
    R1和R2相同或不同；
    n＝0,1,2,3,4,5；n≥2时,多个R1之间相同或不同；
    m＝0,1,2,3,4,5；m≥2时,多个R2之间相同或不同；
    W选自
    Figure PCTCN2015095758-appb-100003
    其中
    Figure PCTCN2015095758-appb-100004
    左侧与苯环相连；其中：Z选自氧或氮；R6选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、芳基、芳烷基、杂芳基或杂芳烷基；
    X选自氧或氢；
    通式(I)中：
    R'为L型或D型氨基酸残基或氨基酸衍生物的残基，如通式(III)所示，或者，R'不存在：
    Figure PCTCN2015095758-appb-100005
    R'为L型或D型氨基酸残基或氨基酸衍生物的残基时，
    Figure PCTCN2015095758-appb-100006
    的C端与
    Figure PCTCN2015095758-appb-100007
    的N端连接，N端与
    Figure PCTCN2015095758-appb-100008
    的C端连接；
    R'不存在时，
    Figure PCTCN2015095758-appb-100009
    与
    Figure PCTCN2015095758-appb-100010
    以酰胺键或C-N键链接；
    R4与R5各自独立选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、芳基、芳烷基、杂芳基和杂芳烷基；R4与R5相同或不同；
    通式(I)中：
    R"为通式(IV)所示：
    Figure PCTCN2015095758-appb-100011
    其中：
    Y选自氧、氮或硫，并且：
    Y为氮时，R””为R7和R8，R”为
    Figure PCTCN2015095758-appb-100012
    Y为氧时，R””为R9，R”为-OR9；
    Y为硫时，R””为R10，R”为-SR10；
    其中：R7、R8、R9、R10可以相同或不同，各自独立选自氢、烷基、环烷基、杂烷基、杂环基、烯基、炔基、芳基、芳烷基、杂芳基或杂芳烷基；
    通式(I)中：
    R”'选自氢或烷基；
    A＝碳；
    L选自氢、烷基、取代烷基、芳基或取代芳基；
    D为碳或不存在，t＝0,1,2,3；并且：
    当D为碳，B为碳时：A与B之间为碳碳双键或碳碳单键，K与B、D之间为环系关系；或者，A与B之间为碳碳双键或碳碳单键，K与B连接且K与D不相连；
    当K与B、D之间为环系关系时，K选自碳数为2到8烷基、杂烷基、碳数 为3到8烯基，或者，K与B、D之间共同形成芳基、取代芳基、杂芳基或取代杂芳基；
    当K与B连接且K与D不相连时，K选自氢、烷基、杂烷基、环烷基、杂环基、烯基、炔基、羟基、烷氧基、芳氧基、芳基、芳烷基、杂芳基或杂芳烷基；
    当D为碳，B为硫时：则A与B之间为碳硫单键，K不存在；
    当D不存时：B为碳，K为氢；
    所述烷基、环烷基、杂烷基、杂环基、烯基、炔基、芳基、芳烷基、杂芳基和杂芳烷基各自可为未取代或任选独立的被一或多个选自以以下部分的取代基：羟基、烷氧基、芳氧基、硫代、硫代烷基、芳硫基、氨基、酰胺基、烷氨基、芳氨基、烷基磺酰基、芳基磺酰基、亚磺酰基氨基、烷基、芳基、杂芳基、烷基亚磺酰胺基、芳基亚磺酰胺基、酮基、羧基、烷氧羰基、羧酰胺基、烷氧羰基氨基、烷氧羰基氧基、烷基脲基、芳基脲基、卤代、氰基或硝基。
  2. 根据权利要求1所述的三肽化合物，其特征在于，所述R基团
    Figure PCTCN2015095758-appb-100013
    选自下列结构：
    Figure PCTCN2015095758-appb-100014
    Figure PCTCN2015095758-appb-100015
  3. 根据权利要求1所述的三肽化合物，其特征在于，所述R'基团
    Figure PCTCN2015095758-appb-100016
    选自下列结构：
    Figure PCTCN2015095758-appb-100017
    Figure PCTCN2015095758-appb-100018
    Figure PCTCN2015095758-appb-100019
    其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
  4. 根据权利要求1所述的三肽化合物，其特征在于，
    当Y为氧时，R9为选自下列的基团：
    甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、环丙基、环丁基、环戊基、环己基、环庚基或下列结构：
    Figure PCTCN2015095758-appb-100020
    Figure PCTCN2015095758-appb-100021
  5. 根据权利要求1所述的三肽化合物，其特征在于，当Y为氮时，R"为选自下列的基团：
    Figure PCTCN2015095758-appb-100022
    Figure PCTCN2015095758-appb-100023
    其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
  6. 根据权利要求1所述的三肽化合物，其特征在于，当Y为硫时，R"为选自下列的基团：
    Figure PCTCN2015095758-appb-100024
    Figure PCTCN2015095758-appb-100025
    其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
  7. 根据权利要求1所述的三肽化合物，其特征在于，所述通式(I)选自下列通式结构：
    Figure PCTCN2015095758-appb-100026
    其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
  8. 权利要求1所述的三肽化合物，其特征在于，选自下列结构的化合物：
    Figure PCTCN2015095758-appb-100027
    Figure PCTCN2015095758-appb-100028
    Figure PCTCN2015095758-appb-100029
    Figure PCTCN2015095758-appb-100030
    Figure PCTCN2015095758-appb-100031
    Figure PCTCN2015095758-appb-100032
    Figure PCTCN2015095758-appb-100033
    Figure PCTCN2015095758-appb-100034
    Figure PCTCN2015095758-appb-100035
    Figure PCTCN2015095758-appb-100036
    Figure PCTCN2015095758-appb-100037
    Figure PCTCN2015095758-appb-100038
    Figure PCTCN2015095758-appb-100039
    Figure PCTCN2015095758-appb-100040
    Figure PCTCN2015095758-appb-100041
    Figure PCTCN2015095758-appb-100042
    Figure PCTCN2015095758-appb-100043
    其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
  9. 权利要求1、4、7或8所述化合物中Y为氧时的化合物的水解产物。
  10. 权利要求1-8中任一权利要求所述化合物的对映体、互变异构体、立体异构体、旋转异构体、非对映异构体或外消旋体。
  11. 权利要求1-8中任一权利要求所述化合物药学上可接受的盐和药学上可接受的酯，所述药学上可接受的盐包括药学上可接受的酸式盐和药学上可接受的碱式盐，所述药学上可以接受的酸式盐包括下列酸中其中之一所形成的盐：硫酸、 硫酸氢、盐酸、氢溴酸、磷酸、硝酸、碳酸、硼酸、甲磺酸、苯磺酸、对甲基苯磺酸、甲酸、乙酸、丙酸、丁酸、丙酮酸、马来酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、苯甲酸、樟脑酸、富马酸、草酸、琥珀酸、樟脑磺酸、顺丁烯二酸、水杨酸或α-乳酸；所述药学上可以接受的碱式盐包括下列碱中其中之一所形成的盐：锂、钠、钾等碱金属，镁、钙、等碱土金属，氢氧化锂、氢氧化钠、氢氧化钾、氢化锂、氢化钠、丁基锂、铵、三乙胺、二异丙基乙基胺、鸟氨酸、精氨酸、赖氨酸或组氨酸；所述药学上可接受的酯包括化合物中羟基或酚羟基与酸形成的酯。
  12. 权利要求1-8中任一权利要求所述化合物的溶剂化混合物，所述溶剂为水、甲醇、乙醇、异丙醇、丁醇、乙酸乙酯和DMSO中的一种或两种以上的组合。
  13. 权利要求1所述的化合物的制备方法，其特征在于，制备方法包括：
    Figure PCTCN2015095758-appb-100044
    Figure PCTCN2015095758-appb-100045
    c:与步骤a相对应的脱保护方法；
    e:方法同b；
    f:方法同c；
    g:方法同b；
    g'：还原胺化；
    h：酯水解条件；
    其中，“*”代表手性中心，含有“*”的所述化合物包含该结构式的所有手性构型同分异构体。
  14. 权利要求1-8中任一权利要求所述化合物用于制备预防、治疗或延缓高血压及其并发症药物的应用，所述并发症包括：冠心病、心绞痛、急性心力衰竭、慢性充血性心力衰竭、心肌梗塞及其后遗症、充血性心脏病、心肌缺血、心肌炎、心肌纤维化、心肌肥大、动脉粥样硬化、良性小动脉肾硬化症、恶性小动脉肾硬化症、血管生长异常和重塑、血管发生相关的疾病(如新血管黄斑变性)、醛固酮过多症、心律失常、肾病、糖尿病、脑卒中、血栓症、肾衰竭(如：糖尿病肾病)、高血脂、肥胖症、高血糖、视网膜动脉硬化症、高血压眼底病变中的一种或几种。
  15. 一种药物组合物，其特征在于，该药物组合物包括：权利要求1-8中任何一项所述的化合物、权利要求1-8中任何一项所述的化合物药学上可接受的盐、权利要求1-8中任何一项所述的化合物药学上可接受的载体、赋形剂、稀释剂。
  16. 权利要求14所述药物组合物用于制备预防、治疗或延缓高血压及其并发症药物的应用，所述并发症包括：冠心病、心绞痛、心力衰竭(急性或慢性充血性心力衰竭)、心肌梗塞及其后遗症、充血性心脏病、心肌缺血、心肌炎、心肌纤维化、心肌肥大、动脉粥样硬化、良性小动脉肾硬化症、恶性小动脉肾硬化症、血管生长异常和重塑、血管发生相关的疾病(如新血管黄斑变性)、醛固酮过多 症、心律失常、肾病、糖尿病、脑卒中、血栓症、肾衰竭(如：糖尿病肾病)、高血脂、肥胖症、高血糖、视网膜动脉硬化症、高血压眼底病变中的一种或几种。
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KR1020177017351A KR102098783B1 (ko) 2014-11-27 2015-11-27 트리펩티드 화합물, 이의 제조방법 및 이의 용도
ES15863217T ES2897916T3 (es) 2014-11-27 2015-11-27 Compuesto tripéptido, método de preparación del mismo y aplicación del mismo
MYPI2017701895A MY193996A (en) 2014-11-27 2015-11-27 Tripeptide compound, preparation method therefor, and application thereof
PL15863217T PL3225627T3 (pl) 2014-11-27 2015-11-27 Mieszanka tripeptydowa, sposób jej wytwarzania i jej zastosowanie
SG11201704235SA SG11201704235SA (en) 2014-11-27 2015-11-27 Tripeptide compound, preparation method therefor, and application thereof
RU2017121590A RU2685709C2 (ru) 2014-11-27 2015-11-27 Трипептидное соединение, способ его получения и его применение
AU2015353118A AU2015353118B2 (en) 2014-11-27 2015-11-27 Tripeptide compound, preparation method therefor, and application thereof
JP2017527865A JP6689848B2 (ja) 2014-11-27 2015-11-27 トリペプチド化合物、その調製方法及びその用途
DK15863217.4T DK3225627T5 (da) 2014-11-27 2015-11-27 Tripeptidforbindelse, fremgangsmåde til fremstilling deraf og anvendelse deraf
US15/529,633 US11358985B2 (en) 2014-11-27 2015-11-27 Tripeptide compound, preparation method therefor, and application thereof
EP15863217.4A EP3225627B9 (en) 2014-11-27 2015-11-27 Tripeptide compound, preparation method therefor, and application thereof
SI201531768T SI3225627T1 (sl) 2014-11-27 2015-11-27 Spojina, postopek za njeno pripravo in njena uporaba
CA2968595A CA2968595C (en) 2014-11-27 2015-11-27 Tripeptide compound having angiotensin converting enzyme inhibiting activity, preparation method thereof, and application thereof
IL252448A IL252448B (en) 2014-11-27 2017-05-23 A tripeptide compound, a method for its preparation and its application
CY20211100983T CY1125043T1 (el) 2014-11-27 2021-11-11 Ενωση τριπεπτιδιο, μεθοδος παρασκευης αυτης, και εφαρμογη αυτης

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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107056788A (zh) * 2017-03-23 2017-08-18 河南工程学院 一种咪唑烷酮类衍生物及其合成方法
CN107337711A (zh) * 2017-07-26 2017-11-10 盐城卫生职业技术学院 一种抗高血压活性肽Citn‑Pro‑Hyp及应用和药物组合物
CN107337712A (zh) * 2017-07-26 2017-11-10 盐城卫生职业技术学院 一种抗高血压活性肽Orn‑Hyp‑Pro及应用和药物组合物
CN112830884B (zh) * 2019-11-22 2024-06-14 深圳市高盈医药科技开发有限公司 一种丹参素衍生物及其制备方法及其医药用途
US12552767B2 (en) 2020-12-03 2026-02-17 Merck Sharp & Dohme Llc 3-heteroaryl pyrrolidine and piperidine orexin receptor agonists

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1939912A (zh) * 2005-10-01 2007-04-04 代斌 N－[2－(3－苯基－2－丙烯酰氨基)丙酰基]－噻唑烷酸及其衍生物制备方法

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE252191C (zh)
IL60888A (en) 1978-06-16 1984-07-31 Yeda Res & Dev Substrates and process for the quantitative assay of enzymes
DE3315464A1 (de) 1983-04-28 1984-10-31 Hoechst Ag, 6230 Frankfurt Verfahren zur herstellung von n-alkylierten dipeptiden und deren estern
DE3619633A1 (de) 1986-06-11 1987-12-17 Hoechst Ag Peptide mit einfluss auf die diurese und natriurese, verfahren zu ihrer herstellung, diese enthaltende mittel und ihre verwendung
KR900008794B1 (ko) * 1986-06-11 1990-11-29 티 디 케이 가부시끼가이샤 방전 램프장치
DE3839127A1 (de) * 1988-11-19 1990-05-23 Hoechst Ag Pyrrolidon-2-carbonsaeure-derivate mit psychotroper wirkung
AU740783B2 (en) * 1996-09-18 2001-11-15 Applied Genetics Incorporated Dermatics Pharmaceutical compositions and methods
CA2498757A1 (en) 2002-09-11 2004-03-25 Toaeiyo Ltd. Proline ester and preparation containing the same for percutaneous administration
GB2395195A (en) 2002-11-18 2004-05-19 Cipla Ltd Preparation of perindopril from carboxy-protected precursor, & perindopril monohydrates for use as angiotensin converting enzyme (ACE) inhibitors
JP5341300B2 (ja) 2003-08-01 2013-11-13 カルピス株式会社 アンジオテンシン変換酵素阻害活性又は血圧降下作用を有する剤
CN100415709C (zh) 2006-05-15 2008-09-03 西北大学 β-(3,4-二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途
US20120129818A1 (en) 2009-04-23 2012-05-24 Desikan Rajagopal Compositions and Methods for Treatment of Cardiovascular Disease
CN101607907B (zh) * 2009-06-22 2013-01-23 西北大学 取代的苯甲酸衍生物及其合成方法和用途
JP5799842B2 (ja) 2012-02-03 2015-10-28 秋田県 アンジオテンシン変換酵素阻害ペプチド、該ペプチドを含有するアンジオテンシン変換酵素阻害剤、組成物及び食品、並びに、該ペプチドの製造方法
CN102757479B (zh) 2012-05-09 2014-04-30 北京林业大学 高活性降血压肽及其制备方法
JP2014141462A (ja) 2012-12-27 2014-08-07 Raffinee International Co Ltd ペプチド、並びに、アンジオテンシン変換酵素阻害剤、抗高血圧剤、及び飲食品
CN104945469B (zh) * 2015-06-30 2018-09-28 石狮海星食品有限公司 Ace抑制三肽

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1939912A (zh) * 2005-10-01 2007-04-04 代斌 N－[2－(3－苯基－2－丙烯酰氨基)丙酰基]－噻唑烷酸及其衍生物制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LIU, HUI ET AL.: "Total Synthesis and Biological Evaluation of Grassypeptolide A", CHEM. EUR. J., vol. 19, 27 March 2013 (2013-03-27), pages 6774 - 6784, XP055446065 *
See also references of EP3225627A4 *
WANG, GUIJUN ET AL.: "Preparation of L-proline Based Aeruginosin 298-A Analogs: Optimization of the P1-moiety", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, 19 April 2009 (2009-04-19), pages 3798 - 3803, XP026281679 *

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