CN1261352A - New 'beta'-amino and 'beta'-azidocarboxylic acid derivatives, the production thereof and the use thereof as endothelin receptor an tagonists - Google Patents

New 'beta'-amino and 'beta'-azidocarboxylic acid derivatives, the production thereof and the use thereof as endothelin receptor an tagonists Download PDF

Info

Publication number
CN1261352A
CN1261352A CN98806397A CN98806397A CN1261352A CN 1261352 A CN1261352 A CN 1261352A CN 98806397 A CN98806397 A CN 98806397A CN 98806397 A CN98806397 A CN 98806397A CN 1261352 A CN1261352 A CN 1261352A
Authority
CN
China
Prior art keywords
cooh
alkyl
ome
conh
group
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.)
Pending
Application number
CN98806397A
Other languages
Chinese (zh)
Inventor
W·安贝格
A·克林
D·克林格
H·里歇特
S·赫根勒德
M·拉沙克
L·翁格尔
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.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Publication of CN1261352A publication Critical patent/CN1261352A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/14—Oxygen atoms
    • C07D237/16—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Oncology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Neurology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to carboxylic acid derivatives of formula (I) wherein the constituents have the meaning given in the description. The invention also relates to the production of said derivatives, and to their use as endothelin receptor antagonists.

Description

New beta-amino and β-azido-carboxylic acid derivative, its preparation and as the application of endothelin-receptor antagonists
The present invention relates to new carboxylic acid derivative, its preparation and application.
The peptide that endothelin is made up of 21 amino acid, the synthetic and release by blood vessel endothelium.Endothelin exists with three kinds of isomeric form, i.e. ET-1, ET-2 and ET-3.Hereinafter, " endothelin " or " ET " is meant a kind of of endothelin or all isomeric form.Endothelin is effective vasoconstrictor, and antiotasis is had very strong effect.Known vasoconstriction causes (Nature, 332 (1988) 411-415 owing to endothelin and its receptors bind; FEBS Letters, 231, (1988) 440-444, and Biochem.Biophys, Res.Commun., 154, (1988) 868-875).
Endothelin increases or unusual release causes the vasoconstriction that periphery, kidney and the cerebrovascular continue, and this can cause disease.As reported in the literature, endothelin is relevant with numerous disease, these diseases comprise: hypertension, Acute Myocardial Infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, apoplexy, benign prostatic hyperplasia, atherosclerosis, asthma and prostate cancer (J.Vascular Med.Biology 2, (1990) 207, J.Am.Med.Association 264, (1990) 2868, Nature 344, (1990) 114, N.Engl.J.Med.322, (1989), 205, N.Engl.J.Med.328, (1993) 1732, Nephron 66, (1994) 373, Stroke 25, (1994) 904, Nature 365, (1993) 759, J.Mol.Cell.Cardiol.27, (1995) A234; Cancer Research 56, (1996) 663, NatureMedicine 1, (1995) 944).
Up to now, two kinds of endothelin receptor hypotypes have at least been described in the literature, ET AAnd ET BAcceptor (Nature 348, (1990) 730, Nature 348, (1990) 732).Therefore, the material that suppresses endothelin and one or both receptors bind should produce antagonism to the physiological role of endothelin, is valuable drug therefore.
The purpose of this invention is to provide and ET AAnd/or ET BThe endothelin-receptor antagonists of receptors bind.The present invention relates to beta-amino and the β-azido-carboxylic acid derivative of formula I R wherein 1Be tetrazolium or following formula group Wherein the implication of R is as follows:
A) OR 4Group, wherein R 4Be:
The organic ammonium ion of hydrogen, alkali metal cation, alkaline earth metal cation or physiological tolerance is uncle C for example 1-C 4-alkylammonium or ammonium ion;
C 3-C 8-cycloalkyl, C 1-C 8-alkyl, CH 2-phenyl, it can be replaced by one or more following radicals: halogen, nitro, cyano group, C 1-C 4-alkyl, C 1-C 4-haloalkyl, hydroxyl, C 1-C 4-alkoxyl group, sulfydryl, C 1-C 4-alkylthio, amino, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2
C 3-C 8-alkenyl or C 3-C 8-alkynyl, these groups can have 1-5 halogen atom;
R 4Can also be phenyl, it can have 1-5 halogen atom and/or 1-3 following groups: nitro, cyano group, C 1-C 4-alkyl, C 1-C 4-haloalkyl, hydroxyl, C 1-C 4-alkoxyl group, sulfydryl, C 1-C 4-alkylthio, amino, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2
B) by nitrogen-atoms banded 5-unit hetero-aromatic ring, for example pyrryl, pyrazolyl, imidazolyl and triazolyl, they can have 1 or 2 halogen atom or 1 or 2 C 1-C 4-alkyl or 1 or 2 C 1-C 4-alkoxyl group;
C) following formula group
Wherein k can be 0,1 and 2, and p is 1,2,3 and 4, and R 5Be C 1-C 4-alkyl, C 3-C 8-cycloalkyl, C 3-C 8-alkenyl, C 3-C 8-alkynyl or phenyl, it can be replaced by one or more for example 1-3 following groups:
Halogen, nitro, cyano group, C 1-C 4-alkyl, hydroxyl, C 1-C 4-alkoxyl group, C 1-C 4-alkylthio, amino, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2, sulfydryl;
D) following formula group
Figure A9880639700082
R wherein 6Be:
C 1-C 4-alkyl, C 3-C 8-alkenyl, C 3-C 8-alkynyl, C 3-C 8-cycloalkyl, these groups can have as above at c) under described C 1-C 4-alkoxyl group, C 1-C 4-alkylthio and/or phenyl;
C 1-C 4-haloalkyl or phenyl, it is optional substituted, particularly as at c) cited under the item.
Other substituting group has following implication:
A is NR 7R 8Or azido-;
W and Z can be identical or different, and they are:
Nitrogen or methyne; Condition is if W and Z=methyne, then Q=nitrogen;
X is nitrogen or CR 9
Y is nitrogen or CR 10
Q is nitrogen or CR 11Condition is if Q=nitrogen, then X=CR 9And Y=CR 10
R 2And R 3Can be identical or different, they are:
Phenyl or naphthyl, they can be replaced by one or more following radicals separately: halogen, nitro, cyano group, hydroxyl, sulfydryl, C 1-C 4-alkyl, C 2-C 4-alkenyl, C 2-C 4-alkynyl, C 1-C 4-hydroxyalkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group, phenoxy group, C 1-C 4-halogenated alkoxy, C 1-C 4-alkylthio, amino, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2Perhaps phenyl, it can be by one or more for example 1-3 halogen, nitro, cyano group, C 1-C 4-alkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy or C 1-C 4-alkylthio replaces; Perhaps
Phenyl or naphthyl, they are by direct key, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO 2, NH or N-alkyl link together at the ortho position;
C 5-C 6-cycloalkyl, these groups can be replaced by one or more following radicals separately: halogen, hydroxyl, sulfydryl, carboxyl, nitro, cyano group, C 1-C 4-alkyl, C 2-C 4-alkenyl, C 2-C 4-alkynyl, C 1-C 4-alkoxyl group, C 1-C 4-alkylthio, C 1-C 4-halogenated alkoxy;
R 7Be hydrogen, C 1-C 8-alkyl, C 3-C 8-alkenyl or C 3-C 8-alkynyl, C 1-C 5-alkyl-carbonyl, these groups can be replaced by one or more following radicals separately: halogen, hydroxyl, sulfydryl, carboxyl, nitro, amino, cyano group, C 1-C 4-alkoxyl group, C 3-C 6-alkenyloxy, C 3-C 6-alkynyloxy group, C 1-C 4-alkylthio, C 1-C 4-halogenated alkoxy, C 1-C 4-carbalkoxy, C 3-C 8-alkyl-carbonyl alkyl, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2, C 3-C 8-cycloalkyl, the 5-that contains 1-3 nitrogen-atoms and/or sulphur or Sauerstoffatom or 6-unit's heteroaryloxy or heteroaryl, phenoxy group or phenyl, all described aryl can be replaced one or many for example 1-3 time by following radicals: halogen, hydroxyl, sulfydryl, carboxyl, nitro, cyano group, C 1-C 4-alkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, amino, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2, phenyl or C 1-C 4-alkylthio;
Phenyl or naphthyl, they can be replaced by one or more following radicals separately: halogen, nitro, cyano group, hydroxyl, amino, C 1-C 4-alkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, phenoxy group, C 1-C 4-alkylthio, carboxyl, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2, dioxo methylene radical or dioxo ethylidene;
C 3-C 8-cycloalkyl, these groups can be replaced by the following radicals one or many separately: halogen, hydroxyl, sulfydryl, carboxyl, nitro, cyano group, C 1-C 4-alkyl, C 2-C 4-alkenyl, C 2-C 4-alkynyl, C 1-C 4-alkoxyl group, C 1-C 4-alkylthio, C 1-C 4-halogenated alkoxy or;
R 7By 4 or 5 CH 2Group and R 8Link, obtain 5-or 6-unit ring;
R 8Be hydrogen, C 1-C 4-alkyl;
Perhaps R 8By 4 or 5 CH 2Group and R 7Link, obtain 5-or 6-unit ring;
R 9And R 10Can be identical or different, they are:
Hydrogen, halogen, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, C 3-C 6-alkenyloxy, C 3-C 6-alkynyloxy group, C 1-C 4-alkylthio, C 1-C 4-alkyl-carbonyl, C 1-C 4-carbalkoxy, hydroxyl, NH 2, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2
C 1-C 4-alkyl, C 2-C 4-alkenyl, C 2-C 4-alkynyl, these groups can be replaced by halogen, hydroxyl, sulfydryl, carboxyl, cyano group;
Perhaps CR 9Or CR 10As to R 11Described and CR 11Link, obtain 5-or 6-unit ring;
R 11Be hydrogen, halogen, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, C 3-C 6-alkenyloxy, C 3-C 6-alkynyloxy group, C 1-C 4-alkylthio, C 1-C 4-alkyl-carbonyl, C 1-C 4-carbalkoxy, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2, hydroxyl, carboxyl, cyano group, amino, sulfydryl;
C 1-C 4-alkyl, C 2-C 4-alkenyl, C 2-C 4-alkynyl, these groups can be replaced by the following radicals one or many: halogen, hydroxyl, sulfydryl, carboxyl, cyano group, amino, C 1-C 4-alkoxyl group;
Perhaps CR 11With CR 9Or CR 10Form 5-or 6-unit's alkylene basic ring or alkenylene ring together, they can be by one or two C 1-C 4-alkyl replaces, and wherein one or more methylene radical can be separately by oxygen, sulphur ,-NH or-N (C 1-C 4-alkyl) displacement.
Use herein and hereinafter and be defined as:
Basic metal is for example lithium, sodium, potassium;
Alkaline-earth metal is for example calcium, magnesium, barium;
The organic ammonium ion is protonated amine, for example thanomin, diethanolamine, quadrol, diethylamide or piperazine;
C 3-C 8-cycloalkyl is for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group;
C 1-C 4-haloalkyl can be a straight or branched, for example methyl fluoride, difluoromethyl, trifluoromethyl, chlorodifluoramethyl-, dichlorofluoromethyl, trichloromethyl, 1-fluoro ethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, 2-chloro-2,2-two fluoro ethyls, 2,2-two chloro-2-fluoro ethyls, 2,2,2-three chloroethyls or pentafluoroethyl group;
C 1-C 4-halogenated alkoxy can be a straight or branched, for example difluoro-methoxy, trifluoromethoxy, chlorine difluoro-methoxy, 1-fluorine oxyethyl group, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoro oxyethyl group, 2,2,2-trifluoro ethoxy, 2-chloro-1,1,2-trifluoro ethoxy, 2-fluorine oxyethyl group or five fluorine oxyethyl groups;
C 1-C 4-alkyl can be a straight or branched, for example methyl, ethyl, 1-propyl group, 2-propyl group, 2-methyl-2-propyl group, 2-methyl isophthalic acid-propyl group, 1-butyl or 2-butyl;
C 2-C 4-alkenyl can be a straight or branched, for example vinyl, 1-propylene-3-base, 1-propylene-2-base, 1-propylene-1-base, 2-methyl isophthalic acid-propenyl, 1-butylene base or crotyl;
C 2-C 4-alkynyl can be a straight or branched, for example ethynyl, 1-propine-1-base, 1-propine-3-base, ethyl acetylene-4-base or 2-butyne-4-base;
C 1-C 4-alkoxyl group can be a straight or branched, for example methoxyl group, oxyethyl group, propoxy-, 1-methyl ethoxy, butoxy, 1-methyl propoxy-, 2-methyl propoxy-or 1,1-dimethyl oxyethyl group;
C 3-C 6-alkenyloxy can be a straight or branched, for example allyloxy, 2-butylene-1-base oxygen base or 3-butene-2-Ji oxygen base;
C 3-C 6-alkynyloxy group can be a straight or branched, for example 2-propine-1-base oxygen base, 2-butyne-1-base oxygen base or 3-crotonylene-Ji oxygen base;
C 1-C 4-alkylthio can be a straight or branched, for example methylthio group, ethylmercapto group, rosickyite base, 1-methyl ethylmercapto group, butylthio, 1-methyl-prop sulfenyl, 2-methyl-prop sulfenyl or 1,1-dimethyl ethylmercapto group;
C 1-C 5-alkyl-carbonyl can be a straight or branched, for example ethanoyl, ethyl carbonyl or 2-propyl group carbonyl;
C 1-C 4-carbalkoxy can be a straight or branched, for example methoxycarbonyl, ethoxycarbonyl, the positive third oxygen carbonyl, the different third oxygen carbonyl or positive butoxy carbonyl;
C 3-C 8-alkyl-carbonyl alkyl can be a straight or branched, for example 2-oxo-1-propyl group, 3-oxo-1-butyl or 3-oxo-2-butyl;
C 1-C 8-alkyl can be straight or branched, for example C 1-C 4-alkyl, amyl group, hexyl, heptyl or octyl group;
C 3-C 8-alkenyl can be a straight or branched, for example 1-propylene-3-base, 1-propylene-2-base, 1-propylene-1-base, 2-methyl isophthalic acid-propenyl, 1-butylene-4-base, 2-butylene-3-base, 1-amylene-5-base, 1-hexene-6-base, 3-hexene-6-base, 2-heptene-7-base or 1-octene-8-base;
C 3-C 8-alkynyl can be a straight or branched, for example 1-propine-1-base, 1-propine-3-base, ethyl acetylene-4-base, 2-butyne-4-base, valerylene-5-base, 3-hexin-6-base, 2-heptyne-7-base, 2-octyne-8-base;
Halogen is for example fluorine, chlorine, bromine, iodine.
The invention still further relates to can release type I compound those compounds (being called prodrug).
Preferred prodrug is that those materials of discharging take place under the condition in some body cavity such as stomach, intestines, blood circulation, liver.
The intermediate of Compound I and preparation Compound I, for example II and III can have the carbon atom of one or more asymmetric replacements.This compounds can exist with pure enantiomorph or pure diastereomer or its form of mixtures.The compound that preferably uses enantiomer-pure is as activeconstituents.
The invention still further relates to above-mentioned carboxylic acid derivative at the preparation medicine, particularly prepare ET AAnd/or ET BApplication in the acceptor inhibitor.Such new compound is suitable for use as the antagonist that this paper starts definition.
Begin to prepare wherein by epoxide III that A is the formula II compound (IIa) of azido-, described epoxide III can be for example synthetic according to WO 96/11914 described method.These epoxide III and trinitride such as reaction of sodium azide then.Carry out this reaction with about 1: 1 to 1: 7 mol ratio at 20-150 ℃ by formula III compound and trinitride and make IIa.
This reaction can also be carried out in the presence of thinner.For this reason, can use all to reactant inert solvent.
The example of described solvent is the hydrocarbon of aliphatic, alicyclic and aromatics, they can be chosen wantonly separately by chloro, for example hexane, hexanaphthene, sherwood oil, petroleum naphtha, benzene,toluene,xylene, methylene dichloride, chloroform, monochloroethane and trieline, ethers such as Di Iso Propyl Ether, dibutyl ether, methyl tertiary butyl ether, diox and tetrahydrofuran (THF), nitrile is acetonitrile and propionitrile for example, amides is dimethyl formamide, N,N-DIMETHYLACETAMIDE and N-Methyl pyrrolidone for example, and sulfoxide and sulfone class be dimethyl sulfoxide (DMSO) and tetramethylene sulfone for example.
In addition, this reaction is preferably carried out to the temperature range between the boiling point of solvent or solvent mixture at 0 ℃.
The existence of catalyzer is favourable.Appropriate catalyst is strong organic and mineral acid and Lewis acid.The example comprises that sulfuric acid, hydrochloric acid, trifluoroacetic acid, tosic acid, ether close the fluoroform sulphonate of boron trifluoride and rare earths.
For example, have carboxylic acid derivative and the reaction of formula IV compound of the formula IIa of described implication by substituting group wherein, can preparing wherein, A is the new compound (Ia) of the formula I of azido-.
Figure A9880639700131
R among the formula IV 12Be halogen or R 13-SO 2-, R wherein 13Can be C 1-C 4-alkyl, C 1-C 4-haloalkyl or phenyl, and this paper starts described condition and is applicable to W, X, Y, Z and Q.This reaction preferably in inert solvent or thinner, adds the alkali that suitable alkali promptly influences intermediate II a deprotonation, carries out to the temperature range between the boiling point of solvent in room temperature.
Formula IV compound is known, and wherein some compound can buy or can be according to general known method preparation.
By making wherein R with the suitable alkali of two equivalents 1The intermediate II a that is COOH takes off proton, and reacts with formula IV compound, can directly obtain wherein R 1It is the Ia compounds of COOH.This reaction also can be in inert solvent, carry out to the temperature range between the boiling point of solvent in room temperature.
Operable alkali is basic metal or alkaline earth metal hydride for example sodium hydride, potassium hydride KH or hydrolith, carbonate such as alkaline carbonate be yellow soda ash or salt of wormwood for example, basic metal or alkaline earth metal hydroxides be sodium hydroxide or potassium hydroxide for example, organometallic compound is butyllithium for example, perhaps for example lithium diisopropylamine or Lithamide of alkali metal ammonia compound.
Wherein A is that the new compound (Ib) of amino formula I is prepared by Compound I a.Through type Ia compound and hydrogen react in the presence of catalyzer such as palladium or platinum, in solvent, under 20-100 ℃ temperature and carry out this preparation.Compound I a also can be converted into Ib in the presence of triphenyl phosphine.
If R 1Be ester, can be by general known method with the aminoalkyl groupization among the formula Ib or be converted into acid amides.With acid or alkali the ester group cracking is obtained carboxylic acid then.
Also can be by using the amine open loop, directly preparing wherein by epoxide III, A is the formula II compound (IIc) that replaces amine.Can obtain new formula I compound as mentioned above with material IIc and IV reaction then.
Formula I compound also can be by corresponding carboxylic acid, i.e. R wherein 1Be the formula I compound of COOH, at first be converted into activated form for example carboxylic acid halides, acid anhydrides or acyl imidazoles, then with the latter and suitable oxy-compound HOR with the described carboxylic acid of ordinary method 4Or sulphonamide H 2NSO 2R 6Reaction.This is reflected at and carries out in the conventional solvent and need add alkali usually, and this moment, above mentioned those alkali were suitable for.These two steps can also be simplified, for example, in the presence of dewatering agent such as carbodiimide with carboxylic acid and oxy-compound or sulfuryl amine reaction.
In addition, formula I compound also can be prepared by the salt of corresponding carboxylic acid, in the salt of described corresponding carboxylic acid, and R 1Be that COR and R are OM, wherein M can be alkali metal cation or alkaline earth metal cation of equal value.These salt can react with many formula R-D compounds; wherein D be conventional nucleofuge leavings group for example halogen as chlorine, bromine, iodine or aryl-or alkyl sulphonyl (they are unsubstituted or are replaced by halogen, alkyl or haloalkyl) for example tosyl group and methylsulfonyl, perhaps other leavings group of equal value.Formula R-D compound with active substituent D is known or can easily obtains with general expertise.This reaction can be in conventional solvent, advantageously add alkali carries out, and in this case, above mentioned those alkali are suitable for.R wherein 1The formula I compound that is tetrazolium can adopt with similar method described in the WO 96/11914, by corresponding carboxylic acid (R 1The formula I of=COOH) preparation.
In some cases, must use general known protecting group technology to prepare new Compound I.If for example A is HOCH 2CONH-can be at first with the form protection hydroxyl of benzylic ether, and the suitable stage in reaction process is with its cracking then.
Split by racemize or diastereoisomeric formula I and II compound being carried out conventional racemic modification, can obtain the formula I and the II compound of enantiomer-pure with the alkali of suitable enantiomer-pure, for example, as described in the WO 96/11914.
Consider that from the biological action angle no matter be pure enantiomorph or pure diastereomer or its mixture, preferred formula I carboxylic acid derivative is those compounds that substituting group wherein has following definitions:
A is NR 7R 8Or azido-;
W and Z can be identical or different, and they are:
Nitrogen or methyne; Condition is if W and Z=methyne, then Q=nitrogen;
X is nitrogen or CR 9
Y is nitrogen or CR 10
Q is nitrogen or CR 11Condition is if Q=nitrogen, then X=CR 9And Y=CR 10
In addition, for Q, except above-mentioned condition, following conditions also is suitable for: if Q=CR 11, Y=CR then 10And X=CR 9
R 2And R 3Can be identical or different, they are:
Phenyl or naphthyl, they can be replaced by one or more following radicals separately: halogen, cyano group, hydroxyl, sulfydryl, C 1-C 4-alkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group, phenoxy group, C 1-C 4-halogenated alkoxy, C 1-C 4-alkylthio, amino, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2 or phenyl, it can be by one or more for example 1-3 halogen, cyano group, C 1-C 4-alkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy or C 1-C 4-alkylthio replaces; Perhaps
Phenyl or naphthyl, they are by direct key, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO 2-, NH-or N-alkyl link together at the ortho position;
R 7Be hydrogen, C 1-C 8-alkyl, C 3-C 8-alkenyl or C 3-C 8-alkynyl, C 1-C 5-alkyl-carbonyl, these groups can be replaced by one or more following radicals separately: halogen, hydroxyl, sulfydryl, carboxyl, amino, cyano group, C 1-C 4-alkoxyl group, C 3-C 6-alkenyloxy, C 3-C 6-alkynyloxy group, C 1-C 4-alkylthio, C 1-C 4-halogenated alkoxy, C 1-C 4-carbalkoxy, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2, C 3-C 8-cycloalkyl, the 5-that contains 1-3 nitrogen-atoms and/or sulphur or Sauerstoffatom or 6-unit's heteroaryloxy or heteroaryl, phenoxy group or phenyl, all described aryl can be replaced one or many for example 1-3 time by following radicals: halogen, hydroxyl, sulfydryl, carboxyl, cyano group, C 1-C 4-alkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, amino, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2Or C 1-C 4-alkylthio;
Phenyl or naphthyl, they can be replaced by one or more following radicals separately: halogen, cyano group, hydroxyl, amino, C 1-C 4-alkyl, C 1-C 4-haloalkyl, phenoxy group, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, C 1-C 4-alkylthio, dioxo methylene radical, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2Or dioxo ethylidene;
C 3-C 8-cycloalkyl, these groups can be replaced by the following radicals one or many separately: halogen, hydroxyl, sulfydryl, carboxyl, C 1-C 4-alkyl, C 2-C 4-alkenyl, C 2-C 4-alkynyl, C 1-C 4-alkoxyl group, C 1-C 4-alkylthio, C 1-C 4-halogenated alkoxy;
R 8Be hydrogen;
R 9And R 10Can be identical or different, they are:
Hydrogen, halogen, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, C 1-C 4-alkylthio, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2
C 1-C 4-alkyl, C 2-C 4-alkenyl, these groups can be replaced by halogen, hydroxyl, sulfydryl, cyano group;
Perhaps CR 9Or CR 10As to R 11Described and CR 11Link, obtain 5-or 6-unit ring;
R 11Be hydrogen, halogen, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, C 1-C 4-alkylthio, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2, cyano group;
C 1-C 4-alkyl, C 2-C 4-alkenyl, these groups can be replaced by the following radicals one or many separately: halogen, cyano group, C 1-C 4-alkoxyl group;
Perhaps CR 11With CR 9Or CR 10Form 5-or 6-unit's alkylene basic ring or alkenylene ring together, they can be by one or two C 1-C 4-alkyl replaces, and wherein one or more methylene radical can be separately by oxygen, sulphur ,-NH or-N (C 1-C 4-alkyl) displacement.
No matter be pure enantiomorph or pure diastereomer or its mixture, particularly preferred formula I compound is those compounds that substituting group wherein has following definitions:
A is NR 7R 8Or azido-;
W and Z can be identical or different, and they are:
Nitrogen or methyne; Condition is if W and Z=methyne, then Q=nitrogen;
X is nitrogen or CR 9
Y is nitrogen or CR 10
Q is nitrogen or CR 11Condition is if Q=nitrogen, then X=CR 9And Y=CR 10And if Q=CR 11, Y=CR then 10And X=CR 9
R 2And R 3Can be identical or different, they are:
Phenyl or naphthyl, they can be replaced by one or more following radicals separately: halogen, C 1-C 4-alkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group, phenoxy group, C 1-C 4-alkylthio, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2Perhaps phenyl, it can be by one or more for example 1-3 halogen, C 1-C 4-alkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group or C 1-C 4-alkylthio replaces; Perhaps
Phenyl, they are by direct key, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO 2, NH or N-alkyl link together at the ortho position;
R 7Be hydrogen, C 1-C 8-alkyl, C 3-C 8-alkenyl or C 3-C 8-alkynyl, C 1-C 5-alkyl-carbonyl, these groups can be replaced by one or more following radicals separately: halogen, hydroxyl, carboxyl, amino, C 1-C 4-alkoxyl group, C 1-C 4-alkylthio, C 1-C 4-carbalkoxy, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2, C 3-C 8-cycloalkyl, the 5-that contains 1-3 nitrogen-atoms and/or sulphur or Sauerstoffatom or 6-unit's heteroaryloxy or heteroaryl, phenoxy group or phenyl, wherein said aryl can be replaced one or many for example 1-3 time by following radicals: halogen, hydroxyl, sulfydryl, carboxyl, cyano group, C 1-C 4-alkyl, C 1-C 4-haloalkyl, C 1-C 4-alkoxyl group, amino, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2Or C 1-C 4-alkylthio;
Phenyl or naphthyl, they can be replaced by one or more following radicals separately: halogen, cyano group, C 1-C 4-alkyl, C 1-C 4-haloalkyl, phenoxy group, C 1-C 4-alkoxyl group, C 1-C 4-alkylthio, dioxo methylene radical or dioxo ethylidene;
C 5-C 6-cycloalkyl, these groups can be replaced by the following radicals one or many separately: C 1-C 4-alkyl, C 1-C 4-alkoxyl group;
R 8Be hydrogen;
R 9And R 10Can be identical or different, they are:
Hydrogen, C 1-C 4-alkoxyl group, C 1-C 4-alkylthio, N (C 1-C 4-alkyl) 2
C 1-C 4-alkyl, it can be replaced by halogen;
Perhaps CR 9Or CR 10As to R 11Described and CR 11Link, obtain 5-or 6-unit ring;
R 11Be hydrogen, C 1-C 4-alkoxyl group, C 1-C 4-alkylthio, cyano group;
C 1-C 4-alkyl, it can be replaced by the halogen one or many;
Perhaps CR 11With CR 9Or CR 10Form 5-or 6-unit's alkylene basic ring or alkenylene ring together, they can be by one or two C 1-C 4-alkyl replaces, and wherein one or more methylene radical can be separately by oxygen, sulphur ,-NH or-N (C 1-C 4-alkyl) displacement.
The compounds of this invention provides the potential therapeutic action to following disease: hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, stenocardia, urgency/chronic kidney hypofunction, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxin shock, the organ failure that intracellular toxin causes, intravascular coagulation, postangioplasty restenosis, benign prostatic hyperplasia, ischemic and the renal failure or the hypertension of poisoning and causing, the renal failure that S-Neoral causes, metastatic tumor and mesenchymoma growth, cancer, prostate cancer, the renal failure that contrast medium causes, pancreatitis, gastrointestinal ulceration.
The invention still further relates to by the endothelin-receptor antagonists of formula I and the combination product that renin-the angiotonin system inhibitor is formed.The inhibitor of renin-angiotonin system is blood vessel tension peptide protoenzyme inhibitor, angiotension II antagonists and particularly angiotensin converting enzyme (ACE) inhibitor.
This combination product can be with a kind of pharmaceutical dosage form administration, perhaps with the mode administration of time and spatial isolation.
The factor that need consider for dosage and mode is identical with corresponding one matter.
These combination product are specially adapted to treatment and preventing hypertension and sequela thereof, and are used for the treatment of heart failure.
The invention still further relates to the application of this new compound in the photoaffinity labeling endothelin receptor.Be specially adapted to this purpose be those wherein A be the formula I compound of azido-.
The good efficacy that in following experiment, has shown this compound:
Receptors bind research
Clone's people is expressed ET AOr ET BThe Chinese hamster ovary celI of acceptor is used in conjunction with research.
Membrane prepare
Make and express ET AOr ET BThe Chinese hamster ovary celI of acceptor is being added with 10% foetal calf serum (PAALaboratories GmbH, Linz, No.A15-022), the DMEM NUT MIX F of 1mM glutamine (Gibco No.25030-024), 100U/ml penicillin and 100 μ g/ml Streptomycin sulphates (Gibco, Sigma No.P-0781) 12Substratum (Gibco, No.21331-020) middle growth.After 48 hours, wash this cell with PBS, and 37 ℃, cultivated 5 minutes with containing 0.05% tryptic PBS.Neutralize with substratum then, and with 300 * g centrifugal collecting cell.
In order to prepare film, cell concn is adjusted to 10 8Cells/ml damping fluid (50mMTrisHCl damping fluid, pH 7.4) uses ultrasonic Branson Sonifier 250 (40-70 second/constant/output 20) to decompose then.
Binding analysis
In order to carry out ET AAnd ET BReceptor binding assay, (50mM Tris-HCl, pH 7.4, contain 5mMMnCl with the proteic concentration of every part of analysis of mixtures 50 μ g the film that makes to be suspended in the cultivation damping fluid 2, 40 μ g/ml bacitracin and 0.2%BSA) in, and use 25pM[ 125I]-ET 1(ET A-receptor assay) or 25pM[ 125I]-ET 3(ET B-receptor assay) is being with or without in the presence of the experiment material, cultivating in 25 ℃.Use 10-7M ET 1Measure non-specific binding.After 30 minutes, at Skatron cell harvestor (Skatron, Lier, Norway) in, through GF/B glass fibre filter (Whatman, England) filter, separated free with the bonded radioligand, and leach thing with ice-cooled Tris-HCl damping fluid (pH 7.4, contain 0.2%BSA) washing.Quantitative with Packard 2200 CA liquid scintillation counters to the radioactivity of collecting on the filter.
Experiment in the body of ET antagonist:
The male SD rat that will weigh the 250-300 gram with Amobarbital is anaesthetized, artificial convection, cut-out vagus nerve (vagotomized) and pith.In carotid artery and jugular vein intubate.
Be control animals intravenous administration 1 μ g/kg ET 1, cause blood pressure to continue for a long time obviously to raise.
Using ET 130 minutes before, give experimental group animal intravenous injection (1 mg/kg) experimental compound.In order to measure the ET-antagonist properties, blood pressure and the control animals of experimental group animal compared.
The oral experiment of ET receptor antagonist:
Give body weight 250-300 normotensive male rat (Sprague Dawley, Janvier) the oral experiment material of gram in advance.After 80 minutes, with urethane with Animal Anesthesia, and in carotid artery (to measure blood pressure) and jugular vein (to use big ET/endothelin 1) intubate.
Through after stationary phase, through intravenous administration big ET (20 μ g/kg, administration volume 0.5ml/kg) or ET1 (0.3 μ g/kg, administration volume 0.5ml/kg).Continuous recording blood pressure and heart rate 30 minutes.Obvious and long blood pressure is calculated as area under curve (AUC).For the antagonistic action of determination experiment material, will compare with AUC and the control animals of the animal of this mass treatment.
This new compound can be according to ordinary method oral administration or non-through gi tract (subcutaneous, intravenously, intramuscular, intraperitoneal) administration.Also can be through cavum nasopharyngeum steam or spray delivery.
Dosage depends on patient's age, disease condition and body weight and administering mode.In general, oral dosage every day of activeconstituents is about 0.5-50 mg/kg body weight, and every day, parenterai administration dosage was about 0.1-10 mg/kg body weight.
This new compound can be with the solid or the liquid medicine form administration of routine, for example not dressing or (film) coating tablet, capsule, powder, particle, suppository, solution, ointment, emulsifiable paste or sprays.These formulations can prepare according to ordinary method.For this reason, with activeconstituents and conventional medicine auxiliary agent for example tablet binder, extender, sanitas, tablet disintegrant, flowing regulator, softening agent, wetting agent, dispersion agent, emulsifying agent, solvent, sustained release dosage, antioxidant and/or impelling gas (referring to, H.Sucker etc.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991) process together.The form of administration that obtains of method contains 0.1-90% (weight) activeconstituents usually thus.
Synthetic embodiment
Embodiment 1:
2-hydroxyl-3-azido--3,3-diphenyl-propionic acid methyl esters
3.8 gram (59.0 mmole) sodiumazide and 3.1 gram (59.0 mmole) ammonium chlorides are added in 80 ml methanol.In this suspension, add 5 gram (19.7 mmoles) 3,3-phenylbenzene-2, the epihydric acid 2 methyl esters is then stirring at room 48 hours.This mixture is concentrated, add entry, and with this water of ethyl acetate extraction several times.Then with the organic phase that merges through dried over mgso, evaporation removes and desolvates, resistates is through chromatogram purification.Separate and obtain 1.2 gram (4 mmoles, productive rate 21%) pure products.
Fusing point: 102-103 ℃
1H-NMR(200MHz)：7.2ppm(10H，m)，5.1(1H，d)，3.5(3H，s)，
3.4(1H，d).
Embodiment 2:
2-(4-methoxyl group-6-methyl-2-pyrimidyl oxygen base)-3-azido--3,3-diphenyl-propionic acid methyl esters
With 930 milligrams of (6.7 mmole) salt of wormwood, 1.4 gram (6.7 mmole) 4-methoxyl group-6-methyl-2-methanesulfonyl pyrimidines and 2.0 gram (6.7 mmole) 2-hydroxyl-3-azido-s-3,3-diphenyl-propionic acid methyl esters mixes in 20 milliliters of DMF.Stirred this mixture 2 hours at 80 ℃.Cooling adds entry, uses ethyl acetate extraction then.With the organic phase dried over mgso that merges, evaporation removes and desolvates.Separate crude product oil 2.9 grams and directly carry out next step reaction.
Embodiment 3:
2-(4-methoxyl group-6-methyl-2-pyrimidyl oxygen base)-3-amino-3,3-diphenyl-propionic acid methyl esters
With 2.8 gram (6.7 mmole) 2-(4-methoxyl group-6-methyl-2-pyrimidyl oxygen base)-3-azido-s-3,3-diphenyl-propionic acid methyl esters is dissolved in 20 milliliters/40 ml methanol/ethyl acetate, adds spatula point palladium carbon.With purging with hydrogen behind the nitrogen blow device, under normal atmosphere and room temperature, stirred this solution 3 hours then.After transforming fully, leach palladium carbon, and evaporation is except that desolvating.Isolate 2.9 gram crystallizations and directly carry out next step reaction.
Embodiment 4:
2-(4-methoxyl group-6-methyl-2-pyrimidyl oxygen base)-3-amino-3,3-diphenyl-propionic acid (I-375)
In the mixture of 6.4 milliliters of dioxs and 3.2 milliliters of 1N potassium hydroxide solutions, add 840 milligrams of (2.1 mmole) 2-(4-methoxyl group-6-methyl-2-pyrimidyl oxygen base)-3-amino-3,3-diphenyl-propionic acid methyl esters, and stirred these mixtures 2 hours at 80 ℃.Cooling adds entry and carries out acidifying, uses ethyl acetate extraction then.With the organic phase that dried over mgso merges, evaporation removes and desolvates.Resistates is stirred with ether, separate obtaining 190 milligrams of (0.5 mmole, productive rate 25%) crystallizations.
1H-NMR(360MHz/DMSO/303K)：7.7ppm(1H，breit)，7.4(4H，m)，7.2
(6H，m)，5.91H，breit)，5.1(1H，s)，3.2(3H，breit)，2.1
(3H，s).
1H-NMR(360MHz/DMSO/323K)：7.7PPm(1H，breit)，7.4(4H，m)，
7.2(6H，m)，5.9(1H，s)，5.1(1H，s)，3.2(3H，s)，
2.1(3H，s).
The preparation that 3-hydrogen-2-hydroxy-2-methyl-1H-cyclopenta [I] is luxuriant and rich with fragrance
3M ether (26.49mmol) solution of 8.83ml methylmagnesium-bromide is added drop-wise to 5.00g 2 under shielding gas, in luxuriant and rich with fragrance (21.19mmol) suspension in the 20ml ether of 3-dihydro-2-oxo--1H-cyclopenta [I].Reflux after 3 hours, product is hydrolyzed by adding 10ml 2N hydrochloric acid carefully.With extracted with diethyl ether mixture 3 times, with saturated NaHSO 3Solution, saturated NaHCO 3Solution and less water are shaken with organic phase, at Na 2SO 4Last dry, evaporating solns obtains colourless solid.
Productive rate: 4.68g (89%)
MS：??????M +：248m/e(33％)
M +-CH 3CO：205m/e(100％)NMR(CDCl 3，600MHz)：
The position 1The H chemical shift Multiplicity Intensity ???? 13The C chemical shift
4，5 1-3，6-8 OH(C-OH) CH 2Me ??8.68-8.70 ??7.77-7.79 ??7.59-7.63 ??1.98 ??3.44 ??1.66 ???????m ???????m ???????m ???????bs ??2d(J＝15，8Hz) ???????s ????2 ????2 ????4 ????1 ????4 ????3 126.71 125.83 124.76 123.22 season C:129.83 130.27 123.09 135.02 79.49 48.06 28.46
The 1H-2-methyl cyclopentadiene is [I] luxuriant and rich with fragrance preparation also
4.56g 3-hydrogen-2-hydroxy-2-methyl-1H-cyclopenta [I] luxuriant and rich with fragrance (18.39mmol) heated in 300ml toluene with 0.25g tosic acid mono-hydrate in water separator dewatered in 1 hour.After with the ether dilution, the solution of green blue look becomes blush.The solution that obtains shakes with saturated sodium hydrogen carbonate solution, with dried over mgso and evaporation.Obtain beige material like this, this material can (sherwood oil: fritted glass filter ethyl acetate) filters fast and purifies by filling flash distillation silica gel.
Productive rate: 4.02g (95%)
MS：??????M +：230m/e(100％)
M 1-Me：215m/e(38％)
Ultimate analysis:
C 18H 14
C:(calculates) 93.87 (discoveries) 93.63
H:(calculates) 6.13 (discovery) 6.17NMR (250MHz CDCl 3):
Figure A9880639700231
The position ?? 1The H chemical shift Multiplicity Intensity ?? 13The C chemical shift
4,5 1-3,6-8 9 season .C:11 Me ??8.68-8.75 ??8.10-8.13 ??7.93-7.95 ??7.53-7.65 ??7.07 ??3.74 ??2.33 ??????m ??????m ??????m ??????m ??????bs ??????s ??????bs ????2 ????1 ????1 ????4 ????1 ????2 ????3 ??126.65?126.27 ??125.51?125.14 ??124.60?124.39 ??123.61?123.43 ??123.25 ??127.50?128.30 ??129.64?130.19 ??137.05?140.22 ??42.95 ??16.94
The preparation that 1H-2-phenyl cyclopenta [I] is luxuriant and rich with fragrance
With 1g 2,3-dihydro-2-oxo--1H-cyclopenta [I] luxuriant and rich with fragrance (4.31mmol) at the solution of 100ml toluene in 0 ℃ of 3M ether (6mmol) solution that is added drop-wise to the 2ml phenyl-magnesium-bromide.Allow mixture rise to room temperature and stirred 2 hours.After saturated ammonium chloride solution hydrolysis, mixture extracted with diethyl ether, organic phase be with the washing of saturated sodium chloride solution, and be dry and be evaporated to dried on sal epsom.Residue is dissolved in the 100ml toluene, and refluxed 2 hours with the 100mg tosic acid.After adding saturated sodium hydrogen carbonate solution, use the extracted with diethyl ether mixture, organic phase is dry and evaporation on sal epsom.After the flash chromatography method is separated, (sherwood oil: ethyl acetate=50: 1) obtain colourless acicular 1H-2-phenyl cyclopenta [I] phenanthrene.
Productive rate: 0.45g (36%)
MS：??????M *+：292m/e(100％)
M +-Ph:215m/e (6%) ultimate analysis:
C 23H 16
C:(calculates) 94.48 (discoveries) 94.66
H:(calculates) 5.52 (discovery) 5.63NMR (CDCl 3, 600MHz):
The position ?? 1The H chemical shift Multiplicity Intensity ?? 13The C chemical shift
1 2+3,45 6+7,89 11 o-Ph m-Ph p-Ph season C ????8.02 ????7.62-7.56 ????8.68 ????8.72 ????7.66-7.64 ????8.20 ????7.79 ????4.20 ????7.75 ????7.42 ????7.29 ????d(J＝7.7Hz) ????m ????d(J＝8.2Hz) ????d(J＝7.1Hz) ????m ????d(J＝7.0Hz) ????s ????s ????d(J＝7.3Hz) ????t(J＝7.3Hz) ????t(J＝7.3Hz) ????1 ????2 ????1 ????1 ????2 ????1 ????1 ????2 ????2 ????2 ????1 ??123.84 ??126.85，125.25 ??123.51 ??123.34 ??125.87，126.50 ??124.29 ??124.43 ??39.22 ??125.50 ??128.79 ??127.39 ??146.43，139.97 ??137.74，136.03 ??130.33，129.48 ??128.93，127.56
The general method that preparation 1-trimethyl silyl cyclopenta [I] is luxuriant and rich with fragrance
Luxuriant and rich with fragrance (10mmol) is added in the 20ml tetrahydrofuran (THF) at the beginning with each cyclopenta [I], and refrigerative mixes with the 1.6M hexane solution of 10mmol n-Butyl Lithium simultaneously in ice.Allow mixture rise to room temperature, and stir and spend the night.Bottle-green solution evaporation is extremely done.
Table I
Nr. ?R 1 ?R 2，R 3 ?A W X Q Y Z
I-1 COOH ?Ph ?CF 3CONH- CH C-Me N C-Me N
I-2 COOH ?Ph ?CF 3CONH- CH C-OMe N C-Me N
I-3 COOH ?4-F-Ph ?N 3 CH C-Me N C-OMe N
I-4 COOH ?4-F-Ph ?N 3 CH The C-ethyl N C-Me N
I-5 COOH ?Ph ?3，4-Di-OMe-Ph-CH 2-CONH- N N C-Me C-OMe CH
I-6 COOH ?Ph ?3，4-Di-OMe-Ph-CH 2-CONH- N C-OMe C-Me N CH
I-7 COOH ?4-Cl-Ph ?N3 N C-Me CH C-Me N
I-8 COOH ?4-F-Ph ?N 3 N C-Me N C-OMe N
I-9 COOH ?4-F-Ph ?N 3 N The C-ethyl N C-Me N
I-10 COOH ?4-Me-Ph ?N 3 N C-OMe CH C-Me N
I-11 COOH ?Ph ?N 3 N C-CF 3 CH C-OMe N
I-12 COOH ?Ph Ethyl-CONH- N The C-ethyl CH C-Me N
I-13 COOH ?Ph Ethyl-CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe N
Nr. R 1 R 2，R 3 A W X Q ?Y ?Z
I-14 COOH Ph N 3 N C-SMe CH C-Me ?N
I-15 COOH Ph N 3 N C-CH 2-CH 2-CH 2-CH 2-C C-OMe ?N
I-16 COOH Ph 3-OMe-4-OH-Ph-CH 2-CONH- CH C-Me N ?C-OMe ?N
I-17 COOH Ph 3-OMe-4-OH-Ph-CH 2-CONH- CH The C-ethyl N ?C-Me ?N
I-18 COOH Ph N 3 N ????C-S-CH 2-CH 2-C ?C-OMe ?N
I-19 COOH 4-Cl-Ph N 3 N C-Me N ?C-Me ?N
I-20 COOH Ph N 3 N C-NH(CH 3) N ?C-NH(CH 3) ?N
I-21 COOH Ph CF 3CONH- N C-OMe C-Me ?N ?CH
I-22 COOH Ph CF 3CONH- N N C-Me ?C-OMe ?N
I-23 COOH Ph N 3 N The C-ethyl N The C-ethyl ?N
I-24 COOH Ph N 3 N N CH ?C-OMe ?CH
I-25 COOH Ph 3，4-Di-OMe-Ph-CH 2-CONH- N C-Me N ?C-OMe ?N
I-26 COOH Ph 3，4-Di-OMe-Ph-CH 2-CONH- N The C-ethyl N ?C-Me ?N
I-27 COOH Ph N 3 N C-OMe CH ?N ?CH
I-28 COOH 4-F-Ph N 3 N ????C-O-CH 2-CH 2-C ?C-OMe ?N
I-29 COOH 4-F-Ph N 3 N C-Me N ?C-Me ?N
I-30 COOH 4-Me-Ph N 3 N N C-Me ?C-OMe ?N
I-31 COOH Ph N 3 CH The C-ethyl N ?C-Me ?CH
I-32 COOH Ph Ethyl-CONH- N C-OMe CH ?C-Me ?N
I-33 COOH Ph Ethyl-CONH- N C-OMe CH ?C-OMe ?N
I-34 COOH Ph N 3 CH C-Me N The C-ethyl ?N
I-35 COOH 4-Cl-Ph N 3 CH C-OMe N ?C-Me ?N
Nr. R 1 ?R 2，R 3 A W X Q Y ?Z
I-36 COOH ?Ph 3-OMe-4-OH-Ph-CH 2-CONH- CH C-Me N C-Me ?N
I-37 COOH ?Ph 3-OMe-4-OH-Ph-CH 2-CONH- CH C-OMe N C-Me ?N
I-38 COOMe ?Ph N 3 CH C-Me N C-OMe ?N
I-39 COOH ?Ph N 3 ?CH C-OMe N C-OMe ?N
I-40 COOH ?4-F-Ph H 2N- N C-Me CH C-Me ?CH
I-41 COOH ?Ph CF 3CONH- N The C-ethyl N C-Me ?N
I-42 COOH ?Ph CF 3CONH- N N C-Me C-OMe ?CH
I-43 COOH ?4-F-Ph H 2N- N C-Me CH C-Me ?N
I-44 COOH ?4-Cl-Ph H 2N- N C-OMe CH C-Me ?N
I-45 COOH ?Ph 3，4-Di-OMe-Ph-CH 2-CONH- N ????C-O-CH 2-CH 2-C C-OMe ?N
I-46 COOH ?Ph 3，4-Di-OMe-Ph-CH 2-CONH- N C-Me N C-Me ?N
I-47 COOH ?Ph H 2N- N C-CF 3 CH C-OMe ?N
I-48 COOH ?4-F-Ph N 3 N The C-ethyl CH C-Me ?N
I-49 COOH ?4-F-Ph N 3 N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-50 COOH ?Ph H 2N- N The C-ethyl CH C-CF 3 ?N
I-51 COOH ?Ph H 2N- N ????C-CH 2-CH 2-CH 2-C The C-ethyl ?N
I-52 COOH ?Ph CH 3CONH- CH The C-ethyl N C-Me ?N
I-53 COOH ?Ph Ethyl-CONH- N C-Me CH C-Me ?N
I-54 COOH ?Ph H 2N- N ????C-O-CH 2-CH 2-C The C-ethyl ?N
I-55 COOH ?2-F-Ph H 2N- N C-Me N C-Me ?N
I-56 COOH ?Ph 3-OMe-4-OH-Ph-CH 2-CONH- N N C-Me C-OMe ?N
Nr. R 1 R 2，R 3 ?A W X Q ?Y ?Z
I-57 COOH Ph ?3-OMe-4-OH-Ph-CH 2-CONH- CH C-Me N C-Me CH
I-58 COOH Ph ?H 2N- N C-Me N C-SMe N
I-59 COOH Ph ?H 2N- N The C-ethyl N C-CF 3 N
I-60 COOH Ph ?H 2N- N N CH C-OMe CH
I-61 COOH Ph ?CF 3CONH- N C-Me N C-Me N
I-62 COOH Ph ?CF 3CONH- N C-Me N C-OMe N
I-63 COOH Ph ?H 2N- N C-OMe CH N CH
I-64 COOH Ph ?H 2N- N C-Me C-Me N N
I-65 COOH Ph ?3，4-Di-OMe-Ph-CH 2-CONH- N The C-ethyl CH C-Me N
I-66 COOH Ph ?3，4-Di-OMe-Ph-CH 2-CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe N
I-67 COOH 4-F-Ph ?H 2N- N N C-Me C-OMe N
I-68 COOH 4-F-Ph ?N 3 N C-OMe CH C-Me N
I-69 COOH 4-F-Ph ?N 3 N C-OMe CH C-OMe N
I-70 COOH Ph ?H 2N- N C-Me CH C-Me CH
I-71 COOH F-Cl-Ph ?H 2N- CH C-Me N C-Me N
I-72 COOH Ph ?CH 3CONH- CH C-Me N C-Me CH
I-73 COOH Ph ?CH 3CONH- CH C-Me N C-Me N
I-74 COOH Ph ?CH 3CONH- CH C-OMe N C-Me N
I-75 COOH Ph ?CH 3CONH- CH C-Me N C-OMe N
I-76 COOH Ph ?H 2N- CH C-OMe N C-OMe N
I-77 COOH Ph ?H 2N- CH C-Me N The C-ethyl N
I-78 COOH Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N N C-Me C-OMe CH
Nr. R 1 R 2，R 3 ?A W X Q Y Z
I-79 COOH ?Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N C-OMe C-Me N CH
I-80 COOH ?Ph ?H 2N- N C-N(CH 3) 2 N C-N(CH 3) 2 N
I-81 COOH ?4-F-Ph ?CH 3CONH- N C-Me CH C-Me N
I-82 COOH ?4-F-Ph ?CH 3CONH- N C-OMe CH C-Me N
I-83 COOH ?Ph ?CF 3CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe N
I-84 COOH ?Ph ?CF 3CONH- N ????C-O-CH 2-CH 2-C C-OMe N
I-85 COOH ?4-Cl-Ph ?CH 3CONH- N C-OMe CH C-CF 3 N
I-86 COOH ?Ph ?CH 3CONH- N The C-ethyl CH C-Me N
I-87 COOH ?Ph ?3，4-Di-OMe-Ph-CH 2-CONH- N C-OMe CH C-Me N
I-88 COOH ?Ph ?3，4-Di-OMe-Ph-CH 2-CONH- N C-OMe CH C-OMe N
I-89 COOH ?Ph ?CH 3CONH- N ????C-CH 2-CH 2-CH 2-C C-Me N
I-90 COOH ?Ph ?4-OMe-Ph-CONH- CH The C-ethyl N C-Me N
I-91 COOH ?4-F-Ph ?N 3 N C-Me CH C-Me N
I-92 COOH ?Ph ?CH 3CONH- N ????C-O-CH 2-CH 2-C C-Me N
I-93 COOH ?Ph ?CH 3CONH- N C-CF 3 N C-Me N
I-94 COOH ?Ph ?CH 3CONH- N C-OMe C-Me N CH
I-95 COOH ?Ph ?CH 3CONH- N N C-Me C-OMe N
I-96 COOH ?4-F-Ph ?CH 3CONH- N C-Me N C-OMe N
I-97 COOH ?4-F-Ph ?CH 3CONH- N The C-ethyl N C-Me N
I-98 COOH ?Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N C-Me N C-OMe N
I-99 COOH ?Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N The C-ethyl N C-Me N
I-100 COOH ?Ph ?CH 3CONH- N C-Me C-Me CH CH
Nr. R 1 R 2，R 3 ?A W X Q Y ?Z
I-101 COOH Ph ?CH 3CONH- N CH C-Me N ?CH
I-102 COOH Ph ?CH 3CONH- N N C-Me C-Me ?N
I-103 COOH Ph ?CF 3CONH- N C-OMe CH C-OMe ?N
I-104 COOH Ph ?CF 3CONH- N The C-ethyl CH C-Me ?N
I-105 COOH Ph ?CH 3CONH- N C-Me CH C-Me ?CH
I-106 COOH Ph ?CH 3CONH- CH C-Me C-Me CH ?N
I-107 COOH Ph Cyclopropyl-CONH- CH The C-ethyl N C-Me ?N
I-108 COOH Ph ?3，4-Di-OMe-Ph-CH 2-CONH- N C-Me CH C-Me ?N
I-109 COOH 4-Cl-Ph ?CH 3CONH- CH C-OMe N C-Me ?N
I-110 COOH Ph ?4-OMe-Ph-CONH- CH C-Me N C-Me ?N
I-111 COOH Ph ?4-OMe-Ph-CONH- CH C-OMe N C-Me ?N
I-112 COOH 4-Me-Ph ?CH 3CONH- CH C-Me N C-OMe ?N
I-113 COOH 4-CF 3-Ph ?CH 3CONH- CH The C-ethyl N C-Me ?N
I-114 COOH Ph ?CH 3CONH- N The C-ethyl N C-Me ?N
I-115 COOH Ph ?CH 3CONH- N N C-Me C-OMe ?CH
I-116 COOH Ph ?HO-(CH 2) 2-CONH- N C-Me CH C-Me ?N
I-117 COOH Ph Benzyl-O-(CH 2) 2-CONH- N C-OMe CH C-Me ?N
I-118 COOH Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N ????C-O-CH 2-CH 2-C C-OMe ?N
I-119 COOH Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N C-Me N C-Me ?N
I-120 COOH 4-F-Ph Ethyl-CONH- N C-OMe CH C-OMe ?N
I-121 COOH 4-F-Ph Ethyl-CONH- N The C-ethyl CH C-Me ?N
I-122 COOH 4-Cl-Ph Ethyl-CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-123 COOH Ph ?CF 3CONH- N C-Me CH C-Me ?N
Nr. R 1 ?R 2，R 3 A W X Q ?Y Z
I-124 COOH ?Ph CF 3CONH- N C-OMe CH C-Me N
I-125 COOMe ?Ph Ethyl-CONH- N ????C-O-CH 2-CH 2-C C-OMe N
I-126 COOH ?Ph HO-(CH 2) 2-CONH- N C-Me N C-Me N
I-127 COOH ?Ph Cyclopropyl-CONH- ?CH C-Me N C-Me N
I-128 COOH ?Ph Cyclopropyl-CONH- CH C-OMe N C-Me N
I-129 COOH ?Ph HO-(CH 2) 2-CONH- N C-Me N C-OMe N
I-130 COOH ?Ph 4-OMe-Ph-CONH- N C-OMe C-Me N CH
I-131 COOH ?Ph 4-OMe-Ph-CONH- N N C-Me C-OMe N
I-132 COOH ?Ph Benzyl-O-(CH 2) 2-CONH- N The C-ethyl N C-Me N
I-133 COOH ?Ph Benzyl-O-(CH 2) 2-CONH- ?N N C-Me C-OMe CH
I-134 COOH ?Ph CH 3CONH- N C-Me N C-Me N
I-135 OOOH ?Ph CH 3CONH- N C-Me N C-OMe N
I-136 COOH ?4-F-Ph Ethyl-CONH- N C-OMe C-Me N CH
I-137 COOH ?Ph HO-(CH 2) 2-CONH- N N C-Me C-OMe N
I-138 COOH ?Ph 3-OMe-4-OH-Ph-CH 2-CONH- N The C-ethyl CH C-Me N
I-139 COOH ?Ph 3-OMe-4-OH-Ph-CH 2-CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe N
I-140 COOH ?Ph Ethyl-CONH- CH C-Me N C-Me CH
I-141 COOH ?Ph Ethyl-CONH- CH C-CF 3 N C-CF 3 N
I-142 COOH ?Ph HO-(CH 2) 2-CONH- CH C-OMe CH C-Me N
I-143 COOH ?Ph (CH 3) 2N- CH C-OMe N C-Me N
I-144 COOH ?Ph (CH 3) 2N- CH The C-ethyl N C-Me N
I-145 COOH ?Ph Ethyl-CONH- CH C-CF 3 N C-OMe N
I-146 COOH ?Ph HO-(CH 2) 2-CONH- CH The C-ethyl N C-Me N
Nr. R 1 R 2，R 3 ?A W X ?Q ?Y ?Z
I-147 COOH Ph Cyclopropyl-CONH- N C-OMe C-Me N ?CH
I-148 COOH Ph Cyclopropyl-CONH- N N C-Me C-OMe ?N
I-149 COOH 4-Cl-Ph ?CH 3NH- N C-Me CH C-CF 3 ?N
I-150 COOH Ph ?4-OMe-Ph-CONH- N The C-ethyl N C-Me ?N
I-151 COOH Ph ?4-OMe-Ph-CONH- N N C-Me C-OMe ?CH
I-152 COOH Ph ?CH 3NH- N C-SMe CH C-Me ?N
I-153 COOH Ph ?CH 3NH- N C-OMe CH The C-ethyl ?N
I-154 COOH Ph ?CH 3CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-155 COOH Ph ?CH 3CONH- N ????C-O-CH 2-CH 2-C C-OMe ?N
I-156 COOH Ph ?CH 3NH- N The C-ethyl CH C-Me ?N
I-157 COOH Ph ?CH 3NH- ?N ????C-CH 2-CH 2-CH 2-C C-Me ?N
I-158 COOH Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N C-OMe CH C-Me ?N
I-159 COOH Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N C-OMe CH C-OMe ?N
I-160 COOH Ph ?CH 3NH- N ????C-S-CH 2-CH 2-C C-OMe ?N
I-161 COOH 4-F-Ph ?CH 3NH- N C-Me N C-Me ?N
I-162 COOH 4-F-Ph ?CH 3NH- N C-Me N C-OMe ?N
I-163 COOH Ph ?(CH 3) 2N- N N C-Me C-OMe ?N
I-164 COOH Ph ?(CH 3) 2N- CH C-Me N C-Me ?N
I-165 COOH Ph ?CH 3NH- N The C-ethyl N The C-ethyl ?N
I-166 COOH Ph ?CH 3NH- N N CH C-OMe ?CH
I-167 COOH Ph Cyclopropyl-CONH- N The C-ethyl N C-Me ?N
I-168 COOH Ph Cyclopropyl-CONH- N N C-Me C-OMe ?CH
I-169 COOH Ph Ethyl-NH- N C-OMe C-Me N ?CH
?Nr. R 1 R 2，R 3 A W X Q ?Y ?Z
I-170 COOH ?Ph 4-OMe-Ph-CONH- N C-Me N ?C-Me ?N
I-171 COOH ?Ph 4-OMe-Ph-CONH- N C-Me N ?C-OMe ?N
I-172 COOH ?Ph Ethyl-NH- N N C-Me ?C-OMe ?N
I-173 COOH ?Ph CH 3NH- CH C-Me N The C-ethyl ?N
I-174 COOH ?Ph CH 3CONH- N C-OMe CH ?C-OMe ?N
I-175 COOH ?Ph CH 3CONH- N The C-ethyl CH ?C-Me ?N
I-176 COOH ?4-F-Ph CH 3NH- CH C-Me N ?C-OMe ?N
I-177 COOH ?4-Cl-Ph CH 3NH- CH The C-ethyl N ?C-Me ?N
I-178 COOH ?Ph Benzyl-NH- CH The C-ethyl N ?C-Me ?N
I-179 COOH ?Ph 3-OMe-4-OH-Ph-CH 2-CONH- N C-Me CH ?C-Me ?N
I-180 COOH ?Ph (CH 2) 5N- N C-Me CH ?C-Me ?N
I-181 COOH ?Ph (CH 3) 2N- N C-SMe CH ?C-Me ?N
I-182 COOH ?Ph (CH 3) 2N- N The C-ethyl CH The C-ethyl ?N
I-183 COOH ?Ph (CH 3) 2N- N N C-Me ?C-OMe ?CH
I-184 COOH ?Ph (CH 3) 2N- N C-OMe C-Me ?N ?CH
I-185 COOH ?4-F-Ph (CH 3) 2N- N The C-ethyl CH ?C-Me ?N
I-186 COOH ?Ph (CH 3) 2N- N ????C-CH 2-CH 2-CH 2-C The C-ethyl ?N
I-187 COOH ?Ph Cyclopropyl-CONH- N C-Me N ?C-Me ?N
I-188 COOH ?Ph Cyclopropyl-CONH- N C-Me N ?C-OMe ?N
I-189 COOH ?Ph (CH 3) 2N- N ????C-O-CH 2-CH 2-C ?C-Me ?N
I-190 COOH ?Ph 4-OMe-Ph-CONH- N ????C-CH 2-CH 2-CH 2-C ?C-OMe ?N
I-191 COOH ?Ph 4-OMe-Ph-CONH- N ????C-O-CH 2-CH 2-C ?C-OMe ?N
I-192 COOH ?Ph (CH 3) 2N- N C-NH(CH 3) N ?C-NH(CH 3) ?N
Nr. R 1 R 2，R 3 A W X Q ?Y Z
I-193 COOH Ph (CH 3) 2N- N C-N(CH 3) 2 N C-N(CH 3) 2 N
I-194 COOH Ph CH 3CONH- N C-Me CH C-Me N
I-195 COOH Ph CH 3CONH- N C-OMe CH C-Me N
I-196 COOH Ph (CH 3) 2N- N The C-ethyl N The C-ethyl N
I-197 COOH Ph (CH 3) 2N- N N CH C-OMe CH
I-198 COOH Ph Benzyl-NH- CH C-Me N C-Me N
I-199 COOH Ph Benzyl-NH- CH C-Me N C-OMe N
I-200 COOH 4-F-Ph (CH 3) 2N- N C-OMe C-Me N CH
I-201 COOH 4-F-Ph (CH 3) 2N- N N C-Me C-OMe N
I-202 COOH Ph (CH 2) 4N- CH C-Me N C-Me N
I-203 COOH Ph (CH 3) 2N- N C-Me N C-OMe N
I-204 COOH Ph (CH 3) 2N- N The C-ethyl N C-Me N
I-205 COOH Ph (CH 3) 2N- CH C-OMe N C-CF 3 N
I-206 COOH Ph (CH 3) 2N- CH The C-ethyl N The C-ethyl N
I-207 COOH Ph Cyclopropyl-CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe N
I-208 COOH Ph Cyclopropyl-CONH- N ????C-O-CH 2-CH 2-C C-OMe N
I-209 COOH Ph CCl 3CONH- N C-Me CH C-Me N
I-210 COOH Ph 4-OMe-Ph-CONH- N C-OMe CH C-OMe N
I-211 COOH Ph 4-OMe-Ph-CONH- N The C-ethyl CH C-Me N
I-212 COOH Ph CF 3CONH- N C-OH C-F C-Me N
I-213 COOH Ph CF 3CONH- N C-OMe C-Me C-OMe N
I-214 COOH Ph H 2N- CH C-Me N C-OMe N
I-215 COOH Ph H 2N- CH The C-ethyl N C-Me N
I-216 COOH Ph CF 3CONH- N The C-ethyl C-Me CH N
Nr. R 1 R 2，R 3 A W X Q ?Y Z
I-217 COOH ?Ph CF 3CONH- N ????C-CH 2-CH 2-CH 2-CH 2-C ?C-OMe N
I-218 COOH ?Ph Benzyl-NH- N C-OMe C-Me ?N CH
I-219 COOH ?Ph Benzyl-NH- N N C-Me ?C-OMe N
I-220 COOH ?Ph CF 3CONH- N ????C-O-CH 2-CH 2-C The C-ethyl N
I-221 COOH ?Ph CF 3CONH- N The C-ethyl N The C-ethyl N
I-222 COOH ?Ph CF 3CONH- N C-Me C-Me ?CH CH
I-223 COOH ?Ph (CH 3) 2N- N ????C-O-CH 2-CH 2-C ?C-OMe N
I-224 COOH ?Ph (CH 3) 2N- N C-Me N ?C-Me N
I-225 COOH ?Ph CF 3CONH- N ????C-CH＝CH-CH＝CH-C ?C-Me N
I-226 COOH ?4-F-Ph CF 3CONH- N N C-Me ?C-OMe CH
I-227 COOH ?Ph Cyclopropyl-CONH- N C-OMe CH ?C-OMe N
I-228 COOH ?Ph Cyclopropyl-CONH- N The C-ethyl CH ?C-Me N
I-229 COOH ?4-F-Ph CF 3CONH- N C-OMe C-Me ?N CH
I-230 COOH ?Ph 4-OMe-Ph-CONH- N C-Me CH ?C-Me N
I-231 COOH ?Ph 4-OMe-Ph-CONH- N C-OMe CH ?C-Me N
I-232 COOH ?4-Cl-Ph CF 3CONH- N N C-Me ?C-OMe N
I-233 COOMe ?Ph CF 3CONH- CH C-Me N ?C-Me N
I-234 COOH ?Ph H 2N- CH C-Me N ?C-Me N
I-235 COOH ?Ph H 2N- CH C-OMe N ?C-Me N
I-236 COOH ?4-F-Ph CF 3CONH- CH C-OMe N ?C-Me N
I-237 COOH ?4-F-Ph CF 3CONH- CH C-Me N ?C-OMe N
I-238 COOH ?Ph Benzyl-NH- N The C-ethyl N ?C-Me N
I-239 COOH ?Ph Benzyl-NH- N N C-Me ?C-OMe CH
I-240 COOH ?Ph CF 3CONH- CH The C-ethyl N The C-ethyl N
Nr. R 1 R 2，R 3 ?A W ?X Q Y Z
I-241 COOH Ph Ethyl-OCH 2CONH- N C-Me CH C-Me N
I-242 COOH Ph ?Ph-OCH 2CONH- N C-OMe CH C-Me N
I-243 COOH Ph ?(CH 3) 2N- N The C-ethyl CH C-Me N
I-244 COOH Ph ?(CH 3) 2N- N ????C-CH 2-CH 2-CH 2-C C-OMe N
I-245 COOH Ph ?4-OMe-Ph-OCH 2CONH- N C-OMe CH C-OMe N
I-246 COOH Ph I-sec.-propyl-OCH 2CONH- N The C-ethyl CH C-Me N
I-247 COOH Ph Cyclopropyl-CONH- N C-Me CH C-Me N
I-248 COOH Ph Cyclopropyl-CONH- N C-OMe CH C-Me N
I-249 COOH Ph ?MeOCH 2CONH- N ????C-CH 2-CH 2-CH 2-C C-Me N
I-250 COOH Ph ?HOCH 2CONH- CH C-Me N C-OMe N
I-251 COOH Ph ?HOCH 2CONH- CH The C-ethyl N C-Me N
I-252 COOH Ph ?MeOCH 2CONH- N ????C-O-CH 2-CH 2-C The C-ethyl N
I-253 COOH Ph Ethyl-OCH 2CONH- N C-Me N C-Me N
I-254 COOH Ph ?H 2N- N N C-Me C-OMe N
I-255 COOH Ph ?H 2N- CH C-Me N C-Me CH
I-256 COOH Ph ?3，4-Di-OMe-Ph-O-CH 2CONH- N C-Me N C-OMe N
I-257 COOH 4-F-Ph ?MeOCH 2CONH- N The C-ethyl N C-Me N
I-258 COOH Ph Benzyl-NH- N C-Me N C-Me N
I-259 COOH Ph Benzyl-NH- N C-Me N C-OMe N
I-260 COOH 4-F-Ph ?MeOCH 2CONH- N N C-Me C-OMe CH
I-261 COOH Ph ?4-Cl-Ph-OCH 2CONH- N C-OMe C-Me N CH
I-262 COOH Ph I-sec.-propyl-OCH 2CONH- N N C-Me C-OMe N
I-263 COOH Ph ?(CH 3) 2N- N C-OMe CH C-Me N
?Nr. R 1 R 2，R 3 A W ?X Q ?Y ?Z
I-264 COOH Ph (CH 3) 2N- N ?C-OMe CH ?C-OMe ?N
I-265 COOH Ph Normal-butyl-OCH 2CONH- CH ?C-Me N ?C-Me ?CH
I-266 COOH Ph N-propyl-OCH 2CONH- CH ?C-Me N ?C-Me ?N
I-267 COOH Ph t-Bu-CH 2CONH- CH ?C-Me N ?C-OMe ?N
I-268 COOH Ph t-Bu-CH 2CONH- CH The C-ethyl N ?C-Me ?N
I-269 COOH Ph I-sec.-propyl-OCH 2CONH- CH ?C-OMe N ?C-Me ?N
I-270 COOH Ph HOCH 2CONH- CH ?C-Me N ?C-Me ?N
I-271 COOH Ph HOCH 2CONH- CH ?C-OMe N ?C-Me ?N
I-272 COOH Ph 3，4-Di-OMe-Ph-O-CH 2CONH- CH ?C-Me N The C-ethyl ?N
I-273 COOH Ph 3，4-Di-OMe-Ph-O-CH 2CONH- CH The C-ethyl N ?C-Me ?N
I-274 COOH Ph H 2N- N ?C-OMe C-Me ?N ?CH
I-275 COOH Ph H 2N- N ?C-OMe CH ?N ?N
I-276 COOH Ph Normal-butyl-CONH- N ?C-Me CH ?C-Me ?N
I-277 COOH Ph Normal-butyl-CONH- N ?C-OMe CH ?C-Me ?N
I-278 COOH Ph Benzyl-NH- N ????C-CH 2-CH 2-CH 2-C ?C-OMe ?N
I-279 COOH Ph Benzyl-NH- N ????C-O-CH 2-CH 2-C ?C-OMe ?N
I-280 COOH Ph N-propyl-CONH- N ?C-OMe CH ?C-OMe ?N
I-281 ?COOH Ph I-sec.-propyl-CONH- N The C-ethyl CH ?C-Me ?N
I-282 COOH Ph I-sec.-propyl-CONH- N ????C-CH 2-CH 2-CH 2-C ?C-OMe ?N
I-283 COOH Ph CH 3NH- CH The C-ethyl N ?C-Me ?N
I-284 COOH Ph (CH 3) 2N- N ?C-Me CH ?C-Me ?N
I-285 COOH Ph Cyclohexyl-CONH- N ????C-O-CH 2-CH 2-C ?C-OMe ?N
I-286 COOH Ph Cyclohexyl-CONH- N ?C-Me ?N ?C-Me ?N
Nr. R 1 R 2，R 3 A W X Q ?Y Z
I-287 COOH Ph t-Bu-CH 2CONH- N N C-Me C-OMe N
I-288 COOH Ph t-Bu-CH 2CONH- CH C-Me N C-Me N
I-289 COOH Ph N-hexyl-CONH- N C-Me N C-OMe N
I-290 COOH Ph HOCH 2CONH- N N C-Me C-OMe N
I-291 COOH Ph HOCH 2CONH- CH C-Me N C-Me CH
I-292 COOH Ph 3-hexene-1-base-CONH- N The C-ethyl N C-Me N
I-293 COOH Ph CH 3-CH＝CH-CONH- N N C-Me C-OMe CH
I-294 COOH Ph H 2N- N The C-ethyl N C-Me N
I-295 COOH Ph H 2N- N N C-Me C-OMe CH
I-296 COOH Ph CH 3-CH＝CH-CONH- N C-OMe C-Me N CH
I-297 COOH Ph N-propyl-CONH- N N C-Me C-OMe N
I-298 COOH Ph Benzyl-NH- N C-OMe CH C-OMe N
I-299 COOH Ph Benzyl-NH- N The C-ethyl CH C-Me N
I-300 COOH Ph N-propyl-CONH- CH C-Me N C-Me N
I-301 COOH Ph 3-hexene-1-base-CONH- CH C-Me N C-OMe N
I-302 COOH 4-F-Ph t-Bu-CH 2CONH- CH The C-ethyl N C-Me N
I-303 COOH Ph CH 3NH- CH C-Me N C-Me N
I-304 COOH Ph CH 3NH- CH C-Me N C-OMe N
I-305 COOH Ph Cyclobutyl-CONH- N C-Me CH C-Me N
I-306 COOH Ph Cyclobutyl-CONH- N C-OMe CH C-Me N
I-307 COOH Ph t-Bu-CH 2CONH- N N C-Me C-OMe CH
I-308 COOH Ph t-Bu-CH 2CONH- N C-OMe C-Me N CH
I-309 COOH Ph Cyclopentyl-CONH- N C-OMe CH C-OMe N
I-310 COOH Ph HOCH 2CONH- N N C-Me C-OMe CH
Nr. ?R 1 R 2，R 3 ??A W ?X Q ?Y Z
I-311 COOH ?Ph ??HOCH 2CONH- N ?C-OMe C-Me N CH
I-312 COOH ?Ph Cyclopentyl-CONH- N The C-ethyl CH C-Me N
I-313 COOH ?Ph Cyclohexyl-CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe N
I-314 COOH ?Ph ??H 2N- N ?C-Me N C-Me N
I-315 COOH ?Ph ??H 2N- N ?C-Me N C-OMe N
I-316 COOH ?Ph Cyclopropyl-CONH- N ????C-O-CH 2-CH 2-C The C-ethyl N
I-317 COOH ?Ph Cyclopropyl-CONH- N The C-ethyl N The C-ethyl N
I-318 COOH ?Ph Benzyl-NH- N ?C-Me CH C-Me N
I-319 COOH ?Ph Benzyl-NH- N ?C-OMe CH C-Me N
I-320 COOH ?4-F-Ph Cyclopropyl-CONH- N ?C-Me N C-OMe N
I-321 COOH ?4-F-Ph Cyclopropyl-CONH- N The C-ethyl N C-Me N
I-322 COOH ?Ph Cyclobutyl-CONH- N ?N C-Me C-OMe CH
I-323 COOH ?Ph ??CH 3NH- N ?C-OMe C-Me N CH
I-324 COOH ?Ph ??CH 3NH- N ?N C-Me C-OMe N
I-325 COOH ?Ph Cyclobutyl-CONH- N ?C-OMe C-Me N CH
I-326 COOH ?Ph Cyclopentyl-CONH- N ?N C-Me C-OMe N
I-327 COOH ?Ph ??t-Bu-CH 2CONH- N ?C-Me N C-OMe N
I-328 COOH ?Ph ??t-Bu-CH 2CONH- N The C-ethyl N C-Me N
I-329 COOH ?Ph Cyclopentyl-CONH- CH ?C-Me N C-Me N
I-330 COOH ?Ph ??HOCH 2CONH- N ?C-Me N C-OMe N
I-331 COOH ?Ph ??HOCH 2CONH- N The C-ethyl N C-Me N
I-332 COOH ?Ph Cyclohexyl-CONH- CH ?C-OMe N C-Me N
I-333 COOH ?Ph Cyclohexyl-CONH- CH The C-ethyl N C-Me N
I-334 COOH ?Ph ??H 2N- N ????C-CH 2-CH 2-CH 2-C C-OMe N
Nr. R 1 R 2，R 3 ?A W X Q ?Y Z
I-335 COOH Ph ?H 2N- N ????C-O-CH 2-CH 2-C C-OMe N
I-336 COOH Ph ?3，4-Di-Cl-Ph-CH 2-CONH- N ?C-Me CH C-Me N
I-337 COOH Ph ?3，4-Di-Cl-Ph-CH 2-CONH- N ?C-OMe CH C-Me N
I-338 COOH Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- CH ?C-Me N C-OMe N
I-339 COOH Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- CH The C-ethyl N C-Me N
I-340 COOH 4-F-Ph ?3，4-Di-OMe-Ph-CH 2-CONH- N ?C-OMe CH C-OMe N
I-341 COOH Ph ?3，4-Di-Me-Ph-CH 2-CONH- N The C-ethyl CH C-Me N
I-342 COOH Ph ?3，4-Di-Me-Ph-CH 2-CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe N
I-343 COOH Ph ?CH 3NH- N The C-ethyl N C-Me N
I-344 COOH Ph ?CH 3NH- N ?N C-Me C-OMe CH
I-345 COOH Ph ?3，4-Di-Cl-Ph-CH 2-CONH- N ????C-O-CH 2-CH 2-C C-OMe N
I-346 COOH Ph ?3，4-Di-Me-Ph-CH 2-CONH- N ?C-Me N C-Me N
I-347 COOH Ph ?t-Bu-CH 2CONH- N ????C-O-CH 2-CH 2-C C-OMe N
I-348 COOH Ph ?t-Bu-CH 2CONH- N ?C-Me N C-Me N
I-349 COOH Ph ?3，5-Di-OMe-Ph-CH 2-CONH- N ?C-Me N C-OMe N
I-350 COOH Ph ?HOCH 2CONH- N ????C-O-CH 2-CH 2-C C-OMe N
I-351 COOH Ph ?HOCH 2CONH- N ?C-Me N C-Me N
I-352 COOH Ph ?3，5-Di-OMe-Ph-CH 2-CONH- N The C-ethyl N C-Me N
I-353 COOH Ph ?2，3-Di-OMe-Ph-CH 2-CONH- N ?N C-Me C-OMe CH
I-354 COOH Ph ?H 2N- N ?C-OMe CH C-OMe N
I-355 COOH Ph ?H 2N- N The C-ethyl CH C-Me N
I-356 COOH Ph ?3，5-Di-Me-Ph-CH 2-CONH- N ?C-OMe C-Me N CH
I-357 COOH Ph ?3，5-Di-OMe-Ph-CH 2-CONH- N ?N C-Me C-OMe N
I-358 COOH Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- CH ?C-Me N C-Me N
Nr. ?R 1 R 2，R 3 ?A W X Q ?Y ?Z
I-359 ?COOH ?Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- CH C-OMe N C-Me ?N
I-360 ?COOH ?Ph ?2，5-Di-OMe-Ph-CH 2-CONH- CH C-Me N C-Me ?CH
I-361 ?COOH ?Ph ?3，5-Di-OMe-Ph-CH 2-CONH- CH C-Me N C-Me ?N
I-362 ?COOH ?Ph ?2，4-Di-OMe-Ph-CH 2-CONH- CH C-OMe N C-Me ?N
I-363 ?COOH ?Ph ?CH 3NH- N C-Me N C-Me ?N
I-364 ?COOH ?Ph ?CH 3NH- N C-Me N C-OMe ?N
I-365 ?COOH ?Ph ?3，4，5-Tri-OMe-Ph-CH 2-CONH- CH C-Me N C-OMe ?N
I-366 ?COOH ?Ph ?3，4，5-Tri-OMe-Ph-CH 2-CONH- CH The C-ethyl N C-Me ?N
I-367 ?COOH ?Ph ?t-Bu-CH 2CONH- N The C-ethyl CH C-Me ?N
I-368 ?COOH ?Ph ?t-Bu-CH 2CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-369 ?COOH ?Ph ?3，4-Di-Cl-Ph-(CH 2) 2-NH- N C-Me CH C-Me ?N
I-370 ?COOH ?Ph ?HOCH 2CONH- N The C-ethyl CH C-Me ?N
I-371 ?COOH ?Ph ?HOCH 2CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-372 ?COOH ?Ph ?3，4-Di-Cl-Ph-(CH 2) 2-NH- N C-OMe CH C-Me ?N
I-373 ?COOH ?Ph ?3，4-Di-Me-Ph-(CH 2) 2-NH- N C-OMe CH C-OMe ?N
I-374 ?COOH ?Ph ?H 2N- N C-Me CH C-Me ?N
I-375 ?COOH ?Ph ?H 2N- N C-OMe CH C-Me ?N
I-376 ?COOH ?Ph ?3，4-Di-Me-Ph-(CH 2) 2-NH- N The C-ethyl CH C-Me ?N
I-377 ?COOH ?Ph ?2，4-Di-OMe-Ph-(CH 2) 2-NH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-378 ?COOH ?Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N C-OMe C-Me N ?CH
I-379 ?COOH ?Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N N C-Me C-OMe ?N
I-380 ?COOH ?Ph ?3，4，5-Tri-OMe-Ph-(CH 2) 2-NH- N ????C-O-CH 2-CH 2-C C-OMe ?N
Nr. R 1 R 2，R 3 ?A W ?X Q Y ?Z
I-381 COOH Ph ?3，4，5-Tri-OMe-Ph-(CH 2) 2-NH- N ?C-Me N C-Me ?N
I-382 COOH Ph ?3，4-Di-Me-Ph-(CH 2) 2-NH- N ?C-Me N C-OMe ?N
I-383 COOH Ph ?CH 3NH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-384 COOH Ph ?CH 3NH- N ????C-O-CH 2-CH 2-C C-OMe ?N
I-385 COOH Ph ?3，5-Di-OMe-Ph-(CH 2) 2-NH- N The C-ethyl N C-Me ?N
I-386 COOH Ph ?3，5-Di-OMe-Ph-(CH 2) 2-NH- N ?N C-Me C-OMe ?CH
I-387 COOH Ph ?t-Bu-CH 2CONH- N ?C-OMe CH C-Me ?N
I-388 COOH Ph ?t-Bu-CH 2CONH- N ?C-OMe CH C-OMe ?N
I-389 COOH Ph ?2，4-Di-OMe-Ph-(CH 2) 2-NH- N ?C-OMe C-Me N ?CH
I-390 COOH Ph ?HOCH 2CONH- N ?C-OMe CH C-Me ?N
I-391 COOH Ph ?HOCH 2CONH- N ?C-OMe CH C-OMe ?N
I-392 COOH Ph ?3，4-Di-Me-Ph-(CH 2) 2-NH- N ?N C-Me C-OMe ?N
I-393 COOH Ph ?3，4-Di-Me-Ph-(CH 2) 2-NH- CH ?C-Me N C-Me ?N
I-394 COOH Ph ?N 3 CH The C-ethyl N C-Me ?N
I-395 COOH Ph ?H 2N- N ?C-Me CH C-Me ?CH
I-396 COOH 4-F-Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- CH ?C-OMe N C-Me ?N
I-397 COOH 4-F-Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- CH ?C-Me N C-OMe ?N
I-398 COOH Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N The C-ethyl N C-Me ?N
I-399 COOH Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N ?N C-Me C-OMe ?CH
I-400 COOH Ph ?3，4-Di-Me-Ph-(CH 2) 2-NH- CH The C-ethyl N C-Me ?N
I-401 COOH Ph 4-OMe-benzyl-NH- N ?C-Me CH C-Me ?N
I-402 COOH Ph 3,4-Di-OMe-benzyl-NH- N ?C-OMe CH C-Me ?N
I-403 COOH Ph ?CH 3NH- N ?C-OMe CH C-OMe ?N
Nr. ?R 1 ?R 2，R 3 ?A W ?X Q ?Y Z
I-404 ?COOH ?Ph ?CH 3NH- N The C-ethyl CH C-Me ?N
I-405 ?COOH ?Ph 4-Cl-benzyl-NH- N ?C-OMe CH C-OMe ?N
I-406 ?COOH ?Ph 4-OH-benzyl-NH- N The C-ethyl CH C-Me ?N
I-407 ?COOH ?Ph ?MeOCH 2CONH- CH ?C-OMe N C-Me ?N
I-408 ?COOH ?Ph ?MeOCH 2CONH- CH ?C-Me N C-OMe ?N
I-409 ?COOH ?Ph ?MeOCH 2CONH- CH The C-ethyl N C-Me ?N
I-410 ?COOH ?Ph ?t-Bu-CH 2CONH- N ?C-Me CH C-Me ?N
I-411 ?COOH ?Ph 3,4-Di-OMe-benzyl-NH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-412 ?COOH ?Ph ?Ph-NH- CH The C-ethyl N C-Me ?N
I-413 ?COOH ?Ph ?HOCH 2CONH- N ?C-Me CH C-Me ?N
I-414 ?COOH ?Ph 4-OMe-benzyl-NH- N ????C-O-CH 2-CH 2-C C-OMe ?N
I-415 ?COOH ?Ph 3-OMe-4-OH-benzyl-NH- N ?C-Me N C-Me ?N
I-416 ?COOH ?Ph ?N 3 CH ?C-OMe N C-Me ?N
I-417 ?COOH ?Ph ?N 3 CH ?C-Me N C-OMe ?N
I-418 ?COOH ?Ph 4-Me-benzyl-NH- N ?C-Me N C-OMe ?N
I-419 ?COOH ?Ph 3,4-Di-Me-benzyl-NH- N The C-ethyl N C-Me ?N
I-420 ?COOH ?Ph ?3，7-Di-OMe-Ph-(CH 2) 2-NH- N ?C-Me N C-Me ?N
I-421 ?COOH ?Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N ?C-Me N C-OMe ?N
I-422 ?COOH ?Ph 4-Me-benzyl-NH- N ?N C-Me C-OMe ?CH
I-423 ?COOH ?Ph 3-Cl-benzyl-NH- N ?C-OMe C-Me N ?CH
I-424 ?COOH ?Ph 2-Cl-benzyl-NH- N ?N C-Me C-OMe ?N
I-425 ?COOH ?Ph ?CH 3NH- N ?C-Me CH C-Me ?N
I-426 ?COOH ?Ph ?CH 3NH- N ?C-OMe CH C-Me ?N
I-427 ?COOH ?Ph 3,5-Di-OMe-benzyl-NH- CH ?C-Me N C-Me ?N
Nr. R 1 R 2，R 3 ?A W X Q ?Y ?Z
I-428 COOH 4-F-Ph Benzyl-NH- CH C-Me N C-OMe ?N
I-429 COOH Ph ?MeOCH 2CONH- CH C-Me N C-Me ?CH
I-430 COOH Ph ?MeOCH 2CONH- CH C-Me N C-Me ?N
I-431 COOH 4-F-Ph Benzyl-NH- CH The C-ethyl N C-Me ?N
I-432 COOH Ph ?Ph-NH- CH C-Me N C-Me ?N
I-433 COOH Ph ?Ph-NH- CH C-OMe N C-Me ?N
I-434 COOH Ph ?3-Cl-4-OH-Ph-CH 2-CONH- N C-Me CH C-Me ?N
I-435 COOH Ph ?3-Cl-4-OH-Ph-CH 2-CONH- N C-OMe CH C-Me ?N
I-436 COOH Ph ?N 3 CH C-Me N C-Me ?CH
I-437 COOH Ph ?N 3 CH C-Me N C-Me ?N
I-438 COOH Ph ?3-Me-4-OH-Ph-CH 2-CONH- N C-OMe CH C-OMe ?N
I-439 COOH Ph ?3-Me-4-OH-Ph-CH 2-CONH- N The C-ethyl CH C-Me ?N
I-440 COOH Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-441 COOH Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N ????C-O-CH 2-CH 2-C C-OMe ?N
I-442 COOH Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N ????C-CH 2-CH 2-CH 2-C The C-ethyl ?N
I-443 COOH Ph ?3-OMe-4-OH-Ph-CH 2-CONH- N ????C-O-CH 2-CH 2-C C-Me ?N
I-444 COOH Ph ?2-OMe-4-OH-Ph-CH 2-CONH- N C-Me N C-Me ?N
I-445 COOH Ph Ethyl-CONH- CH C-Me N C-OMe ?N
I-446 COOH Ph Ethyl-CONH- CH The C-ethyl N C-Me ?N
I-447 COOH Ph ?3-Cl-4-OH-Ph-CH 2-CONH- N C-Me N C-OMe ?N
I-448 COOH Ph ?3，4-Di-OH-Ph-CH 2-CONH- N The C-ethyl N C-Me ?N
I-449 COOH Ph ?MeOCH 2CONH- N C-OMe C-Me N ?CH
Nr. R 1 R 2，R 3 ?A W X Q Y Z
I-450 COOH ?Ph ?MeOCH 2CONH- N ?N C-Me C-OMe N
I-451 COOH ?Ph ?3，4-Di-OH-Ph-CH 2-CONH- N ?N C-Me C-OMe CH
I-452 COOH ?Ph ?Ph-NH- N ?C-OMe C-Me N CH
I-453 COOH ?Ph ?Ph-NH- N ?N C-Me C-OMe N
I-454 COOH ?Ph ?3-OH-4-OMe-Ph-CH 2-CONH- N ?C-OMe C-Me N CH
I-455 COOH ?Ph ?3-OH-4-OMe-Ph-CH 2-CONH- N ?N C-Me C-OMe N
I-456 COOH ?Ph ?N 3 N ?C-OMe C-Me N CH
I-457 COOH ?Ph ?N 3 N ?N C-Me C-OMe N
I-458 COOH ?Ph ?2-Cl-4-OH-Ph-CH 2-CONH- CH ?C-Me N C-Me CH
I-459 COOH ?Ph ?3-Cl-4-OH-Ph-CH 2-CONH- CH ?C-Me N C-Me N
I-460 COOH ?Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N ?C-OMe CH C-OMe N
I-461 COOH ?Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N The C-ethyl CH C-Me N
I-462 COOH ?Ph ?3-OMe-4-SMe-Ph-CH 2-CONH- CH ?C-OMe N C-Me N
I-463 COOH ?Ph ?3-OMe-4-SMe-Ph-CH 2-CONH- CH ?C-Me N C-OMe N
I-464 COOH ?Ph ?3，4-Di-OH-Ph-CH 2-CONH- CH The C-ethyl N C-Me N
I-465 COOH ?Ph Ethyl-CONH- CH ?C-Me N C-Me N
I-466 COOH ?Ph Ethyl-CONH- CH ?C-OMe N C-Me N
I-467 COOH ?Ph ?Ph-NH- N ?C-CF 3 CH C-Me N
I-468 COOH ?4-F-Ph ?Ph-NH- N ?C-OMe CH C-Me N
I-469 COOH ?Ph ?MeOCH 2CONH- N The C-ethyl N C-Me N
I-470 COOH ?Ph ?MeOCH 2CONH- N ?N C-Me C-OMe CH
Nr. R 1 R 2，R 3 ?A W X ?Q Y Z
I-471 COOH 4-Cl-Ph ?Ph-NH- N C-OMe CH C-OMe N
I-472 COOH Ph ?Ph-NH- N The C-ethyl N C-Me N
I-473 COOH Ph ?Ph-NH- N N C-Me C-OMe CH
I-474 COOH 4-Me-Ph ?Ph-NH- N The C-ethyl CH C-Me N
I-475 COOH Ph ?Ph-NH- N ????C-CH 2-CH 2-CH 2-C C-Me N
I-476 COOH Ph ?N 3 N The C-ethyl N C-Me N
I-477 COOH Ph ?N 3 N N C-Me C-OMe CH
I-478 COOH Ph ?Ph-NH- N ????C-O-CH 2-CH 2-C C-Me N
I-479 COOH Ph ?Ph-NH- N C-N(CH 3) 2 N C-N(CH 3) 2 N
I-480 COOH Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N C-Me CH C-Me N
I-481 COOH Ph ?3，4-Di-OMe-Ph-(CH 2) 2-NH- N C-OMe CH C-Me N
I-482 COOH Ph ?Ph-NH- N The C-ethyl N The C-ethyl N
I-483 COOH Ph ?Ph-NH- CH The C-ethyl CH C-Me N
I-484 COOH Ph ?Ph-NH- N N C-OMe CH CH
I-485 COOH Ph Ethyl-CONH- N N C-Me C-OMe N
I-486 COOH Ph Ethyl-CONH- CH C-Me N C-Me CH
I-487 COOH 4-F-Ph ?Ph-NH- N C-OMe C-Me N CH
I-488 COOH 4-F-Ph ?Ph-NH- N N C-Me C-OMe N
I-489 COOH Ph ?MeOCH 2CONH- N C-Me N C-Me N
I-490 COOH Ph ?MeOCH 2CONH- N C-Me N C-OMe N
I-491 COOMe Ph ?Ph-NH- CH C-Me N C-Me N
I-492 COOH Ph ?Ph-NH- N C-Me N C-Me N
I-493 COOH Ph ?Ph-NH- N C-Me N C-OMe N
I-494 COOH Ph ?Ph-NH- CH C-OMe N The C-ethyl N
I-495 COOH Ph ?4-Cl-Ph-NH- CH The C-ethyl N C-Me N
Nr. R 1 R 2，R 3 ?A W X ?Q ?Y ?Z
I-496 COOH ?Ph ?N 3 N C-Me N C-Me ?N
I-497 COOH ?Ph ?N 3 N C-Me N C-OMe ?N
I-498 COOH ?Ph Benzyl-OCH 2CONH- N C-Me CH C-Me ?N
I-499 COOH ?Ph Benzyl-OCH 2CONH- N C-OMe CH C-Me ?N
I-500 COOH ?Ph ?3，4-Di-OMe-Ph-CH 2-CONH- CH C-Me N C-OMe ?N
I-501 COOH ?Ph ?3，4-Di-OMe-Ph-CH 2-CONH- CH The C-ethyl N C-Me ?N
I-502 COOH ?4-F-Ph ?HOCH 2CONH- N C-OMe CH C-OMe ?N
1-503 COOH ?4-F-Ph ?N 3 CH C-Me N C-Me ?N
I-504 COOH ?4-F-Ph ?N 3 CH C-OMe N C-Me ?N
I-505 COOH ?4-F-Ph ?HOCH 2CONH- N The C-ethyl CH C-Me ?N
I-506 COOH ?Ph ?HOCH 2CONH- N ????C-CH 2-CH 2-CH 2-C C-Me ?N
I-507 COOH ?Ph Ethyl-CONH- N N C-Me C-OMe ?CH
I-508 COOH ?Ph Ethyl-CONH- N C-OMe C-Me N ?CH
I-509 COOH ?Ph ?HOCH 2CONH- N ????C-S-CH 2-CH 2-C C-OMe ?N
I-510 COOH ?Ph Benzyl-OCH 2CONH- N C-Me N C-Me ?N
I-511 COOH ?Ph ?MeOCH 2CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-512 COOH ?Ph ?MeOCH 2CONH- N ????C-O-CH 2-CH 2-C C-OMe ?N
I-513 COOH ?4-Me-Ph ?HOCH 2CONH- N C-Me N C-OMe ?N
I-514 COOH ?Ph ?Ph-NH- N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-515 COOH ?Ph ?Ph-NH- N ????C-O-CH 2-CH 2-C C-OMe ?N
I-516 COOH ?Ph ?HOCH 2CONH- N The C-ethyl N The C-ethyl ?N
I-517 COOH ?Ph 4-OMe-benzyl-OCH 2CONH- N N C-Me C-OMe ?CH
I-518 COOH ?Ph ?N 3 N ????C-CH 2-CH 2-CH 2-C C-OMe ?N
I-519 COOH ?Ph ?N 3 N ????C-O-CH 2-CH 2-C C-OMe ?N
Nr. R 1 R 2，R 3 A W X Q Y Z
I-520 COOH Ph 4-OMe-benzyl-OCH 2CONH- N C-OMe C-Me N CH
I-521 COOH 4-F-Ph ?HOCH 2CONH- N N C-Me C-OMe N
I-522 COOH Ph ?3，4-Di-OMe-Ph-CH 2-CONH- CH C-Me N C-Me N
I-523 COOH Ph ?3，4-Di-OMe-Ph-CH 2-CONH- CH C-OMe N C-Me N
I-524 COOH 4-Cl-Ph ?HOCH 2CONH- CH C-Me N C-Me CH
I-525 COOH 4-F-Ph ?N 3 N N C-Me C-OMe N
I-526 COOH 4-F-Ph ?N 3 CH C-Me N C-Me CH
I-527 COOH Ph ?Ph-OCH 2CONH- CH C-Me N C-Me N
I-528 COOH Ph ?4-OMe-Ph-OCH 2CONH- CH C-OMe N C-Me N
I-529 COOH Ph Ethyl-CONH- N C-Me N C-OMe N
I-530 COOH Ph Ethyl-CONH- N The C-ethyl N C-Me N
I-531 COOH Ph Benzyl-OCH 2CONH- CH C-Me N C-OMe N
I-532 COOH 4-F-Ph ?HOCH 2CONH- CH The C-ethyl N C-Me N
I-533 COOH Ph ?MeOCH 2CONH- N C-Me CH C-Me N
I-534 COOH Ph ?MeOCH 2CONH- N C-OMe CH C-Me N
I-535 COOH Ph ?MeOCH 2CONH- N C-OMe CH C-OMe N
I-536 COOH Ph ?MeOCH 2CONH- N The C-ethyl CH C-Me N
I-537 COOH Ph ?4-OH-Ph-CONH- N C-Me CH C-Me N
I-538 COOH Ph ?Ph-NH- N C-OMe CH C-OMe N
I-539 COOH Ph ?Ph-NH- N The C-ethyl CH C-Me N
I-540 COOH Ph ?4-SMe-Ph-CONH- N C-OMe CH C-Me N
I-541 COOH Ph ?4-NO 2-Ph-CONH- N C-OMe CH C-OMe N
I-542 COOH Ph ?N 3 N C-OMe CH C-OMe N
I-543 COOH Ph ?N 3 N The C-ethyl CH C-Me N
Nr. R 1 R 2，R 3 ?A W X Q ?Y Z
I-544 COOH Ph ?4-Cl-Ph-CONH- N The C-ethyl CH C-Me N
I-545 COOH Ph 4-ethyl-Ph-CONH- N ????C-CH 2-CH 2-CH 2-C C-OMe N
I-546 COOH Ph ?3，4-Di-OMe-Ph-CH 2-CONH- N N C-Me C-OMe N
I-547 COOH Ph ?3，4-Di-OMe-Ph-CH 2-CONH- CH C-Me N C-Me CH
I-548 COOH 4-F-Ph ?4-OMe-Ph-CONH- N ????C-O-CH 2-CH 2-C C-OMe N
I-549 COOH 4-F-Ph ?N 3 N N C-Me C-OMe CH
I-550 COOH 4-F-Ph ?N 3 N C-OMe C-Me N CH
I-551 COOH Ph ?4-Cl-Ph-CONH- N C-Me N C-Me N
I-552 COOH Ph ?3，4-Di-OMe-Ph-CONH- N C-Me N C-OMe N
I-553 COOH Ph Ethyl-CONH- N ????C-O-CH 2-CH 2-C C-OMe N
I-554 COOH Ph Ethyl-CONH- N C-Me N C-Me N
I-555 COOH Ph ?3，4-Di-OMe-Ph-CONH- N The C-ethyl N C-Me N
I-556 COOH Ph ?4-Cl-Ph-CONH- N N C-Me C-OMe CH
I-557 COOH Ph ?CF 3CONH- CH C-Me N C-OMe N
I-558 COOH Ph ?CF 3CONH- CH The C-ethyl N C-Me N
I-559 COOH Ph ?3，4-Di-Cl-Ph-CONH- N C-OMe C-Me N CH
I-560 COOH Ph ?Ph-NH- N C-Me CH C-Me N
I-561 COOH Ph ?Ph-NH- N C-OMe CH C-Me N
I-562 COOH Ph ?3-OMe-4-OH-Ph-CONH- N N C-Me C-OMe N
I-563 COOH Ph ?3-Cl-Ph-CONH- CH C-Me N C-Me N
I-564 COOH Ph ?N 3 N C-Me CH C-Me N
I-565 COOH Ph ?N 3 N C-OMe CH C-Me N
I-566 COOH Ph ?2-Cl-Ph-CONH- CH C-OMe N C-Me N
I-567 COOH Ph ?4-NO 2-Ph-CONH- CH The C-ethyl N C-Me N
Embodiment 11: as mentioned above following compounds is carried out binding analysis, measure the binding data of acceptor.Gained the results are shown in the table 2.Table 2 receptors bind data (K iValue)
Compound ?ET A[nM/l] ET B[nM/l]
I-174 ?83 ?＞7000
I-227 ?225 ?2800
I-334 ?600 ?6400
I-354 ?50 ?＞6400
I-375 ?300 ?7300
I-388 ?1000 ?7000
I-518 ?14 ?460
I-535 ?35 ?7000
I-541 ?1000 ?＞7000
I-542 ?60 ?2200

Claims (10)

1. the salt of the beta-amino of formula I and β-azido-carboxylic acid derivative and physiological tolerance thereof and the possible pure form of the pure and mild diastereo-isomerism of enantiomerism
Figure A9880639700021
R wherein 1Be tetrazolium or following formula group
Figure A9880639700022
Wherein the implication of R is as follows: a) OR 4Group, wherein R 4Be: the organic ammonium ion of hydrogen, alkali metal cation, alkaline earth metal cation or physiological tolerance; C 3-C 8-cycloalkyl, C 1-C 8-alkyl, they are optional substituted, CH 2-phenyl, it is optional substituted, C 3-C 8-alkenyl or C 3-C 8-alkynyl, they are optional substituted, perhaps phenyl, it is optional substituted; B) by nitrogen-atoms banded 5-unit hetero-aromatic ring; C) following formula group
Figure A9880639700023
Wherein k can be 0,1 and 2, and p is 1,2,3 and 4, and R 5Be
C 1-C 4-alkyl, C 3-C 8-cycloalkyl, C 3-C 8-alkenyl, C 3-C 8-alkynyl or optional substituted phenyl; D) following formula group
R wherein 6Be:
C 1-C 4-alkyl, C 3-C 8-alkenyl, C 3-C 8-alkynyl, C 3-C 8-cycloalkyl, these groups can have C 1-C 4-alkoxyl group, C 1-C 4-alkylthio and/or phenyl;
C 1-C 4-haloalkyl or phenyl, they are optional substituted.
A is NR 7R 8Or azido-;
W and Z can be identical or different, and they are:
Nitrogen or methyne; Condition is if W and Z=methyne, then Q=nitrogen;
X is nitrogen or CR 9
Y is nitrogen or CR 10
Q is nitrogen or CR 11Condition is if Q=nitrogen, then X=CR 9And Y=CR 10
R 2And R 3Can be identical or different, they are:
Phenyl or naphthyl, they are optional substituted, perhaps
Phenyl or naphthyl, they are by direct key, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO 2, NH or N-alkyl link together at the ortho position,
C 5-C 6-cycloalkyl, it is optional substituted;
R 7Be hydrogen, C 1-C 8-alkyl, C 3-C 8-alkenyl or C 3-C 8-alkynyl, C 1-C 5-alkyl-carbonyl, these groups can be optional substituted;
Phenyl or naphthyl, they are optional substituted;
Optional substituted C 3-C 8-cycloalkyl;
Perhaps R 7By 4 or 5 CH 2Group and R 8Link, obtain 5-or 6-unit ring;
R 8Be hydrogen, C 1-C 4-alkyl;
Perhaps R 8By 4 or 5 CH 2Group and R 7Link, obtain 5-or 6-unit ring;
R 9And R 10Can be identical or different, they are:
Hydrogen, halogen, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, C 3-C 6-alkenyloxy, C 3-C 6-alkynyloxy group, C 1-C 4-alkylthio, C 1-C 4-alkyl-carbonyl, C 1-C 4-carbalkoxy, hydroxyl, NH 2, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2
C 1-C 4-alkyl, C 2-C 4-alkenyl, C 2-C 4-alkynyl, these groups can be optional substituted;
Perhaps CR 9Or CR 10As described below and CR 11Link, obtain 5-or 6-unit ring;
R 11Be hydrogen, halogen, C 1-C 4-alkoxyl group, C 1-C 4-halogenated alkoxy, C 3-C 6-alkenyloxy, C 3-C 6-alkynyloxy group, C 1-C 4-alkylthio, C 1-C 4-alkyl-carbonyl, C 1-C 4-carbalkoxy, NH (C 1-C 4-alkyl), N (C 1-C 4-alkyl) 2, hydroxyl, carboxyl, cyano group, amino, sulfydryl;
C 1-C 4-alkyl, C 2-C 4-alkenyl, C 2-C 4-alkynyl, these groups can be optional substituted;
Perhaps CR 11With CR 9Or CR 10Form 5-or 6-unit alkylene basic ring or alkenylene ring together, they can be optional substituted, and wherein one or more methylene radical can be separately by oxygen, sulphur ,-NH or-N (C 1-C 4-alkyl) displacement.
2. the beta-amino of claim 1 or β-azido-carboxylic acid derivative is in the purposes of treatment in the disease.
3. the Compound I of claim 2 is as the purposes of endothelin-receptor antagonists.
4. the application of the beta-amino of claim 1 or β-azido-carboxylic acid derivative I in the medicine of the disease that preparation treatment level of ET raises.
5. the application of the beta-amino of claim 1 or β-azido-carboxylic acid derivative I in treatment chronic heart failure, restenosis, hypertension, pulmonary hypertension, urgency/chronic kidney hypofunction, cerebral ischemia, benign prostatic hyperplasia and prostate cancer.
6. the application of the inhibitor of the beta-amino of claim 1 or β-azido-carboxylic acid derivative I and renin-angiotonin system such as blood vessel tension peptide protoenzyme inhibitor, angiotension II antagonists and particularly angiotensin converting enzyme (ACE) inhibitor, blended ACE/ neutral endopeptidase (NEP) inhibitor, Beta receptor blockers combination.
7. the pharmaceutical preparation that is used for oral, non-administration in stomach and intestine or enteron aisle, with regard to every single dose, except the pharmaceutical auxiliary agent of routine, it also contains the carboxylic acid derivative I of at least a claim 1.
8. formula II compound
Figure A9880639700051
Radicals R wherein 1, R 2, R 3With described in the definition such as claim 1 of A.
9. the application of the raw material of the synthetic endothelin-receptor antagonists of formula II compound conduct,
Figure A9880639700052
Radicals R wherein 1, R 2, R 3With described in the definition such as claim 1 of A.
10. be used as the following formula structure fragment of structural unit in the endothelin-receptor antagonists
Figure A9880639700053
Radicals R wherein 1, R 2, R 3With described in the definition such as claim 1 of A.
CN98806397A 1997-06-19 1998-06-05 New 'beta'-amino and 'beta'-azidocarboxylic acid derivatives, the production thereof and the use thereof as endothelin receptor an tagonists Pending CN1261352A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19726146A DE19726146A1 (en) 1997-06-19 1997-06-19 New ß-amino and ß-azidopcarboxylic acid derivatives, their preparation and use as endothelin receptor antagonists
DE19726146.9 1997-06-19

Publications (1)

Publication Number Publication Date
CN1261352A true CN1261352A (en) 2000-07-26

Family

ID=7833081

Family Applications (1)

Application Number Title Priority Date Filing Date
CN98806397A Pending CN1261352A (en) 1997-06-19 1998-06-05 New 'beta'-amino and 'beta'-azidocarboxylic acid derivatives, the production thereof and the use thereof as endothelin receptor an tagonists

Country Status (22)

Country Link
EP (1) EP0994861A1 (en)
JP (1) JP2002504130A (en)
KR (1) KR20010013981A (en)
CN (1) CN1261352A (en)
AR (1) AR015893A1 (en)
AU (1) AU8213398A (en)
BG (1) BG104022A (en)
BR (1) BR9810182A (en)
CA (1) CA2294050A1 (en)
CO (1) CO4950605A1 (en)
DE (1) DE19726146A1 (en)
HR (1) HRP980331A2 (en)
HU (1) HUP0002714A3 (en)
ID (1) ID24346A (en)
IL (1) IL133104A0 (en)
NO (1) NO996268D0 (en)
NZ (1) NZ502319A (en)
PL (1) PL337507A1 (en)
SK (1) SK176299A3 (en)
TR (1) TR199903159T2 (en)
WO (1) WO1998058916A1 (en)
ZA (1) ZA985277B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109422664A (en) * 2017-08-23 2019-03-05 中国科学院福建物质结构研究所 A kind of interferon regulation agent and its preparation method and application

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19806438A1 (en) * 1998-02-17 1999-08-19 Basf Ag New pyrimidinyloxy-propionic acid derivatives useful as endothelin receptor antagonists in treatment of e.g. cardiac insufficiency, restenosis, hypertension, kidney failure, asthma and prostate cancer
DE19858779A1 (en) * 1998-12-18 2000-06-21 Basf Ag New 3-acylamino-propionic acid and 3-sulfonylamino-propionic acid derivatives useful as endothelin receptor antagonists in treatment of e.g. cardiovascular and renal disorders, migraine and cancer
DE19924892A1 (en) * 1999-06-01 2000-12-07 Basf Ag New carboxylic acid derivatives with aryl-substituted nitrogen heterocycles, their production and use as endothelin receptor antagonists
WO2002064573A1 (en) * 2001-02-14 2002-08-22 Abbott Gmbh & Co. Kg Novel carboxylic acid derivatives containing alkyl substituted triazines, production of the same and use thereof as endothelin receptor antagonists
EP1632821B1 (en) 2004-09-01 2012-05-30 Océ-Technologies B.V. Intermediate transfer member with a cleaning member
US7790770B2 (en) * 2005-11-23 2010-09-07 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
AU2008282773B8 (en) 2007-07-31 2013-03-07 Gilead Sciences, Inc. Metabolites and derivatives of ambrisentan

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5136060A (en) * 1989-11-14 1992-08-04 Florida State University Method for preparation of taxol using an oxazinone
DE4411225A1 (en) * 1994-03-31 1995-10-05 Basf Ag Use of carboxylic acid derivatives as a drug
DE19614533A1 (en) * 1996-04-12 1997-10-16 Basf Ag New alpha-hydroxy acid derivatives, their production and use

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109422664A (en) * 2017-08-23 2019-03-05 中国科学院福建物质结构研究所 A kind of interferon regulation agent and its preparation method and application
CN109422664B (en) * 2017-08-23 2022-02-18 中国科学院福建物质结构研究所 Interferon regulator and its prepn and use

Also Published As

Publication number Publication date
DE19726146A1 (en) 1998-12-24
AU8213398A (en) 1999-01-04
HRP980331A2 (en) 1999-02-28
ZA985277B (en) 1999-12-20
HUP0002714A2 (en) 2001-05-28
IL133104A0 (en) 2001-03-19
CA2294050A1 (en) 1998-12-30
AR015893A1 (en) 2001-05-30
NO996268L (en) 1999-12-17
JP2002504130A (en) 2002-02-05
KR20010013981A (en) 2001-02-26
BG104022A (en) 2001-04-30
ID24346A (en) 2000-07-13
WO1998058916A1 (en) 1998-12-30
PL337507A1 (en) 2000-08-28
BR9810182A (en) 2000-08-08
HUP0002714A3 (en) 2001-07-30
SK176299A3 (en) 2000-06-12
CO4950605A1 (en) 2000-09-01
TR199903159T2 (en) 2000-07-21
NZ502319A (en) 2002-03-01
NO996268D0 (en) 1999-12-17
EP0994861A1 (en) 2000-04-26

Similar Documents

Publication Publication Date Title
US9655897B2 (en) Heterocyclyl pyrimidine analogues as TYK2 inhibitors
US11020398B2 (en) Amino-pyrrolopyrimidinone compounds and methods of use thereof
US6670367B1 (en) Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives, their preparation and use as mixed ETA/ETB endothelin receptor antagonists
US10597375B2 (en) Halogen-substituted heterocyclic compound
US6440975B1 (en) Amino acid derivatives, the preparation and use thereof as endothelin antagonists
US7074836B1 (en) Para-terphenyl compounds
US20110230472A1 (en) Ring-fused azole derivative having pi3k-inhibiting activity
US10150728B2 (en) Alkylene derivatives
RU2007116725A (en) DIAMINO-ALKANE ASPARAGIN PROTEASE INHIBITORS
US6686369B1 (en) α-hydrdroxylic acid derivatives, their production and use
IL278122B2 (en) Pteridinone compounds and uses thereof
US20150246938A1 (en) Novel olefin derivative
TW202144337A (en) EGFR inhibitor and preparation method and use thereof
US6448248B1 (en) Heterocyclic carboxylic acid derivatives, the production and use thereof as endothelin receptor antagonists
CN1261352A (en) New 'beta'-amino and 'beta'-azidocarboxylic acid derivatives, the production thereof and the use thereof as endothelin receptor an tagonists
US20100003191A1 (en) Aurone derivative-containing composition for diagnosis
US5604178A (en) N-(substituted amino)pyrrole derivatives, and herbicidal compositions
US6358983B1 (en) Heterocyclically substituted α-hydroxycarboxylic acid derivatives, method for producing the same and their use as endothelin receptor antagonists
US5683964A (en) N-(substituted amino)imide derivatives, preparation process thereof, and herbicidal composition
KR930011304B1 (en) Pyridazinon derivatives
WO2023051261A1 (en) Imine compound and use thereof
CN101547707A (en) Aurone derivative-containing composition for diagnosis

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication