CN1902169A - 4-biarylyl-1-phenylazetidin-2-ones - Google Patents

4-biarylyl-1-phenylazetidin-2-ones Download PDF

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CN1902169A
CN1902169A CN 200480039695 CN200480039695A CN1902169A CN 1902169 A CN1902169 A CN 1902169A CN 200480039695 CN200480039695 CN 200480039695 CN 200480039695 A CN200480039695 A CN 200480039695A CN 1902169 A CN1902169 A CN 1902169A
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fluorophenyl
group
alkyl
amino
compound
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爱德华多·马丁内斯
约翰·J.·塔利
斯蒂芬·安东内利
蒂莫西·C.·巴登
雷吉娜·伦德里根－苏西
韦恩·C.·谢雷尔
杨晶晶
丹尼尔·P.·齐默
布赖恩·卡利
马克·G.·柯里
彼得·S.·约尔吉
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Microbia Inc
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Microbia Inc
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Abstract

4-Biarylyl-1-phenylazetidin-2-ones useful for the treatment of hypercholesterolemia are disclosed. The compounds are of a general formula (I) in which formula (II) represents an aryl or heteroaryl residue, Ar represents an aryl residue; U is a two to six atom chain; and the R's represent substituents.

Description

4-dibenzyl-1-phenyl azetidine alkane-2-ketone
The cross reference of related application
The application requires respectively on November 10th, 2003, on March 3rd, 2004, on July 30th, 2004 and the U.S. Provisional Application 60/518698,60/549577,60/592529 of submission on September 28th, 2004 and 60/614005 right of priority.The full content of above-mentioned application is incorporated herein by reference at this.
Technical field
The present invention relates to can be used for to treat the 4-dibenzyl-1-phenyl azetidine alkane-2-ketone compounds of hypercholesterolemia and the optimum and malignant tumour relevant with cholesterol.
Background technology
U.S. Pat 6498156, United States Patent (USP) continuation application USRE 37721 and PCT application WO 02/50027 have described 1,4-biphenyl azetidine-2-ketone and their application in the treatment lipid metabolism disorders, the disclosure of above-mentioned application is incorporated herein by reference at this.
Summary of the invention
A first aspect of the present invention is the compound about being shown below:
Figure A20048003969500491
This compound comprises compound Φ and the Ψ that two classes are close:
Wherein,
Figure A20048003969500502
Expression aryl or heteroaryl residue;
Ar represents aromatic yl residue;
R 1Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 2Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 4Expression be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three or four residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 4fFor-OH ,-SH or B (OH) 2
R 5gExpression be positioned on the Ar be independently selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 5hExpression be positioned on the Ar be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
U is C 2-6Alkylidene group, wherein, one or more-CH 2-can be selected from-S-,-S (O)-,-SO 2-,-O-,-C (=O)-,-CHOH-,-NH-, CHF, CF 2,-CH (O-low alkyl group)-,-CH (O-lower acyl)-,-CH (OSO 3H)-,-CH (OPO 3H 2)-,-CH (OB (OH) 2)-or-residue among the NOH-replaces, and condition is:
(1) adjacent-CH 2-residue can not by-S-,-S (O)-,-SO 2-or-O-replaces; And
(2)-S-,-S (O)-,-SO 2-,-O-and-the NH-residue can not be only by single carbon separately;
Except U aBe not-CH 2CH 2CH (OH)-in addition, U aIdentical with U.
When two rings of xenyl residue are not all further replaced, the R among Φ and the Ψ 5gBe not-CH, 2,5-dimethoxy, 2,6-dimethoxy or halogen.
When Expression 2, during 5-thienyl residue, the R among Φ and the Ψ 5gIt is not the 2-hydroxyl.
Subclass comprises the biphenyl compounds of general formula I-VII:
Figure A20048003969500541
In formula I, R 1And R 2Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy (carboalkoxy), acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate and the carboxylamine sugar; R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group; R 4Expression be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-, two, three or four residues in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate and the carboxylamine sugar; R 5fExpression be independently selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate, carboxylamine sugar and-NuR 6R 7R 8X -In one, two, three, four or five residues; R 6Be C 1-20Hydrocarbon or and R 7Form five yuan to seven-membered ring; R 7Be alkyl or and R 6Form five yuan to seven-membered ring; R 8Be alkyl or and R 6And R 7Form second five yuan together to seven-membered ring; And X is a negatively charged ion.
In formula II, R 1a, R 4aAnd R 5aIn one be-Q-A-N +R 9R 10R 11X -, and two other is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and benzyloxy; R 2aExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy; R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group; Q be selected from direct key ,-O-,-S-,-NH-,-CH 2O-,-CH 2NH-,-C (=O) ,-CONH-,-NHCO-,-O (C=O)-,-(C=O) O-,-NHCONH-,-OCONH-and-NHCOO-; A is selected from C 2-20Hydrocarbon, carbonatoms are the substituted alkyl of 2-20, substituted aryl, substituted arylalkyl and C 4-50Oxa alkyl, and, when Q be direct key ,-C (=O) or-during O (C=O), A can also be methylene radical; R 9Be C 1-20Hydrocarbon or with A or R 10Form five yuan to seven-membered ring; R 10Be alkyl, form two keys or and R with A 9Form five yuan to seven-membered ring; R 11Be alkyl or and R 10Or R 9Form second five yuan together to seven-membered ring; X is a negatively charged ion.
In formula III, R 2bExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy; R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group; R 1b, R 4bAnd R 5bIn one be R 12, and two other be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate, carboxylamine sugar; R 12Be (C 0-C 30) alkylidene group-G n, wherein, the one or more-CH in the described alkylidene group 2-residue can by-S-,-SO-, SO 2-,-O-,-NH-,-N (alkyl)-,-N (phenyl)-,-N (alkyl phenyl)-,-N +(alkyl) 2-,-N +(phenyl) 2-,-N +(alkyl phenyl) 2-,-C (=O)-,-C (=S), CH=CH-,-C=C-, phenylene or-N[(C=O) alkylidene group COOH]-replace; G is selected from-SO 3H ,-PO 3H 2,-O-PO 3H 2,-COOH ,-C (N=H) NH 2, polyol, sugar, glucosiduronate, carboxylamine sugar ,-N +R 6aR 7aR 8aX -With monocycle or dicyclo trialkyl ammonium alkyl residue; R 6aBe C 1-20Hydrocarbon; R 7aBe alkyl; R 8aBe alkyl; N is 1,2,3,4 or 5; X is a negatively charged ion.
In the compound of formula IV, R 1cAnd R 2cExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, hydroxyl amidino groups, guanidine radicals, dialkyl group guanidine radicals, phenyl, benzyl, phenoxy group, benzyloxy, glucosiduronate and the carboxylamine sugar; R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group; R 4cExpression be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-, two, three or four residues in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, glucosiduronate and the carboxylamine sugar; R 5fExpression be independently selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate, carboxylamine sugar and-N +R 6R 7R 8X -In one, two, three, four or five residues.
In the compound of formula V, R 1a, R 2aAnd R 4aExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH separately 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy; R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group; R 5cFor-Q-A-N +R 9R 10R 11X -Q be selected from direct key ,-O-,-S-,-NH-,-CH 2O-,-CH 2NH-,-C (=O) ,-CONH-,-NHCO-,-CH 2NH (C=O)-,-O (C=O)-,-(C=O) O-,-NHCONH-,-OCONH-and-NHCOO-; A is selected from C 2-20Hydrocarbon, carbonatoms are the substituted alkyl of 2-20, substituted aryl, substituted arylalkyl and C 4-50Oxa alkyl, and, when Q be direct key ,-C (=O) or-O (C=O)-time, A can also be methylene radical.
In formula VI, R 2bExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy; R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group; R 1d, R 4dAnd R 5dIn one be R 12a, and two other be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy glucose and R 12a
R 12For Perhaps work as R 5dBe R 12aThe time, R 12aAlso can be (C 0-C 30) alkylidene group-G n, wherein, the one or more-CH in the described alkylidene group 2-residue can by-S-,-SO-, SO 2-,-O-,-NH-,-N (alkyl)-,-N (phenyl)-,-N (alkyl phenyl)-,-N +(alkyl) 2-,-N +(phenyl) 2-,-N +(alkyl phenyl) 2-,-C (=O)-,-C (=S), CH=CH ,-C=C-, phenylene or-N[(C=O) alkylidene group COOH]-replace; G is selected from-SO 3H ,-PO 3H 2,-O-PO 3H 2,-COOH ,-C (N=H) NH 2, polyol, sugar, glucosiduronate, carboxylamine sugar ,-N +R 6AR 7aR 8aX -With monocycle or dicyclo trialkyl ammonium alkyl residue; R 13Be selected from direct key ,-C=C-,-OCH 2,-C (=O)-and-CHOH-; R 14Be selected from-OH and-OC (=O) alkyl; R 15Be selected from-CH 2OH ,-CH 2OC (=O) alkyl and-the COO-alkyl; J is 1,2,3,4 or 5; K is 0,1,2,3,4 or 5; N is 1,2,3,4 or 5.
In the compound of formula VII, R 1e, R 2aAnd R 4eBe selected from hydrogen, halogen, hydroxyl, low alkyl group, OCH independently of one another 3, OCF 2H, OCF 3, CH 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy; R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group; R 5eBe selected from
Figure A20048003969500591
(C 0-C 30) alkylidene group-G n, wherein, the one or more-CH in the described alkylidene group 2-residue can by-S-,-SO-, SO 2-,-O-,-NH-,-N (alkyl)-,-N (phenyl)-,-N (alkyl phenyl)-,-N +(alkyl) 2-,-N +(phenyl) 2-,-N +(alkyl phenyl) 2-,-C (=O)-,-C (=S), CH=CH ,-C=C-, phenylene or-N[(C=O) alkylidene group COOH]-replace.
A second aspect of the present invention is about a kind of pharmaceutical preparation, said preparation contains the pharmacology acceptable carrier and of the present inventionly has an acceptable opposite anionic compound of pharmacology, and said preparation also randomly contains one or more in the following material: (1) cholesteral biosynthesis inhibitor; (2) cholesteryl ester transfer protein (cholesterol ester transfer protein, CETP) inhibitor; (3) bile acid chelating agent; (4) nicotinic acid or derivatives thereof; (5) peroxysome hyperplasia factor activator receptor alpha agonists; (6) acyl-CoA: cholesterol acyltransferase (cholesterol acyltransferase, ACAT) inhibitor; (7) obesity control medicine; (8) hypoglycemic agents; (9) oxidation inhibitor; (10) anti-hypertension compound.
A third aspect of the present invention is about preventing and/or treating the method for the lipid metabolism disorders that comprises hyperlipidaemia, atherosclerosis and arteriosclerosis symptom; Inhibition is by the method that absorbs cholesterol in the intestines; Reduce the blood plasma of LDL cholesterol or the method for serum-concentration; The method of reducing cholesterol and the cholesteryl ester concentration in blood plasma or serum; Reduce C-activated protein (C-reactive protein, blood plasma CRP) or the method for serum-concentration; Reduce the blood plasma of tri-glyceride or the method for serum-concentration; Reduce the blood plasma of apolipoprotein B or the method for serum-concentration; Improve high-density lipoprotein (HDL) (high density lipoprotein, HDL) method of the blood plasma of cholesterol or serum-concentration; Improve the method for the defecate (fecal excretion) of cholesterol; Treatment needs the method for the clinical symptom of cholesterol absorption inhibitor treatment; Reduce the method for the generation of cardiovascular disorder dependent event; Gu reduce at least a non-cholesterol sterol or the blood plasma of 5 α-alkanol (stanol) or the method for tissue concentration; The method of treatment or prevention vascular inflammation; Prevent, treat or improve the method for Alzheimer symptom; At least a amyloid beta (amyloid β peptide) generation in blood flow and/or brain or the method for level that regulation and control are individual; The method of the amount of regulation and control ApoE isoform 4 in blood flow and/or brain; Prevent and/or treat the method for obesity; The method of the generation of prevention or minimizing xanthomatosis.These methods comprise and give compound described herein.
A fourth aspect of the present invention is about being used to prevent or the method and composition of the tumour that treatment is relevant with cholesterol.It comprises that the compound of the present invention with the treatment significant quantity gives the danger of tangible generating cholesterol related neoplasms or the patient who has shown the cholesterol related neoplasms.It comprises compound of the present invention and at least a other carcinostatic agent for the treatment of significant quantity simultaneously.
A fifth aspect of the present invention is about a kind of goods, and these goods comprise container, operation instruction and above-mentioned pharmaceutical preparation.This operation instruction is used to have the described pharmaceutical preparation that is selected from following purposes: prevention or treatment lipid metabolism disorders; Inhibition is by absorbing cholesterol in the intestines; Gu reduce the blood plasma or the tissue concentration of at least a non-cholesterol sterol or 5 α-alkanol; Reduce the blood plasma or the serum-concentration of LDL cholesterol; Reducing cholesterol or the cholesteryl ester concentration in blood plasma or serum; Improve the defecate of cholesterol; Reduce the incidence of cardiovascular disorder dependent event; Reduce the blood plasma or the serum-concentration of C-activated protein; Treatment or prevention vascular inflammation; Reduce the blood plasma or the serum-concentration of tri-glyceride; Improve the blood plasma or the serum-concentration of high density lipoprotein cholesterol; Reduce the blood plasma or the serum-concentration of apolipoprotein B; Prevent, treat or improve the Alzheimer symptom; The generation of regulation and control amyloid beta; The amount of regulation and control ApoE isoform 4 in blood flow and/or brain; Prevent and/or treat obesity; The incidence of prevention or minimizing xanthomatosis; And prevention or the treatment tumour relevant with cholesterol.
Embodiment
The represented compound of following formula Φ, Ψ and I-VII is by the inhibitor that absorbs cholesterol in the intestines.Therefore, they can be used for treatment and prevention lipid metabolism disorders such as hypercholesterolemia and hyperlipidaemia.Because the effect of these compounds in blood lipid reducing, they can be used for treatment and prevention of arterial sclerosis.Described compound can advantageously be used in combination with other lipid lowerers, and described other lipid lowerers comprises cholesteral biosynthesis inhibitor such as HMG CoA reductase inhibitor (HMG-CoA reductase inhibitor).The HMG-CoA reductase inhibitor comprises " Statins (statins) ": lovastatin, simvastatin (simvastatin), pravastatin, rochovastatin (rosuvastatin), Mevastatin, A Fatading (atorvatatin), Cerivastatin (cerivatatin), pitavastatin (pitavastatin), fluorine cuts down Chinese violet, shellfish is cut down his spit of fland (bervastatin), crilvastatin (crilvastatin), card cuts down his spit of fland (carvastatin), upright his spit of fland (rivastatin) of cutting down, this upright his spit of fland (sirrivastatin) of cutting down, glenvastatin (glenvastatin) and Dalvastatin (dalvastatin).The lipotropism matter that can be used in combination with compound of the present invention is crossed the further tabulation of example of multiple medicines referring to 5-6 hurdle and the WO04/004778 of US 6498156, and their disclosed contents are incorporated herein by reference at this.As mentioned above, said preparation can further contain at least a bile acid chelating agent.Described sequestrant comprises Colestyramine (cholestyramine), colestipol, hydrochloric acid colesevelam (colesevelam hydrochloride).Said preparation can also contain the nicotinic acid or derivatives thereof.Described nicotinic acid derivates comprises pentaerythritol tetranicotinate (niceritrol), nicofuranose (nicofuranose), Olbetam (acipimox).Said preparation can also contain peroxysome hyperplasia factor activator receptor alpha agonists.Peroxysome hyperplasia factor activator receptor alpha agonists can be Carboxymethylcellulose (fibric acid) derivative.Described fiber acid derivative comprises fenofibrate (fenofibrate), clofibrate (clofibrate), gemfibrozil (gemfibrozil), Win-35833 (ciprofibrate), bezafibrate (bezafibrate), S-8527 (clinofibrate), binifibrate (binifibrate) and lifibrate (lifibrol).Said preparation can also contain the CETP inhibitor.The example of CETP inhibitor is Nature.406, compound JTT-705 that confirms among (6792): the 203-7 (2000) and the Compound C P-529414 (torcetrapib) described in US 20030186952 and the WO2000/017164.The example of CETP inhibitor can also be referring to Current Opinion in Investigational Drugs.4 (3): 291-297 (2003).Said preparation can also contain the ACTA inhibitor.The example of ACTA inhibitor is the compound a vasimibe that confirms among Current Opinion inInvestigational Drugs.3 (9): the 291-297 (2003), and the Compound C L-277 among ClinPharmacol Ther.48 (2): the 189-94 (1990), 082.Said preparation can also contain the obesity control medicine.The example of obesity controller comprises internal organ hormone fragment peptide YY 3-36(PYY 3-36) (N.ENGL.J.Med.349:941,2003; IKPEAPGE DASPEELNRY YASLRHYLNLVTRQRY) or its variant, glucagon-like-peptide-1 (glucagon-like peptide-1, glp-1), exendin (inhibitor of glp-1), sibutramin (sibutramine), PHENTERMINE (phentermine), the two first morphines (phendimetrazine) of benzene, didrex (Didrex), orlistat (Xenical), hydrochloric acid diethyl propionic acid (Tenuate), fluoxetine (Prozac), Wellbutrin, Chinese ephedra (ephedra), chromium, gamboge (garcinia cambogia), benzocaine, black wrack (focusvesiculosus), chitosan, Herba Cassiae Nomamis (nomame herba), Galega officinalis L (Goat ' s Rue, FrenchLilac), conjugated linolic acid, the L-carnitine, fiber (this blue nurse grass (psyllium), psyllium (plantago), guar-bean (guar) fiber), caffeine, trans-dehydroandrosterone (dehydroepiandrosterone), cadbait (glue eel grass (teucrium chamaedrys)), B-hydroxy-beta-methylbutyrate, ATL-962 (Alizyme PLC), T71 (Tularik, Inc.; Boulder CO), motilin antagonist (a ghrelinantagonist), A Kangpu Leah [Acomplia, Rimonabant (rimonabant)], AOD9604, alpha-lipoic acid (alpha-lipoic acid, alpha-LA) and pyruvate (pyruvate).Said preparation can also contain hypoglycemic agents.The example of hypoglycemic agents comprises peroxysome hyperplasia factor activator agent receptor y agonist (for example, rosiglitazone (rosiglitazone), pioglitazone (pioglitazone), ciglitazone (ciglitazone); And metformin (metformin), phenformin (phenformin), carbutamide (carbutamide), tolbutamide (tolbutamide), acetohexamide (acetohexamide), tolazamide (tolazamide), P-607 (chlorpropamide), glyburide (glyburide) [glibenclamide], Glipizide (glipizide) and gliclazide (gliclazide)).Said preparation can also contain oxidation inhibitor.The example of oxidation inhibitor comprises probucol (probucol) and AGI-1067.
Said preparation can also contain anti-hypertension compound.The example of described anti-hypertension compound comprises thiazides derivative, Beta-3 adrenergic blocker, calcium channel blocker, angiotensin converting enzyme (angiotension-converting-enzyme, ACE) inhibitor and angiotensin II receptor antagonists.The example of described thiazides derivative comprises hydrochlorothiazide, chlorothiazide and polythiazide.The example of described Beta-3 adrenergic blocker comprises atenolol USP 23 (atenolol), metoprolol (metoprolol), Proprasylyte (propranolol), timolol (timolol), carvedilol (carvedilol), nadolol (nadolol) and bisoprolol (bisoprolol).The example of described calcium channel blocker comprises Isrodipine, verapamil, nitrendipine, amlodipine, nifedipine, nicardipine, Isrodipine, felodipine, nisoldipine and Odizem.The example of described angiotensin converting enzyme inhibitor comprises delapril, captopril, enalapril, lisinopril, quinapril, perindopril, benazepril, Trolapril, fosinopril, Ramipril and Ceranapril.The example of described angiotensin II receptor antagonists comprises Candesartan (candesartan), Irb (irbesartan), Olmesartan (olmesartan), telmisartan (telmisartan) and A Pushatan (aprosartan).
In one embodiment, preparation of the present invention contains compound of the present invention and Statins.In another embodiment, preparation of the present invention also contains the medicine that is selected from nicotinic acid, sequestrant and the Bei Te class.In another embodiment, preparation of the present invention contains compound of the present invention, Statins, nicotinic acid, sequestrant and Bei Te class.
The invention still further relates to the method for prevention or the treatment patient tumour relevant, the danger of the tumour that the tangible generating cholesterol of described patient is relevant or shown the tumour that cholesterol is correlated with cholesterol.Described tumour can be the optimum or malignant tumour of prostate gland, mammary gland, uterine endometrium and colon.Compound of the present invention can give with at least a other carcinostatic agent, described other carcinostatic agent can for steroid class antiandrogen, non-steroid class antiandrogen, oestrogenic hormon, diethylstilbestrol, conjugated estrogen hormone, selective estrogen receptor modulators (selective estrogen receptor modulator, SERM), Taxan (taxane) and LHRH (luteinizing hormone-releasing hormone (LRH)) analogue.PCT application WO 2004/010948 has provided the test of the ultimate principle of the effect that shows therapy and combination treatment, and the disclosed content of this application is incorporated herein by reference at this.
Therefore compound of the present invention can reduce the formation of intravital cholesterol levels and epoxy cholesterol, suppresses the optimum and malignant tumour relevant with cholesterol or the cell of being correlated with cholesterol is grown or the generation of cell lump and further developing.For example, composition disclosed herein can be used for treating and/or preventing benign prostatomegaly, can also treat and/or prevent the tumour relevant with prostate gland, colon, uterine endometrium or mammary tissue.
Composition of the present invention contains the above-claimed cpd of effective dose or pharmacology significant quantity or treatment significant quantity, and can contain at least a other carcinostatic agent, be used for the treatment of or prevent benign prostatomegaly or other and cholesterol-associated optimum or malignant tumour, especially relevant tumour with prostate gland, colon, uterine endometrium or mammary tissue.The example that can be used for the carcinostatic agent of method and composition of the present invention comprises steroid class antiandrogen or non-steroid class antiandrogen, as finasteride (PROSCA_), cyproterone (cyproterone acetate, CPA), flutamide (4 '-nitro-3 '-trifluoromethyl isobutyryl aniline), Bi Kalu amine (bicalutamide) (CASODEX_) and Nilutamide; Oestrogenic hormon, diethylstilbestrol (DES), conjugated estrogen hormone are (for example, PREMARIN_); Selective estrogen receptor modulators is as tamoxifen, raloxifene (raloxifene), droloxifene (droloxifene) and Chinese mugwort phenol of many former times (idoxifene); Taxan, as taxol (paclitaxel) (TAXOL_) and docetaxel (docetaxel) (TAXOTERE_); With the LHRH analogue, as goserelin acetate (ZOLADEX_) and hydrochloric acid Leuprolide (LUPRON_).
Method of the present invention is corresponding to composition and preparation.It comprises that azetidinone of the present invention one or more in following material with the treatment significant quantity need the patient of this treatment: (a) steroid class antiandrogen or non-steroid class antiandrogen; (b) oestrogenic hormon; (c) diethylstilbestrol (DES); (d) conjugated estrogen hormone; (e) selective estrogen receptor modulators; (f) Taxan; (g) LHRH analogue.Term " selective estrogen receptor modulators " comprises estrogen agonist and antagonist, is meant the compound that combines, suppresses bone conversion (bone turnover) and prevent bone to run off with estrogen receptor.Especially, estrogen agonist is for can be attached to the estrogen receptor site of mammalian tissues and to imitate the compound of the estrogen function in this tissue.Estrogen antagonist is for can be attached to the estrogen receptor site of mammalian tissues and to block the compound of the estrogen function in this tissue.The example of SERM comprises tamoxifen (US patent 4536516), 4-trans-Hydroxytamoxifen (US patent 4623660), raloxifene (US patent 4418068), Chinese mugwort phenol of many former times (idoxifene) (US patent 4839155) and droloxifene (droloxifene).Taxan can be referring to US patent 6395770,6380405 and 6239167.As mentioned above, azetidinone of the present invention can also be used in combination with steroid class antiandrogen or non-steroid class antiandrogen.
Specific compound of the present invention can have additional advantage: when oral, they suppress the level of serum cholesterol and/or LDL and himself obviously are not absorbed in the Mammals recycle system simultaneously.Therefore because it is not obvious that serum level is low to moderate, still less observe side effect such as medicine interacts.
Subclass according to the present invention comprises the compound of formula Φ and Ψ, and wherein, U is selected from-CH 2CH 2CH (OH)-,-SCH 2CH 2-,-S (O) CH 2CH 2-,-SCH 2C (=O)-,-SCH 2CH (OH)-, CH (OH) CH 2CH 2-and-(CH 2) 4-, the left end of this chain is the tie point with the azetidinone ring, the right-hand member of this chain is the tie point with phenyl ring.Other subclass of the compound of formula Φ and Ψ comprises Φ A and Ψ A.
Figure A20048003969500651
Further subclass comprises the compound of Φ A and Ψ A, wherein, has R 5Ring in contraposition,
For example:
Figure A20048003969500661
In another subclass, R 1Can be hydrogen or 4-fluorine; R 2Can be the 4-fluorine; And R 4Can be hydrogen or hydroxyl.In another subclass, R 4And R 5It all is hydroxyl.
Other subclass of the present invention comprises following compound: R wherein 1, R 1a, R 2, R 2a, R 4And R 4aBe independently selected from the compound of hydrogen, halogen, hydroxyl and methoxyl group; R 1, R 2, R 4And R 5Be selected from the compound of hydrogen, sugar, glucosiduronate and carboxylamine sugar; R 3Be selected from the compound of hydrogen and hydroxyl; R 4Or R 4aCompound for hydrogen; R 5Or R 5aBe selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, CF 3, alkyl sulphonyl and aryl sulfonyl compound.The example of the compound of formula II comprises wherein R 1a, R 4aAnd R 5aIn one be-Q-A-N +R 9R 10R 11X -Compound ,-Q-A-is selected from C 2-20Hydrocarbon ,-O-(C 2-20Hydrocarbon) ,-NH-(C 2-20Hydrocarbon) ,-NHCO-(C 2-20Hydrocarbon) and C 4-20Oxa alkyl.In these compounds, R 9, R 10And R 11Be (1) low alkyl group or benzyl, or (2) or R 9, R 10And R 11Form the diazabicyclooctane quaternary ammonium together:
Figure A20048003969500662
Perhaps (3) R 9, R 10And R 11Form the quinine quaternary ammonium (quinuclidiniumquat) that is shown below together:
Figure A20048003969500671
Compounds more of the present invention are quaternary salt, i.e. cationic.Therefore, they will exist with the form of salt.Other compound of formula I can contain alkali or sour residue, and the form that they can salt is existed.In the claims, the acid of mentioning comprises its salt.Therefore; for example; claimed 4 '-{ (2S; 3R)-3-[(3S) 3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } claim of-3 '-Hydroxybiphenyl-3-sulfonic acid also contained 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sodium sulfonate.Term " the acceptable salt of pharmacology " is meant the salt that has from the counter ion of the acceptable nontoxic bronsted lowry acids and bases bronsted lowry of pharmacology.When described compound contains quaternary ammonium (quat) or alkaline residue, be applicable to that the acceptable base addition salt of pharmacology of compound of the present invention comprises mineral acid, organic acid, and be the water (it generally provides hydroxide radical anion) under the situation of quaternary ammonium.Example comprises oxyhydroxide, acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, carbonate, camsilate (camphorsulfonate), Citrate trianion, esilate (ethanesulfonate), fumarate, gluconate, glutaminate, glycollate, bromide, muriate, isethionic acid ester (isethionate), lactic acid salt, maleate, malate, mandelate, mesylate, mucus hydrochlorate (mucate), nitrate, embonate (pamoate), pantothenate, phosphoric acid salt, succinate, vitriol, tartrate, trifluoroacetate, tosilate, vinegar aminobenzoic acid salt (acetamidobenzoate), adipate, alginate (alginate), para-aminosalicylic acid salt (aminosalicylate), anhydromethylene-citric acid salt (anhydromethylenecitrate), ascorbate salt, aspartate, Ca-EDTA salt, camphorate (camphorate), d-camphorsulfonic acid salt (camsylate), caprate, hexanoate, octylate, cinnamate, cyclamate (cyclamate), dichloroacetic acid salt, edetate (EDTA), ethanedisulphonate (edisylate), embonate (embonate), estolate, esilate (esylate), fluorochemical, formate, gentisate, gluceptate (gluceptate), glucuronic acid, glycerophosphate, glycollate, glycollylarsanilate, hexylresorcinate, hippurate (hippurate), Hydroxynaphthoate, iodide, Lactobionate (lactobionate), malonate, mesylate (mesylate), napadisylate, napsylate (napsylate), nicotinate (nicotinate), oleate, Orotate (orotate), oxalate, oxa-glutarate (oxoglutarate), palmitate, pectinic acid salt (pectinate), pectinic acid salt polymkeric substance, the phenylethyl barbiturate(s), picrate, Pidolic Acid salt (pidolate), propionic salt, thiocyanate-(rhodanide), salicylate, sebacate, stearate, tannate, theoclate, tosylate (tosylate) etc.When compound contains sour residue, the acceptable base addition salt of suitable pharmacology that is used for The compounds of this invention comprises ammonium, the metal-salt that obtains by aluminium, calcium, lithium, magnesium, potassium, sodium and zinc, perhaps by Methionin, N, the organic salt that N '-dibenzyl-ethylenediamin, chloroprocaine (chloroprocaine), choline, diethanolamine, quadrol, meglumine (N-methyl glucoside amine) and PROCAINE HCL, PHARMA GRADE (procaine) obtain.Other base addition salt comprises the base addition salt that is obtained by following material: methylarecaidin, arginine, barium, benzene bright (benethamine), N, N '-two benzyl Edamines (benzathine), trimethyl-glycine, bismuth, Clemizole, copper, dimethylethanolamine, diethylamine, DEAE diethylaminoethanol, epolamine, quadrol, iron, ferrous, glucosamine, glucosamine, Histidine, breathe out amine (hydrabamine), imidazoles, Isopropylamine, manganese, inferior manganese (manganous), methyl glucoside amine, morpholine, morpholine ethanol (morpholineethanol), the n-ethyl morpholine, the n-ethyl piperidine, piperazine, piperidines, versamid 900, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, trolamine and tromethane (tromethamine).
In the specific subclass compound of formula III, VI and VII, R 1bBe R 12R 2bAnd R 4bBe selected from hydrogen, halogen, hydroxyl and methoxyl group; R 12Be (C 6-C 20) alkylidene group-G, wherein, the one or more-CH in the described alkylidene group 2-residue can by-O-,-NH-,-N (alkyl)-,-C (=O)-or-CH=CH-replaces; G is selected from-SO 3H, polyol and sugar.In another embodiment, R 5Be R 12R 1, R 2And R 4Be selected from hydrogen, halogen, hydroxyl and methoxyl group; R 12Be (C 6-C 20) alkylidene group-G, wherein, the one or more-CH in the described alkylidene group 2-residue can by-O-,-NH-,-N (alkyl)-,-C (=O)-or-CH=CH-replaces; G is selected from-SO 3H, polyol and sugar.
Definition
In whole specification sheets, term and substituting group keep their definition.
Alkyl comprises straight chain hydrocarbon, branched-chain hydrocarbon, cyclic hydrocarbon structure and their combination.Unless special qualification the, this term are meant carbonatoms and are 20 or are lower than 20 alkyl.Low alkyl group is meant that carbonatoms is 1,2,3,4,5 and 6 alkyl.The example of low alkyl group comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl etc., is preferably methyl.Alkyl and alkylidene group are preferably C 20Or following (for example, C 1, C 2, C 3, C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, C 12, C 13, C 14, C 15, C 16, C 17, C 18, C 19, C 20).Cycloalkyl is the subclass of alkyl, comprises that carbonatoms is 3,4,5,6,7 and 8 cyclic hydrocarbon radical.The example of naphthenic hydrocarbon comprises cyclopropyl, cyclobutyl, cyclopentyl, norcamphane base (norbornyl), adamantyl (adamantyl) etc.
C 1-C 20Hydrocarbon (for example, C 1, C 2, C 3, C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, C 12, C 13, C 14, C 15, C 16, C 17, C 18, C 19, C 20) comprise alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl and their combination.Example comprises benzyl, styroyl, cyclohexyl methyl, camphoryl (camphoryl) and naphthalene ethyl.Term " phenylene " be meant the neighbour shown in the following formula,, the contraposition residue:
Alcoxyl (alkoxy) and alkoxyl group (alkoxyl) are meant that carbonatoms is that 1,2,3,4,5,6,7 or 8 the oxygen that passes through is connected to straight chain, side chain, the group of cyclic configuration and their combination on the precursor structure.Example comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, cyclohexyloxy etc.Lower alkoxy is meant the group that contains 1-4 carbon atom.Be preferably methoxyl group.
Oxoalkyl group (oxaalkyl) is meant the alkyl residue that wherein one or more carbon (and the hydrogen that links to each other) are replaced by oxygen.Example comprises methoxy propoxy-, 3,6,9-three oxygen decyls etc.Oxoalkyl group can be the common implication in this area (referring to Naming and Indexing of Chemical Substances forChemical Abstracts, American Chemical Society publishes), 196, and do not have The restriction of 127 (a)], that is, it is meant that oxygen wherein combines the compound of (formation ehter bond) with adjacent atom by singly-bound.Similarly, alkylthio (thiaalkyl) and azepine alkyl (azaalkyl) refer to that respectively wherein one or more carbon are by the alkyl residue of sulphur or nitrogen replacement.Example comprises ethylamino ethyl and methylthio group propyl group.
Polyol is meant compound or the residue with a plurality of-OH group.Polyol is appreciated that into the alkyl that a plurality of c h bonds are replaced by the C-OH key.The example of common polyol comprises glycerine, erythritol, Sorbitol Powder, Xylitol, N.F,USP MANNITOL and inositol.The empirical formula of linear poly-hydroxy residue is generally-C yH 2y+1O y, the empirical formula of ring-type poly-hydroxy residue is generally-C yH 2y-1O y, wherein, y is preferably 3,4,5 and 6.Cyclic polyhydroxy compound also comprises the sugar that is reduced, for example sorbitol.
Acyl group (acyl) is meant that carbonatoms is 1,2,3,4,5,6,7 or 8 saturated, unsaturated and aromatic group and their combination that the carbonyl functional group is connected to straight chain on the precursor structure, side chain, cyclic configuration of passing through.One or more carbon of acyl residue can be replaced by nitrogen, oxygen or sulphur, as long as remain on carbonyl with the tie point of precursor structure.Example comprises formyl radical, ethanoyl, propionyl, isobutyryl, tert-butoxycarbonyl, benzyl acyl group, benzyloxycarbonyl etc.Lower acyl is meant the group that contains 1-4 carbon.
Aryl and heteroaryl refer to that respectively aromatic ring or hetero-aromatic ring are as substituting group.Heteroaryl contains a kind of, two or three heteroatoms that is selected from oxygen, nitrogen or sulphur.The two all refers to five yuan of monocycles or hexa-atomic aromatic ring or hetero-aromatic ring, nine yuan or ten yuan aromatic rings of dicyclo or hetero-aromatic ring and three ring ten ternarys or ten quaternary aromatic ring or hetero-aromatic rings.The example of hexa-atomic, seven yuan, eight yuan, nine yuan, ten yuan, ten monobasics, ten binary, ten ternarys and ten quaternary carbon aromatic rings comprises benzene, naphthalene, indane, 1,2,3,4-tetraline and fluorenes, five yuan, example hexa-atomic, seven yuan, eight yuan, nine yuan and ten yuan hetero-aromatic rings comprise imidazoles, pyridine, indoles, thiophene, benzopyrone (benzopyranone), thiazole, furans, benzoglyoxaline, quinoline, isoquinoline 99.9, quinoxaline, pyrimidine, pyrazine, tetrazolium and pyrazoles.
Arylalkyl is meant the alkyl residue that is connected to aromatic ring.Example comprises benzyl, styroyl etc.
Substituted alkyl; aryl; cycloalkyl; heterocyclic radicals etc. are meant that three hydrogen atoms at the most of each residue wherein are by halogen; haloalkyl; hydroxyl; lower alkoxy; carboxyl; carbalkoxy (being also referred to as carbalkoxy); acid amides (being also referred to as alkyl amino carbonyl); cyano group; carbonyl; nitro; amino; alkylamino; dialkyl amido; sulfydryl; alkylthio; sulfoxide; sulfone; acyl amino; amidino groups; phenyl; phenmethyl; heteroaryl; phenoxy group; the alkyl that benzyloxy or heteroaryloxy (heteroaryloxy) are replaced; aryl; cycloalkyl; or heterocyclic radical.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " sugar " uses its common implication, as Hawley ' s Condensed Chemical Dictionary, 12 ThEdition, Richard J.Lewis, Sr.; Defined among the Van Nostrand Reinhold Co.New York.It contains any carbohydrate of being made up of one or two sucrose base.Monose (so-called simple sugars) is that the chain of 2-7 is formed by carbonatoms.A carbon ribbon has the aldehyde formula oxygen or the keto-acid oxygen that can be combined into acetal or ketal form.Remaining carbon generally has hydrogen atom and hydroxyl (perhaps hydroxyl protecting group, as acetic ester).The monose that can be regarded as " sugar " among the application comprises pectinose, ribose, wood sugar, ribulose, xylulose, ribodesose, semi-lactosi, glucose, seminose, fructose, sorbose, tagatose (tagatose), Fucose, 6-deoxyglucose (quinovose), rhamnosyl, mannoheptulose and sedoheptulose.Disaccharides comprises sucrose, lactose, maltose and cellobiose.Unless special the qualification, term " sugar " not only refers to D-sugar but also refer to L-sugar.Described sugar can also be protected.Sugar can connect (seeing US patent 5756470) by oxygen or connect (seeing PCT application WO 2002/066464) by carbon, and the two disclosed content is incorporated herein by reference at this.
The sugar or the C-glycosyl compound that are connected by the carbon that is reduced are also contained among the present invention.The sugar that is reduced (as sorbitol) that can be classified as polyol or sugar also is known as sugar alcohol (alditol).Sugar alcohol is the polyol with following general formula: HOCH 2[CH (OH)] nCH 2OH (in form can obtaining) by the carbonyl of reduction aldose.
Term " glucosiduronate " uses its common implication, is meant the glucoside of glucuronic acid.
Term " carboxylamine sugar " is meant that one or more hydroxyl derived monose, disaccharides or oligosaccharides for carbamate, especially phenylcarbamate and substituted phenylcarbamate (referring to people such as Detmers, Biochim Biophys.Acta 1486,243-252 (2000), the document is incorporated herein by reference at this).Carboxylamine sugar is preferably:
The example of the quaternary ammonium in the range of definition of monocycle or dicyclo trialkyl ammonium alkyl (trialkylammoniumal) residue comprises:
Term " prodrug " is meant active higher compound in vivo.Prodrug generally changes into medicine by the enzymatic action in mammiferous liver or the blood.Chemical compound lot of the present invention can not be absorbed in the systemic circulation by chemically modified, and activates in vivo by the intersexes of enzyme in chemical action (as the acid-catalyzed cleavage in the stomach) or the gi tract and microflora in this case.
When characterizing variable, once talked about R 9Can with A or R 10Form five yuan to seven-membered ring; R 10Can form two keys or and R with A 9Form five yuan to seven-membered ring; R 11Can form second five yuan to seven-membered ring.These rings can have various degrees of unsaturation (from being saturated to aromatics fully), can contain heteroatoms, and can be replaced by low alkyl group or alkoxyl group.
When characterizing variable, once talked about the R base as R 5Expression is independently selected from, two, three, four or five residues in the variable-definition tabulation.Following structrual description the implication of above-mentioned language.In this example, R 5Represent three residue :-CH 3,-OH and-OCH 3
Figure A20048003969500741
Described variable defines when introducing, and keeps this definition in whole specification sheets.Therefore, for example, R 3Always be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group, but according to the standard patent practice, in the dependent claims, R 3Can be restricted to the subclass of these values.Using superscript to distinguish those connects similar and has the residue of overlapping Ma Kushi group (Markush group).For example, be positioned at 1 of azetidinone and go up substituting group that the phenyl ring of (being on the nitrogen) links to each other and always remember and be R 1, still according to the member of the Ma Kushi group that defines, this substituting group can be R 1, R 1a, R 1bOr R 1cFor simplicity, when being multiple subordinate, dependent claims can be quoted R 1Deng.Be in order to limit the relevant variable R in each claim that it quotes like this 1, R 1a, R 1b, R 1cDeng suitable value.Therefore, and claim " as any described compound among the claim 1-8, wherein, R 1Be selected from hydrogen, halogen, hydroxyl and methoxyl group " be in order further to limit the corresponding R in the claim 6 1aCorresponding R in substituting group, the claim 7 1bCorresponding R in substituting group and the claim 8 1cSubstituting group.
Can recognize that compound of the present invention can exist with the radio-labeling form, compound promptly of the present invention can contain one or more atomic masses or total mass number and the different atom that exists naturally.The radio isotope of hydrogen, carbon, phosphorus, fluorine and chlorine comprises respectively 3H, 14C, 35S, 18F and 36Cl.Other the radioisotopic compound that contains these radio isotope and/or other atom also within the scope of the invention.Tritium promptly 3H and carbon-14 are promptly 14The C radio isotope is owing to being easy to preparation and surveying, and is therefore preferred especially.The radio-labeled compound of formula I-VIII of the present invention and prodrug thereof can use the method for well known to a person skilled in the art to be prepared.Easily, described radio-labeled compound can replace nonradioactive labeling's reagent to be prepared with the radio-labeling reagent that is easy to obtain by disclosed method in embodiment and the route map.
The meaning of term " method of treatment or prevention " is improvement, prevention or alleviation symptom relevant with lipid metabolism disorders and/or effect.Be meant at this used term " prevention " to give medicine in advance with prevention or relax acute events, perhaps under the situation of chronic disease, reduce the possibility or the seriousness of this illness.The those of ordinary skill of medical field (field that claim to a method of the present invention relates to) can recognize that term " prevention " is not an absolute concepts.At medical field, term " prevention " is construed as and prophylactically gives possibility or the seriousness of medicine fully to reduce illness, this applicant of the present invention just meaning in the claims.Comprise prevention (prophylaxis) this used " treatment " patient.In this application, many documents have been mentioned.These documents are incorporated herein by reference at this with its disclosed full content, just as writing out herein.
Term " Mammals " uses its meaning in dictionary.For example, term " Mammals " comprises mouse, hamster, rat, ox, sheep, pig, goat and horse, monkey, dog (for example, Canis), cat, rabbit, cavy and the primate that comprises the people.
As described in laid-open U.S. Patents application US 20030119757, described compound can be used for treatment or prevention vascular inflammation; As US patent 6080778 with as described in the laid-open U.S. Patents application US20030013699, described compound can be used for preventing, treating or improve the generation or the level of symptom, regulation and control amyloid beta and the ApoE isoform 4 of Alzheimer; As described in laid-open U.S. Patents application US 20030119809, described compound can be used for preventing or reducing the generation of xanthomatosis.The content of above-mentioned patent disclosure is incorporated herein by reference at this.
Compound described herein has two or more asymmetric centers, therefore can produce enantiomer, diastereomer and other stereoisomeric forms in any ratio.According to the absolute stereo chemistry, each chiral centre can be defined as (R)-or (S)-.The present invention includes all possible isomer and their racemic form and optically pure form.Optically active (R)-and (S)-isomer or (D)-and (L)-isomer can use chiral synthon or chiral reagent preparation, perhaps use routine techniques to split.When compound described herein has the two keys of alkene or other how much center of asymmetries, remove nonspecific qualification, described compound comprises E and Z geometrical isomer.Similarly, in all tautomers are also included within.
Diagram at the compound of this used racemize, ambiscalemic and scalemic or enantiomer-pure is taken from Maehr J.Chem.Ed.62,114-120 (1985): use real or empty wedge shape to represent the absolute configuration of chiral element; Wavy line and single thin line represent that there is not any stereochemistry problem in the key of its representative; Real or empty black body-line is the geometric description symbol, and the relative configuration shown in showing is still represented racemize character; Wedge profile and chain line or dotted line are represented the compound of the uncertain enantiomer-pure of absolute configuration.Therefore, formula XI comprises a pair of pure enantiomer:
Figure A20048003969500761
Be meant pure R, S:
Pure S, R:
Wherein,
Figure A20048003969500772
Be meant R, S and S, the racemic mixture of R promptly has trans relative configuration on the beta-lactam ring.
Term " mapping excessive (enatiomeric excess, ee) " has been conventionally known to one of skill in the art, and is defined as and is used for ab is split as a+b:
Term " mapping is excessive " relates to term " polarimetry purity " early, and the two measures same phenomenon.The value of ee is from 0 to 100 value, and 0 is racemize, and 100 is pure single enantiomer.The compound that before may be called 98% polarimetry purity is expressed as 96%ee now more accurately.In other words, 90%ee represents a kind of enantiomer of existence 95% in the measured material and 5% another kind of enantiomer.
The configuration that is chosen in the carbon-carbon double bond of this appearance just is not in order to specify specific configuration, therefore, can be Z, E or the two mixture with arbitrary proportion at this carbon-carbon double bond that optionally is described as E for convenience's sake.
The term of " protection (protecting) ", " removing protection (deprotecting) " and " shielded (protected) " functional group appears relating in whole application.This term has been understood well by those skilled in the art, uses under the situation that relates to the method for handling in succession with a series of reagent.In these cases, blocking group be meant be used for in treating processes if the group of not protecting functional group that undesirable reaction then will take place to shelter.The blocking group prevention still can be removed to expose primary functional group subsequently in the reaction of this step.After finishing, the reaction that described functional group may get involved carries out described removing or " removing protection ".Therefore, when as in the method for the invention when having specified the order of reagent, those of ordinary skill in the art is easy to expect being suitable as the group of " blocking group ".The suitable group that is used for this purpose has description at the standard textbook of chemical field, as the Protective Group in Organic Synthesis[John Wiley ﹠amp that T.W.Greene showed; Sons, New York, 1991], it is incorporated herein by reference at this.Should be specifically noted that " Protection for the Hydroxyl Group, Including 1,2-and 1,3-Diols " these several chapters (10-86 page or leaf).
Initialism Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifyl, tosyl group and methylsulfonyl respectively.The comprehensive tabulation of the initialism that the organic chemist uses is referring to each first phase of Journal of Organic Chemistry.This tabulation is generally the form of title for " Standard List of Abbrevations ", is incorporated herein by reference at this.
Although the compound of formula Φ, Ψ and I-VIII can be taken with unprocessed chemical substance, be preferably the form that is prepared as pharmaceutical composition.According to a further aspect, the invention provides pharmaceutical composition, this pharmaceutical composition contains compound or their pharmacological-acceptable salt or the solvate of formula Φ, Ψ or I-VIII, and their one or more pharmaceutical carriers, and one or more optional other therapeutic components.Described carrier must be that the meaning of " acceptable " is must be compatible with other composition in the preparation and harmless to its recipient.
Described preparation comprises the preparation that is suitable for oral administration, non-enteron aisle (comprising subcutaneous, intracutaneous, intramuscular, intravenously and intraarticular) administration, rectal administration and part (comprise skin, contain clothes, hypogloeeis and intraocular) administration.Can select only route of administration according to recipient's illness and disturbance state.Preparation can exist with unit dosage form easily, and can be prepared with the known any method of pharmaceutical field.All methods all comprise the compound of formula Φ, Ψ or I-VIII or the acceptable salt of their pharmacology or solvate (" activeconstituents ") and the carrier-bound step that constitutes one or more attachment components.Usually, described preparation prepares by following steps: the solid carrier of activeconstituents and liquid carrier or high dispersing or the two are evenly combined nearly, if necessary product is configured as required preparation then.
The preparation that is suitable for oral administration of the present invention can be discrete unit such as capsule, cachet or the tablet that contains the predetermined amount activeconstituents separately; Powder or granule; Solution in waterborne liquid or the non-aqueous liquid or suspensoid; Perhaps oil-in-water-type liquid emulsion or water-in-oil-type liquid emulsion.Activeconstituents also can be bolus, electuary or paste.
Tablet can randomly make by compacting or moulding with one or more attachment components.Compressed tablets randomly is mixed with the free-flowing form of tackiness agent, lubricant, inert diluent, lubricant, tensio-active agent or dispersion agent such as powder or particulate activeconstituents by compacting in suitable machine and makes.The moulding tablet is by will being made by the mixture forming of the wetting powder compounds of inertia liquid diluent in suitable machine.Tablet can be by randomly dressing or indentation (score), and can prepare described tablet so that activeconstituents wherein continues to discharge, postpones to discharge or discharge controllably.
Pharmaceutical composition can comprise " the acceptable inert support of pharmacology ", this expression comprises one or more inert excipients, and described inert excipient comprises starch, polyol, granulating agent, Microcrystalline Cellulose, thinner, lubricant, tackiness agent, disintegrating agent etc.If desired, the tablet of disclosed composition can be used the water or the non-water technology coatings of standard, and " pharmacology acceptable carrier " also comprises the controlled release means.
Composition of the present invention can also randomly contain other therapeutic component, anti-caking agent, sanitas, sweeting agent, tinting material, flavour agent, siccative, softening agent, dyestuff etc.Certainly these optional ingredients must be compatible with compound of the present invention, to guarantee described stability of formulation.
The example that is used as the vehicle of pharmacology acceptable carrier, the acceptable inert support of pharmacology and aforesaid extra composition includes but not limited to:
Tackiness agent: W-Gum, yam starch, other starch, gelatin, natural or synthetic gum such as Sudan Gum-arabic, sodium alginate, Lalgine (alginic acid), other alginates, Powdered tragacanth gum (powdered tragacanth), guar gum, Mierocrystalline cellulose and derivative thereof are (as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, Xylo-Mucine), polyvinylpyrrolidone, methylcellulose gum, pregelatinized Starch is (for example by Colorcon, Ltd. STARCH 1500_ of Chu Shouing and STARCH 1500LM_), Vltra tears, Microcrystalline Cellulose (for example, by FMCCorporation, Marcus Hook, PA, the AVICEL that USA sells TM, as AVICEL-PH-101 TM,-103 TMWith-105 TM) or their mixture;
Weighting agent: talcum, lime carbonate (for example particle or powder), secondary calcium phosphate, calcium phosphate, calcium sulfate (for example particle or powder), Microcrystalline Cellulose, powdery cellulose, dextrates (dextrates), kaolin, N.F,USP MANNITOL, silicic acid, sorbyl alcohol, starch, pregelatinized Starch or their mixture;
Disintegrating agent: agar-agar, Lalgine, lime carbonate, Microcrystalline Cellulose, croscarmellose sodium (croscarmellose sodium), polyvinylpolypyrrolidone (Crospovidone), Polacrilin potassium (Polacrilin Potassium), Explotab, potato or tapioca (flour), other starch, pregelatinized Starch, clay, other phycocolloid (algins), other Mierocrystalline celluloses, natural gum or their mixture;
Lubricant: calcium stearate, Magnesium Stearate, mineral oil, light mineral oil, glycerine, sorbyl alcohol, N.F,USP MANNITOL, polyoxyethylene glycol, other dibasic alcohol, stearic acid, sodium lauryl sulphate, talcum, hydrogenated vegetable oil is (as peanut oil, Oleum Gossypii semen, Trisun Oil R 80, sesame oil, sweet oil, Semen Maydis oil and soybean oil), Zinic stearas, ethyl oleate, Laurate ethyl, agar, silicate (syloid) silica gel (AEROSIL200, W.R.Grace Co., Baltimore, MD USA), agglomerative aerosol (the Degussa Co. of synthetic silica, Plano, TX USA), pyrogenic silica (CAB-O-SIL, Cabot Co., Boston, MA USA), perhaps their mixture;
Anti-caking agent: Calucium Silicate powder, Magnesium Silicate q-agent, silicon-dioxide, colloid silica, talcum or their mixture;
Biocide: benzalkonium chloride, benzethonium chloride, phenylformic acid, phenylcarbinol, butyl p-hydroxybenzoate, cetylpyridinium chloride, cresols, butylene-chlorohydrin, dehydrogenation acetic acid, ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, phenol, phenylethyl alcohol, Phenylmercuric Acetate, Phenylmercurinitrate, potassium sorbate, propylparaben, Sodium Benzoate, sodium dehydroacetate, Sodium Propionate, Sorbic Acid, thimersol, Thymus vulgaris (thymo) or their mixture; And
Drug coating: Xylo-Mucine, cellulose acetate-phthalate, ethyl cellulose, gelatin, pharmaceutical glaze (pharmaceutical glaze), hydroxypropylcellulose, Vltra tears, hydroxypropylmethylcellulose phthalate, methylcellulose gum, polyoxyethylene glycol, polyvinyl acetate phthalic ester (polyvinyl acetate phthalate), shellac, sucrose, titanium dioxide, palm wax, Microcrystalline Cellulose or their mixture.
Adult oral dosage is generally 0.005 milligram-10 gram/sky.The present invention can contain a certain amount of compound of the present invention usually easily with tablet or other formulation that discrete unit provides, described compound is effective under this dosage or its multiple, for example, described unit contains 5 milligrams-500 milligrams, is generally about 10 milligrams-200 milligrams.The accurate amount that gives patient's compound is decided by the doctor in charge.Yet the dosage of use will be by following factor decision, the definite situation and the severity thereof of the disorder that comprise patient's age and sex, will treat.
Conjoint therapy can be by giving two or more medicines of preparing separately or realizing by two or more medicines that give in same preparation.Conjoint therapy also comprises other integrated processes.For example, two kinds of medicines are prepared together, take with the independent preparation that contains the third medicine then.Although described two or more medicines in the conjoint therapy can be taken simultaneously, and nonessential.For example, first kind of medicine (the perhaps combination of medicine) can be at second kind of medicine (the perhaps combination of medicine) several minutes, several days or take in a few week before.Therefore, described two or more medicines can be in several minutes each other, in each other 1,2,3,6,9,12,15,18 or 24 hour, in each other 1,2,3,4,5,6,7,8,9,10,12,14 day, perhaps in 2,3,4,5,6,7,8,9 or 10 weeks each other, take.In some cases, at interval may be longer.In many cases, two or more medicines of using in the conjoint therapy are suitable for being present in simultaneously in patient's body, but this is also nonessential.Conjoint therapy can also comprise twice or repeatedly take one or more used in conjoint therapy medicines.For example,, can take successively with arbitrary combination by one or many so if conjoint therapy uses medicine X and medicine Y, for example, in the following order: X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y etc.
Use rat cholesterol absorption model (Rat Cholesterol Absorption Model) to analyze intravital hypolipemia medicine.This model is based on by (2002) such as Burnett, Bioorg, Med.Chem.Lett.2002 Feb 11; 12 (3): 315-8 and J.Lipid Res.1999 Oct; 40 (10): the described model of 1747-57.Body weight is that the female Sprague-Dawley rat of 150-250 gram is divided into 3 groups and overnight fasting.Test compounds in animal (4-6/group) oral 300 microlitre sweet oil or other suitable carrier.After 30 minutes, every oral 3-5 microcurie in 300 microlitre sweet oil of rat 3The H-cholesterol.After three hours, collect 200 microlitre serum, use the scintillating liquid vortex, and in scintillometer, measure radioactivity.Suppress percentage and be defined as 100 * (1-C Test/ C Contrast), wherein, C TestAnd C ContrastBe meant the use test compound respectively and have only in the serum of contrast of carrier 3The H level.Measure the inhibition percentage numerical value of fixed dosage.ED 50Be meant in the given test compounds serum 3The H level is the dosage of a half of highest level.
Use mouse cholesterol absorption model (Mouse Cholesterol Absorption Model) to analyze intravital hypolipemia medicine.Body weight is that the female CD-1 mouse of 20-30 gram is divided into 3-8 group and overnight fasting.Animal (3-8/group) test compounds of oral 200 microlitres in sweet oil or other suitable carrier.After 30 minutes, every oral 3-5 microcurie of mouse is in 200 microlitre sweet oil 3The H-cholesterol.After three hours, collect 100 microlitre serum,, and in scintillometer, measure radioactivity with the scintillating liquid vortex.Suppress percentage and ED 50Definition such as above rat cholesterol absorption model.
Use the hyperlipidemia hamster to analyze intravital hypolipemia medicine.Hamster is divided into six groups and feed with the in check diet of cholesterol (Purina Chow#5001 contains 0.5% cholesterol) and to raise 7 days.The monitoring diet consumption is to measure the exposure of dietary cholesterol exposure in face of test compounds.Raise from feeding, to take one time test compounds every day for animal.Per os tube feed dosage is 0.2 milliliter the Semen Maydis oil (control group) or the solution (or suspension) of 0.2 milliliter of test compounds and Semen Maydis oil.All animals dying or the physical condition difference are implemented euthanasia.After seven days, make Animal Anesthesia by his life of intramuscular (IM) injection gram, and with disconnected first sacrifice of animal.Collect blood in the valve tube (vacutainer tube) that contains EDTA with the analysed for plasma lipid, hepatectomize and organize lipid with analysis.According to Schnitzer-Polokoff, Comp.Biochem.Physiol. such as R., 99A, 4,665-670 (1991) disclosed method is analyzed lipid, and the data note is done lipid decrement compared with the control.
Use the acute cholesterol absorption model of hamster (Hamster Acute Cholesterol AbsorptionModel) to analyze intravital hypolipemia medicine.Body weight is that the male Syria hamster of 120 grams is divided into 3-6 group and overnight fasting.Animal (3-6/group) test compounds of oral 200 microlitres in sweet oil or other suitable carrier.After 30 minutes, every mouse is oral in 3-5 microcurie 200 microlitre sweet oil 3The H-cholesterol.After three hours, collect 100-200 microlitre serum,, and in scintillometer, measure radioactivity with the scintillating liquid vortex.Suppress percentage and ED 50Definition such as above rat cholesterol absorption model.
People's such as use Hilgers Caco-2 cell monolayer model [Pharm.Res.7,902 (1990)] is measured the bio-absorbable of compound described herein.
Pharmacokinetics:, use rat to carry out bioavailability study in order to study the pharmacokinetics of compound.Compound is become appropriate formulations: contain 5% alcoholic acid sweet oil and be used for oral; The water that contains the 2%DMSO:20% cyclodextrin is used for vein and gives.Intravenously gives the CD rat (200-250 gram) of independent groups to compound by tail vein injection, and perhaps per os gives the CD rat (200-250 gram) of independent groups by gavage.Collect serum at different time points, use the existence of LC/MS/MS detection method analysis of compounds.Use contains the water of 30% acetonitrile with 15 times of diluted samples, use sample extraction sampler (sample extraction cartridge) (Waters Oasis HLB Direct Connect) to be expelled in the water that contains 5% methyl alcohol that flow velocity is 3.2 ml/min then, washed 30 seconds, be loaded into reversed-phase HPLC post (50 * 2.1 millimeters of Thermo Electron Betasil C18 Pioneer, 5 microns of particle diameters) then.Sample is from reversed-phase HPLC post gradient elution (mobile phase A: the dH that contains the 5mM ammonium acetate 2O, Mobile phase B: the acetonitrile that contains 20% methyl alcohol; From the 40%B gradient to 95%B and kept 3 minutes, get back to starting condition then and made the pillar balance 1 minute in 4 minutes, flow velocity is 0.3 ml/min).Use Micromass Quattro Micro (the Waters Corp. that operates under the MRM pattern; Milford, MA) three sections quadrupole tandom mass spectrometers detect.Normal concentration curve with compound is a basic calculation concentration.Use MassLynx software (WatersCorp.; Milford MA) calculates the absolute concentration of the test compounds in each serum sample.By Microsoft Excel, Summit Software PK Solutions 2.0 or GraphPad Prism (GraphPad Software, Inc., San Diego, the data that obtain in CA) generate concentration and time relation figure, with generation pharmacokinetics curve.For the animal that oral and intravenously is taken, use trapezoidal method by software by the data computation area under a curve (AUC of concentration to the time n, n for the test time, minute or hour).Bioavailability (F) between equation below using calculates at the trial:
F=(AUC Oral* Dose Intravenously)/(AUC Intravenously* Dose Oral)
Use above-mentioned rat cholesterol absorption model measurement representational compound of the present invention.Compound of the present invention shows restraining effect as shown in Table 1 and Table 2.
Table 1
Figure A20048003969500851
1Inhibiting rate % during 10 mg/kg
2Inhibiting rate % during 3 mg/kg
3Inhibiting rate % during 5 mg/kg
Figure A20048003969500861
Figure A20048003969500871
Table 2
Figure A20048003969500882
4The tie point with azetidine represented in asterisk
Figure A20048003969500891
50.1 the inhibiting rate % during mg/kg
60.3 the inhibiting rate % during mg/kg
Figure A20048003969500901
Usually, compound of the present invention can use the parent material, reagent and the conventional synthesis step that are easy to obtain to prepare by total reaction scheme as follows or the described method of its modification.In these reactions, can use they self variant known but not described here.
When parent material is suitable substituted azetidinone, can passes through the method described in WO 02/50027, WO 97/16424, WO 95/26334, WO 95/08532 and the WO 93/02048 and obtain.These apply for that disclosed content is incorporated herein by reference at this.
Show the method that is used to obtain compound of the present invention below.Although the detailed of each embodiment that does not provide in table 1 and the table 2 synthesized, following step has been described described method.Other compound uses the synthetic similar mode with the compound that is exemplified to prepare.
Embodiment
Embodiment 1 preparation intermediates 4-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } the phenyl trifluoromethanesulfonate methanesulfonates
(3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-(150.4 milligrams of 4-(4-hydroxyphenyl) azetidines-2-ketone, 0.367 milli rubs) and 4-methylamino pyridine (9.4 milligrams, 0.077 rub in the least) be dissolved in methylene dichloride (10.0 milliliters).Use syringe to add triethylamine (100 microlitres, 72.6 milligrams, 0.717 milli rubs), add solid N-phenyl trifluoromethanesulfonate methylsulfonyl imines (N-phenyltrifluoromethanesulfonimide) (143.6 milligrams, 0.402 milli rubs) then.At room temperature stirring reaction is 3.5 hours, pours (40 milliliters) in the water then into and extracts with 1: 1 ethyl acetate and hexane (75 milliliters).Water (40 milliliters) and salt solution (40 milliliters) washing organic layer, dry on sodium sulfate then, filter, concentrate, and, obtain 4-{ (2S for transparent film (finally becoming white solid) with chromatography (12 gram silica gel, 10% to 90% ethyl acetate-hexane) purifying, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } phenyl trifluoromethanesulfonate methanesulfonates (190.8 milligrams, yield 96%); 121.6 ℃ of fusing points; R f(0.38 2: 3 ethyl acetate-hexanes); 1H NMR (300MHz, CDCl 3) δ 7.41 (d, J=8.7Hz, 2H), 7.31-7.26 (m, 4H), 7.19 (dd, J=9.0,4.6Hz, 2H), 7.01 (t, J=8.7Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 4.71 (t, J=6.0Hz, 1H), 4.67 (d, J=2.3Hz, 12H), 3.10-3.04 (m, 1H), 2.08-1.86 (m, 4H) ppm; MS[M-OH] 524.5
Embodiment 2 preparations (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 '-Hydroxybiphenyl-4 base) azetidine-2-ketone
4-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } (162.5 milligrams of phenyl trifluoromethanesulfonate methanesulfonates, 0.30 milli rubs) and four (triphenyl phosphine) palladium (0) (17.3 milligrams, 0.015 rub in the least) be dissolved in toluene (2.5 milliliters).Add 2.0M wet chemical (0.3 milliliter) and contain the ethanolic soln (1.0 milliliters) of 4-hydroxyphenyl boric acid (57.9 milligrams, 0.42 rubs in the least).The vigorous stirring reaction is 5 hours under reflux temperature and in the nitrogen atmosphere, water (2.5 milliliters) dilution then, extract with ethyl acetate (3 * 10 milliliters), wash with salt solution (10 milliliters), dry on sodium sulfate, filter, concentrate, and with chromatography (12 the gram silica gel, 10% to 100% ethyl acetate-hexane) purifying, obtain for transparent film (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 '-Hydroxybiphenyl-4 base) azetidine-2-ketone (112 milligrams, yield 77%); 110 ℃ of fusing points; R f(0.5 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.5 (d, J=9.0Hz, 2H), 7.4 (d, J=9.0Hz, 2H), 7.3 (m, 6H), 6.9 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.15 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS[M+H] 486.5
Use identical method to obtain:
Embodiment 3 (3R, 4S)-4-xenyl-4-base-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Figure A20048003969500931
For transparent film (3R, 4S)-4-xenyl-4-base-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone (11.8 milligrams, yield 54%); Use chromatography (4 gram silica gel, 10% to 100% ethyl acetate-hexane) and reversed-phase HPLC (21 millimeters posts, 50% to 100% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying; R f(0.47 3: 2 ethyl acetate-hexanes); 1HNMR (300MHz, CD 3OD) δ 7.63 (d, J=8.3Hz, 2H), 7.61-7.58 (m, 2H), 7.45-7.39 (m, 4H), 7.35-7.28 (m, 5H), 7.02 (t, J=8.8Hz, 2H), 7.00 (t, J=8.8Hz, 2H), 4.63 (t, J=5.7Hz, 1H), 3.15-3.00 (m, 1H), 2.05-1.84 (m, 5H) ppm; MS[M-OH] 452.5
Embodiment 4 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-4 base) azetidine-2-ketone
For nearly pure white (off white) solid (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-4 base) azetidine-2-ketone (110 milligrams, yield 76%, 4 hours reaction times); With chromatography (12 gram silica gel, 10% to 100% ethyl acetate-hexane) purifying; 107 ℃ of fusing points; R f(0.5 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.6 (d, J=8.9Hz, 2H), 7.3 (d, J=8.9Hz, 2H), 7.2 (m, 6H), 6.9 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.15 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS[M+H] 486.5
Embodiment 5 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 '-methoxyl biphenyl base-4 base) azetidine-2-ketone
Figure A20048003969500942
For white solid (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 '-methoxyl biphenyl base-4 base) azetidine-2-ketone (86 milligrams, yield 67%, 16 hours reaction times); With chromatography (12 gram silica gel, 10% to 100% ethyl acetate-hexane) purifying; 103 ℃ of fusing points; R f(0.75 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.4 (m, 4H), 7.3 (m, 6H), 6.9 (m, 6H), 4.75 (m, 1H), 4.65 (s, 1H), 3.85 (s, 3H), 3.2 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS[M-OH] 482.5
Embodiment 6 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(6-Hydroxybiphenyl-3-yl) azetidine-2-ketone
Figure A20048003969500951
For white solid (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(6-Hydroxybiphenyl-3-yl) azetidine-2-ketone (36 milligrams, yield 40%, 16 hours reaction times); With chromatography (12 gram silica gel, 10% to 100% ethyl acetate-hexane) purifying; 113 ℃ of fusing points; R f(0.70 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.5-6.9 (m, 16H), 4.75 (m, 1H), 4.65 (s, 1H), 3.2 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS[M+H] 486.5
Embodiment 7 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2 '-Hydroxybiphenyl-4-yl) azetidine-2-ketone
For white solid (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2 '-Hydroxybiphenyl-4-yl) azetidine-2-ketone (74 milligrams, yield 51%, 2 hours reaction times); With chromatography (12 gram silica gel, 10% to 100% ethyl acetate-hexane) purifying; 101 ℃ of fusing points; R f(0.50 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.6 (d, J=9.0Hz, 2H), 7.4 (d, J=9.0Hz, 2H), 7.25 (m, 6H), 6.9 (m, 6H), 6.3 (s, 1H), 4.65 (m, 2H), 3.1 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS[M+H] 486.5
Embodiment 8 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4 '-(methylsulfonyl) xenyl-4 base] azetidine-2-ketone
Figure A20048003969500961
For white solid (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4 '-(methylsulfonyl) xenyl-4 base] azetidine-2-ketone (80 milligrams, yield 79%, 4 hours reaction times); With chromatography (12 gram silica gel, 10% to 100% ethyl acetate-hexane) purifying; 111 ℃ of fusing points; R f(0.40 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 8.1 (d, J=9.3Hz, 2H), 7.8 (d, J=9.3Hz, 2H), 7.6 (d, J=8.1Hz, 2H), 7.5 (d, J=8.1Hz, 2H), 7.3 (m, 5H), 6.9 (m, 3H), 6.3 (s, 1H), 4.7 (m, 1H), 4.6 (s, 1H), 3.1 (s, 4H), 2.1-1.9 (m, 4H) ppm; MS[M-OH] 530.6
Embodiment 9 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 ', 4 ', 5 '-trimethoxy xenyl-4-yl) azetidine-2-ketone
Figure A20048003969500971
For white solid (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 ', 4 ', 5 '-trimethoxy xenyl-4-yl) azetidine-2-ketone (93 milligrams, yield 90%, 2 hours reaction times); With chromatography (12 gram silica gel, 10% to 100% ethyl acetate-hexane) purifying; 103 ℃ of fusing points; R f(0.4 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.6 (d, J=9.0Hz, 2H), 7.5 (d, J=9.0Hz, 2H), 7.3 (m, 4H), 7.0 (m, 4H), 6.8 (s, 2H), 4.7 (m, 1H), 4.6 (s, 1H), 3.9 (s, 9H), 3.1 (s, 1H), 2.1-1.9 (m, 4H) ppm; MS[M-OH] 542.6
Embodiment 10 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3 '-(methylsulfonyl) xenyl-4-yl] azetidine-2-ketone
For white solid (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3 '-(methylsulfonyl) xenyl-4-yl] azetidine-2-ketone (92 milligrams, yield 90%, 2 hours reaction times); With chromatography (12 gram silica gel, 10% to 100% ethyl acetate-hexane) purifying; 104 ℃ of fusing points; R f(0.45 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 8.2-6.8 (m, 15H), 4.7 (m, 1H), 4.65 (s, 1H), 3.2 (m, 1H), 3.1 (s, 3H), 2.1-1.9 (m, 4H) ppm; MS[M-OH] 530.6
Embodiment 11 (3R, 4S)-4-(2 ', 3 '-dimethoxy xenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
For white solid (3R, 4S)-4-(2 ', 3 '-dimethoxy xenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone (132.0 milligrams, yield 90%, 2 hours reaction times); With chromatography (12 gram silica gel, 10% to 100% ethyl acetate-hexane) purifying; 101 ℃ of fusing points; R f(0.70 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.6 (d, J=8.5Hz, 2H), 7.4 (d, J=8.5Hz, 2H), 7.3 (m, 5H), 7.0 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.9 (s, 3H), 3.7 (s, 3H), 3.3 (s, 1H), 2.1-1.9 (m, 4H) ppm; MS[M-OH] 512.6
Embodiment 12 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-methoxymethyl biphenyl base-4-yl) azetidine-2-ketone
For transparent foaming (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-methoxymethyl biphenyl base-4-yl) azetidine-2-ketone (36.1 milligrams, yield 77%); With chromatography (12 gram silica gel, 5% to 95% ethyl acetate-hexane) purifying; R f(0.52 40% ethyl acetate-hexane); 1HNMR (300MHz, CDCl 3) δ 7.58 (d, J=8.7Hz, 2H), 7.30 (m, 7H), 7.15 (dt, J=13.5,1.5Hz, 1H), 7.09 (t, J=2.4Hz, 1H), 7.00 (t, J=10.4Hz, 2H), 6.92 (m, 3H), 4.73 (t, J=6.2Hz, 1H), 4.67 (d, J=2.1Hz, 1H), 3.86 (s, 3H), 1.95 (m, 4H); MS[M-OH] 482.5
Embodiment 13 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-formaldehyde
Figure A20048003969500992
For 4 ' of transparent foaming-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-formaldehyde (32.7 milligrams, yield 67%); With chromatography (12 gram silica gel, 5% to 95% ethyl acetate-hexane) purifying; R f(0.72 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 10.09 (s, 1H), 8.09 (d, J=1.8Hz, 1H), 7.85 (m, 2H), 7.62 (m, 3H), 7.44 (d, J=7.8Hz, 2H), 7.27 (m, 4H), 7.03 (t, J=8.6Hz, 2H), 6.95 (t, J=8.8Hz, 2H), 4.74 (m, 1H), 4.70 (d, J=2.4Hz, 1H), 3.14 (m, 1H), 1.95 (m, 4H) ppm; MS[M-OH] 480.5
Embodiment 14 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-nitrile
For 4 ' of transparent foaming-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-nitrile (32.5 milligrams, yield 57%); With chromatography (12 gram silica gel, 5% to 95% ethyl acetate-hexane) purifying; R f(0.69 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.84 (m, 1H), 7.79 (m, 1H), 7.64 (m, 1H), 7.55 (m, 3H), 7.44 (d, J=6.6Hz, 2H), 7.28 (m, 4H), 7.02 (t, J=8.9Hz, 2H), 6.95 (t, J=8.9Hz, 2H), 4.75 (t, J=6.2Hz, 2H), 4.68 (d, J=2.1Hz, 1H), 3.13 (m, 1H), 2.01 (m, 4H) ppm; MS[M-OH] 477.5
Embodiment 15 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-N, N-dimethyl diphenyl base-4-sulphonamide
Figure A20048003969501011
For 4 ' of weak yellow foam-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-N, N-dimethyl diphenyl base-4-sulphonamide (39.6 milligrams, yield 73%); With chromatography (12 gram silica gel, 5% to 95% ethyl acetate-hexane) purifying; R f(0.50 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.83 (d, J=5.4Hz, 2H), 7.72 (d, J=8.1Hz, 2H), 7.61 (D, J=8.1Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.25 (m, 4H), 7.02 (t, J=8.4,9.0Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 4.74 (t, J=5.5Hz, 1H), 4.69 (d, J=1.8Hz, 1H), 3.13 (m, 1H), 2.75 (s, 6H), 2.01 (m, 4H) ppm; MS[M-OH] 559.7
Embodiment 16 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-(methylol) xenyl-4-yl) azetidine-2-ketone
For transparent foaming (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-(methylol) xenyl-4-yl) azetidine-2-ketone (37.3 milligrams, yield 80%); With chromatography (12 gram silica gel, 5% to 95% ethyl acetate-hexane) purifying; R f(0.43 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.59 (m, 3H), 7.49 (m, 2H), 7.37 (m, 3H), 7.27 (m, 4H), 7.02 (t, J=8.7Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 4.74 (m, 1H), 4.67 (d, J=2.4Hz, 1H), 3.14 (m, 1H), 1.99 (m, 4H) ppm; MS[M-OH] 482.5
Embodiment 17 (3R, 4S)-4-[(4 '-(dimethylamino) xenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Figure A20048003969501022
(3R, 4S)-4-[(4 '-(dimethylamino) xenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl for white foam] azetidine-2-ketone (35.4 milligrams, yield 79%); With chromatography (12 gram silica gel, 5% to 95% ethyl acetate-hexane) purifying; R f(0.78 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.53 (m, 4H), 7.31 (m, 8H), 7.02 (t, J=8.7Hz, 2H), 6.94 (t, J=8.7Hz, 2H), 4.73 (m, 1H), 4.64 (d, J=2.1Hz, 1H), 3.14 (m, 1H), 3.10 (s, 6H), 1.97 (m, 4H) ppm; MS[M+H] 513.6
Embodiment 18 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(methylol) phenyl] azetidine-2-ketone
For transparent film (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(methylol) phenyl] azetidine-2-ketone (37.2 milligrams, yield 75%, impurity 7%); With chromatography (12 gram silica gel, 5% to 95% ethyl acetate-hexane) purifying; R f(0.43 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.57 (m, 4H), 7.44 (d, J=8.4Hz, 2H), 7.38 (d, J=8.4Hz, 2H), 7.27 (m, 4H), 7.02 (t, J=8.9Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 4.73 (m, 3H), 4.66 (d, J=2.4Hz, 1H), 3.12 (m, 1H), 1.97 (m, 4H) ppm; MS[M-OH] 482.5
Embodiment 19 preparations (3R, 4S)-4-(2 '-bromo-5 '-xenol-4 base)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Figure A20048003969501041
(3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-(19.2 milligrams of 4-(3 '-xenol-4 base) azetidines-2-ketone, 0.04 milli rubs) be dissolved in chloroform (0.4 milliliter), and at room temperature add tetrabutylammonium tribromide (18.8 milligrams, 0.04 milli rub).After ten minutes, add saturated aqueous sodium thiosulfate (2 milliliters), react with cancellation.Mixture is poured in the separating funnel, dry on sodium sulfate with methylene dichloride (4 * 10 milliliters) extraction, filter, concentrate.With chromatography (12 gram silica gel, 5% to 95% ethyl acetate-hexane) use reversed-phase HPLC (21 millimeters posts then, 50% to 100% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying (3R, 4S)-and 4-(2 '-bromo-5 '-xenol-4 base)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone, obtain (3R for transparent foaming, 4S)-and 4-(2 '-bromo-5 '-xenol-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone (8.0 milligrams, yield 34%); R f(0.51 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.49 (d, J=8.7Hz, 2H), 7.40 (m, 4H), 7.29 (m, 4H), 7.02 (t, J=8.7Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 6.80 (d, J=3.3,1H), 6.73 (dd, J=3.0,3.0Hz, 1H), 4.74 (t, J=6.2Hz, 2H), 4.67 (d, J=2.1Hz, 1H), 3.14 (m, 1H), 1.99 (m, 4H) ppm; MS[M-OH] 547.4
Embodiment 20 preparations 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-base β-L-Glucopyranose carbonyl acid (glucopyranosiduronic acid)
Step 1: preparation (1S)-1-(4-fluorophenyl)-3-[(3R, 4S)-and 1-(4-fluorophenyl)-2-oxo-4-(4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-phenyl) azetidine-3-yl] the propyl-acetic acid ester
4-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } phenyl trifluoromethyl sulphonate (0.16 milligram, 0.35 milli rub) is dissolved in methylene dichloride (2 milliliters).Toward wherein adding diacetyl oxide (0.04 milliliter, 0.45 milli rubs), triethylamine (0.08 milliliter, 0.60 milli rubs) and 4-Dimethylamino pyridine (18.3 milligrams, 0.15 milli rubs).At room temperature reacted 18 hours, water (5 milliliters) dilution then, and with dichloromethane extraction (10 milliliters).With methylene dichloride (3 * 10 milliliters) aqueous layer extracted once more, organic fraction is merged, dry on sodium sulfate, filter, concentrate.With chromatography (12 gram silica gel; 5% to 95% ethyl acetate-hexane) the described residue of purifying; obtain (1S)-1-(4-fluorophenyl)-3-[(3R for transparent film; 4S)-and 1-(4-fluorophenyl)-2-oxo-4-(4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-phenyl) azetidine-3-yl] propyl-acetic acid ester (0.20 gram; 0.35 milli rubs yield 100%).
Step 2: preparation (1S)-1-(4-fluorophenyl)-3-[(2S, 3R)-and 1-(4-fluorophenyl)-2-(3 '-Hydroxybiphenyl-4-yl)-4-aza-oxo-cyclobutane-3-yl] the propyl-acetic acid ester
Product of step 1 (0.2 gram, 0.35 milli rubs) and four (triphenyl phosphine) palladium (0) (20.3 milligrams, 0.018 milli rubs) are dissolved in toluene (10 milliliters).Add the wet chemical (0.35 milliliter) of 2.0M and contain the ethanolic soln (2.5 milliliters) of 4-hydroxyphenyl boric acid (67.8 milligrams, 0.49 rubs in the least).The vigorous stirring reaction is 4 hours under reflux temperature and in the nitrogen atmosphere, water (2.5 milliliters) dilution then, extract with ethyl acetate (3 * 10 milliliters), wash with salt solution (10 milliliters), dry on sodium sulfate, filter, concentrate, and with chromatography (12 the gram silica gel, 5% to 95% ethyl acetate-hexane) purifying, obtain (1S)-1-(4-fluorophenyl)-3-[(2S for transparent film, 3R)-1-(4-fluorophenyl)-2-(3 '-Hydroxybiphenyl-4-yl)-4-aza-oxo-cyclobutane-3-yl] propyl-acetic acid ester (157 milligrams, yield 85%).
Step 3: preparation (1S)-1-(4-fluorophenyl)-3-[(3R; 4S)-1-(4-fluorophenyl)-2-oxo-4-{3 '-[2; 3; 4-three-oxy-acetyl-6-hydroperoxyl radical-β-L-glucosyl group-hexanedial (hexodialdo)-1,5-pyrans glycosyl) the oxygen base] xenyl-4-yl } azetidine-3-yl) the propyl-acetic acid ester
The product of step 2 (69.4 milligrams, 0.132 milli rubs) and 2,3,4-three-oxy-acetyl-1-O-(2,2,2-trifluoro second imino-)-D-Glucopyranose methyl esters (49.0 milligrams, 0.110 milli rubs) and toluene (3 * 15 milliliters) azeotropic, vacuum-drying 18 hours.In methylene dichloride (1.1 milliliters), reaction is cooled to-25 ℃ with the exsiccant slurry suspension.Add the boron trifluoride Anaesthetie Ether compound (boron trifluoride diethyl etherate) of distillation (passing through calcium chloride) just, be reflected under-25 ℃ and kept 2 hours, in about 3.5 hours, be increased to 10 ℃ then.With saturated aqueous ammonium chloride (2 milliliters) diluted mixture thing; extract with ethyl acetate (3 * 10 milliliters); wash with salt solution (10 milliliters); dry on sodium sulfate; filter; concentrate; with chromatography (12 gram silica gel; 5% to 95% ethyl acetate-hexane) purifying, obtain (1S)-1-(4-fluorophenyl)-3-[(3R into white foam, 4S)-1-(4-fluorophenyl)-2-oxygen-4-{3 '-[2; 3; 4-three-oxy-acetyl-6-hydroperoxyl radical-β-L-glucosyl group-hexanedial-1,5-pyrans glycosyl) the oxygen base] xenyl-4-yl } azetidine-3-yl) propyl-acetic acid ester (57.2 milligrams is that basic yield is 87% with the raw material that reclaims).
Step 4: preparation 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-base β-L-Glucopyranose carbonyl acid
The product of step 3 (57.2 milligrams, 0.068 milli rubs) is dissolved in 1: 1 methyl alcohol-triethylamine (2.8 milliliters).In this solution, add entry (4.25 milliliters).With TLC (methylene dichloride that contains 5% acetic acid and 15% methyl alcohol) monitoring reaction process, finish reaction after 19 hours.Methyl alcohol and triethylamine are fallen in vacuum-evaporation, with 1N hydrochloric acid (1.4 milliliters) acidifying residue, extract with ethyl acetate (20 milliliters), wash with salt solution (5 milliliters), dry on sodium sulfate, filter, concentrate, and with chromatography (10 the gram silica gel, the methylene dichloride that contains 5% acetic acid and 15% methyl alcohol) purifying, obtain for nearly pure white foamy 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-base β-L-Glucopyranose carbonyl acid (32.6 milligrams, yield 73%); R f(0.37 the dichloromethane solution that contains 5% acetate and 15% methyl alcohol); 1H NMR (300MHz, CD 3OD) δ 7.63 (d, J=7.8Hz, 2H), 7.43 (d, J=8.1Hz, 2H), 7.33 (m, 7H), 7.06 (m, 5H), 5.03 (m, 1H), 4.63 (t, J=5.1,5.1Hz, 2H), 3.94 (m, 3H), 3.13 (m, 1H), 1.91 (m, 4H) ppm; MS[M-H] 660.6
Embodiment 21 preparations 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-carboxylic acid
Figure A20048003969501071
4-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } (51.1 milligrams of phenyl trifluoromethyl sulphonates, 0.094 milli rubs) and 3-carboxyl phenyl boric acid (21.9 milligrams, 0.132 rub in the least) be dissolved in 1: 1 toluene and ethanol (2 milliliters).Add 2.0M wet chemical (0.14 milliliter), and solution is outgased.Add four (triphenyl phosphine) palladium (0) (5.1 milligrams, 0.005 milli rubs), the vigorous stirring reaction is 2 hours under reflux temperature and in the nitrogen atmosphere.The refrigerative reaction product is poured (15 milliliters) in the methylene dichloride into, adds entry (3 milliliters), with the 5% sodium pyrosulfate aqueous solution pH is transferred to 3.Use methylene dichloride (2 * 5 milliliters) aqueous layer extracted after the layering.The organic extraction that merges is dry on sodium sulfate, filter, concentrate, and with chromatography (12 the gram silica gel, the methylene dichloride that contains 5% methyl alcohol) purifying, obtain for 4 ' of colourless foam-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-carboxylic acid (41.9 milligrams, yield 86%); R f(0.15 the methylene dichloride that contains 5% methyl alcohol); 1H NMR (300MHz, CDCl 3) δ? 8.31 (m, 1H), 8.09 (dt, J=7.8,1.5Hz, 1H), 7.79-7.39 (m, 6H), and 7.23-7.32 (m, 4H), 6.90-7.02 (m, 4H), 4.75 (t, J=5.7Hz, 1H), 4.69 (d, J=2.1Hz), 3.12 (m, 1H), 2.10-1.90 (m, 4H) ppm; MS[M-H] 512.5
Use identical method to obtain:
Embodiment 22 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-4-carboxylic acid
Figure A20048003969501081
For 4 ' of white foam-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-4-carboxylic acid (21.0 milligrams, yield 67%); With chromatography (12 restrain silica gel, contain the methylene dichloride of 5% methyl alcohol) purifying; R f(0.14 the methylene dichloride that contains 5% methyl alcohol); 1H NMR (300MHz, CDCl 3) δ? 8.17 (d, J=8.4Hz, 2H), 7.65 (t, J=8.1Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.33-7.24 (m, 4H), 7.04-6.92 (m, 4H), 4.77 (t, J=5.7Hz, 1H), 4.70 (d, J=2.1Hz, 1H), 3.15 (m, 1H), 1.92-2.09 (m, 4H) ppm; MS[M-H] 512.5
Embodiment 23 preparations (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-nitrobiphenyl base-4-yl) azetidine-2-ketone
4-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } (50.0 milligrams of phenyl trifluoromethyl sulphonates, 0.092 milli rubs) and 3-oil of mirbane boric acid (21.6 milligrams, 0.129 rub in the least) be dissolved in 1: 1 toluene and ethanol (2 milliliters).Add 2.0M wet chemical (0.092 milliliter), and solution is outgased.Add four (triphenyl phosphine) palladium (0) (5.7 milligrams, 0.005 milli rubs), the vigorous stirring reaction is 2 hours under reflux temperature and in the nitrogen atmosphere.The refrigerative reaction product is poured (15 milliliters) in the methylene dichloride into.Use methylene dichloride (2 * 5 milliliters) aqueous layer extracted after the layering.The organic extraction that merges is dry on sodium sulfate, filter, concentrate, and with chromatography (12 the gram silica gel, 5% to 50% ethyl acetate-hexane) purifying, obtain for transparent film (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-nitrobiphenyl base-4-yl) azetidine-2-ketone (45.0 milligrams, yield 95%); R f(0.33 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ? 8.42 (m, 1H), 8.21 (ddd, J=8.1,2.4,1.2Hz, 1H), 7.89 (ddd, J=7.9,1.5,1.2Hz, 1H), 7.63 (d, J=8.1Hz, 2H), 7.45 (d, J=8.1Hz, 2H), 7.33-7.22 (m, 4H), 7.04-6.92 (m, 4H), 4.76 (t, J=6.0Hz, 1H), 4.71 (d, J=2.1Hz), 3.14 (m, 1H), 1.91-2.11 (m, 4H) ppm; MS[M-OH] 497.5
Use identical method to obtain:
Embodiment 26 N-(4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl) ethanamide
For the N-of white foam (4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-yl) ethanamide (18.8 milligrams, yield 44%); With chromatography (12 gram silica gel, 50% ethyl acetate-hexane) purifying; R f(0.07 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.81 (b, 1H), 7.72-7.19 (m, 12H), 6.99 (t, J=8.7Hz, 2H), 6.93 (t, J=9.0Hz, 2H), 4.72 (t, J=5.7Hz, 1H), 4.65 (d, J=2.1Hz, 1H), 3.13 (m, 1H), 2.17 (s, 3H), 2.04-1.88 (m, 4H) ppm; MS[M-OH] 509.6
Embodiment 28 (3R, 4S)-4-(4 '-phenylaniline base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Figure A20048003969501102
For brown film (3R, 4S)-4-(4 '-phenylaniline base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone (42.0 milligrams, yield 95%); With chromatography (12 gram silica gel, 50% ethyl acetate-hexane) purifying; R f(0.32 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.52 (d, J=8.1Hz, 2H), 7.39-7.23 (m, 8H), 7.00 (t, J=8.7Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 6.74 (d, J=8.4Hz, 2H), 4.72 (t, J=5.7Hz, 1H), 4.63 (d, J=2.4Hz, 1H), 3.14 (m, 1H), 2.11-1.91 (m, 4H) ppm; MS[M+H] 485.5
Embodiment 29 (3R, 4S)-1-(2 ', 3 '-difluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 ', 4 '-difluorophenyl-4-yl) azetidine-2-ketone
Figure A20048003969501111
For transparent film (3R, 4S)-1-(2 ', 3 '-difluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 ', 4 '-difluorophenyl-4-yl) azetidine-2-ketone (36.9 milligrams, yield 86%); With chromatography (12 gram silica gel, 5% to 50% ethyl acetate-hexane) purifying; R f(0.51 50% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.55 (dd, J=8.3,1.5Hz, 2H), 7.41 (d, J=6.9Hz, 2H), 7.32-7.22 (m, 4H), 7.19-7.12 (m, 3H), 7.01 (t, J=8.7Hz, 2H), 6.95 (t, J=9.0Hz, 2H), 4.74 (t, J=6.0Hz, 1H), 4.68 (d, J=2.7Hz, 1H), 3.14 (m, 1H), 2.07-1.90 (m, 4H) ppm; MS[M-OH] 488.5
Embodiment 31 1-[4-(4-{ (2S, 3R)-2-(3 '-Hydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxyl-3-hydrocinnamyl]-4-aza-oxo-cyclobutane-1-yl } phenyl) butyl]-1-azonia dicyclo [2.2.2] octane muriate
Figure A20048003969501121
Use following method to prepare quaternary salt.Under the Suzuki condition, (the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base } phenyl) boric acid and 4-bromstyrol and four (triphenyl phosphine) palladium (0) and the coupling in toluene-alcohol solvent of 2.0M wet chemical.The product and the Sulfuryl chloride isocyanate that obtain react in ether solvent, carry out alkaline water then and handle (alkali aqueous work-up), generate beta-lactam.Use anti-form-1; 2-cyclohexane diamine and CuI; by in solvent decane-dioxane, reacting amide proton and aryl exchange with 4-iodophenyl carbonyl allyl group (acid by commercially available acquisition generates by borane reduction and allyl chloroformate protection).Use suitable alkali such as diisopropyl amide lithium to remove protection on 3 of the beta-lactams; use then the tertiary butyl { [(1S)-4-iodo-1-phenyl butyl] oxygen base } dimethylsilane (by the acid of commercially available acquisition by the TERT-BUTYL DIMETHYL CHLORO SILANE protection and carry out funk Si Taiyin reaction (Finkelstein reaction) with sodium iodide and generate) carry out cancellation, obtain the intermediate product that 3-replaces.Use ammonium formiate and four (triphenyl phosphine) palladium (0) to remove allyloxy carbonic ether protecting group in tetrahydrofuran (THF), the alcohol that obtains changes into bromide with carbon tetrabromide and triphenylphosphine in methylene dichloride.Use contains the acetonitrile of 48% hydrofluoric acid the silicomethane protecting group is got rid of from phenylcarbinol and phenol.Compound that obtains and tertiary amine such as quinuclidine (quinuclidine) reaction, with the HPLC purifying and by the chloride ion exchange column, obtain 1-[4-(4-{ (and 2S, 3R)-2-(3 '-Hydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxyl-3-hydrocinnamyl]-4-aza-oxo-cyclobutane-1-yl phenyl) butyl]-1-azonia dicyclo [2.2.2] octane muriate.
Route map I below the embodiment 32 has described the general preparation method of the cholesterol absorption inhibitor shown in the general formula 32.Imines 2 makes by 4-cyano-aniline and suitable aldehyde are refluxed in Virahol.With titanium tetrachloride imines 2 and phenyl oxazolidinones compound 3 are carried out condensation, use N then, the uncle-n-butyl ammonium fluoride of O-two pivalyl amine and a katalysis is carried out cyclisation, obtains azetidinone 4.In ethanol and ammonium hydroxide, under hydrogen atmosphere, become amine 5 with the cyano reduction of excessive Raney's nickel (Raney Nickel) with 4.With suitable acid chloride [Br (CH 2) nCOCl] carry out acidylate, react in acetonitrile with hydrofluoric acid then and remove the silyl protecting group, then obtain final product 32 with the taurine reaction.Should be noted in the discussion above that in this route map taurine is explanation for example just, many functional groups can replace its position.
Route map I
Figure A20048003969501141
Embodiment 33
Following route map II has described the general preparation method of the cholesterol absorption inhibitor shown in the general formula 33.Aldehyde 7 makes by 4-bromobenzaldehyde and 3-benzonitrile ylboronic acid are carried out the Suzuki coupling.Imines 8 makes by 4-cyano-aniline and aldehyde 7 are refluxed in Virahol.With titanium tetrachloride imines 8 and phenyl oxazolidinones compound 3 are carried out condensation, use N then, the uncle-n-butyl ammonium fluoride of O-two pivalyl amine and a katalysis is carried out cyclisation, obtains azetidinone 9.In ethanol and ammonium hydroxide, under hydrogen atmosphere, become amine 10 with the cyano reduction of excessive Raney's nickel (Raney Nickel) with 9.With suitable acid chloride [Br (CH 2) nCOCl] carry out acidylate, react in acetonitrile with hydrofluoric acid then and remove the silicomethane protecting group, then obtain final product 11 with the taurine reaction.Should be noted in the discussion above that in this route map taurine is explanation for example just, many functional groups can replace its position.
Route map II
Embodiment 34
Following route map III has described the general preparation method of the cholesterol absorption inhibitor shown in the general formula 34.Imines makes by 4-cyano-aniline and 4-bromobenzene acetaldehyde are carried out condensation, then carry out condensation with titanium tetrachloride and phenyl oxazolidinones compound 3, use N then, the uncle-n-butyl ammonium fluoride of O-two pivalyl amine and a katalysis is carried out cyclisation, obtains azetidinone 12.Acetonitrile with hydrofluoric acid containing is removed the silicomethane protecting group, has used the palladium of katalysis to be coupled on valeryl two boron [bis (pina colato) diboron] then, obtains compound 13.Carry out the Suzuki coupling with intermediate product 20, obtain compound 14.In ethanol and ammonium hydroxide under hydrogen atmosphere with excessive Raney's nickel (Raney Nickel) with cyano reduction, and remove acetate groups with triethylamine-methanol-water, obtain 15.With suitable acid chloride [Br (CH 2) nCOCl] carry out acidylate, then obtain final product 16 with the taurine reaction.Should be noted in the discussion above that in this route map taurine is explanation for example just, many functional groups can replace its position.
Route map III
Synthesizing of intermediate product 20: 3-alkoxyl phenyl lithium and Glucopyranose lactone 17 (glucopyranolactone) reaction, use triethyl silicane and boron trifluoride Anaesthetie Ether compound with the hemiketal reductive cleavage then, obtain the glucosides 18 of benzyl protection.Use palladium catalyst and three normal-butyl stannic hydrides to remove allyl group, use palladium carbon under hydrogen atmosphere, to reduce then, obtain phenyl glucosides 19.Obtain CF with N-phenyl trifluoromethanesulfonate sulfonyl methane imine reaction 3SO 2, use the pyridine that contains acetic anhydride to carry out acidylate (peracetylation), obtain intermediate product 20.
Figure A20048003969501191
Embodiment 35 (4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxo pentanoyl]-1,3-oxazolidine-2-ketone
(10.08g, 47.9mmol) (6.8mL, 4.94g 48.8mmol) are dissolved in tetrahydrofuran (THF) (50mL) to 5-(4-fluorophenyl)-5 oxy pentanoic acids with triethylamine.Reaction is cooled to-5 ℃ (ice/brine bath), and (6.0mL 5.87g 48.7mmol), stirs mixture heating up to room temperature ice 1.5 hours dropwise to add the triethyl Acetyl Chloride 98Min. fast.Reaction was cooled to-5 ℃ (ice/brine bath) 30 minutes once more, passed through Celte _Filter, with cold 1: 1 hexane-tetrahydrofuran (THF) (60mL) and hexane (120mL) washing.Filtrate concentrated and be dissolved in N, dinethylformamide (16mL), add in this mixture solid (S)-phenyl-2-oxazolidone (8.47g, 47.8mmol) with the 4-4-Dimethylamino pyridine (8.57g, 70.2mmol).At room temperature stirring reaction is 20 hours, pour (400mL) and usefulness ethyl acetate extraction (2 * 300mL) in the 1.0N hydrochloric acid into, water (400mL), saturated sodium bicarbonate solution (400mL) and salt solution (200mL) washing organic layer, dry on sodium sulfate, filter and concentrate.Surplus materials obtains purifying by the crystallisation process that slowly cooled to room temperature from the Virahol (75mL) of heat in 16 hours.Crystal is filtered and washs, obtain (4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxygen pentanoyl into white crystalline solid with cold Virahol (50mL)]-1,3-oxazolidine-2-ketone (13.87g, yield 78%); Fusing point 114.; R f(0.29 1: 2 ethyl acetate-hexane); 1HNMR (300MHz, CDCl 3) δ 8.03-7.98 (m, 2H), 7.37-7.19 (m, 5H), 7.14 (t, J=8.7Hz, 2H), 4.72-4.64 (m, 1H), and 4.25-4.15 (m, 2H), 3.32 (dd, J=13.3,3.4Hz, 1H), 3.12-3.01 (m, 4H), 2.78 (dd, J=13.3,9.6Hz, 1H), 2.15 (quint.J=7.2Hz, 2H) ppm
Embodiment 36 (4S)-4-benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyl pentanoyl]-1,3-oxazolidine-2-ketone
(4S)-and 4-benzyl-3-[5-(4-fluorophenyl)-5-oxo pentanoyl]-1,3-oxazolidine-2-ketone (13.87g37.54mmol) is dissolved in methylene dichloride (40mL).Add borine-sulfuration methyl mixture (3.6mL, approximately 38mmol) in the independent flask, contain 1.0M_-1-methyl-3,3-phenylbenzene tetrahydrochysene-3H-pyrroles [1,2-c] [1,3,2] toluene of oxazaborole (1.9mL, 1.9mmol) and methylene dichloride (20mL).This mixture is cooled to-5 ℃ (ice/brine bath), in 5 minutes, dropwise adds ketone solution by sleeve pipe.5 ℃ of following stirring reactions 5.5 hours, slowly add methyl alcohol (9mL), 5% superoxol (30mL) and the 1M thiosulfonic acid aqueous solution (20mL) then respectively.Pour (500mL) and usefulness ethyl acetate extraction (500mL) in the water into, water (500mL), saturated sodium bicarbonate solution (300mL) and salt solution (300mL) washing organic layer, dry on sodium sulfate, filter and concentrate, obtain (4S)-4-benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyl pentanoyl]-1,3-oxazolidine-2-ketone uses in subsequent reactions without purifying; R f(0.14 1: 2 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.37-7.24 (m, 5H), 7.19 (d, J=7.3Hz, 2H), 7.02 (t, J=8.9Hz, 2H), 4.72-4.61 (m, 2H), 4.21-4.13 (m, 2H), 3.27 (dd, J=13.2,3.0Hz, 1H), and 2.99-2.94 (m, 2H), 2.74 (dd, J=13.2,9.6Hz, 1H), 2.27 (brs, 1H), 1.88-1.66 (m, 4H) ppm; MS[M-OH] +354.0
Embodiment 37 (4S)-4-benzyl-3-[(5S)-the 5-{[tertiary butyl (dimethyl) silyl] the oxygen base }-5-(4-fluorophenyl) pentanoyl]-1,3-oxazolidine-2-ketone
Figure A20048003969501221
(4S)-the 4-benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyl pentanoyl]-1; 3-oxazolidine-2-ketone (37.54mmol) is dissolved in N; dinethylformamide (40mL); add imidazoles (2.97g then; 43.6mmol) and the tert-butyldimethylsilyl chloride thing (6.12g, 40.6mmol).At room temperature stirring reaction is 19 hours, pours in the 1.0N hydrochloric acid (500mL) into and with ethyl acetate extraction (500mL), and water (2 * 500mL) and salt solution (300mL) washing organic layer, dry on sodium sulfate, filter also and concentrate.Surplus materials obtains purifying by being heated to boiling point and slowly cooling to room temperature crystallization from methyl alcohol (55mL) at 18 hours.Crystal is filtered and wash with cold Virahol (45mL), obtain (4S)-4-benzyl-the 3-[(5S)-5-{[tertiary butyl (dimethyl) silyl for white crystalline solid] the oxygen base }-5-(4-fluorophenyl) pentanoyl]-1,3-oxazolidine-2-ketone (16.04g, yield 88%); 87.6 ℃ of fusing points; R f(0.66 1: 2 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.36-7.18 (m, 7H), 6.99 (t, J=8.7Hz, 2H), 4.69-4.61 (m, 2H), 4.18-4.13 (m, 2H), 3.27 (dd, J=13.5,3.2Hz, 1H), 2.96-2.89 (m, 2H), 2.73 (dd, J=13.5,9.7Hz, 1H), 1.82-1.63 (m, 4H), 0.88 (s, 9H), 0.04 (s, 3H) ,-0.15 (s, 3H) ppm; MS[M-OSi (CH 3) 2C (CH 3) 3] +354.0
Embodiment 38.N-{ (1E)-[2-(allyloxy)-4-bromo phenyl] methylene radical } aniline
Figure A20048003969501231
(4.02g, 20.0mmol) [by the 3-bromophenol according to Casiraghi, et.al.JournalOrganic and Bio-Organic Chemistry (1978), the method for 318-21 makes] is dissolved in anhydrous dimethyl formamide (13mL) to the 4-bromosalicylaldehyde.(3.9g 28.0mmol), obtains yellow suspension to add solid carbonic acid potassium.By syringe add bromopropylene (allyl bromide) (2.6mL, 3.63g, 30.0mmol).At room temperature stirring reaction is 17 hours, then dilute with water and with 1: 1 ethyl acetate-hexane extraction three times.The organic layer water (5 *) and the salt water washing that merge, dry on sodium sulfate, filter and concentrate, obtain 2-(allyloxy)-4-bromobenzene formaldehyde (4.83g, yield 100%) into yellow solid, use in subsequent reactions without purifying; R f(0.38 1: 9 ethyl acetate-hexane); MS[M+H] +241.0
(5.05g 20.9mmol) is dissolved in Virahol (18mL) and intensification to 2-(allyloxy)-4-bromobenzene formaldehyde.Just (1.99g 21.3mmol) adds with Virahol (4mL) distillatory aniline, and reaction is heated to 50 ℃.In 30 minutes, form yellow mercury oxide, add Virahol (5mL) to help stirring.50 ℃ of following stirring reactions 16 hours, this moment, proton N MR showed do not have aldehyde to exist.Stirring makes the reaction cooling.Mixture is with hexane (20mL) dilution, and solid filtering and with mother liquor washing then with hexane wash and dry, obtains N-{ (1E)-[2-(the allyloxy)-4-bromo phenyl] methylene radical into buff powder } aniline (5.69g, yield 86%); ' H NMR (300MHz, δ 8.87 (s, 1H), 8.03 (d, J=8.4Hz, 1H), 7.43-7.36 (m, 2H), 7.27-7.17 (m, 4H), 7.099 (d, J=1.8Hz, 1H), 6.06 (ddt, J=17.2,10.5,5.3Hz, 1H), 5.43 (AB q, J=17.3,3.0Hz, 1H), 5.33 (AB q, J=10.5,2.8Hz, 1H), 4.62 (ddd, 5.2,1.5,1.5Hz, 2H) ppm
Embodiment 39 (3R, 4S)-4-(4-bromo-2-hydroxy phenyl)-the 3-[(3S)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-1-phenyl azetidine alkane-2-ketone
2-(allyloxy)-4-bromobenzene formaldehyde (2.79g; 8.83mmol) and (4S)-the 4-benzyl-3-[(5S)-the 5-{[tertiary butyl (dimethyl) silyl] the oxygen base }-5-(4-fluorophenyl) pentanoyl]-1; (3.3g 6.8mmol) adds in the three neck round-bottomed flasks of the 100ml with thermometer and nitrogen inlet 3-oxazolidine-2-ketone together.Add anhydrous methylene chloride (60mL), obtain pale yellow solution, this solution is cooled to-30 ℃.By syringe add diisopropylethylamine (2.3mL, 1.71g, 13.2mmol).Be that (0.86mL, 1.48g 7.82mmol), obtain red tan solution dropwise to add titanium tetrachloride in 6 minutes under-28 ℃ to-26 ℃ the condition at internal temperature.Under-30 to-25 ℃ temperature, stirring reaction is 3 hours under nitrogen atmosphere, is cooled to-35 ℃ then, and carries out cancellation with Glacial acetic acid (6mL) in 6 minutes.Pour reactant into cold (0 ℃) 7% tartaric acid solution (125mL).Add ethyl acetate (200mL), stirring makes mixture be warming up to room temperature.Add 5% sodium sulfite solution (60mL), separately with each layer.With ethyl acetate extraction (2 * 200mL) water layers.The organic layer that merges saturated sodium bicarbonate solution, water and salt water washing, dry on sodium sulfate, filter, concentrate, and with chromatography (120 restrain silica gel, and 1% to 90% ethyl acetate-hexane) purifying, obtain (4S)-3-[(2R, 5S)-2-[(S)-[2-(allyloxy)-4-bromo phenyl] (anilino) methyl]-the 5-{[tertiary butyl (dimethyl) silyl] the oxygen base }-5-(4-fluorophenyl) pentanoyl]-1,3-oxazolidine-2-ketone (4.54g, yield 83%); R f(0.38 1: 4 ethyl acetate-hexane); MS[M+H] 801.0
(4S)-3-[(2R; 5S)-2-[(S)-[2-(allyloxy)-4-bromo phenyl] (anilino) methyl]-the 5-{[tertiary butyl (dimethyl) silyl] the oxygen base }-5-(4-fluorophenyl) pentanoyl]-1; 3-oxazolidine-2-ketone (1.2g; 1.5mmol) be dissolved in anhydrous methyl tertiary butyl ether (10mL); at room temperature, under nitrogen atmosphere, stir.Add N, (1.1mL 4.5mmol), adds catalytic amount (approximately 5mg) 4-butyl ammonium fluoride trihydrate to O-two trimethyl silyl ethanamides subsequently.At room temperature stirring reaction is 19 hours, with Glacial acetic acid (160 microlitre) cancellation at room temperature, separates between ethyl acetate and water and separates.The water layer ethyl acetate extraction.The organic layer that merges saturated sodium bicarbonate solution, water and salt water washing, dry on sodium sulfate, filter, concentrate, and, obtain (3R with chromatography (120 gram silica gel, 1% to 85% ethyl acetate-hexane) purifying, 4S)-4-[2-(allyloxy)-4-bromo phenyl]-3[(3S)-{ [tertiary butyl (dimethyl) silyl] oxygen base }-3-(4-fluorophenyl) propyl group]-1-phenyl azetidine alkane-2-ketone (816mg, yield 87%); R f(0.56 1: 4 ethyl acetate-hexane)
(3R, 4S)-4-[2-(allyloxy)-4-bromo phenyl]-3[(3S)-{ [tertiary butyl (dimethyl) silyl] oxygen base }-3-(4-fluorophenyl) propyl group]-(1.34g 2.15mmol) is dissolved in deoxidation tetrahydrofuran (THF) (20mL) to 1-phenyl azetidine alkane-2-ketone.With morphine (1.8mL, 1.8g, 20.6mmol) with other deoxidation tetrahydrofuran (THF) (5mL) add as.Reactant with nitrogen purge and add four (triphenyl phosphine) palladium (0) (220mg, 19mmol).Reactant is used nitrogen purge once more.After at room temperature keeping 1.5 hours, reactant dilutes with ethyl acetate, with 1N hydrochloric acid, saturated sodium bicarbonate solution, water and salt water washing, dry on sodium sulfate, filter, concentrate, and, obtain (3R with chromatography (40 gram silica gel, 6% to 80% ethyl acetate-hexane) purifying, 4S)-and 4-(4-bromo-2-hydroxy phenyl)-the 3-[(3S)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-1-phenyl azetidine alkane-2-ketone (1.04g, yield 83%); R f(0.38 1: 4 ethyl acetate-hexane) 1H NMR (300MHz, CDCl 3), δ 7.28-7.18 (m, 6H), 7.09-6.92 (m, 6H), 5.91 (s, 1H), 4.93 (d, J=2.3Hz, 1H), 4.65 (t, J=5.4Hz, 1H), 3.06 (ddd, J=4.8,2.3,2.3Hz, 1H), 1.98-1.77 (m, 4H), 0.86 (s, 9H), 0.006 (s, 3H), 0.16 (s, 3H) ppm; MS[M-H] +581.7
Embodiment 40 (3R, 4S)-4-(the 4-bromo-2-{[tertiary butyl (dimethyl) silyl] the oxygen base } phenyl)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-1-phenyl azetidine alkane-2-ketone
Figure A20048003969501261
(3R, 4S)-and 4-(4-bromo-2-hydroxy phenyl)-the 3-[(3S)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-1-phenyl azetidine alkane-2-ketone (1.04g, 1.79mmol) be dissolved in anhydrous methylene chloride (5mL), add anhydrous N, dinethylformamide (5mL), at room temperature, under nitrogen atmosphere, stir.Add 2, the 6-lutidine (1.0mL, 920mg, 8.6mmol), dropwise add then t-butyldimethylsilyl trifluoromethayl sulfonic acid ester (1.2mL, 1.38g, 5.22mmol).At room temperature, stirring reaction 2.25 hours under nitrogen atmosphere.Add 2, the 6-lutidine (0.25mL, 230mg, 2.15mmol), dropwise add then t-butyldimethylsilyl trifluoromethayl sulfonic acid ester (0.4mL, 460mg, 1.74mmol)., at room temperature total coreaction is after 4.5 hours, and reaction separates each layer with ethyl acetate and water dilution.The water layer ethyl acetate extraction, the organic layer that merges 0.5N hydrochloric acid, saturated sodium bicarbonate solution, water (4 times) and salt water washing, dry on sodium sulfate, filter, concentrate, and with chromatography (40 the gram silica gel, 1% to 85% ethyl acetate-hexane) purifying, obtain (3R, 4S)-4-(the 4-bromo-2-{[tertiary butyl (dimethyl) silyl] the oxygen base } phenyl)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-1-phenyl azetidine alkane-2-ketone (1.23g, yield 99%); R f(0.57 1: 4 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 7.33-7.14 (m, 6H), 7.09-6.91 (m, 6H), 4.99 (d, J=2.3Hz, 1H), 4.62 (t, J=5.6Hz, 1H), 3.06 (ddd, J=4.9,2.5,2.3Hz, 1H), 1.97-1.69 (m, 4H), 1.03 (s, 9H), 0.84 (s, 9H), 0.33 (s, 3H), 0.29 (s, 3H) ,-0.01 (s, 3H) ,-0.20 (s, 3H) ppm
Embodiment 41 5-bromo-2-{ (2S, 3R)-3-[(3S)-the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } the phenylacetic acid ester
Figure A20048003969501271
(3R, 4S)-4-(4-bromo-2-hydroxy phenyl)-the 3-[(3S)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-(293mg 0.50mmol) is dissolved in anhydrous methylene chloride (3mL) to 1-phenyl azetidine alkane-2-ketone.Add the 4-Dimethylamino pyridine (183mg, 1.5mmol), then add acetic anhydride (280 microlitres, 302mg, 3.0mmol).After one hour, reaction is filtered by silica gel plug (a plug of silicagel), and uses the methylene dichloride wash-out.Solvent is concentrated, with methylbenzene azeotropic, with chromatography (40 gram silica gel, 1% to 85% ethyl acetate-hexane) purifying, obtain 5-bromo-2-{ (2S, 3R)-and 3-(the 3S)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } phenylacetic acid ester (245mg, yield 78%); R f(0.47 1: 4 ethyl acetate-hexane); 1HNMR (300MHz, CDCl 3), δ 7.387.16 (m, 9H), 7.14-6.94 (m, 3H), 4.69 (t, J=5.4Hz, 1H), 4.64 (d, 2.3Hz, 1H), 3.06 (ddd, J=4.7,2.3,2.2Hz, 1H), 2.30 (s, 3H), 1.97-1.78 (m, 4H), 0.89 (s, 9H), 0.032 (s, 14 (s, 3H) ppm; MS[M-OSi (CH 3) 2C (CH 3) 3] +493.8
Embodiment 42 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
Figure A20048003969501281
Use the Suzuki coupling method, by using deoxidation toluene (3 milliliters) and deoxidation ethanol (1 milliliter) with 5-bromo-2-{ (2S, 3R)-and 3-(the 3S)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } phenylacetic acid ester (100mg, 0.16mmol) and 3-hydroxyphenyl boric acid (29mg, 0.21mmol) combination.Adding 2.0M wet chemical (0.31mL 0.31mmol), uses the nitrogen purge container, and adding four (triphenyl phosphine) palladium (0) (9mg, 0.008mmol), the container nitrogen purge.Reaction is heated to 70 ℃ and kept 1.5 hours, cooling, and dilute with water is with ethyl acetate extraction (2x).The organic layer water and the salt water washing that merge, dry on sodium sulfate, filter, concentrate, and, obtain 4-{ (2S with chromatography (40 gram silica gel, 20% to 90% ethyl acetate-hexane) purifying, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-base acetic ester (70mg, yield 69%); R f(0.34 1: 2 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 7.34-7.17 (m, 10H), 7.06-6.90 (m, 5H), 6.79 (ddd, J=8.1,2.5,0.8Hz, 1H), 6.03 (br s, 1H), 4.67 2.3Hz, 1H), 4.64 (t, 5.6Hz, 3.26 (ddd, 4.8,2.5,2.4Hz, 2.27 (s, 3H), 1.94-1.73 (m, 4H), 0.84 (s, 9H) ,-0.02 (s, 3H) ,-0.19 (s, 3H) ppm; MS[M-OSi (CH 3) 2C (CH 3) 3] +508.0
4-{ (2S, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-(70mg 0.11mmol) is dissolved in methyl alcohol (2.45mL) to 3-base acetic ester.Dropwise add entry (0.7mL), add triethylamine (2.2mL) then, at room temperature stirring reaction is 1 hour.Add toluene (3mL) and methyl alcohol (5mL), to react and concentrate, obtain 69 milligrams of (3R, 4S)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-(3,3 '-dihydroxybiphenyl base-4-yl)-and 1-phenyl azetidine alkane-thick product of 2-ketone, this thick product uses without purifying.
(3R, 4S)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-(3,3 '-dihydroxybiphenyl base-4-yl)-(73mg 0.122mmol) is dissolved in acetonitrile (5mL) and being transferred in the polypropylene circular cone bottle to 1-phenyl azetidine alkane-2-ketone.Dropwise add 48% hydrofluoric acid (1mL), at room temperature stirring reaction is 1 hour.With 1N sodium hydroxide (24mL) cancellation reaction, and be transferred to and contain in the flask that pH is 7.4 phosphate buffered saline buffer (24mL).PH with solution transfers to 7.5-8.0 and uses ethyl acetate extraction (3 *) with saturated sodium bicarbonate solution.The organic layer that merges saturated sodium bicarbonate solution (2 *), water and salt water washing, dry on sodium sulfate, filter, concentrate, and with chromatography (12 restrain silica gel, and 40% to 100% ethyl acetate-hexane) purifying, obtain (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone (53mg, yield 69%)); 1H NMR (300MHz, CDCl 3), δ 7.30-7.13 (m, 7H), 7.08-6.85 (m, 8H), 6.78 (ddd, J=8.1,2.3,0.9Hz, 1H), 5.04 (d, J=2.3Hz, 1H), 4.61 (t, J=5.9Hz, 1H), 3.07 (ddd, J=5.7,1.8,1.5Hz, 1H), 2.08-1.80 (m, 4H) ppm; MS[M+H] +584.0[M-H] -582.0
Embodiment 43 (3R, 4S)-4-(3-bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Figure A20048003969501291
Use the step identical with embodiment 39 to synthesize, initial substance is 4-fluoroaniline and 3-bromobenzaldehyde.
As described in embodiment 42, use 48% hydrofluoric acid to remove benzylic TBDMS protecting group.With chromatography (silica gel, 10% to 60% ethyl acetate-hexane) purifying, obtain (3R, 4S)-4-(3-bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone (86mg); 1H NMR (300MHz, CDCl 3), δ 7.50-7.45 (m, 2H), 7.33-7.18 (m, 6H), 7.07-6.91 (m, 4H), 4.72 (t, J=5.8Hz, 1H), 4.57 (t, J=2.4Hz, 1H), 3.10 (ddd, J=4.8,2.4,2.4Hz, 1H), 2.12 (br s, 2.06-1.86 (m, 4H) ppm; MS[M+HCO 2] -516.0
Embodiment 44 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-3-yl) azetidine-2-ketone
Under as embodiment 42 described standard Suzuki conditions, (3R, 4S)-and 4-(3-bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] (43mg is 0.091mmol) with 3-hydroxyphenyl boric acid (18mg, 0.13mmol) coupling for azetidine-2-ketone.With chromatography (silica gel, 10% to 90% ethyl acetate-hexane) purifying, obtain (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-3-yl) azetidine-2-ketone (19.7mg, yield 45%); R f(0.30 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 7.57-7.40 (m, 3H), 7.34-7.22 (m, 6H), 7.10 (ddd, J=7.7,1.6,0.9Hz, 1H), 7.04-6.90 (m, 5H), 6.84 (ddd, 8.2,2.6,0.9Hz, 1H), 5.10 (br s, 4.72 (t, J=5.9Hz, 1H), 4.67 (d, J=2.4Hz, 1H), 3.16 (ddd, J=5.0,2.6,2.4Hz, 1H), 2.26 (br 1H), 2.08-1.88 (m, 4H) ppm
Embodiment 45 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 '-Hydroxybiphenyl-3-yl) azetidine-2-ketone
Under as embodiment 42 described standard Suzuki conditions, (3R, 4S)-and 4-(3-bromophenyl)-1-(4-bromophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] (42mg is 0.089mmol) with 4-hydroxyphenyl boric acid (18mg, 0.13mmol) coupling for azetidine-2-ketone.With chromatography (silica gel, 10% to 90% ethyl acetate-hexane) purifying, obtain (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 '-Hydroxybiphenyl-3-yl) azetidine-2-ketone (27mg, yield 63%); R f(0.31 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 7.54-7.37 (m, 6H), 7.32-7.22 (m, 4H), 7.04-6.87 (m, 6H), 5.24 (br s, 1H), 4.72 (t, J=6.0Hz, 1H), 4.67 (d, J=2.4Hz, 1H), 3.17 (ddd, J=5.3,2.5,2.4Hz, 1H), 2.26 (br s, 1H), 2.09-1.88 (m, 4H) ppm
Embodiment 46 (3R, 4S)-4-(4-bromophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
Figure A20048003969501312
Use the step identical with embodiment 39 to synthesize, initial substance is aniline and 4-bromobenzaldehyde.As described in embodiment 42, use 48% hydrofluoric acid to remove benzylic TBDMS protecting group.With chromatography (silica gel, 10% to 90% ethyl acetate-hexane) purifying, obtain for transparent film (3R, 4S)-4-(4-bromophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone (982.6mg, all yields 75%); R f(0.45 2: 3 ethyl acetate-hexanes); 1H NMR (300MHz, CDCl 3), δ 7.49 (d, J=8.3Hz, 2H), 7.31-7.19 (m, 8H), 7.07-6.98 (m, 3H), 4.70 (t, J=6.1Hz, 1H), 4.61 (d, J=2.5Hz, 1H), 3.04 (dt, J=7.4,2.3Hz, 1H), 2.24 (br s, 1H), 2.03-1.86 (m, 4H) ppm
Embodiment 47 (3R, 4S)-4-(5-bromopyridine-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
Figure A20048003969501321
Use the step identical with embodiment 39 synthetic, initial substance is aniline and 5-bromo-2 pyridine carboxylic aldehyde (use Wang etc., Tetrahedron Letters 41 (2000), and the described method of 4335-4338 prepares).As described in embodiment 42, use 48% hydrofluoric acid to remove benzylic TBDMS protecting group.With chromatography (12 gram silica gel, 15% to 90% ethyl acetate-hexane) purifying, obtain for transparent film (3R, 4S)-4-(5-bromopyridine-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone (23.3mg, total recovery 3%); R f(0.07 1: 4 ethyl acetate-alkane); 1H NMR (300MHz, CDCl 3), δ 8.66 (d, J=2.3Hz, 1H), 7.80 (dd, J=8.3,2.3Hz, 1H), 7.34-7,29 (m, 3H), and 7.24-7.17 (m, 4H), 7.09-6.99 (m, 3H), 4.82 (d, J=2.5Hz, 1H), 4.75-4.71 (m, 1H), 3.21 (dt, J=7.0,2.3Hz, 1H), 2.31-1.89 (m, 5H) ppm
Embodiment 48 (3R, 4S)-4-(5-bromo-2 thienyls)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
Figure A20048003969501331
Use the step identical with embodiment 39 to synthesize, initial substance is aniline and 5-bromo-2 thiophene carboxylic aldehyde.As described in embodiment 42, use 48% hydrofluoric acid to remove benzyl TBDMS protecting group.With chromatography (40 gram silica gel, 15% to 90% ethyl acetate-hexane) purifying, obtain for white solid (3R, 4S)-4-(5-bromo-2 thienyls)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone (212.4mg, total recovery 23%); R f(0.13 1: 4 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 7.36-7.21 (m, 6H), 7.10-7.06 (m, 1H), 7.02 (t, J=8.7Hz, 2H), 6.89 (dd, J=19.7,3.8Hz, 2H), 4.83 (d, J=2.4Hz, 1H), 4.71 (t, J=5.7Hz, 1H), 3.25-3.19 (m, 1H), 2.20 (br s, 1H), 2.01-1.83 (m, 4H) ppm
Embodiment 49 (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl) pyridine-2 base]-1-phenyl azetidine alkane-2-ketone
Under as embodiment 42 described standard Suzuki conditions, (3R, 4S)-4-(5-bromopyridine-2 base)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-(23mg is 0.051mmol) with 3-hydroxyphenyl boric acid (9.2mg, 0.067mmol) coupling for 1-phenyl azetidine alkane-2-ketone.With chromatography (4 gram silica gel, 15% to 100% ethyl acetate-hexane) purifying, obtain for transparent film (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl) pyridine-2-yl]-1-phenyl azetidine alkane-2-ketone (20.7mg, yield 87%); R f(0.14 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 8.88 (d, J=2.2Hz, 1H), 7.88 (dd, J=8.2,2.3Hz, 1H), and 7.86-7.80 (m, 1H), 7.39-7.22 (m, 7H), 7.12-7.02 (m, 3H), 6.96 (t, J=8.7Hz, 2H), 6.96-6.91 (m, 1H), 4.97 (d, J=2.3Hz, 1H), 4.76-4.72 (m, 1H), 3.28-3.22 (m, 1H), 3.20 (br s, 1H), and 2.17-1.90 (m, 4H), 1.80 (br s, 1H) ppm; MS[M+H] +469.0
Embodiment 50 (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)-2-thienyl]-1-phenyl azetidine alkane-2-ketone
Figure A20048003969501341
Under as embodiment 42 described standard Suzuki conditions, (3R, 4S)-4-(5-bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-(90.2mg is 0.196mmol) with 3-hydroxyphenyl boric acid (32.2mg, 0.233mmol) coupling for 1-phenyl azetidine alkane-2-ketone.With chromatography (12 gram silica gel, 15% to 100% ethyl acetate-hexane) purifying, obtain for transparent foaming (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)-2-thienyl]-1-phenyl azetidine alkane-2-ketone (77.6mg, yield 84%); R f(0.36 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 7.31-6.93 (m, 14H), 6.70 (ddd, J=8.0,2.3,1.0Hz, 4.89-4.88 (m, 1H), 4.64-4.59 (m, 1H), 3.77 (br s, 2H), 3.25-3.21 (m, 1H), 1.97-1.83 (m, 4H) ppm; MS[M-OH] +456.0
Embodiment 51 (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(4-hydroxyphenyl)-2-thienyl]-1-phenyl azetidine alkane-2-ketone
Figure A20048003969501351
Under as embodiment 42 described standard Suzuki conditions, (3R, 4S)-4-(5-bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-(69.8mg is 0.152mmol) with 4-hydroxyphenyl boric acid (25.2mg, 0.183mmol) coupling for 1-phenyl azetidine alkane-2-ketone.With chromatography (12 gram silica gel, 15% to 100% ethyl acetate-hexane) purifying, obtain for transparent foaming (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(4-hydroxyphenyl)-2-thienyl]-1-phenyl azetidine alkane-2-ketone (40.7mg, yield 56%); R f(0.39 1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 7.64-7.60 (m, 4H), 7.56-7.48 (m, 5H), and 7.33-7.27 (m, 2H), 7.25-7.20 (m, 2H), 7.07 (d, J=8.6Hz, 2H), 6.81 (br s, 1H), 5.14 (d, J=2.3Hz, 1H), and 5.00-4.95 (m, 1H), 3.57-3.50 (m, 1H), 2.29-2.11 (m, 4H) ppm; MS[M+H] +474.0
Embodiment 53 4 '-(2S, 3R)-3-[(3S/R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sodium sulfonate
Figure A20048003969501361
5-bromo-2-{ (2S, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } (140.0mg 0.223mmol) is dissolved in acetonitrile (8.0mL) and 48% hydrofluoric acid (0.8mL) in the Falcon_ test tube to the phenylacetic acid ester.At room temperature stirring reaction is 4 hours, pour into then in the 0.5M potassiumphosphate (50mL), with the extraction of 1: 1 ethyl acetate-hexane (50 milliliters), with saturated sodium bicarbonate (50mL) and salt solution (50mL) washing, dry on sodium sulfate, filter, concentrate, and with chromatography (12 the gram silica gel, 15% to 90% ethyl acetate-hexane) purifying, obtain for transparent foaming 5-bromo-2-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl) 3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl phenylacetic acid ester (114.5mg, yield 100% yield); R f(0.11 1: 4 ethyl acetate-hexane).
5-bromo-2-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl) 3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } phenylacetic acid ester (114.5mg, 0.223mmol) (48.3mg 0.287mol) is dissolved in toluene (3.0mL) and ethanol (1.5mL) to and 3-thioanisole boric acid (3-thioanisoleboronic acid).Add the 2.0M aqueous sodium carbonate (0.215mL, 0.43mmol) and solid four (triphenyl phosphine) palladium (0) (14.4mg 0.0125mmol), vacuumizes container or with nitrogen purge (3x).Under 60 ℃, under nitrogen atmosphere, vigorous stirring reaction 4 hours pours in the 0.2N hydrochloric acid (50mL) then, with 1: 1 ethyl acetate-hexane extraction, with salt solution (50mL) washing, dry on sodium sulfate, filter and concentrate, obtain being directly used in the mix products of next step, for (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3-hydroxyl-3 '-(methylthio group) xenyl-4-yl]-1-phenyl azetidine alkane-2-ketone, R fBe 0.79 (2: 1 ethyl acetate-hexanes), for 4-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl) 3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl-3 '-(methylthio group) xenyl-3-yl acetate, R fBe 0.84 (2: 1 ethyl acetate-hexanes).
(3R with 1: 1,4S)-3-[(3S)-3-(4-fluorophenyl) 3-hydroxypropyl]-4-[3-hydroxyl-3 '-(methylthio group) xenyl-4-yl]-1-phenyl azetidine alkane-2-ketone and 4-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl) 3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } mixture (0.223mmol) of-3 '-(methylthio group) xenyl-3-yl acetate is dissolved in methylene dichloride (10mL) and is cooled to 0 ℃.With in the LCMS monitoring, progressively add the 3-chloroperoxybenzoic acid (64.3mg, 0.373mmol), to make the aryl sulfoxide.Add when finishing, reactant is poured in 1/4th saturated sodium hydrogen carbonate solutions (50mL), dry on sodium sulfate with the extraction of 1: 1 ethyl acetate-hexane (75mL) with salt solution (50mL) washing, filter also concentrated.Residue is dissolved in methylene dichloride (10mL) and (100 148.7mg 0.708mmol) realize that Pummerer resets by adding trifluoroacetic anhydride.At room temperature stirring reaction is 4 hours, and (121.7mg is 0.705mmol) to change into sulfone to add the 3-chloroperoxybenzoic acid then.Mixture at room temperature stirred 15 minutes, concentrated, and was dissolved in 3: 3: 1 methyl alcohol-triethylamine-water (7mL), with hydrolysis acetic ester and trifluoroacetic acid ester group.Stirring reaction is 2 hours under the room temperature, concentrates and be dissolved in methylene dichloride (10mL).Adding 3-chloroperoxybenzoic acid (49.2mg, 0.285mmol), so that compound oxidation is become sulfonic acid.Be placed under the room temperature stirring reaction 10 minutes, with the dilution of 1: 1 ethyl acetate-hexane (50mL), and with 1% saturated sodium bicarbonate solution (3 * 50mL) extract.Water layer 1.0N hydrochloric acid (approximately 10mL) acidifying, with ethyl acetate (2 * 75mL) extractions, dilute with triethylamine (1.0mL), concentrate, with reversed-phase HPLC (PolarisC18-A 10 μ 250 * 21.2mm post, 25% to 100% acetonitrile-0.1% trifluoroacetic acid in water) purifying, and by the Dowex_ sodium ion exchange resin, obtain being nearly pure white solid 4 '-{ (2S, 3R)-3-[(3S/R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sodium sulfonate (45.3mg, yield 36%); 1H NMR (300MHz, CDCl 3), δ 8.04-6.98 (m, 16H), 5.17 (d, J=2.2Hz, 0.66H), 5.14 (d, J=2.2Hz, 0.33H), 4.70-4.60 (m, 1H), 3.21-3.14 (m, 1H), 2.09-1.89 (m, 4H) ppm; MS[M-Na] -546.0
Embodiment 54 (3R, 4S)-3-[(3S)-the 3{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-(3 '-Hydroxybiphenyl-4-yl)-1-phenyl azetidine alkane-2-ketone
Figure A20048003969501381
At room temperature, under nitrogen atmosphere, (3R, 4S)-4-(3 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-4-yl)-the 3-[(3S)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-1-phenyl azetidine alkane-2-ketone stirs in anhydrous methanol (20mL).(0.10g, 1.72mmol), reaction mixture at room temperature stirred 1.5 hours to add Potassium monofluoride.Pour solution into ethyl acetate and water (2x), 10% sodium bicarbonate aqueous solution, water and salt water washing successively.Organic solution is at dry on the sodium sulfate, filtration, concentrated and use ethyl acetate-hexane (composition: 5% ethyl acetate to 50%) pass through chromatography purification on silica gel, obtain (3R for white foam, 4S)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-(3 '-Hydroxybiphenyl-4-yl)-1-phenyl azetidine alkane-2-ketone (0.46g, yield 92%); 1H NMR (300MHz, CDCl 3), δ 7.57 (d, J=8.2, Hz, 2H,) 7.37 (d, J=8.2Hz, 2H), 6.9-7 4 (m, 12H), 6.8 (m, 1H), 4.9 (br s, 1H), 4.67 (t, J=6.0Hz, 1H), 4.63 (d, J=2.5Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.0 (m, 4H), 0.87 (s, 9H), 0.02 (s, 3H) ,-0.16 (s, 3H)
Embodiment 55 (4 '-(2S, 3R)-3-[(3S)-the 3-{ tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) triflate
Figure A20048003969501391
At room temperature, under nitrogen atmosphere, (3R, 4S)-3-[(3S)-and the 3-{ tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-(0.46g 0.79mmol) stirs in anhydrous methanol (15mL) 4-(3 '-Hydroxybiphenyl-4-yl)-1-phenyl azetidine alkane-2-ketone.Add successively N-phenyl trifluoromethanesulfonate sulfonyl methane imines (0.39g, 1.09mmol), (0.23mL, (0.02g, 0.2mmol), reaction mixture at room temperature stirred 2 hours 1.65mmol and 4-(diformazan ammonia) pyridine triethylamine.Solution is poured into 0.5N hydrochloric acid (20mL), and uses ethyl acetate extraction.Organic phase is water, 10% sodium bicarbonate aqueous solution, water and salt water washing successively.Organic solution is in drying, filtration, solvent removed in vacuo on the sodium sulfate and use ethyl acetate-hexane (composition: 5% ethyl acetate to 50%) pass through chromatography purification on silica gel, obtain being 4 ' of white foam-{ (2S, 3R)-3-[(3S)-and the 3-{ tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) triflate (0.56g, 100%); 1H NMR (300MHz, CDCl3), δ 6.9-7.3 (m, 17H), 4.68 (t, J=5.7Hz, 1H), 4.65 (d, J=2.5Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.0 (m, 6H), 0.88 (s, 9H), 0.02 (s, 3H) ,-0.16 (s, 3H).
Embodiment 56 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) phosphoric acid
Figure A20048003969501401
Use is set in normal light absorption ratio, has fixed the pre-PersonalChemistry that stirs of hold-time and 30 seconds TMThe microwave instrument reacts.With 4 '-{ (2S, 3R)-3-[(3S)-and the 3-{ tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) triflate (0.27g, 0.38mmol), dimethyl phosphite (0.070mL, 0.76mmol), triethylamine (0.15mL, 1.08mmol) and toluene (4mL) pack in 10 milliliters of bottles.Nitrogen is blown over the solution 5 minutes of stirring, adds four (triphenyl phosphine) palladium (0) (0.1g), and solution covers and sealing with nitrogen.Reaction mixture heated 11 minutes down at 160 ℃, was cooled to room temperature then, and diluted with ethyl acetate.Use 0.5M hydrochloric acid (20mL, water (3x) and salt water washing yellow solution successively.Organic solution is dry on sodium sulfate, filters, and under reduced pressure rotary evaporation removes and desolvates.Use ethyl acetate-hexane (composition: 5% ethyl acetate to 100%) on silica gel, pass through chromatography purification, obtain pure for white foam (4 '-(2S, 3R)-3-[(3S)-the 3-{ tertiary butyl (dimethyl) silyl] the oxygen base-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl xenyl-3-yl) dimethyl phosphate. 1H?NMR(300MHz，CDCl3)，δ8.00(dt，J＝142，1.5Hz，1H)，7.60(d，J＝8.5Hz，2H)，7.40(d，J＝8.5Hz，2H)，6.9-7.8(m，12H)，4.68(t，J＝5.7Hz，4.64(d，J＝2.4Hz，3.81(d，J＝0.9Hz，1H)，3.77(d，J＝0.9Hz，1H)，3.0-3.1(m，1H)，1.8-2.2(m，4H)，0.88(s，9H)，0.02(s，3H)，-0.16(s，3H)ppm。
Under nitrogen atmosphere, (4 '-{ (2S, 3R)-3-[(3S)-and the 3-{ tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) dimethyl phosphate (0.32g, 0.47mmol) solution in anhydrous methanol (15mL) cools off in ice bath, in 5 minutes, splash into trimethylammonium bromide silane (0.30mL, 2.27mmol).Reaction mixture at room temperature stirred 3 hours, was poured into frozen water (20mL) then and used ethyl acetate extraction.Organic solution is water (2x) and salt water washing successively.Organic solution is dry on sodium sulfate, filters, and under reduced pressure rotary evaporation removes and desolvates.Residue reversed-phase HPLC (Polaris C18-A 10 μ 250 * 21.2mm post, 20% to 700% acetonitrile-0.1% trifluoroacetic acid in water) purifying, obtain (4 '-{ (2S for white powder, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) phosphoric acid (0.25g, 99%); 1H NMR (300MHz, CDCl3), δ 8.04 (br d, J=14.2Hz, 1H), 7.68 (d, J=8.5Hz, 2H), 7.50 (d, J=8.5Hz, 2H), 7.0-7.8 (m, 12H), 4.93 (d, J=2.2Hz, 1H), 4.63 (t, J=5.2Hz, 1H), 3.1-3.2 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS[M-H] -531, [2M-H] -1061
Embodiment 57 (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-4-yl)-1-phenyl azetidine alkane-2-ketone
Use with embodiment 42 described identical modes and synthesize (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-4-yl)-1-phenyl azetidine alkane-2-ketone.At room temperature, in 40 ml polypropylene containers of screw cap are housed, with (3R, 4S)-4-(3 '-{ [tertiary butyl (dimethyl) silyl] oxygen } xenyl-4-yl)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] oxygen }-3-(4-fluorophenyl) propyl group]-(0.60g 0.86mmol) stirs in acetonitrile (18mL) 1-phenyl azetidine alkane-2-ketone.(48% aqueous solution, 2.0mL 48mmol), at room temperature continue to stir to spend the night to splash into hydrofluoric acid.Reaction mixture is poured into by in 1M sodium phosphate (45mL, pH 7.4) the buffered 1N aqueous sodium hydroxide solution (45mL), by adding 10% sodium hydrogen carbonate solution pH value of solution is transferred to 8 then.Mixture ethyl acetate extraction, organic solution are used 10% sodium hydrogen carbonate solution (2x), water (2x) and salt water washing successively.Organic solution is dry on sodium sulfate, filters, and under reduced pressure rotary evaporation removes and desolvates.Use ethyl acetate-hexane (composition: 10% ethyl acetate to 60%) on silica gel, pass through chromatography purification, obtain the pure (3R of white foam that is, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-4-yl)-1-phenyl azetidine alkane-2-ketone (0.35g, 87%); ' H NMR (300MHz, CDCl 3), δ 7.56 (d, J=8.2, Hz, 2H), 7.39 (d, J=8.2Hz, 2H), 7.0-7.3 (m, 12H), 6.80-6.86 (m, 1H), 5.00 (br s, 1H), 4.74 (t, J=6.2Hz, 1H), 4.69 (d, J=2.2Hz, 1H), 3.1-3.2 (m, 1H), 2.20 (br s, 1H), 1.8-2.1 (m, 4H) ppm; MS[M+HCO 2 -] -512
Embodiment 58 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-xenyl-3-base triflate
At room temperature, under nitrogen atmosphere, (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-(0.353g 0.77mmol) stirs in anhydrous methylene chloride (15mL) 4-(3 '-Hydroxybiphenyl-4-yl)-1-phenyl azetidine alkane-2-ketone.
Add successively phenyl trifluoromethanesulfonate sulfonyl methane imines (0.38g, 1.69mmol), (0.23mL, 1.65mmol) (0.02g, 0.2mmol), reaction mixture at room temperature stirred 1 hour triethylamine with the 4-Dimethylamino pyridine.Solution is poured into 0.5N hydrochloric acid (20mL) and uses ethyl acetate extraction.Organic phase is water, 10% sodium hydrogen carbonate solution and salt water washing successively.Organic solution is dry on sodium sulfate, filters, and under reduced pressure rotary evaporation removes and desolvates.Use ethyl acetate-hexane (composition: 10% ethyl acetate to 60%) on silica gel, pass through chromatography purification, obtain the pure 4 '-{ (2S of white foam that is, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-xenyl-3-base triflate (0.35g, 76%); ' H NMR (300MHz, CDCl3), δ 7.0-7.6 (m, 17H), 4.74 (t, J=6.4Hz, 1H), 4.72 (d, J=2.2Hz, 1H), 3.1-3.2 (m, 1H), 2.16 (br s, 1H), 1.9-2.1 (m, 4H) ppm; MS[M+HCO 2 -] -644
Embodiment 59 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-xenyl-3-yl) boric acid
At room temperature, in 40 milliliters of screw cap containers, 4 '-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-xenyl-3-base triflate (0.15g, 0.25mmol), two valeryl two boron (Bis (pinacolato) diboron) (0.70g, 0.27mmol), Potassium ethanoate (0.80g, 0.81mmol) and dichloro [1,1 '-two (diphenylphosphino) ferrocene] (0.020g 0.03mmol) merges in methyl-sulphoxide (7mL) palladium (II).Mixture covers with nitrogen atmosphere, and container closure is reflected at 80 ℃ of following heated overnight.Reaction mixture is cooled to room temperature, is poured in the water and uses ethyl acetate extraction.Organic phase is water, 10% sodium hydrogen carbonate solution and salt water washing successively.Organic solution is dry on sodium sulfate, filters, and under reduced pressure rotary evaporation removes and desolvates.Use ethyl acetate-hexane (composition: 5% ethyl acetate to 70%) on silica gel, pass through chromatography purification, obtain the pure (3R of white foam that is, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[3 '-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) xenyl-4-yl] azetidine-2-ketone (0.097g, 67%); ' H NMR (300MHz, CDCl3), δ 8.01 (br s, 1H), 7.75-7.85 (m, 1H), 7.0-7.7 (m, 15H), 4.74 (t, J=6.2Hz, 1H), 4.69 (d, J=2Hz, 1H), 3.0-3.2 (m, 1H), 1.50 (br s, IH), 1.8-2.1 (m, 4H), 1.35 (s, 6H), 1.24 (s, 6H) ppm; MS[M+HCO 2 -] -577
(3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[3 '-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) xenyl-4-yl] (0.020g 0.034mmol) at room temperature is dissolved in ethanol (3mL) and water (1mL) to azetidine-2-ketone.(0.10g, 1.2mmol), mixture at room temperature stirred 2 hours fast to add solid sodium carbonate.Solution is poured into 0.5N hydrochloric acid (4mL) and uses ethyl acetate extraction.Organic phase is water (2x) and salt water washing successively, and is dry on sodium sulfate then, filters, and under reduced pressure rotary evaporation removes and desolvates.Residue reversed-phase HPLC (Polaris C18-A 10 μ 250 * 21.2mm post, 40% to 50% acetonitrile-0.1% trifluoroacetic acid in water) purifying, obtain (4 '-{ (2S for white powder, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-xenyl-3-yl) boric acid (0.012g, 70%); ' H NMR (300MHz, CD 3OD), δ 7.83 (br s, 1H), 7.0-7.7 (m, 16H), 4.92 (d, J=2.7Hz, 4.63 (t, J=6.2Hz, 1H), 3.1-3.2 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS[M+HCO 2 -] -540
Embodiment 60 [3-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] dimethyl phosphate
Figure A20048003969501451
At room temperature, under nitrogen atmosphere, (0.50g 3.89mmol) stirs in anhydrous methylene chloride (20mL) the 3-chlorophenol.
Add successively phenyl trifluoromethanesulfonate sulfonyl methane imines (1.8g, 5.0mmol), (0.90mL, 6.4mmol) (0.10g, 0.8mmol), reaction mixture at room temperature stirred 2 hours triethylamine with the 4-Dimethylamino pyridine.Solution is poured into 0.5N hydrochloric acid (20mL) and uses ethyl acetate extraction.Organic phase is water, 10% sodium hydrogen carbonate solution and salt water washing successively.Organic solution is dry on sodium sulfate, filters, and under reduced pressure rotary evaporation removes and desolvates.Use ethyl acetate-hexane (composition: 5% to 50% ethyl acetate) on silica gel, pass through chromatography purification, obtain the 3-chlorophenol triflate (0.92g, 91%) of pure colorless oil; ' H NMR (300MHz, CDCl 3), δ 7.16-7.50 (m) ppm
Use is set in normal light absorption ratio, has fixed the pre-PersonalChemistry that stirs of hold-time and 30 seconds TMThe microwave instrument reacts.With 3-chlorophenol trifluoromethayl sulfonic acid ester (0.60g, 2.30mmol), dimethyl phosphite (0.42mL, 4.58mmol), triethylamine (0.64mL, 4.59mmol) and toluene (4mL) pack in 10 milliliters of bottles.Nitrogen is blown over the solution 5 minutes of stirring, adds four (triphenyl phosphine) palladium (0) (0.1g), and solution covers and sealing with nitrogen.Reaction mixture heated 11 minutes down at 160 ℃, was cooled to room temperature then, and diluted with ethyl acetate.Water (3x) and salt water washing yellow solution successively.Organic solution is dry on sodium sulfate, filters, and under reduced pressure rotary evaporation removes and desolvates.Use ethyl acetate-hexane (composition: 5% ethyl acetate to 100%) on silica gel, pass through chromatography purification, obtain dimethyl (3-chlorophenol) phosphoric acid ester (0.27g, 57%) of pure colorless oil; ' H NMR (300MHz, CDCl 3), δ 7.77 (br d, J=13.7Hz, 1H), 7.68 (ddt, J=13.0,7.5,1.4Hz, 1H), 7.53 (dquint, J=8.0,1.1Hz, 1H), 7.38-7.45 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H) ppm; MS[M+H] +221, [2M+H] +441
Under nitrogen atmosphere, two (dibenzenyl acetone) palladiums (0) (Bis (dibenzylidine acetone) palladium (0)) (0.10g, 0.17mmol) and tricyclohexyl phosphine (tricyclohexylphosphine) (0.12g 0.43mmol) stirred in dried dioxane (1.0mL) 30 minutes.Dimethyl (3-chloro-phenyl-) phosphoric acid ester (0.50g, 2.26mmol), two valeryl two boron (0.70g, 0.27mmol) and Potassium ethanoate (0.30g 0.30mmol) at room temperature sneaks under nitrogen atmosphere in the dried dioxane (3.0mL) in the independent flask.Part palladium catalyst solution (0.20mL) is injected the flask of chloride substituted phosphate, this mixture heating up to 80 ℃.After 4 hours and 8 hours, in mixture, inject the described catalyst solution of 0.2mL in heating under 80 ℃ respectively, continue heated overnight down at 80 ℃ then.Reaction mixture filters by Celite_, removes by rotary evaporation under reduced pressure and desolvates.Use ethyl acetate-hexane (composition: 0% ethyl acetate to 80%) on silica gel, pass through chromatography purification, obtain [3-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] dimethyl phosphate (0.41g) of colorless oil. 1HNMR shows raw-material 60: 40 mixture of product and recovery.This mixing need not be further purified two and be used for ensuing reaction. 1H?NMR(300MHz，CDCl 3)，δ8.22(d，J＝13.2Hz，1H)，7.95-8.00(m，1H)，7.88(ddt，J＝13.0，7.5，1.4Hz，1H)，7.43-7.50(m，1H)，3.76(s，3H)，3.73(s，3H)MS[M+H] +312，[2M+H] +625
Embodiment 61 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphoric acid
Figure A20048003969501471
(3R, 4S)-4-(the 4-bromo-2-{[tertiary butyl (dimethyl) silyl] the oxygen base } phenyl)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-1-phenyl azetidine alkane-2-ketone (0.080g, 0.11mmol), [3-(4 for thick dimethyl, 4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) xenyl-4-yl] azetidine-2-yl) phenyl] phosphoric acid salt (amounts to 0.054g, reality is 0.030g, 0.096mmol) and the 2M wet chemical (0.12mL 0.24mmol) sneaks into ethanol (1.0mL) and toluene (3.0mL).When stirring, in mixture, lead to 5 minutes nitrogen, solution is carried out deoxygenation.Add four (triphenyl phosphine) palladium (0) (0.05g), under nitrogen atmosphere, be reflected at 70 ℃ and heated 3 hours down.Reaction is cooled to room temperature, with ethyl acetate dilution, water and salt water washing, dry on the sodium sulfate and concentrate by rotary evaporation under reduced pressure.Use ethyl acetate-hexane (composition: 10% ethyl acetate to 80%) on silica gel, pass through the chromatography purification product, obtain (3 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-4 '-{ (2S for colorless slurry, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) dimethyl phosphate (0.065g, 84%). 1H?NMR(300MHz，CDCl 3)，δ6.9-8.0(m，16H)，5.09(d，J＝2.2Hz，1H)，4.64(d，J＝6.1Hz，1H)，3.79(d，J＝2.4Hz，3H)，3.76(d，J＝2.4Hz，3H)，3.05-3.15(m，1H)，1.8-2.0(m，4H)，1.06(s，9H)，0.85(s，9H)，0.36(s，3H)，0.33(s，3H)，0.00(s，3H)，-0.20(s，3H)ppm
At room temperature, under nitrogen atmosphere, (3 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-4 '-{ (2S, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) (0.047g 0.058mmol) stirs in anhydrous methanol (2mL) dimethyl phosphate.(0.02g, 0.34mmol), reaction mixture at room temperature stirred 30 minutes to add Potassium monofluoride.Solution is poured in the ethyl acetate, and water (2x) and salt water washing successively.Organic solution is dry on sodium sulfate, and removes solvent by rotary evaporation under reduced pressure.Obtain for (the 4 '-{ (2S of flint glass shape, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 ' Hydroxybiphenyl-3-yl) dimethyl phosphate (0.041g, 100%) is directly used in next step reaction without purifying; MS[M-H] +688
Under nitrogen atmosphere, (4 '-{ (2S in anhydrous methylene chloride (5mL), 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 ' Hydroxybiphenyl-3-yl) dimethyl phosphate (0.041g, 0.059mmol) solution cools off in ice, in 5 minutes, splash into trimethylammonium bromide silane (0.030mL, 0.30mmol).Reaction mixture at room temperature stirred 3 hours, added methyl alcohol (1mL) then, and reaction divides between water and ethyl acetate.Organic solution is water (2x) and salt water washing successively.Organic solution is dry on sodium sulfate, and removes solvent by rotary evaporation under reduced pressure.Residue reversed-phase HPLC (Polaris C18-A 10 μ 250 * 21.2mm post, 30% to 59% acetonitrile-0.1% trifluoroacetic acid in water) purifying, obtain (4 '-{ (2S for white powder, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphoric acid (0.014g, 44%); 1H NMR (300MHz, CDCl 3), δ 8.0 (d, J=13.6Hz, 1H), 6.9-7.8 (m, 15H), 5.17 (d, J=2.1Hz, 1H), 4.63 (d, J=5.2Hz, 1H), 3.15-3.25 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS[M-H] +546, [2M-H] +1093
Embodiment 62 (1S)-2,3,4,6-four-O-ethanoyl-1,5-dehydration-1-(3-bromophenyl)-D-sorbitol
Figure A20048003969501491
Under 0 ℃, (1.0g 5.55mmol) is dissolved in 5mL acetic anhydride and the 7mL pyridine D-Glucopyranose.Add in this mixture the 4-Dimethylamino pyridine (200mg, 1.63mmol), stirring reaction when being warming up to room temperature.After 18 hours, TLC (40% ethyl acetate-hexane) shows the starting material completely consumed and forms higher flow cracks (running spot).Reactant is poured in the 50mL water and extracts in methylene dichloride (in 3 * 50mL).Organic layer merges, and (filtration concentrates for 3 * 20mL) washings, drying on sodium sulfate with 1N hydrochloric acid; with column chromatography (50g silica gel, 40% ethyl acetate-hexane) purifying, obtain 1,2; 3,4, and 6-five-O-ethanoyl D-Glucopyranose (2.10g, 5.37mmol).
Under 0 ℃, 1,2,3,4, (1.0g 2.60mmol) is dissolved in 20mL of methylene dichloride and 1.90mL Hydrogen bromide (33%, in acetate), stirring reaction when being warming up to room temperature then to 6-five-O-ethanoyl D-Glucopyranose.After 18 hours, TLC (40% ethyl acetate-hexane) shows the starting material completely consumed and forms higher flow cracks (running spot).Reactant is with slowly dilution of saturated sodium bicarbonate (25mL), extract in methylene dichloride (in 2 * 100mL), dry on sodium sulfate, filter, concentrate, do not carried out 2,3,4 of purifying, 6-four-O-ethanoyl-α-D-glucopyranosyl bromide.
Magnesium (0) (400mg) is suspended in 17 milliliters of anhydrous diethyl ethers, adds 100 microlitre glycol dibromides in this suspension.Add 1 with the speed of controlling the appropriateness backflow, and the 3-dibromobenzene (3.8g, 16.08mmol).After Grignard forms and finishes (magnesium consumes and will reflect cooling), dropwise add 2,3,4,6-four-O-ethanoyl-α-D-glucopyranosyl bromide (0.34g, 0.80mmol is in the 8mL anhydrous diethyl ether).Reaction refluxed 5 hours, was cooled to room temperature, was poured in the separating funnel of 20mL water.Flask washes and joins in the separating funnel with 50mL ether and 3mL acetate (for the dissolving magnesium salts).After the layering, collect water layer and vacuum concentration.White pulpous state solid is dissolved in 15mL pyridine and the 10mL diacetyl oxide.After at room temperature reacting 20 hours, be poured in the 150mL water and extract in methylene dichloride (in 3 * 150mL).Organic layer merges, with 1N hydrochloric acid (3 * 50mL) washings, drying on sodium sulfate, filter, concentrate, with column chromatography (12g silica gel, 5 to 95% ethyl acetate-hexane) purifying, obtain (1S)-2,3,4 for white foam, 6-four-O-ethanoyl-1,5-dehydration-1-(3-bromophenyl)-D-sorbitol (0.178g, 0.36mmol, yield 45%); R f(0.4 40% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 7.44 (m, and 2H) 7.25 (m, 2H), 5.27-5.35 (m, 1H), 5.21 (t, J=9.6Hz, 1H), 5.03 (t, J=9.7Hz, 1H), 4.36 (d, J=9.9Hz, 1H), 4.23-4.32 (m, 1H) 4.08-4.18 (m, 1H) 3.80-3.85 (m, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.84 (s, 3H) ppm; MS[M+H] +488.4
Embodiment 63 uses the method identical with embodiment 62 synthetic, and different is with 1,4-dibromobenzene replacement 1,3-dibromobenzene.
Obtain (1S)-2,3,4,5-four-O-ethanoyl-1,5-dehydration-1-(4-bromobenzene)-D-sorbitol (yield 45%, white wax).R f(0.3 40% ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3), δ 7.47 (d, J=8.4Hz, 2H), 7.31 (d, J=8.2H), 5.31 (d, J=9.3Hz, 1H), 5.21 (t, J=9.9Hz, 1H), 5.09 (t, J=9.6Hz, 1H), 4.37 (d, J=9.9Hz, 1H), 4.12-4.33 (m, 2H), 3.83 (m, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.83 (s, 3H) ppm; MS[M+H] +488.4
Embodiment 64. (1S)-1,5-dehydration-1-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyphenyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-sorbitol
(3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4; 5; 5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] azetidine-2-ketone (51.3mg; 0.102mmol) and (1S)-2; 3,4,6-four-O-ethanoyl-1; (35.5mg 0.073mmol) is dissolved in 2.0mL toluene and the 0.25mL ethanol 5-dehydration-1-(3-bromophenyl)-D-sorbitol.Add the 4N salt of wormwood of 0.075mL in the mixture, add 0.5 milligram of four (triphenyl phosphine) palladium (0) then.Argon-degassed three times of entire reaction thing, reflux is 4 hours then.Reaction is cooled to room temperature, dilute with 5 ml waters, and (3 * 25mL) extracts with ethyl acetate.Organic layer merges; dry on sodium sulfate, filter, concentrate; with column chromatography (12g silica gel; 5 to 95% ethyl acetate-hexane) purifying, obtain to clarifying buttery 10.5mg (13%) (1S)-2,3; 4; 6-four-O-ethanoyl-1,5-dehydration-1-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-sorbitol.
(1S)-2; 3; 4; 6-four-O-ethanoyl-1; 5-dehydration-1-(4 '-{ (2S; 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-(10.5mg 0.013mmol) is dissolved in 0.30mL methyl alcohol and 0.30mL triethylamine to the D-sorbitol, dropwise adds entry (0.80 milliliter) then.The xanchromatic mixture at room temperature stirs and spends the night.The LCMS confirmation raw materials consumption of solution has been fallen, and forms the material of removing protection fully.The mixture vacuum concentration, and by reversed-phase HPLC (250 * 21.2 millimeters posts of Polaris C18-A 10 μ, 30% to 95% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying, obtain for white powder 2.8mg (35%) (1S)-1,5-dehydration-1-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo 1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-sorbitol; 1H NMR (300MHz, CD 3OD) δ 7.65 (d, J=11.1Hz, 2H), 7.54-7.23 (m, 1H), and 7.05-6.89 (m, 3H), 4.61 (t, J=6.3Hz, 1H), 4.19 (d, J=9.0Hz, 1H), 3.87 (d, J=10.7Hz, 1H), 3.73-3.63 (m, 1H), 3.49-3.36 (m, 3H) 3.22-3.18 (m, 2H), 1.89 (m, 4H) ppm; MS[M-OH] +596.5
Embodiment 65 (1S)-1,5-dehydration-1-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
(3R, 4S)-4-(the 4-bromo-2-{[tertiary butyl (dimethyl) silyl] the oxygen base } phenyl)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-(0.42g 0.60mmol) is dissolved in 15 milliliters of dioxanes of sealed tube 1-phenyl azetidine alkane-2-ketone.Add two valeryl two boron (0.170.66mmol), potassium acetate (0.18g, 1.83mmol) and dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride affixture (14.6mg, 0.mmol), the reactant argon-degassed, and under 85 ℃, heated 24 hours.Mixture is cooled to room temperature, with 50mL ethyl acetate-hexane dilution in 1: 1, with 100mL 0.1N hydrochloric acid and the water washing of 2 * 100mL salt.Collected organic layer, partial concentration, wash with 50 milliliters of ethyl acetate by 10 gram filtered through silica gel to half volume, and vacuum concentration.
Brown oil (the 3R that obtains; 4S)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base } 3-(4-fluorophenyl) propyl group]-the 4-[2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-4-(4; 4,5,5-tetramethyl--1; 3; 2-two oxa-s pentaborane-2-yl) phenyl]-1-phenyl azetidine alkane-2-ketone and (1S)-2,3,4; 6-four-O-ethanoyl-1,5-dehydration-1-(3-bromophenyl)-D-sorbitol is dissolved in 4.0mL toluene and the 0.5mL ethanol.Add 0.150mL salt of wormwood, add 7 milligram of four (triphenyl phosphine) palladium (0) then.Argon-degassed three times of entire reaction thing, reflux is 1.5 hours then.Reaction is cooled to room temperature, dilute with 25 ml waters, and (3 * 75mL) extracts with 1: 1 hexane-ethyl acetate.Organic layer merges; dry on sodium sulfate; filter; concentrate; with column chromatography (12g silica gel; 5 to 95% ethyl acetate-hexane) purifying; obtain to clarifying buttery 41.6mg (27%) (1S)-2; 3; 4; 6-four-O-ethanoyl-1,5-dehydration-1-(3 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-4 '-(and 2S, 3R)-3-[(3S)-the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-sorbitol.
This material is dissolved in 0.80mL methyl alcohol and the 0.80 milliliter of triethylamine immediately, dropwise adds water (2.3mL) then.Yellow mixture at room temperature stirred 24 hours, extract in 1: 1 ethyl acetate-hexane (3 * 100mL), dry and vacuum concentration on sodium sulfate, obtain (1S)-1,5-dehydration-1-(3 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-4 '-(and 2S, 3R)-3-[(3S)-the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-sorbitol.
By with (1S)-1; 5-dehydration-1-(3 '-{ [tertiary butyl (dimethyl) silyl] oxygen base } 4 '-{ (2S; 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-sorbitol is dissolved in the 5mL acetonitrile and adds 2.5mL 48% hydrofluoric acid, finishes final removal protection.Mixture at room temperature stirred 1.5 hours, with 70mL 1N sodium hydroxide and 50mL pH is the neutralization of 7.4 1M sodium phosphate buffer, extract in ethyl acetate (2 * 100mL), with saturated sodium bicarbonate (2 * 25mL) washings, use dried over sodium sulfate, filter and vacuum concentration.Crude samples reversed-phase HPLC (250 * 21.2 millimeters posts of Polaris C18-A 10 μ, 30% to 95% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying, obtain 7.9mg (74%) and be (1S)-1 of white solid, 5-dehydration-1-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyphenyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol; 1HNMR (300MHz, CD 3OD) δ 7.49 (dd, J=6.6Hz, 4H), 7.21 (m, 7H), 7.15 (d, J=7.8Hz, 1H), 7.07-6.97 (m, 5H), 5.13 (d, J=2.1Hz, 1H), 4.61 (m, 1H), 4.15 (d, J=9.3Hz, 1H), 3.90 (d, J=12Hz, 1H), 3.70 (m, and 1H) 3.41 (m, 4H), 3.16 (m, 1H), 1.99-1.93 (m, 4H) ppm; MS[M-OH] +612.6
Embodiment 66 (1S)-1,5-dehydration-1-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
Figure A20048003969501541
Use the method identical with embodiment 65 to obtain, different is usefulness (1S)-2,3,4; 6-four-O-ethanoyl-1,5-dehydration-1-(4-bromophenyl)-D-sorbitol replaces (1S)-2,3; 4,6-four-O-ethanoyl-1,5-dehydration-1-(3-bromophenyl)-D-sorbitol.(1S)-1,5-dehydration-1-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyphenyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-D-glucose (yield 20%, white solid). 1H?NMR(300MHz，CD 3OD)δ7.49(dd，J＝8.1Hz，4H)，7.35-7.16(m，8H)，7.05-6.97(m，4H)，5.15(d，J＝1.8Hz，1H)，4.61(m，1H)，4.16(d，J＝9.6Hz，1H)，3.90(d，J＝11.1Hz，1H)，3.71(m，1H)，3.42(m，4H)，3.16(m，1H)，2.02-1.93(m，4H)ppm；MS[M-OH] +612.6
Embodiment 67 (2S/2R, 3S, 4S, 6R, 7R, 8S)-and 3-O-t-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-two oxa-s-2-(3-bromophenyl)-two ring [3.3.0] octanes
Figure A20048003969501551
Under-78 ℃, in 30 minutes, n-Butyl Lithium (31.5mL, 41.0mmol, 1.3M hexane) joins by addition funnel and is dissolved with 1, and (9.64g, 41.0mmol is in anhydrous tetrahydro furan 4.94mL) (30mL) for the 3-dibromobenzene.Addition funnel stirred 30 minutes down at-78 ℃ with anhydrous tetrahydro furan (15mL) flushing, reactant.Under-78 ℃, add in this solution and be dissolved in 30 milliliters of 5-O-t-butyldimethylsilyl-1 in the anhydrous tetrahydro furan, 2-O-isopropylidene-Glucuronic acid lactone (4.5g, 13.6mmol) [according to Tetrahedron Asymmetry 7: 9,2761, (1996) preparation], stirring reaction 2 hours.Add saturated ammonium chloride (20mL) cancellation reaction, be warming up to room temperature then.Reactant is poured in ethyl acetate (30mL) and the water (10mL), carries out layering.(2 * 20mL) extract water layer with ethyl acetate.The organic layer that merges is dry on anhydrous sodium sulphate, filters, and concentrates and with chromatography (1: 1 ethyl acetate-hexane) purifying, obtain (2S/2R, 3S, 4S for colourless viscosity oily matter, 6R, 7R, 8S)-3-O-t-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1, the non-enantiomer mixture (4.77g, yield 72%) of 5-two oxa-s-2-(3-bromophenyl)-two ring [3.3.0] octanes, R f(0.51 3: 1 hexane-ethyl acetate)
Embodiment 68 (6S)-6-C-(3-the bromophenyl)-6-O-[tertiary butyl (dimethyl) silyl]-1,2-O-(1-methyl ethylidene)-α-D-glucopyranose
Figure A20048003969501561
Sodium borohydride (11.1mg, 0.29mmol) at room temperature add (2S/2R, 3S, the 4S that are dissolved in straight alcohol (4mL) to, 6R, 7R, 8S)-3-O-t-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1 is in 5-two oxa-s-2-(3-bromophenyl)-two ring [3.3.0] octanes.At room temperature stirring reaction is 1 hour.TLC analyzes (3: 1 hexane-ethyl acetate) and shows that all initial lactols (lactol) are consumed, and adds 1 milliliter of saturated ammonium chloride solution, and stirring reaction is up to stopping bubbling.Reactant is poured in ethyl acetate (30mL) and the water (10 milliliters), carries out layering.Water layer is with 2 * 20 milliliters of ethyl acetate extractions.The organic extract that merges is dry on anhydrous sodium sulphate, filter, concentrate and with chromatography (1: 3 ethyl acetate-hexane) purifying, obtain (6S)-6-C-(3-the bromophenyl)-6-O-[tertiary butyl (dimethyl) silyl for white waxy solid]-1,2-O-(1-methyl ethylidene)-α-D-glucopyranose (125mg, yield 88%); Fusing point 76-77 ℃; R f0.24 (3: 1 hexanes: ethyl acetate); 1H NMR (300MHz, CDCl 3) δ 7.51-7.17 (m, 4H), 5.95 (d, J=3.6Hz, 1H), 4.90 (s, 1H), 4.53 (d, J=3.9Hz, 1H), 4.32 (d, J=2.7Hz, 1H), 4.09 (dd, J=2.7Hz, J=8.4Hz, 1H), 3.75 (d, J=7.2Hz, 1H), 2.76-2. (br s, 2H), 1.46 (s, 3H), 1.31 (s, 3H), 0.92 (s, 9H), 0.11 (s, 3H) ,-0.10 (s, 3H) ppm
Embodiment 69 (6R)-6-C-(3-bromophenyl)-1,2-O-(1-methyl ethylidene)-α-D-glucofuranose
Tertiary butyl Neutral ammonium fluoride (1M is arranged in tetrahydrofuran (THF), 3.14 milliliters) dropwise adds (the 2S/2R of anhydrous tetrahydro furan (30 milliliters) under 0 ℃, 3S, 4S, 6R, 7R, 8S)-3-O-t-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-two oxa-s-2-(3-bromophenyl)-two ring [3.3.0] octane (1.53g, 3.14mmol) and Glacial acetic acid (188.4mg, 3.14mmol, 180 μ L) in.0 ℃ of following stirring reaction 30 minutes, be warming up to room temperature and restir then 30 minutes.TLC analyzes (3: 1 hexane-ethyl acetate) and shows that the starting material completely consumed falls.Reactant is poured in the ethyl acetate (30mL), with saturated sodium bicarbonate (10mL) and salt solution (2 * 10mL) washings.(2 * 20mL) extract water layer with ethyl acetate.The organic extract that merges is dry on anhydrous sodium sulphate, filters, and concentrates and with chromatography (35g, 40% ethyl acetate-hexane) purifying obtains (2S/2R, 3S into white solid, 4S, 6R, 7R, 8S)-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-two oxa-s-2-(3-bromophenyl)-two ring [3.3.0] octanes (1.146g, yield 98%); R f(0.18 3: 1 hexane-ethyl acetate).
(116mg 3.1mmol) at room temperature joins (2S/2R, 3S, 4S, the 6R that is dissolved in straight alcohol (5mL) to sodium borohydride, 7R, 8S)-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-two oxa-s-2-(3-bromophenyl)-two ring [3.3.0] octanes (1.15g, 3.1mmol) in.At room temperature stirring reaction is 1 hour.TLC analyzes (2: 1 hexane-ethyl acetate) and shows that all initial lactols are consumed.Add 1 milliliter of saturated ammonium chloride solution, stirring reaction is up to stopping bubbling.Reactant is poured in ethyl acetate (30mL) and the water (10 milliliters), carries out layering.Water layer extracts with ethyl acetate (2 * 20 milliliters).The organic extract that merges is dry on anhydrous sodium sulphate, filter, concentrate and, obtain (6R)-6-C-(3-bromophenyl)-1 into white solid with chromatography (2: 1 ethyl acetate-hexanes) purifying, 2-O-(1-methyl ethylidene)-α-D-glucofuranose (511mg, yield 89%); Fusing point 172-173 ℃; R f(0.19 2: 1 ethyl acetate-hexanes); 1H NMR (300MHz, CDCl 3/ CD 3OD) δ 7.62-7.61 (m, 1H), 7.42-7.38 (m, 1H), 7.21 (t, J=7.5Hz, 5.94 (d, J=3.9Hz, 1H), 4.86 (d, J=4.5Hz, 1H), 4.48 (d, J=3.3Hz, 1H), 4.24 (d, J=2.4Hz, 1H), 4.14-4.10 (m, 1H), 3.79-3.74 (m, 1H), 1.38 (s, 3H), 1.30 (s, 3H) ppm
Embodiment 70 (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] azetidine-2-ketone
Figure A20048003969501581
(3R, 4S)-4-(4-bromobenzene)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone (45.1mg, 10mmol), two valeryl two boron (27.7mg, 11mmol), potassium acetate (29.7mg, 0.30mmol) and dichloro [1,1 '-two (diphenylphosphino) ferrocene] (2.4mg 0.003mmol) is dissolved in the anhydrous dimethyl sulphoxide (600 μ L) palladium (II) methylene dichloride affixture.Container is found time and with argon cleaning three times, and sealing then is 80 ℃ of heating 16 hours down.Lcms analysis shows residual some starting material that have, so adds a part of catalyzer and two valeryl two boron again, and the solution degassing and continuation were heated 2 hours.Reactant dilutes in methylene dichloride (30mL) and filters by Celite_.Filtrate is with the water washing of 2 * 10mL.The water layer that merges is with 3 * 10mL dichloromethane extraction.The organic phase that merges is dry on anhydrous sodium sulphate, filters, and vacuum concentration.Product chromatography (12g, 20-50% ethyl acetate-hexane) purifying, obtain being brown foamy (3R, 4S)-3-[(3S)-3-(4-fluorophenyl) 3-hydroxypropyl]-1-phenyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] azetidine-2-ketone (41.9mg, yield 85%); R f(1: 1 ethyl acetate-hexane); 1H NMR (300MHz, CDCl 3) δ 7.81 (d, J=8.1Hz, 1H), 7.35-7.18 (m, 9H), 7.04-6.97 (m, 3H), 4.70 (t, J=5.7Hz, 1H), 4.65 (d, J=2.1Hz, 1H), 3.08 (dt, J=7.7,2.5,1H), 2.02-1.87 (m, 4H), 1.33 (s, 12H) ppm
Embodiment 71 (6S)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-Glucopyranose
(3R, 4S)-3-[(3S)-3-(4-fluorophenyl) 3-hydroxypropyl]-1-phenyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] azetidine-2-ketone (26.8mg, 0.05mmol), (6S)-6-C-(3-the bromophenyl)-6-O-[tertiary butyl (dimethyl) silyl]-1,2-O-(1-methyl ethylidene)-α-D-glucofuranose (18.1mg, 0.04mmol) and salt of wormwood (40 microlitres, the 4N aqueous solution) be dissolved in 1: 1 toluene: in the ethanol (cumulative volume is 1 milliliter).By container being found time and cleaning three times, make the solution degassing with argon gas.
(2.2mg, 0.002mmol), solution outgases twice to add four (triphenyl phosphine) palladium (0).Reactant heated 1 hour down at 85 ℃.The initial glucoside of LCMS and TLC (1: 1 hexane-ethyl acetate) analysis revealed consumes.Reactant dilutes in ethyl acetate (30 milliliters), and water (2 * 10mL) washings.(2 * 10mL) extract the water washing liquor that merges with ethyl acetate.The organic extract that merges is dry on anhydrous sodium sulphate, filter, vacuum-drying, and with chromatography (12 the gram silica gel, 20-50% ethyl acetate-hexane) purifying, obtain (6S)-6-O-[tertiary butyl (dimethyl) silyl for white foam]-6-C-(4 '-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-1,2-O-(1-methyl ethylidene)-α-D-glucofuranose (13.5mg, yield 45%); R f(0.23 1: 1 hexane-ethyl acetate); 1H NMR (300MHz, CDCl 3) δ 7.58-7.22 (m, 13H), 7.07-6.98 (m, 4H), 5.97 (d, J=3.9Hz, 1H), 4.98 (d, 4Hz, 1H), 4.73 (t, J=6.3Hz, 1H), 4.69 (d, J=2.1Hz, 1H), 4.54 (d, J=3.9Hz, 1H), 4.37 (d, J=2.4Hz, 1H), 3.87-3.86 (m, 1H), 3.13-3.09 (m, 1H), 2.04-1.86 (m, 4H), 1.43 (s, 3H), 1.31 (s, 3H), 0.94 (s, 9H), 0.12 (s, 3H) ,-0.09 (s, 3H) ppm
In polypropylene centrifuge tube, (6S)-the 6-O-[tertiary butyl (dimethyl) silyl]-6-C-(4 '-(2S, 3R)-3-[(3S)-3-methyl ethylidene)-(13.5mg 0.017mmol) is dissolved in the acetonitrile (5mL) α-D-Glucopyranose.At room temperature add 48% hydrofluoric acid (500 μ L), stirring reaction is 16 hours under the LCMS monitoring.When finishing, (1.27g, 12mmol) and just in time the water of capacity is with dissolved solids to add the solid sodium carbonate of equal amount.Reactant carries out layering with ethyl acetate (20mL) dilution.(3 * 10mL) extract the aqueous solution with ethyl acetate.The organic extract saturated sodium carbonate that merges. (2 * 10mL) extractions, dry on anhydrous sodium sulphate, filter, vacuum concentration, and, obtain (6S)-6-C-(4 '-{ (2S with reversed-phase HPLC (250 * 21.2 millimeters posts of PolarisC18-A 10 μ, 30% to 95% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-D-Glucopyranose (5.5mg, 51%); 1H NMR (300MHz, CDCl 3/ CD 3OD) δ 7.64-7.58 (m, 2H), 7.48-7.21 (m, 12H), 7.08-6.98 (m, 3H), and 5.12-5.07 (m, 1.4H), 4.73 (d, J=2.4Hz, 1H), 4.66 (t, J=5.7Hz, 1H), 4.39 (d, J=7.5Hz, 0.6H), 4.00 (dd, J=1.5Hz, J=9.6Hz, 0.6H), 3.76-3.56 (m), 3.23-3.10 (m, 1.5H), 2.01-1.90 (m, 4H) ppm; MS[M+H] +630.0
Embodiment 72 (6R)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-Glucopyranose
Figure A20048003969501611
Use the method acquisition identical with embodiment 71, the different products that are to use embodiment 68 and 70 are as starting material.(6R)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-D-Glucopyranose (2.4mg, yield 53%); 1HNMR (300MHz, CDCl 3/ 0.1%CD 3OD) δ 7.64-7.58 (m, 2H), 7.49-7.23 (m, 12H), 7.08-6.98 (m, 3H), 5.06 (d, J=3.6Hz, 0.6H), 4.91 (d, J=6.0Hz, 1H), 4.72 (d, J=4.8Hz, 1H), 4.66 (t, J=5.4Hz, 1H), 4.42 (d, J=7.8Hz, 0.4H), 4.07-4.02 (m, 1H), 3.69-3.66 (m, 1H), 3.16-3.11 (m, 1H), 1.96-1.91 (m, 4H) ppm; MS[M+H] +630.0
Embodiment 73 (6S)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-Glucopyranose
(3R, 4S)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base } 3-(4-fluorophenyl) propyl group]-the 4-[2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl]-1-phenyl azetidine alkane-2-ketone (53.0mg, 0.07mmol), (6S)-and 6-C-(3-the bromophenyl)-6-O-[tertiary butyl (dimethyl) silyl]-1,2-O-(1-methyl ethylidene)-α-D-glucofuranose (24.1mg, 0.05mmol) and salt of wormwood (50 microlitres, the 4N aqueous solution) be dissolved in 1: 1 toluene: in the ethanol (cumulative volume is 1 milliliter).By container being found time and cleaning three times, make the solution degassing with argon gas.(4.0mg, 0.003mmol), solution outgases twice to add four (triphenyl phosphine) palladium (0).Reactant heated 1 hour down at 85 ℃.The initial glucoside of LCMS and TLC (1: 1 hexane-ethyl acetate) analysis revealed consumes.Reactant dilutes in ethyl acetate (30 milliliters), and water (2 * 10mL) washings.(2 * 10mL) extract the water washing liquor that merges with ethyl acetate.The organic extract that merges is dry on anhydrous sodium sulphate, filter, vacuum-drying, and with chromatography (12 the gram silica gel, 5-50% ethyl acetate-hexane) purifying, obtain (6S)-6-O-{[tertiary butyl (dimethyl) silyl for white foam]-6-C-(4 '-{ (2S, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-1,2-O-(1-methyl ethylidene)-α-D-glucofuranose (10.5mg, yield 20%); 1H NMR (300MHz, CDCl 3) δ 7.44-7.18 (m, 13H), 7.05-6.93 (m, 3H), 5.97 (d, J=3.9Hz, 1H), 5.03 (d, J=2.1Hz, 1H), 4.95 (d, J=2.4Hz, 1H), 4.67 (m, 1H), 4.56 (t, J=4.8Hz, 1H), 4.10 (dd, J=7.6,3.0Hz, 1H), 3.87 (m, 1H), 3.12 (m, 1.94-1.89 (m, 4H), 1.44 (s, 3H), 1.31 (s, 3H), 0.93 (s, 9H), 0.86 (s, 9H), 11 (s, 3H), 0.01 (s, 3H) ,-0.11 (s, 3H) ,-0.16 (s, 3H) ppm
In polypropylene centrifuge tube, (6S)-the 6-O-{[tertiary butyl (dimethyl) silyl]-6-C-(4 '-{ (2S, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] oxygen }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-1,2-O-(1-methyl ethylidene)-α-D-glucofuranose is dissolved in the acetonitrile (5mL).At room temperature add 48% hydrofluoric acid (750 μ L), stirring reaction is 16 hours under the LCMS monitoring.When finishing, (1.91g, 18mmol) and just in time the water of capacity is with dissolved solids to add the solid sodium carbonate of 1 equal amount.Reactant carries out layering with ethyl acetate (20mL) dilution.(3 * 10mL) extract the aqueous solution with ethyl acetate.The organic extract saturated sodium carbonate that merges. (2 * 10mL) extractions, dry on anhydrous sodium sulphate, filter, vacuum concentration, and with reversed-phase HPLC (250 * 21.2 millimeters posts of Polaris C18-A 10 μ, 30% to 95% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying, obtain (6S)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl-3 '-Hydroxybiphenyl-3-yl)-D-Glucopyranose (17.8mg); 1H NMR (300MHz, CDCl 3/ CD 3OD) δ 7.52-6.83 (m, 16H), 5.05-5.00 (m, 2H), 4.50 (m, 1H), 4.34 (m, 1H), 3.94 (m, 1H), 3.72-3.59 (m, 2H), 2.91 (m, 1H), 1.95-1.77 (m, 4H) ppm; MS[M-OH] +627.8
Embodiment 74 (6R)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-Glucopyranose
Figure A20048003969501641
Use the mode identical to obtain with embodiment 73.With reversed-phase HPLC (250 * 21.2 millimeters posts of Polaris C18-A10 μ, 30% to 95% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying, obtain (6R)-6-C-(4 '-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-D-Glucopyranose (4.1mg, yield 70%); 1HNMR (300MHz, CDCl 3/ CD 3OD) δ 7.55-6.90 (m, 16H), 5.08-2.06 (m, 1H), 5.01-5.00 (m, 1H), 4.86 (d, J=4.5Hz, 1H), 4.60 (t, J=1Hz, 1H), 4.39 (d, J=8.1Hz, 1H), 4.02-3.97 (m, 1H), and 3.70-3.64 (m, 1H), 3.52-3.49 (m, 1H), 1.96-1.85 (m, 4H) ppm; MS[M-OH] +627.8
Embodiment 75 (6S)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
(6S)-6-C-(4 '-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-(7.1mg 0.01mmol) is dissolved in 80: 20 acetonitrile-waters (1mL) to the D-Glucopyranose.(0.4mg, 0.01mmol), stirring reaction is 30 minutes under the LCMS monitoring at room temperature to add sodium borohydride.When finishing, reactant was with 80: 20 acetonitriles: water (3mL) dilution, filter by Whatman0.45 micron glass microfiber filters then, with reversed-phase HPLC (250 * 21.2 millimeters posts of PolarisC18-A 10 μ, 30% to 95% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying, obtain (6S)-6-C-(4 '-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-D-sorbitol (1.4mg, yield 22%). 1HNMR(300MHz，CDCl 3/CD 3OD)δ7.37-6.89(m，16H)，5.08(d，J＝2.4Hz，1H)，4.97-4.95(m，4.60(t，J＝6.0Hz，1H)，3.92(m，1H)，3.76-3.56(m，6H)，2.01-1.82(m，4H)ppm；MS[M-OH] +629.8
Embodiment 76 6-O-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-the D-Glucopyranose
Figure A20048003969501661
Diethyl azepine dicarboxylic ester (192.4mg; 1.11mmol; 172 μ L) under 0 ℃, dropwise add to and be dissolved in 1 of dry tetrahydrofuran (2 milliliters); 2; 3, and 4-four-O-ethanoyl-β-D-Glucopyranose (350.0mg, 1.01mmol), 3-bromophenol (174.0mg; 11mmol) and triphenylphosphine (115.0mg, 0.44mmol) in.Reactant is warming up to room temperature and stirred 16 hours.Reactant dilutes in ethyl acetate (30mL), and (2 * 10mL) wash with 5% sodium pyrosulfate.Isolating organic solution is dry on anhydrous sodium sulphate, filters, and vacuum concentration is also used chromatography (20% ethyl acetate-methylene dichloride) purifying, obtains 1,2,3,4-four-O-ethanoyl-6-O-(3-bromophenyl)-β-D-Glucopyranose (357mg, yield 71%).
At room temperature triethylamine (1mL) is added to be dissolved in 5: 1 methanol-water (6mL) 1,2,3,4-four-O-ethanoyl-6-O-(3-bromophenyl)-β-D-Glucopyranose (200mg, 0.40mmol) in.With LCMS and TLC (20% ethyl acetate-methylene dichloride) monitoring reaction process.When finishing, vacuum is removed solvent, the 6-O-that is not further purified (3-bromophenyl)-β-D-Glucopyranose.
T-butyldimethylsilyl trifluoromethayl sulfonic acid ester (442mg, 1.67mmol, 383 microlitres) under 0 ℃, dropwise add to 6-O-(the 3-bromophenyl)-β-D-Glucopyranose that is dissolved in methylene dichloride (3 milliliters) and 4-Dimethylamino pyridine (219mg, 1.79mmol) in.Reactant is heated to room temperature and stirred 16 hours.Reactant dilutes in methylene dichloride (30mL), and (2 * 10mL) wash with 5% sodium pyrosulfate.Isolating organic solution is dry on anhydrous sodium sulphate, filter, vacuum concentration and with chromatography (50% ethyl acetate-methylene dichloride) purifying, obtain 6-O-(3-bromophenyl)-β-D-Glucopyranose two-the O-[tertiary butyl (dimethyl) silyl] ether (98.9mg, yield 44%); R f=0.14 (50% ethyl acetate-hexane).
(3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] azetidine-2-ketone (141.5mg, 0.27mmol), 6-O-(3-bromophenyl)-β-D-Glucopyranose is two-the O-[tertiary butyl (dimethyl) silyl] ether (98.9mg, 0.18mmol) and salt of wormwood (175 microlitres, the 2M aqueous solution) be dissolved in 1: 1 toluene-ethanol (cumulative volume is 1mL).By container being found time and, solution being outgased with argon cleaning three times.
(10.0mg, 0.009mmol), solution outgases twice to add four (triphenyl phosphine) palladium.Reactant heated 1 hour down at 85 ℃.The initial glucoside of LCMS and TLC (1: 1 hexane-ethyl acetate) analysis revealed consumes.Reactant dilutes in ethyl acetate (30 milliliters), and water (2 * 10mL) washings.(2 * 10mL) extract the water washing liquor that merges with ethyl acetate.The organic extract that merges is dry on anhydrous sodium sulphate, filter, vacuum-drying, and with chromatography (12 the gram silica gel, 5-50% ethyl acetate-hexane) purifying, obtain 6-O-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-yl)-β-D-Glucopyranose is two-the O-[tertiary butyl (dimethyl) silyl] ether (113mg, yield 74%); 1H NMR (300MHz, CDCl 3) δ 7.56 (d, J=7.8Hz, 2H), 7.10 (m, 8H), 7.01-6.80 (m, 6H), 4.70 (t, J=5.4Hz, 1H), 4.64 (d, J=1.8Hz, 1H), 4.56 (d, J=6.9Hz, 1H), 4.35-4.32 (m, 1H), 4.16-4.07 (m, 1H), 3.68-3.58 (m, 2H), 3.51-3.46 (m, 1H), 3.38-3.32 (m, 1H), 3.11-3.09 (m, 1H), 1.98-1.88 (m, 4H), 0.91 (s, 9H), 0.91 (s, 9H), 0.14 (s, 6H), 0.13 (s, 6H) ppm
In polypropylene centrifuge tube, 6-O-(4 '-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-β-D-Glucopyranose is two-the O-[tertiary butyl (dimethyl) silyl] and (82.3mg 0.09mmol) is dissolved in the acetonitrile (10mL) ether.At room temperature add 48% hydrofluoric acid (1mL), reaction under the LCMS monitoring.When finishing, (2.54g, 24mmol) and just in time the water of capacity is with dissolved solids to add the solid sodium carbonate of 1 equal amount.Reactant carries out layering with ethyl acetate (20mL) dilution.(3 * 10mL) extract the aqueous solution with ethyl acetate.The organic extract saturated sodium carbonate that merges. (2 * 10mL) extractions, dry on anhydrous sodium sulphate, filter, vacuum concentration, and with reversed-phase HPLC (250 * 21.2 millimeters posts of Polaris C18-A 10 μ, 30% to 95% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying, obtain 6-O-(4 '-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-D-Glucopyranose (54.3mg, yield 89%); 1H NMR (300MHz, CDCl 3/ 1%CD 3OD) δ 7.58 (d, J=7.8Hz, 2H), 7.39-7.24 (m, 7H), 7.17-7.14 (m, 2H), 7.04-6.92 (m, 5.23 (d, J=3.9Hz, 0.6H), 4.71 (d, J=1.8Hz, 1H), 4.66 (t, J=5.7Hz, 1H), 4.58 (d, J=8.1Hz, 0.4H), 4.40-4.30 (m, 1H), 4.25-4.14 (m, 1H), 3.57-3.48 (m, 2H), and 3.16-3.11 (m, 1H), 2.04-1.85 (m, 4H) ppm; MS[M-OH] +630.0
Embodiment 77 methyl 6-O-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-α-D-glucopyranoside
Figure A20048003969501681
Diethyl azepine dicarboxylic ester (192.4mg, 1.11mmol, 172 μ L) under 0 ℃, dropwise add the methyl 2 that is dissolved in dry tetrahydrofuran (2 milliliters) to, 3,4-three-O-phenyl-α-D-glucopyranoside (184.8mg, 0.40mmol), the 3-bromophenol (72.3mg, 0.42mmol) and triphenylphosphine (115.0mg, 0.44mmol) in.Reactant is warming up to room temperature and stirred 16 hours.Reactant dilutes in ethyl acetate (30mL), and (2 * 10mL) wash with 5% sodium pyrosulfate.Isolating organic solution is dry on anhydrous sodium sulphate, filters, and vacuum concentration is also used chromatography (20% ethyl acetate-methylene dichloride) purifying, obtain methyl 2,3,4-three-O-phenyl-6-O-(3-bromophenyl)-α-D-glucopyranoside (216mg, yield 87%).
(3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl) 3-hydroxypropyl]-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] and azetidine-2-ketone (64.1mg, 0.12mmol), methyl 2,3,4-three-O-phenyl-6-O-(3-bromophenyl)-α-D-glucopyranoside (54.6mg, 0.09mmol) and salt of wormwood (88 microlitres, the 2M aqueous solution) be dissolved in 1: 1 toluene-ethanol (cumulative volume is 1mL).By container being found time and, solution being outgased with argon cleaning three times.(5.1mg, 0.004mmol), solution outgases twice to add four (triphenyl phosphine) palladium.Reactant heated 1 hour down at 85 ℃.The initial glucoside of LCMS and TLC (1: 1 hexane-ethyl acetate) analysis revealed consumes.Reactant dilutes in ethyl acetate (30 milliliters), and water (2 * 10mL) washings.(2 * 10mL) extract the water washing liquor that merges with ethyl acetate.The organic extract that merges is dry on anhydrous sodium sulphate, filter, vacuum-drying, and, obtain methyl 2 with chromatography (12 gram silica gel, 5-50% ethyl acetate-hexane) purifying, 3,4-three-O-benzyl-6-O-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-α-D-glucopyranoside (70.0mg, yield 85%); 1HNMR (300MHz, CDCl 3) δ 7.55 (d, J=8.1Hz, 2H), 7.39-6.84 (m, 29H), 5.01 (d, J=10.8Hz, 1H), 4.89-4.80 (m, 3H), 4.73-4.64 (m, 4H), 4.52 (d, J=11.1Hz, 1H), 4.15-4.12 (m, 2H), 4.08-4.-1 (m, 1H), and 3.94-3.90 (m, 1H), 3.77-3.71 (m, 1H), 3.62 (dd, J=3.6Hz, J=9.6Hz, 1H), 3.39 (s, 3H), and 3.13-3.10 (m, 1H), 2.03-1.89 (m, 4H) ppm
Methyl 2,3,4-three-O-benzyl-6-O-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-(70mg 0.08mmol) is dissolved in the straight alcohol (3 milliliters) α-D-glucopyranoside.Add 10%Pd/C (wet, 14% w/w) and with container sealing.Under balloon pressure, wash and solution is outgased by emptying with hydrogen.With TLC (1: 1 hexane-ethyl acetate) monitoring reaction.When finishing, by the Celite_ filtering catalyst, with extra washing with alcohol.The filtrate vacuum concentration is also used preliminary HPLC (Polaris C18-A 10 μ 250 * 21.2mm post, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) purifying, obtain methyl-6-O-(4 '-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-α-D-glucopyranoside (18.1mg, yield 36%); 1HNMR (300MHz, CD 3OD) δ 7.58 (d, J=8.4Hz, 2H), 7.23 (m, 7H), 7.17-7.14 (m, 2H), 7.04-6.92 (m, 5H), 4.80 (d, J=3.9Hz, 1H), 4.70 (d, J=2.4Hz, 1H), 4.67 (t, J=5.7Hz, 1H), 4.37-4.33 (m, 1H), 4.26-4.21 (m, 1H), 3.92-3.87 (m, 1H), 3.74-3.3.42 (s, 3H), 3.18-3.10 (m, 1H), 2.01-1.88 (m, 4H) MS[M-OH] +644.0
Embodiment 78 6-O-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-the D-sorbitol
Figure A20048003969501701
Sodium borohydride (1.6mg, 0.04mmol) at room temperature add to be dissolved in 80: 20 acetonitrile-water (1 milliliter) 6-O-(4 '-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-yl)-the D-Glucopyranose (26.3mg, 0.04mmol) in.With the LCMS monitoring, at room temperature stirring reaction is 10 minutes.When finishing, reactant was with 80: 20 acetonitriles: water (3mL) dilution, filter by Whatman0.45 micron glass microfiber filters then, with reversed-phase HPLC (250 * 21.2 millimeters posts of Polaris C18-A 10 μ, 30% to 95% acetonitrile-the contain water of 0.1% trifluoroacetic acid) purifying, obtain 6-O-(4 '-{ (2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-D-sorbitol (21.2mg, yield 80%). 1H?NMR(300MHz，CD 3OD)δ7.58(d，J＝8.1Hz，2H)，7.39-7.24(m，7H)，7.17-7.15(m，2H)，7.04-6.92(m，1H)，4.71(d，J＝2.1Hz，1H)，4.68(t，J＝6.3Hz，1H)，4.31-4.27(m，1H)，4.19-4.14(m，1H)，4.08-4.02(m，1H)，3.97-3.95(m，1H)，3.86-3.65(m，4H)，3.14-3.12(m，1H)，2.01-1.88(m，4H)ppm；MS[M+HCO 2] -694.0
Route map IV
Figure A20048003969501711
Route map IV represents to prepare the general method of the cholesterol absorption inhibitor of general formula I V-3.Imines IV-2 makes by aniline and suitable aldehyde are refluxed in Virahol.The ester enolate IV-1 condensation of imines IV-2 and compound obtains azetidinone IV-3.When X is sulphur, can use the suitable oxygenant of 1 equal amount such as MCPBA to change into sulfoxide, use 2 equal amounts with synthetic sulfone.When X is nitrogen, can use 1 normal suitable oxygenant that secondary amine is changed into oxyamine (removing the protection back).
The following examples are according to above-mentioned method preparation.
Embodiment 81 (3R, 4S)-4-(3 ', 4 '-dimethoxy-biphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 82 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3 '-(methylthio group) xenyl-4-yl] azetidine-2-ketone
Embodiment 83 (3R, 4S)-4-[3 '-(dimethylamino) xenyl-4-yl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 84 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4 '-vinyl xenyl-4-yl] azetidine-2-ketone
Embodiment 85 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl }-5-methoxyl biphenyl base-2-formaldehyde
Embodiment 86 (3R, 4S)-4-(3 '-phenylaniline base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 87 (3R, 4S)-4-[4-(2,3-dihydroxyl-1,4-benzo dioxine-6-yl) phenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 88 (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-4-yl) acetic acid
Embodiment 89 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl }-3-Hydroxybiphenyl-4-carboxylate methyl ester
Embodiment 90 (3R, 4S)-4-(3 ', 5 '-dimethyl diphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 91 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(2-naphthyl) phenyl] azetidine-2-ketone
Embodiment 92 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3 '-(trifluoromethyl) xenyl-4-yl] azetidine-2-ketone
Embodiment 93 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-methyl biphenyl-4-yl) azetidine-2-ketone
Embodiment 94 (3R, 4S)-4-(4 '-fluoro-3 '-methyl biphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 95 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-base-β-L-glucopyranoside
Embodiment 96 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[2 ', 3 ', 4 '-trimethoxy xenyl-4-yl] azetidine-2-ketone
Embodiment 97 (3R, 4S)-4-(2 ', 4 '-dimethoxy-biphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 98 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2 '-methyl biphenyl-4-yl) azetidine-2-ketone
Embodiment 99 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-4-formaldehyde
Embodiment 100 (3R, 4S)-4-(3 '-ethoxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 101 (3R, 4S)-4-(4 '-ethoxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 102 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 '-hydroxyl-3 '-methoxyl biphenyl base-4-yl) azetidine-2-ketone
Embodiment 103 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-propoxy-xenyl-4-yl) azetidine-2-ketone
Embodiment 104 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl }-5-Hydroxybiphenyl-2-formaldehyde
Embodiment 105 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-isopropoxy xenyl-4-yl) azetidine-2-ketone
Embodiment 106 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl }-4-Hydroxybiphenyl-4-carboxylic acid
Embodiment 107 (3R, 4S)-4-(3 ', 5 '-dimethoxy-biphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-propoxy-xenyl-4-yl) azetidine-2-ketone
Embodiment 108 (3R, 4S)-4-(2 ', 4 '-dimethoxy-biphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-propoxy-xenyl-4-yl) azetidine-2-ketone
Embodiment 109 (3R, 4S)-4-(3 '-butoxy xenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-propoxy-xenyl-4-yl) azetidine-2-ketone
Embodiment 110 4 '-(2S, 3R)-1-4-(fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl }-3-Hydroxybiphenyl-4-carboxylic acid
Embodiment 111 (3R, 4S)-4-(3 '-fluoro-5 '-methoxyl biphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 112 (3R, 4S)-4-(3 '-fluoro-5 '-Hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 113 (1S)-1,5-dehydration-1-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-the L-sorbitol
Embodiment 114 (3R, 4S)-4-(3 ', 5 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 115 (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl) boric acid
Embodiment 116 (1R)-1,5-dehydration-1-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-4-yl)-the L-sorbitol
Embodiment 117 2,6-dehydration-1-deoxidation-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-D-glycerol-D-gulo-heptitol
Embodiment 118 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-sulfonic acid
Embodiment 119 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-sulfydryl xenyl-4-yl) azetidine-2-ketone
Embodiment 120 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl }-N, N, N-trimethylammonium xenyl-3-ammonium
Embodiment 121 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 122 (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl) phosphoric acid
Embodiment 123 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3 '-(methyl sulphonyl) xenyl-4-yl] azetidine-2-ketone
Embodiment 124 (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3 '-Hydroxybiphenyl-4-yl] azetidine-2-ketone
Embodiment 125 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone
Embodiment 126 [4-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] dimethyl phosphate
Use with [3-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phosphenylic acid dimethyl ester (embodiment 60) similar methods replaces the 3-chlorophenol to make as starting material with the 4-chlorophenol.Obtain [4-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] dimethyl phosphate product (90%) of little light yellow oil 1H NMR (300MHz, CDCl 3) δ 7.86-7.95 (m, 2H), 7.84-7.82 (m, 2H), 7.43-7.50 (m, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 1.34 (s, 12H) ppm; MS 312, [2M+H] 625.
Embodiment 127 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphoric acid
Use the method identical with embodiment 61 to make, [4-(4,4,5 for the usefulness dimethyl, 5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] [3-(4,4 for phosphoric acid ester replacement dimethyl, 5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl) phenyl] phosphoric acid ester (embodiment 60).By reversed-phase HPLC (250 * 21.2 millimeters posts of Polaris C18-A 10 μ, the water that contains 30% to 59% acetonitrile-0.1% trifluoroacetic acid) final purifying, obtain for white powder (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl-3 '-Hydroxybiphenyl-4-yl) phosphoric acid (62%). 1H?NMR(300MHz，CD 3OD)δ7.8(dd，J＝8.0，13.0Hz，1H)，7.68(dd，J＝3.2，8.0Hz，1H)，6.9-7.4(m，14H)，5.17(d，J＝2.1Hz，1H)，4.60-4.66(m，1H)，3.13-3.22(m，1H)，1.8-2.1(m，4H)ppm；MS[M-H]546，[2M-H]1093。
Embodiment 128 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sodium sulfonate
5-bromo-2-{ (2S, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxygen-1-phenyl azetidine alkane-2-yl } phenylacetic acid ester (850.0mg, 1.36mmol) and 4-thioanisole boric acid (252mg 1.50mmol) is dissolved in dioxane (13.6mL).Add cesium carbonate (882 milligrams, 2.71mmol) and solid four (triphenyl phosphine) palladium (0) (113mg 0.21mmol), vacuumizes container or with nitrogen purge (3x).Under 80 ℃, under nitrogen atmosphere, vigorous stirring reaction 4 hours is cooled off then and (0.70mL is 7.3mmol) with 4-dimethylamino-pyridine (6mg, 1.52mmol) reaction with acetic anhydride.After 15 minutes, mixture pours in the 1.0N hydrochloric acid (60mL), with the extraction of 1: 1 ethyl acetate-hexane (60 milliliters), wash with salt solution (60mL), dry on sodium sulfate, filter and concentrate, by chromatography (40g silica gel, 5% to 50% ethyl acetate-hexane) purifying, obtain 4-{ (2S for white foam, 3R)-3-[(3S)-3-([tertiary butyl (dimethyl) silyl] oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl }-4 '-(methylthio group) xenyl-3-base-acetic ester (478mg, yield 52%); R fBe 0.41 (1: 4 ethyl acetate-hexane).
4-{ (2S, 3R)-3-[(3S)-and the 3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-3-(4-fluorophenyl) propyl group]-4-oxo-1-phenyl azetidine alkane-2-yl }-4 '-(methylthio group) xenyl-3-base-acetic ester (478 milligrams 0.713mmol) are dissolved in the methylene dichloride (20 milliliters) and are cooled to 0 ℃.In with TLC and LCMS monitoring, progressively add the 3-chloroperoxybenzoic acid (64.3mg, 0.373mmol), to make the aryl sulfoxide.Add when finishing, reactant is poured in 1/4th saturated sodium hydrogen carbonate solutions (60mL), with methylene dichloride (60 milliliters) and ethyl acetate (60mL) extraction, the organic layer of merging is dry on sodium sulfate, filters also concentrated with toluene.Residue is dissolved in methylene dichloride (10mL) and (250 microlitres, 372mg 1.77mmol) realize that Pummerer resets by adding trifluoroacetic anhydride.At room temperature stirring reaction is 8.5 hours, concentrates with toluene then and with the solution dilution of the methyl alcohol (3.0 milliliters), triethylamine (3.0 milliliters) and the water (1.0 milliliters) that outgas.2.75 after hour, this golden yellow solution concentration is transferred in the polypropylene Falcon_ test tube that 10.0 acetonitriles are housed, and dilutes with 48% hydrofluoric acid (1.0mL).At room temperature stirring reaction is 4 hours, be poured into 0.5M potassiumphosphate (50 milliliters) then, extract with ethyl acetate (60 milliliters), water (60 milliliters) and salt solution (60 milliliters) washing, dry on sodium sulfate, filter, concentrate, and with chromatography (40 gram silica gel, 10% to 100% ethyl acetate-hexane) purifying, obtain the mixture (desired substance of some impurity and oxidation) of compound.Residue is used for next step.
Residue is dissolved in methylene dichloride (10 milliliters), dropwise add the 3-chloroperoxybenzoic acid be arranged in 10 milliliters of methylene dichloride (489mg, 2.83mmol).Use methylene dichloride (5mL) to help transfer of material, mixture at room temperature stirred 15 minutes.Add triethylamine (4mL) cancellation reaction, concentrate, being dissolved in methyl alcohol filters by 0.45 micron Whatman_ strainer, concentrate once more, with reversed-phase HPLC (250 * 21.2 millimeters posts of PolarisC18-A 10 μ, the water that contains 5% to 100% acetonitrile-0.1% trifluoroacetic acid) purifying is also handled with the Dowex_ sodium ion exchange resin, obtain being lilac solid 4 '-{ (2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sodium sulfonate (249.0mg, yield 57%); 1H NMR (300MHz, CD 3OD) δ 7.88 (d, 6Hz, 2H), 7.59 (d, J=8.6Hz, 2H), 7.35-7.19 (m, 7H), and 7.14-7.11 (m, 2H), 7.03-6 97 (m, 3H), 5.14 (d, J=2.2Hz, 1H), and 4.63-4.59 (m, 1H), 3.17-3.08 (m, 1H), 2.04-1.87 (m, 4H) ppm; MS[M-Na] 546.0
Compound shown in table 3, table 4 and the following formula VIII also within the scope of the invention.
Figure A20048003969501791
In these embodiments, R 1With 2 be independently selected from H, F, CN, Cl, CH 3, OCH 3, OCF 3, OCF 2H, CF 3, CF 2H and CH 2F; R 4Be selected from H, Cl, CH 3, OCH 3, OH, B (OH) 2And SH; R 5Be selected from OH, SO 3H, PO 3H 2, CH 2OH, COOH, CHO, D-sorbitol, C-glycosyl (glysosyl) compound and sugar, and only allow a R substituting group on aromatic ring arbitrarily.For example, work as R 5During for-OH, other all substituting groups on corresponding aromatic ring are H.Certainly, when given R base be that hydrogen is (such as R 1), other all substituting groups on corresponding aromatic ring also are H.In table 4, work as R 4When the position of substitution is defined as 3-, replace the ortho position that occurs in the azetidinone ring.In table 4, work as R 4When the position of substitution is defined as 2-, replace occur in the azetidinone ring between the position.
Every row in the table 3 has defined the subclass of the substituent uniqueness of R, and the R substituting group can mode repeatedly systematically be replaced to advance formula VIII on by the position that every row limited of table 4, obtain the specific compound in the formula VIII scope.For example, in the 1st row of table 3, R 1Be H, R 2Be F, R 4Be OH, R 5Be OH.The position that is limited according to table 4 the 1st row (is R 1Be the ortho position, R 2Be the ortho position, R 4Be 3-, R 5Be the ortho position) this group R group is replaced into formula VIII, obtain
Figure A20048003969501801
(3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
Similar, the value of using table 3 the 1st row is according to table 4 the 2nd row replacement formula VIII, obtain (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone.Table 5-20 comprises by according to the position that every row limited by table 4 the capable listed substituting group of table 3 1-16 being replaced the into resulting compound of formula VIII.Should be understood that the listed compound of table 5-20 is just systematically replaced to advance a little subclass of the resulting compound of formula VIII repeatedly by the position that every row limited of table 4 substituting group that each row in the table 3 is listed by basis.
Table 3
Group R1 R2 R4 R5
1 H F OH OH
2 H F OH The D-sorbitol
3 H F OH SO 3H
4 H F OH PO 3H 2
5 H H OH OH
6 H H OH The D-sorbitol
7 H H OH SO 3H
8 H H OH PO 3H 2
9 H Cl OH OH
10 H Cl OH The D-sorbitol
11 H Cl OH SO 3H
12 H Cl OH PO 3H 2
13 F H OH OH
14 F H OH The D-sorbitol
15 F H OH SO 3H
16 F H OH PO 3H 2
17 F F OH OH
18 F F OH The D-sorbitol
19 F F OH SO 3H
20 F F OH PO 3H 2
21 F Cl OH OH
22 F Cl OH The D-sorbitol
23 F Cl ?OH SO 3H
24 F Cl ?OH PO 3H 2
25 Cl H ?OH OH
26 Cl H ?OH The D-sorbitol
27 Cl H ?OH SO 3H
28 Cl H ?OH PO 3H 2
29 Cl F ?OH OH
30 Cl F ?OH The D-sorbitol
31 Cl F ?OH SO 3H
32 Cl F ?OH PO 3H 2
33 Cl Cl ?OH OH
34 Cl Cl ?OH The D-sorbitol
35 Cl Cl ?OH SO 3H
36 Cl Cl ?OH PO 3H 2
37 H H ?H OH
38 H H ?H The D-sorbitol
39 H H ?H SO 3H
40 H H ?H PO 3H 2
41 H H ?H CHO
42 H H ?H COOH
43 H H ?H CH 2OH
44 H H ?H Sugar
45 H H ?H The C-glycosyl compound
46 H H ?OH CHO
47 H H ?OH COOH
48 H H ?OH CH 2OH
49 H H ?OH Sugar
50 H H ?OH The C-glycosyl compound
51 H H ?CH 3 OH
52 H H ?CH 3 The D-sorbitol
53 H H ?CH 3 SO 3H
54 H H ?CH 3 PO 3H 2
55 H H ?CH 3 CHO
56 H H ?CH 3 COOH
57 H H ?CH 3 CH 2OH
58 H H ?CH 3 Sugar
59 H H ?CH 3 The C-glycosyl compound
60 H H ?Cl OH
61 H ?H Cl The D-sorbitol
62 H ?H Cl SO 3H
63 H ?H Cl PO 3H 2
64 H ?H Cl CHO
65 H ?H Cl COOH
66 H ?H Cl CH 2OH
67 H ?H Cl Sugar
68 H ?H Cl The C-glycosyl compound
69 H ?H B(OH) 2 OH
70 H ?H B(OH) 2 The D-sorbitol
71 H ?H B(OH) 2 SO 3H
72 H ?H B(OH) 2 PO 3H 2
73 H ?H B(OH) 2 CHO
74 H ?H B(OH) 2 COOH
75 H ?H B(OH) 2 CH 2OH
76 H ?H B(OH) 2 Sugar
77 H ?H B(OH) 2 The C-glycosyl compound
78 H ?H SH OH
79 H ?H SH The D-sorbitol
80 H ?H SH SO 3H
81 H ?H SH PO 3H 2
82 H ?H SH CHO
83 H ?H SH COOH
84 H ?H SH CH 2OH
85 H ?H SH Sugar
86 H ?H SH The C-glycosyl compound
87 H ?H OCH 3 OH
88 H ?H OCH 3 The D-sorbitol
89 H ?H OCH 3 SO 3H
90 H ?H OCH 3 PO 3H 2
91 H ?H OCH 3 CHO
92 H ?H OCH 3 COOH
93 H ?H OCH 3 CH 2OH
94 H ?H OCH 3 Sugar
95 H ?H OCH 3 The C-glycosyl compound
96 H ?F H OH
97 H ?F H The D-sorbitol
98 H F H SO 3H
99 H F H PO 3H 2
100 H F H CHO
101 H F H COOH
102 H F H CH 2OH
103 H F H Sugar
104 H F H The C-glycosyl compound
105 H F OH CHO
106 H F OH COOH
107 H F OH CH 2OH
108 H F OH Sugar
109 H F OH The C-glycosyl compound
110 H F CH 3 OH
111 H F CH 3 The D-sorbitol
112 H F CH 3 SO 3H
113 H F CH 3 PO 3H 2
114 H F CH 3 CHO
115 H F CH 3 COOH
116 H F CH 3 CH 2OH
117 H F CH 3 Sugar
118 H F CH 3 The C-glycosyl compound
119 H F Cl OH
120 H F Cl The D-sorbitol
121 H F Cl SO 3H
122 H F Cl PO 3H 2
123 H F Cl CHO
124 H F Cl COOH
125 H F Cl CH 2OH
126 H F Cl Sugar
127 H F Cl The C-glycosyl compound
128 H F B(OH) 2 OH
129 H F B(OH) 2 The D-sorbitol
130 H F B(OH) 2 SO 3H
131 H F B(OH) 2 PO 3H 2
132 H F B(OH) 2 CHO
133 H F B(OH) 2 COOH
134 H F B(OH) 2 CH 2OH
135 H F B(OH) 2 Sugar
136 H F B(OH) 2 The C-glycosyl compound
137 H F SH OH
138 H F SH The D-sorbitol
139 H F SH SO 3H
140 H F SH PO 3H 2
141 H F SH CHO
142 H F SH COOH
143 H F SH CH 2OH
144 H F SH Sugar
145 H F SH The C-glycosyl compound
146 H F OCH 3 OH
147 H F OCH 3 The D-sorbitol
148 H F OCH 3 SO 3H
149 H F OCH 3 PO 3H 2
150 H F OCH 3 CHO
151 H F OCH 3 COOH
152 H F OCH 3 CH 2OH
153 H F OCH 3 Sugar
154 H F OCH 3 The C-glycosyl compound
155 H Cl H OH
156 H Cl H The D-sorbitol
157 H Cl H SO 3H
158 H Cl H PO 3H 2
159 H Cl H CHO
160 H Cl H COOH
161 H Cl H CH 2OH
162 H Cl H Sugar
163 H Cl H The C-glycosyl compound
164 H Cl OH CHO
165 H Cl OH COOH
166 H Cl OH CH 2OH
167 H Cl OH Sugar
168 H Cl OH The C-glycosyl compound
169 H Cl CH 3 OH
170 H Cl CH 3 The D-sorbitol
171 H Cl CH 3 SO 3H
172 H Cl CH 3 PO 3H 2
173 H Cl CH 3 CHO
174 H Cl CH 3 COOH
175 H Cl CH 3 CH 2OH
176 H Cl CH 3 Sugar
177 H Cl CH 3 The C-glycosyl compound
178 H Cl Cl OH
179 H Cl Cl The D-sorbitol
180 H Cl Cl SO 3H
181 H Cl Cl PO 3H 2
182 H Cl Cl CHO
183 H Cl Cl COOH
184 H Cl Cl CH 2OH
185 H Cl Cl Sugar
186 H Cl Cl The C-glycosyl compound
187 H Cl B(OH) 2 OH
188 H Cl B(OH) 2 The D-sorbitol
189 H Cl B(OH) 2 SO 3H
190 H Cl B(OH) 2 PO 3H 2
191 H Cl B(OH) 2 CHO
192 H Cl B(OH) 2 COOH
193 H Cl B(OH) 2 CH 2OH
194 H Cl B(OH) 2 Sugar
195 H Cl B(OH) 2 The C-glycosyl compound
196 H Cl SH OH
197 H Cl SH The D-sorbitol
198 H Cl SH SO 3H
199 H Cl SH PO 3H 2
200 H Cl SH CHO
201 H Cl SH COOH
202 H Cl SH CH 2OH
203 H Cl SH Sugar
204 H Cl SH The C-glycosyl compound
205 H Cl OCH 3 OH
206 H Cl OCH 3 The D-sorbitol
207 H Cl OCH 3 SO 3H
208 H Cl OCH 3 PO 3H 2
209 H Cl OCH 3 CHO
210 ?H Cl OCH 3 COOH
211 ?H Cl OCH 3 CH 2OH
212 ?H Cl OCH 3 Sugar
213 ?H Cl OCH 3 The C-glycosyl compound
214 ?H CN H OH
215 ?H CN H The D-sorbitol
216 ?H CN H SO 3H
217 ?H CN H PO 3H 2
218 ?H CN H CHO
219 ?H CN H COOH
220 ?H CN H CH 2OH
221 ?H CN H Sugar
222 ?H CN H The C-glycosyl compound
223 ?H CN OH OH
224 ?H CN OH The D-sorbitol
225 ?H CN OH SO 3H
226 ?H CN OH PO 3H 2
227 ?H CN OH CHO
228 ?H CN OH COOH
229 ?H CN OH CH 2OH
230 ?H CN OH Sugar
231 ?H CN OH The C-glycosyl compound
232 ?H CN CH 3 OH
233 ?H CN CH 3 The D-sorbitol
234 ?H CN CH 3 SO 3H
235 ?H CN CH 3 PO 3H 2
236 ?H CN CH 3 CHO
237 ?H CN CH 3 COOH
238 ?H CN CH 3 CH 2OH
239 ?H CN CH 3 Sugar
240 ?H CN CH 3 The C-glycosyl compound
241 ?H CN Cl OH
242 ?H CN Cl The D-sorbitol
243 ?H CN Cl SO 3H
244 ?H CN Cl PO 3H 2
245 ?H CN Cl CHO
246 ?H CN Cl COOH
247 ?H CN Cl CH 2OH
248 H CN Cl Sugar
249 H CN Cl The C-glycosyl compound
250 H CN B(OH) 2 OH
251 H CN B(OH) 2 The D-sorbitol
252 H CN B(OH) 2 SO 3H
253 H CN B(OH) 2 PO 3H 2
254 H CN B(OH) 2 CHO
255 H CN B(OH) 2 COOH
256 H CN B(OH) 2 CH 2OH
257 H CN B(OH) 2 Sugar
258 H CN B(OH) 2 The C-glycosyl compound
259 H CN SH OH
260 H CN SH The D-sorbitol
261 H CN SH SO 3H
262 H CN SH PO 3H 2
263 H CN SH CHO
264 H CN SH COOH
265 H CN SH CH 2OH
266 H CN SH Sugar
267 H CN SH The C-glycosyl compound
268 H CN OCH 3 OH
269 H CN OCH 3 The D-sorbitol
270 H CN OCH 3 SO 3H
271 H CN OCH 3 PO 3H 2
272 H CN OCH 3 CHO
273 H CN OCH 3 COOH
274 H CN OCH 3 CH 2OH
275 H CN OCH 3 Sugar
276 H CN OCH 3 The C-glycosyl compound
277 H CH 3 a H OH
278 H CH 3 a H The D-sorbitol
279 H CH 3 a H SO 3H
280 H CH 3 a H PO 3H 2
281 H CH 3 a H CHO
282 H CH 3 a H COOH
283 H CH 3 a H CH 2OH
284 ?H CH 3 a H Sugar
285 ?H CH 3 a H The C-glycosyl compound
286 ?H CH 3 a OH OH
287 ?H CH 3 a OH The D-sorbitol
288 ?H CH 3 a OH SO 3H
289 ?H CH 3 a OH PO 3H 2
290 ?H CH 3 a OH CHO
291 ?H CH 3 a OH COOH
292 ?H CH 3 a OH CH 2OH
293 ?H CH 3 a OH Sugar
294 ?H CH 3 a OH The C-glycosyl compound
295 ?H CH 3 a CH 3 OH
296 ?H CH 3 a CH 3 The D-sorbitol
297 ?H CH 3 a CH 3 SO 3H
298 ?H CH 3 a CH 3 PO 3H 2
299 ?H CH 3 a CH 3 CHO
300 ?H CH 3 a CH 3 COOH
301 ?H CH 3 a CH 3 CH 2OH
302 ?H CH 3 a CH 3 Sugar
303 ?H CH 3 a CH 3 The C-glycosyl compound
304 ?H CH 3 a Cl OH
305 ?H CH 3 a Cl The D-sorbitol
306 ?H CH 3 a Cl SO 3H
307 ?H CH 3 a Cl PO 3H 2
308 ?H CH 3 a Cl CHO
309 ?H CH 3 a Cl COOH
310 ?H CH 3 a Cl CH 2OH
311 ?H CH 3 a Cl Sugar
312 ?H CH 3 a Cl The C-glycosyl compound
313 ?H CH 3 a B(OH) 2 OH
314 ?H CH 3 a B(OH) 2 The D-sorbitol
315 ?H CH 3 a B(OH) 2 SO 3H
316 ?H CH 3 a B(OH) 2 PO 3H 2
317 ?H CH 3 a B(OH) 2 CHO
318 ?H CH 3 a B(OH) 2 COOH
319 ?H CH 3 a B(OH) 2 CH 2OH
320 ?H CH 3 a B(OH) 2 Sugar
321 ?H CH 3 a B(OH) 2 The C-glycosyl compound
322 ?H CH 3 a SH OH
323 ?H CH 3 a SH The D-sorbitol
324 ?H CH 3 a SH SO 3H
325 ?H CH 3 a SH PO 3H 2
326 ?H CH 3 a SH CHO
327 ?H CH 3 a SH COOH
328 ?H CH 3 a SH CH 2OH
329 ?H CH 3 a SH Sugar
330 ?H CH 3 a SH The C-glycosyl compound
331 ?H CH 3 a OCH 3 OH
332 ?H CH 3 a OCH 3 The D-sorbitol
333 ?H CH 3 a OCH 3 SO 3H
334 ?H CH 3 a OCH 3 PO 3H 2
335 ?H CH 3 a OCH 3 CHO
336 ?H CH 3 a OCH 3 COOH
337 ?H CH 3 a OCH 3 CH 2OH
338 ?H CH 3 a OCH 3 Sugar
339 ?H CH 3 a OCH 3 The C-glycosyl compound
340 ?H OCH3 b H OH
341 ?H OCH3 b H The D-sorbitol
342 ?H OCH3 b H SO 3H
343 ?H OCH3 b H PO 3H 2
344 ?H OCH3 b H CHO
345 ?H OCH3 b H COOH
346 ?H OCH3 b H CH 2OH
347 ?H OCH3 b H Sugar
348 ?H OCH3 b H The C-glycosyl compound
349 ?H OCH3 b OH OH
350 ?H OCH3 b OH The D-sorbitol
351 ?H OCH3 b OH SO 3H
352 ?H OCH3 b OH PO 3H 2
353 ?H OCH3 b OH CHO
354 ?H OCH3 b OH COOH
355 ?H OCH3 b OH CH 2OH
356 ?H OCH3 b OH Sugar
357 ?H OCH3 b OH The C-glycosyl compound
358 ?H OCH3 b CH 3 OH
359 ?H OCH3 b CH 3 The D-sorbitol
360 ?H OCH3 b CH 3 SO 3H
361 ?H OCH3 b CH 3 PO 3H 2
362 ?H OCH3 b CH 3 CHO
363 ?H OCH3 b CH 3 COOH
364 ?H OCH3 b CH 3 CH 2OH
365 ?H OCH3 b CH 3 Sugar
366 ?H OCH3 b CH 3 The C-glycosyl compound
367 ?H OCH3 b Cl OH
368 ?H OCH3 b Cl The D-sorbitol
369 ?H OCH3 b Cl SO 3H
370 ?H OCH3 b Cl PO 3H 2
371 ?H OCH3 b Cl CHO
372 ?H OCH3 b Cl COOH
373 ?H OCH3 b Cl CH 2OH
374 ?H OCH3 b Cl Sugar
375 ?H OCH3 b Cl The C-glycosyl compound
376 ?H OCH3 b B(OH) 2 OH
377 ?H OCH3 b B(OH) 2 The D-sorbitol
378 ?H OCH3 b B(OH) 2 SO 3H
379 ?H OCH3 b B(OH) 2 PO 3H 2
380 ?H OCH3 b B(OH) 2 CHO
381 ?H OCH3 b B(OH) 2 COOH
382 H OCH3 b B(OH) 2 CH 2OH
383 H OCH3 b B(OH) 2 Sugar
384 H OCH3 b B(OH) 2 The C-glycosyl compound
385 H OCH3 b SH OH
386 H OCH3 b SH The D-sorbitol
387 H OCH3 b SH SO 3H
388 H OCH3 b SH PO 3H 2
389 H OCH3 b SH CHO
390 H OCH3 b SH COOH
391 H OCH3 b SH CH 2OH
392 H OCH3 b SH Sugar
393 H OCH3 b SH The C-glycosyl compound
394 H OCH3 b OCH 3 OH
395 H OCH3 b OCH 3 The D-sorbitol
396 H OCH3 b OCH 3 SO 3H
397 H OCH3 b OCH 3 PO 3H 2
398 H OCH3 b OCH 3 CHO
399 H OCH3 b OCH 3 COOH
400 H OCH3 b OCH 3 CH 2OH
401 H OCH3 b OCH 3 Sugar
402 H OCH3 b OCH 3 The C-glycosyl compound
403 F H H OH
404 F H H The D-sorbitol
405 F H H SO 3H
406 F H H PO 3H 2
407 F H H CHO
408 F H H COOH
409 F H H CH 2OH
410 F H H Sugar
411 F H H The C-glycosyl compound
412 F H OH CHO
413 F H OH COOH
414 F H OH CH 2OH
415 F H OH Sugar
416 F H OH The C-glycosyl compound
417 F ?H CH 3 OH
418 F ?H CH 3 The D-sorbitol
419 F ?H CH 3 SO 3H
420 F ?H CH 3 PO 3H 2
421 F ?H CH 3 CHO
422 F ?H CH 3 COOH
423 F ?H CH 3 CH 2OH
424 F ?H CH 3 Sugar
425 F ?H CH 3 The C-glycosyl compound
426 F ?H Cl OH
427 F ?H Cl The D-sorbitol
428 F ?H Cl SO 3H
429 F ?H Cl PO 3H 2
430 F ?H Cl CHO
431 F ?H Cl COOH
432 F ?H Cl CH 2OH
433 F ?H Cl Sugar
434 F ?H Cl The C-glycosyl compound
435 F ?H B(OH) 2 OH
436 F ?H B(OH) 2 The D-sorbitol
437 F ?H B(OH) 2 SO 3H
438 F ?H B(OH) 2 PO 3H 2
439 F ?H B(OH) 2 CHO
440 F ?H B(OH) 2 COOH
441 F ?H B(OH) 2 CH 2OH
442 F ?H B(OH) 2 Sugar
443 F ?H B(OH) 2 The C-glycosyl compound
444 F ?H SH OH
445 F ?H SH The D-sorbitol
446 F ?H SH SO 3H
447 F ?H SH PO 3H 2
448 F ?H SH CHO
449 F ?H SH COOH
450 F ?H SH CH 2OH
451 F ?H SH Sugar
452 F ?H SH The C-glycosyl compound
453 F ?H OCH 3 OH
454 ?F ?H OCH 3 The D-sorbitol
455 ?F ?H OCH 3 SO 3H
456 ?F ?H OCH 3 PO 3H 2
457 ?F ?H OCH 3 CHO
458 ?F ?H OCH 3 COOH
459 ?F ?H OCH 3 CH 2OH
460 ?F ?H OCH 3 Sugar
461 ?F ?H OCH 3 The C-glycosyl compound
462 ?F ?F H OH
463 ?F ?F H The D-sorbitol
464 ?F ?F H SO 3H
465 ?F ?F H PO 3H 2
466 ?F ?F H CHO
467 ?F ?F H COOH
468 ?F ?F H CH 2OH
469 ?F ?F H Sugar
470 ?F ?F H The C-glycosyl compound
471 ?F ?F OH CHO
472 ?F ?F OH COOH
473 ?F ?F OH CH 2OH
474 ?F ?F OH Sugar
475 ?F ?F OH The C-glycosyl compound
476 ?F ?F CH 3 OH
477 ?F ?F CH 3 The D-sorbitol
478 ?F ?F CH 3 SO 3H
479 ?F ?F CH 3 PO 3H 2
480 ?F ?F CH 3 CHO
481 ?F ?F CH 3 COOH
482 ?F ?F CH 3 CH 2OH
483 ?F ?F CH 3 Sugar
484 ?F ?F CH 3 The C-glycosyl compound
485 ?F ?F Cl OH
486 ?F ?F Cl The D-sorbitol
487 ?F ?F Cl SO 3H
488 ?F ?F Cl PO 3H 2
489 ?F ?F Cl CHO
490 ?F ?F Cl COOH
491 ?F F Cl CH 2OH
492 ?F F Cl Sugar
493 ?F F Cl The C-glycosyl compound
494 ?F F B(OH) 2 OH
495 ?F F B(OH) 2 The D-sorbitol
496 ?F F B(OH) 2 SO 3H
497 ?F F B(OH) 2 PO 3H 2
498 ?F F B(OH) 2 CHO
499 ?F F B(OH) 2 COOH
500 ?F F B(OH) 2 CH 2OH
501 ?F F B(OH) 2 Sugar
502 ?F F B(OH) 2 The C-glycosyl compound
503 ?F F SH OH
504 ?F F SH The D-sorbitol
505 ?F F SH SO 3H
506 ?F F SH PO 3H 2
507 ?F F SH CHO
508 ?F F SH COOH
509 ?F F SH CH 2OH
510 ?F F SH Sugar
511 ?F F SH The C-glycosyl compound
512 ?F F OCH 3 OH
513 ?F F OCH 3 The D-sorbitol
514 ?F F OCH 3 SO 3H
515 ?F F OCH 3 PO 3H 2
516 ?F F OCH 3 CHO
517 ?F F OCH 3 COOH
518 ?F F OCH 3 CH 2OH
519 ?F F OCH 3 Sugar
520 ?F F OCH 3 The C-glycosyl compound
521 ?F Cl H OH
522 ?F Cl H The D-sorbitol
523 ?F Cl H SO 3H
524 ?F Cl H PO 3H 2
525 ?F Cl H CHO
526 ?F Cl H COOH
527 ?F Cl H CH 2OH
528 F Cl H Sugar
529 F Cl H The C-glycosyl compound
530 F Cl OH CHO
531 F Cl OH COOH
532 F Cl OH CH 2OH
533 F Cl OH Sugar
534 F Cl OH The C-glycosyl compound
535 F Cl CH 3 OH
536 F Cl CH 3 The D-sorbitol
537 F Cl CH 3 SO 3H
538 F Cl CH 3 PO 3H 2
539 F Cl CH 3 CHO
540 F Cl CH 3 COOH
541 F Cl CH 3 CH 2OH
542 F Cl CH 3 Sugar
543 F Cl CH 3 The C-glycosyl compound
544 F Cl Cl OH
545 F Cl Cl The D-sorbitol
546 F Cl Cl SO 3H
547 F Cl Cl PO 3H 2
548 F Cl Cl CHO
549 F Cl Cl COOH
550 F Cl Cl CH 2OH
551 F Cl Cl Sugar
552 F Cl Cl The C-glycosyl compound
553 F Cl B(OH) 2 OH
554 F Cl B(OH) 2 The D-sorbitol
555 F Cl B(OH) 2 SO 3H
556 F Cl B(OH) 2 PO 3H 2
557 F Cl B(OH) 2 CHO
558 F Cl B(OH) 2 COOH
559 F Cl B(OH) 2 CH 2OH
560 F Cl B(OH) 2 Sugar
561 F Cl B(OH) 2 The C-glycosyl compound
562 F Cl SH OH
563 F Cl SH The D-sorbitol
564 F Cl SH SO 3H
565 ?F Cl SH PO 3H 2
566 ?F Cl SH CHO
567 ?F Cl SH COOH
568 ?F Cl SH CH 2OH
569 ?F Cl SH Sugar
570 ?F Cl SH The C-glycosyl compound
571 ?F Cl OCH 3 OH
572 ?F Cl OCH 3 The D-sorbitol
573 ?F Cl OCH 3 SO 3H
574 ?F Cl OCH 3 PO 3H 2
575 ?F Cl OCH 3 CHO
576 ?F Cl OCH 3 COOH
577 ?F Cl OCH 3 CH 2OH
578 ?F Cl OCH 3 Sugar
579 ?F Cl OCH 3 The C-glycosyl compound
580 ?F CN H 3H
581 ?F CN H The D-sorbitol
582 ?F CN H SO 3H
583 ?F CN H PO 3H 2
584 ?F CN H CHO
585 ?F CN H COOH
586 ?F CN H CH 2OH
587 ?F CN H Sugar
588 ?F CN H The C-glycosyl compound
589 ?F CN OH OH
590 ?F CN OH The D-sorbitol
591 ?F CN OH SO 3H
592 ?F CN OH PO 3H 2
593 ?F CN OH CHO
594 ?F CN OH COOH
595 ?F CN OH CH 2OH
596 ?F CN OH Sugar
597 ?F CN OH The C-glycosyl compound
598 ?F CN CH 3 OH
599 ?F CN CH 3 The D-sorbitol
600 ?F CN CH 3 SO 3H
601 ?F CN CH 3 PO 3H 2
602 ?F CN CH 3 CHO
603 ?F CN CH 3 COOH
604 ?F CN CH 3 CH 2OH
605 ?F CN CH 3 Sugar
606 ?F CN CH 3 The C-glycosyl compound
607 ?F CN Cl OH
608 ?F CN Cl The D-sorbitol
609 ?F CN Cl SO 3H
610 ?F CN Cl PO 3H 2
611 ?F CN Cl CHO
612 ?F CN Cl COOH
613 ?F CN Cl CH 2OH
614 ?F CN Cl Sugar
615 ?F CN Cl The C-glycosyl compound
616 ?F CN B(OH) 2 OH
617 ?F CN B(OH) 2 The D-sorbitol
618 ?F CN B(OH) 2 SO 3H
619 ?F CN B(OH) 2 PO 3H 2
620 ?F CN B(OH) 2 CHO
621 ?F CN B(OH) 2 COOH
622 ?F CN B(OH) 2 CH 2OH
623 ?F CN B(OH) 2 Sugar
624 ?F CN B(OH) 2 The C-glycosyl compound
625 ?F CN SH OH
626 ?F CN SH The D-sorbitol
627 ?F CN SH SO 3H
628 ?F CN SH PO 3H 2
629 ?F CN SH CHO
630 ?F CN SH COOH
631 ?F CN SH CH 2OH
632 ?F CN SH Sugar
633 ?F CN SH The C-glycosyl compound
634 ?F CN OCH 3 OH
635 ?F CN OCH 3 The D-sorbitol
636 ?F CN OCH 3 SO 3H
637 ?F CN OCH 3 PO 3H 2
638 ?F CN OCH 3 CHO
639 ?F CN OCH 3 COOH
640 ?F CN OCH 3 CH 2OH
641 ?F CN OCH 3 Sugar
642 ?F CN OCH 3 The C-glycosyl compound
643 ?F CH 3 a H OH
644 ?F CH 3 a H The D-sorbitol
645 ?F CH 3 a H SO 3H
646 ?F CH 3 a H PO 3H 2
647 ?F CH 3 a H CHO
648 ?F CH 3 a H COOH
649 ?F CH 3 a H CH 2OH
650 ?F CH 3 a H Sugar
651 ?F CH 3 a H The C-glycosyl compound
652 ?F CH 3 a OH OH
653 ?F CH 3 a OH The D-sorbitol
654 ?F CH 3 a OH SO 3H
655 ?F CH 3 a OH PO 3H 2
656 ?F CH 3 a OH CHO
657 ?F CH 3 a OH COOH
658 ?F CH 3 a OH CH 2OH
659 ?F CH 3 a OH Sugar
660 ?F CH 3 a OH The C-glycosyl compound
661 ?F CH 3 a CH 3 OH
662 ?F CH 3 a CH 3 The D-sorbitol
663 ?F CH 3 a CH 3 SO 3H
664 ?F CH 3 a CH 3 PO 3H 2
665 ?F CH 3 a CH 3 CHO
666 ?F CH 3 a CH 3 COOH
667 ?F CH 3 a CH 3 CH 2OH
668 ?F CH 3 a CH 3 Sugar
669 ?F CH 3 a CH 3 The C-glycosyl compound
670 ?F CH 3 a Cl OH
671 ?F CH 3 a Cl The D-sorbitol
672 ?F CH 3 a Cl SO 3H
673 ?F CH 3 a Cl PO 3H 2
674 ?F CH 3 a Cl CHO
675 ?F CH 3 a Cl COOH
676 ?F CH 3 a Cl CH 2OH
677 ?F CH 3 a Cl Sugar
678 ?F CH 3 a Cl The C-glycosyl compound
679 ?F CH 3 a B(OH) 2 OH
680 ?F CH 3 a B(OH) 2 The D-sorbitol
681 ?F CH 3 a B(OH) 2 SO 3H
682 ?F CH 3 a B(OH) 2 PO 3H 2
683 ?F CH 3 a B(OH) 2 CHO
684 ?F CH 3 a B(OH) 2 COOH
685 ?F CH 3 a B(OH) 2 CH 2OH
686 ?F CH 3 a B(OH) 2 Sugar
687 ?F CH 3 a B(OH) 2 The C-glycosyl compound
688 ?F CH 3 a SH OH
689 ?F CH 3 a SH The D-sorbitol
690 ?F CH 3 a SH SO 3H
691 ?F CH 3 a SH PO 3H 2
692 ?F CH 3 a SH CHO
693 ?F CH 3 a SH COOH
694 ?F CH 3 a SH CH 2OH
695 ?F CH 3 a SH Sugar
696 ?F CH 3 a SH The C-glycosyl compound
697 ?F CH 3 a OCH 3 OH
698 ?F CH 3 a OCH 3 The D-sorbitol
699 ?F CH 3 a OCH 3 SO 3H
700 ?F CH 3 a OCH 3 PO 3H 2
701 ?F CH 3 a OCH 3 CHO
702 ?F CH 3 a OCH 3 COOH
703 ?F CH 3 a OCH 3 CH 2OH
704 ?F CH 3 a OCH 3 Sugar
705 ?F CH 3 a OCH 3 The C-glycosyl compound
706 ?F OCH3 b H OH
707 ?F OCH3 b H The D-sorbitol
708 ?F OCH3 b H SO 3H
709 ?F OCH3 b H PO 3H 2
710 ?F OCH3 b H CHO
711 ?F OCH3 b H COOH
712 ?F OCH3 b H CH 2OH
713 ?F OCH3 b H Sugar
714 ?F OCH3 b H The C-glycosyl compound
715 ?F OCH3 b OH OH
716 ?F OCH3 b OH The D-sorbitol
717 ?F OCH3 b OH SO 3H
718 ?F OCH3 b OH PO 3H 2
719 ?F OCH3 b OH CHO
720 ?F OCH3 b OH COOH
721 ?F OCH3 b OH CH 2OH
722 ?F OCH3 b OH Sugar
723 ?F OCH3 b OH The C-glycosyl compound
724 ?F OCH3 b CH 3 OH
725 ?F OCH3 b CH 3 The D-sorbitol
726 ?F OCH3 b CH 3 SO 3H
727 ?F OCH3 b CH 3 PO 3H 2
728 ?F OCH3 b CH 3 CHO
729 ?F OCH3 b CH 3 COOH
730 ?F OCH3 b CH 3 CH 2OH
731 ?F OCH3 b CH 3 Sugar
732 ?F OCH3 b CH 3 The C-glycosyl compound
733 ?F OCH3 b Cl OH
734 ?F OCH3 b Cl The D-sorbitol
735 ?F OCH3 b Cl SO 3H
736 ?F OCH3 b Cl PO 3H 2
737 ?F OCH3 b Cl CHO
738 ?F OCH3 b Cl COOH
739 F OCH3 b Cl CH 2OH
740 F OCH3 b Cl Sugar
741 F OCH3 b Cl The C-glycosyl compound
742 F OCH3 b B(OH) 2 OH
743 F OCH3 b B(OH) 2 The D-sorbitol
744 F OCH3 b B(OH) 2 SO 3H
745 F OCH3 b B(OH) 2 PO 3H 2
746 F OCH3 b B(OH) 2 CHO
747 F OCH3 b B(OH) 2 COOH
748 F OCH3 b B(OH) 2 CH 2OH
749 F OCH3 b B(OH) 2 Sugar
750 F OCH3 b B(OH) 2 The C-glycosyl compound
751 F OCH3 b SH OH
752 F OCH3 b SH The D-sorbitol
753 F OCH3 b SH SO 3H
754 F OCH3 b SH PO 3H 2
755 F OCH3 b SH CHO
756 F OCH3 b SH COOH
757 F OCH3 b SH CH 2OH
758 F OCH3 b SH Sugar
759 F OCH3 b SH The C-glycosyl compound
760 F OCH3 b OCH 3 OH
761 F OCH3 b OCH 3 The D-sorbitol
762 F OCH3 b OCH 3 SO 3H
763 F OCH3 b OCH 3 PO 3H 2
764 F OCH3 b OCH 3 CHO
765 F OCH3 b OCH 3 COOH
766 F OCH3 b OCH 3 CH 2OH
767 F OCH3 b OCH 3 Sugar
768 F OCH3 b OCH 3 The C-glycosyl compound
769 Cl H H OH
770 Cl H H The D-sorbitol
771 Cl H H SO 3H
772 Cl H H PO 3H 2
773 Cl H H CHO
774 Cl H H COOH
775 Cl H H CH 2OH
776 Cl H H Sugar
777 Cl H H The C-glycosyl compound
778 Cl H OH CHO
779 Cl H OH COOH
780 Cl H OH CH 2OH
781 Cl H OH Sugar
782 Cl H OH The C-glycosyl compound
783 Cl H CH 3 OH
784 Cl H CH 3 The D-sorbitol
785 Cl H CH 3 SO 3H
786 Cl H CH 3 PO 3H 2
787 Cl H CH 3 CHO
788 Cl H CH 3 COOH
789 Cl H CH 3 CH 2OH
790 Cl H CH 3 Sugar
791 Cl H CH 3 The C-glycosyl compound
792 Cl H Cl OH
793 Cl H Cl The D-sorbitol
794 Cl H Cl SO 3H
795 Cl H Cl PO 3H 2
796 Cl H Cl CHO
797 Cl H Cl COOH
798 Cl H Cl CH 2OH
799 Cl H Cl Sugar
800 Cl H Cl The C-glycosyl compound
801 Cl H B(OH) 2 OH
802 Cl H B(OH) 2 The D-sorbitol
803 Cl H B(OH) 2 SO 3H
804 Cl H B(OH) 2 PO 3H 2
805 Cl H B(OH) 2 CHO
806 Cl H B(OH) 2 COOH
807 Cl H B(OH) 2 CH 2OH
808 Cl H B(OH) 2 Sugar
809 Cl H B(OH) 2 The C-glycosyl compound
810 Cl ?H SH OH
811 Cl ?H SH The D-sorbitol
812 Cl ?H SH SO 3H
813 Cl ?H SH PO 3H 2
814 Cl ?H SH CHO
815 Cl ?H SH COOH
816 Cl ?H SH CH 2OH
817 Cl ?H SH Sugar
818 Cl ?H SH The C-glycosyl compound
819 Cl ?H OCH 3 OH
820 Cl ?H OCH 3 The D-sorbitol
821 Cl ?H OCH 3 SO 3H
822 Cl ?H OCH 3 PO 3H 2
823 Cl ?H OCH 3 CHO
824 Cl ?H OCH 3 COOH
825 Cl ?H OCH 3 CH 2OH
826 Cl ?H OCH 3 Sugar
827 Cl ?H OCH 3 The C-glycosyl compound
828 Cl ?F H OH
829 Cl ?F H The D-sorbitol
830 Cl ?F H SO 3H
831 Cl ?F H PO 3H 2
832 Cl ?F H CHO
833 Cl ?F H COOH
834 Cl ?F H CH 2OH
835 Cl ?F H Sugar
836 Cl ?F H The C-glycosyl compound
837 Cl ?F OH CHO
838 Cl ?F OH COOH
839 Cl ?F OH CH 2OH
840 Cl ?F OH Sugar
841 Cl ?F OH The C-glycosyl compound
842 Cl ?F CH 3 OH
843 Cl ?F CH 3 The D-sorbitol
844 Cl ?F CH 3 SO 3H
845 Cl ?F CH 3 PO 3H 2
846 Cl ?F CH 3 CHO
847 Cl ?F CH 3 COOH
848 Cl ?F CH 3 CH 2OH
849 Cl ?F CH 3 Sugar
850 Cl ?F CH 3 The C-glycosyl compound
851 Cl ?F Cl OH
852 Cl ?F Cl The D-sorbitol
853 Cl ?F Cl SO 3H
854 Cl ?F Cl PO 3H 2
855 Cl ?F Cl CHO
856 Cl ?F Cl COOH
857 Cl ?F Cl CH 2OH
858 Cl ?F Cl Sugar
859 Cl ?F Cl The C-glycosyl compound
860 Cl ?F B(OH) 2 OH
861 Cl ?F B(OH) 2 The D-sorbitol
862 Cl ?F B(OH) 2 SO 3H
863 Cl ?F B(OH) 2 PO 3H 2
864 Cl ?F B(OH) 2 CHO
865 Cl ?F B(OH) 2 COOH
866 Cl ?F B(OH) 2 CH 2OH
867 Cl ?F B(OH) 2 Sugar
868 Cl ?F B(OH) 2 The C-glycosyl compound
869 Cl ?F SH OH
870 Cl ?F SH The D-sorbitol
871 Cl ?F SH SO 3H
872 Cl ?F SH PO 3H 2
873 Cl ?F SH CHO
874 Cl ?F SH COOH
875 Cl ?F SH CH 2OH
876 Cl ?F SH Sugar
877 Cl ?F SH The C-glycosyl compound
878 Cl ?F OCH 3 OH
879 Cl ?F OCH 3 The D-sorbitol
880 Cl ?F OCH 3 SO 3H
881 Cl ?F OCH 3 PO 3H 2
882 Cl ?F OCH 3 CHO
883 Cl ?F OCH 3 COOH
884 Cl ?F OCH 3 CH 2OH
885 Cl F OCH 3 Sugar
886 Cl F OCH 3 The C-glycosyl compound
887 Cl Cl H OH
888 Cl Cl H The D-sorbitol
889 Cl Cl H SO 3H
890 Cl Cl H PO 3H 2
891 Cl Cl H CHO
892 Cl Cl H COOH
893 Cl Cl H CH 2OH
894 Cl Cl H Sugar
895 Cl Cl H The C-glycosyl compound
896 Cl Cl OH CHO
897 Cl Cl OH COOH
898 Cl Cl OH CH 2OH
899 Cl Cl OH Sugar
900 Cl Cl OH The C-glycosyl compound
901 Cl Cl CH 3 OH
902 Cl Cl CH 3 The D-sorbitol
903 Cl Cl CH 3 SO 3H
904 Cl Cl CH 3 PO 3H 2
905 Cl Cl CH 3 CHO
906 Cl Cl CH 3 COOH
907 Cl Cl CH 3 CH 2OH
908 Cl Cl CH 3 Sugar
909 Cl Cl CH 3 The C-glycosyl compound
910 Cl Cl Cl OH
911 Cl Cl Cl The D-sorbitol
912 Cl Cl Cl SO 3H
913 Cl Cl Cl PO 3H 2
914 Cl Cl Cl CHO
915 Cl Cl Cl COOH
916 Cl Cl Cl CH 2OH
917 Cl Cl Cl Sugar
918 Cl Cl Cl The C-glycosyl compound
919 Cl Cl B(OH) 2 OH
920 Cl Cl B(OH) 2 The D-sorbitol
921 Cl Cl B(OH) 2 SO 3H
922 Cl Cl B(OH) 2 PO 3H 2
923 Cl Cl B(OH) 2 CHO
924 Cl Cl B(OH) 2 COOH
925 Cl Cl B(OH) 2 CH 2OH
926 Cl Cl B(OH) 2 Sugar
927 Cl Cl B(OH) 2 The C-glycosyl compound
928 Cl Cl SH OH
929 Cl Cl SH The D-sorbitol
930 Cl Cl SH SO 3H
931 Cl Cl SH PO 3H 2
932 Cl Cl SH CHO
933 Cl Cl SH COOH
934 Cl Cl SH CH 2OH
935 Cl Cl SH Sugar
936 Cl Cl SH The C-glycosyl compound
937 Cl Cl OCH 3 OH
938 Cl Cl OCH 3 The D-sorbitol
939 Cl Cl OCH 3 SO 3H
940 Cl Cl OCH 3 PO 3H 2
941 Cl Cl OCH 3 CHO
942 Cl Cl OCH 3 COOH
943 Cl Cl OCH 3 CH 2OH
944 Cl Cl OCH 3 Sugar
945 Cl Cl OCH 3 The C-glycosyl compound
946 Cl CN H OH
947 Cl CN H The D-sorbitol
948 Cl CN H SO 3H
949 Cl CN H PO 3H 2
950 Cl CN H CHO
951 Cl CN H COOH
952 Cl CN H CH 2OH
953 Cl CN H Sugar
954 Cl CN H The C-glycosyl compound
955 Cl CN OH OH
956 Cl CN OH The D-sorbitol
957 Cl CN OH SO 3H
958 Cl CN OH PO 3H 2
959 Cl CN OH CHO
960 Cl CN OH COOH
961 Cl CN OH CH 2OH
962 Cl CN OH Sugar
963 Cl CN OH The C-glycosyl compound
964 Cl CN CH 3 OH
965 Cl CN CH 3 The D-sorbitol
966 Cl CN CH 3 SO 3H
967 Cl CN CH 3 PO 3H 2
968 Cl CN CH 3 CHO
969 Cl CN CH 3 COOH
970 Cl CN CH 3 CH 2OH
971 Cl CN CH 3 Sugar
972 Cl CN CH 3 The C-glycosyl compound
973 Cl CN Cl OH
974 Cl CN Cl The D-sorbitol
975 Cl CN Cl SO 3H
976 Cl CN Cl PO 3H 2
977 Cl CN Cl CHO
978 Cl CN Cl COOH
979 Cl CN Cl CH 2OH
980 Cl CN Cl Sugar
981 Cl CN Cl The C-glycosyl compound
982 Cl CN B(OH) 2 OH
983 Cl CN B(OH) 2 The D-sorbitol
984 Cl CN B(OH) 2 SO 3H
985 Cl CN B(OH) 2 PO 3H 2
986 Cl CN B(OH) 2 CHO
987 Cl CN B(OH) 2 COOH
988 Cl CN B(OH) 2 CH 2OH
989 Cl CN B(OH) 2 Sugar
990 Cl CN B(OH) 2 The C-glycosyl compound
991 Cl CN SH OH
992 Cl CN SH The D-sorbitol
993 Cl CN SH SO 3H
994 Cl CN SH PO 3H 2
995 Cl CN SH CHO
996 Cl CN SH COOH
997 Cl CN SH CH 2OH
998 Cl CN SH Sugar
999 Cl CN SH The C-glycosyl compound
1000 Cl CN OCH 3 OH
1001 Cl CN OCH 3 The D-sorbitol
1002 Cl CN OCH 3 SO 3H
1003 Cl CN OCH 3 PO 3H 2
1004 Cl CN OCH 3 CHO
1005 Cl CN OCH 3 COOH
1006 Cl CN OCH 3 CH 2OH
1007 Cl CN OCH 3 Sugar
1008 Cl CN OCH 3 The C-glycosyl compound
1009 Cl CH 3 a H OH
1010 Cl CH 3 a H The D-sorbitol
1011 Cl CH 3 a H SO 3H
1012 Cl CH 3 a H PO 3H 2
1013 Cl CH 3 a H CHO
1014 Cl CH 3 a H COOH
1015 Cl CH 3 a H CH 2OH
1016 Cl CH 3 a H Sugar
1017 Cl CH 3 a H The C-glycosyl compound
1018 Cl CH 3 a OH OH
1019 Cl CH 3 a OH The D-sorbitol
1020 Cl CH 3 a OH SO 3H
1021 Cl CH 3 a OH PO 3H 2
1022 Cl CH 3 a OH CHO
1023 Cl CH 3 a OH COOH
1024 Cl CH 3 a OH CH 2OH
1025 Cl CH 3 a OH Sugar
1026 Cl CH 3 a OH The C-glycosyl compound
1027 Cl CH 3 a CH 3 OH
1028 Cl CH 3 a CH 3 The D-sorbitol
1029 Cl CH 3 a CH 3 SO 3H
1030 Cl CH 3 a CH 3 PO 3H 2
1031 Cl CH 3 a CH 3 CHO
1032 Cl CH 3 a CH 3 COOH
1033 Cl CH 3 a CH 3 CH 2OH
1034 Cl CH 3 a CH 3 Sugar
1035 Cl CH 3 a CH 3 The C-glycosyl compound
1036 Cl CH 3 a Cl OH
1037 Cl CH 3 a Cl The D-sorbitol
1038 Cl CH 3 a Cl SO 3H
1039 Cl CH 3 a Cl PO 3H 2
1040 Cl CH 3 a Cl CHO
1041 Cl CH 3 a Cl COOH
1042 Cl CH 3 a Cl CH 2OH
1043 Cl CH 3 a Cl Sugar
1044 Cl CH 3 a Cl The C-glycosyl compound
1045 Cl CH 3 a B(OH) 2 OH
1046 Cl CH 3 a B(OH) 2 The D-sorbitol
1047 Cl CH 3 a B(OH) 2 SO 3H
1048 Cl CH 3 a B(OH) 2 PO 3H 2
1049 Cl CH 3 a B(OH) 2 CHO
1050 Cl CH 3 a B(OH) 2 COOH
1051 Cl CH 3 a B(OH) 2 CH 2OH
1052 Cl CH 3 a B(OH) 2 Sugar
1053 Cl CH 3 a B(OH) 2 The C-glycosyl compound
1054 Cl CH 3 a SH OH
1055 Cl CH 3 a SH The D-sorbitol
1056 Cl CH 3 a SH SO 3H
1057 Cl CH 3 a SH PO 3H 2
1058 Cl CH 3 a SH CHO
1059 Cl CH 3 a SH COOH
1060 Cl CH 3 a SH CH 2OH
1061 Cl CH 3 a SH Sugar
1062 Cl CH 3 a SH The C-glycosyl compound
1063 Cl CH 3 a OCH 3 OH
1064 Cl CH 3 a OCH 3 The D-sorbitol
1065 Cl CH 3 a OCH 3 SO 3H
1066 Cl CH 3 a OCH 3 PO 3H 2
1067 Cl CH 3 a OCH 3 CHO
1068 Cl CH 3 a OCH 3 COOH
1069 Cl CH 3 a OCH 3 CH 2OH
1070 Cl CH 3 a OCH 3 Sugar
1071 Cl CH 3 a OCH 3 The C-glycosyl compound
1072 Cl OCH3 b H OH
1073 Cl OCH3 b H The D-sorbitol
1074 Cl OCH3 b H SO 3H
1075 Cl OCH3 b H PO 3H 2
1076 Cl OCH3 b H CHO
1077 Cl OCH3 b H COOH
1078 Cl OCH3 b H CH 2OH
1079 Cl OCH3 b H Sugar
1080 Cl OCH3 b H The C-glycosyl compound
1081 Cl OCH3 b OH OH
1082 Cl OCH3 b OH The D-sorbitol
1083 Cl OCH3 b OH SO 3H
1084 Cl OCH3 b OH PO 3H 2
1085 Cl OCH3 b OH CHO
1086 Cl OCH3 b OH COOH
1087 Cl OCH3 b OH CH 2OH
1088 Cl OCH3 b OH Sugar
1089 Cl OCH3 b OH The C-glycosyl compound
1090 Cl OCH3 b CH 3 OH
1091 Cl OCH3 b CH 3 The D-sorbitol
1092 Cl OCH3 b CH 3 SO 3H
1093 Cl OCH3 b CH 3 PO 3H 2
1094 Cl OCH3 b CH 3 CHO
1095 Cl OCH3 b CH 3 COOH
1096 Cl OCH3 b CH 3 CH 2OH
1097 Cl ?OCH3 b CH 3 Sugar
1098 Cl ?OCH3 b CH 3 The C-glycosyl compound
1099 Cl ?OCH3 b Cl OH
1100 Cl ?OCH3 b Cl The D-sorbitol
1101 Cl ?OCH3 b Cl SO 3H
1102 Cl ?OCH3 b Cl PO 3H 2
1103 Cl ?OCH3 b Cl CHO
1104 Cl ?OCH3 b Cl COOH
1105 Cl ?OCH3 b Cl CH 2OH
1106 Cl ?OCH3 b C1 Sugar
1107 Cl ?OCH3 b Cl The C-glycosyl compound
1108 Cl ?OCH3 b B(OH) 2 OH
1109 Cl ?OCH3 b B(OH) 2 The D-sorbitol
1110 Cl ?OCH3 b B(OH) 2 SO 3H
111l Cl ?OCH3 b B(OH) 2 PO 3H 2
1112 Cl ?OCH3 b B(OH) 2 CHO
1113 Cl ?OCH3 b B(OH) 2 COOH
1114 Cl ?OCH3 b B(OH) 2 CH 2OH
1115 Cl ?OCH3 b B(OH) 2 Sugar
1116 Cl ?OCH3 b B(OH) 2 The C-glycosyl compound
1117 Cl ?OCH3 b SH OH
1118 Cl ?OCH3 b SH The D-sorbitol
1119 Cl ?OCH3 b SH SO 3H
1120 Cl ?OCH3 b SH PO 3H 2
1121 Cl ?OCH3 b SH CHO
1122 Cl ?OCH3 b SH COOH
1123 Cl ?OCH3 b SH CH 2OH
1124 Cl ?OCH3 b SH Sugar
1125 Cl ?OCH3 b SH The C-glycosyl compound
1126 Cl ?OCH3 b OCH 3 OH
1127 Cl ?OCH3 b OCH 3 The D-sorbitol
1128 Cl ?OCH3 b OCH 3 SO 3H
1129 Cl ?OCH3 b OCH 3 PO 3H 2
1130 Cl ?OCH3 b OCH 3 CHO
1131 Cl ?OCH3 b OCH 3 COOH
1132 Cl ?OCH3 b OCH 3 CH 2OH
1133 Cl ?OCH3 b OCH 3 Sugar
1134 Cl ?OCH3 b OCH 3 The C-glycosyl compound
1135 CN ?H H OH
1136 CN ?H H The D-sorbitol
1137 CN ?H H SO 3H
1138 CN ?H H PO 3H 2
1139 CN ?H H CHO
1140 CN ?H H COOH
1141 CN ?H H CH 2OH
1142 CN ?H H Sugar
1143 CN ?H H The C-glycosyl compound
1144 CN ?H OH OH
1145 CN ?H OH The D-sorbitol
1146 CN ?H OH SO 3H
1147 CN ?H OH PO 3H 2
1148 CN ?H OH CHO
1149 CN ?H OH COOH
1150 CN ?H OH CH 2OH
1151 CN ?H OH Sugar
1152 CN ?H OH The C-glycosyl compound
1153 CN ?H CH 3 OH
1154 CN ?H CH 3 The D-sorbitol
1155 CN ?H CH 3 SO 3H
1156 CN ?H CH 3 PO 3H 2
1157 CN ?H CH 3 CHO
1158 CN ?H CH 3 COOH
1159 CN ?H CH 3 CH 2OH
1160 CN ?H CH 3 Sugar
1161 CN ?H CH 3 The C-glycosyl compound
1162 CN ?H Cl OH
1163 CN ?H Cl The D-sorbitol
1164 CN ?H Cl SO 3H
1165 CN ?H Cl PO 3H 2
1166 CN ?H Cl CHO
1167 CN H Cl COOH
1168 CN H Cl CH 2OH
1169 CN H Cl Sugar
1170 CN H Cl The C-glycosyl compound
1171 CN H B(OH) 2 OH
1172 CN H B(OH) 2 The D-sorbitol
1173 CN H B(OH) 2 SO 3H
1174 CN H B(OH) 2 PO 3H 2
1175 CN H B(OH) 2 CHO
1176 CN H B(OH) 2 COOH
1177 CN H B(OH) 2 CH 2OH
1178 CN H B(OH) 2 Sugar
1179 CN H B(OH) 2 The C-glycosyl compound
1180 CN H SH OH
1181 CN H SH The D-sorbitol
1182 CN H SH SO 3H
1183 CN H SH PO 3H 2
1184 CN H SH CHO
1185 CN H SH COOH
1186 CN H SH CH 2OH
1187 CN H SH Sugar
1188 CN H SH The C-glycosyl compound
1189 CN H OCH 3 OH
1190 CN H OCH 3 The D-sorbitol
1191 CN H OCH 3 SO 3H
1192 CN H OCH 3 PO 3H 2
1193 CN H OCH 3 CHO
1194 CN H OCH 3 COOH
1195 CN H OCH 3 CH 2OH
1196 CN H OCH 3 Sugar
1197 CN H OCH 3 The C-glycosyl compound
1198 CN F H OH
1199 CN F H The D-sorbitol
1200 CN F H SO 3H
1201 CN F H PO 3H 2
1202 CN F H CHO
1203 CN F H COOH
1204 CN ?F H CH 2OH
1205 CN ?F H Sugar
1206 CN ?F H The C-glycosyl compound
1207 CN ?F OH OH
1208 CN ?F OH The D-sorbitol
1209 CN ?F OH SO 3H
1210 CN ?F OH PO 3H 2
1211 CN ?F OH CHO
1212 CN ?F OH COOH
1213 CN ?F OH CH 2OH
1214 CN ?F OH Sugar
1215 CN ?F OH The C-glycosyl compound
1216 CN ?F CH 3 OH
1217 CN ?F CH 3 The D-sorbitol
1218 CN ?F CH 3 SO 3H
1219 CN ?F CH 3 PO 3H 2
1220 CN ?F CH 3 CHO
1221 CN ?F CH 3 COOH
1222 CN ?F CH 3 CH 2OH
1223 CN ?F CH 3 Sugar
1224 CN ?F CH 3 The C-glycosyl compound
1225 CN ?F Cl OH
1226 CN ?F Cl The D-sorbitol
1227 CN ?F Cl SO 3H
1228 CN ?F Cl PO 3H 2
1229 CN ?F Cl CHO
1230 CN ?F Cl COOH
1231 CN ?F Cl CH 2OH
1232 CN ?F Cl Sugar
1233 CN ?F Cl The C-glycosyl compound
1234 CN ?F B(OH) 2 OH
1235 CN ?F B(OH) 2 The D-sorbitol
1236 CN ?F B(OH) 2 SO 3H
1237 CN ?F B(OH) 2 PO 3H 2
1238 CN ?F B(OH) 2 CHO
1239 CN ?F B(OH) 2 COOH
1240 CN ?F B(OH) 2 CH 2OH
1241 CN F B(OH) 2 Sugar
1242 CN F B(OH) 2 The C-glycosyl compound
1243 CN F SH OH
1244 CN F SH The D-sorbitol
1245 CN F SH SO 3H
1246 CN F SH PO 3H 2
1247 CN F SH CHO
1248 CN F SH COOH
1249 CN F SH CH 2OH
1250 CN F SH Sugar
1251 CN F SH The C-glycosyl compound
1252 CN F OCH 3 OH
1253 CN F OCH 3 The D-sorbitol
1254 CN F OCH 3 SO 3H
1255 CN F OCH 3 PO 3H 2
1256 CN F OCH 3 CHO
1257 CN F OCH 3 COOH
1258 CN F OCH 3 CH 2OH
1259 CN F OCH 3 Sugar
1260 CN F OCH 3 The C-glycosyl compound
1261 CN Cl H OH
1262 CN Cl H The D-sorbitol
1263 CN Cl H SO 3H
1264 CN Cl H PO 3H 2
1265 CN Cl H CHO
1266 CN Cl H COOH
1267 CN Cl H CH 2OH
1268 CN Cl H Sugar
1269 CN Cl H The C-glycosyl compound
1270 CN Cl OH OH
1271 CN Cl OH The D-sorbitol
1272 CN Cl OH SO 3H
1273 CN Cl OH PO 3H 2
1274 CN Cl OH CHO
1275 CN Cl OH COOH
1276 CN Cl OH CH 2OH
1277 CN Cl OH Sugar
1278 CN Cl OH The C-glycosyl compound
1279 CN Cl CH 3 OH
1280 CN Cl CH 3 The D-sorbitol
1281 CN Cl CH 3 SO 3H
1282 CN Cl CH 3 PO 3H 2
1283 CN Cl CH 3 CHO
1284 CN Cl CH 3 COOH
1285 CN Cl CH 3 CH 2OH
1286 CN Cl CH 3 Sugar
1287 CN Cl CH 3 The C-glycosyl compound
1288 CN Cl Cl OH
1289 CN Cl Cl The D-sorbitol
1290 CN Cl Cl SO 3H
1291 CN Cl Cl PO 3H 2
1292 CN Cl Cl CHO
1293 CN Cl Cl COOH
1294 CN Cl Cl CH 2OH
1295 CN Cl Cl Sugar
1296 CN Cl Cl The C-glycosyl compound
1297 CN Cl B(OH) 2 OH
1298 CN Cl B(OH) 2 The D-sorbitol
1299 CN Cl B(OH) 2 SO 3H
13O0 CN Cl B(OH) 2 PO 3H 2
1301 CN Cl B(OH) 2 CHO
1302 CN Cl B(OH) 2 COOH
1303 CN Cl B(OH) 2 CH 2OH
1304 CN Cl B(OH) 2 Sugar
1305 CN Cl B(OH) 2 The C-glycosyl compound
1306 CN Cl SH OH
1307 CN Cl SH The D-sorbitol
1308 CN Cl SH SO 3H
1309 CN Cl SH PO 3H 2
1310 CN Cl SH CHO
1311 CN Cl SH COOH
1312 CN Cl SH CH 2OH
1313 CN Cl SH Sugar
1314 CN Cl SH The C-glycosyl compound
1315 CN Cl OCH 3 OH
1316 CN Cl OCH 3 The D-sorbitol
1317 CN Cl OCH 3 SO 3H
1318 CN Cl OCH 3 PO 3H 2
1319 CN Cl OCH 3 CHO
1320 CN Cl OCH 3 COOH
1321 CN Cl OCH 3 CH 2OH
1322 CN Cl OCH 3 Sugar
1323 CN Cl OCH 3 The C-glycosyl compound
1324 CN CN H OH
1325 CN CN H The D-sorbitol
1326 CN CN H SO 3H
1327 CN CN H PO 3H 2
1328 CN CN H CHO
1329 CN CN H COOH
1330 CN CN H CH 2OH
1331 CN CN H Sugar
1332 CN CN H The C-glycosyl compound
1333 CN CN OH OH
1334 CN CN OH The D-sorbitol
1335 CN CN OH SO 3H
1336 CN CN OH PO 3H 2
1337 CN CN OH CHO
1338 CN CN OH COOH
1339 CN CN OH CH 2OH
1340 CN CN OH Sugar
1341 CN CN OH The C-glycosyl compound
1342 CN CN CH 3 OH
1343 CN CN CH 3 The D-sorbitol
1344 CN CN CH 3 SO 3H
1345 CN CN CH 3 PO 3H 2
1346 CN CN CH 3 CHO
1347 CN CN CH 3 COOH
1348 CN CN CH 3 CH 2OH
1349 CN CN CH 3 Sugar
1350 CN CN CH 3 The C-glycosyl compound
1351 CN CN Cl OH
1352 CN CN Cl The D-sorbitol
1353 CN CN Cl SO 3H
1354 CN CN Cl PO 3H 2
1355 CN CN Cl CHO
1356 CN CN Cl COOH
1357 CN CN Cl CH 2OH
1358 CN CN Cl Sugar
1359 CN CN Cl The C-glycosyl compound
1360 CN CN B(OH) 2 OH
1361 CN CN B(OH) 2 The D-sorbitol
1362 CN CN B(OH) 2 SO 3H
1363 CN CN B(OH) 2 PO 3H 2
1364 CN CN B(OH) 2 CHO
1365 CN CN B(OH) 2 COOH
1366 CN CN B(OH) 2 CH 2OH
1367 CN CN B(OH) 2 Sugar
1368 CN CN B(OH) 2 The C-glycosyl compound
1369 CN CN SH OH
1370 CN CN SH The D-sorbitol
1371 CN CN SH SO 3H
1372 CN CN SH PO 3H 2
1373 CN CN SH CHO
1374 CN CN SH COOH
1375 CN CN SH CH 2OH
1376 CN CN SH Sugar
1377 CN CN SH The C-glycosyl compound
1378 CN CN OCH 3 OH
1379 CN CN OCH 3 The D-sorbitol
1380 CN CN OCH 3 SO 3H
1381 CN CN OCH 3 PO 3H 2
1382 CN CN OCH 3 CHO
1383 CN CN OCH 3 COOH
1384 CN CN OCH 3 CH 2OH
1385 CN CN OCH 3 Sugar
1386 CN CN OCH 3 The C-glycosyl compound
1387 CN CH 3 a H OH
1388 CN CH 3 a H The D-sorbitol
1389 CN CH 3 a ?H SO 3H
1390 CN CH 3 a ?H PO 3H 2
1391 CN CH 3 a ?H CHO
1392 CN CH 3 a ?H COOH
1393 CN CH 3 a ?H CH 2OH
1394 CN CH 3 a ?H Sugar
1395 CN CH 3 a ?H The C-glycosyl compound
1396 CN CH 3 a ?OH OH
1397 CN CH 3 a ?OH The D-sorbitol
1398 CN CH 3 a ?OH SO 3H
1399 CN CH 3 a ?OH PO 3H 2
1400 CN CH 3 a ?OH CHO
1401 CN CH 3 a ?OH COOH
1402 CN CH 3 a ?OH CH 2OH
1403 CN CH 3 a ?OH Sugar
1404 CN CH 3 a ?OH The C-glycosyl compound
1405 CN CH 3 a ?CH 3 OH
1406 CN CH 3 a ?CH3 The D-sorbitol
1407 CN CH 3 a ?CH 3 SO 3H
1408 CN CH 3 a ?CH 3 PO 3H 2
1409 CN CH 3 a ?CH 3 CHO
1410 CN CH 3 a ?CH 3 COOH
1411 CN CH 3 a ?CH 3 CH 2OH
1412 CN CH 3 a ?CH 3 Sugar
1413 CN CH 3 a ?CH 3 The C-glycosyl compound
1414 CN CH 3 a ?Cl OH
1415 CN CH 3 a ?Cl The D-sorbitol
1416 CN CH 3 a ?Cl SO 3H
1417 CN CH 3 a ?Cl PO 3H 2
1418 CN CH 3 a ?Cl CHO
1419 CN CH 3 a ?Cl COOH
1420 CN CH 3 a ?Cl CH 2OH
1421 CN ?CH 3 a Cl Sugar
1422 CN ?CH 3 a Cl The C-glycosyl compound
1423 CN ?CH 3 a B(OH) 2 OH
1424 CN ?CH 3 a B(OH) 2 The D-sorbitol
1425 CN ?CH 3 a B(OH) 2 SO 3H
1426 CN ?CH 3 a B(OH) 2 PO 3H 2
1427 CN ?CH 3 a B(OH) 2 CHO
1428 CN ?CH 3 a B(OH) 2 COOH
1429 CN ?CH 3 a B(OH) 2 CH 2OH
1430 CN ?CH 3 a B(OH) 2 Sugar
1431 CN ?CH 3 a B(OH) 2 The C-glycosyl compound
1432 CN ?CH 3 a SH OH
1433 CN ?CH 3 a SH The D-sorbitol
1434 CN ?CH 3 a SH SO 3H
1435 CN ?CH 3 a SH PO 3H 2
1436 CN ?CH 3 a SH CHO
1437 CN ?CH 3 a SH COOH
1438 CN ?CH 3 a SH CH 2OH
1439 CN ?CH 3 a SH Sugar
1440 CN ?CH 3 a SH The C-glycosyl compound
1441 CN ?CH 3 a OCH 3 OH
1442 CN ?CH 3 a OCH 3 The D-sorbitol
1443 CN ?CH 3 a OCH 3 SO 3H
1444 CN ?CH 3 a OCH 3 PO 3H 2
1445 CN ?CH 3 a OCH 3 CHO
1446 CN ?CH 3 a OCH 3 COOH
1447 CN ?CH 3 a OCH 3 CH 2OH
1448 CN ?CH 3 a OCH 3 Sugar
1449 CN ?CH 3 a OCH 3 The C-glycosyl compound
1450 CN ?OCH3 b H OH
1451 CN ?OCH3 b H The D-sorbitol
1452 CN ?OCH3 b H SO 3H
1453 CN ?OCH3 b H PO 3Hx
1454 CN OCH3 b H CHO
1455 CN OCH3 b H COOH
1456 CN OCH3 b H CH 2OH
1457 CN OCH3 b H Sugar
1458 CN OCH3 b H The C-glycosyl compound
1459 CN OCH3 b OH OH
1460 CN OCH3 b OH The D-sorbitol
1461 CN OCH3 b OH SO 3H
1462 CN OCH3 b OH PO 3H 2
1463 CN OCH3 b OH CHO
1464 CN OCH3 b OH COOH
1465 CN OCH3 b OH CH 2OH
1466 CN OCH3 b OH Sugar
1467 CN OCH3 b OH The C-glycosyl compound
1468 CN OCH3 b CH 3 OH
1469 CN OCH3 b CH 3 The D-sorbitol
1470 CN OCH3 b CH 3 SO 3H
1471 CN OCH3 b CH3 PO 3H 2
1472 CN OCH3 b CH 3 CHO
1473 CN OCH3 b CH 3 COOH
1474 CN OCH3 b CH 3 CH 2OH
1475 CN OCH3 b CH 3 Sugar
1476 CN OCH3 b CH 3 The C-glycosyl compound
1477 CN OCH3 b Cl OH
1478 CN OCH3 b Cl The D-sorbitol
1479 CN OCH3 b Cl SO 3H
1480 CN OCH3 b Cl PO 3H 2
1481 CN OCH3 b Cl CHO
1482 CN OCH3 b Cl COOH
1483 CN OCH3 b Cl CH 2OH
1484 CN OCH3 b Cl Sugar
1485 CN OCH3 b Cl The C-glycosyl compound
1486 CN OCH3 b B(OH) 2 OH
1487 CN OCH3 b B(OH) 2 The D-sorbitol
1488 CN OCH3 b B(OH) 2 SO 3H
1489 CN OCH3 b B(OH) 2 PO 3H 2
1490 CN OCH3 b B(OH) 2 CHO
1491 CN OCH3 b B(OH) 2 COOH
1492 CN OCH3 b B(OH) 2 CH 2OH
1493 CN OCH3 b B(OH) 2 Sugar
1494 CN OCH3 b B(OH) 2 The C-glycosyl compound
1495 CN OCH3 b SH OH
1496 CN OCH3 b SH The D-sorbitol
1497 CN OCH3 b SH SO 3H
1498 CN OCH3 b SH PO 3H 2
1499 CN OCH3 b SH CHO
1500 CN OCH3 b SH COOH
1501 CN OCH3 b SH CH 2OH
1502 CN OCH3 b SH Sugar
1503 CN OCH3 b SH The C-glycosyl compound
1504 CN OCH3 b OCH 3 OH
1505 CN OCH3 b OCH 3 The D-sorbitol
1506 CN OCH3 b OCH 3 SO 3H
1507 CN OCH3 b OCH 3 PO 3H 2
1508 CN OCH3 b OCH 3 CHO
1509 CN OCH3 b OCH 3 COOH
1510 CN OCH3 b OCH 3 CH 2OH
1511 CN OCH3 b OCH 3 Sugar
1512 CN OCH3 b OCH 3 The C-glycosyl compound
1513 CH 3 a H H OH
1514 CH 3 a H H The D-sorbitol
1515 CH 3 a H H SO 3H
1516 CH 3 a H H PO 3H 2
1517 CH 3 a H H CHO
1518 CH 3 a H H COOH
1519 CH 3 a H H CH 2OH
1520 CH 3 a H H Sugar
1521 CH 3 a ?H H The C-glycosyl compound
1522 CH 3 a ?H OH OH
1523 CH 3 a ?H OH The D-sorbitol
1524 CH 3 a ?H OH SO 3H
1525 CH 3 a ?H OH PO 3H 2
1526 CH 3 a ?H OH CHO
1527 CH 3 a ?H OH COOH
1528 CH 3 a ?H OH CH 2OH
1529 CH 3 a ?H OH Sugar
1530 CH 3 a ?H OH The C-glycosyl compound
1531 CH 3 a ?H CH 3 OH
1532 CH 3 a ?H CH 3 The D-sorbitol
1533 CH 3 a ?H CH 3 SO 3H
1534 CH 3 a ?H CH 3 PO 3H 2
1535 CH 3 a ?H CH 3 CHO
1536 CH 3 a ?H CH 3 COOH
1537 CH 3 a ?H CH 3 CH 2OH
1538 CH 3 a ?H CH 3 Sugar
1539 CH 3 a ?H CH 3 The C-glycosyl compound
1540 CH 3 a ?H Cl OH
1541 CH 3 a ?H Cl The D-sorbitol
1542 CH 3 a ?H Cl SO 3H
1543 CH 3 a ?H Cl PO 3H 2
1544 CH 3 a ?H Cl CHO
1545 CH 3 a ?H Cl COOH
1546 CH 3 a ?H Cl CH 2OH
1547 CH 3 a ?H Cl Sugar
1548 CH 3 a ?H Cl The C-glycosyl compound
1549 CH 3 a ?H B(OH) 2 OH
1550 CH 3 a ?H B(OH) 2 The D-sorbitol
1551 CH 3 a ?H B(OH) 2 SO 3H
1552 CH 3 a ?H B(OH) 2 PO 3H 2
1553 CH 3 a ?H B(OH) 2 CHO
1554 CH 3 a ?H B(OH) 2 COOH
1555 CH 3 a ?H B(OH) 2 CH 2OH
1556 CH 3 a ?H B(OH) 2 Sugar
1557 CH 3 a ?H B(OH) 2 The C-glycosyl compound
1558 CH 3 a ?H SH OH
1559 CH 3 a ?H SH The D-sorbitol
1560 CH 3 a ?H SH SO 3H
1561 CH 3 a ?H SH PO 3H 2
1562 CH 3 a ?H SH CHO
1563 CH 3 a ?H SH COOH
1564 CH 3 a ?H SH CH 2OH
1565 CH 3 a ?H SH Sugar
1566 CH 3 a ?H SH The C-glycosyl compound
1567 CH 3 a ?H OCH 3 OH
1568 CH 3 a ?H OCH 3 The D-sorbitol
1569 CH 3 a ?H OCH 3 SO 3H
1570 CH 3 a ?H OCH 3 PO 3H 2
1571 CH 3 a ?H OCH 3 CHO
1572 CH 3 a ?H OCH 3 COOH
1573 CH 3 a ?H OCH 3 CH 2OH
1574 CH 3 a ?H OCH 3 Sugar
1575 CH 3 a ?H OCH 3 The C-glycosyl compound
1576 CH 3 a ?F H OH
1577 CH 3 a ?F H The D-sorbitol
1578 CH 3 a ?F H SO 3H
1579 CH 3 a ?F H PO 3H 2
1580 CH 3 a ?F H CHO
1581 CH 3 a ?F H COOH
1582 CH 3 a ?F H CH 2OH
1583 CH 3 a ?F H Sugar
1584 CH 3 a ?F H The C-glycosyl compound
1585 CH 3 a F OH OH
1586 CH 3 a F OH The D-sorbitol
1587 CH 3 a F OH SO 3H
1588 CH 3 a F OH PO 3H 2
1589 CH 3 a F OH CHO
1590 CH 3 a F OH COOH
1591 CH 3 a F OH CH 2OH
1592 CH 3 a F OH Sugar
1593 CH 3 a F OH The C-glycosyl compound
1594 CH 3 a F CH 3 OH
1595 CH 3 a F CH 3 The D-sorbitol
1596 CH 3 a F CH 3 SO 3H
1597 CH 3 a F CH 3 PO 3H 2
1598 CH 3 a F CH 3 CHO
1599 CH 3 a F CH 3 COOH
1600 CH 3 a F CH 3 CH 2OH
1601 CH 3 a F CH 3 Sugar
1602 CH 3 a F CH 3 The C-glycosyl compound
1603 CH 3 a F Cl OH
1604 CH 3 a F Cl The D-sorbitol
1605 CH 3 a F Cl SO 3H
1606 CH 3 a F Cl PO 3H 2
1607 CH 3 a F Cl CHO
1608 CH 3 a F Cl COOH
1609 CH 3 a F Cl CH 2OH
1610 CH 3 a F Cl Sugar
1611 CH 3 a F Cl The C-glycosyl compound
1612 CH 3 a F B(OH) 2 OH
1613 CH 3 a F B(OH) 2 The D-sorbitol
1614 CH 3 a F B(OH) 2 SO 3H
1615 CH 3 a F B(OH) 2 PO 3H 2
1616 CH 3 a F B(OH) 2 CHO
1617 CH 3 a F B(OH) 2 COOH
1618 CH 3 a F B(OH) 2 CH 2OH
1619 CH 3 a F B(OH) 2 Sugar
1620 CH 3 a F B(OH) 2 The C-glycosyl compound
1621 CH 3 a F SH OH
1622 CH 3 a F SH The D-sorbitol
1623 CH 3 a F SH SO 3H
1624 CH 3 a F SH PO 3H 2
1625 CH 3 a F SH CHO
1626 CH 3 a F SH COOH
1627 CH 3 a F SH CH 2OH
1628 CH 3 a F SH Sugar
1629 CH 3 a F SH The C-glycosyl compound
1630 CH 3 a F OCH 3 OH
1631 CH 3 a F OCH 3 The D-sorbitol
1632 CH 3 a F OCH 3 SO 3H
1633 CH 3 a F OCH 3 PO 3H 2
1634 CH 3 a F OCH 3 CHO
1635 CH 3 a F OCH 3 COOH
1636 CH 3 a F OCH 3 CH 2OH
1637 CH 3 a F OCH 3 Sugar
1638 CH 3 a F OCH 3 The C-glycosyl compound
1639 CH 3 a Cl H OH
1640 CH 3 a Cl H The D-sorbitol
1641 CH 3 a Cl H SO 3H
1642 CH 3 a Cl H PO 3H 2
1643 CH 3 a Cl H CHO
1644 CH 3 a Cl H COOH
1645 CH 3 a Cl H CH 2OH
1646 CH 3 a Cl H Sugar
1647 CH 3 a Cl H The C-glycosyl compound
1648 CH 3 a Cl OH OH
1649 CH 3 a Cl OH The D-sorbitol
1650 CH 3 a Cl OH SO 3H
1651 CH 3 a Cl OH PO 3H 2
1652 CH 3 a Cl OH CHO
1653 CH 3 a Cl OH COOH
1654 CH 3 a Cl OH CH 2OH
1655 CH 3 a Cl OH Sugar
1656 CH 3 a Cl OH The C-glycosyl compound
1657 CH 3 a Cl CH 3 OH
1658 CH 3 a Cl CH 3 The D-sorbitol
1659 CH 3 a Cl CH 3 SO 3H
1660 CH 3 a Cl CH 3 PO 3H 2
1661 CH 3 a Cl CH 3 CHO
1662 CH 3 a Cl CH 3 COOH
1663 CH 3 a Cl CH 3 CH 2OH
1664 CH 3 a Cl CH 3 Sugar
1665 CH 3 a Cl CH 3 The C-glycosyl compound
1666 CH 3 a Cl Cl OH
1667 CH 3 a Cl Cl The D-sorbitol
1668 CH 3 a Cl Cl SO 3H
1669 CH 3 a Cl Cl PO 3H 2
1670 CH 3 a Cl Cl CHO
1671 CH 3 a Cl Cl COOH
1672 CH 3 a Cl Cl CH 2OH
1673 CH 3 a Cl Cl Sugar
1674 CH 3 a Cl Cl The C-glycosyl compound
1675 CH 3 a Cl B(OH) 2 OH
1676 CH 3 a Cl B(OH) 2 The D-sorbitol
1677 CH 3 a Cl B(OH) 2 SO 3H
1678 CH 3 a Cl B(OH) 2 PO 3H 2
1679 CH 3 a Cl B(OH) 2 CHO
1680 CH 3 a Cl B(OH) 2 COOH
1681 CH 3 a Cl B(OH) 2 CH 2OH
1682 CH 3 a Cl B(OH) 2 Sugar
1683 CH 3 a Cl B(OH) 2 The C-glycosyl compound
1684 CH 3 a Cl SH OH
1685 CH 3 a Cl SH The D-sorbitol
1686 CH 3 a Cl SH SO 3H
1687 CH 3 a Cl SH PO 3H 2
1688 CH 3 a Cl SH CHO
1689 CH 3 a Cl SH COOH
1690 CH 3 a Cl SH CH 2OH
1691 CH 3 a Cl SH Sugar
1692 CH 3 a Cl SH The C-glycosyl compound
1693 CH 3 a Cl OCH 3 OH
1694 CH 3 a Cl OCH 3 The D-sorbitol
1695 CH 3 a Cl OCH 3 SO 3H
1696 CH 3 a Cl OCH 3 PO 3H 2
1697 CH 3 a Cl OCH 3 CHO
1698 CH 3 a Cl OCH 3 COOH
1699 CH 3 a Cl OCH 3 CH 2OH
1700 CH 3 a Cl OCH 3 Sugar
1701 CH 3 a Cl OCH 3 The C-glycosyl compound
1702 CH 3 a CN H OH
1703 CH 3 a CN H The D-sorbitol
1704 CH 3 a CN H SO 3H
1705 CH 3 a CN H PO 3H 2
1706 CH 3 a CN H CHO
1707 CH 3 a CN H COOH
1708 CH 3 a CN H CH 2OH
1709 CH 3 a CN H Sugar
1710 CH 3 a CN H The C-glycosyl compound
1711 CH 3 a CN OH OH
1712 CH 3 a CN OH The D-sorbitol
1713 CH 3 a CN OH SO 3H
1714 CH 3 a CN OH PO 3H 2
1715 CH 3 a CN OH CHO
1716 CH 3 a CN OH COOH
1717 CH 3 a CN OH CH 2OH
1718 CH 3 a CN OH Sugar
1719 CH 3 a CN OH The C-glycosyl compound
1720 CH 3 a CN CH 3 OH
1721 CH 3 a CN CH 3 The D-sorbitol
1722 CH 3 a CN CH 3 SO 3H
1723 CH 3 a CN CH 3 PO 3H 2
1724 CH 3 a CN CH 3 CHO
1725 CH 3 a CN CH 3 COOH
1726 CH 3 a CN CH 3 CH 2OH
1727 CH 3 a CN CH 3 Sugar
1728 CH 3 a CN CH 3 The C-glycosyl compound
1729 CH 3 a CN Cl OH
1730 CH 3 a CN Cl The D-sorbitol
1731 CH 3 a CN Cl SO 3H
1732 CH 3 a CN Cl PO 3H 2
1733 CH 3 a CN Cl CHO
1734 CH 3 a CN Cl COOH
1735 CH 3 a CN Cl CH 2OH
1736 CH 3 a CN Cl Sugar
1737 CH 3 a CN Cl The C-glycosyl compound
1738 CH 3 a CN B(OH) 2 OH
1739 CH 3 a CN B(OH) 2 The D-sorbitol
1740 CH 3 a CN B(OH) 2 SO 3H
1741 CH 3 a CN B(OH) 2 PO 3H 2
1742 CH 3 a CN B(OH) 2 CHO
1743 CH 3 a CN B(OH) 2 COOH
1744 CH 3 a CN B(OH) 2 CH 2OH
1745 CH 3 a CN B(OH) 2 Sugar
1746 CH 3 a CN B(OH) 2 The C-glycosyl compound
1747 CH 3 a CN SH OH
1748 CH 3 a CN SH The D-sorbitol
1749 CH 3 a CN SH SO 3H
1750 CH 3 a CN SH PO 3H 2
1751 CH 3 a CN SH CHO
1752 CH 3 a CN SH COOH
1753 CH 3 a CN SH CH 2OH
1754 CH 3 a CN SH Sugar
1755 CH 3 a CN SH The C-glycosyl compound
1756 CH 3 a CN OCH 3 OH
1757 CH 3 a CN OCH 3 The D-sorbitol
1758 CH 3 a CN OCH 3 SO 3H
1759 CH 3 a CN OCH 3 PO 3H 2
1760 CH 3 a CN OCH 3 CHO
1761 CH 3 a CN OCH 3 COOH
1762 CH 3 a CN OCH 3 CH 2OH
1763 CH 3 a CN OCH 3 Sugar
1764 CH 3 a CN OCH 3 The C-glycosyl compound
1765 CH 3 a CH 3 a H OH
1766 CH 3 a CH 3 a H The D-sorbitol
1767 CH 3 a CH 3 a H SO 3H
1768 CH 3 a CH 3 a H PO 3H 2
1769 CH 3 a CH 3 a H CHO
1770 CH 3 a CH 3 a H COOH
1771 CH 3 a CH 3 a H CH 2OH
1772 CH 3 a CH 3 a H Sugar
1773 CH 3 a CH 3 a H The C-glycosyl compound
1774 CH 3 a CH 3 a OH OH
1775 CH 3 a CH 3 a OH The D-sorbitol
1776 CH 3 a CH 3 a OH SO 3H
1745 CH 3 a CN B(OH) 2 Sugar
1746 CH 3 a CN B(OH) 2 The C-glycosyl compound
1747 CH 3 a CN SH OH
1748 CH 3 a CN SH The D-sorbitol
1749 CH 3 a CN SH SO 3H
1750 CH 3 a CN SH PO 3H 2
1751 CH 3 a CN SH CHO
1752 CH 3 a CN SH COOH
1753 CH 3 a CN SH CH 2OH
1754 CH 3 a CN SH Sugar
1755 CH 3 a CN SH The C-glycosyl compound
1756 CH 3 a CN OCH 3 OH
1757 CH 3 a CN OCH 3 The D-sorbitol
1758 CH 3 a CN OCH 3 SO 3H
1759 CH 3 a CN OCH 3 PO 3H 2
1760 CH 3 a CN OCH 3 CHO
1761 CH 3 a CN OCH 3 COOH
1762 CH 3 a CN OCH 3 CH 2OH
1763 CH 3 a CN OCH 3 Sugar
1764 CH 3 a CN OCH 3 The C-glycosyl compound
1765 CH 3 a CH 3 a H OH
1766 CH 3 a CH 3 a H The D-sorbitol
1767 CH 3 a CH 3 a H SO 3H
1768 CH 3 a CH 3 a H PO 3H 2
1769 CH 3 a CH 3 a H CHO
1770 CH 3 a CH 3 a H COOH
1771 CH 3 a CH 3 a H CH 2OH
1772 CH 3 a CH 3 a H Sugar
1773 CH 3 a CH 3 a H The C-glycosyl compound
1774 CH 3 a CH 3 a OH OH
1775 CH 3 a CH 3 a OH The D-sorbitol
1776 CH 3 a CH 3 a OH SO 3H
1777 CH 3 a CH 3 a OH PO 3H 2
1778 CH 3 a CH 3 a OH CHO
1779 CH 3 a CH 3 a OH COOH
1780 CH 3 a CH 3 a OH CH 2OH
1781 CH 3 a CH 3 a OH Sugar
1782 CH 3 a CH 3 a OH The C-glycosyl compound
1783 CH 3 a CH 3 a CH 3 OH
1784 CH 3 a CH 3 a CH 3 The D-sorbitol
1785 CH 3 a CH 3 a CH 3 SO 3H
1786 CH 3 a CH 3 a CH 3 PO 3H 2
1787 CH 3 a CH 3 a CH 3 CHO
1788 CH 3 a CH 3 a CH 3 COOH
1789 CH 3 a CH 3 a CH 3 CH 2OH
1790 CH 3 a CH 3 a CH 3 Sugar
1791 CH 3 a CH 3 a CH 3 The C-glycosyl compound
1792 CH 3 a CH 3 a Cl OH
1793 CH 3 a CH 3 a Cl The D-sorbitol
1794 CH 3 a CH 3 a Cl SO 3H
1795 CH 3 a CH 3 a Cl PO 3H 2
1796 CH 3 a CH 3 a Cl CHO
1797 CH 3 a CH 3 a Cl COOH
1798 CH 3 a CH 3 a Cl CH 2OH
1799 CH 3 a CH 3 a Cl Sugar
1800 CH 3 a CH 3 a Cl The C-glycosyl compound
1801 CH 3 a CH 3 a B(OH) 2 OH
1802 CH 3 a CH 3 a B(OH) 2 The D-sorbitol
1803 CH 3 a CH 3 a B(OH) 2 SO 3H
1804 CH 3 a CH 3 a B(OH) 2 PO 3H 2
1805 CH 3 a CH 3 a B(OH) 2 CHO
1806 CH 3 a CH 3 a B(OH) 2 COOH
1807 CH 3 a CH 3 a B(OH) 2 CH 2OH
1808 CH 3 a CH 3 a B(OH) 2 Sugar
1809 CH 3 a CH 3 a B(OH) 2 The C-glycosyl compound
1810 CH 3 a CH 3 a SH OH
1811 CH 3 a CH 3 a SH The D-sorbitol
1812 CH 3 a CH 3 a SH SO 3H
1813 CH 3 a CH 3 a SH PO 3H 2
1814 CH 3 a CH 3 a SH CHO
1815 CH 3 a CH 3 a SH COOH
1816 CH 3 a CH 3 a SH CH 2OH
1817 CH 3 a CH 3 a SH Sugar
1818 CH 3 a CH 3 a SH The C-glycosyl compound
1819 CH 3 a CH 3 a OCH 3 OH
1820 CH 3 a CH 3 a OCH 3 The D-sorbitol
1821 CH 3 a CH 3 a OCH 3 SO 3H
1822 CH 3 a CH 3 a OCH 3 PO 3H 2
1823 CH 3 a CH 3 a OCH 3 CHO
1824 CH 3 a CH 3 a OCH 3 COOH
1825 CH 3 a CH 3 a OCH 3 CH 2OH
1826 CH 3 a CH 3 a OCH 3 Sugar
1827 CH 3 a CH 3 a OCH 3 The C-glycosyl compound
1828 CH 3 a OCH3 b H OH
1829 CH 3 a OCH3 b H The D-sorbitol
1830 CH 3 a OCH3 b H SO 3H
1831 CH 3 a OCH3 b H PO 3H 2
1832 CH 3 a OCH3 b H CHO
1833 CH 3 a OCH3 b H COOH
1834 CH 3 a OCH3 b H CH 2OH
1835 CH 3 a OCH3 b H Sugar
1836 CH 3 a OCH3 b H The C-glycosyl compound
1837 CH 3 a OCH3 b OH OH
1838 CH 3 a OCH3 b OH The D-sorbitol
1839 CH 3 a OCH3 b OH SO 3H
1840 CH 3 a OCH3 b OH PO 3H 2
1841 CH 3 a OCH3 b OH CHO
1842 CH 3 a OCH3 b OH COOH
1843 CH 3 a OCH3 b OH CH 2OH
1844 CH 3 a OCH3 b OH Sugar
1845 CH 3 a OCH3 b OH The C-glycosyl compound
1846 CH 3 a OCH3 b CH 3 OH
1847 CH 3 a OCH3 b CH 3 The D-sorbitol
1848 CH 3 a OCH3 b CH 3 SO 3H
1849 CH 3 a OCH3 b CH 3 PO 3H 2
1850 CH 3 a OCH3 b CH 3 CHO
1851 CH 3 a OCH3 b CH 3 COOH
1852 CH 3 a OCH3 b CH 3 CH 2OH
1853 CH 3 a OCH3 b CH 3 Sugar
1854 CH 3 a OCH3 b CH 3 The C-glycosyl compound
1855 CH 3 a OCH3 b Cl OH
1856 CH 3 a OCH3 b Cl The D-sorbitol
1857 CH 3 a OCH3 b Cl SO 3H
1858 CH 3 a OCH3 b Cl PO 3H 2
1859 CH 3 a OCH3 b Cl CHO
1860 CH 3 a OCH3 b Cl COOH
1861 CH 3 a OCH3 b Cl CH 2OH
1862 CH 3 a OCH3 b Cl Sugar
1863 CH 3 a OCH3 b Cl The C-glycosyl compound
1864 CH 3 a OCH3 b B(OH) 2 OH
1865 CH 3 a OCH3 b B(OH) 2 The D-sorbitol
1866 CH 3 a OCH3 b B(OH) 2 SO 3H
1867 CH 3 a OCH3 b B(OH) 2 PO 3H 2
1868 CH 3 a OCH3 b B(OH) 2 CHO
1869 CH 3 a OCH3 b B(OH) 2 COOH
1870 CH 3 a OCH3 b B(OH) 2 CH 2OH
1871 CH 3 a OCH3 b B(OH) 2 Sugar
1872 CH 3 a OCH3 b B(OH) 2 The C-glycosyl compound
1873 CH 3 a OCH3 b SH OH
1874 CH 3 a OCH3 b SH The D-sorbitol
1875 CH 3 a OCH3 b SH SO 3H
1876 CH 3 a OCH3 b SH PO 3H 2
1877 CH 3 a OCH3 b SH CHO
1878 CH 3 a OCH3 b SH COOH
1879 CH 3 a OCH3 b SH CH 2OH
1880 CH 3 a OCH3 b SH Sugar
1881 CH 3 a OCH3 b SH The C-glycosyl compound
1882 CH 3 a OCH3 b OCH 3 OH
1883 CH 3 a OCH3 b OCH 3 The D-sorbitol
1884 CH 3 a OCH3 b OCH 3 SO 3H
1885 CH 3 a OCH3 b OCH 3 PO 3H 2
1886 CH 3 a OCH3 b OCH 3 CHO
1887 CH 3 a OCH3 b OCH 3 COOH
1888 CH 3 a OCH3 b OCH 3 CH 2OH
1889 CH 3 a OCH3 b OCH 3 Sugar
1890 CH 3 a OCH3 b OCH 3 The C-glycosyl compound
1891 OCH3 b H H OH
1892 OCH3 b H H The D-sorbitol
1893 OCH3 b H H SO 3H
1894 OCH3 b H H PO 3H 2
1895 OCH3 b H H CHO
1896 OCH3 b H H COOH
1897 OCH3 b H H CH 2OH
1898 OCH3 b H H Sugar
1899 OCH3 b H H The C-glycosyl compound
1900 OCH3 b H OH OH
1901 OCH3 b H OH The D-sorbitol
1902 OCH3 b H OH SO 3H
1903 OCH3 b H OH PO 3H 2
1904 OCH3 b H OH CHO
1905 OCH3 b H OH COOH
1906 OCH3 b H OH CH 2OH
1907 OCH3 b H OH Sugar
1908 OCH3 b H OH The C-glycosyl compound
1909 OCH3 b H CH3 OH
1910 OCH3 b H CH3 The D-sorbitol
1911 OCH3 b H CH3 SO 3H
1912 OCH3 b H CH3 PO 3H 2
1913 OCH3 b H CH3 CHO
1914 OCH3 b H CH3 COOH
1915 OCH3 b H CH3 CH 2OH
1916 OCH3 b H CH3 Sugar
1917 OCH3 b H CH3 The C-glycosyl compound
1918 OCH3 b H Cl OH
1919 OCH3 b H Cl The D-sorbitol
1920 OCH3 b H Cl SO 3H
1921 OCH3 b H Cl PO 3H 2
1922 OCH3 b H Cl CHO
1923 OCH3 b H Cl COOH
1924 OCH3 b H Cl CH 2OH
1925 OCH3 b H Cl Sugar
1926 OCH3 b H Cl The C-glycosyl compound
1927 OCH3 b H B(OH) 2 OH
1928 OCH3 b H B(OH) 2 The D-sorbitol
1929 OCH3 b H B(OH) 2 SO 3H
1930 OCH3 b H B(OH) 2 PO 3H 2
1931 OCH3 b H B(OH) 2 CHO
1932 OCH3 b H B(OH) 2 COOH
1933 OCH3 b H B(OH) 2 CH 2OH
1934 OCH3 b H B(OH) 2 Sugar
1935 OCH3 b H B(OH) 2 The C-glycosyl compound
1936 OCH3 b H SH OH
1937 OCH3 b H SH The D-sorbitol
1938 OCH3 b H SH SO 3H
1939 OCH3 b H SH PO 3H 2
1940 OCH3 b ?H SH CHO
1941 OCH3 b ?H SH COOH
1942 OCH3 b ?H SH CH 2OH
1943 OCH3 b ?H SH Sugar
1944 OCH3 b ?H SH The C-glycosyl compound
1945 OCH3 b ?H OCH3 OH
1946 OCH3 b ?H OCH3 The D-sorbitol
1947 OCH3 b ?H OCH3 SO 3H
1948 OCH3 b ?H OCH3 PO 3H 2
1949 OCH3 b ?H OCH3 CHO
1950 OCH3 b ?H OCH3 COOH
1951 OCH3 b ?H OCH3 CH 2OH
1952 OCH3 b ?H OCH3 Sugar
1953 OCH3 b ?H OCH3 The C-glycosyl compound
1954 OCH3 b ?F H OH
1955 OCH3 b ?F H The D-sorbitol
1956 OCH3 b ?F H SO 3H
1957 OCH3 b ?F H PO 3H 2
1958 OCH3 b ?F H CHO
1959 OCH3 b ?F H COOH
1960 OCH3 b ?F H CH 2OH
1961 OCH3 b ?F H Sugar
1962 OCH3 b ?F H The C-glycosyl compound
1963 OCH3 b ?F OH OH
1964 OCH3 b ?F OH The D-sorbitol
1965 OCH3 b ?F OH SO 3H
1966 OCH3 b ?F OH PO 3H 2
1967 OCH3 b ?F OH CHO
1968 OCH3 b ?F OH COOH
1969 OCH3 b ?F OH CH 2OH
1970 OCH3 b ?F OH Sugar
1971 OCH3 b ?F OH The C-glycosyl compound
1972 OCH3 b ?F CH3 OH
1973 OCH3 b ?F CH3 The D-sorbitol
1974 OCH3 b ?F CH3 SO 3H
1975 OCH3 b ?F CH3 PO 3H 2
1976 OCH3 b ?F CH3 CHO
1977 OCH3 b ?F CH3 COOH
1978 OCH3 b ?F CH3 CH 2OH
1979 OCH3 b ?F CH3 Sugar
1980 OCH3 b ?F CH3 The C-glycosyl compound
1981 OCH3 b ?F Cl OH
1982 OCH3 b ?F Cl The D-sorbitol
1983 OCH3 b ?F Cl SO 3H
1984 OCH3 b ?F Cl PO 3H 2
1985 OCH3 b ?F Cl CHO
1986 OCH3 b ?F Cl COOH
1987 OCH3 b ?F Cl CH 2OH
1988 OCH3 b ?F Cl Sugar
1989 OCH3 b ?F Cl The C-glycosyl compound
1990 OCH3 b ?F B(OH) 2 OH
1991 OCH3 b ?F B(OH) 2 The D-sorbitol
1992 OCH3 b ?F B(OH) 2 SO 3H
1993 OCH3 b ?F B(OH) 2 PO 3H 2
1994 OCH3 b ?F B(OH) 2 CHO
1995 OCH3 b ?F B(OH) 2 COOH
1996 OCH3 b ?F B(OH) 2 CH 2OH
1997 OCH3 b ?F B(OH) 2 Sugar
1998 OCH3 b ?F B(Oh) 2 The C-glycosyl compound
1999 OCH3 b ?F SH OH
2000 OCH3 b ?F SH The D-sorbitol
2001 OCH3 b ?F SH SO 3H
2002 OCH3 b ?F SH PO 3H 2
2003 OCH3 b ?F SH CHO
2004 OCH3 b ?F SH COOH
2005 OCH3 b ?F SH CH 2OH
2006 OCH3 b ?F SH Sugar
2007 OCH3 b ?F SH The C-glycosyl compound
2008 OCH3 b F OCH3 OH
2009 OCH3 b F OCH3 The D-sorbitol
2010 OCH3 b F OCH3 SO 3H
2011 OCH3 b F OCH3 PO 3H 2
2012 OCH3 b F OCH3 CHO
2013 OCH3 b F OCH3 COOH
2014 OCH3 b F OCH3 CH 2OH
2015 OCH3 b F OCH3 Sugar
2016 OCH3 b F OCH3 The C-glycosyl compound
2017 OCH3 b Cl H OH
2018 OCH3 b Cl H The D-sorbitol
2019 OCH3 b Cl H SO 3H
2020 OCH3 b Cl H PO 3H 2
2021 OCH3 b Cl H CHO
2022 OCH3 b Cl H COOH
2023 OCH3 b Cl H CH 2OH
2024 OCH3 b Cl H Sugar
2025 OCH3 b Cl H The C-glycosyl compound
2026 OCH3 b Cl OH OH
2027 OCH3 b Cl OH The D-sorbitol
2028 OCH3 b Cl OH SO 3H
2029 OCH3 b Cl OH PO 3H 2
2030 OCH3 b Cl OH CHO
2031 OCH3 b Cl OH COOH
2032 OCH3 b Cl OH CH 2OH
2033 OCH3 b Cl OH Sugar
2034 OCH3 b Cl OH The C-glycosyl compound
2035 OCH3 b Cl CH3 OH
2036 OCH3 b Cl CH3 The D-sorbitol
2037 OCH3 b Cl CH3 SO 3H
2038 OCH3 b Cl CH3 PO 3H 2
2039 OCH3 b Cl CH3 CHO
2040 OCH3 b Cl CH3 COOH
2041 OCH3 b Cl CH3 CH 2OH
2042 OCH3 b Cl CH3 Sugar
2043 OCH3 b Cl CH3 The C-glycosyl compound
2044 OCH3 b Cl Cl OH
2045 OCH3 b Cl Cl The D-sorbitol
2046 OCH3 b Cl Cl SO 3H
2047 OCH3 b Cl Cl PO 3H 2
2048 OCH3 b Cl Cl CHO
2049 OCH3 b Cl Cl COOH
2050 OCH3 b Cl Cl CH 2OH
2051 OCH3 b Cl Cl Sugar
2052 OCH3 b Cl Cl The C-glycosyl compound
2053 OCH3 b Cl B(OH) 2 OH
2054 OCH3 b Cl B(OH) 2 The D-sorbitol
2055 OCH3 b Cl B(OH) 2 SO 3H
2056 OCH3 b Cl B(OH) 2 PO 3H 2
2057 OCH3 b Cl B(OH) 2 CHO
2058 OCH3 b Cl B(OH) 2 COOH
2059 OCH3 b Cl B(OH) 2 CH 2OH
2060 OCH3 b Cl B(OH) 2 Sugar
2061 OCH3 b Cl B(OH) 2 The C-glycosyl compound
2062 OCH3 b Cl SH OH
2063 OCH3 b Cl SH The D-sorbitol
2064 OCH3 b Cl SH SO 3H
2065 OCH3 b Cl SH PO 3H 2
2066 OCH3 b Cl SH CHO
2067 OCH3 b Cl SH COOH
2068 OCH3 b Cl SH CH 2OH
2069 OCH3 b Cl SH Sugar
2070 OCH3 b Cl SH The C-glycosyl compound
2071 OCH3 b Cl OCH3 OH
2072 OCH3 b Cl OCH3 The D-sorbitol
2073 OCH3 b Cl OCH3 SO 3H
2074 OCH3 b Cl OCH3 PO 3H 2
2075 OCH3 b Cl OCH3 CHO
2076 OCH3 b Cl OCH3 COOH
2077 OCH3 b Cl OCH3 CH 2OH
2078 OCH3 b Cl OCH3 Sugar
2079 OCH3 b Cl OCH3 The C-glycosyl compound
2080 OCH3 b CN H OH
2081 OCH3 b CN H The D-sorbitol
2082 OCH3 b CN H SO 3H
2083 OCH3 b CN H PO 3H 2
2084 OCH3 b CN H CHO
2085 OCH3 b CN H COOH
2086 OCH3 b CN H CH 2OH
2087 OCH3 b CN H Sugar
2088 OCH3 b CN H The C-glycosyl compound
2089 OCH3 b CN OH OH
2090 OCH3 b CN OH The D-sorbitol
2091 OCH3 b CN OH SO 3H
2092 OCH3 b CN OH PO 3H 2
2093 OCH3 b CN OH CHO
2094 OCH3 b CN OH COOH
2O95 OCH3 b CN OH CH 2OH
2096 OCH3 b CN OH Sugar
2097 OCH3 b CN OH The C-glycosyl compound
2098 OCH3 b CN CH3 OH
2099 OCH3 b CN CH3 The D-sorbitol
2100 OCH3 b CN CH3 SO 3H
2101 OCH3 b CN CH3 PO 3H 2
2102 OCH3 b CN CH3 CHO
2103 OCH3 b CN CH3 COOH
2104 OCH3 b CN CH3 CH 2OH
2105 OCH3 b CN CH3 Sugar
2106 OCH3 b CN CH3 The C-glycosyl compound
2107 OCH3 b CN Cl OH
2108 OCH3 b CN Cl The D-sorbitol
2109 OCH3 b CN Cl SO 3H
2110 OCH3 b CN Cl PO 3H 2
2111 OCH3 b CN Cl CHO
2112 OCH3 b CN Cl COOH
2113 OCH3 b CN Cl CH 2OH
2114 OCH3 b CN Cl Sugar
2115 OCH3 b CN Cl The C-glycosyl compound
2116 OCH3 b CN B(OH) 2 OH
2117 OCH3 b CN B(OH) 2 The D-sorbitol
2118 OCH3 b CN B(OH) 2 SO 3H
2119 OCH3 b CN B(OH) 2 PO 3H 2
2120 OCH3 b CN B(OH) 2 CHO
2121 OCH3 b CN B(OH) 2 COOH
2122 OCH3 b CN B(OH) 2 CH 2OH
2123 OCH3 b CN B(OH) 2 Sugar
2124 OCH3 b CN B(OH) 2 The C-glycosyl compound
2125 OCH3 b CN SH OH
2126 OCH3 b CN SH The D-sorbitol
2127 OCH3 b CN SH SO 3H
2128 OCH3 b CN SH PO 3H 2
2129 OCH3 b CN SH CHO
2130 OCH3 b CN SH COOH
2131 OCH3 b CN SH CH 2OH
2132 OCH3 b CN SH Sugar
2133 OCH3 b CN SH The C-glycosyl compound
2134 OCH3 b CN OCH3 OH
2135 OCH3 b CN OCH3 The D-sorbitol
2136 OCH3 b CN OCH3 SO 3H
2137 OCH3 b CN OCH3 PO 3H 2
2138 OCH3 b CN OCH3 CHO
2139 OCH3 b CN OCH3 COOH
2140 OCH3 b CN OCH3 CH 2OH
2141 OCH3 b CN OCH3 Sugar
2142 OCH3 b CN OCH3 The C-glycosyl compound
2143 OCH3 b CH 3 a H OH
2144 OCH3 b CH 3 a ?H The D-sorbitol
2145 OCH3 b CH 3 a ?H SO 3H
2146 OCH3 b CH 3 a ?H PO 3H 2
2147 OCH3 b CH 3 a ?H CHO
2148 OCH3 b CH 3 a ?H COOH
2149 OCH3 b CH 3 a ?H CH 2OH
2150 OCH3 b CH 3 a ?H Sugar
2151 OCH3 b CH 3 a ?H The C-glycosyl compound
2152 OCH3 b CH 3 a ?OH OH
2153 OCH3 b CH 3 a ?OH The D-sorbitol
2154 OCH3 b CH 3 a ?OH SO 3H
2155 OCH3 b CH 3 a ?OH PO 3H 2
2156 OCH3 b CH 3 a ?OH CHO
2157 OCH3 b CH 3 a ?OH COOH
2158 OCH3 b CH 3 a ?OH CH 2OH
2159 OCH3 b CH 3 a ?OH Sugar
2160 OCH3 b CH 3 a ?OH The C-glycosyl compound
2161 OCH3 b CH 3 a ?CH3 OH
2162 OCH3 b CH 3 a ?CH3 The D-sorbitol
2163 OCH3 b CH 3 a ?CH3 SO 3H
2164 OCH3 b CH 3 a ?CH3 PO 3H 2
2165 OCH3 b CH 3 a ?CH3 CHO
2166 OCH3 b CH 3 a ?CH3 COOH
2167 OCH3 b CH 3 a ?CH3 CH 2OH
2168 OCH3 b CH 3 a ?CH3 Sugar
2169 OCH3 b CH 3 a ?CH3 The C-glycosyl compound
2170 OCH3 b CH 3 a ?Cl OH
2171 OCH3 b CH 3 a ?Cl The D-sorbitol
2172 OCH3 b CH 3 a ?Cl SO 3H
2173 OCH3 b CH 3 a ?Cl PO 3H 2
2174 OCH3 b CH 3 a ?Cl CHO
2175 OCH3 b CH 3 a ?Cl COOH
2176 OCH3 b CH 3 a Cl CH 2OH
2177 OCH3 b CH 3 a Cl Sugar
2178 OCH3 b CH 3 a Cl The C-glycosyl compound
2179 OCH3 b CH 3 a B(OH) 2 OH
2180 OCH3 b CH 3 a B(OH) 2 The D-sorbitol
2181 OCH3 b CH 3 a B(OH) 2 SO 3H
2182 OCH3 b CH 3 a B(OH) 2 PO 3H 2
2183 OCH3 b CH 3 a B(OH) 2 CHO
2184 OCH3 b CH 3 a B(OH) 2 COOH
2185 OCH3 b CH 3 a B(OH) 2 CH 2OH
2186 OCH3 b CH 3 a B(OH) 2 Sugar
2187 OCH3 b CH 3 a B(OH) 2 The C-glycosyl compound
2188 OCH3 b CH 3 a SH OH
2189 OCH3 b CH 3 a SH The D-sorbitol
2190 OCH3 b CH 3 a SH SO 3H
2191 OCH3 b CH 3 a SH PO 3H 2
2192 OCH3 b CH 3 a SH CHO
2193 OCH3 b CH 3 a SH COOH
2194 OCH3 b CH 3 a SH CH 2OH
2195 OCH3 b CH 3 a SH Sugar
2196 OCH3 b CH 3 a SH The C-glycosyl compound
2197 OCH3 b CH 3 a OCH3 OH
2198 OCH3 b CH 3 a OCH3 The D-sorbitol
2199 OCH3 b CH 3 a OCH3 SO 3H
2200 OCH3 b CHx a OCH3 PO 3H 2
2201 OCH3 b CH 3 a OCH3 CHO
2202 OCH3 b CH 3 a OCH3 COOH
2203 OCH3 b CH 3 a OCH3 CH 2OH
2204 OCH3 b CH 3 a OCH3 Sugar
2205 OCH3 b CH 3 a OCH3 The C-glycosyl compound
2206 OCH3 b OCH3 b H OH
2207 OCH3 b OCH3 b H The D-sorbitol
2208 OCH3 b OCH3 b H SO 3H
2209 OCH3 b OCH3 b H PO 3H 2
2210 OCH3 b OCH3 b H CHO
2211 OCH3 b OCH3 b H COOH
2212 OCH3 b OCH3 b H CH 2OH
2213 OCH3 b OCH3 b H Sugar
2214 OCH3 b OCH3 b H The C-glycosyl compound
2215 OCH3 b OCH3 b OH OH
2216 OCH3 b OCH3 b OH The D-sorbitol
2217 OCH3 b OCH3 b OH SO 3H
2218 OCH3 b OCH3 b OH PO 3H 2
2219 OCH3 b OCH3 b OH CHO
2220 OCH3 b OCH3 b OH COOH
2221 OCH3 b OCH3 b OH CH 2OH
2222 OCH3 b OCH3 b OH Sugar
2223 OCH3 b OCH3 b OH The C-glycosyl compound
2224 OCH3 b OCH3 b CH3 OH
2225 OCH3 b OCH3 b CH3 The D-sorbitol
2226 OCH3 b OCH3 b CH3 SO 3H
2227 OCH3 b OCH3 b CH3 PO 3H 2
2228 OCH3 b OCH3 b CH3 CHO
2229 OCH3 b OCH3 b CH3 COOH
2230 OCH3 b OCH3 b CH3 CH 2OH
2231 OCH3 b OCH3 b CH3 Sugar
2232 OCH3 b OCH3 b CH3 The C-glycosyl compound
2233 OCH3 b OCH3 b Cl OH
2234 OCH3 b OCH3 b Cl The D-sorbitol
2235 OCH3 b OCH3 b Cl SO 3H
2236 OCH3 b OCH3 b Cl PO 3H 2
2237 OCH3 b OCH3 b Cl CHO
2238 OCH3 b OCH3 b Cl COOH
2239 OCH3 b OCH3 b Cl CH 2OH
2240 OCH3 b OCH3 b Cl Sugar
2241 OCH3 b OCH3 b Cl The C-glycosyl compound
2242 OCH3 b OCH3 b B(OH) 2 OH
2243 OCH3 b ?OCH3 b B(OH) 2 The D-sorbitol
2244 OCH3 b ?OCH3 b B(OH) 2 SO 3H
2245 OCH3 b ?OCH3 b B(OH) 2 PO 3H 2
2246 OCH3 b ?OCH3 b B(OH) 2 CHO
2247 OCH3 b ?OCH3 b B(OH) 2 COOH
2248 OCH3 b ?OCH3 b B(OH) 2 CH 2OH
2249 OCH3 b ?OCH3 b B(OH) 2 Sugar
2250 OCH3 b ?OCH3 b B(OH) 2 The C-glycosyl compound
2251 OCH3 b ?OCH3 b SH OH
2252 OCH3 b ?OCH3 b SH The D-sorbitol
2253 OCH3 b ?OCH3 b SH SO 3H
2254 OCH3 b ?OCH3 b SH PO 3H 2
2255 OCH3 b ?OCH3 b SH CHO
2256 OCH3 b ?OCH3 b SH COOH
2257 OCH3 b ?OCH3 b SH CH 2OH
2258 OCH3 b ?OCH3 b SH Sugar
2259 OCH3 b ?OCH3 b SH The C-glycosyl compound
2260 OCH3 b ?OCH3 b OCH3 OH
2261 OCH3 b ?OCH3 b OCH3 The D-sorbitol
2262 OCH3 b ?OCH3 b OCH3 SO 3H
2263 OCH3 b ?OCH3 b OCH3 PO 3H 2
2264 OCH3 b ?OCH3 b OCH3 CHO
2265 OCH3 b ?OCH3 b OCH3 COOH
2266 OCH3 b ?OCH3 b OCH3 CH 2OH
2267 OCH3 b ?OCH3 b OCH3 Sugar
2268 OCH3 b ?OCH3 b OCH3 The C-glycosyl compound
aRandomly by one, two or three F replacements
bRandomly replaced by two or three F
Table 4
Group # R1 R2 R4 R5
1 Adjacent Adjacent 3- Adjacent
2 Adjacent Adjacent 3- Between
3 Adjacent Adjacent 3- Right
4 Adjacent Adjacent 2- Adjacent
5 Adjacent Adjacent 2- Between
6 Adjacent Adjacent 2- Right
7 Adjacent Between 3- Adjacent
8 Adjacent Between 3- Between
9 Adjacent Between 3- Right
10 Adjacent Between 2- Adjacent
11 Adjacent Between 2- Between
12 Adjacent Between 2- Right
13 Adjacent Right 3- Adjacent
14 Adjacent Right 3- Between
15 Adjacent Right 3- Right
16 Adjacent Right 2- Adjacent
17 Adjacent Right 2- Between
18 Adjacent Right 2- Right
19 Between Adjacent 3- Adjacent
20 Between Adjacent 3- Between
21 Between Adjacent 3- Right
22 Between Adjacent 2- Adjacent
23 Between Adjacent 2- Between
24 Between Adjacent 2- Right
25 Between Between 3- Adjacent
26 Between Between 3- Between
27 Between Between 3- Right
28 Between Between 2- Adjacent
29 Between Between 2- Between
30 Between Between 2- Right
31 Between Right 3- Adjacent
32 Between Right 3- Between
33 Between Right 3- Right
34 Between Right 2- Adjacent
35 Between Right 2- Between
36 Between Right 2- Right
37 Right Adjacent 3- Adjacent
38 Right Adjacent 3- Between
39 Right Adjacent 3- Right
40 Right Adjacent 2- Adjacent
41 Right Adjacent 2- Between
42 Right Adjacent 2- Right
43 Right Between 3- Adjacent
44 Right Between 3- Between
45 Right Between 3- Right
46 Right Between 2- Adjacent
47 Right Between 2- Between
48 Right Between 2- Right
49 Right Right 3- Adjacent
50 Right Right 3- Between
51 Right Right 3- Right
52 Right Right 2- Adjacent
53 Right Right 2- Between
54 Right Right 2- Right
Table 5 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be F, R 4Be OH, R 5Be OH (i.e. the 1st of table 3 the row).
1 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
2 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
3 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
4 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
5 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-the 1-phenyl azetidine
Alkane-2-ketone
6 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
7 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
8 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
9 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
10 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
11 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
12 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
13 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
14 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
15 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
16 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
17 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
18 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
Table 6 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resultingization
Compound, wherein R 1Be H, R 2Be F, R 4Be OH, R 5Be D-sorbitol (i.e. the 2nd of table 3 the row).
1 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
2 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
3 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
4 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
5 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
6 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
7 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
8 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
9 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
10 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
11 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
12 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
13 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
14 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine
Alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
15 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
16 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
17 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
18 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
Table 7 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be F, R 4Be OH, R 5Be SO 3H (i.e. the 3rd of table 3 the row).
1 4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-sulfonic acid
2 4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid
3 4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid
4 4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-sulfonic acid
5 4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-sulfonic acid
6 4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-sulfonic acid
7 4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-sulfonic acid
8 4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid
9 4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid
10 4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-sulfonic acid
11 4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-sulfonic acid
12 4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-sulfonic acid
13 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-sulfonic acid
14 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid
15 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid
16 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-sulfonic acid
17 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-sulfonic acid
18 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-sulfonic acid
Table 8 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be F, R 4Be OH, R 5Be PO 3H (i.e. the 4th of table 3 the row).
1 (4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl) phosphonic acids
2 (4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids
3 (4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-hydroxyl
Base xenyl-4-yl) phosphonic acids
4 (4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl) phosphonic acids
5 (4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl) phosphonic acids
6 (4 '-(2S, 3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl) phosphonic acids
7 (4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl) phosphonic acids
8 (4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids
9 (4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphonic acids
10 (4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl) phosphonic acids
11 (4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl) phosphonic acids
12 (4 '-(2S, 3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl) phosphonic acids
13 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl) phosphonic acids
14 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids
15 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphonic acids
16 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl) phosphonic acids
17 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl) phosphonic acids
18 (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl) phosphonic acids
Table 9 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be H, R 4Be OH, R 5Be OH (i.e. the 5th of table 3 the row).
1 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-hydroxyl-3-phenyl propyl]-1-phenyl azetidine alkane-2-ketone
2 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-hydroxyl-3-phenyl propyl]-1-phenyl azetidine alkane-2-ketone
3 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-hydroxyl-3-phenyl propyl]-1-phenyl azetidine alkane-2-ketone
4 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-hydroxyl-3-phenyl propyl]-1-phenyl azetidine alkane-2-ketone
5 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-hydroxyl-3-phenyl propyl]-1-phenyl azetidine alkane-2-ketone
6 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-hydroxyl-3-phenyl propyl]-1-phenyl azetidine alkane-2-ketone
Table 10 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be H, R 4Be OH, R 5Be D-sorbitol (i.e. the 6th of table 3 the row).
1 (1S)-1,5-dehydration-1-(3 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-2-yl)-the D-sorbitol
2 (1S)-1,5-dehydration-1-(3 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-sorbitol
3 (1S)-1,5-dehydration-1-(3 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-4-yl)-the D-sorbitol
4 (1S)-1,5-dehydration-1-(2 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-2-yl)-the D-sorbitol
5 (1S)-1,5-dehydration-1-(2 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-sorbitol
6 (1S)-1,5-dehydration-1-(2 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-4-yl)-the D-sorbitol
Table 11 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be H, R 4Be OH, R 5Be SO 3H (i.e. the 7th of table 3 the row).
1 3 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-2-sulfonic acid
2 3 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-sulfonic acid
3 3 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-4-sulfonic acid
4 2 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-2-sulfonic acid
5 2 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-sulfonic acid
6 2 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-4-sulfonic acid
Table 12 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be H, R 4Be OH, R 5Be PO 3H (i.e. the eighth row of table 3).
1 (3 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-2-yl) phosphonic acids
2 (3 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) phosphonic acids
3 (3 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-4-yl) phosphonic acids
4 (2 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-2-yl) phosphonic acids
5 (2 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) phosphonic acids
6 (2 '-hydroxyl-4 '-2S, 3R)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-4-yl) phosphonic acids
Table 13 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be Cl, R 4Be OH, R 5Be OH (i.e. the 9th of table 3 the row).
1 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
2 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
3 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
4 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
5 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
6 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
7 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
8 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
9 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
10 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-the 1-phenyl azetidine
Alkane-2-ketone
11 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
12 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
13 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
14 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
15 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
16 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
17 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
18 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone
Table 14 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be Cl, R 4Be OH, R 5Be D-sorbitol (i.e. the 10th of table 3 the row).
1 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
2 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
3 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
4 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine
Alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
5 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
6 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
7 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
8 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
9 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
10 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
11 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
12 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
13 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
14 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
15 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
16 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
17 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
18 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
Table 15 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be Cl, R 4Be OH, R 5Be SO 3H (i.e. the 11st of table 3 the row).
1 4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-sulfonic acid
2 4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid
3 4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid
4 4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-sulfonic acid
5 4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-sulfonic acid
6 4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-sulfonic acid
7 4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-sulfonic acid
8 4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid
9 4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid
10 4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-sulfonic acid
11 4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-sulfonic acid
12 4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-sulfonic acid
13 4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-hydroxyl
Base xenyl-2-sulfonic acid
14 4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid
15 4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid
16 4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-sulfonic acid
17 4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-sulfonic acid
18 4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-sulfonic acid
Table 16 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be H, R 2Be Cl, R 4Be OH, R 5Be PO 3H (i.e. the 12nd of table 3 the row).
1 (4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl) phosphonic acids
2 (4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids
3 (4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphonic acids
4 (4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl) phosphonic acids
5 (4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl) phosphonic acids
6 (4 '-(2S, 3R)-3-[(3S)-3-(2-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl) phosphonic acids
7 (4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl) phosphonic acids
8 (4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids
9 (4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphonic acids
10 (4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl) phosphonic acids
11 (4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl) phosphonic acids
12 (4 '-(2S, 3R)-3-[(3S)-3-(3-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl) phosphonic acids
13 (4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl) phosphonic acids
14 (4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids
15 (4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphonic acids
16 (4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl) phosphonic acids
17 (4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl) phosphonic acids
18 (4 '-(2S, 3R)-3-[(3S)-3-(4-chloro-phenyl-)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl) phosphonic acids
Table 17 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be F, R 2Be H, R 4Be OH, R 5Be OH (i.e. the 13rd of table 3 the row).
1 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
2 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] nitrogen heterocyclic
Butane-2-ketone
3 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
4 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
5 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
6 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
7 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
8 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
9 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
10 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
11 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
12 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
13 (3R, 4S)-4-(2 ', 3-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
14 (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
15 (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
16 (3R, 4S)-4-(2,2 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
17 (3R, 4S)-4-(2,3 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
18 (3R, 4S)-4-(2,4 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxyl-3-phenyl propyl] azetidine-2-ketone
Table 18 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be F, R 2Be H, R 4Be OH, R 5Be D-sorbitol (i.e. the 14th of table 3 the row).
1 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(2-fluorophenyl)-3[(3S)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
2 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(2-fluorophenyl)-3[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
3 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(2-fluorophenyl)-3[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
4 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(2-fluorophenyl)-3[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
5 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(2-fluorophenyl)-3[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
6 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(2-fluorophenyl)-3[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl base]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
7 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(3-fluorophenyl)-3[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
8 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(3-fluorophenyl)-3[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
9 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(3-fluorophenyl)-3[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
10 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(3-fluorophenyl)-3[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
11 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(3-fluorophenyl)-3[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
12 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(3-fluorophenyl)-3[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
13 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(4-fluorophenyl)-3[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
14 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(4-fluorophenyl)-3[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
15 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(4-fluorophenyl)-3[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
16 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(4-fluorophenyl)-3[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl)-the D-sorbitol
17 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(4-fluorophenyl)-3[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl)-the D-sorbitol
18 (1S)-1,5-dehydration-1-(4 '-2S, 3R)-1-(4-fluorophenyl)-3[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl)-the D-sorbitol
Table 19 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be F, R 2Be H, R 4Be OH, R 5Be SO 3H (i.e. the 15th of table 3 the row).
1 4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-sulfonic acid
2 4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid
3 4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid
4 4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-sulfonic acid
5 4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl nitrogen
Heterocycle butane-2-yl }-2 '-Hydroxybiphenyl-3-sulfonic acid
6 4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-sulfonic acid
7 4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-sulfonic acid
8 4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid
9 4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid
10 4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-sulfonic acid
11 4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-sulfonic acid
12 4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-sulfonic acid
13 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-sulfonic acid
14 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid
15 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid
16 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-sulfonic acid
17 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-sulfonic acid
18 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-sulfonic acid
Table 20 has been listed the position that is limited according to all row by table 4 formula VIII has been replaced resulting compound, wherein R 1Be F, R 2Be H, R 4Be OH, R 5Be PO 3H (i.e. the 16th of table 3 the row).
1 (4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl) phosphonic acids
2 (4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids
3 (4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphonic acids
4 (4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl) phosphonic acids
5 (4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl) phosphonic acids
6 (4 '-(2S, 3R)-1-(2-fluorophenyl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl) phosphonic acids
7 (4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl) phosphonic acids
8 (4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids
9 (4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphonic acids
10 (4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl) phosphonic acids
11 (4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl) phosphonic acids
12 (4 '-(2S, 3R)-1-(3-fluorophenyl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl) phosphonic acids
13 (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-2-yl) phosphonic acids
14 (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl
Azetidine-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids
15 (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphonic acids
16 (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-2-yl) phosphonic acids
17 (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-3-yl) phosphonic acids
18 (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxyl-3-phenyl propyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-2 '-Hydroxybiphenyl-4-yl) phosphonic acids

Claims (138)

1, a kind of compound that is shown below:
Wherein, Expression aryl or heteroaryl residue;
Ar represents aromatic yl residue;
R 1Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 2Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 4Expression be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three or four residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 5gExpression be positioned on the Ar be independently selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
U is C 2-6Alkylidene group, wherein one or more-CH 2-can be selected from-S-,-S (O)-,-SO 2-,-O-,-C (=O)-,-CHOH-,-NH-, CHF, CF 2,-CH (O-low alkyl group)-,-CH (O-lower acyl)-,-CH (OSO 3H)-,-CH (OPO 3H 2)-,-CH (OB (OH) 2)-or-group among the NOH-substitutes, and condition is:
(1) works as R 4And R 5gAny one do not comprise hydroxyl, amino, low alkyl group ,-O-low alkyl group, carbalkoxy ,-B (OH) 2,-PO 3H 2Or-SO 3During H, R 5gCan not be-CN, 2,5-dimethoxy, 2,6-dimethoxy or halogen;
(2) when Expression 2, during the 5-thienyl, R 5gCan not be the 2-hydroxyl;
(3) adjacent among the U-CH 2-residue can not by-S-,-S (O)-,-SO 2-or-O-is alternative; And
(4) among the U-S-,-S (O)-,-SO 2-,-O-and-the NH-residue can not be only by single carbon atom separately.
2, a kind of compound that is shown below:
Wherein, Expression aryl or heteroaryl residue;
Ar represents aromatic yl residue;
R 1Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 2Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 4Expression be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three or four residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 5gExpression be positioned on the Ar be independently selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one to five residue in sugar, polyol, glucosiduronate and the carboxylamine sugar;
U aBe C 2-6Alkylidene group, wherein, one or more-CH 2-can be selected from-S-,-S (O)-,-SO 2-,-O-,-C (=O)-,-CHOH-,-NH-, CHF, CF 2,-CH (O-low alkyl group)-,-CH (O-lower acyl)-,-CH (OSO 3H)-,-CH (OPO 3H 2)-,-CH (OB (OH) 2)-or-group among the NOH-replaces, and its condition is:
(1) works as R 4And R 5gAny one do not comprise hydroxyl, amino, low alkyl group ,-O-low alkyl group, carbalkoxy ,-B (OH) 2,-PO 3H 2Or-SO 3During H, R 5gCan not be-CN, 2,5-dimethoxy, 2,6-dimethoxy or halogen;
(2) when
Figure A2004800396950005C1
Expression 2, during the 5-thienyl, R 5gCan not be the 2-hydroxyl;
(3) U aIn adjacent-CH 2-residue can not by-S-,-S (O)-,-SO 2-or-O-is alternative;
(4) U aIn-S-,-S (O)-,-SO 2-,-O-and-the NH-residue can not be only by single carbon atom separately; And
(5) U aCan not be-CH 2CH 2CH (OH)-, wherein the left end of this chain is the tie point with azetidinone, and the right-hand member of this chain is the tie point with phenyl ring.
3, a kind of compound that is shown below:
Figure A2004800396950006C1
Wherein,
Figure A2004800396950006C2
Expression aryl or heteroaryl residue;
Ar represents aromatic yl residue;
R 1Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 2Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
R 4fFor-OH ,-SH or-B (OH) 2
R 5hExpression be positioned on the Ar be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, ethylenedioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, carboxyalkyl, amide group, alkyl sulfoxide, acyl amino, amidino groups ,-PO 3H 2,-SO 3H ,-B (OH) 2, one, two, three, four or five residues in sugar, polyol, glucosiduronate and the carboxylamine sugar;
U is C 2-6Alkylidene group, wherein one or more-CH 2-can be selected from-S-,-S (O)-,-SO 2-,-O-,-C (=O)-,-CHOH-,-NH-, CHF, CF 2,-CH (O-low alkyl group)-,-CH (O-lower acyl)-,-CH (OSO 3H)-,-CH (OPO 3H 2)-,-CH (OB (OH) 2)-or-group among the NOH-substitutes, and its condition is:
(1) adjacent among the U-CH 2-residue can not by-S-,-S (O)-,-SO 2-or-O-is alternative; And
(2) among the U-S-,-S (O)-,-SO 2-,-O-and-the NH-residue can not be only by single carbon atom separately.
4, compound as claimed in claim 2, wherein, U aBe selected from-SCH 2CH 2-,-S (O) CH 2CH 2-,-S (O) CH 2CH (OH)-,-SCH 2C (=O)-,-SCH 2CH (OH)-, CH (OH) CH 2CH 2-,-CH (OH) CH 2CH (OH)-,-(CH 2) 3CH (OH)-and-(CH 2) 4-, the left end of this chain is the tie point with azetidinone, and the right-hand member of this chain is the tie point with phenyl ring.
5, as claim 1 or 3 described compounds, wherein, U aBe selected from-CH 2CH 2CH (OH)-,-SCH 2CH 2-,-S (O) CH 2CH 2-,-S (O) CH 2CH (OH)-,-SCH 2C (=O)-,-SCH 2CH (OH)-, CH (OH) CH 2CH 2-,-CH (OH) CH 2CH (OH)-,-(CH 2) 3CH (OH)-and-(CH 2) 4-, the left end of this chain is the tie point with azetidinone, and the right-hand member of this chain is the tie point with phenyl ring.
6, compound as claimed in claim 5, wherein, U is-CH 2CH 2CH (OH)-.
7, as any described compound among the claim 1-4, wherein,
R 1Represent one or two residue;
R 2Represent one or two residue;
R 4Represent one or two residue; And
R 5Represent one or two residue.
8, compound as claimed in claim 7, wherein,
R 1Represent a residue;
R 2Represent a residue;
R 4Represent a residue; And
R 5Represent a residue.
9, a kind of compound that is shown below:
Wherein, R 1And R 2Expression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, hydroxyl amidino groups, guanidine radicals, dialkyl group guanidine radicals, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate and the carboxylamine sugar;
R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group;
R 4Expression be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-, two, three or four residues in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate and the carboxylamine sugar;
R 5fExpression be independently selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate, carboxylamine sugar and-N +R 6R 7R 8X -In one to five residue;
R 6Be C 1-20Hydrocarbon or and R 7Form five yuan to seven-membered ring;
R 7Be alkyl or and R 6Form five yuan to seven-membered ring;
R 8Be alkyl or and R 6Or R 7Form second five yuan together to seven-membered ring;
X is a negatively charged ion.
10, a kind of compound that is shown below:
Figure A2004800396950010C1
Wherein, R 2aExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy;
R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group;
R 1a, R 4aAnd R 5aIn one be-Q-A-N +R 9R 10R 11X -, and two other be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and benzyloxy;
Q be selected from direct key ,-O-,-S-,-NH-, CH 2O-, CH 2NH-,-C (=O) ,-CONH-,-NHCO-,-CH 2NH (C=O)-,-O (C=O)-,-(C=O) O-,-NHCONH-,-OCONH-and-NHCOO-;
A is selected from C 2-20Hydrocarbon, carbonatoms are the substituted alkyl of 2-20, substituted aryl, substituted arylalkyl and C 4-50Oxa alkyl, and, when Q be direct key ,-C (=O) or-O (C=O)-time, A can also be methylene radical;
R 9Be C 1-20Hydrocarbon or with A or R 10Form five yuan to seven-membered ring;
R 10Be alkyl, form two keys or and R with A 9Form five yuan to seven-membered ring;
R 11Be alkyl or and R 10Or R 9Form second five yuan together to seven-membered ring;
X is a negatively charged ion.
11, a kind of compound that is shown below:
Wherein, R 2bExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy;
R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group;
R 1b, R 4bAnd R 5bIn one be R 12, and R 1b, R 4bAnd R 5bIn two other be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate and carboxylamine sugar;
R 6aBe C 1-20Hydrocarbon;
R 7aBe alkyl;
R 8aBe alkyl;
R 12Be (C 0-C 30) alkylidene group-G n, the one or more-CH in the wherein said alkylidene group 2-residue can by-S-,-SO-, SO 2-,-O-,-NH-,-N (alkyl)-,-N (phenyl)-,-N (alkyl phenyl)-,-N +(alkyl) 2-,-N +(phenyl) 2-,-N +(alkyl phenyl) 2-,-C (=O)-,-C (=S) ,-CH=CH-,-C=C-, phenylene or-N[(C=O) alkylidene group COOH]-substitute;
G is selected from-SO 3H ,-PO 3H 2,-O-PO 3H 2,-COOH ,-C (N=H) NH 2, polyol, sugar, glucosiduronate, carboxylamine sugar ,-N +R 6aR 7aR 8aX -With monocycle or dicyclo trialkyl ammonium alkyl residue;
N is 1,2,3,4 or 5;
X is a negatively charged ion.
12, a kind of compound that is shown below:
Wherein, R 1cAnd R 2cExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-SH ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, hydroxyl amidino groups, guanidine radicals, dialkyl group guanidine radicals, phenyl, benzyl, phenoxy group, benzyloxy, glucosiduronate and the carboxylamine sugar;
R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group;
R 4cExpression be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-, two, three or four residues in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, glucosiduronate and the carboxylamine sugar;
R 5fExpression be independently selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, amide group, alkyl sulfoxide, acyl amino, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy, sugar, glucosiduronate, carboxylamine sugar and-N +R 6R 7R 8X -In one, two, three, four or five residues;
R 6Be C 1-20Hydrocarbon or and R 7Form five yuan to seven-membered ring;
R 7Be alkyl or and R 6Form five yuan to seven-membered ring;
R 8Be alkyl or and R 6Or R 7Form second five yuan together to seven-membered ring;
X is a negatively charged ion.
13, a kind of compound that is shown below:
Figure A2004800396950014C1
Wherein, R 1a, R 2aAnd R 4aExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF separately 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy;
R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group;
R 5cFor-Q-A-N +R 9R 10R 11X -
Q be selected from direct key ,-O-,-S-,-NH-, CH 2O-, CH 2NH-,-C (=O) ,-CONH-,-NHCO-,-CH 2NH (C=O)-,-O (C=O)-,-(C=O) O-,-NHCONH-,-OCONH-and-NHCOO-;
A is selected from C 2-20Hydrocarbon, carbonatoms are the substituted alkyl of 2-20, substituted aryl, substituted arylalkyl and C 4-50Oxa alkyl, and, when Q be direct key ,-C (=O) or-O (C=O)-time, A can also be methylene radical;
R 9Be C 1-20Hydrocarbon or with A or R 10Form five yuan to seven-membered ring;
R 10Be alkyl, form two keys or and R with A 9Form five yuan to seven-membered ring;
R 11Be alkyl or and R 10Or R 9Form second five yuan together to seven-membered ring;
X is a negatively charged ion.
14, a kind of compound that is shown below:
Figure A2004800396950015C1
Wherein, R 2bExpression is independently selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy;
R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group;
R 1d, R 4dAnd R 5dIn one be R 12a, and R 1d, R 4dAnd R 5dIn two other be independently selected from hydrogen, halogen, hydroxyl, low alkyl group ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group, benzyloxy and R 12a
R 6aBe C 1-20Hydrocarbon;
R 7aBe alkyl;
R 8aBe alkyl;
R 12For
Figure A2004800396950016C1
Perhaps work as R 5dBe R 12aThe time, R 12aAlso can be (C 0-C 30) alkylidene group-G n, the one or more-CH in the wherein said alkylidene group 2-residue can by-S-,-SO-, SO 2-,-O-,-NH-,-N (alkyl)-,-N (phenyl)-,-N (alkyl phenyl)-,-N +(alkyl) 2-,-N +(phenyl) 2-,-N +(alkyl phenyl) 2-,-C (=O)-,-C (=S), CH=CH ,-C=C-, phenylene or-N[(C=O) alkylidene group COOH]-substitute;
G is selected from-SO 3H ,-PO 3H 2,-O-PO 3H 2,-COOH ,-C (N=H) NH 2, polyol, sugar, glucosiduronate, carboxylamine sugar ,-N +R 6aR 7aR 8aX -With monocycle or dicyclo trialkyl ammonium alkyl residue;
R 13Be selected from direct key ,-C=C-,-OCH 2,-C (=O)-and-CHOH-;
R 14Be selected from-OH and-OC (=O) alkyl;
R 15Be selected from-CH 2OH ,-CH 2OC (=O) alkyl and-the COO-alkyl;
J is 1,2,3,4 or 5;
K is 0,1,2,3,4 or 5;
N is 1,2,3,4 or 5;
X is a negatively charged ion.
15, a kind of compound that is shown below:
Wherein, R 1e, R 2aAnd R 4eBe selected from hydrogen, halogen, hydroxyl, low alkyl group, OCF independently of one another 2H, OCF 3, CF 2H, CH 2F ,-O-low alkyl group, methylene-dioxy, hydroxyl low-grade alkyl ,-CN, CF 3, nitro ,-one or two residue in S-low alkyl group, amino, alkylamino, dialkyl amido, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, alkyl sulphonyl, aryl sulfonyl, acyl group, carboxyl, carbalkoxy, acyl amino, alkyl sulfoxide, amide group, amidino groups, phenyl, benzyl, phenoxy group and the benzyloxy;
R 3Be selected from hydrogen, hydroxyl, fluorine ,-the O-low alkyl group and-the O-acyl group;
R 5eBe selected from
Figure A2004800396950017C2
(C 0-C 30) alkylidene group-G n, wherein, the one or more-CH in the described alkylidene group 2-residue can by-S-,-SO-, SO 2-,-O-,-NH-,-N (alkyl)-,-N (phenyl)-,-N (alkyl phenyl)-,-N +(alkyl) 2-,-N +(phenyl) 2-,-N +(alkyl phenyl) 2-,-C (=O)-,-C (=S), CH=CH ,-C=C-, phenylene or-N[(C=O) alkylidene group COOH]-substitute;
G is selected from-SO 3H ,-P (O) OH 2,-O-P (O) OH 2,-COOH ,-C (N=H) NH 2, polyol, sugar, glucosiduronate, carboxylamine sugar ,-N +R 6aR 7aR 8aX -With monocycle or dicyclo trialkyl ammonium alkyl residue;
R 6aBe C 1-20Hydrocarbon;
R 7aBe alkyl;
R 8aBe alkyl;
R 13Be selected from direct key ,-C=C-,-OCH 2,-C (=O)-and-CHOH-;
R 14Be selected from-OH and-OC (=O) alkyl;
R 15Be selected from-CH 2OH ,-CH 2OC (=O) alkyl and-the COO-alkyl;
J is 1,2,3,4 or 5;
K is 0,1,2,3,4 or 5;
X is a negatively charged ion.
16, as claim 1,2,4 and 9-15 in any described compound, wherein, R 1, R 2And R 4Be selected from hydrogen, halogen, hydroxyl and methoxyl group.
17, as any described compound among the claim 1-4,9,11 and 15, wherein, R 1, R 2, R 4And R 5Be selected from sugar, glucosiduronate and carboxylamine sugar.
18, as any described compound among the claim 1-4,9,11 and 15, wherein, R 1, R 2, R 4And R 5In at least one be selected from SO 3H and PO 3H 2
19, as any described compound among the claim 9-15, wherein, R 3Be selected from hydrogen and hydroxyl.
20, as claim 1,2,4 and 9-15 in any described compound, wherein, R 4Be hydrogen.
21, as claim 1,2,4 and 9-15 in any described compound, wherein, R 4Be hydroxyl.
22, as any described compound among claim 1-4 and the 9-15, wherein, R 5Be selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, CF 3, alkyl sulphonyl, aryl sulfonyl, methylol, formyl radical, cyano group, N, N-dimethyl sulfonamido, carboxyl, nitro, kharophen, dialkyl amido, methylthio group, vinyl, methylene-dioxy, ethylenedioxy, carboxymethyl ,-PO 3H 2, sulfydryl ,-SO 3H ,-B (OH) 2, trialkyl ammonium positively charged ion, sugar and glucosiduronate.
23, as claim 1,2 or 3 described compounds, it has with following formula:
Figure A2004800396950019C1
24, compound as claimed in claim 23, it has with following formula:
Figure A2004800396950019C2
25, compound as claimed in claim 24, it has with following formula:
26, compound as claimed in claim 24, it has with following formula:
27, compound as claimed in claim 26, it has with following formula:
Figure A2004800396950021C1
28, compound as claimed in claim 27, wherein, R 1Be hydrogen.
29, a kind of compound that is shown below:
Figure A2004800396950021C2
Wherein, R 1iAnd R 2iBe independently selected from hydrogen, fluorine, chlorine, CH 3, CN, OCH 3, OCF 3, OCF 2H, CF 3, CF 2H and CH 2F;
R 4iBe selected from hydrogen, fluorine, chlorine, CH 3, OCH 3, OH, B (OH) 2And SH;
R 5iBe selected from OH, SO 3H, PO 3H 2, CH 2OH, COOH, CHO and sugar.
30, compound as claimed in claim 29, wherein, R 5iBe OH, the structural formula of this compound is:
Figure A2004800396950022C1
31, compound as claimed in claim 29, wherein, R 5iFor-SO 3H, the structural formula of this compound is:
Figure A2004800396950022C2
32, compound as claimed in claim 29, wherein, R 5iFor-PO 3H 2, the structural formula of this compound is:
Figure A2004800396950022C3
33, compound as claimed in claim 29, wherein, R 5iBe the D-sorbitol, the structural formula of this compound is:
Figure A2004800396950023C1
34, compound as claimed in claim 30, wherein, R 5iBe OH, the structural formula of this compound is:
35, compound as claimed in claim 31, wherein, R 5iFor-SO 3H, the structural formula of this compound is:
Figure A2004800396950024C1
36, compound as claimed in claim 32, wherein, R 5iFor-PO 3H 2, the structural formula of this compound is:
37, compound as claimed in claim 33, wherein, R 5iBe the D-sorbitol, the structural formula of this compound is:
38, compound as claimed in claim 34, wherein, R 5iBe OH, the structural formula of this compound is:
39, compound as claimed in claim 34, wherein, R 5iBe OH, the structural formula of this compound is:
Figure A2004800396950025C2
40, compound as claimed in claim 35, wherein, R 5iFor-SO 3H, the structural formula of this compound is:
Figure A2004800396950026C1
41, compound as claimed in claim 35, wherein, R 5iFor-SO 3H, the structural formula of this compound is:
42, compound as claimed in claim 36, wherein, R 5iFor-PO 3H 2, the structural formula of this compound is:
43, compound as claimed in claim 36, wherein, R 5iFor-PO 3H 2, the structural formula of this compound is:
Figure A2004800396950027C2
44, compound as claimed in claim 37, wherein, R 5iBe the D-sorbitol, the structural formula of this compound is:
Figure A2004800396950028C1
45, compound as claimed in claim 37, wherein, R 5iBe the D-sorbitol, the structural formula of this compound is:
Figure A2004800396950028C2
46, as any described compound among the claim 29-45, wherein, R 4iBe OH.
47, compound as claimed in claim 46, wherein, R 4iOrtho position at the azetidine ring.
48, as any described compound among the claim 29-45, wherein, R 5iBe ortho-substituent.
49, as any described compound among the claim 29-45, wherein, R 5iBe meta-substituent.
50, as any described compound among the claim 29-45, wherein, R 5iBe para-orienting group.
51, as any described compound among the claim 29-45, wherein, R 1iAnd R 2iBe selected from hydrogen, chlorine and fluorine.
52, compound as claimed in claim 51, wherein, R 1iBe hydrogen.
53, compound as claimed in claim 29, wherein, described sugar is the D-sorbitol.
54, as any described compound among the claim 1-4, it has with following formula:
Figure A2004800396950029C1
55, as any described compound in claim 1-3 and 29, wherein,
R 1Be hydrogen or 4-fluorine;
R 2Be the 4-fluorine;
R 4Be hydrogen or hydroxyl.
56, as claim 10 or 13 described compounds, wherein, R 1, R 4And R 5In one be-Q-A-N +R 9R 10R 11X -,
-Q-A-is selected from C 2-20Hydrocarbon ,-O-(C 2-20Hydrocarbon) ,-NH-(C 2-20Hydrocarbon) ,-NHCO-(C 2-20Hydrocarbon) and C 4-20Oxa alkyl;
R 9Be low alkyl group or phenyl, and R 10And R 11Be low alkyl group, perhaps R 9, R 10And R 11Form the diazabicyclooctane quaternary ammonium that is shown below together:
Figure A2004800396950030C1
Perhaps R 9, R 10And R 11Form the quinine quaternary ammonium that is shown below together:
Figure A2004800396950030C2
57, as any described compound in the claim 1,2,9 and 12, the structural formula of this compound is:
Figure A2004800396950031C1
Wherein, R 1And R 2Be selected from hydrogen, halogen ,-OH and methoxyl group;
R 3Be selected from hydrogen and hydroxyl;
R 5Be selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, CF 3, alkyl sulphonyl and aryl sulfonyl.
58, as any described compound in the claim 1,2,9 and 12, the structural formula of this compound is:
Figure A2004800396950031C2
Wherein, R 1And R 2Be selected from hydrogen, halogen ,-OH and methoxyl group;
R 3Be selected from hydrogen and hydroxyl;
R 5Be selected from halogen, hydroxyl, low alkyl group ,-O-low alkyl group, CF 3, alkyl sulphonyl and aryl sulfonyl.
59, compound as claimed in claim 58, it has with following formula:
60, compound as claimed in claim 59, it has with following formula:
61, compound as claimed in claim 11, wherein,
R 1bBe R 12
R 2bAnd R 4bBe selected from hydrogen, halogen, hydroxyl and methoxyl group;
R 12Be (C 6-C 20) alkylidene group-G n, the one or more-CH in the wherein said alkylidene group 2-residue can by-O-,-NH-,-N (alkyl)-,-C (=O)-or-CH=CH-substitutes;
G is selected from-SO 3H ,-PO 3H 2, polyol and sugar.
62, as claim 11,14 or 15 described compounds, wherein,
R 5Be R 12
R 1, R 2And R 4Be selected from hydrogen, halogen, hydroxyl and methoxyl group;
R 12Be (C 6-C 20) alkylidene group-G n, the one or more-CH in the wherein said alkylidene group 2-residue can by-O-,-NH-,-N (alkyl)-,-C (=O)-or-CH=CH-substitutes;
G is selected from-SO 3H ,-PO 3H 2, polyol and sugar.
63, as any described compound among claim 1-4,8-15 and the 29-45, wherein, the substituting group on 3 and 4 of azetidine-2-ketone is a cis relative configuration.
64, as any described compound among claim 1-4,8-15 and the 29-45, wherein, the substituting group on 3 and 4 of azetidine-2-ketone is trans relative configuration.
65, as the described compound of claim 64, wherein, the substituting group on 3 of azetidine-2-ketone is the R absolute configuration, and the substituting group on 4 of azetidine-2-ketone is the S absolute configuration.
66, as any described compound among the claim 1-3, wherein, U for wherein at least one-CH 2-quilt-CHOH-alternate (C 2-C 6)-alkylidene group.
67, a kind of compound, it is selected from following group:
(1) (1R)-1,5-dehydration-1-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-4-yl)-the L-sorbitol,
(2) (1S)-1,5-dehydration-1-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl)-the L-sorbitol,
(3) (1S)-1,5-dehydration-1-(4 '-2S, 3R)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol,
(4) (1S)-1,5-dehydration-1-(4 '-(2S, 3R)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl)-the D-sorbitol,
(5) (1S)-1,5-dehydration-1-(4 '-(2S, 3R)-3[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-sorbitol,
(6) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2 ', 3 ', 4 '-trimethoxy xenyl-4-yl) azetidine-2-ketone,
(7) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-4-yl) azetidine-2-ketone,
(8) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-sulfydryl xenyl-4-yl) azetidine-2-ketone,
(9) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-methoxyl biphenyl base-4-yl) azetidine-2-ketone,
(10) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-nitrobiphenyl base-4-yl) azetidine-2-ketone,
(11) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 '-hydroxyl-3 '-methoxyl biphenyl base-4-yl) azetidine-2-ketone,
(12) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 '-vinyl xenyl-4-yl) azetidine-2-ketone,
(13) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3 '-(methylol) xenyl-4-yl] azetidine-2-ketone,
(14) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3 '-(methyl sulphonyl) xenyl-4-yl] azetidine-2-ketone,
(15) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(2-naphthyl) phenyl] azetidine-2-ketone,
(16) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4 '-(methylol) xenyl-4-yl] azetidine-2-ketone,
(17) (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4 '-(methyl sulphonyl) xenyl-4-yl] azetidine-2-ketone,
(18) (3R, 4S)-1-xenyl-4-base-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-4-yl) azetidine-2-ketone,
(19) (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3 '-Hydroxybiphenyl-4-yl)-1-phenyl azetidine alkane-2-ketone,
(20) (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3-hydroxyl-3 '-(methyl sulphonyl) xenyl-4-yl)-1-phenyl azetidine alkane-2-ketone,
(21) (3R, 4S)-4-(2 ', 3 '-difluoro biphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(22) (3R, 4S)-4-(2 ', 4 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(23) (3R, 4S)-4-(2 '-bromo-5 '-Hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(24) (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(25) (3R, 4S)-4-(3,3 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone,
(26) (3R, 4S)-4-(3,4 '-dihydroxybiphenyl base-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl azetidine alkane-2-ketone,
(27) (3R, 4S)-4-(3 ', 5 '-dihydroxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(28) (3R, 4S)-4-(3 ', 5 '-dimethoxy-biphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(29) (3R, 4S)-4-(3 '-butoxy xenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(30) (3R, 4S)-4-(3 '-ethoxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(31) (3R, 4S)-4-(3 '-fluoro-5 '-Hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(32) (3R, 4S)-4-(3 '-fluoro-5 '-methoxyl biphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(33) (3R, 4S)-4-(4 '-phenylaniline base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(34) (3R, 4S)-4-(4 '-ethoxybiphenyl base-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(35) (3R, 4S)-4-[4-(2,3-dihydro-1,4-benzo dioxine-6-yl) phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(36) (3R, 4S)-4-[4 '-(dimethylamino) xenyl-4-yl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] azetidine-2-ketone,
(37) (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl) boric acid,
(38) (4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-yl) phosphonic acids,
(39) (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl) phosphonic acids,
(40) (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) boric acid,
(41) (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl) phosphonic acids,
(42) (6R)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-Glucopyranose,
(43) (6R)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-Glucopyranose,
(44) (6S)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-sorbitol,
(45) (6S)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-yl)-the D-Glucopyranose,
(46) (6S)-6-C-(4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl } xenyl-3-yl)-the D-Glucopyranose,
(47) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl }-3-Hydroxybiphenyl-4-formic acid,
(48) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl }-4-Hydroxybiphenyl-3-formic acid,
(49) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl }-5-Hydroxybiphenyl-2-formaldehyde,
(50) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-formaldehyde,
(51) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-formic acid,
(52) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-sulfonic acid,
(53) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-base-β-L-glucopyranoside,
(54) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-3-base-β-L-Glucopyranose carbonyl acid,
(55) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-4-formic acid,
(56) 4 '-(2S, 3R)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-3-sulfonic acid,
(57) 6-O-4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-yl)-the D-sorbitol,
(58) 6-O-4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-yl)-the D-Glucopyranose,
(59) 4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl } xenyl-4-methyl-formiate,
(60) methyl-6-O-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-yl)-α-D-glucopyranoside,
(61) N-(4 '-(2S, 3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-2-yl xenyl-3-yl) ethanamide,
(62) (4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-yl) phosphonic acids,
(63) 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sulfonic acid, and
(64) 4 '-(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenyl azetidine alkane-2-yl }-3 '-Hydroxybiphenyl-4-sodium sulfonate.
68, as any described compound among the claim 9-15, wherein, X is the acceptable negatively charged ion of pharmacology.
69, a kind of pharmaceutical preparation, it contains just like any described compound and pharmacology acceptable carrier among claim 1-4,9-15, the 29-45,61 and 67.
70, as the described pharmaceutical preparation of claim 69, it also contains cholesteral biosynthesis inhibitor.
71, as the described pharmaceutical preparation of claim 70, wherein, described cholesteral biosynthesis inhibitor is the HMG-CoA reductase inhibitor.
72, as the described pharmaceutical preparation of claim 71, wherein, described HMG-CoA reductase inhibitor is selected from following group: lovastatin, simvastatin, pravastatin, rochovastatin, Mevastatin, A Fatading, Cerivastatin, pitavastatin, fluorine cut down Chinese violet, shellfish and cut down his spit of fland, crilvastatin, card and cut down his spit of fland, upright his spit of fland, this upright his spit of fland, glenvastatin and Dalvastatin cut down cut down.
73, as the described pharmaceutical preparation of claim 69, it also contains at least a bile acid chelating agent.
74, as the described pharmaceutical preparation of claim 73, wherein, described at least a bile acid chelating agent is selected from following group: Colestyramine, colestipol, hydrochloric acid colesevelam and their mixture.
75, as the described pharmaceutical preparation of claim 69, it also contains at least a nicotinic acid or derivatives thereof that is selected from following group: nicotinic acid, pentaerythritol tetranicotinate, nicofuranose, Olbetam and their mixture.
76, as the described pharmaceutical preparation of claim 69, it also contains at least a peroxysome hyperplasia factor activated receptors alpha activators.
77, as the described pharmaceutical preparation of claim 76, wherein, described peroxysome hyperplasia factor activated receptors alpha activators is a fiber acid derivative.
78, as the described pharmaceutical preparation of claim 77, wherein, described fiber acid derivative is selected from fenofibrate in following group, clofibrate, gemfibrozil, Win-35833, bezafibrate, S-8527, binifibrate, lifibrol and their mixture.
79, as the described pharmaceutical preparation of claim 69, it also contains at least a cholesteryl ester transfer protein (CETP) inhibitor.
80, as the described pharmaceutical preparation of claim 69, it also contains at least a obesity control medicine.
81, as the described pharmaceutical preparation of claim 69, it also contains at least a acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor.
82, as the described pharmaceutical preparation of claim 69, it also contains at least a hypoglycemic drug.
83, as the described pharmaceutical preparation of claim 82, wherein, described at least a hypoglycemic drug is a peroxysome hyperplasia factor activator agent receptor y agonist.
84, as the described pharmaceutical preparation of claim 83, wherein, described peroxysome hyperplasia factor activator agent receptor y agonist is selected from following group: rosiglitazone, pioglitazone or ciglitazone.
85, as the described pharmaceutical preparation of claim 82, wherein, described at least a hypoglycemic drug is for reducing the medicine that endogenous hepatic glucose generates.
86, as the described pharmaceutical preparation of claim 85, wherein, described medicine is N1,N1-Dimethylbiguanide or phenformin.
87, as the described pharmaceutical preparation of claim 82, wherein, described at least a hypoglycemic drug is for strengthening the medicine that Regular Insulin discharges from pancreas.
88, as the described pharmaceutical preparation of claim 87, wherein, described medicine is carbutamide, tolbutamide, acetohexamide, tolazamide, P-607, Glyburide, Glipizide or gliclazide.
89, as the described pharmaceutical preparation of claim 69, it also contains at least a oxidation inhibitor.
90, as the described pharmaceutical preparation of claim 89, wherein, described oxidation inhibitor is probucol or AGI-1067.
91, a kind of goods comprise container, operation instruction and together as the described pharmaceutical preparation of claim 69, and wherein, this operation instruction is with being described pharmaceutical preparation for following purpose administration: prevention or treatment lipid metabolism disorders; Gu reduce the blood plasma or the tissue concentration of at least a non-cholesterol sterol or 5 α-alkanol; Reduce the blood plasma or the serum-concentration of LDL cholesterol; Reducing cholesterol or the cholesteryl ester concentration in blood plasma or serum; Improve the defecate of cholesterol; Reduce the incidence of coronary heart disease dependent event; Reduce the blood plasma or the serum-concentration of C-activated protein (CRP); Treatment or prevention vascular inflammation; Reduce the blood plasma or the serum-concentration of tri-glyceride; Improve the blood plasma or the serum-concentration of high density lipoprotein cholesterol; Reduce the blood plasma or the serum-concentration of apolipoprotein B.
92, as the described pharmaceutical preparation of claim 69, it is used for the treatment of the tumour relevant with cholesterol, and also contains at least a other carcinostatic agent.
93, as the described pharmaceutical preparation of claim 92, wherein, described at least a other carcinostatic agent is selected from following group: steroid class antiandrogen, non-steroid class antiandrogen, oestrogenic hormon, diethylstilbestrol, conjugated estrogen hormone, selective estrogen receptor modulators, Taxan and LHRH analogue.
94, as the described pharmaceutical preparation of claim 93, wherein, described non-steroid class antiandrogen is selected from following group: finasteride, flutamide, Bi Kalu amine and Nilutamide.
95, as the described pharmaceutical preparation of claim 93, wherein, described selective estrogen receptor modulators is selected from following group: tamoxifen, raloxifene, droloxifene and Ai Duo former times phenol.
96, as the described pharmaceutical preparation of claim 93, wherein, described Taxan is selected from following group: taxol and docetaxel.
97, as the described pharmaceutical preparation of claim 93, wherein, described LHRH analogue is selected from following group: goserelin acetate and hydrochloric acid Leuprolide.
98, a kind of goods comprise container, operation instruction and as the described pharmaceutical preparation of claim 69, wherein, this operation instruction is the described pharmaceutical preparation for following purpose administration together: prevent, treat or improve the Alzheimer symptom; The generation of regulation and control amyloid beta; The amount of regulation and control ApoE isoform 4 in blood flow and/or brain; The incidence of prevention or minimizing xanthomatosis; And prevention or the treatment tumour relevant with cholesterol.
99, as the described pharmaceutical preparation of claim 69, it also contains at least a anti-hypertension compound.
100, as the described pharmaceutical preparation of claim 99, wherein, described anti-hypertension compound is the thiazides derivative.
101, as the described pharmaceutical preparation of claim 100, wherein, described thiazides derivative is selected from following group: hydrochlorothiazide, chlorothiazide and polythiazide.
102, as the described pharmaceutical preparation of claim 99, wherein, described anti-hypertension compound is the Beta-3 adrenergic blocker.
103, as the described pharmaceutical preparation of claim 102, wherein, described Beta-3 adrenergic blocker is selected from following group: atenolol USP 23, metoprolol, Proprasylyte, timolol, carvedilol, nadolol and bisoprolol.
104, as the described pharmaceutical preparation of claim 99, wherein, described anti-hypertension compound is a calcium channel blocker.
105, as the described pharmaceutical preparation of claim 104, wherein, described calcium channel blocker is selected from following group: Isrodipine, verapamil, nitrendipine, amlodipine, nifedipine, nicardipine, Isrodipine, felodipine, nisoldipine and Odizem.
106, as the described pharmaceutical preparation of claim 99, wherein, described anti-hypertension compound is angiotensin converting enzyme (ACE) inhibitor.
107, as the described pharmaceutical preparation of claim 106, wherein, described angiotensin converting enzyme inhibitor is selected from following group: delapril, captopril, enalapril, lisinopril, quinapril, perindopril, benazepril, Trolapril, fosinopril, Ramipril and Ceranapril.
108, as the described pharmaceutical preparation of claim 99, wherein, described anti-hypertension compound is an angiotensin II receptor antagonists.
109, as the described pharmaceutical preparation of claim 108, wherein, described angiotensin II receptor antagonists is selected from following group: Candesartan, Irb, Olmesartan, telmisartan and A Pushatan.
110, a kind of method for the treatment of lipid metabolism disorders, comprise together with the treatment significant quantity as Mammals as described in any described compound gives among claim 1-4,9-15, the 29-45,61 and 67.
111, as the described method of claim 110, wherein, described lipid metabolism disorders is a hyperlipidaemia.
112, as the described method of claim 110, wherein, described lipid metabolism disorders is an arteriosclerosis.
113, as the described method of claim 110, wherein, described lipid metabolism disorders is a Sitosterolemia.
114, a kind of method that suppresses Mammals intestinal absorption cholesterol, it comprises as Mammals as described in any described compound gives with the amount that suppresses cholesterol absorption effectively among claim 1-4,9-15, the 29-45,61 and 67.
Gu 115, a kind of at least a non-cholesterol sterol or the blood plasma of 5 α-alkanol or method of tissue concentration of reducing, it comprises needs the Mammals of this treatment with significant quantity as any described compound among claim 1-4,9-15, the 29-45,61 and 67.
116, a kind of blood plasma of Mammals LDL cholesterol or method of serum-concentration of reducing, it comprise with as any described compound among claim 1-4,9-15, the 29-45,61 and 67 with Mammals as described in the amount of reducing cholesterol gives effectively.
117, the method for a kind of reducing cholesterol and the cholesteryl ester concentration in mammalian plasma or serum, it comprise with as any described compound among claim 1-4,9-15, the 29-45,61 and 67 with Mammals as described in the amount of reducing cholesterol and cholesteryl ester gives effectively.
118, a kind of method that improves the defecate of Mammals cholesterol, it comprises Mammals as described in giving with the amount of the defecate that improves the Mammals cholesterol effectively as any described compound among claim 1-4,9-15, the 29-45,61 and 67.
119, the method that needs the clinical symptom of cholesterol absorption inhibitor in a kind of prevention or the treatment Mammals, it comprise with the treatment significant quantity as Mammals as described in any described compound gives among claim 1-4,9-15, the 29-45,61 and 67.
120, a kind of method that reduces the cardiovascular dependent event incidence of Mammals, it comprises as Mammals as described in any described compound gives with the amount that reduces cardiovascular dependent event incidence effectively among claim 1-4,9-15, the 29-45,61 and 67.
121, the blood plasma of a kind of reduction Mammals C-activated protein (CRP) or the method for serum-concentration, it comprise with the treatment significant quantity as Mammals as described in any described compound gives among claim 1-4,9-15, the 29-45,61 and 67.
122, the method for a kind of treatment or prevention Mammals blood vessel inflammation, it comprises and will give individuality as any described compound among claim 1-4,9-15, the 29-45,61 and 67, and the level of the C-activated protein of described individuality shows and has vascular inflammation or potential vascular inflammation.
123, a kind of method that reduces the blood plasma or the serum-concentration of Mammals tri-glyceride, it comprise with the treatment significant quantity as Mammals as described in any described compound gives among claim 1-4,9-15, the 29-45,61 and 67.
124, a kind of method that improves the blood plasma or the serum-concentration of Mammals high density lipoprotein cholesterol, it comprise with the treatment significant quantity as Mammals as described in any described compound gives among claim 1-4,9-15, the 29-45,61 and 67.
125, a kind of method that reduces the blood plasma or the serum-concentration of Mammals apolipoprotein B, it comprise with the treatment significant quantity as Mammals as described in any described compound gives among claim 1-4,9-15, the 29-45,61 and 67.
126, a kind of method for the treatment of at least a vascular disorder when preventing or reducing the muscle deterioration side effect relevant with the HMG-CoA reductase inhibitor as far as possible, it comprises the individuality that needs with at least a HMG-CoA reductase inhibitor as any described compound among claim 1-4,9-15, the 29-45,61 and 67.
127, a kind of method of regulating and control the individual amount of ApoE isoform 4 in blood flow and/or brain, it comprises at least a individuality that needs this treatment as any described compound compositions among claim 1-4,10-16, the 22-44,59 and 64 of containing of significant quantity.
128, a kind of prevention, treatment or improve the method for Alzheimer symptom, it comprises at least a individuality that needs this treatment as any described compound compositions among claim 1-4,10-16, the 22-44,59 and 64 of containing of significant quantity.
129, the method for the level in amyloid beta steroid blood flow and/or the brain in a kind of generation of regulating and control amyloid beta in the individuality or the regulation and control individuality, it may further comprise the steps: with at least a individuality that needs this treatment as any described compound compositions among claim 14,10-16, the 22-44,59 and 64 of containing of significant quantity.
130, the method for the tumour that a kind of prevention or treatment are relevant with cholesterol, it comprises the patient who gives the dangerous of tangible generating cholesterol related neoplasms or shown the cholesterol related neoplasms as any described compound among claim 1-4,9-15, the 29-45,61 and 67 with significant quantity.
131, as the method for the described prevention of claim 130 or the treatment tumour relevant with cholesterol, wherein, described cholesterol related neoplasms is selected from following group: benign prostatauxe, optimum breast tumor, optimum endometrial tumors and optimum colon tumor.
132, as the method for the described prevention of claim 130 or the treatment tumour relevant with cholesterol, wherein, described cholesterol related neoplasms is selected from following group: malignant prostate hypertrophy, breast cancer tumour, uterine endometrium tumor and colorectal carcinoma tumour.
133, the method for the tumour that a kind of prevention or treatment are relevant with cholesterol, it comprises the patient who gives the dangerous of tangible generating cholesterol related neoplasms or shown the cholesterol related neoplasms with at least a other carcinostatic agent as any described compound among claim 1-4,9-15, the 29-45,61 and 67 with significant quantity.
134, the method for the tumour that a kind of prevention or treatment are relevant with cholesterol, it comprises will need the patient of this prevention or treatment as the described pharmaceutical preparation of claim 69.
135, a kind of prevention or reduce the method for xanthomatosis incidence in the individuality, it comprises needs the individuality of this treatment with significant quantity as any described compound among claim 1-4,10-16, the 22-44,59 and 64.
136, a kind of compound that is shown below:
Figure A2004800396950048C1
Wherein,
U is C 2-6Alkylidene group, wherein one or more-CH 2-can be selected from-S-,-S (O)-,-SO 2-,-O-,-C (=O)-,-CHOH-,-NH-, CHF, CF 2,-CH (O-low alkyl group)-,-CH (O-lower acyl)-,-CH (OSO 3H)-,-CH (OPO 3H 2)-,-CH (OB (OH) 2)-or-residue among the NOH-substitutes;
R 1jAnd R 2jBe independently selected from hydrogen, fluorine and chlorine; And
R 5jBe selected from SO 3H, PO 3H 2, sugar and glucosiduronate.
137, as the described compound of claim 136, wherein, R 1jBe hydrogen.
138, as the described compound of claim 136, wherein, R 2jBe fluorine.
CN 200480039695 2003-11-10 2004-11-10 4-biarylyl-1-phenylazetidin-2-ones Pending CN1902169A (en)

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CN102224135A (en) * 2008-11-24 2011-10-19 Nsab神经研究瑞典公司分公司 Novel 3-phenyl-azetidine derivatives useful as modulators of cortical catecholaminergic neurotransmission

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102224135A (en) * 2008-11-24 2011-10-19 Nsab神经研究瑞典公司分公司 Novel 3-phenyl-azetidine derivatives useful as modulators of cortical catecholaminergic neurotransmission

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