CN101475565B - Anti-hypertension compound, and preparation, pharmaceutical composition and use thereof - Google Patents

Anti-hypertension compound, and preparation, pharmaceutical composition and use thereof Download PDF

Info

Publication number
CN101475565B
CN101475565B CN200910076875A CN200910076875A CN101475565B CN 101475565 B CN101475565 B CN 101475565B CN 200910076875 A CN200910076875 A CN 200910076875A CN 200910076875 A CN200910076875 A CN 200910076875A CN 101475565 B CN101475565 B CN 101475565B
Authority
CN
China
Prior art keywords
butyl
biphenyl
tetrazolium
methyl
normal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN200910076875A
Other languages
Chinese (zh)
Other versions
CN101475565A (en
Inventor
王建民
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to CN200910076875A priority Critical patent/CN101475565B/en
Priority to PCT/CN2009/000602 priority patent/WO2010083633A1/en
Publication of CN101475565A publication Critical patent/CN101475565A/en
Application granted granted Critical
Publication of CN101475565B publication Critical patent/CN101475565B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

The invention provides antihypertensive compounds, methods for preparing the same, the pharmaceutical compositions of the same and the uses of the same. The antihypertensive compounds are compounds ofa general formula (I) or pharmaceutically acceptable salts, solvates, polycrystals, antipodes or a racemic mixture of the same, wherein R1, R2, R3, and R4 are H, substituted alkyls, substituted cyclohexyls, substituted alkylthios, substituted alkoxyls, substituted aryls, substituted aralkyls independently, or R1 and R2 form substituted cyclohexyls together, or R2 and R3 form substituted heterocyclyls. The compounds are absorbed by gastrointestinal tracts through the active transportation of a PepT1 transporter, and decomposed by enzymes in intestinal tracts and the liver to form iosartan slowly, so the iosartan is kept in the blood for a longer time and stable blood concentration contributes to the improvement of curative effects and reduction of side reactions.

Description

Anti-hypertension compound and preparation method thereof, pharmaceutical composition and purposes
Technical field
The present invention relates to class anti-hypertension compound and preparation method thereof, and the pharmaceutical composition and the purposes of such anti-hypertension compound aspect the preparation antihypertensive drug that comprise such anti-hypertension compound.
Background technology
Hypertension is a kind of common disease, frequently-occurring disease, also is one of most important Hazard Factor in the cardiovascular and cerebrovascular diseases.Hypertensive major complications---cerebral apoplexy, heart trouble and kidney disease serious harm human health, it causes death, disability rate is high, brings white elephant for individual, family and society.Because the change of The development in society and economy and people life style, China resident hypertension morbidity is sustainable growth trend, national resident's nutrition in 2002 and investigation of health conditions result show that China adult hypertension morbidity estimates that up to 18.8% there is hyperpietic 1.6 hundred million in the whole nation.Yet people are very low to hypertensive awareness, treatment rate and inverse amplification factor, develop new antihypertensive medicine and have great importance.
FDA (Food and Drug Adminstration) (FDA) has ratified (Merck of Merck company in April nineteen ninety-five; CO) Kai Fa first is as the antihypertensive agent losartan (Losartan) of angiotensin II receptor antagonists.It is a kind of novel depressor, has the specificity and the selectivity of height as I receptor (AT1 type) antagonist of Angiotensin II.This medicine and active metabolite thereof can block the vasoconstriction effect and the aldosterone effect of Angiotensin II, and its mechanism mainly is that blocking-up is present in many tissues, as the AT1 acceptor of the Angiotensin II in blood vessel and the suprarenal gland.This mechanism of action with ACE inhibitor is different, and ACE inhibitor is to block the effect that angiotensin I is converted into the saccharase of Angiotensin II, and therefore, the Angiotensin II that other approach produces can not be blocked by ACE inhibitor.And this product has blocked the angiotensin-ii receptor binding site, thus can be more single-minded, suppress the effect of Angiotensin II more completely.
But this drug half-life only is 1.5-2 hour, and bioavailability is 25-35%.Also expose some untoward reactions of this medicine in the clinical application, wherein the most serious side reaction of normal report is the headache that losartan causes, and incidence is 10%～20%.The most general untoward reaction comprises that also anaemia reaction, the investigation that 184 dialysis patients are carried out show, has 18 patients' hemoglobin concentration to descend in the hemodialysis patients that 24 are taken losartan.In addition, this medicine also causes the generation of untoward reactions such as hyperglycemia, vasodilation and acute pancreatitis.
Prodrug (prodrug) is meant with the method for chemically modified and changes the derivative of the non-activity that forms by original active medicine that this derivative can discharge original active medicine performance curative effect through enzymatic or non-enzymatic reaction in vivo.Itself does not have biological activity prodrug, and it changes activated material into through internal metabolism, and the purpose of this process is to increase bioavailability of medicament, strengthens target, particularly can reduce the toxicity and the side effect of medicine.Therefore, for action time of prolonging losartan (Losartan), increase curative effect and enlarge its application in the hypertension disease, particularly reduce its side reaction, it is carried out structure of modification and obtain effectively to be applied to clinical losartan prodrug through screening being very important.
Summary of the invention
Therefore, the objective of the invention is the structure of losartan (Losartan) is carried out various derivatizes, and a large amount of losartan derivatives carried out pharmacologically active screening, to obtain to be used for the compound of hypertension disease as the prodrug of losartan (Losartan).
The present invention to losartan [1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl alcohol, 1-[2 '-(1H-tetrazol-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-n-butyl-4-chloro-imidazol-5-yl-methanol] structure carry out the derivatize transformation, and its derivative is carried out the pharmacological testing screening, the result shows that the class new compound shown in the general formula (I) can be used as the prodrug of losartan, producing losartan through enzymolysis in vivo. these compounds can interact with Erepsin transporter (as PepT1), make them in enteron aisle, be absorbed by active transport, produce more stable losartan Plasma Concentration through enzymolysis again, can reduce the toxicity and the side effect of medicine effectively. the compound shown in the general formula (I) also comprises the enantiomorph or the racemic mixture of this compound, or their pharmacy acceptable salt, solvate or polymorphs body (polymorphs). the invention still further relates to the pharmaceutical composition and purposes and its preparation method of this compounds in the preparation antihypertensive drug that comprise this compounds.
Figure G2009100768759D00031
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
Compound shown in a kind of general formula (I) or its pharmacy acceptable salt, its solvate, its polymorphs body, its enantiomorph or its racemic mixture,
Figure G2009100768759D00032
Wherein, R 1, R 2, R 3With R 4Be H independently, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional alkylthio that replaces, the optional alkoxyl group that replaces, the optional aryl that replaces, the optional aralkyl that replaces, or R 1With R 2Form the optional cycloalkyl that replaces together, or R 2With R 3Form the optional heterocyclic radical that replaces together, or R 3With R 4Form the optional heterocyclic radical that replaces together.
Specifically, abovementioned alkyl is selected from unsubstituted or through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals, sulfydryl, phenyl, indyl, imidazolyl, the C that hydroxy phenyl replaces 1-C 8The straight or branched alkyl; Above-mentioned cycloalkyl is selected from C unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals 3-C 8Cycloalkyl; Above-mentioned aryl is selected from phenyl unsubstituted or that replace through halogen, amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group; Above-mentioned aralkyl is selected from the C that aryl replaces 1-C 8The straight or branched alkyl; Above-mentioned heterocyclic radical is selected from unsubstituted or through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, five yuan or hexa-member heterocycle base and indyl that amide group replaces.
In a specific embodiments, R 1With R 2Be H independently, C unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals, sulfydryl, phenyl, indyl, imidazolyl, hydroxy phenyl 1-C 6The straight or branched alkyl; Or C unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals 3-C 8Cycloalkyl; Or R 1With R 2Form cyclopropane base, tetramethylene base, pentamethylene base or cyclohexyl with the C that is connected.
In another specific embodiments, R 2With R 3Form pyrrolidyl or piperidyl with C that is connected and N.
In another specific embodiments, R 3With R 4Be H independently, C unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals, sulfydryl, indyl, imidazolyl, hydroxy phenyl 1-C 3The straight or branched alkyl.
Preferably, R 3With R 4Be H; R 1And R 2In one of be H, another be selected from H ,-CH 3,-CH 2CH 3,-SCH 3,-CH (R 5) R 6,-CH 2CH (R 5) R 6, R wherein 5And R 6In one of be selected from H ,-CH 3Or-CH 2CH 3Another is H, C 1-C 3Straight chain, branched-chain alkyl or cyclopropane base; R 5Or R 6Choose wantonly and replaced: amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals, sulfydryl, phenyl, indyl, imidazolyl and hydroxy phenyl by one or more following groups.
More preferably, R 3With R 4Be H; R 1And R 2In one of be H, another be selected from H ,-CH 3,-CH 2CH 3,-CH 2CH (CH 3) CH 3,-CH (CH 3) CH 3,-CH (CH 3) CH 2CH 3,-CH 2CH 2CONH 2,-CH 2CONH 2,-CH 2CH 2COOH ,-CH 2COOH ,-SCH 3,-CH 2SH ,-CH 2OH ,-CH (OH) CH 3,-CH 2CH 2SCH 3,-CH 2C 6H 5,-CH 2C 6H 4(OH) ,-CH 2CH 2CH 2CH 2NH 2,
Figure G2009100768759D00041
The preferred one group of compound of the present invention comprises:
1) tetramethyleneimine-2-formic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
2) tetramethyleneimine-2-formic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
3) piperidines-2-formic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
4) piperidines-2-formic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
5) azepan-2-formic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
6) azepan-2-formic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
7) 1-amino cyclopentyl acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
8) 1-dimethylamino chaulmoogric acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
9) 1-methylamino-chaulmoogric acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
10) the amino cyclohexylenedinitrilotetraacetic acid 1-[2 ' of 1--(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
11) 1-methylamino-cyclohexylenedinitrilotetraacetic acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
12) 2-methyl-2-(tetramethyleneimine-1-yl) propionic acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
13) 4-methyl-2-methylamino-valeric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
14) 4-methyl-2-methylamino-valeric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
15) 2-dimethylamino-4-methylvaleric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
16) 2-dimethylamino-4-methylvaleric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
17) 2-(tetramethyleneimine-1-yl) propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
18) 2-(tetramethyleneimine-1-yl) propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
19) 2-dimethylamino acetate 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
20) 2-methylamino-acetate 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
21) 5-guanidine radicals-2-methylamino-valeric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
22) 5-guanidine radicals-2-methylamino-valeric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
23) 2-dimethylamino-5-guanidine radicals valeric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
24) 2-dimethylamino-5-guanidine radicals valeric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
25) (S)-and 4-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-3-methylamino--4-ketobutyric acid;
26) (R)-and 4-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-3-methylamino--4-ketobutyric acid;
27) (S)-and 4-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-3-dimethylamino-4-ketobutyric acid;
28) (R)-and 4-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-3-dimethylamino-4-ketobutyric acid;
29) 2-methylamino-succsinic acid (S)-1-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-yl methyl esters 4-ethyl ester;
30) 2-methylamino-succsinic acid (R)-1-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-yl methyl esters 4-ethyl ester;
31) 2-dimethylamino succsinic acid (S)-1-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-yl methyl esters 4-ethyl ester;
32) 2-dimethylamino succsinic acid (R)-1-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-yl methyl esters 4-ethyl ester;
33) 3-sulfydryl-2-methylamino-propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
34) 3-sulfydryl-2-methylamino-propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
35) 2-dimethylamino-3-thiohydracrylic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
36) 2-dimethylamino-3-thiohydracrylic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
37) 4-amino-2-methylamino--4-ketobutyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
38) 4-amino-2-methylamino--4-ketobutyric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
39) 4-amino-2-dimethylamino-4-ketobutyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
40) 4-amino-2-dimethylamino-4-ketobutyric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
41) 5-amino-2-methylamino--5-oxopentanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
42) 5-amino-2-methylamino--5-oxopentanoic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
43) 5-amino-2-dimethylamino-5-oxopentanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
44) 5-amino-2-dimethylamino-5-oxopentanoic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
45) (S)-and 5-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-4-methylamino--5-oxopentanoic acid;
46) (R)-and 5-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-4-methylamino--5-oxopentanoic acid;
47) (S)-and 5-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-4-dimethylamino-5-oxopentanoic acid;
48) (R)-and 5-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-4-dimethylamino-5-oxopentanoic acid;
49) 2-dimethylamino pentanedioic acid (S)-1-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-yl methyl esters 5-methyl esters;
50) 2-dimethylamino pentanedioic acid (R)-1-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-yl methyl esters 5-methyl esters;
51) 2-methylamino-pentanedioic acid (S)-1-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-yl methyl esters 5-methyl esters;
52) 2-methylamino-pentanedioic acid (R)-1-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-yl methyl esters 5-methyl esters;
53) 3-(1H-imidazoles-2-yl)-2-methylamino-propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
54) 3-(1H-imidazoles-2-yl)-2-methylamino-propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
55) 2-dimethylamino-3-(1H-imidazoles-2-yl) propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
56) 2-dimethylamino-3-(1H-imidazoles-2-yl) propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
57) 3-methyl-2-methylamino-valeric acid (2S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
58) 3-methyl-2-methylamino-valeric acid (2R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
59) 2-dimethylamino-3 methylvaleric acid (2S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
60) 2-dimethylamino-3 methylvaleric acid (2R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
61) 6-amino-2-methylamino-caproic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
62) 6-amino-2-methylamino-caproic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
63) 6-amino-2-dimethylamino caproic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
64) 6-amino-2-dimethylamino caproic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
65) 2-methylamino--4-methylmercapto butyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
66) 2-methylamino--4-methylmercapto butyric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
67) 2-dimethylamino-4-methylmercapto butyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
68) 2-dimethylamino-4-methylmercapto butyric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
69) 2-methylamino--3-phenylpropionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
70) 2-methylamino--3-phenylpropionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
71) 2-dimethylamino-3-phenylpropionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
72) 2-dimethylamino-3-phenylpropionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
73) 1-methylpyrrolidin-2-formic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
74) 1-methylpyrrolidin-2-formic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
75) 3-hydroxyl-2-methylamino-propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
76) 3-hydroxyl-2-methylamino-propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
77) 2-dimethylamino-3-hydroxy-propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
78) 2-dimethylamino-3-hydroxy-propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
79) 2-methylamino--3-hydroxybutyric acid (2S, 3S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
80) 2-methylamino--3-hydroxybutyric acid (2R, 3S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
81) 2-dimethylamino-3-hydroxybutyric acid (2S, 3S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
82) 2-dimethylamino-3-hydroxybutyric acid (2R, 3S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
83) 3-(4-hydroxy phenyl)-2-methylamino-propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
84) 3-(4-hydroxy phenyl)-2-methylamino-propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
85) 2-dimethylamino-3-(4-hydroxy phenyl) propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
86) 2-dimethylamino-3-(4-hydroxy phenyl) propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
87) 3-methyl-2-methylamino-butyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
88) 3-methyl-2-methylamino-butyric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
89) 2-dimethylamino-3 Methylbutanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
90) 2-dimethylamino-3 Methylbutanoic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
91) 3-(1H-indol-3-yl)-2-methylamino-propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
92) 3-(1H-indol-3-yl)-2-methylamino-propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
93) 2-dimethylamino-3-(1H-indol-3-yl) propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
94) 2-dimethylamino-3-(1H-indol-3-yl) propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
95) 2-methyl-2-methylamino-propionic acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
96) 2-dimethylamino-2 Methylpropionic acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
97) 1-methylamino-cyclopropionate 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
98) 1-dimethylamino cyclopropionate 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
99) 1-methylamino-ring butyric acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
100) 1-dimethylamino ring butyric acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
101) 2-Padil (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
102) 2-Padil (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
103) 2-amino-4-methylvaleric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
104) 2-amino-4-methylvaleric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
105) 2-alanine (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
106) 2-alanine (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
107) 2-amino-5-guanidine radicals valeric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
108) 2-amino-5-guanidine radicals valeric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
109) (S)-and 4-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-3-amino-4-ketobutyric acid;
110) (R)-and 4-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-3-amino-4-ketobutyric acid;
111) 2,4-diamino-4-ketobutyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
112) 2,4-diamino-4-ketobutyric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
113) 2-amino-3-mercaptopropionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
114) 2-amino-3-mercaptopropionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
115) 2,5-diamino-5-oxopentanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
116) 2,5-diamino-5-oxopentanoic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
117) (S)-and 5-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-4-amino-5-oxopentanoic acid;
118) (R)-and 5-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-4-amino-5-oxopentanoic acid;
119) 2-amino-3-(1H-imidazoles-2-yl) propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
120) 2-amino-3-(1H-imidazoles-2-yl) propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
121) 2-amino-3 methylvaleric acid (2S, 3R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
122) 2-amino-3 methylvaleric acid (2R, 3R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
123) 2,6-diaminocaproic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
124) 2,6-diaminocaproic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
125) 2-amino-4-methylmercapto butyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
126) 2-amino-4-methylmercapto butyric acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
127) 2-amino-3-phenylpropionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
128) 2-amino-3-phenylpropionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
129) tetramethyleneimine-2-acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
130) 2-amino-3-hydroxy-propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
131) 2-amino-3-hydroxy-propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
132) 2 amino 3 hydroxybutyric acid (2S, 3S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
133) 2 amino 3 hydroxybutyric acid (2R, 3S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
134) 2-amino-3-(4-hydroxy phenyl) propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
135) 2-amino-3-(4-hydroxy phenyl) propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
136) 2-amino-3-(1H-indol-3-yl) propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
137) 2-amino-3-(1H-indol-3-yl) propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
138) 2-amino-2-methyl propionic acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
139) the amino cyclopropionate 1-[2 ' of 1--(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
140) the amino ring of 1-butyric acid 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
141) 2-methylamino-propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
142) 2-methylamino-propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
143) 2-dimethylamino propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
144) 2-dimethylamino propionic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
145) 2-amino-3 Methylbutanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
146) 2-amino-3 Methylbutanoic acid (R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters.
Wherein, more preferably following compounds:
101) 2-Padil (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
103) 2-amino-4-methylvaleric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
105) 2-alanine (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
107) 2-amino-5-guanidine radicals valeric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-butyl-4-chlorine imidazoles-5-base methyl esters;
109) (S)-and 4-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-3-amino-4-ketobutyric acid;
111) 2,4-diamino-4-ketobutyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
113) 2-amino-3-mercaptopropionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
115) 2,5-diamino-5-oxopentanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
117) (S)-and 5-{1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-yl } methoxyl group-4-amino-5-oxopentanoic acid;
119) 2-amino-3-(1H-imidazoles-2-yl) propionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
121) 2-amino-3 methylvaleric acid (2S, 3R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
123) 2,6-diaminocaproic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
125) 2-amino-4-methylmercapto butyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
127) 2-amino-3-phenylpropionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
129) tetramethyleneimine-2-acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
145) 2-amino-3 Methylbutanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters.
Wherein, following compounds most preferably:
101) 2-Padil (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
103) 2-amino-4-methylvaleric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
105) 2-alanine (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
115) 2,5-diamino-5-oxopentanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
121) 2-amino-3 methylvaleric acid (2S, 3R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
123) 2,6-diaminocaproic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
125) 2-amino-4-methylmercapto butyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
127) 2-amino-3-phenylpropionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
129) tetramethyleneimine-2-acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
145) 2-amino-3 Methylbutanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters.
The present invention also provides the preparation method of above-claimed cpd or its pharmacy acceptable salt, its solvate, its polymorphs body, its enantiomorph or its racemic mixture, it comprises compound shown in compound shown in the formula (II) and the formula (III) is reacted compound shown in the formula of making (I)
Figure G2009100768759D00151
Wherein, R 1, R 2, R 3With R 4Definition the same.
The present invention also provides a kind of combination antihypertensive, wherein comprises above-claimed cpd or its pharmacy acceptable salt, its solvate, its polymorphs body, its enantiomorph or its racemic mixture.This pharmaceutical composition can also comprise that one or more are selected from hypolipidemic, for example Statins; Hypertensin enzymeinhibitor depressor; Angiotensin receptor II antagonist depressor; Calcium antagonist depressor; The medicine of receptor blocking agent and hydragog(ue).This pharmaceutical composition also can comprise one or more pharmaceutically acceptable carrier and/or vehicle.
The present invention also provides above-claimed cpd or its pharmacy acceptable salt, its solvate, its polymorphs body, its enantiomorph or its racemic mixture prevent and/or treat purposes in the medicine of hypertension and relative disease thereof in preparation. and wherein, a hypertensive example is a pulmonary hypertension. and the hypertension relative disease can be coronary heart disease, heart brain and kidney blood vessel diseases and/or migraine. above-claimed cpd or its pharmacy acceptable salt, its solvate, its polymorphs body, its enantiomorph or its racemic mixture can be used for preparation simultaneously, respectively or order medicine that the patient of hypertension and relative disease thereof is carried out administration.
Unless specify in addition, otherwise following term used in the present invention has following definition:
" alkyl " used in the present invention speech is meant the saturated straight chain with 1 to 8 carbon atom or the non-annularity alkyl of side chain.Representational straight chain saturated alkyl comprises methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl; Representational saturated branched-chain alkyl comprises sec.-propyl, sec-butyl, isobutyl-, the tertiary butyl, isopentyl, the 2-methyl butyl, the 3-methyl butyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, 2, the 3-dimethylbutyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,3-dimethyl hexyl, 2,4-dimethyl hexyl, 2,5-dimethyl hexyl, 2,2-dimethyl amyl group, 2,2-dimethyl hexyl, 3,3-dimethyl amyl group, 3,3-dimethyl hexyl, 4,4-dimethyl hexyl, the 2-ethyl pentyl group, the 3-ethyl pentyl group, the 2-ethylhexyl, the 3-ethylhexyl, the 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, 2-methyl-4-ethyl pentyl group, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethyl amyl group, 3, the 3-diethylhexyl, 2, the 2-diethylhexyl, 3,3-diethylhexyl etc.The alkyl that compound of the present invention comprised can be optionally replaced by one or more following substituting groups: for example amino, alkylamino, alkoxyl group, alkyl alkylthio base, sulfur alkyl aryl, halogen, acyl group, nitro, hydroxyl, cyano group, aryl, aralkyl, aryloxy, arylthio, fragrant amino, carbocylic radical, carbon epoxy group(ing), carbocyclic ring sulfenyl, carbocyclic ring amino, heterocyclic radical, heterocyclic oxy group, heterocyclic amino group, heterocycle sulfenyl etc.In addition, any carbon in the alkyl can be replaced by oxygen, sulphur or nitrogen.Wherein, low alkyl group more is applicable to compound of the present invention.
" alkylidene group " used in the present invention speech is meant (for example, { CH of the alkyl or cycloalkyl with at least two tie points that is connected with at least 2 groups 2-, { CH 2CH 2-,
Figure G2009100768759D00161
Deng, tie point represented in its bracket).Alkylidene group can be substituted or be unsubstituted.
" aralkyl " used in the present invention or speech such as " arylalkyls " are meant the aryl that is connected to other group via alkylidene group.Aromatic alkyl group can be through replacing or being unsubstituted.
" alkoxyl group " used in the present invention speech is meant that alkyl is connected to other group via Sauerstoffatom.Alkoxy base can be substituted or be unsubstituted.
" cycloalkyl " used in the present invention speech is meant the saturated cyclic alkyls with 3 to 8 carbon atoms.Representative cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl.Group of naphthene base can be substituted or be unsubstituted.
" heterocycle " used in the present invention or speech such as " heterocyclic radicals " are meant and comprise heteroatomic saturated or undersaturated cyclic group, comprising aromatic heterocycle (being heteroaryl), typically be 3 to 7 yuan of rings.3 to 7 yuan of heterocycles can comprise nearly 4 heteroatoms.Typically, has at least one carbon atom on the heterocycle.Heteroatoms is independently selected from nitrogen, and it can be through oxidation or quaternary ammoniated; Oxygen; Sulphur.Described heterocycle can connect via any heteroatoms or carbon atom.Representative heterocycle comprises Lin Ji, sulfo-Lin Ji, pyrryl, pyrrolidyl, N-hexahydropyridine base, hexahydropyrazine base, Oxyranyle, propylene oxide base, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base etc.Heteroatoms can oneself knows by those skilled in the art protecting group replace, for example, the hydrogen on the nitrogen can be replaced by tertbutyloxycarbonyl.Moreover heterocyclic radical can replace including but not limited to halogen atom, alkyl or aryl optionally by one or more substituting groups.Only consider the desmotrope of the described heterocyclic radical that is substituted in this definition.Heterocyclic radical can be substituted or be unsubstituted.
" heteroaralkyl " used in the present invention or speech such as " heteroarylalkyls " are meant via alkylidene group and connect the heteroaryl that base is connected in another group. heteroaralkyl can be substituted or be unsubstituted.
When specific substituting group occurred repeatedly in certain structure or group, substituent consistence was mutually independently under every kind of situation, and promptly other this substituent situation can be identical or different in substituting group and described structure or the group.Moreover, for specific specific embodiments of the present invention and the indivedual substituting groups in the example compound, even clearly do not indicate it for preferably or do not spell out preferred its and other substituent combination, also preferably so indivedual substituting groups with and with other this type of substituent combination of The compounds of this invention.The compounds of this invention utilizes its chemical structure and/or chemical name to be defined.When the chemical structure and the chemical name of while reference compound, and the two is then determined the character of described compound when contradicting each other by its chemical structure.The substituting group that forms stable compound of the present invention can be replacement or unsubstituted alkyl, alkylidene group, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, aralkyl, heteroaryl or heteroaralkyl.The substituent example of alkyl, alkylidene group, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, aralkyl, heteroaryl or heteroaralkyl comprise alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl ,-C (O) NR 5R 6,-NR 5C (O) R 6, halogen ,-OR 5, cyano group, nitro, halogenated alkoxy ,-C (O) R 5,-NR 5R 6,-C (O) OR 5,-OC (O) R 5,-R 7C (O) NR 5R 6,-OC (O) NR 5R 6,-NR 5C (O) OR 6,-S (O).R wherein 5, R 6With R 7Be selected from H ,-CH 3Or CH 2CH 3In addition, alkyl, cycloalkyl, alkylidene group, heterocyclic radical, and any saturated part of thiazolinyl, cycloalkenyl group, alkynyl, aralkyl or heteroaralkyl can also by=O ,=S ,=N-R 5Replace.When heterocyclic radical, heteroaryl or heteroaralkyl contained nitrogen-atoms, it can be substituted or be unsubstituted; When the aromatics ring nitrogen of heteroaryl had substituting group, described nitrogen can form quaternary amine.The substituting group that the present invention conceived and the selection of variable only are in order to form stable compound with combination.
Used " stablizing " speech of the present invention is meant that compound has the stability that can be produced out and keeps the integrity that self can be used in realization purpose described in the invention, for example gives to therapeutic object.Typically, described compound keeps stable and reaches 90 days at least under the situation that does not have excessive moisture under the temperature below 40 ℃ or 40 ℃.
Unless indicate separately, otherwise contain reactive functional group, also comprise its derivative through protection such as but not limited to carboxyl, hydroxyl or amino The compounds of this invention." through the derivative of protection " is meant the compound that its reactive moieties is blockaded by one or more protecting groups.The due care base of carboxyl comprises benzyl, the tertiary butyl etc.; Amino due care base with amide group comprises ethanoyl, tertbutyloxycarbonyl, benzyl oxygen carbonyl etc.; The due care base of hydroxyl comprises benzyl, methoxyl methyl etc.; Other suitable protecting group is known by the person of ordinary skill in the field, referring to T.W.Greene, and Protective Groupsin Organic Synthesis 4th Edition, 2006, its full content is all introduced the present invention as a reference.
" The compounds of this invention " used in the present invention speech and similar noun are meant the arbitrary compound shown in the general formula (I) or their pharmacy acceptable salts and solvate; enantiomorph and racemic mixture or polymorphs body also comprise its derivative through protection.
" pharmacy acceptable salt " used in the present invention speech is meant by acidity in the arbitrary compound shown in the general formula (I) and the formed salt of basic group, salt as an example includes but not limited to, vitriol, Citrate trianion, acetate, oxalate, muriate, bromide, iodide, nitrate, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, lactic acid salt, salicylate, the acid Citrate trianion, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate salt, succinate, maleic acid salt, gentisate, fumarate, gluconate, glucuronate, glucarate, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate and pamoic acid (promptly 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoic acid) salt). " pharmacy acceptable salt " speech also refers to have acid functional groups arbitrary compound shown in the general formula (I) of (for example carboxylic-acid functional base) and pharmaceutically acceptable inorganic or salt that organic bases forms. suitably alkali includes but not limited to the oxyhydroxide of basic metal (for example sodium or potassium); The oxyhydroxide of alkaline-earth metal (for example calcium and magnesium); The oxyhydroxide of other metal (for example aluminium and zinc); Inorganic amine and organic amine, the list that for example is unsubstituted or is replaced by hydroxyl-, two-or trialkylamine; Cyclohexanediamine; Tributylamine; Pyridine; N-methyl-N-ethamine; Diethylamine; Triethylamine; Single-, two-or three-(2-hydroxyl low-grade alkyl amine), for example single-, two-or three-(2-hydroxyethyl) amine, 2-hydroxyl TERTIARY BUTYL AMINE or three (methylol) amine; N, N-two low alkyl groups-N-(hydroxyl low-grade alkyl) amine, N for example, N-dimethyl-N-(2-hydroxyethyl) amine; N-methyl D-glucosamine; And amino acid, for example arginine, Methionin etc.
" pharmaceutically acceptable solvate " used in the present invention speech is that one or more solvent molecules combine the solvate that forms with one or more molecules of the arbitrary compound shown in the general formula (I).Solvate one speech comprises hydrate (for example, semihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate etc.).
" significant quantity " is meant the amount of the compound that reaches advantageous effects when compound gives object, perhaps has the amount of the active compound of expectation in vivo or in vitro.With regard to anticancer, with respect to treating, favourable clinical effectiveness comprises: the degree or the seriousness of the symptom relevant with described disease or imbalance alleviate, and/or the life-span of described object and/or quality of life raising.The accurate amount that gives the compound of object need be looked type and the seriousness and the described Properties of Objects of disease or symptom, and for example health condition, age, sex, body weight reach the tolerance of medicine is decided; Also to decide on the degree of disease.The person of ordinary skill in the field can determine suitable dosage according to above-mentioned factor and other factors.
Compound of the present invention may contain one or more symmetry centre, therefore has steric isomer, for example mirror image isomer or non-mirror image isomer.According to the present invention, comprise that the chemical structure described in the invention of The compounds of this invention has contained the geometrical isomer of all corresponding compounds, mirror image isomer and steric isomer, that is to say the mixture that comprises pure stereoisomers (for example, pure geometrical isomer, pure mirror image isomer or pure non-mirror image isomer) and mirror image isomer, non-mirror image isomer or geometrical isomer.In some cases, mirror image isomer, non-mirror image isomer or geometrical isomer have the toxicity or the kinetic property of more superior active or improvement.In this case, mirror image isomer, non-mirror image isomer or the geometrical isomer of preferred The compounds of this invention.
Racemic mixture used in the present invention is meant about 50% mirror image isomer and the about 50% corresponding mirror image isomer with respect to all symmetry centre of intramolecularly.All pure mirror image isomers of the arbitrary compound shown in the general formula (I), pure non-mirror image isomer or racemic mixture are contained in the present invention.
Mirror image isomer and non-mirror image isomer mixture can utilize the method for generally knowing, for example chiral gas chromatography, chiral hplc, make compound become the crystallization method of chirality salt composite or make the method for compound crystallization in chiral solvent, be split as its mirror image isomer.Also can utilize the asymmetric synthesis method of generally knowing, make mirror image isomer and non-mirror image isomer with the intermediate product of pure non-mirror image isomer or pure mirror image isomer.
When the clinical administration of human time-like that is used for, The compounds of this invention typically gives with the form of isolating form or isolating medical composition." separation " used in the present invention be meant adopt prior art with The compounds of this invention from (a) natural origin, for example plant or cell are preferably bacterial cultures; Or (b) purifying in the synthetic organic chemical reactions mixture.Used " purifying " of the present invention be meant after separation, contains at least 95% the simplification compound of the present invention that accounts for separated product weight in the separated product, is preferably at least 98%.
The present invention only considers to produce the substituent selection and the combination of stable compound structure.Such selection is conspicuous with combination for the person of ordinary skill in the field, and does not need undo experimentation to determine.
Compound of the present invention is used to prepare the purposes of antihypertensive drug. formula (I) thus shown in compound can be in vivo decomposed and produce losartan performance antihypertensive function by esterase or amino acid lytic enzyme. because the singularity of these compound structures (special construction partly is amino acid or amino acid analogue), they can be interacted by PepT1 transporter identification abundant in the gi tract. and this effect makes these compounds be absorbed by gi tract by active transport. and, in by the process of gastrointestinal absorption, these compounds do not participate in the metabolic process of glucuronic acidization. after being absorbed by gi tract, these compounds are decomposed by esterase or amino acid lytic enzyme in enteron aisle and in the liver, producing losartan lentamente, prolonged the time that losartan stops in the blood in vivo like this. so stable Plasma Concentration that produces will help increasing curative effect and reduce side reaction. and experimental pharmacokinetic study shows that described compound can be used as prodrug and decomposes the generation losartan in vivo in the animal body of the present invention.
Pharmaceutical application and preparation
Compound of the present invention or its pharmacy acceptable salt itself can give the patient, perhaps can be with the mode administration of pharmaceutical composition, wherein with them and suitable carrier or mixed with excipients.
Route of administration
That suitable route of administration can include but not limited to is oral, in rectum, mucous membrane, intramuscular, subcutaneous, the marrow, intravenously, intraperitoneal or intranasal administration.Preferred route of administration is oral and intravenous administration.Perhaps can give compound, for example topical application or be injected directly into the focus zone of patient body in the mode of part rather than whole body.
Composition/preparation
Pharmaceutical composition of the present invention can be according to the method that oneself knows in the affiliated technical field, for example mixing, dissolving, granulation, system drageeing, grinding, the emulsification by routine, encapsulates, holds back or freeze drying process prepares.
Can use one or more to help compound is processed into the pharmaceutically acceptable carrier of pharmaceutical preparation in a usual manner, for example vehicle and auxiliary material come the compounding pharmaceutical composition.The preparation that is fit to depends on selected route of administration; These preparations are that oneself knows for affiliated technical field technician, and include but not limited to following:
For oral administration, can mix by the pharmaceutically acceptable carrier that will know in active compound and the affiliated technical field and prepare.These carriers can make compound of the present invention be formulated into tablet, pill, lozenge, drageeing, capsule, liquid, gel, syrup, suspensoid etc. to be used for the oral absorption of patient.The pharmaceutical preparation that orally uses can also use solid excipient to prepare, and randomly grinds the mixture of gained and is processed into granular mixture, then adds other suitable auxiliary material if desired, obtains tablet or drageeing core.The nonrestrictive example of the vehicle that some are useful is a weighting agent, and is for example sugared, as lactose, sucrose, mannitol or Sorbitol Powder; Mierocrystalline cellulose, for example methylcellulose gum, Vltra tears, Xylo-Mucine; Starch, for example W-Gum, wheat starch, rice starch and yam starch; And other material, as gelatin and polyvinylpyrrolidone (PVP); Lubricant, for example sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc.; If necessary, can add disintegrating agent, as starch, methylcellulose gum, cross-linked polyvinylpyrrolidone, agar or Lalgine.Can also use salt, as sodiun alginate.
The drageeing core has suitable dressing usually.For this purpose, can use dense sugar soln, it can randomly contain gum arabic, talcum, polyvinylpyrrolidone, carbomer gel (carbopolgel), ethylene glycol and/or titanium dioxide and the suitable organic solvent or the mixture of solvent.Dyestuff or pigment can be added tablet or drageeing dressing to identify or to characterize the various combination of active compound doses.The pharmaceutical composition that can orally use also comprises the pressing capsule of being made by gelatin, the capsule of being made by gelatin and softening agent such as glycerine or Sorbitol Powder etc. soft, sealing.The capsule of pressing can contain with as the weighting agent of lactose, as the tackiness agent of starch and/or as the lubricant of talcum or Magnesium Stearate, and the stablizer blended activeconstituents of choosing wantonly.In soft capsule, can or be suspended in appropriate liquid with the active compound dissolving, in fatty oil, whiteruss or liquid macrogol.Stablizer can also be added in these preparations.
Rectal administration also adopts the form of preparation, and wherein with The compounds of this invention and low melting point is water-soluble or insoluble solid, for example the fatty acid ester of theobroma oil, vegetables oil, polyoxyethylene glycol or polyoxyethylene glycol is mixed.
Pharmaceutical composition of the present invention can also comprise suitable solid or gel phase carrier or vehicle. and the example of these carriers or vehicle includes but not limited to lime carbonate, calcium phosphate, sugar, starch, derivatived cellulose, gelatin and polymkeric substance, as polyoxyethylene glycol.
Activeconstituents of the present invention can utilize known controlled release mode of person of ordinary skill in the field or e Foerderanlage to give, and the example is including but not limited to United States Patent (USP) the 3rd, 845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,120,548; 5,073,543; 5,639,476; 5,354,556; Put down in writing in 5,733, No. 566, above-mentioned patent is all introduced the present invention for your guidance.These controlled release modes or e Foerderanlage can be used for providing the slowly-releasing or the controlled release of one or more activeconstituentss, use for example Vltra tears, other polymeric matrixs, gel, permeable membrane, osmosis system, laminated coating, particulate, liposome, microsphere or its composition, so that the performance of carrying out required release in proportion to be provided.The person of ordinary skill in the field can easily select known suitable controlled release conditioning agent and activeconstituents of the present invention and use.Therefore, the single unit dosage that is applicable to that oral administration gives has been contained in the present invention, such as but not limited to the tablet that is applicable to controlled release, capsule, casing sheet or film garment piece.All controlled release pharmaceutical products all have the common objective that promotes pharmacological agent.Ideally, adopt controlled release preparation carry out pharmacological agent optimum design be characterized as use minimum medicine, in shortest time internal therapy or controlling symptoms.The advantage of controlled release conditioning agent comprises reduces pharmaceutical activity prolongation, medicine frequency or the compliance of patients increase.In addition, the controlled release conditioning agent can be used for the time that influence is active or other characteristics (for example content of medicine in blood) take place, thereby can influence the generation of side effect.
Compound of the present invention can provide with the form of pharmacy acceptable salt, and wherein claimed compounds can form the form of electronegative or positively charged.The example of the salt of the positively charged that compound can form includes but not limited to quaternary ammonium salt, and wherein nitrogen-atoms and suitable acid-respons form example hydrochloric acid salt, vitriol, carbonate, lactic acid salt, tartrate, maleate, succinate.The electronegative salt of compound formation of the present invention includes but not limited to the hydroxy-acid group and suitable alkali by The compounds of this invention, as sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca (OH) 2) wait and react sodium, potassium, calcium and the magnesium salts that forms.
Clinical application
Can give the patient with the The compounds of this invention of treatment significant quantity, be used for the treatment of essential hypertension, as pulmonary hypertension and coronary heart disease, heart brain and kidney blood vessel diseases or migraine etc.
Uniting the examples for compounds of using and being used for the treatment of high blood pressure disease with compound of the present invention includes but not limited to: 1) hypolipidemic, for example suppress cholesterol synthetic Statins (statins) medicine, as Cerivastatin (cerivastatin), Pravastatin (pravastatin), Simvastatin (simvastatin), lovastatin (lovastatin), Zarator (atorvastatin), fluvastatin (fluvastatin), itavastatin (itavastatin) or their salt etc.; 2) depressor, for example hypertensin enzymeinhibitor depressor: captopril (captopril), enalapril (enalapril), delapril (delapril) etc.; Angiotensin receptor II antagonist depressor: candesartan Cilexetil (candesartan cilexetil), Candesartan (candesartan), losartan (losartan), LOSARTAN POTASSIUM (losartan potassium), Eprosartan (eprosartan), valsartan (valsartan), termisartan, irbesartan (irbesartan), Tasosartan (tasosartan), Olmesartan (olmesartan), olmesartan medoxomill (olmesartan medoxomil) etc.; Calcium antagonist depressor: Manidipine (manidipine), nifedipine (nifedipine), amlodipine (amlodipine), efonidipine (efonidipine), nicardipine (nicardipine) etc.; Beta receptor resistance resistance agent: metoprolol (metoprolol), atenolol USP 23 (atenolol), Proprasylyte (propranolol), carvedilol (carvedilol), pindolol (pindolol) etc., and hydragog(ue), perhaps their analogue or derivative etc.
Dosage
Correct dosage depends on the severity and the process of disease, previous treatment, patient's general health and different sexes are to differential responses of medicine etc., all these is in treatment doctor's knowledge, in the scope of experience and judgement. usually, the suitable effective dosage ranges of The compounds of this invention is every experimenter 5-200mg/ days, preferred range is 5-50mg/ days. the required dosage preferred allocation becomes 1,2,3,4 or more a plurality of divided dose, they gave with the suitable timed interval in all day. and these divided doses can be with unit dosage, for example contain 5-50mg, the unit dosage administration of preferred 5-20mg activeconstituents. preferably, by weight in patients, the dosage of The compounds of this invention is about 0.1mg/kg to 1.0mg/kg, about every day 1 to 2 time.
In case observe patient's doing well,improving, if expectation can give maintenance dose by the treatment doctor.Can be reduced to the level of keeping after the improvement as the dosage of the function of patient reaction, frequency or the two.When these remissions to the expectation level the time, can stopped treatment.If symptomatic recurrence, some patient may need secular intermittent therapy.
Embodiment
To understand the present invention more up hill and dale with reference to above detailed description and the following examples, following examples are only as the nonrestrictive concrete example of the present invention.
The general preparation method of compound is as follows shown in the formula (I):
Compound shown in compound shown in the formula (II) and the formula (III) is reacted,
Figure G2009100768759D00241
R wherein 1, R 2, R 3With R 4With above described.
The reaction of compound can be at inert solvent shown in compound shown in the formula (II) and the formula (III), for example in acetonitrile or the dimethyl formamide, under the temperature of room temperature to 50 ℃, carry out, with 1-(3-dimethylamino) propyl group-3-ethyl carbodiimide and N-hydroxybenzotriazole catalyzing and condensing.If protecting group is arranged, protecting group compound shown in the acquisition formula (I) afterwards can removed.
Compound is known in the document shown in compound shown in the formula (II) and the formula (III), perhaps can make by the known method of person of ordinary skill in the field, perhaps can buy from commercial channels.
Embodiment 1:
105) 2-alanine (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters
At room temperature, with 1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl alcohol (422mg, 1.0mmol) be dissolved in the anhydrous dimethyl formamide (8mL), solution placed 0 ℃ ice bath, and adding N-tert-butoxycarbonyl-L-L-Ala (378mg, 2.0mmol), 1-(3-dimethylamino) propyl group-3-ethyl-carbodiimide hydrochloride (383mg, 2.0mmol), N-hydroxybenzotriazole (270mg, 2.0mmol) and N-methylmorpholine (202mg, 2.0mmol). this reaction mixture was stirred 30 minutes under 0 ℃ temperature, at room temperature stirred 24 hours. (150mL) dilutes above-mentioned reaction mixture with water, and extracting with ethyl acetate (200mL). organic extract is successively with aqueous citric acid solution (10%), water and saturated nacl aqueous solution washing, again with anhydrous sodium sulfate drying and concentrate and to obtain crude product. by silica gel column chromatography (ethyl acetate/normal hexane/acetate (v/v/v)=80/100/3) purifying crude product obtain 470mg compound 2-(N-tert-butoxycarbonyl) alanine (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters (79.2%).
With 2-(N-tert-butoxycarbonyl) alanine (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters (672mg, 1.13mmol) be dissolved in anhydrous acetonitrile (5mL) and add p-methyl benzenesulfonic acid (975mg, 5.67mmol).This reaction mixture at room temperature stirred after 3.0 hours concentrate.Enriched material is dissolved in Virahol/CH 2Cl 2((v/v)=1/3,150ml) in.Alkalize to pH～9.0 with saturated sodium bicarbonate aqueous solution.Virahol/CH 2Cl 2The organic extraction layer is with the saturated nacl aqueous solution washing with behind the anhydrous sodium sulfate drying, and (10% (w/v) 0.53ml) to form the solid crystal of white, is the Citrate trianion of the described compound of title to the aqueous isopropanol of dropping citric acid.This compound is C 25H 28ClN 7O 2, the calculated value of MS-ESI (m/z) is 493.2; Measured value 492.4 (100, MH -).
Embodiment 2:
103) 2-amino-4-methylvaleric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters
According to the method preparation of describing among the embodiment 1, except using N-tert-butoxycarbonyl-L-leucine in place N-tert-butoxycarbonyl-L-L-Ala.The compound of gained is C 28H 34ClN 7O 2, the calculated value of MS-ESI (m/z) is 535.2; Measured value be 534.1 (100, MH -).
Embodiment 3:
101) 2-Padil (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters
According to the method preparation of describing among the embodiment 1, replace N-tert-butoxycarbonyl-L-L-Ala except using N-tert-butoxycarbonyl-L-glycine.The compound of gained is C 24H 26ClN 7O 2, the calculated value of MS-ESI (m/z) is 479.2; Measured value be 478.7 (100, MH -).
Embodiment 4:
115) 2,5-diamino-5-oxopentanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters
According to the method preparation of describing among the embodiment 1, replace N-tert-butoxycarbonyl-L-L-Ala except using N-tert-butoxycarbonyl-altheine.The compound of gained is C 27H 31ClN 8O 3, the calculated value of MS-ESI (m/z) is 550.2; Measured value be 551.5 (100, MH +).
Embodiment 5:
123) 2,6-diaminocaproic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters
According to the method preparation of describing among the embodiment 1, replace N-tert-butoxycarbonyl-L-L-Ala except using N-tert-butoxycarbonyl-L-Methionin.The compound of gained is C 28H 35ClN 8O 2, the calculated value of MS-ESI (m/z) is 550.3; Measured value be 551.5 (100, MH +).
Embodiment 6:
125) 2-amino-4-methylmercapto butyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters
According to the method preparation of describing among the embodiment 1, replace N-tert-butoxycarbonyl-L-L-Ala except using N-tert-butoxycarbonyl-L-methionine(Met).The compound of gained is C 27H 32ClN 7O 2S, the calculated value of MS-ESI (m/z) is 553.2; Measured value be 554.4 (100, MH +).
Embodiment 7:
127) 2-amino-3-phenylpropionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters
According to the method preparation of describing among the embodiment 1, replace N-tert-butoxycarbonyl-L-L-Ala except using N-tert-butoxycarbonyl-L-phenylalanine.The compound of gained is C 31H 32ClN 7O 2, the calculated value of MS-ESI (m/z) is 569.2; Measured value be 570.5 (100, MH +).
Embodiment 8:
129) tetramethyleneimine-2-acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters
According to the method preparation of describing among the embodiment 1, replace N-tert-butoxycarbonyl-L-L-Ala except using N-tert-butoxycarbonyl-L-proline(Pro).The compound of gained is C 27H 30ClN 7O 2, the calculated value of MS-ESI (m/z) is 519.2; Measured value be 520.6 (100, MH +).
Embodiment 9:
121) 2-amino-3 methylvaleric acid (2S, 3R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-just-butyl-4-chlorine imidazoles-5-base methyl esters
According to the method preparation of describing among the embodiment 1, replace N-tert-butoxycarbonyl-L-L-Ala except using N-tert-butoxycarbonyl-L-Isoleucine.The compound of gained is C 28H 34ClN 7O 2, the calculated value of MS-ESI (m/z) is 535.3; Measured value be 534.6 (100, MH -).
Embodiment 10:
145) 2-amino-3 Methylbutanoic acid (2S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters
According to the method preparation of describing among the embodiment 1, replace N-tert-butoxycarbonyl-L-L-Ala except using N-tert-butoxycarbonyl-L-Xie Ansuan.The compound of gained is C 27H 32ClN 7O 2, the calculated value of MS-ESI (m/z) is 521.2; Measured value be 520.6 (100, MH -).
Pharmaceutical research in the animal body
Pharmacokinetics experiment: compound shown in the formula (I) (numbering is respectively 101,103,105,115,121,123,125,127,129 and 145 compound) has been carried out the mouse pharmacokinetic.
Mouse is divided into 9 groups, 5 every group.Medicine to be measured is water-soluble, or water and 1, (v/v=1: in the mixed solution 1), be contrast with losartan (5.8mg/kg), medicine to be measured is also with the single dose gastric infusion of 5.8mg/kg for the 2-propylene glycol.Administration is feeding after 4 hours.The blood drawing time was respectively after the administration 15,30,45 minutes and 1,2,4,7,10 and 15 hour.The blood drawing amount is 0.5-1mL, is put in the pipe of containing heparin.Blood plasma obtains by centrifugal.All plasma samples need place-20 ℃ to preserve down.Behind acetonitrile removal plasma proteins, get supernatant liquor analysis.HPLC/MS/MS detects the Plasma Concentration of losartan.The analytical results of Plasma Concentration shows:
The highest Plasma Concentration of compound 101 is 0.504 μ M, and area under the drug-time curve (AUC) is 318 μ Mhr, and bioavailability is 19%, and the transformation period is 1.89 hours;
The highest Plasma Concentration of compound 103 is 0.544 μ M, and area under the drug-time curve (AUC) is 532 μ Mhr, 33% of bioavailability, and the transformation period is 4.5 hours;
The highest Plasma Concentration of compound 105 is 0.399 μ M, and area under the drug-time curve (AUC) is 365 μ Mhr, 22% of bioavailability, and the transformation period is 33.2 hours;
The highest Plasma Concentration of compound 115 is 0.214 μ M, and area under the drug-time curve (AUC) is 209 μ Mhr, 13% of bioavailability, and the transformation period is 1.78 hours;
The highest Plasma Concentration of compound 121 is 1.05 μ M, and area under the drug-time curve (AUC) is 560 μ Mhr, 34% of bioavailability, and the transformation period is 12.5 hours;
The highest Plasma Concentration of compound 123 is 0.359 μ M, and area under the drug-time curve (AUC) is 254 μ Mhr, 15% of bioavailability, and the transformation period is 8.18 hours;
The highest Plasma Concentration of compound 125 is 0.333 μ M, and area under the drug-time curve (AUC) is 209 μ Mhr, 13% of bioavailability, and the transformation period is 3.9 hours;
The highest Plasma Concentration of compound 127 is 0.644 μ M, and area under the drug-time curve (AUC) is 342 μ Mhr, 20% of bioavailability, and the transformation period is 2.02 hours;
The highest Plasma Concentration of compound 129 is 0.76 μ M, and area under the drug-time curve (AUC) is 406 μ Mhr, 24% of bioavailability, and the transformation period is 2.78 hours;
The highest Plasma Concentration of compound 145 is 0.751 μ M, and area under the drug-time curve (AUC) is 482 μ Mhr, 29% of bioavailability, and the transformation period is 1.97 hours;
Experimental pharmacokinetic study proves that prodrug that compound of the present invention can be used as losartan decomposes in vivo and produces losartan and then reach hypotensive purpose in the above-mentioned animal body.
Those skilled in the art will be readily appreciated that the present invention is very suitable for reaching described purpose and realizes institute of the present invention inherent target and advantage.Composition of the present invention, method, process, treatment, specific compound are the representative of preferred specific embodiments at present, and they are exemplary, it should be interpreted as limiting the scope of the invention.The person of ordinary skill in the field will expect wherein change and other use, these changes and application are included in the scope by the defined inventive concept of scope of claim.

Claims (14)

1. the compound shown in the general formula (I) or its pharmacy acceptable salt, its enantiomorph or its racemic mixture,
Figure F2009100768759C00011
Wherein, R 1, R 2, R 3With R 4Be H independently, the optional alkyl that replaces, the optional cycloalkyl that replaces, alkylthio, alkoxyl group, the optional aryl that replaces, the optional aralkyl that replaces, or R 1With R 2Form the optional cycloalkyl that replaces together, or R 2With R 3Form the optional heterocyclic radical that replaces together, or R 3With R 4Form the optional heterocyclic radical that replaces together,
The alkyl of described optional replacement is selected from C unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals, sulfydryl, phenyl, indyl, imidazolyl, hydroxy phenyl 1-C 8The straight or branched alkyl; The cycloalkyl of described optional replacement is selected from C unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals 3-C 8Cycloalkyl; The aryl of described optional replacement is selected from phenyl unsubstituted or that replace through halogen, amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group; The aralkyl of described optional replacement is selected from the C that aryl replaces 1-C 8The straight or branched alkyl; The heterocyclic radical of described optional replacement is selected from quinary heterocyclic radical, hexa-member heterocycle base or indyl unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group; Described alkylthio is C 1-C 8Straight or branched alkyl sulfenyl; Described alkoxyl group is C 1-C 8The straight or branched alkyl oxy.
2. compound according to claim 1 or its pharmacy acceptable salt, its enantiomorph or its racemic mixture is characterized in that, described R 1With R 2Be H independently, C unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals, sulfydryl, phenyl, indyl, imidazolyl, hydroxy phenyl 1-C 6The straight or branched alkyl; Or C unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals 3-C 8Cycloalkyl; Or R 1With R 2Form cyclopropane base, tetramethylene base, pentamethylene base or cyclohexyl with the C that is connected.
3. compound according to claim 1 or its pharmacy acceptable salt, its enantiomorph or its racemic mixture is characterized in that, described R 2With R 3Form pyrrolidyl or piperidyl with C that is connected and N.
4. compound according to claim 1 or its pharmacy acceptable salt, its enantiomorph or its racemic mixture is characterized in that, described R 3With R 4Be H independently, C unsubstituted or that replace through amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals, sulfydryl, indyl, imidazolyl, hydroxy phenyl 1-C 3The straight or branched alkyl.
5. compound according to claim 1 or its pharmacy acceptable salt, its enantiomorph or its racemic mixture is characterized in that, described R 3With R 4Be H; R 1And R 2In one of be H, another be selected from H ,-CH 3,-CH 2CH 3,-SCH 3,-CH (R 5) R 6Or-CH 2CH (R 5) R 6, R wherein 5And R 6In one of be selected from H ,-CH 3Or-CH 2CH 3Another is H, C 1-C 3Straight chain, branched-chain alkyl or cyclopropane base; R 5Or R 6Randomly replaced: amino, hydroxyl, carboxyl, alkoxyl group, alkylthio, aminocarboxyl, acyl group, amide group, guanidine radicals, sulfydryl, phenyl, indyl, imidazolyl and hydroxy phenyl by one or more following groups.
6. compound according to claim 1 or its pharmacy acceptable salt, its enantiomorph or its racemic mixture is characterized in that, described R 3With R 4Be H; R 1And R 2In one of be H, another be selected from H ,-CH 3,-CH 2CH 3,-CH 2CH (CH 3) CH 3,-CH (CH 3) CH 3,-CH (CH 3) CH 2CH 3,-CH 2CH 2CONH 2,-CH 2CONH 2,-CH 2CH 2COOH ,-CH 2COOH ,-SCH 3,-CH 2SH ,-CH 2OH ,-CH (OH) CH 3,-CH 2CH 2SCH 3,-CH 2C 6H 5,-CH 2C 6H 4(OH) ,-CH 2CH 2CH 2CH 2NH 2,
Figure F2009100768759C00021
With
Figure F2009100768759C00022
7. compound according to claim 1 or its pharmacy acceptable salt, its enantiomorph or its racemic mixture is characterized in that, described compound is selected from:
101) 2-Padil (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
103) 2-amino-4-methylvaleric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
105) 2-alanine (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
115) 2,5-diamino-5-oxopentanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
121) 2-amino-3 methylvaleric acid (2S, 3R)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
123) 2,6-diaminocaproic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] and methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
125) 2-amino-4-methylmercapto butyric acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
127) 2-amino-3-phenylpropionic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
129) tetramethyleneimine-2-acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters;
145) 2-amino-3 Methylbutanoic acid (S)-1-[2 '-(1H-tetrazolium-5-yl)-1 ', 1-biphenyl-4-yl] methyl-2-normal-butyl-4-chlorine imidazoles-5-base methyl esters.
8. according to the preparation method of each described compound or its pharmacy acceptable salt, its enantiomorph or its racemic mixture in the claim 1 to 7, it comprises compound shown in compound shown in the formula (II) and the formula (III) is reacted compound shown in the formula of making (I)
Wherein, R 1, R 2, R 3With R 4With each described definition in the claim 1 to 7.
9. a combination antihypertensive wherein comprises according to each described compound or its pharmacy acceptable salt, its enantiomorph or its racemic mixture in the claim 1 to 7.
10. pharmaceutical composition according to claim 9 is characterized in that, described pharmaceutical composition also comprises one or more pharmaceutically acceptable carrier and/or vehicle.
11. prevent and/or treat purposes in the medicine of hypertension and relative disease thereof in preparation according to each described compound or its pharmacy acceptable salt, its enantiomorph or its racemic mixture in the claim 1 to 7.
12. purposes according to claim 11 is characterized in that, described hypertension is pulmonary hypertension.
13. purposes according to claim 11 is characterized in that, described hypertension relative disease is coronary heart disease, heart brain and kidney blood vessel diseases and/or migraine.
14. purposes according to claim 11, it is characterized in that compound or its pharmacy acceptable salt, its enantiomorph or its racemic mixture shown in the described formula (I) be used to prepare simultaneously, respectively or order medicine that the patient of hypertension and relative disease thereof is carried out administration.
CN200910076875A 2009-01-23 2009-01-23 Anti-hypertension compound, and preparation, pharmaceutical composition and use thereof Expired - Fee Related CN101475565B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN200910076875A CN101475565B (en) 2009-01-23 2009-01-23 Anti-hypertension compound, and preparation, pharmaceutical composition and use thereof
PCT/CN2009/000602 WO2010083633A1 (en) 2009-01-23 2009-05-27 Compounds uesed for anti-hypertension, preparation methods, compositions and uses thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN200910076875A CN101475565B (en) 2009-01-23 2009-01-23 Anti-hypertension compound, and preparation, pharmaceutical composition and use thereof

Publications (2)

Publication Number Publication Date
CN101475565A CN101475565A (en) 2009-07-08
CN101475565B true CN101475565B (en) 2010-05-12

Family

ID=40836348

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200910076875A Expired - Fee Related CN101475565B (en) 2009-01-23 2009-01-23 Anti-hypertension compound, and preparation, pharmaceutical composition and use thereof

Country Status (2)

Country Link
CN (1) CN101475565B (en)
WO (1) WO2010083633A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107468685B (en) * 2016-06-08 2021-06-01 科贝源(北京)生物医药科技有限公司 Pharmaceutical composition and compound for treating hypertension and heart failure

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1676523A (en) * 2004-04-02 2005-10-05 北京德众万全药物技术开发有限公司 Method for preparing antihypertension losartan
CN1915990A (en) * 2006-09-06 2007-02-21 浙江海正药业股份有限公司 Method for preparingLosartan

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1676523A (en) * 2004-04-02 2005-10-05 北京德众万全药物技术开发有限公司 Method for preparing antihypertension losartan
CN1915990A (en) * 2006-09-06 2007-02-21 浙江海正药业股份有限公司 Method for preparingLosartan

Also Published As

Publication number Publication date
WO2010083633A1 (en) 2010-07-29
CN101475565A (en) 2009-07-08

Similar Documents

Publication Publication Date Title
US20210161863A1 (en) Preparation and use of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in the treatment of conditions affected by monoamine neurotransmitters
CN105753814A (en) Substituted nitrogen heterocyclic derivative and application thereof
CA2954401C (en) Substituted 2-thioxo-imidazolidin-4-ones and spiro analogues thereof, active anti-cancer ingredient, pharmaceutical composition, medicinal preparation, method for treating prostate cancer
CN102421434A (en) Oral formulations of diphenylsulfonamide endothelin and angiotensin ii receptor agonists to treat elevated blood pressure and diabetic nephropathy
HUE031999T2 (en) Cyclic n,n'-diarylthioureas and n,n'-diarylureas as androgen receptor antagonists, anti-cancer agent, method for producing and using same
WO2002017913A1 (en) Medicinal compositions for preventing or treating heart failure
CN101594857A (en) The crystal form of aliskiren hemifumarate
CN101412690A (en) Medicinal acid addition salt of silodosin, and preparation and medicament use thereof
JP2023521169A (en) Methods of treating diabetic kidney disease
CN103896923B (en) A kind of Hypoglycemics, its preparation method, comprise its medical composition and its use
CN109503548B (en) Butylphthalide derivative and preparation method and application thereof
CN105693817A (en) Tripeptide compound and preparation method and application thereof
CN102459215A (en) 3-(4-aminophenyl)-2-furancarboxylic acid derivative and pharmaceutically acceptable salt thereof
CN101475565B (en) Anti-hypertension compound, and preparation, pharmaceutical composition and use thereof
CN100532381C (en) Antineoplastic compound, medicament composition and use thereof
CN101243074A (en) Heterocyclic compounds
CN103006648A (en) Maleic acid levorotation amlodipine drug active pharmaceutical composition and preparation method thereof
AU2009262319A1 (en) Salts of methyl 2-((R))-(3-chlorophenyl) ((R)-1-((S)-2- (methylamino)-3((R)-tetrahydro-2H-pyran-3-yl) propylcarbamoyl) piperidin-3-yl)methoxy)ethylcarbamate
RU2586978C2 (en) Daidzein derivative, pharmaceutically acceptable salt and method for production thereof, as well as pharmaceutical composition containing same
CN102241644B (en) Alpha-azyl-3-aryl propionamido thiazole derivative, preparation method and purpose thereof
CN102796093B (en) Thiomorpholine-containing pyrrole derivatives and their preparation method and use
CN101684103B (en) Compound with 1,2,4-triazole structure and preparation method and application thereof
KR100881040B1 (en) Medicinal composition
CN102503954B (en) Imidazole derivative and preparation method and application thereof
WO2023225163A1 (en) Methods of treating focal segmental glomerulosclerosis with atrasentan

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20100512

Termination date: 20170123

CF01 Termination of patent right due to non-payment of annual fee