CN102232069A - N-acetylneuraminic acid compounds, pharmaceutical composition, preparation method and uses thereof - Google Patents

N-acetylneuraminic acid compounds, pharmaceutical composition, preparation method and uses thereof Download PDF

Info

Publication number
CN102232069A
CN102232069A CN2010800030651A CN201080003065A CN102232069A CN 102232069 A CN102232069 A CN 102232069A CN 2010800030651 A CN2010800030651 A CN 2010800030651A CN 201080003065 A CN201080003065 A CN 201080003065A CN 102232069 A CN102232069 A CN 102232069A
Authority
CN
China
Prior art keywords
compound
hydroxyl
dihydropyran
formula
protective embankment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN2010800030651A
Other languages
Chinese (zh)
Other versions
CN102232069B (en
Inventor
赵庆杰
李剑峰
熊瑞生
沈敬山
朱维良
蒋华良
沈竞康
卢敬泰
金汉祚
南基烨
成百麟
申宇镇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bioinformatics & Molecular Des
Shanghai Institute of Materia Medica of CAS
Original Assignee
Bioinformatics & Molecular Des
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bioinformatics & Molecular Des, Shanghai Institute of Materia Medica of CAS filed Critical Bioinformatics & Molecular Des
Priority to CN201080003065.1A priority Critical patent/CN102232069B/en
Publication of CN102232069A publication Critical patent/CN102232069A/en
Application granted granted Critical
Publication of CN102232069B publication Critical patent/CN102232069B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06V—IMAGE OR VIDEO RECOGNITION OR UNDERSTANDING
    • G06V30/00—Character recognition; Recognising digital ink; Document-oriented image-based pattern recognition
    • G06V30/40—Document-oriented image-based pattern recognition
    • G06V30/41—Analysis of document content
    • G06V30/414—Extracting the geometrical structure, e.g. layout tree; Block segmentation, e.g. bounding boxes for graphics or text
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Abstract

N-acetylneuraminic acid compounds of formula as follows, pharmaceutical composition, preparation method and uses thereof are disclosed. The compounds can inhibit surface neuraminidase of influenza virus, thus can be used for resisting influenza virus, especially, for treating infections caused by the influenza virus which has resistance to other anti-flu drugs such as zanamivir and oseltamivir.

Description

N-acetylneuraminic acid compounds, pharmaceutical composition, preparation method and uses thereof
N-acetyl-neuraminate class compound, its pharmaceutical composition and its production and use technical field
The present invention relates to N-acetyl-neuraminate class compound, its pharmaceutical composition and its production and use.These compounds can suppress virus surface neuraminidase, thus can be applied to the treatment of relevant disease.Background technology
Neuraminidase is present in the surface of the virion such as many influenza viruses, parainfluenza virus, mumps virus.Because it can be catalyzed the α -one glycoside bond crackings between terminal nerve propylhomoserin and adjacent glycosyl, destroy acceptor, virion is dissociated, so as to aggravate infection symptoms.Therefore, by suppressing the activity of neuraminidase, the surface that progeny virus departs from infection cell can be blocked, so as to prevent secondary infection.So, it is considered that it can be used for treating or preventing influenza with the material for suppressing neuraminidase activity.
Most known neuraminidase inhibitor is the analog of neuraminic acid, such as dehydrogenation-the Ν of 2- deoxidations -2,3- bis--n acetylneuraminic acid n (DANA) and its derivative.The derivative of DANA a series of is described in international patent application WO91/16320, they all have certain inhibitory activity to neuraminidase in vivo and in vitro.Other DANA derivatives are disclosed in WO98/06712, in the international patent application such as WO97/06157 WO01/81331.Zanamivir is exactly the neuraminidase inhibitor of first listing, but, because the compound polarity is very big, its oral administration biaavailability is very low (2-3%), it cannot be administered orally, it is necessary to spray is made, pass through nasal cavity inhalation-type drug administration, very big inconvenience is brought to patient medication, the production cost of preparation is also increased.On the other hand, influenza virus is also easy to produce drug resistance to marketed drug such as zanamivir, its Wei of department difficult to understand.Therefore, find new reactive compound and then to develop new anti-influenza virus medicament extremely urgent.There is the activity of inhibitory action finding new infected by influenza During compound, the inventors discovered that the novel N-acetyl-neuraminate class compound with obvious anti-influenza virus activity of a class formation.The content of the invention
Therefore, the main object of the present invention is to provide the new suppression virus of a class, particularly suppresses the N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates of influenza virus.
Another object of the present invention is to provide the preparation method of the N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates.
The a further object of the present invention is to provide a kind of effective anti-viral pharmaceutical compositions for suppressing neuraminidase.
It is yet another object of the invention to provide above-mentioned N-acetyl-neuraminate class compound or the purposes of their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates and pharmaceutical composition, the N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates and its pharmaceutical composition can effectively suppress neuraminidase, it is thus neuraminidase inhibitor, can be applied to the viral disease of correlation and its treatment of infection.
According to an aspect of the present invention, the present invention provides the N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates shown in below formula：
R1Represent OR5、 SR5、 NR5R6、 N(OR5) R6 or N (NR5R6) R6;
R2Represent H, C1-20Protective embankment base, the d_ of CM protective embankments epoxide substitution5Protective embankment base, COR5Or CONR5R6;
,N.
R3Represent N3、 NR7R8、 NHC(=NR9)NR5R10 N=PPh3 ^ R11； R4Represent COOR5、 CONR5R6Or CON (OR5)R6 ;
R5Represent H, d.H) protective embankment base, C3.8Ring protective embankment base, C2.1()Alkenyl, C2.1() alkynyl, pentafluorophenyl group, aryl, CONR14R15、 COOR14、 COR14, not necessarily replaced by one or more hydroxyl protecting group five yuan or hexa-atomic monosaccharide groups or by one or more following substituent groups.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl or.Alkynyl： NR14R15、 NR14COR15、 C02R14、 OR14、 C3_8Ring protective embankment base and aryl;
R6Represent H, Cwo protective embankment base, ring protective embankment base, Cwo alkenyls, Cwo alkynyls, aryl, COR14, not necessarily replaced by one or more hydroxyl protecting group five yuan or hexa-atomic monosaccharide groups or the C^H by one or more following substituent groups) and protective embankment base： NR14R14、 COR14, C3-8Ring protective embankment base, CN, N3、 OR14And aryl；
Or R5And R6The nitrogen-atoms being connected with them collectively forms cyclic structure, the cyclic structure can be saturated or unsaturated, and can contain one or more hetero atoms in N, 0 and S, the cyclic structure can also not necessarily by halogen, Cwo protective embankments base, d-do protective embankments epoxide, ring protective embankment base,.Alkenyl,.Alkynyl, CF3, CN or N02Substitution；
R7And R8H, CN, d. are represented independently of one another6Protective embankment base, C3.8Ring protective embankment base, C2.6Alkenyl, C2_6Alkynyl or C2_6Hydrocarbon chain, not necessarily containing a NR in the hydrocarbon chain11Group, the hydrocarbon chain is not necessarily selected from oxo base by 14（Carbonyl）And d_6The group of protective embankment base is replaced, and the d_6Protective embankment base is not necessarily replaced by hydroxyl or aryl；
R9And R1G11, d_ is represented independently of one another6Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, C2-1O alkynyls, NR14R15、 OR14, CN or N02;
R11And R12Represent independently of one another H,.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, Cwo alkynyls,.Protective embankment epoxide, COOR5、 CONR14R15Or aryl；Or not necessarily by hydroxyl, amino, amido, COOR5Or d_6The Cwo protective embankment bases of protective embankment epoxide substitution； R14And R1511, d_ is represented independently of one another6Protective embankment base, C3_8Ring protective embankment base or aryl；Wherein, the aryl refers to aromatic carbocyclic ring or heterocyclic group, and is not necessarily substituted.When the aryl is substituted, suitable substituent includes protective embankment base, d_4Protective embankment epoxide, halogen, nitro, trifluoromethyl, amino, amino, phenyl and the benzyl of the substitution of protective embankment base.Suitably, the aryl is replaced by 13 above-mentioned substituents.
Herein, protective embankment base includes the alkyl of the saturation of straight or branched.
Herein, alkenyl refers to straight or branched, the alkyl containing one or more carbon-to-carbon double bonds.
Herein, alkynyl refers to straight or branched, the alkyl containing one or more carbon-to-carbon triple bonds.
In above-mentioned definition, the compound of formula 1. can contain one or more chiral centres, therefore stereoisomer, i.e. enantiomter or diastereoisomer, or its mixture may be present.The compound of the present invention can be the single stereoisomer of general formula compound or the mixture of each stereoisomer.Can be by routine techniques by diastereomeric separation, for example, the non-enantiomer mixture Tong Guo Fen Walk crystallizations or chromatogram (including HPLC) by general formula compound or its suitable salt or derivatives thereof are separated.Also it can be prepared by corresponding optically pure intermediate or the single enantiomer of formula is prepared by fractionation, chiral post separation can be used during fractionation, or by reacting the diastereomeric salt to be formed point Walk crystallizations with optically active acid or alkali.
The pharmaceutically acceptable salt of compound refers to shown in formula of the present invention, according to the method for chemically conventional salt formation, compound shown in formula and suitable acid or the salt of alkali formation, the example of such as suitable acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic, lactic acid, salicylic acid, butanedioic acid, p-methyl benzenesulfonic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene -2- sulfonic acid and benzene sulfonic acid, other acid such as oxalic acid, although itself is not pharmaceutically acceptable, but available for the salt prepared as intermediate, the intermediate be used for prepare the compounds of this invention and its Pharmaceutically acceptable acid-addition salts；With alkali metal (such as sodium of the salt, such as formula 1. shown compound of alkali formation：), alkaline-earth metal (such as magnesium：), ammonium or NR4+(wherein R is d_4Protective embankment base:) salt.Preferably, in formula compound：
R1Represent OR5、 NR5R6Or N (OR5)R6;
R2Represent H, COR5Or CONR5R6;
R3Represent NR7R8、 NHC(=NR9)NR5R1()OrNΛ ", it is α configurations； R4Represent COOR5、 CONR5R6Or CON (OR5)R6 ;
R5And R6Represent independently of one another.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, C2_1QAlkynyl, aryl or not necessarily by one or more be selected from d-C6Five yuan or hexa-atomic monosaccharide groups of the substituent substitution in protective embankment base, trimethyl silicon substrate, benzyl and acetyl group；Or by OR14、 C3_8What ring protective embankment base or aryl replaced.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl or C3-1O block bases；
Or R5And R6The nitrogen-atoms being connected with them collectively forms cyclic structure, the cyclic structure can be saturated or unsaturated, and one or more hetero atoms in N, 0 and S can be contained, the cyclic structure can also be not necessarily by halogen, Cwo protective embankments base, d-do protective embankments epoxide, C3_8Ring protective embankment base,.Alkenyl or.Alkynyl substituted；
R7And R811, CN, d_ are represented independently of one another6Protective embankment base, C3_8Ring protective embankment base,（2_6Alkenyl, C2_6Alkynyl or (_6Hydrocarbon chain, not necessarily containing a NR in the hydrocarbon chain11Group, the hydrocarbon chain is not necessarily selected from oxo base by 14（Carbonyl）And d_6The group of protective embankment base is replaced, and the d_6Protective embankment base is not necessarily replaced by hydroxyl or aryl；
R9And R1GD. is represented independently of one another6Protective embankment base, NR14R15、 OR14, CN or N02;
R11And R12Represent H, d.u independently of one another) protective embankment base, C3.8Ring protective embankment base, COOR5Or aryl；Or not necessarily by hydroxyl, amino, amido, COOR5Or d_6Protective embankment epoxide Substitution.Protective embankment base；
R14And R1511, d_ is represented independently of one another6Protective embankment base, C3_8Ring protective embankment base or aryl；Wherein, the aryl is defined as above.It is highly preferred that in formula compound：
R1Represent NR5R6Or N (OR5)R6;
R2Represent H or COR5;
R3For α configurations；
R3Represent NR7R8Or NHC (=NR9)NR5R10;
R4Represent COOR5Or CON (OR5)R6;
R5And R6Represent independently of one another.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, C2_1QAlkynyl, rhamanopyranosyl, mannose group, glucosyl group, the protective embankment base being optionally substituted by a hydroxyl group, the C being optionally substituted by a hydroxyl group3_8Ring protective embankment base, the C being optionally substituted by a hydroxyl group3_1QAlkenyl is optionally substituted by a hydroxyl group C3_1QAlkynyl；Or R5And R6The nitrogen-atoms being connected with them collectively forms cyclic structure, and the cyclic structure can be saturated or unsaturated, it is possible to which, containing one or more hetero atoms in N, 0 and S, the cyclic structure can also be not necessarily by Cwo protective embankments base, C3_8Ring protective embankment base,.Alkenyl or.Alkynyl substituted；
R7And R8H, CN, d. are represented independently of one another6Protective embankment base, C3.8Ring protective embankment base, C2.6Alkenyl, C2_6Alkynyl or C2_6Hydrocarbon chain, not necessarily containing a NR in the hydrocarbon chain11Group, the hydrocarbon chain is not necessarily selected from oxo base by 1 or 2（Carbonyl）And d_6The group of protective embankment base is replaced, and the protective embankment base is not necessarily replaced by hydroxyl or aryl, and the aryl includes phenyl, naphthyl, pyridine radicals, imidazole radicals and thienyl, and is not necessarily substituted；When the aryl is substituted, the substituent includes protective embankment base, d_4Protective embankment epoxide, nitro, amino, phenyl and benzyl；And the substituted aryl is with 13 above-mentioned substituents；
R9And R1GC is represented independently of one another1-6Protective embankment base, N, OH, CN or N02 ;
R11And R12Represent 11, d.u independently of one another) protective embankment base, C3.8Ring protective embankment base or COOR5。 Enter again the preferred compounds of a Walk as following formula 1. shown in：
R1Represent NR5R6 ;
R2Represent H;
R3N or NHC (=NH) N is represented, it is α configurations；
R4Represent COOR5;
R5And R6Represent independently of one another.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, C2_1QAlkynyl, mannose group, glucosyl group or the Cwo protective embankment bases being optionally substituted by a hydroxyl group；Or R5And R6The nitrogen-atoms being connected with them collectively forms cyclic structure, and the cyclic structure can be saturated or unsaturated, it is possible to which, containing one or more hetero atoms in N, 0 and S, the cyclic structure can also be not necessarily by Cwo protective embankments base, C3_8Ring protective embankment base, C2_1QAlkenyl or C2_1QAlkynyl substituted.Such as the cyclic structure can be morpholinyl, thiomorpholine base, piperazinyl.Particular compound specifically preferred according to the invention includes：
(2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-methylamino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid (compound of embodiment 22),
(2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-methylamino -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid (compound of embodiment 23),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid (compound of embodiment 24),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid (compound of embodiment 25),
(2 chi ^, ^) -3- acetamidos -2- [(- 1,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- methyl formates (compound of embodiment 27),
(2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-ethylamino- -2,-oxygen ethyl] -4- amino - 3,4- dihydropyran -6- formic acid (compound of embodiment 28),
(2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-ethylamino- -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid (compound of embodiment 30),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-diethylin -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid (compound of embodiment 31),
(2 chi ^, ^) -3- acetamidos -2- [(- 1,-acetoxyl group -2,-diethylin -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- methyl formates (compound of embodiment 32),
(2 chi ^, ^) -3- acetamidos -2- [(- 1,-acetoxyl group -2,-diethylin -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- methyl formates (compound of embodiment 34),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-diethylin -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid (compound of embodiment 35),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid (compound of embodiment 36),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid (compound of embodiment 37),
(2, ^, ^ 3- acetamidos -2- [05) -1,-hydroxyl -2,-amino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid（The compound of embodiment 42),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-isopropylamine base -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid (compound of embodiment 43),
(2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-azanol base -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid (compound of embodiment 44),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-cyclohexylamino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid（The compound of embodiment 45),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-cyclohexyl amido -2,-oxygen ethyl] -4- ammonia Base -3,4- dihydropyran -6- formic acid (compound of embodiment 47),
(2, ^, ^ 3- acetamidos -2- [05) -1,-hydroxyl -2,-amino -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid (compounds of embodiment 48：)、
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-isopropylamine amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid (compound of embodiment 49),
(2 chi ^, ^) and -3- acetamidos -2- [(- 1,-hydroxyl -2,-two（Ethoxy）Amido -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid (compound of embodiment 116),
(2R, ^S 3- acetamidos -2- [C)-l,-hydroxyl -2,-two（Ethoxy）Amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
(2i R, ^S 3- acetamidos -2- [(5 1,-hydroxyl -2,-ethoxy amido -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid (；The compound of embodiment 117),
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-ethoxy amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid (compound of embodiment 120),
(2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid (compounds of embodiment 118:)、
(2R, 3R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- methyl formates (compound of embodiment 121),
(2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid (compounds of embodiment 123：)、
(2i R, ^S 3- acetamidos-2- [(5)-1,-hydroxyl-2,-(tetrahydrochysene-2,4,5- trihydroxies-6- (methylol)-2-pyrans-3- bases amino)-2 ,-oxygen ethyl]-4- amino-3,4- dihydropyran-6- formic acid (compound of embodiment 119) and
(2R, ^S 3- acetamidos-2- [(5 1 ,-hydroxyl-2 ,-(tetrahydrochysene-2,4,5- trihydroxies-6- (methylol)-2-pyrans-3- bases amino)-2 ,-oxygen ethyl]-4- guanidine radicals-3,4- dihydropyran-6- formic acid.
Ben is invented to be included into the particularly preferred particular compounds of Yi Walk： (2R, ^S 3- acetamidos -2- [(5)-Γ-hydroxyl -2,-dimethylamino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
(2R, ^ 3- acetamidos -2- [(- 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
(2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-diethylin -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
(2R, ^ 3- acetamidos -2- [(5 1,-hydroxyl -2,-diethylin -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
(2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
(2R, ^S 3- acetamidos -2- [(5 1,-hydroxyl -2,-two（Ethoxy）Amido -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
(2R, ^S 3- acetamidos -2- [C)-r- hydroxyl -2,-two（Ethoxy）Amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
(2R, ^S 3- acetamidos -2- [(5 1,-hydroxyl -2,-ethoxy amido -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
(2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-ethoxy amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
( R, ^ 3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
(2R, ^S) -3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
(2R, ^S 3- acetamidos-2- [(5)-1 ,-hydroxyl-2,-(tetrahydrochysene-2,4,5- trihydroxies-6- (methylol)-2-pyrans-3- bases amino)-2,-oxygen ethyl]-4- amino-3,4- dihydropyran-6- formic acid and (2R, ^S 3- acetamidos -2- [(5 1,-hydroxyl -2,-(tetrahydrochysene -2,4,5- trihydroxies -6- (hydroxyl first Base)-2-pyrans-3- bases amino)-2 ,-oxygen ethyl]-4- guanidine radicals-3,4- dihydropyran-6- formic acid.According to another aspect of the present invention, the present invention provides the N-acetyl-neuraminate class compound shown in formula or the preparation method of their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, and this method includes any one of following methods：
(1) as R in logical formula (I) compound1For OH, R2It is not H, R3For N3, R4For COOR5, and R5When being not H; that is formula (la) compound; can be by leading to formula (II) compound (Carbohydrate Research; 2008,343,14; 2459-2462.) prepared by oxicracking; if desired, being then deprotected, lead to the R of formula (II) compound2And R4Substituent definition is with logical formula (I) compound：
(II) (la)
Oxicracking is completed suitably by Liang Walk.Suitably mono- Walk are completed using periodate, such as use sodium metaperiodate, are suitably completed in suitable solvent, such as water-containing organic solvent, such as aqueous methanol.Suitable agent for oxicracking bis- Walk can be chlorite, such as sodium chlorite, it suitably there are buffer, such as alkali metal or alkali earth metal phosphate, such as potassium dihydrogen phosphate, and in water-containing organic solvent, such as aqueous mixture of alcohol and hydrocarbon, the aqueous mixture of such as tert-butyl alcohol and cyclohexene.
(2) as R in logical formula (I) compound1For OR5Or SR5When, i.e. formula (Ic) compound can pass through corresponding formula (ib) compound（R in general formula compound1Represent OH) and quilt
R5The oxygen-containing or sulfur-containing compound of substitution is prepared by condensation reaction：
(lb) (lc) (R1=OR5,SR5、
(3) as R in logical formula (I) compound1For NR5R6、 N(OR5) R6 or N (NR5R6) R6When, i.e. formula (Id) compound can pass through corresponding formula (lb) compound（R in general formula compound1Represent OH) and-R5R6、 -(OR5)R6Or-(NR5R6)R6Substituted nitrogen-containing compound reacts to prepare.Suitably, carboxyl is activated before being reacted with amine.Appropriate activation method is clear for those skilled in the art, and including for example changing into phenyl-pentafluoride epoxide.Aminating reaction can be completed easily in appropriate organic solvent, such as in ether, such as in THF.
(lb) (Id) (R1=NR5R6,N(OR5)R6, N(NR5R6)R6、
(4) when in logical formula (I) compound R be When, i.e. formula (if) compound can pass through corresponding formula (Ie) compound（R in general formula compound3Represent N3) and by R11With
R12Substituted acetylene compound reacts to prepare.Suitably, preparing needs to carry out under catalyst.Appropriate catalysis process will readily suggest themselves to those skilled in the art, such as cuprous ion catalysis.
(5) as R in logical formula (I) compound3During for N, i.e. formula (Ig) compound can pass through corresponding formula (Ie) compound（R in general formula compound3Represent N3) prepared by the reduction reaction of azido：
(le) (ig)
Can be using any of method completion reduction reaction that azido compound is transformed into amine.Appropriate method description is described in the examples below, and in such as International Patent Application Publication WO93/12105 and WO95/00503.Suitably, using Lindlar catalysts, the compound reduction that hydrogen or formic acid etc. can provide reactive hydrogen completes reaction.
(6) as R in logical formula (I) compound3For NR7R8When, i.e. formula (Ih) compound can be from formula (Ig) compound（R in general formula compound3For N) by with by R7And R8Substituted compound reacts to prepare, such as with containing R7And R8Halide, acid anhydrides, acyl halide derivative of substituent etc. react to prepare through conventional N functions dough, but not limited to this.Appropriate preparation method will readily suggest themselves to those skilled in the art.
(7) as R in logical formula (I) compound3For NHC (=NR14)NR15R16When, i.e. formula (Π) compound can be from formula (Ih) compound（The R of formula 1. in compound3For NR7R8) logical Guanidinated reaction is crossed to prepare.Appropriate introducing guanidine radicals and its method for derivative will readily suggest themselves to those skilled in the art.Especially as R in general formula compound3For NHC (=NH:>NH2When, i.e. formula (Ik) compound for example passes through formula (Ig) compound（R in general formula compound3For N) and guanylpyrazole or its salt or derivative（It is preferred that guanylpyrazole）Intermediate formula (Ij) compound is passed through in reaction（R in logical formula (I) compound3For NHCN) prepare.
(8) as R in logical formula (I) compound3Represent N3, R4For CONR5R6When, i.e. formula (Im) compound can pass through and lead to formula (II) compound accordingly（R in general formula compound3Represent
N3, R4For COOR5, and R5It is not H) react and obtain with the basic salt of azanol or derivatives thereof.Appropriate method for transformation is clear for those skilled in the art, and including for example using N OH/KOH.
9) formula (Ih) compound（Wherein R3For NR7R8) or formula (Ii) compound (wherein R3For NHC (=NR14)NR15R16:) can also be from formula (Im) compound（R in logical formula (I) compound3Represent N3, R4For CONR5R6) by with the above method（5) similar azido restoring method is reduced, and then Jin mono- Walk react to prepare.Appropriate preparation method will readily suggest themselves to those skilled in the art.
(10) the other compounds of formula 1. can be prepared by mutually being converted by the functional group between formula different compounds 1..For example, wherein R2It can be prepared for H compound by not being H compound； R7And R8Corresponding R can not passed through for H compound7And/or R8Prepared for H compound； R4For COOR5、 CONR5R6Or CON (OR5)R6Compound can be with R4Mutually converted for COOH compound.
It will be understood by those skilled in the art that in order to prevent side reaction, one or more of protection molecule sensitive group may be needed in any stage of the above method；In any of reaction sequence Appropriate later stages can remove protectiveness group.
Protectiveness group for preparing general formula compound can use conventional method.For example, see " Greene's protective groups in organic synthesis ", Peter G. M. Wuts standing grain mouthful Theodora W. Greene (A John Wiley ＆ Sons, Inc., 2007).
Traditional amido protecting group can include：Such as fragrant protective embankment base, such as benzyl, diphenyl methyl or trityl group；And acyl group, such as N- benzyloxycarbonyls or tert-butoxycarbonyl.
Hydroxyl can be by following radical protection：Such as fragrant protective embankment base, such as benzyl, diphenyl methyl or trityl group；Acyl group, such as acetyl group；Silicon protectiveness group, such as trimethyl first silicon protective embankment base, or be used as tetrahydrofuran derivatives.
Carboxylic acid group can be suitably protected as methyl esters or diphenyl methyl esters.
Any protectiveness group existed can be removed with conventional method.
When needs are with salt, such as when the form of acid-addition salts isolates the compounds of this invention, this (can preferably use the acid of equivalent by using appropriate acid：) handle the free alkali of formula 1. to complete.
According to another aspect of the invention, the pharmaceutical composition of the present invention contains N-acetyl-neuraminate class compound or their any prodrug forms shown in one or more above-mentioned formulas of therapeutically effective amount, their officinal salt or pharmaceutical acceptable solvates, and one or more pharmaceutical acceptable carrier or diluent.
In accordance with a further aspect of the present invention, 1. compound can be as prodrug forms application, so as to improve bioavilability or improve the physicochemical property of such compound for formula.Such as in general formula compound R4Represent COOR5(R5Be H) compound can also be used as R4Represent the prodrug forms of COOH compound.The polarity reduction of compound, is conducive to patient to be administered orally.
The N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates of the present invention and its pharmaceutical composition can effectively suppress nerve Due to the variability of influenza virus, current existing neuraminidase inhibitor gradually produces drug resistance, heretofore described is the novel compounds with neuraminic acid enzyme inhibition activity and internal anti-influenza virus activity, and with the relatively high bioavilability being expected, possible drug candidate and more more options are provided for the prevention and treatment of influenza.Embodiment
The following example Jin mono- Walk explain the compound of the present invention and its synthesis of intermediate, but do not limit the scope of the invention.
^ NMR are in Mercury-400 nuclear magnetic resonance chemical analysers (Varian companies：) on complete,lU NMR observing frequency is 300MHz or 400MHz.Conventional abbreviations are as follows：S, it is unimodal；D, it is bimodal；T, triplet；Q, quartet；M, multiplet.Mass spectroscopy is in MAT-95 types mass spectrograph (Thermo Finnigan companies）It is upper to complete, ionize mode EI 70V, 200 °C of source temperature, LR resolution ratio 1000.High resolution mass spectrum is by Finnigan MAT, Bruker Daltonics FTMS-7 type Instrument measurings.
Embodiment 1 (^)-[(2 ^) -3- acetamido -4- azidos -6- (methoxycarbonyl group -3,4- dihydropyran -2,】- 2- acetoxy acids
7-0- acetyl group-N- acetyl group -2,4- dideoxy -2,3- dehydrogenation -4a- azido-D- neuraminic acid methyl esters (1.6 g; 4.3 mmol) (Carbohydrate Research, 2008,343; 12,2459-2462.) it is dissolved in CH3In OH and 0 (48 mL and 16 mL) mixed solution, NaI0 is added4(1.84 g, 8.6 mmol, 2.0 eq.), are stirred at room temperature after 30 min, filtering, and be concentrated under reduced pressure to obtain white solid.White solid is dissolved in t-BuOH (27 mL;) in, cyclohexene (2.7 mL) is added, NaC10 is then added into system again2(2.87 g) K P04Water (18.5 mL) solution of (2.87 g).Solution is changed into bright orange-yellow from colourless, is stirred at room temperature after 2 h, stops reaction.Ethyl acetate (50 mL) and O (100 mL) are added into reaction solution, point liquid discards acetic acid Methacrylate layer, water layer is adjusted after pH=l 2 with 6 M HC1 solution, is extracted with ethyl acetate (75 mL x 5), merges organic phase, anhydrous MgS04After drying, filtering, be concentrated under reduced pressure white solid the g of title compound 1.765, yield： 100%.
¾ NMR (300 MHz, DMSO): δ 8.19 (1 H, d, J = 9.3 Hz, NH), 5.89 (1 H, d, J = 2.5 Hz, 3-H), 5.22 (1 H, d, J = 2.1 Hz, 7-H), 4.56 (1 H, dd, J = 2.1 Hz, J = 10.9 Hz, 6-H), 4.43 (1 H, dd, J =2.3 Hz, J = 9.4 Hz, 4-H), 4.07 (1 H, d, J = 10.5 Hz, 5-H), 3.71 (3 H, s, CH3), 2.05 (3 H, s, OAc), 1.79 (3 H, s, NAc); HRMS(ESI):M/z calculated values： C13H16N408[M+H]+357.1. measured values： 356.3.(2 3 the ^) -3- acetyl of embodiment 2 female -2- [(5)-l,-acetoxyl group -2,-phenyl-pentafluoride epoxide -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
The compound of embodiment 1 (855 mg, 2.4 mmol) is dissolved in DMF (8 mL), pyridine (0.2 mL, 2.5 mmol, l leq.) and CF is added3COOC6F5(l . l l mL, 0.63 g/mL,
2.5 mmol, l l eq.), it is stirred at room temperature after 2 h, stops reaction.Ethyl acetate (32 mL) is added into reaction solution, successively with 1 M HC1 (30 mL 3), saturation NaHCO3(30 mL 3), saturation NaCl solution (30mL x 1) are washed, anhydrous MgS04After drying, filtering, be concentrated under reduced pressure into has solid precipitation just, and petroleum ether, which is added dropwise, to be made to crystallize to obtain the mg of title compound 523, yield： 42%
¾ NMR (300 MHz, CDC13): δ 6.05 (1 H, d, J = 2.6 Hz, 3-H), 5.78 (1 H, d, J = 2.7 Hz, 7-H), 5.61 (1 H, d, J = 8.7 Hz, NH), 4.99 (1 H, dd, J =
2.6 Hz, J = 10.4 Hz, 6-H), 4.47 (1 H, dd, J = 2.7 Hz, J = 9.2 Hz, 4-H), 4.09 (1 H, dd, J = 9.1 Hz, J = 19.0 Hz, 5-H), 3.81 (3 H, s, CH3), 2.27 (3 H: s, OAc), 2.06 (3 H, s, NAc); LRMS(ESI): m/z [M+H]+ = 544.9。 Female-the 2- of (2 3 the ^) -3- acetyl of embodiment 3 [(5)-l,-acetoxyl group -2,-first female -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
By the compound of embodiment 1 (35 mg, 0.1 mmol) and 1- ethyls -3- (3- dimethylamine propyls) carbodiimide (EDCI) (21 mg, 0.11 mmol) it is dissolved in THF (0.5 mL), I-hydroxybenzotriazole (HOBtX15 mg are added under the conditions of frozen water cooling, 0.11 mmol), it is stirred at room temperature after 10 min, add the aqueous solution (12 μ of methylamine, 0.11 mmol), TLC displays reaction is complete after 2.5 h, stops reaction.It is concentrated under reduced pressure into dry, column chromatography for separation (C C12: CH3OH = 60:Kv/v the mg of title compound 27 of white solid, yield)) are obtained： 75%.
¾ NMR (400 MHz, CDC13): δ 7.26 (1 H, d, J = 8.9 Hz, NHCO), 6.49 (1 H, d, J = 4.7 Hz, NH), 5.91 (1 H, d, J = 2.2 Hz, 3-H), 5.40 (1 H, d, J = 1.7 Hz, 7-H), 4.49 (1 H, dd, J = 1.8 Hz, J = 8.7 Hz, 6-H), 4.35 (1 H, dd, J = 9.4 Hz, J = 9.8 Hz, 5-H), 4.26 (1 H, dd, J = 2.4 Hz, J = 6.7 Hz, 4-H), 3.77 (3 H, s, CH3), 2.87 (1 H, d, NHCH3), 2.22 (3 H, s, OAc), 1.97 (3 H, s, NAc); 13C NMR (400 MHz, CDC1320.82 (OCOCH): 3), 23.00 (NHCOCH3), 26.26 (NHCH3), 48.45 (C-5), 52.53 (OCH3), 58.80 (C-4), 70.59 (C-7), 77.32 (C-6), 108.34 (C-3), 144.70 (C-2), 161.47 (COO), 168.90 (C=0), 169.84 (C=0), 170.61 (C=0)。
Female-the 2- of (2 the ^^) -3- acetyl of embodiment 4 [(5) -1,-acetoxyl group -2,-second female -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
According to method same as Example 3, methylamine is replaced to prepare title compound yield using ethamine： 67%. ¾ NMR (300 MHz, CDC13): δ 6.53 (1 H, d, J = 9.4 Hz, NH), 6.32 (1 H, m, NH), 5.95 (1 H, d, J = 2.4 Hz, 3-H), 5.42 (1 H, d, J = 1.9 Hz, 7-H), 4.53 (1 H, dd, J = 2.1 Hz, J = 10.4 Hz, 6-H), 4.33 (1 H, dd, J = 9.4 Hz, J = 19.1 Hz, 5-H), 4.25 (1 H, dd, J = 2.5 Hz, J = 8.9 Hz, 4-H), 3.78 (3
H, s, CH3), 3.49 (1 H, m, CH), 3.22 (1 H, m, CH), 2.24 (3 H, s, OAc),
I .98 (3 H, s, NAc), 1.20 (3 H, t, J = 7.1 Hz, CH3); HRMS(ESI):M/z calculated values： C15H22N507[M+H]+384.1519, measured value： 384.1535.Embodiment 5 (2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-amino -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
The compound of embodiment 2 (369 mg, 0.73 mmol) is dissolved in THF (15 mL), ammonia methanol (0.2 mL, 0.87 mmol, 1.2 eq.) is slowly added into, is stirred at room temperature after 30 min, stops reaction.After being concentrated under reduced pressure, column chromatography for separation EtOAc:Petroleum ether=1:L v/v) obtain the mg of title compound 206, yield： 80%.
¾ NMR (300 MHz, CDC13):δ 6.59 (1 H, s, NH), 6.49 (1 H, s,), NH 6.06 (1 H, d, J=6.6 Hz, NH), 5.96 (1 H, s, 3-H), 5.44 (1 H, s, 7-H), 4.56 (1 H, d, J=5.1 Hz, 6-H), 4.28 (1 H, s, 4-H standing grain mouthful 5-H), 3.79 (3 H, s, CH3), 2.23 (3 H, s, OAc), 1.98 (3 H, s, NAc); LRMS(ESI): mlz [M+Na]+ = 378.0.(2 the ^^) -3- acetyl of embodiment 6 female -2- [(5) -1,-acetoxyl group -2,-dimethylamino -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
According to method same as Example 5, use Inscribe compound；Yield： 86%.
¾ NMR (300 MHz, CDC13): δ 6.24 (1 Η, d, J = 6.8 Hz, NH), 6.05 (1 H, d, J = 3.6 Hz, 7-H), 5.87 (1 H, d, J = 2.1 Hz, 3-H), 4.74 (1 H, t, J = 6.5 Hz, 4-H), 4.58 (1 H, dd, J = 3.7 Hz, J = 6.3 Hz, 6-H), 4.12 (1 H, dd, J = 7.1 Hz, J = 14.4 Hz, 5-H), 3.81 (3 H, s, CH3), 3.13 (3 H, s, CH3), 2.99 (3 H, s, CH3), 2.15 (3 H, s, OAc), 1.99 (3 H, s, NAc); HRMS (EI):M/z calculated values： C15H22N507[M+H]+ 384.1519;Measured value： 384.1527.(2 3 the ^) -3- acetyl of embodiment 7 female -2- [(5)-l,-acetoxyl group -2,-diethylin -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
According to method same as Example 5, ammonia methanol is replaced to prepare title compound using diethylamide；Yield： 90%.
¾ NMR (300 MHz, CDC13): δ 6.29 (1 H, d, J = 7.5 Hz, NH), 6.05 (1 H, d, J = 3.6 Hz, 3-H), 5.87 (1 H, d, J = 6.3 Hz, 7-H), 4.75 (1 H, t, J = 6.3 Hz, 6-H), 4.56 (1 H, dd, J = 3.6 Hz, J = 6.3 Hz, 4-H), 4.03 (1 H, dt, J = 6.9 Hz, J = 13.8 Hz, 5-H), 3.80 (3 H, s, CH3), 3.37 (4 H, m, 2CH2), 2.15 (3 H, s, OAc), 1.99 (3 H, s, NAc), 1.15 (6 H, m, 2CH3); LRMS(EI): mlz [M+H]+ = 412.0.Female-the 2- of (2 3 the ^) -3- acetyl of embodiment 8 [(5)-l,-acetoxyl group -2, female -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
By the compound of embodiment 2 (2R, 3R, ^) -3- acetamidos -2- [C)-r- acetoxyl group -2,-phenyl-pentafluoride epoxide -2,-oxygen ethyl] -4- azido -3,4- dihydropyran -6- methyl formates (200 mg, 0.04 mmol) it is dissolved in THF (5 mL), add hydroxylamine hydrochloride (30 mg, 0.043 mmol, 1.1 eq.) and diisopropylethylamine (DIPEA) (7.5 μ, 0.043 mmol, 1.1 eq.), it is stirred at room temperature after 30 min, stops reaction.After being concentrated under reduced pressure, column chromatography for separation EtOAc) obtain the mg of title compound 131, yield： 92%.
¾ NMR (300 MHz, D20): δ 6.20 (1 H, d, J = 2.8 Hz, 3-H), 5.57 (1 H, d, J = 2.2 Hz, 7-H), 4.66 (1 H, t, J = 2.1 Hz, J = 10.5 Hz, 6-H), 4.51 (1 H, dd, J = 2.9 Hz, J = 9.6 Hz, 4-H), 4.29 (1 H, t, J = 9.9 Hz, 5-H), 3.89 (3 H, s, CH3), 2.28 (3 H, s, OAc), 2.09 (3 H, s, NAc) ; LRMS(ESI): mlz [M+Na]+ = 478.1.Embodiment 9 (2 3 ^) -3- acetyl JKS-2- [(5)-l,-acetoxyl group -2,-cyclopentamine base -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
According to method same as Example 5, ammonia methanol is replaced to prepare title compound using cyclopentamine；Yield： 98%.
¾ NMR (300 MHz, CDC13): δ 6.78 (1 H, d, J = 8.3 Hz, NH), 5.99 (1 H, d, J = 3.0 Hz, 3-H), 5.56 (1 H, d, J = 4.4 Hz, 7-H), 4.66 (1 H, dd, J = 4.8 Hz, J = 9.1 Hz, 6-H), 4.56 (1 H, dd, J = 2.8 Hz, J = 7.8 Hz, 4-H), 4.11 (1 H, dt, J = 8.5 Hz, J = 16.5 Hz, 5-H), 3.69 (4 H, m, 2CH2), 3.79 (3 H, s, CH3), 2.16 (3 H, s, OAc), 1.99 (3 H, s, NAc), 1.92 (4 H, m, 2CH2); LRMS(ESI): mlz [M+H]+= 410.0.Female-the 2- of (2 3 the ^) -3- acetyl of embodiment 10 [(5) -1,-acetoxyl group -2,-diformazan female -2,-oxygen ethyl】- 4- azido-N base -3,4- dihydropyran -6- formamides The compound of embodiment 6 (100 mg, 0.26 mmol) is dissolved in CH3In OH (5mL), NH is added2OH/KOH/CH3OH solution (1.0 mL, 0.72 mmol), is stirred at room temperature after lOmin, and TLC display reactions are complete, add glacial acetic acid regulation system pH=6.5.Title compound reaction solution, can without processing, Zhi connect for Xia Walk reaction.
HRMS(ESI):M/z calculated values： C12H18N606Na [M+Na]+365.1186, measured value： 365.1181.Female-the 2- of (2 ^, the ^) -3- acetyl of embodiment 11 [(5) -1,-hydroxyl -2,-diformazan female -2,-oxygen ethyl】- 4- amino-N base -3,4- dihydropyran -6- formamides
Lindlar lO mg are added into the reaction solution of embodiment 10) catalyst, room temperature normal pressure hydrogenation reacted after 48 h, and TLC display reactions are complete, stop reaction, and glacial acetic acid regulation system pH=6.5 are added to reaction system.After being filtered with diatomite, reversed-phase silica gel column chromatography separates to obtain the mg of title compound 16, yield： 20%.
¾ NMR (300 MHz, D20): δ 5.76 (1 H, d, J = 2.3 Hz, 3-H), 4.56 (1 H, dd, J = 2.0 Hz, J = 9.8 Hz, 6-H), 4.37 (1 H, t, J = 9.5 Hz, 5-H), 4.31 (1 H, dd, J = 2.2 Hz, J = 9.6 Hz, 4-H), 3.14 (3 H, s, CH3), 3.05 (3 H, s, CH3), 2.15 (3 H, s, NAc); HRMS(ESI):M/z calculated values： C12¾。N406Na [M+Na]+339.1281, measured value：339.1266 ο embodiments 12 (2 ^) -3- acetyl JKS-2- [(5)-l,-acetoxyl group -2,-methylamino -2,-oxygen ethyl】- 4- [4, methyl isophthalic acid, 2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
By the compound of embodiment 3 (60 mg, 0.16 mmol) ethanol water (0.5 mL) is dissolved in, add propilolic alcohol (11 μ, 0.16 mmol), add SODIUM ASCORBATE (0.38 mL newly prepared, 30% mmol, 25 mg/mL), the cupric sulfate pentahydrate aqueous solution (0.21 mL, 5% mmol, 0.4 mg/mL), under the conditions of lucifuge, 18 h are stirred at room temperature, solvent is removed under reduced pressure.With ethyl acetate:Methanol=25:1/it is eluant, eluent, column chromatography for separation obtains title compound (48 mg, 70%)
¾ NMR (400 MHz, CDC13):δ 7.72 (1 H, s, CH), 7.44 (1 H, d, J=9.2 Hz, NH), 6.42 (the Hz of 1 H, d, J=4.1, NH), 6.03 (1 H, d, J=2.1 Hz, 3-H), 5.71 (1 H, the Hz of dd, J=2.5 Hz, J=10.6,4-H), 5.61 (1 H, s, 7-H), 4.85 (1 H, d, J=1.3 Hz, J=10.7 Hz, 6-H), 4.77 (2 H, s, CH2), 4.56 (1 H, dt, J = 10.5 Hz, J = 20.1 Hz, 5-H), 3.79 (3 H, s, CH3), 2.91 (3 H, d, J = 4.8 Hz, CH3), 2.18 (3 H, s, OAc), 1.80 (3 H, s, NHAc);HRMS (EI) m/z calculated values： Ci7H23N508 [M]+425.1547, measured value： 425.1512.
(2 the ^) -3- acetyl of embodiment 13 female -2- [(5) -1, base -2,-first JKS-2,-oxygen ethyl】- 4- [4, methyl isophthalic acid, 2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
The compound of embodiment 12 (20 mg, 0.04 mmol) is dissolved in methanol (0.4 mL), NaOH methanol solution (0.17 mL, 0.16 mmol, 24 mg/mL) is then added.It is stirred at room temperature after 2 h, TLC display reactions are complete, then adds the (H of Dowex 50W x 8+), regulation system pH is 7.After filtering, be concentrated under reduced pressure to obtain title compound (16 mg, 92%).
¾ NMR (400 MHz, DMSO):δ 8.27 (1 H, d, J=8.8 Hz, NH), 7.90 (1 H, s, CH), the 7.79 (Hz of 1 H, d, J=4.8,), 5.81 NH (the Hz of 1 H, d, J=2.3,3-H), 5.57 (the Hz of 1 H, dd, J=1.9, J=9.7 Hz, 4-H), 4.51 (2 H, m, 6-H and 7-H), 4.47 (2 H, s, CH2), 4.29 (1 H, dt, J = 10.2 Hz, J = 18.1 Hz, 5-H), 2.62 (2 H, d, J = 3.7 Hz, CH3), 1.75 (3 H, s, NHAc); HRMS(ESI): [M+H]+ = 369.9;HRMS (EI) m/z calculated values： C14H21N507Na [M+Na]+392.1182, measured value： 392.1170.
[(5) -1,-acetoxyl group -2,-methylamino -2,-oxygen ethyl foretells 4- [4,-methoxycarbonyl group -1,2,3- triazoles -1 to the female -2- of (2 3 the ^) -3- acetyl of embodiment 14】- 3,4- dihydropyran -6- methyl formates
According to embodiment 12 identical method, replace propilolic alcohol to prepare title compound using Methyl propiolate；Yield： 72%.
¾ NMR (400 MHz, CDC13): δ 8.26 (1 H, s, CH), 7.30 (1 H, t, J = 9.6 Hz, NH), 6.43 (1 H, d, J = 4.9 Hz, NH), 6.04 (1 H, d, J = 2.2 Hz, 3-H); 5.80 (1 H, dd, J = 2.3 Hz, J = 10.0 Hz, 4-H), 5.57 (1 H, d, J = 1.6 Hz, 7-H), 4.90 (1 H, dd, J = 1.7 Hz, J = 10.8 Hz, 6-H), 4.57 (1 H, dt, J = 9.7 Hz, J = 19.8 Hz, 5-H), 3.93 (3 H, s, CH3), 3.80 (3 H, s, CH3), 2.92 (3 H, d J = 4.8 Hz, CH3), 2.19 (3 H, s, OAc), 1.83 (3 H, s, NHAc);HRMS (EI) m/z calculated values： C18H24N509[M+H]+454.0574, measured value： 454.1603.
(2 the ^) -3- acetyl of embodiment 15 female -2- [(5) -1, base -2,-first JKS-2,-oxygen ethyl】- 4- [4,-carboxyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
According to the identical method of embodiment 13, prepare title compound by raw material of the compound of embodiment 14；Yield： 92%.
¾ NMR (400 MHz, DMSO): δ 8.63 (1 H, s, CH), 7.82 (1 H, m, NH), 5.91 (1 H, d, J = 2.3 Hz, 3-H), 5.60 (1 H, dd, J = 1.9 Hz, J = 9.8 Hz, 4-H), 4.58 (1 H, d, J = 11.3 Hz, 6-H), 4.33 (1 H, m, 5-H), 4.09 (1 H, s, 7-H), 2.64 (5 H, d, J = 3.6 Hz, CH3), 1.74 (3 H, s, NHAc);HRMS (ESI) m/z calculated values： C14H17N508Na [M+Na]+406.0975, measured value： 406.0991.
(2 3 the ^) -3- acetyl of embodiment 16 female -2- [(5) -1,-acetoxyl group -2,-methylamino -2,-oxygen ethyl】- 4- [4,-(3 "-aminophenyls -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
According to embodiment 12 identical method, replace propilolic alcohol to prepare title compound using phenylacetylene；Yield： 61%.
¾ NMR (400 MHz, CDC13): δ 7.92 (1 H, s, CH), 7.82 (2 H, d, J = 7.3 Hz, PhH), 7.43 (2 H, t, J = 7.3 Hz, PhH), 7.34 (1 H, t, J = 7.3 Hz, PhH), 6.98 (1 H, d, J = 9.7 Hz, NH), 6.37 (1 H, d, J = 5.5 Hz, NH), 6.09 (1 H, d, J = 2.4 Hz, 3-H), 5.79 (1 H, dd, J = 2.6 Hz, J = 10.1 Hz, 4-H), 5.61 (1 H, d, J = 1.5 Hz, 7-H), 4.88 (1 H, dd, J = 1.9 Hz, J = 10.6 Hz, 6-H), 4.66 (1 H, dt, J = 9.9 Hz, J = 20.0 Hz, 5-H), 3.81 (3 H, s, CH3), 2.93 (3 H, d, J = 5.1 Hz, CH3), 2.22 (3 H, s, OAc), 1.82 (3 H, s, NHAc);HRMS (EI) m/z calculated values： C22H26N507 [M+H]+472.1832, measured value：472.1809 embodiment 17 (2 ^) -3- acetyl female -2- [(5) -1, base -2,-first JKS-2,-oxygen ethyl】- 4- [4,-(3,-aminophenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
According to the identical method of embodiment 13, prepare title compound by raw material of the compound of embodiment 16；Yield： 90%.
¾ NMR (400 MHz, DMSO): δ 8.59 (1 H, s, CH), 8.25 (1 H, d, J = 8.7 Hz, NH), 7.85 (2 H, d, J = 7.8 Hz, PhH), 7.80 (1 H, d, J = 4.8 Hz, NH), 7.42 (2 H, t, J = 7.5 Hz, PhH), 7.31 (1 H, t, J = 7.5 Hz, PhH), 5.90 (1 H, d, J = 2.0 Hz, 3-H), 5.61 (1 H, d, J = 10.0 Hz, 4-H), 4.59 (1 H, d, J = 11.1 Hz, 6-H), 4.31 (1 H, dt, J = 10.0 Hz, J = 20.5 Hz, 5-H), 4.08 (1 H, s, 7-H), 2.64 (3 H, d, J = 3.7 Hz, CH3), 1.74 (3 H, s, NHAc); HRMS(ESI): [M+H]+= 415.9;HRMS (EI) m/z calculated values： C19H21N506Na [M+Na]+438.1390, measured value：438.1367 embodiment 18 (2 3 ^-3- acetamidos -2- [(5) -1,-acetoxyl group -2,-ring penta female -2,-oxygen ethyl】- 4- [4,-methoxycarbonyl group -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
According to embodiment 12 identical method, using the compound of embodiment 9 as raw material, replace propilolic alcohol to prepare title compound using Methyl propiolate；Yield： 55%.
¾ NMR (400 MHz, DMSO): δ 8.86 (1 H, s, CH), 6.08 (1 H, d, J = 2.7 Hz, 3-H), 5.61 (1 H, dd, J = 2.3 Hz, J = 9.6 Hz, 6-H), 5.31 (1 H, d, J = 2.4 Hz, 7-H), 4.74 (1 H, dd, J = 2.7 Hz, J = 10.3 Hz, 4-H), 4.39 (1 H, t, J = 10.0 Hz, 5-H), 3.87 (1 H, m, CH), 3.83 (3 H, m, CH3), 3.74 (3 H, m, CH3), 3.31 (3 H, m, CH2 + CH), 2.04 (3 H, s, OAc), 1.87 (4 H, m, 2CH2), 1.66 (3 H, s, NHAc); HRMS(ESI): [M]+ =494.0, 516.1;HRMS (ESI) m/z calculated values： C21H27N509Na [M-H]+516.1706, measured value： 516.1714.
(2 the ^) -3- acetyl of embodiment 19 female -2- [(5) -1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl】- 4- [4,-carboxyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
According to the identical method of embodiment 13, prepare title compound by raw material of the compound of embodiment 18；Yield： 76%.
¾ NMR (400 MHz, DMSO): δ 8.62 (1 H, s, CH), 5.87 (1 H, d, J = 2.1 Hz, 3-H), 5.60 (1 H, d, J = 2.2 Hz, J = 9.5 Hz, 6-H), 4.56 (1 H, dd, J = 2.4 Hz, J = 10.3 Hz, 4-H), 4.33 (1 H, d, J = 2.1 Hz, 7-H), 4.24 (1 H, t, J = 9.8 Hz, 5-H), 3.74 (1 H, m, CH), 3.30 (3 H, m, CH2 + CH), 1.80 (4 H, m, 2CH2), 1.71 (3 H, s, NHAc); HRMS(ESI): [M+H]+= 424.0, 445.9;HRMS (ESI) m/z calculated values： C17H21N508Na [M+Na]+446.1288, measured value：(2 3 ^-3- acetamidos -2- [(5) -1,-acetoxyl group -2,-cyclopentamine base -2,-oxygen ethyls of 446.1266 embodiment 20】- 4- [4,-(3 "-aminophenyls -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
According to the identical method of embodiment 12, using the compound of embodiment 9 as raw material, use Cyclopropyl acethlene replaces propilolic alcohol to prepare title compound；Yield： 38%.
¾ NMR (400 MHz, DMSO): δ 7.83 (1 H, s, CH), 5.97 (1 H, d, J = 2.4 Hz, 3-H), 5.47 (1 H, dd, J = 2.6 Hz, J = 9.5 Hz, 6-H), 5.25 (1 H, d, J = 2.8 Hz, 7-H), 4.68 (1 H, dd, J = 2.5 Hz, J = 9.9 Hz, 4-H), 4.27 (1 H, t, J = 10.0 Hz, 5-H), 3.82 (1 H, m, CH), 3.71 (3 H, m, CH3), 3.27 (3 H, m, CH2 + CH), 2.03 (3 H, s, OAc), 1.85 (4 H, m, 2CH2), 1.68 (3 H, s, NHAc), 0.86 (2 H, m, CH2), 0.67 (2 H, m, CH2); HRMS(ESI): [M]+ = 498.2, 510.1.(2 the ^) -3- acetyl of embodiment 21 female -2- [(5)-l,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl】- 4- [4,-(3,-aminophenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
According to the identical method of embodiment 13, prepare title compound by raw material of the compound of embodiment 20；Yield： 90%.
¾ NMR (400 MHz, CDC13): δ 7.79 (1 H, s, CH), 5.83 (1 H, d, J = 2.5 Hz, 3-H), 5.51 (1 H, d, J = 2.3 Hz, J = 9.3 Hz, 6-H), 4.55 (1 H, dd, J = 2.5 Hz, J = 10.2 Hz, 4-H), 4.29 (1 H, d, J = 2.5 Hz, 7-H), 4.13 (1 H, t, J = 9.9 Hz, 5-H), 3.75 (1 H, m, CH), 3.25 (3 H, m, CH2 + CH), 1.83 (4 H, m, 2CH2), 1.73 (3 H, s, NHAc), 0.86 (2 H, m, CH2), 0.67 (2 H, m, CH2); HRMS(ESI): [M+H]+= 420.0, 442.1;HRMS (ESI) m/z calculated values： C19H25N506Na [M]+442.1703, measured value： 442.1705.
Female-the 2- of (2 3 the ^) -3- acetyl of embodiment 22 [(S)-l, base -2,-first female -2,-oxygen ethyl】- 4- amino -3,4- dihydropyran -6- formic acid
N
By the compound of embodiment 3 (78 mg, 0.21 mmol) it is dissolved in 0.3 mL O, add 1,8- diazacyclos [5,4,0] ^-alkene -7 (DBU) (0.22 mL, 1.47 mmol, 7.0 eq.), it is stirred at room temperature after 2 h, TLC display reactions are complete.Add after Lindlar catalyst (8 mg), be passed through after 24 h of reaction to reaction system, TLC display reactions are complete, stop reaction.Insoluble matter is filtered to remove, spent ion exchange resin separates to obtain the mg of title compound 42, yield: 70% o
¾ NMR (300 MHz, D20): δ 5.71 (1 H, d, J = 2.6 Hz, 3-H), 4.53 (1 H, d, J = 10.9 Hz, 6-H), 4.42 (1 H, s, 7-H), 4.34 (1 H, t, J = 9.9 Hz, 5-H), 4.15 (1 H, dd, J = 1.4 Hz, J = 9.2 Hz, 4-H), 2.8 HN7 (3 H, s, CH3), 2.12 (3 H, s NAc); MS (ESI): mlz (%) = 287.1 (100) [M + H+]. LRMS(ESI): mlz [M+Na]+ = 288.0.Embodiment 23 2R^4S) and-^zm -2- [S)-v^-v-^-v- oxygen ethyls】- 4- guanidine radicals -3,4- dihydropyran -6- formic acid
By the compound of embodiment 22 (10 mg, 0.035 mmol) it is dissolved in 0.3 mL 0, add guanylpyrazole mono-hydrochloric salts (7.6 mg, 0.042 mmol, 1.5 eq) and imidazoles (11.8 mg, 0.17 mmol, 5.0 eq.), stir after 24 h, add 4 and drip Et3N, continues to stir after 12 h,
TLC display reactions are complete.Reaction solution spent ion exchange resin is separated off part material, then (eluant, eluent is separated with reversed-phase silica gel column chromatography：Water：) obtain the mg of title compound 8.4, yield 74%.
¾ NMR (400 MHz, D20): δ 5.64 (1 H, d, J = 2.5 Hz, 3-H), 4.54 (1H: dd, J = 1.9 Hz, J = 10.4 Hz, 6-H), 4.46 (1 H, dd, J = 2.4 Hz, J = 6.8 Hz, 4- H), 4.39 (1 H, dd, J = 2.0 Hz, J = 4.5 Hz, 7-H), 4.26 (1 H, t, J = 10.1 Hz,
5- H), 2.84 (3 H, s, CH3), 2.04 (3 H, s, NAc); LRMS(ESI): mlz [M+H]+= 330.1.Embodiment 24 2R^4S) -3,-zm -2- [S)-v^-v-^-v- oxygen ethyls】- 4- amino -3,4- dihydropyran -6- formic acid
According to the identical method of embodiment 22, prepare title compound by raw material of the compound of embodiment 6；Yield： 70%.
¾ NMR (300 MHz, D20): δ 5.74 (1 H, d, J = 2.1 Hz, 3-H), 4.90 (1 H, d, J = 2.1 Hz, 7-H), 4.54 (1 H, dd, J = 2. 1 Hz, J = 9.6 Hz, 6-H), 4.35 (1 H, t, J = 9.6 Hz, 5-H), 4.28 (1 H, dd, J = 2.4 Hz, J = 9.3 Hz, 4-H), 3.12 (3 H, s, CH3), 3.03 (3 H, s, CH3), 2.13 (3 H, s, NAc); HRMS(EI):M/z calculated values： C12H19N306Na [M+Na]+324.1172, measured value： 324.1163.Embodiment 25 (, ^) female -2- of -3- acetyl [(5) -1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl】- 4- guanidine radicals -3,4- dihydropyran -6- formic acid
According to the identical method of embodiment 23, prepare title compound by raw material of the compound of embodiment 24；Yield： 74%.
¾ NMR (300 MHz, D20): δ 5.72 (1 H, d, J = 3.2 Hz, 3-H), 4.55 (1 H, dd, J = 4.2 Hz, J = 8.2 Hz, 6-H), 4.42 (1 H, dd, J = 3.0 Hz, J = 7.8 Hz, 4-H), 4.21 (1 H, t, J = 7.9 Hz, 5-H), 3.13 (3 H, s, CH3), 3.00 (3 H, s, CH3) 2.06 (3 H, s, NAc); 13C NMR (400 MHz, D20): δ 19.03, 33.14, 45.23, 46.40, 63.49, 73.83, 100.57, 146.05, 154.19, 165.96, 168.50, 171.87; HRMS(ESI):M/z calculated values： C13H21N506 [M+H]+344.1570, measured value： 344.1577.
Embodiment 26 (2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl】- 4- triphenylphosphines Asia is female -3,4- dihydropyran -6- methyl formates
The compound of embodiment 4 (30 mg, 0.07 mmol) is dissolved in THF (2.0 mL), PPh is added3(20 mg, 0.07 mmol, 1.05 eq.), are stirred at room temperature after 18 h, and be concentrated under reduced pressure to obtain grease.Prepare plate (C C12: CH3OH = 30:L (v/v)) separate to obtain the mg of title compound 15, yield： 30%.
¾ NMR (300 MHz, CDC13): δ 8.20 (1 H, d, J = 7.8 Hz, NH), 7.73 (18 H, m, 18PhH), 6.56 (1 H, m, NH), 5.45 (1 H, d, J = 1.5 Hz, 7-H), 5.40 (1 H, d, J = 2.1 Hz, 3-H), 4.98 (1 H, dd, J = 1.5 Hz, J = 10.2 Hz, 6-H), 4.82 (1 H, m, 4-H), 4.14 (1 H, dt, J = 10.5 Hz, J = 17.7 Hz, 5-H), 3.67 (3
H, s, CH3), 3.39 (1 H, m, CH), 3.18 (1 H, m, CH), 2.23 (3 H, s, OAc),
I .76 (3 H, s, NAc), 1.12 (3 H, t, J = 7.2 Hz, CH3); LRMS(ESI): mlz [M+H]+ = 618.3.Embodiment 27 (2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl】- 4- amino -3,4- dihydropyran -6- methyl formates
The compound of embodiment 4 (30 mg, 0.07 mmol) is dissolved in THF (2.0 mL), PPh is added3(20 mg, 0.07 mmol, 1.05 eq.), are stirred at room temperature after 18 h, and be concentrated under reduced pressure to obtain grease.Prepare plate (C C12: CH3OH = 10:1 (ν/ν) separates to obtain the mg of title compound 24, Yield： 50%.
¾ NMR (300 MHz, CDC13): δ 5.87 (1 H, d, J = 2.5 Hz, 3-H), 5.08 (1 H, d, J = 1.8 Hz, 7-H), 4.30 (1 H, dd, J = 1.6 Hz, J = 10.4 Hz, 6-H), 3.76 (1 H, t, J = 9.9 Hz, 5-H), 3.68 (3 H, s, CH3), 3.40 (1 H, m, 4-H), 3.24 (1 H, m, CH), 2.99 (1 H, m, CH), 2.11 (3 H, s, OAc), 1.79 (3 H, s, NAc), 1.03 (3 H, t, J = 7.1 Hz, CH3); LRMS(ESI): mlz [M+Na]+ = 380.1.Embodiment 28 (2 3 ^) -3- acetyl JKS-2- [(5)-l, ~ base -2,-second JKS-2,-oxygen ethyl】- 4- amino -3,4- dihydropyran -6- formic acid
By the compound of embodiment 26 (15 mg, 0.024 mmol) it is dissolved in the mixed solution of methanol (0.75 mL) and water (0.75 mL), add KOH (0.3 mL), it is stirred at room temperature after 16 h, with 2 mol/L hydrochloric acid conditioning solution pH=6-7, the title compound of light yellow solid is obtained after being concentrated under reduced pressure.Can not be purified, directly connect for lower Walk reactions.
LRMS(ESI): mlz [M-H]+= 300.1.Embodiment 29 (2 3 ^) -3- acetyl JKS-2- [(5)-l, ~ base -2,-second JKS-2,-oxygen ethyl】- 4- [2,3 ,-two tertbutyloxycarbonyl guanidine radicals】- 3,4- dihydropyran -6- formic acid
In the mixed solution that the compound of embodiment 28 is dissolved in methanol (0.2 mL) and THF (0.2 mL), then Ν is added, the tertbutyloxycarbonyls of Ν '-two guanylpyrazole (10.4 mg, 0.04 mmol), it is stirred at room temperature after 24 h, it is concentrated under reduced pressure, prepares plate (C C12: CH30H = 6:1 (ν/ν)) separate to obtain the mg of title compound 10, yield： 76%.
LRMS(ESI): mlz [M+Na]+ = 566.1。 (2 3 the ^)-3- acetamidos of embodiment 30-2- [(5)-1, base-2 ,-ethylamino--2 ,-
The compound of embodiment 29 (10 mg, 0.02 mmol) is dissolved in CH2C12In (0.2 mL), CF is then added3COOH (0.1 mL), is stirred at room temperature after 2 h, be concentrated under reduced pressure into it is dry, ion exchange resin separate white solid the mg of title compound 6, yield： 96%.
¾ NMR (300 MHz, D20): δ 5.65 (1 H, d, J = 2.4 Hz, 3-H), 4.55 (1 H: dd, J = 2.1 Hz, J = 10.5 Hz, 6-H), 4.48 (1 H, dd, J = 2.4 Hz, J = 12.0 Hz,
4- H), 4.39 (1 H, d, J=2.1 Hz, 7-H), 4.28 (Hz of 1 H, dt, J=7.8 Hz, J=17.7,
5- H), 3.33 (4 H, dt, J = 7.2 Hz, J = 14.4 Hz, CH2), 2.07 (3 H, s, NAc), 1.17 (6 H, t, J = 7.2 Hz, CH3).Embodiment 31 (2 3 ^) -3- acetyl J S-2- [- l,-hydroxyl -2,-diethylin -2,-oxygen ethyl】- 4- amino -3,4- dihydropyran -6- formic acid
According to the identical method of embodiment 22, prepare target compound by raw material of the compound of embodiment 7；Yield： 93%.
¾ NMR (300 MHz, D20): δ 5.73 (1 H, d, J = 1.8 Hz, 3-H), 4.74 (1 H, d, J = 3.0 Hz, 7-H), 4.4 7 (1 H, dd, J = 2.7 Hz, J = 9.0 Hz, 6-H), 4.23 (1 H, dt, J = 9.6 Hz, J = 18.6 Hz, 5-H), 4.20 (1 H, dd, J = 2.1 Hz, J = 10.5 Hz, 4-H), 3.43 (4 H, m, 2CH2), 2.10 (3 H, s, NAc), 1.23 (3 H, t, J = 7.2 Hz, CH3), 1.15 (3 H, t, J = 7.2 Hz, CH3); LRMS(ESI): mlz [M+H]+ = (2 3 the ^) -3- acetyl of embodiment 32 JKS-2- [- l,-acetoxyl group -2,-diethyl-r- ethyls】- 4- amino -3,4- dihydropyran -6- methyl formates
By the compound of embodiment 7（10 mg, 0.02 mmol) it is dissolved in THF (0.5 mL) and Η20 (4.4,0.2 mmol, 10 eq.) in, add PPh3(7 mg, 0.02 mmol), is stirred at room temperature after 48 h, stops reaction.After being concentrated under reduced pressure, plate (C C1 are prepared2: CH3OH=6/l (v/v)) separate to obtain the mg of title compound 4, yield： 43%
¾ NMR (300 MHz, CDC13): δ 6.94 (1 H, d, J = 8.7 Hz, NH), 6.05 (1 H, d, J = 3.0 Hz, 3-H), 5.80 (1 H, d, J = 4.5 Hz, 7-H), 4.57 (1 H, dd, J = 4.8 Hz, J = 8.4 Hz, 6-H), 3.97 (1 H, dt, J = 8.4 Hz, J = 16.5 Hz, 5-H), 3.78 (3 H, s, CH3), 3.73 (2 H, m, CH and 4-H), 3.35 (3 H, m, CH and CH2), 2.19 (3 H, s, OAc), 1.99 (3 H, s, NAc), 1.13 (6 H, t, J = 6.9 Hz, 2CH3); LRMS(ESI):Mlz [M+Na] +=408.3 embodiment 33 (2 3 ^) -3- acetyl J S-2- [- l,-acetoxyl group -2,-diethyl female -2,-oxygen ethyl】- 4- [2,3 ,-two tertbutyloxycarbonyl guanidine radicals】- 3,4- dihydropyran -6- formic acid
The compound of embodiment 32 (60 mg, 0.16 mmol) is dissolved in absolute methanol (2 mL), N2Under protection, Ν, THF (2 mL) solution of the tertbutyloxycarbonyls of Ν '-two guanylpyrazole (60 mg, 0.19 mmol) is added dropwise.It is stirred at room temperature after 48 h, rotation solvent to the greatest extent, directly with preparing plate (CH2C12: CH3OH 10:1 (ν/ν) is separated, and obtains the mg of title compound 78 of white solid, yield： 80%
ln NMR (300 MHz, CDC13): δ 11.40 (1 H, s, NH), 8.52 (1 H, d, J : 8.3 Hz, NH), 6.66 (1 H, d, J = 8.5 Hz, NH), 5.92 (1 H, d, J = 2.3 Hz, 3-H): 5.65 (1 H, d, J = 4.2 Hz, 7-H), 5.21 (1 H, dd, J = 2.2 Hz, J = 10.3 Hz, 4-H), 4.55 (1 H, dd, J = 4.3 Hz, J = 10.7 Hz, 6-H), 4.25 (1 H, dt, J = 9.9 Hz, J = 18.8 Hz, 5-H), 3.84 (3 H, s, CH3), 3.36 (4 H, m, 2CH2), 2.23 (3 H, s, OAc), 1.91 (3 H, s, NAc), 1.52 (9 H, s, 3CH3), 1.51 (9 H, s, 3CH3), 1.16 (3 H, t, J = 6.9 Hz, CH3); LRMS(ESI): mlz [M+H]+= 628.1.Embodiment 34 (2 3 ^) -3- acetyl J S-2- [- l,-acetoxyl group -2,-diethyl-r-, ethyl】- 4- guanidine radicals -3,4- dihydropyran -6- methyl formates j
The compound of embodiment 33 (4 mg, 0.03 mmol) is dissolved in anhydrous CH2C12In (0.5 mL), N2Under protection, CF is added3COOH (0.2 mL) solution.It is stirred at room temperature after 5 h, rotation solvent to the greatest extent obtains title compound 3mg, can be directly used for Xia Walk reactions.
LRMS(ESI): mlz [M+H]+= 372.2.Female-the 2- of (2 the ^) -3- acetyl of embodiment 35 [(5) -1, base -2,-diethyl female -2,-oxygen ethyl】- 4- guanidine radicals -3,4- dihydropyran -6- formic acid
By the compound of embodiment 34 (R, ^) -3- acetamidos -2- [C)-r- acetoxyl group -2,-diethylin -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- methyl formates (3 mg, 0.01 mmol) are dissolved in H2In O (0.2 mL) and the 1 M NaOH aqueous solution (2 μ), it is stirred at room temperature after 15 h, stops reaction.Cationic ion-exchange resin separates to obtain the mg of title compound 2, yield： 73% o
¾ NMR (300 MHz, D20): δ 5.79 (1 H, d, J = 3.3 Hz, 3-H), 4.80 (1 H, d, J = 5.7 Hz, 7-H), 4.61 (1 H, t, J = 6.0 Hz, 6-H), 4.43 (1 H, dd, J = 3.3 Hz, J = 6.6 Hz, 4-H), 4.23 (1 H, dt, J = 9.0 Hz, J = 15.9 Hz, 5-H), 3.49 (4 H, m, CH2), 2.11 (3 H, s, NAc), 1.29 (6 H, t, J = 7.2 Hz, 2CH3); LRMS(ESI): mlz [M+H]+= 372.2.(2 the ^) -3- acetyl of embodiment 36 female -2- [(5)-l,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl】- 4- amino -3,4- dihydropyran -6- formic acid
According to the identical method of embodiment 22, prepare title compound by raw material of the compound of embodiment 9；Yield： 90%.
¾ NMR (400 MHz, D20): δ 5.74 (1 H, d, J = 3.0 Hz, 3-H), 4.70 (1 H:D, J=2.5 Hz, 7-H), 4.52 (1 H, the Hz of t, J=2.7 Hz, J=10.2,6-H), 4.34 (the Hz of 1 H, t J=9.4,5-H), 4.27 (1 H, dd, J=2.2 Hz, J=9.4 Hz, 4-H), 3.58 (4 H, m, 2CH2), 2.12 (3 H, s, NAc), 1.97 (4 H, m, 2C¾) ; LR-ESI-MS: [M+Na]+ = 350.1.(2 the ^) -3- acetyl of embodiment 37 female -2- [(5)-l,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl】- 4- guanidine radicals -3,4- dihydropyran -6- formic acid
According to the identical method of embodiment 23, prepare title compound by raw material of the compound of embodiment 36；Yield： 80%.
¾ NMR (300 MHz, D20): δ 5.73 (1 H, d, J = 3.0 Hz, 3-H), 4.67 (1 H, d, J = 4.5 Hz, 7-H), 4.55 (1 H, dd, J = 4.5 Hz, J = 8.4 Hz, 6-H), 4.43 (1 H, dd, J = 3.0 Hz, J = 7.5 Hz, 5-H), 4.237 (1 H, t, J = 8.1 Hz, 5-H), 3.69 (1 H, m, CH), 3.51 (3 H, m, CH + CH2), 2.06 (3 H, s, NAc), 1.95 (4 H, m, 2CH2); HRMS(ESI): [M+H]+= 370.2.Embodiment 38-41
According to method same as Example 5, the compound of embodiment 2 is reacted from different amine, the compound of embodiment 38 41 is prepared respectively.
Hz, J = 5.8 Hz, 4-H), 4.06 (1 H, dt, J = 6.4 Hz, J = 13.7 Hz, 5-H), 3.81 (3 H, s, CH3), 3.54 (4 H, m, 2CH2), 2.15 (3 H, s, OAc), 1.99 (3 H, s, NAc), 1.57 (6 H, m, 3C¾); HRMS (ESI):M/z calculated values： C18H26N507 [M+H]+424.1832, measured value： 424.1861.
(2 3 ^) -3- acetamidos -2- [(5 1,-acetoxyl group
- 2,-N methyl piperazine base -2,-oxygen ethyl】- 4- azidos
- 3,4- dihydropyran -6- methyl formates
lH NMR (300 MHz, CDC13): δ 6.19 (1 Η, d, J = 7.7 Hz, NH), 6.07 (1 H, d, J = 3.8 Hz, 3-H), 5.88 (1 H, d, J = 6.2 Hz, 7-H), 4.72 (1 H, t, J = 6.4 Hz, 6-H), 4.48 (1 H, dd, J = 3.9
Hz, J = 5.9 Hz, 4-H), 4.11 (1 H, dt, J = 7.7 Hz, J = 14.7 Hz, 5-H), 3.81 (3 H, m, OCH3), 3.65 (4 H, m, 2CH2), 2.41 (4 H, m, 2CH2), 2.30 (3 H, s, CH3), 2.15 (3 H, s, OAc), 1.99 (3 H, s, NAc). LRMS(ESI): m/z [M+H]+ = 438.0.
(2 3 ^) -3- acetamidos -2- [(5 l,-acetoxyl group -2,-cyclohexyl amido -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
lH NMR (400 MHz, CDC13): δ 6.90 (1 H, d, J = 9.7 Hz, NH), 6.18 (1 H, d, J = 8.4 Hz,
NH), 5.92 (1 H, d, J = 2.6 Hz, 3-H), 5.37 (1 H, d, J = 2.0 Hz, 7-H), 4.48 (1 H, t, J = 1.8 Hz, J = 10.5 Hz, 6-H), 4.35 (1 H, dd, J = 9.5 Hz, J = 19.8 Hz, 5-H), 4.29 (1 H, dd, J = 2.4
Hz, J = 9.2 Hz, 4-H), 3.77 (4 H, m, OCH3 + CH), 2.23 (3 H, s, OAc), 1.97 (3 H, s, NAc), 1.73 (6 H, m, 3C¾), 1.29 (4 H, m, 2CH2). LRMS(ESI): mlz [M+H]+=438.0. embodiments 42-47
According to the identical method of embodiment 31, the compound of embodiment 42 47 is correspondingly prepared by embodiment 5,38,8,39 41 respectively.
(6 H, q, J = 7.5 Hz, 2CH3); HRMS(ESI): m/z [M+Na]+ = 394.2.
(2 3 ^) -3- acetamidos -2- [(5) -1,-hydroxyl -2,-azanol base -2,-oxygen ethyl】- 4- amino -3,4- dihydropyran -6- formic acid
Rf = 0.13 (n-BuOH: HAc: H20 = 3: 1 : 1); lH/work-, NMR (300 MHz, D20): δ 5.74 (1 H, d, J =
〇 2.2 Hz, 3-H), 4.55 (1 H, s, 7-H), 4.53 (1 H, t, work
J = 1.3 Hz, J = 10.6 Hz, 6-H), 4.39 (1 H, t, J
= 9.6 Hz, 5-H), 4.21 (1 H, dd, J = 2.2 Hz, J = 9.4 Hz, 4-H), 2.14 (3 H, s, NAc); HRMS(ESI):M/z calculated values： C1()H15N307Na [M+Na]+312.0808, measured value： 312.0823.
(2 3 ^) -3- acetamidos -2- [(5) -1,-hydroxyl -2,-cyclohexylamino -2,-oxygen ethyl】- 4- amino -3,4- dihydropyran -6- formic acid
lH NMR (300 MHz, D20):δ 5.72 (1 H, d, J=1.8 Hz, 3-H), 4.89 (the Hz of 1 H, d, J=1.8,7-H), 4.45 (1 H, dd, J=2.1 Hz, J=7.8 Hz, 6-H), 4.24 (2 H, m, 4-H and 5-H), 3.54 (4 H, m, 2CH2), 2.12 (3 H, s, NAc), 1.64 (6 H, m, 3CH2); HRMS(ESI):M/z calculated values： C15H24N306 [M+H]+342.1665, measured value： 342.1660.
2R, 3R, 4S) -2,-acetamido -2- [(5 1,-hydroxyl -2'-N- methyl piperazines base -2,-oxygen ethyl】- 4- amino -3,4-
Dihydropyran -6- formic acid LRMS(ESI): mlz [M+H]+ = 357.1.
(2 3 ^) -3- acetamidos -2- [(5) -1,-hydroxyl -2,-cyclohexyl amido -2,-oxygen ethyl】- 4- amino -3,4- dihydropyran -6- formic acid
lH NMR (300 MHz, D20): δ 5.67 (1 Η, d, J = 1.8 Hz, 3-H), 4.37 (1 H, dd, J = 1.5 Hz, J
47 = 10.5 Hz, 6-H), 4.33 (1 H, d, J = 1.2 Hz, 7-H), 4.04 (1 H, t, J = 8.7 Hz, 5-H), 3.76 (1
H, m, 4-H), 2.12 (3 H, s, NAc), 1.77 (6 H, m, 3C¾); 1.38 (4 H, m, 2CH2); HRMS(ESI):M/z calculated values： C16H26N306 [M+H]+356.1822, measured value： 356.1822.
Embodiment 48-52
According to the identical method of embodiment 23, the compound of embodiment 48 52 is correspondingly prepared by embodiment 42 46 respectively.
316.1.
(2 ！R, ^-3- acetamido -2- [(5)-l,-hydroxyl -2,-isopropylamine base -2,-oxygen ethyl】- 4- guanidine radicals -3,4- dihydropyran -6- formic acid
¾ NMR (300 MHz, D20): δ 5.70 (1 H, d, J = 2.1 Hz, 3-H), 4.49 (1 H, dd, J = 1.5 Hz, J = 10.5 Hz, 6-H), 4.39 (1 H, d, J = 1.2 Hz, 7-H), 4.29 (1 H, t, J = 9.6 Hz, 5-H), 4.09 (2
H, m, 4-H and CH), 2.14 (3 H, s, NAc), 1.25 (6 H, q, J=7.5 Hz, 2CH3); HRMS(ESI): mlz [M+H]+ = 358.2.
(2 ！R, ^-3- acetamido -2- [(5)-l,-hydroxyl -2,-azanol base -2,-oxygen ethyl】- 4- guanidine radicals -3,4- dihydropyran -6- formic acid
LRMS(ESI): mlz [M+Na]+ = 354.1.
(2 ！R, ^-3- acetamido -2- [(5)-l,-hydroxyl -2,-cyclohexylamino -2,-oxygen ethyl】- 4- guanidine radicals -3,4- dihydropyran -6- formic acid
¾ NMR (300 MHz, D20): δ 5.77 (1 H, d, J = 3.0 Hz, 3-H), 4.90 (1 H, d, J = 3.9 Hz, 7-H), 4.58 (1 H, dd, J = 3.9 Hz, J = 7.8 Hz, 6-H), 4.48 (1 H, dd, J = 3.0 Hz, J = 7.2 Hz, 4-H), 4.23 (1 H, t, J = 7.8 Hz, 5-H), 3.62 (4
H, m, 2CH2), 2.11 (3 H, s, NAc), 1.69 (6 H, m, 3CH2); HRMS(ESI):M/z calculated values： C16H25N506Na [M+Na]+406.1703, measured value： 406.1722. (2R, 3R, 4S) -3- acetamidos -2- [(5 1,-hydroxyl
- 2'-N- methyl piperazines base -2,-oxygen ethyl】- 4- guanidine radicals -3,4-
52 dihydropyran -6- formic acid
HRMS(ESI):M/z calculated values： C25H29N507Na
[M+H+Na]+422.1890, measured value：422.1901. embodiment 53-87
According to the identical preparation method of embodiment 12, correspondingly prepare the compound of embodiment 53 87.
Embodiment R5 R6 R12 R11
53 CH3 H H CH(OH)CH3
54 CH3 H H CH2(CH2)2OH
55 CH3 H COOCH3 COOCH3
56 CH3H H cyclopropyl
57 CH3H H 3'- aminophenyls
58 CH3 CH3 H CH2OH
59 CH3 CH3 H CH(OH)CH3
60 CH3 CH3 H CH2(CH2)2OH
61 CH3 CH3 H COOCH3
62 CH3 CH3 COOCH3 COOCH3 CH3 CH3H cyclopropyl
CH3 CH3H phenyl
CH3 CH3H 3'- aminophenyls
CH3CH2 H H CH2OH
CH3CH2 H H CH(OH)CH3
CH3CH2 H H CH2(CH2)2OH
CH3CH2 H H COOCH3
CH3CH2 H COOCH3 COOCH3
CH3CH2H H cyclopropyl
CH3CH2H H phenyl
CH3CH2H H 3'- aminophenyl cyclopenta H CH2OH cyclopenta H CH (OH) CH3Cyclopenta H CH2(CH2)2OH cyclopenta H phenylcyclopentyl H 3'- aminophenyls
CH3CH2 CH3CH2 H CH2OH
CH3CH2 CH3CH2 H CH(OH)CH3
CH3CH2 CH3CH2 H CH2(CH2)2OH
CH3CH2 CH3CH2 H COOCH3
CH3CH2 CH3CH2 COOCH3 COOCH3
CH3CH2 CH3CH2H cyclopropyl 85 CH3CH2 CH3CH2H phenyl
86 CH3CH2 CH3CH2H 3'- aminophenyls
87 OH H H COOCH3
Measured value： 549.1604.
(2 3 ^) -3- acetamidos -2- [(5) -1,-acetoxyl group -2,-dimethylamino -2,-oxygen ethyl】- 4- [4,-cyclopropyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lU NMR (300 MHz, CDC13): δ 7.36 (1 Η, s, CH), 6.57 (1 Η, d, J = 7.8 Hz, NH), 6.12 (1 H, d, J = 2.7 Hz, 3-H), 5.96 (1 H, dd, J = 2.7 Hz, J = 9.0 Hz, 4-H), 5.80 (1 H, d, J = 4.2 Hz, 7-H), 4.94 (1 H, dd, J = 6.9 Hz, J = 12.0 Hz, 6-H), 4.27 (1 H, dt, J = 9.3 Hz, J = 17.1 Hz, 5-H), 3.81 (3 H, s, CH3), 3.17 (2 H, s, CH3), 2.96 (3 H, s, CH3), 2.14 (3 H, s, OAc), 1.94 (1 H, m, CH), 1.91 (3 H, s, NHAc), 0.95 (2 H, m, CH2), 0.82 (2 H, m, CH2); HRMS(EI):M/z calculated values： C20H27N5O7 [M]+449.1910, measured value： 449.1929.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-dimethylamino -2,-oxygen ethyl】- 4- [4,-phenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lU NMR (400 MHz, CDC13): δ 7.92 (1 H, s, CH), 7.80 (2 H, dd, J = 1.4 Hz, J = 8.6 Hz, PhH), 7.37 (4 H, m, PhH), 6.95 (1 H, d, J = 8.1 Hz, NH), 6.18 (1 H, d, J = 2.6 Hz, 3-H), 6.06 (1 H, dd, J = 2.6 Hz, J = 9.2 Hz, 4-H), 5.79 (1 H, d, J = 4.0 Hz, 7-H), 4.98 (1 H, dd, J = 4.1 Hz, J = 9.7 Hz, 6-H), 4.37 (1 H, dt, J = 9.7 Hz, J = 17.6 Hz, 5-H), 3.81 (3 H, s, CH3), 3.18 (3 H, s, CH3), 2.96 (3 H, s, CH3), 2.14 (3 H, s, OAc), 1.90 (3 H, s, NHAc); HRMS(ESI):M/z is calculated: C23H27N507Na [M+Na]+508.1808, measured value： 508.1788.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-dimethylamino -2,-oxygen ethyl】- 4- [4,-(3 "-aminophenyls -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid first vinegar
lH NMR (400 MHz, CDC13): δ 7.86 (1 H, s, CH), 7.17 (3 H, m, PhH), 6.84 (1 H, d, J = 7.8 Hz, PhH), 6.67 (1 H, d, J = 7.8 Hz, NH), 6.17 (1 H, d, J = 2.6 Hz, 3-H), 6.05 (1 H, dd, J = 2.7 Hz, J = 9.1 Hz, 4-H), 5.82 (1 H, d, J = 4.3 Hz, 7-H), 5.00 (1 H, dd, J = 4.1 Hz, J = 9.3 Hz, 6-H), 4.27 (1 H, dt, J = 9.4 Hz, J = 17.2 Hz, 5-H), 3.81 (3 H, s, CH3), 3.16 (3 H, s, CH3), 2.95 (3 H, s, CH3), 2.13 (3 H, s, OAc), 1.91 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： C23H28N607Na [M+Na]+523.1917, measured value： 523.1932.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl】_ 4- [4,-methylol -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates lU NMR (400 MHz, CDC13): δ 7.83 (1 H, s, J = 9.9 Hz, NH), 7.73 (1 H, s, CH), 6.45 (1 H, t, J = 5.5 Hz, NH), 6.04 (1 H, d, J = 2.2 Hz, 3-H), 5.71 (1 H, dd, J = 2.4 Hz, J = 9.8 Hz, 4-H), 5.59 (1 H, d, J = 1.7 Hz, 7-H), 4.85 (1 H, dd, J = 1.8 Hz, J = 10.8 Hz, 6-H), 4.03 (1 H, dt, J = 9.9 Hz, J = 20.2 Hz, 5-H), 4.09 (1 H, s, OH), 3.78 (3 H, s, CH3), 3.53 (1 H, m, CH), 3.23 (1 H, m, CH), 2.16 (3 H, s, OAc), 1.77 (3 H, s, NHAc), 1.22 (3 H, t, J = 7.0 Hz, CH3);HRMS (EI) m/z calculated values： C18H25N508[M]+439.1703, measured value： 439.1698.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl】_ 4- [4,-(1 "-hydroxyethyl) -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
HRMS (EI) m/z calculated values： C19H27N508 [M]+453.1859, measured value： 453.1852.
(2 3 ^) -3- acetamidos -2- [(5) -1,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl】_ 4- [4,-hydroxypropyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lU NMR (400 MHz, CDC13): δ 7.50 (1 H, s, CH), 7.48 (1 H, d, J = 9.5 Hz, NH), 6.36 (1 H, t, J = 5.9 Hz, NH), 6.04 (1 H, d, J = 2.2 Hz, 3-H), 5.64 (1 H, dd, J = 2.2 Hz, J = 9.9 Hz, 4-H), 5.59 (1 H, d, J = 1.8 Hz, 7-H), 4.80 (1 H, dd, J = 1.8 Hz, J = 10.6 Hz, 6-H), 4.60 (1 H, dt, J = 7.5 Hz, J = 15.3 Hz, 5-H), 3.78 (3
H, s, CH3), 3.64 (2 H, m, CH2), 3.55 (1 H, m, CH), 3.23 (1 H, m, CH), 2.82 (2 H, t, J = 7.3 Hz, CH2), 2.19 (3 H, s, OAc), 1.93 (2 H, f, J = 6.6 Hz, J = 13.2 Hz, CH2), 1.75 (3 H, s, NHAc),
I.22 (3 H, t, J = 7.3 Hz, CH3);HRMS (EI) m/z calculated values： C20H29N5O8[M]+467.2016, measured value： 467.1997.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl】_ 4- [4,-methoxycarbonyl group -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lU NMR (300 MHz, CDC13): δ 8.24 (1 H, s, CH), 7.02 (1 H, d, J = 9.6 Hz, NH), 6.34 (1 H, t, J = 6.3 Hz, NH), 6.04 (1 H, d, J = 2.4 Hz, 3-H), 5.78 (1 H, dd, J = 2.4 Hz, J = 10.2 Hz, 4-H), 5.56 (1 H, d, J = 1.8 Hz, 7-H), 4.90 (1 H, dd, J = 1.8 Hz, J = 10.8 Hz, 6-H), 4.56 (1 H, dt, J = 9.9 Hz, J = 20.1 Hz, 5-H), 3.94 (3 H, s, CH3), 3.80 (3 H, s, CH3), 3.55 (1 H, m, CH), 3.27 (1 H, m, CH), 2.20 (3 H, s, OAc), 1.83 (3 H, s, NHAc), 1.23 (1 H, t, J = 7.2 Hz, CH3);HRMS (EI) m/z calculated values： C19H26N509 [M+H]+468.1731, measured value： 468.1725.
1- [(2 3 ^) -3- acetamidos -2- ((5 1,-acetoxyl group -2,-ethylamino- -2, - Oxygen ethyl) -6- methoxycarbonyl groups -3,4- dihydropyran -4】- l, 2,3- triazole -4,5- dicarboxylic acid methyl esters
lH NMR (300 MHz, CDC13): δ 6.61 (1 Η, d, J = 9.6 Hz, NH), 6.33 (1 H, t, J = 6.9 Hz, NH), 6.09 (1 H, d, J = 2.7 Hz, 3-H), 6.00 (1 H, dd, J = 2.4 Hz, J = 9.6 Hz, 4-H), 5.44 (1 H, d, J = 1.5 Hz, 7-H), 4.96 (1 H, dd, J = 1.5 Hz, J = 10.8 Hz, 6-H), 4.59 (1 H, dt, J = 9.6 Hz, J = 19.8 Hz, 5-H), 3.98 (3 H, s, CH3), 3.95 (3 H, s, CH3), 3.79 (3 H, s, CH3), 3.55 (1 H, m, CH), 3.26 (1 H, m, CH), 2.18 (3 H, s, OAc), 1.84 (3 H, s, NHAc), 1.22 (3 H, t, J = 7.2 Hz, CH3);HRMS (EI) m/z calculated values： C21H28N5Ou [M+H]+526.1785, measured value： 526.1787.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl】_ 4- [4,-cyclopropyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lH NMR (300 MHz, CDC13): δ 7.37 (1 H, s, CH), 7.32 (1 H, d, J = 9.9 Hz, NH), 6.31 (1 H, t, J = 6.0 Hz, NH), 6.00 (1 H, d, J = 2.7 Hz, 3-H), 5.63 (1 H, dd, J = 2.4 Hz, J = 10.2 Hz, 4-H), 5.57
71
(1 H, d, J = 1.5 Hz, 7-H), 4.79 (1 H, dd, J = 1.8 Hz, J = 10.8 Hz, 6-H), 4.59 (1 H, dt, J = 9.9 Hz, J = 20.1 Hz, 5-H), 3.77 (3 H, s, CH3), 3.53 (1 H, m, CH), 3.22 (1 H, m, CH), 2.21 (3 H, s, OAc), 1.92 (1 H, m, CH), 1.76 (3 H, s, NHAc), 1.22 (3 H, t, J = 7.2 Hz, CH3), 0.87 (4 H, m, 2CH2);HRMS (EI) m/z calculated values： C20H28N5O7[M+H]+450.1989, measured value： 450.2001.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl】_ 4- [4,-phenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formate lU NMR (300 MHz, CDC13): δ 7.90 (1 H, s, CH), 7.82 (2 H, d, J = 6.9 Hz, PhH), 7.43 (2 H, t, J = 7.2 Hz, PhH), 7.34 (1 H, t, J = 7.5 Hz, PhH), 6.96 (1 H, d, J = 9.6 Hz, NH), 6.31 (1 H, t, J = 7.5 Hz, NH), 6.10 (1 H, d, J = 2.4 Hz, 3-H), 5.77 (1 H, dd, J =
72
2.4 Hz, J = 10.2 Hz, 4-H), 5.60 (1 H, d, J = 1.8 Hz, 7-H), 4.87 (1 H, dd, J = 1.8 Hz, J = 10.8 Hz, 6-H), 4.69 (1 H, dt, J = 9.9 Hz, J = 20.1 Hz, 5-H), 3.80 (3 H, s, CH3), 3.57 (1 H, m, CH), 3.26 (1 H, m, CH), 2.23 (3 H, s, OAc), 1.81 (3 H, s, NHAc), 1.24 (3 H, t, J = 7.2 Hz, CH3); HRMS(EI):M/z calculated values： C23H28N507[M+H]+486.1989, measured value： 486.1984.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl】_ 4- [4,-(3 "-aminophenyls -1,2,3- triazoles -1】- 3,4- dihydropyran -6-
73 methyl formates
lH NMR (300 MHz, CDC13): δ 7.86 (1 H, s, CH), 7.56 (1 H, d, J = 9.9 Hz, NH), 7.34 (1 H, s, PhH), 7.18 (1 H, t, J = 7.8 Hz, PhH), 7.08 (1 H, d, J = 7.8 Hz, PhH), 6.66 (1 H, d, J = 9.3 Hz, NH), 6.31 (1 H, t, J = 5.7 Hz, NH), 6.06 (1 H, d, J = 2.1 Hz, 3-H), 5.77 (1 H, dd, J = 2.4 Hz, J = 10.8 Hz, 4-H), 5.64 (1 H, d, J = 1.5 Hz, 7-H), 4.86 (1 H, dd, J = 1.5 Hz, J = 10.5 Hz, 6-H), 4.67 (1 H, dt, J = 10.2 Hz, J = 20.4 Hz, 5-H), 3.79 (3 H, s, CH3), 3.57 (1 H, m, CH), 3.25 (1 H, m, CH), 2.21 (3 H, s, OAc), 1.75 (3 H, s, NHAc), 1.23 (3 H, t, J = 6.6 Hz, CH3); HRMS(ESI):M/z calculated values： C23H28N607 [M]+500.2020, measured value： 500.2019.
(2 3 ^-3- acetamidos -2- [(5)-l,-acetoxyl group -2,-cyclopentamine base -2,-oxygen ethyls】- 4- [4,-methylol -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lU NMR (400 MHz, DMSO-i 6): δ 8.23 (1 Η, d, J = 9.1 Hz, NH), 7.96 (1 H, s, CH), 6.00 (1 H, d, J = 2.2 Hz, 3-H), 5.55 (1
74 H, dd, J = 2.7 Hz, J = 9.5 Hz, 6-H), 5.28 (1 H, d, J = 2.9 Hz, 7-H), 4.69 (1 H, dd, J = 2.4 Hz, J = 9.8 Hz, 4-H), 4.49 (2 H, m, CH2), 4.36 (1 H, dt, J = 9.5 Hz, J = 16.8 Hz, 5-H), 3.84 (1 H, m, CH), 3.73 (3 H, s, CH3), 3.23 (3 H, m, CH2 + CH), 2.05 (3 H, s, OAc), 1.87 (4 H, m, 2CH2), 1.69 (3 H, s, NHAc); HRMS(ESI): m/z [M+H]+ = 466.0.
(2 ^, ^-3- acetamido -2- [(5)-l,-acetoxyl group -2,-cyclopentamine base -2,-oxygen ethyl】- 4- [4,-(1 "-hydroxyethyl) -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid first vinegar
lH NMR (400 MHz, CDC13): δ 7.64 (1 H, d, J = 2.6 Hz, CH), 7.46 (1 H, d, J = 8.5 Hz, NH), 6.09 (1 H, d, J = 2.0 Hz, 3-H), 5.92 (1 H, d, J = 9.7 Hz, 6-H), 5.58 (1 H, d, J = 2.1 Hz, 7-H),
75
5.04 (1 H, m, CH), 4.92 (1 H, dd, J = 3.2 Hz, J = 10.4 Hz, 4-H), 4.41 (1 H, dd, J = 10.6 Hz, J = 20.7 Hz, 5-H), 4.00 (1 H, m, CH), 3.79 (3 H, m, CH3), 3.52 (3 H, m, C and CH), 2.14 (3 H, s, OAc), 1.94 (4 H, m, 2CH2), 1.84 (3 H, s, NHAc), 1.57 (3 H, dd, J = 3.0 Hz, J = 6.3 Hz, CH3); HRMS(EI):M/z is calculated: C21H29N508[M]+479.2016, measured value： 479.2032.
(2 3 ^-3- acetamidos -2- [(5)-l,-acetoxyl group -2,-cyclopentamine base -2,-oxygen ethyls】- 4- [4,-hydroxypropyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lU NMR (400 MHz, DMSO-i 6): δ 8.20 (1 H, d, J = 9.1 Hz, NH), 7.85 (1 H, s, CH), 6.02 (1 H, d, J = 2.8 Hz, 3-H), 5.49 (1
76
H, dd, J = 2.7 Hz, J = 9.9 Hz, 6-H), 5.28 (1 H, d, J = 2.7 Hz, 7-H), 4.69 (1 H, dd, J = 2.6 Hz, J = 10.1 Hz, 4-H), 4.31 (1 H, dt, J = 9.5 Hz, J = 19.2 Hz, 5-H), 3.84 (1 H, m, CH), 3.73 (3 H, m, CH3), 3.26 (3 H, m, CH2Standing grain mouthful CH), 2.62 (2 H, t, J=7.3 Hz, CH2), 2.05 (3 H, s, OAc), 1.86 (4 H, m, 2CH2), 1.71 (2 H, dt, J = 6.4 Hz, J = 14.3 Hz, CH2), 1.68 (3 H, s, NHAc); HRMS(ESI): mlz [M+Na]+ = 516.2.
(2 ^, ^-3- acetamido -2- [(5)-l,-acetoxyl group -2,-cyclopentamine base -2,-oxygen ethyl】- 4- [4,-phenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lH NMR (400 MHz, DMSO-i 6): δ 8.64 (1 Η, s, CH), 7.84 (1 Η, d, J = 6.9 Hz, PhH), 7.42 (2 H, t, J = 7.6 Hz, PhH), 7.31 (2 H, t, J = 7.6 Hz, PhH), 6.09 (1 H, d, J = 2.7 Hz, 3-H), 5.60 (1
77
H, dd, J = 2.5 Hz, J = 9.9 Hz, 6-H), 5.29 (1 H, d, J = 2.6 Hz, 7-H), 4.74 (1 H, dd, J = 2.6 Hz, J = 10.6 Hz, 4-H), 4.37 (1 H, t, J = 10.3 Hz, 5-H), 3.86 (1 H, m, CH), 3.73 (3 H, s, CH3), 3.31 (3 H, m, C standing grain mouthful CH), 2.03 (3 H, s, OAc), 1.84 (4 H, m, 2CH2),
I .78 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： C25H29N507Na [M+Na]+534.1965, measured value： 534.1990.
(2 3 ^-3- acetamidos -2- [(5)-l,-acetoxyl group -2,-cyclopentamine base -2,-oxygen ethyls】- 4- [4,-(3 "-aminophenyls -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid first vinegar
lU NMR (400 MHz, DMSO-i 6): δ 7.87 (1 H, s, CH), 7.17 (3
H, m, PhH), 6.66 (1 H, d, J = 7.6 Hz, PhH), 6.14 (1 H, d, J =
78 2.6 Hz, 3-H), 6.03 (1 H, d, J = 9.8 Hz, 6-H), 5.63 (1 H, d, J = 3.6 Hz, 7-H), 4.96 (1 H, dd, J = 3.3 Hz, J = 9.6 Hz, 4-H), 4.46 (1 H, dt, J = 9.5 Hz, J = 17.5 Hz, 5-H), 3.95 (1 H, m, CH), 3.80 (3 H, s, CH3), 3.50 (3 H, m, CH2Standing grain mouthful CH), 2.15 (3 H, s, OAc),
I .88 (4 H, m, 2CH2), 1.86 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： C25H3。N607Na [M+Na]+549.2074, measured value： 549.2051.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-diethylin -2,-oxygen ethyl】- 4- [4,-methylol -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lH NMR (400 MHz, CDC13): δ 7.69 (1 H, s, CH), 7.28 (1 H, d, J = 8.0 Hz, NH), 6.09 (1 H, d, J = 2.2 Hz, 3-H), 5.99 (1 H, d, J = 9.2 Hz, 4-H), 5.75 (1 H, d, J = 3.7 Hz, 7-H), 5.04 (1 H, dd, J
79
= 3.7 Hz, J = 9.9 Hz, 6-H), 4.73 (2 H, s, CH2), 4.23 (1 H, dt, J = 9.2 Hz, J = 17.6 Hz, 5-H), 3.78 (3 H, s, CH3), 3.47 (4 H, m, 2CH2), 2.12 (3 H, s, OAc), 1.90 (3 H, s, NHAc), 1.21 (3 H, t, J = 6.8 Hz, CH3), 1.13 (3 H, t, J = 6.8 Hz, CH3); HRMS(ESI):M/z calculated values： C20H29N5O8Na [M+Na]+490.1914, measured value： 490.1916.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-diethylin -2, -
80 oxygen ethyls】- 4- [4,-(1 "-hydroxyethyl) -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid first vinegar lU NMR (400 MHz, CDC13):δ 7.60 (1 H, s, CH), 6.95 (the Hz of 1 H, d, J=7.7,), NH 6.10 (1 H, d, J=2.6 Hz, 3-H), 6.01 (1 H, the Hz of dd, J=2.2 Hz, J=9.2,4-H), 5.77 (1 H, d, J=3.7 Hz, 7-H), 5.02 (2 H, m, CH and 6-H), 4.19 (1 H, m, 5-H), 3.79 (3 H, s, CH3), 3.46 (4 H, m, 2CH2), 2.14 (3 H, s, OAc), 1.90 (3 H, s, NHAc), 1.57 (1 H, dd, J = 4.0 Hz, J = 6.4 Hz, 4-H), 1.21 (3 H, t, J = 7.2 Hz, CH3), 1.13 (3 H, t, J = 7.2 Hz, CH3); HRMS(ESI):M/z calculated values： C21H31N508Na [M+Na]+504.2070, measured value： 504.2056.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-diethylin -2,-oxygen ethyl】- 4- [4,-hydroxypropyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lH NMR (400 MHz, CDC13): δ 7.50 (1 H, s, CH), 7.19 (1 H, d, J = 8.4 Hz, NH), 6.10 (1 H, d, J = 2.2 Hz, 3-H), 5.89 (1 H, dd, J = 2.2 Hz, J = 9.5 Hz, 4-H), 5.74 (1 H, d, J = 4.0 Hz, 7-H), 4.95
81 (1 H, dd, J = 3.7 Hz, J = 9.9 Hz, 6-H), 4.36 (1 H, dt, J = 9.2 Hz, J = 18.4 Hz, 5-H), 3.78 (3 H, s, CH3), 3.65 (3 H, m, CH standing grain mouthful CH2), 3.40 (3 H, m, CH and CH2), 2.81 (2 H, t, J = 7.2 Hz, CH2), 2.11 (3 H, s, OAc), 1.91 (2 H, t, J = 6.4 Hz, CH2), 1.85 (3 H, s, NHAc), 1.19 (3 H, t, J = 7.2 Hz, CH3), 1.13 (3 H, t, J = 6.8 Hz, CH3); HRMS(ESI):M/z calculated values： C22H33N508Na [M+Na]+518.2227, measured value： 518.2222.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-diethylin -2,-oxygen ethyl】- 4- [4,-methoxycarbonyl group -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lH NMR (300 MHz, CDC13): δ 8.14 (1 H, s, CH), 7.23 (1 H, d, J = 8.1 Hz, NH), 6.13 (1 H, dd, J = 2.4 Hz, J = 9.6 Hz, 4-H),
82 6.13 (1 H, d, J = 2.7 Hz, 3-H), 5.74 (1 H, d, J = 3.6 Hz, 7-H), 5.13 (1 H, dd, J = 3.6 Hz, J = 9.9 Hz, 6-H), 4.17 (1 H, dt, J = 9.6 Hz, J = 17.4 Hz, 5-H), 3.92 (3 H, s, CH3), 3.80 (3 H, s, CH3), 3.43 (4 H, m, 2CH2), 2.14 (3 H, s, OAc), 1.96 (3 H, s, NHAc), 1.22 (3 H, t, J = 7.2 Hz, CH3), 1.13 (3 H, t, J = 7.2 Hz, CH3); HRMS(ESI): m/z [M+H]+ = 496.4.
1- [(2 3 ^) -3- acetamidos -2- ((5)-l,-acetoxyl group -2,-diethylin -2,-oxygen ethyl) -6- methoxycarbonyl groups -3,4- dihydropyran -4】- 1,2,3- triazole -4,5- dicarboxylic acid methyl esters
lU NMR (300 MHz, CDC13): δ 6.83 (1 H, d, J = 7.2 Hz, NH),
83 6.43 (1 H, dd, J = 2.4 Hz, J = 9.6 Hz, 4-H), 6.08 (1 H, d, J = 2.1 Hz, 3-H), 5.71 (1 H, d, J = 3.0 Hz, 7-H), 5.17 (1 H, dd, J = 3.0 Hz, J = 10.5 Hz, 6-H), 4.09 (1 H, dt, J = 9.9 Hz, J = 17.1 Hz, 5-H), 3.97 (3 H, s, CH3), 3.93 (3 H, s, CH3), 3.78 (3 H, s, CH3),
3.44 (4 H, m, 2CH2), 2.10 (3 H, s, OAc), 1.92 (3 H, s, NHAc), 1.24 (3 H, t, J = 7.5 Hz, CH3), (3 H, t, J = 6.9 Hz, CH3); HRMS(ESI): mlz [M+Na]+ = 576.3.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-diethylin -2,-oxygen ethyl】- 4- [4,-cyclopropyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lH NMR (300 MHz, CDC13): δ 7.50 (1 Η, s, C-H), 7.32 (1 Η, s,
84 ΝΗ), 6.06 (1 Η, s, C-H), 5.92 (1 Η, s, C-H), 5.75 (1 Η, s, C-H), 4.99 (1 H, s, C-H), 4.42 (1 H, s, C-H), 3.76 (3 H, s, CH3), 3.42 (4 H, m, 2CH2), 2.09 (3 H, s, OAc), 1.90 (3 H, s, NHAc), 1.22 (3 H, t, J = 6.9 Hz, CH3), 1.13 (3 H, s, CH3),.0.99 (4 H, d, J = 6.9 Hz, CH2), 0.99 (4 H, s, CH2); HRMS(ESI): mlz [M+H]+ = 478.3.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-diethylin -2,-oxygen ethyl】- 4- [4,-phenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
lU NMR (400 MHz, CDC13): δ 7.95 (1 H, s, CH), 7.77 (1 H, d,
85 J = 6.9 Hz, NH), 7.40 (5 H, m, PhH), 6.17 (1 H, s, C-H), 6.05 (1 H, d, J = 8.7 Hz, C-H), 6.07 (1 H, d, J = 8.4 Hz, 4-H), 5.80 (1 H, s, C-H), 5.05 (1 H, s, C-H), 4.40 (1 H, s, C-H), 3.81 (3 H, s, CH3), 3.45 (4 H, m, 2CH2), 2.13 (3 H, s, OAc), 1.94 (3 H, s, NHAc), 1.23 (3 H, t, J = 6.9 Hz, CH3), 1.12 (3 H, t, J = 6.6 Hz, CH3); HRMS(ESI): mlz [M+H]+ = 514.4.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-diethylin -2,-oxygen ethyl】- 4- [4,-(3 "-aminophenyls -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid first vinegar
lH NMR (400 MHz, CDC13):δ 7.83 (1 H, s, CH), 7.18 (2 H, t, J=7.7 Hz, NH and PhH), 7.11 (1 H, d, J=7.3 Hz, PhH), 6.67 (the Hz of 1 H, t, J=7.7,), PhH 6.17 (1 H, d, J=1.5 Hz, 3-H), 6.07 (1
86
H, d, J = 8.4 Hz, 4-H), 5.82 (1 H, d, J = 4.4 Hz, 7-H), 5.02 (1 H, dd, J = 4.8 Hz, J = 9.5 Hz, 6-H), 4.21 (1 H, dt, J = 8.4 Hz, J = 16.8 Hz, 5-H), 3.81 (3 H, s, CH3), 3.41 (4 H, m, 2CH2), 2.15 (3 H, s, OAc), 1.92 (3 H, s, NHAc), 1.21 (3 H, t, J = 6.8 Hz, CH3), 1.10 (3 H, t, J = 13.6 Hz, CH3); HRMS(ESI):M/z calculated values： C25H32N607Na [M+Na]+551.2230, measured value： 551.2217.
(2 3 ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-azanol base -2,-oxygen ethyl】_ 4- [4,-methoxycarbonyl group -1,2,3- triazoles -1】- 3,4- dihydropyran -6- methyl formates
87 lU NMR (300 MHz, DMSO-i 6): δ 10.91 (1 H, d, J = 1.5 Hz, OH), 9.08 (1 H, d, J = 1.5 Hz, NH), 8.87 (1 H, s, CH), 8.14 (1 H, d, J = 9.6 Hz, NH), 6.06 (1 H, d, J = 2.4 Hz, 3-H), 5.59 (1 H, dd, J = 2.4 Hz, J = 9.9 Hz, 4-H), 5.32 (1 H, d, J = 1.8 Hz, 7-H),
Embodiment 88 111
According to the identical method of embodiment 13, correspondingly prepare the compound of embodiment 88 111(
101 CH3CH2 H H CH(OH)CH3
102 CH3CH2 H H CH2(CH2)2OH
103 CH3CH2H H cyclopropyl
104 CH3CH2H H phenyl
105 CH3CH2H H 3'- aminophenyls
106 cyclopenta H CH2OH
107 cyclopenta H CH (OH) CH3
108 cyclopenta H CH2(CH2)2OH
109 cyclopenta COOH COOH
110 cyclopenta H phenyl
111 cyclopenta H 3'- aminophenyls Measured value： 420.1514.
(2 3 ^) -3- acetyl JKS-2- [(5 l,-acetoxyl group -2,-methoxyethyl】_ 4- [4,-cyclopropyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, DMSO-i 6): δ 7.79 (1 Η, s, CH), 5.81 (1 Η, d, J = 2.4 Hz, 3-H), 5.51 (1 H, dd, J = 2.0 Hz, J = 7.2 Hz, 4-H),
90 4.55 (1 H, d, J = 10.8 Hz, 6-H), 4.22 (1 H, m, 5-H), 4.05 (1 H, d, J = 4.0 Hz, 7-H), 2.64 (3 H, d, J = 3.6 Hz, CH3), 1.92 (1 H, m, CH), 1.76 (3 H, s, NHAc), 1.17 (3 H, m, CH3), 0.88 (2 H, m, CH2), 0.69 (2 H, m, CH2); HRMS(ESI):M/z calculated values： C16¾。N5062Na [M-H+2Na]+424.1209, measured value： 424.1232.
(2 3 ^) -3- acetamidos -2- [(5)-l,-hydroxyl -2,-methylamino -2,-oxygen ethyl】- 4- [4,-(3,-aminophenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, DMSO-i 6): δ 8.28 (1 H, s, CH), 7.03 (4 H, m, PhH), 6.51 (1 H, d, J = 7.6 Hz, NH), 5.51 (2 H, d, J = 4.5 Hz,
91
3-H and 7-H), 4.46 (1 H, m, CH), 4.29 (1 H, m, CH), 4.05 (1 H, m, CH), 2.65 (3 H, d, J=3.6 Hz, CH3), 1.74 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： C19H22N606Na [M+Na]+453.1499, measured value： 453.1515.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl】- 4- [4, methyl isophthalic acid, 2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, DMSO-i 6): δ 7.92 (1 H, s, CH), 5.80 (1 H, s, 3-H), 5.61 (1 H, d, J = 9.5 Hz, 4-H), 4.60 (1 H, d, J = 9.5 Hz),
92
4.51 (1 H, d, J = 6.1 Hz), 4.49 (2 H, s, CH2), 4.17 (1 H, t, J = 9.5 Hz, 5-H), 3.03 (3 H, s, CH3), 2.88 (3 H, s, CH3), 1.99 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： C15H21N507Na [M+Na]+406.1339, measured value： 406.1330.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl】- 4- [4,-(1 " base ethyl) -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, DMSO-i 6): δ 7.87 (1 H, d, J = 4.8 Hz, CH), 5.88 (1 H, s, 3-H), 5.59 (1 H, s, 4-H), 4.80 (1 H, m, 6-H), 4.61 (1
93
H, m, 7-H), 4.50 (2 H, s, CH2), 4.17 (1 H, t, J = 5.9 Hz, 5-H), 3.02 (3 H, s, CH3), 2.86 (3 H, s, CH3), 1.77 (3 H, s, NHAc), 1.39 (3 H, d, J = 6.2 Hz, CH3); HRMS(ESI):M/z calculated values： Ci6H23N507Na [M+Na]+420.1495, measured value： 420.1503.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl】- 4- [4, propyl group -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, DMSO-i 6): δ 7.79 (1 H, s, CH), 5.72 (1 H,
94
S, 3-H), 5.56 (1 H, d, J=9.2 Hz, 4-H), 4.57 (2 H, t, 6-H and 7-H), 4.13 (1 H, t, J=9.5 Hz, 5-H), 3.40 (2 H, m, CH2), 3.02 (3 H, s, CH3), 2.88 (3 H, s, CH3), 2.61 (2 H, t, J = 7.3 Hz, CH2), 1.76 (3 H, s, NHAc), 1.69 (2 H, t, J = 6.2 Hz, CH2); HRMS(ESI):M/z calculated values： C17H25N507Na [M+Na]+434.1652, measured value： 434.1662.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl】_ 4- [4,-carboxyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
lU NMR (400 MHz, CDC13): δ 8.64 (1 Η, s, CH), 5.91 (1 Η, d, J = 2.1 Hz, 3-H), 5.61 (1 H, dd, J = 2.0 Hz, J = 9.4 Hz, 4-H), 4.60
95
(1 H, dd, J = 2.2 Hz, J = 9.6 Hz, 6-H), 4.50 (1 H, s, 7-H), 4.20 (1
H, t, J = 10.0 Hz, 5-H), 3.02 (3 H, s, CH3), 2.84 (3 H, s, CH3),
I.72 (3 H, s, NHAc); HRMS(ESI):M/z evaluations： C15H19N508Na [M+Na]+420.1131, measured value： 420.1121.
1- [(2 3 ^) -3- acetyl ^ -2- ((5 1, base -2,-diformazan JKS-2,-oxygen ethyl) -6- carboxyls -3,4- dihydropyran -4】- 1,2,3- triazole -4,5- dioctyl phthalate
lU NMR (400 MHz, DMSO-i 6): δ 6.61 (1 H, d, J = 8.8 Hz, NH), 5.92 (1 H, d, J = 2.1 Hz, 3-H), 4.65 (1 H, d, J = 10.0 Hz,
96
4-H), 4.51 (1 H, m, 6-H and 7-H), 4.34 (1 H, m, 5-H), 3.03 (3 H, s, CH3), 2.86 (3 H, s, CH3), 1.65 (3 H, s, NHAc); HRMS(ESI):M/z evaluations： C21H27N5OuNa2 [M+2Na]+486.0849, measured value： 486.0862.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl】_ 4- [4,-cyclopropyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, DMSO-i 6): δ 7.82 (1 H, s, CH), 5.84 (1 H, s, 3-H), 5.55 (1 H, d, J = 8.1 Hz, 4-H), 4.62 (2 H, t, J = 1.5 Hz, J
97 = 8.1 Hz, 6-H), 4.50 (2 H, d, J = 1.1 Hz, 7-H), 4.11 (1 H, t, J = 9.9 Hz, 5-H), 3.03 (2 H, m, CH3), 2.87 (3 H, s, CH3), 1.92 (1 H, m, CH), 1.76 (3 H, s, NHAc), 0.88 (2 H, d, J = 8.4 Hz, CH2) , 0.70 (2 H, s, CH2); HRMS(ESI):M/z calculated values： C17H23N506Na [M+Na]+416.1546, measured value： 416.1500.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl】- 4- [4,-phenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
lU NMR (400 MHz, DMSO-i 6): δ 8.68 (1 H, s, CH), 7.92 (2 H, d, J = 7.2 Hz, PhH), 7.44 (2 H, t, J = 7.2 Hz, PhH), 7.32 (1 H, t, J = 7.6 Hz, PhH), 6.03 (1 H, d, J = 4.8 Hz, 3-H), 5.67 (1 H, dd, J =
98
2.8 Hz, J = 10.4 Hz, 4-H), 5.48 (1 H, t, J = 3.6 Hz, 7-H), 4.66 (1 H, dd, J = 2.0 Hz, J = 10.4 Hz, 6-H), 4.20 (1 H, dt, J = 10.4 Hz, J = 18.0 Hz, 5-H), 3.11 (3 H, s, CH3), 3.05 (3 H, s, CH3), 1.76 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： C2。H23N506Na [M+Na]+452.1546, measured value： 452.1537.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-dimethylamino -2,-oxygen second
99 bases】- 4- [4,-(3,-aminophenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, DMSO-i 6): δ 8.41 (1 H, s, CH), 7.05 (5 H, m, PhH + 2NH), 6.52 (2 H, m, PhH + NH), 5.94 (1 H, d, J = 2.6 Hz, 3-H), 5.64 (1 H, dd, J = 2.2 Hz, J = 9.5 Hz, 4-H), 4.65 (1 H, dd, J = 2.1 Hz, J = 10.1 Hz, 6-H), 4.51 (1 H, d, J = 2.4 Hz, 7-H), 4.21 (1 H, t, J = 9.5 Hz, 5-H), 3.04 (3 H, s, CH3), 2.85 (3 H, s, CH3), 1.76 (3 H, s, NHAc); HRMS(ESI):M/z evaluations： C20H24N6O6Na [M+Na]+467.1655, measured value： 467.1668.
(2 3 ^) -3- acetamidos -2- [(5)-l,-hydroxyl -2,-ethylamino- -2,-oxygen second
100 bases】- 4- [4, methyl isophthalic acid, 2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
HRMS(ESI): [M+Na]+ = 406.1.
(2 3 ^) -3- acetamidos -2- [(5) -1,-hydroxyl -2,-ethylamino- -2,-oxygen second
101 bases】- 4- [4,-(1 " base ethyl) -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
HRMS(ESI): [M+H]+ = 398.2;
(2 3 ^) -3- acetamidos -2- [(5) -1,-hydroxyl -2,-ethylamino- -2,-oxygen ethyl】- 4- [4, propyl group -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid lU NMR (300 MHz, DMSO-i 6): δ 8.23 (1 Η, d, J = 8.7 Hz, NH), 7.80 (1 H, s, CH), 7.68 (1 H, m, NH), 5.97 (1 H, d, J = 5.4
102 Hz, 7-H), 5.84 (1 H, d, J = 2.4 Hz, 3-H), 5.54 (1 H, dd, J = 2.4 Hz, J = 9.9 Hz, 4-H), 5.43 (1 H, t, J = 5.4 Hz, 5-H), 4.53 (1 H, m, 6-H), 4.25 (2 H, m, CH2), 3.16 (2 H, m, CH2), 2.65 (2 H, dt, J =
8.7 Hz, J = 16.2 Hz, CH2), 1.76 (3 H, s, NHAc), 1.72 (2 H, t, J =
7.8 Hz, CH2), 1.04 (3 H, m, CH3); HRMS(ESI): [M+H]+ = 412.3.
(2 3 ^) -3- acetamidos -2- [(5)-l,-hydroxyl -2,-ethylamino- -2,-oxygen ethyl】_ 4- [4,-cyclopropyl -1,2,3- triazoles-l】- 3,4- dihydropyran -6- formic acid lH NMR (300 MHz, DMSO-i 6): δ 8.21 (1 H, d, J = 8.7 Hz, NH), 7.79 (1 H, s, CH), 7.69 (1 H, m, NH), 5.96 (1 H, d, J = 5.4
103 Hz, 7-H), 5.80 (1 H, d, J = 2.4 Hz, 3-H), 5.53 (1 H, dd, J = 2.7 Hz, J = 9.9 Hz, 4-H), 5.37 (1 H, t, J = 5.1 Hz, 5-H), 4.51 (1 H, m, 6-H), 3.14 (2 H, m, CH2), 1.94 (1 H, m, CH), 1.88 (3 H, s, NHAc), 1.04 (3 H, m, CH3), 0.88 (2 H, m, CH2), 0.69 (2 H, m, CH2); HRMS(ESI): m/z [M+H]+ = 394.2.
(2 3 ^) -3- acetamidos -2- [(5)-l,-hydroxyl -2,-ethylamino- -2,-oxygen second
104 bases】- 4- [4,-phenyl -1,2,3- triazoles-l】- 3,4- dihydropyran -6- formic acid
HRMS(ESI): [M+H]+ = 430.2.
(2 3 ^) -3- acetamidos -2- [(5) -1,-hydroxyl -2,-ethylamino- -2,-oxygen second
105 bases】- 4- [4,-(3,-aminophenyl -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
HRMS(ESI): [M+H]+ = 445.2.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl】- 4- [4, methyl isophthalic acid, 2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid
106 lH NMR (400 MHz, DMSO-i 6): δ 8.24 (1 H, d, J = 8.8 Hz, OH), 7.87 (1 H, s, CH), 5.96 (1 H, d, J = 5.7 Hz, OH), 5.84 (1 H, d, J = 2.7 Hz, 3-H), 5.57 (1 H, dd, J = 2.7 Hz, J = 9.5 Hz, 4-H), 4.55 (1 H, dd, J = 2.4 Hz, J = 9.9 Hz, 6-H), 4.47 (2 H, s, CH2), 4.31 (1 H, d, J = 3.0 Hz, 7-H), 4.21 (1 H, t, J = 9.4 Hz, J = 19.4 Hz, 5-H), 3.57 (4 H, m, 2CH2), 1.76 (4 H, m, 2CH2), 1.73 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： C17H23N507Na [M+Na]+432.1495, measured value： 432.1490.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl】- 4- [4 ,-(l " bases ethyl)-l, 2,3- triazole-l】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, CDC13): δ 7.64 (1 Η, d, J = 2.6 Hz, CH), 5.87 (1 H, d, J = 2.0 Hz, 3-H), 5.57 (1 H, d, J = 9.0 Hz, 6-H),
107 4.80 (1 H, d, J = 2.4 Hz, 7-H), 4.56 (1 H, m, CH), 4.32 (1 H, dd, J = 3.0 Hz, J = 10.1 Hz, 4-H), 4.18 (1 H, dd, J = 10.0 Hz, J = 18.7 Hz, 5-H), 3.62 (4 H, m, 2CH2), 1.78 (4 H, m, 2CH2), 1.75 (3 H, s, NHAc), 1.38 (3 H, d, J = 6.5 Hz, CH3); HRMS(ESI):M/z calculated values： C18H25N507Na [M+Na]+446.1652, measured value： 446.1627.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl】- 4- [4, propyl group -1,2,3- triazoles -1】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, DMSO-i 6):δ 7.76 (1 H, s, CH), 5.55 (1 H, s, 3-H), 4.52 (1 H, d, J=10.0 Hz, 6-H), 4.36 (2 H, m, 4-H and
108 7-H), 4.10 (1 H, t, J=9.8 Hz, 5-H), 3.76 (1 H, m, CH), 3.60 (3 H, m, CH and CH2), 2.56 (2 H, t, J = 7.2 Hz, CH2), 1.80 (4 H, m, 2CH2), 1.73 (3 H, s, NHAc), 1.63 (2 H, t, J = 6.3 Hz, CH2); HRMS(ESI):M/z calculated values： C19H27N507Na [M+Na]+460.1808, measured value： 460.1812.
1- [(2 3 ^) -3- Yi Ugly amidos -2- 51, base -2,-cyclopentamine base -2,-oxygen ethyl) -6- carboxyls -3,4- dihydropyran -4】- 1,2,3- triazole -4,5- dioctyl phthalate
lU NMR (400 MHz, DMSO-i 6): δ 6.78 (1 H, m, CH), 5.98 (1 H,
109 d, J = 1.9 Hz, 3-H), 4.61 (1 H, m, CH), 4.46 (1 H, m, CH), 4.34 (1 H, m, CH), 3.75 (4 H, m, 2CH2), 1.80 (4 H, m, 2CH2), 1.66 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： [M]+468.1367, measured value： 468.1340.
(2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl】- 4- [4,-phenyl -1,2,3- triazoles-l】- 3,4- dihydropyran -6- formic acid
lU NMR (400 MHz, DMSO-i 6): δ 8.62 (1 H, s, CH), 7.92 (2 H, t, J = 7.3 Hz, PhH), 7.43 (2 H, t, J = 7.6 Hz, PhH), 7.32 (1 H, t, J
110=7.2 Hz, PhH), 5.69 (1 H, s, 3-H), 5.41 (1 H, s, 6-H), 4.63 (1 H, s, 4-H), 4.48 (1 H, s, 5-H), 4.32 (1 H, d, J=7.8 Hz, 5-H), 4.24 (1 H, m, CH), 3.71 (3 H, m, C standing grain B CH), 1.84 (4 H, m, 2CH2), 1.74 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： C22H25N506Na [M+Na]+478.1703, measured value： 478.1722.
111 (2 3 ^) -3- acetamidos -2- [(5 1,-hydroxyl -2,-cyclopentamine base -2,-oxygen second Base】_ 4- [4,-(3,-aminophenyl -1,2,3- triazoles-l】- 3,4- dihydropyran -6- formic acid lU NMR (400 MHz, DMSO-i 6):(1 H of δ 8.42, s, CH), 7.08 (3 H, m, PhH), 6.54 (1 H, m, PhH), 5.95 (1 H, d, the Hz of J=2.6, 3-H), 5.63 (1 H, dd, the Hz of J=2.3, the Hz of J=9.4, 6-H), 4.62 (1 H, dd, the Hz of J=2.8, the Hz of J=10.2, 4-H), 4.35 (1 H, d, the Hz of J=2.7, 7-H), 4.27 (1 H, t, the Hz of J=9.8, 5-H), 3.79 (1 H, m, CH), 3.28 (3 H, m, C standing grain mouthful CH), 1.76 (4 H, m, 2CH2), 1.74 (3 H, s, NHAc); HRMS(ESI):M/z calculated values： C22H26N606Na [M+Na]+493.1812, measured value：493.1815. embodiment 112 115
Using the title compound of embodiment 2 as raw material, according to method same as Example 5, reacted from different amine or amino sugar, to prepare title compound.
Base】- 4- azido -3,4- dihydropyran -6- methyl formates
¾ NMR (300 MHz, CD3C1): δ 6.83 (1 H, d, J = 7.5 Hz, NH), 5.94 (1 H, d, J = 1.8 Hz, 3-H), 5.41 (1 H, d, J = 1.2 Hz, 7-H), 4.52 (1 H, d, J = 10.5 Hz, 6-H), 4.36 (1 H, dd, J = 9.6 Hz, J = 19.2 Hz, 5-H), 4.28 (1 H, dd, J = 2.1 Hz, J = 9.3 Hz, 4-H), 3.80 (3 H, s, CH3), 3.69 (2 H, m, -CH2OH), 3.05 (2
H, m, -C¾NCO), 2.23 (3 H, s, OAc),
I .98 (3 H, s, NAc); LRMS(ESI): mlz [M+H]+ = 400.4.
(2 ！R, ^) -3- acetamidos -2- [(5)-l,-acetoxyl group -2,-morpholinyl -2,-oxygen ethyl】- 4- azido -3,4- dihydropyran -6- methyl formates
¾ NMR (300 MHz, CD3C1): δ 6.21 (1 H, d, J = 2.7 Hz, NH), 6.05 (1 H, d, J = 3.3 Hz, 3-H), 5.82 (1 H, d, J = 5.4 Hz, 7-H), 4.73 (1 H, t, J = 6 Hz, 6-H),
N3
4.51 (1 H, dd, J = 3.3 Hz, J = 6.3 Hz, 4-H), 4.04 (1 H, dd, J = 7.2 Hz, J = 14.1 Hz, 5-H), 3.81 (3 H, s, CH3), 3.64 (8 H, m, -CH2), 2.15 (3 H, s, OAc), 2.03 (3 H, s, NAc); LRMS(ESI): mlz [M+Na]+ = 448.2. Embodiment 116 119
Using the title compound of embodiment 112 115 as raw material, reference and the identical method of embodiment 22 first carry out reaction with DBU with Lindlar catalyst and prepare the compound of embodiment 116 119 again.
Example structure formula name and1H-NMR, MS data Embodiment 120 (2 3 ^) -3- acetamidos -2- [(5)-l,-hydroxyl -2,-ethoxy amido -2,-oxygen ethyl】- 4- guanidine radicals -3,4- dihydropyran -6- formic acid
The compound of 20 mg embodiments 117 is dissolved in 0 (1.5 mL), add 46 mg guanylpyrazoles mono-hydrochloric salts and 116 DIPEA, be stirred overnight at room temperature, separated after question response is complete with resin cation 15mg faint yellow solids title compound. iH NMR (300 MHz, D20): δ 7.57 (1 Η, d, J = 1.5 Hz, NH), 5.55 (1 H, d, J = 2.1 Hz, 3-H), 4.38 (1 H, dd, J = 1.2 Hz, J = 10.5 Hz, 6-H), 4.27 (1 H, d, J = 3.6 Hz:7-H), 4.21 (1 H, d, J = 10.8 Hz, 5-H), 4.08 (1 H, dd, J = 2.4 Hz, J = 9.6 Hz, 4-H), 3.54 (2 H, t, J = 5.4 Hz, -CH20H), 3.29 (2 H, t, J = 5.1 Hz, -CH2NCO), 1.94 (3 H, s, NAc); LRMS(ESI): mlz [M+Na]+ = 360.3.(2 3 the ^) -3- acetamidos -2- of embodiment 121 [(5)-l,-hydroxyl -2,-morpholinyl -2, base】- 4- amino -3,4- dihydropyran -6- methyl formates The compound of 35 mg embodiments 1 14 is dissolved in CH3In OH (1.0 mL), Lindlar catalyst is added（10 mg) after, it is passed through after 24 h of reaction, TLC display reactions are complete, stop reaction.Resin cation separates to obtain 27 mg products, i.e. title compound.
Embodiment 122 (2 ^, ^) -3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl】- 4- [2,3 ,-two tertbutyloxycarbonyl guanidine radicals】- 3,4- dihydropyran -6- formic acid
The compound of 27 mg embodiments 121 is dissolved in CH3In OH (1.0 mL), 25 bis- tertbutyloxycarbonyl guanylpyrazoles of mg N, N'- are added, 35 degree heating 24 h, TLC display reactions are complete, stop reacting.Concentration of reaction solution, isolate and purify 30 mg white solids title compound.
(2 3 the ^) -3- acetyl of embodiment 123 JKS-2- [(5)-l, ~ base -2,-morpholinyl -2, -
The title compound of 30 mg embodiments 122 is dissolved in 0.5 mL THF/0.5 mL H2In 0,2eq NaOH are added, are stirred at room temperature after 2 h, adjusted pH to neutrality with resin cation, filter out resin, add 0.5 mL CF3In COOH, 2 h are stirred at room temperature, TLC display reactions are complete, concentration of reaction solution crosses the title compound that resin cation obtains 10 mg faint yellow solids. ¾ NMR (300 MHz, CD3OD): δ 5.70 (1 H, d, J = 6.0 Hz, 3-H), 4.82(1 H, d, J = 3.3 Hz, 7-H), 4.54 (1 H, dd, J = 3.3 Hz, J = 8.4 Hz, 6-H), 4.43 (1 H, dd, J = 3.0 Hz, J = 7.8 Hz, 4-H), 4.17 (1 H, t, J = 8.4 Hz, 5-H), 3.66 (8 H, m, -CH2), 2.04 (3 H, s, NAc),; LRMS(ESI): mlz [M+H]+= 386.3.The neuraminic acid enzyme inhibition activity of the compounds of this invention is determined：
Reference literature (S oorg. ＆ Med. Chem. Lett. 2007,17,1655-1658) method, determines the general formula compound infected by influenza H3N2 of present invention inhibitory activity.Measurement result such as following table： H3N2 H5N1 compound (Example No.）
0(μΜ) 0(μΜ)
24 0.67
25 0.028 0.650
31 3.2
35 1.3
37 7.4 as seen from the above table, compound of the present invention has the inhibitory activity of obvious infected by influenza, and the structure of such compound is different from zanamivir, the treatment available for the influenza virus to zanamivir resistance, and compound polarity is reduced, be conducive to being administered orally.
Moreover, in resisiting influenza virus mouse block mold, compound 25 is administered orally, obvious Anti-viral Treatment is demonstrated by 50mg/kg and 100mg/kg dosage, and in dose dependent, show that the compound is not only effective in vitro, it is same effective in animal body.
Thus, the invention provides class formation novelty, the N-acetyl-neuraminate class compound of high activity, such compound and its pharmaceutical composition can be used for resisiting influenza virus, particularly, available for the treatment to zanamivir, the influenza infection difficult to understand for taking charge of other Tamiflu resistances such as its Wei.Moreover, the typical compound polarity of such compound is smaller than zanamivir, Orally-administrable improves oral administration biaavailability.

Claims (1)

  1. Claim
    1st, shown in below formula N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates：
    R1Represent OR5、 SR5、 NR5R6、 N(OR5) R6 or N (NR5R6) R6;
    R2Represent H, C1 -20Protective embankment base, the d_ of CM protective embankments epoxide substitution5Protective embankment base, COR5Or
    CONR'R；
    R represents N3、 NR7R8、 NHC(=NR9)NR5R10 N=PPh3Or R "； R4Represent COOR5、 CONR5R6Or CON (OR5)R6 ;
    R5Represent H, d.H) protective embankment base, C3.8Ring protective embankment base, C2.1()Alkenyl, C2.1() alkynyl, pentafluorophenyl group, aryl, CONR14R15、 COOR14、 COR14, not necessarily replaced by one or more hydroxyl protecting group five yuan or hexa-atomic monosaccharide groups or by one or more following substituent groups.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl or.Alkynyl： NR14R15、 NR14COR15、 C02R14、 OR14、 C 8Ring protective embankment base and aryl；
    R6Represent H, Cwo protective embankment base, ring protective embankment base, Cwo alkenyls, Cwo alkynyls, aryl, COR14, not necessarily replaced by one or more hydroxyl protecting group five yuan or hexa-atomic monosaccharide groups or the C^H by one or more following substituent groups) and protective embankment base： NR14R14、 COR14, C3-8Ring protective embankment base, CN, N3、 OR14And aryl；
    Or R5And R6The nitrogen-atoms being connected with them collectively forms cyclic structure, and the cyclic structure is saturated or unsaturated, and containing one or more hetero atoms in N, 0 and S, The cyclic structure is not necessarily by halogen, Cwo protective embankments base, d-Cu) protective embankment epoxide, C3_8Ring protective embankment base, C2_1QAlkenyl, C2.1QAlkynyl, CF3, CN or N02Substitution;
    R7And R8H, CN, d. are represented independently of one another6Protective embankment base, C3.8Ring protective embankment base, C2.6Alkenyl, C2_6Alkynyl or C2_6Hydrocarbon chain, not necessarily containing a NR in the hydrocarbon chain11Group, the hydrocarbon chain is not necessarily selected from oxo base and d_ by 146The group of protective embankment base is replaced, and the protective embankment base is not necessarily replaced by hydroxyl or aryl；
    R9And R1G11, d_ is represented independently of one another6Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, C2-1O alkynyls, NR14R15、 OR14, CN or N02;
    R11And R12Represent independently of one another H,.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, Cwo alkynyls,.Protective embankment epoxide, COOR5、 CONR14R15Or aryl；Or not necessarily by hydroxyl, amino, amido, COOR5Or d_6The Cwo protective embankment bases of protective embankment epoxide substitution；
    R14And R1511, d_ is represented independently of one another6Protective embankment base, C3_8Ring protective embankment base or aryl；Wherein, the aryl refers to aromatic carbocyclic ring or heterocyclic group, and is not necessarily substituted；When the aryl is substituted, substituent includes protective embankment base, d_4Protective embankment epoxide, halogen, nitro, trifluoromethyl, amino, amino, phenyl and the benzyl of the substitution of protective embankment base；The aryl is replaced by 13 above-mentioned substituents.
    2nd, shown in formula according to claim 1 N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, it is characterised in that wherein,
    R1Represent 0R5、 NR5R6Or N (OR5)R6;
    R2Represent H, COR5Or CONR5R6;
    ,N、
    R3Represent NR7R8、 NHC(=NR9)NR5R1()OrΝΛ ", it is α configurations； R4Represent COOR5、 CONR5R6Or CON (OR5)R6 ;
    R5And R6Represent independently of one another.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, C2_1QAlkynyl, aryl or not necessarily by one or more be selected from d-C6Protective embankment base, trimethyl Five yuan or hexa-atomic monosaccharide groups of the substituent substitution in silicon substrate, benzyl and acetyl group；Or by
    OR14、 C3_8What ring protective embankment base or aryl replaced.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl or C3-1O block bases；
    Or R5And R6The nitrogen-atoms being connected with them collectively forms cyclic structure, the cyclic structure is saturated or unsaturated, and containing one or more hetero atoms in N, 0 and S, the cyclic structure is not necessarily by halogen, Cwo protective embankments base, d-Cu) protective embankment epoxide, C3_8Ring protective embankment base,.Alkenyl or.Alkynyl substituted；
    R7And R811, CN, d_ are represented independently of one another6Protective embankment base, C3_8Ring protective embankment base,（2_6Alkenyl, C2_6Alkynyl or (_6Hydrocarbon chain, not necessarily containing a NR in the hydrocarbon chain11Group, the hydrocarbon chain is not necessarily selected from oxo base and d_ by 146The group of protective embankment base is replaced, and the protective embankment base is not necessarily replaced by hydroxyl or aryl；
    R9And R1GD. is represented independently of one another6Protective embankment base, NR14R15、 OR14, CN or N02;
    R11And R12Represent H, d.u independently of one another) protective embankment base, C3.8Ring protective embankment base, COOR5Or aryl；Or not necessarily by hydroxyl, amino, amido, COOR5Or d_6The substitution of protective embankment epoxide.Protective embankment base；
    R14And R1511, d_ is represented independently of one another6Protective embankment base, C3_8Ring protective embankment base or aryl；The definition of the aryl is identical with claim 1.
    3rd, shown in formula according to claim 2 N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, it is characterised in that wherein,
    R1Represent NR5R6Or N (OR5)R6;
    R2Represent H or COR5 ;
    R3For α configurations；
    R3Represent NR7R8Or NHC (=NR9)NR5R10; R4Represent COOR5Or CON (OR5)R6;
    R5And R6Represent independently of one another.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, C2_1QAlkynyl, rhamanopyranosyl, mannose group, glucosyl group, the protective embankment base being optionally substituted by a hydroxyl group, the C being optionally substituted by a hydroxyl group3_8Ring protective embankment base, the C being optionally substituted by a hydroxyl group3_1QAlkenyl is optionally substituted by a hydroxyl group C3_1QAlkynyl；Or R5And R6The nitrogen-atoms being connected with them collectively forms cyclic structure, and the cyclic structure is saturated or unsaturated, and containing one or more hetero atoms in N, 0 and S, the cyclic structure is not necessarily by Cwo protective embankments base, C3_8Ring protective embankment base, C2_1QAlkenyl or.Alkynyl substituted；
    R7And R8H, CN, d. are represented independently of one another6Protective embankment base, C3.8Ring protective embankment base, C2.6Alkenyl, C2_6Alkynyl or C2_6Hydrocarbon chain, not necessarily containing a NR in the hydrocarbon chain11Group, the hydrocarbon chain is not necessarily selected from oxo base and d_ by 1 or 26The group of protective embankment base is replaced, and the protective embankment base is not necessarily replaced by hydroxyl or aryl；The aryl includes phenyl, naphthyl, pyridine radicals, imidazole radicals and thienyl, and is not necessarily substituted；When the aryl is substituted, the substituent includes protective embankment base, d_4Protective embankment epoxide, nitro, amino, phenyl and benzyl；And the substituted aryl is with 13 above-mentioned substituents；
    R9And R1GC is represented independently of one another1-6Protective embankment base, N, OH, CN or N02;
    R11And R12Represent 11 independently of one another,.Protective embankment base, C3_8Ring protective embankment base or COOR5。
    4th, shown in formula according to claim 3 N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, it is characterised in that wherein,
    R1Represent NR5R6 ;
    R2Represent H;
    R3N or NHC (=NH) N is represented, it is α configurations；
    R4Represent COOR5;
    R5And R6Represent independently of one another.Protective embankment base, C3_8Ring protective embankment base,.Alkenyl, C2_1QAlkynyl, mannose group, glucosyl group or the Cwo protective embankment bases being optionally substituted by a hydroxyl group；Or R5And R6The nitrogen-atoms being connected with them collectively forms cyclic structure, and the cyclic structure is saturated or unsaturated, and containing one or more hetero atoms selected in N, 0 and S, the cyclic structure is not necessarily by Cwo protective embankments base, C3_8Ring protective embankment base, C2_1QAlkenyl or C2_1QAlkynyl substituted.
    5th, shown in formula according to claim 1 N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, it is characterised in that it is selected from：
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-methylamino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-methylamino -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2 chi ^, ^) -3- acetamidos -2- [(- 1,-acetoxyl group -2,-ethylamino- -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- methyl formates,
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-ethylamino- -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-ethylamino- -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-diethylin -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2 chi ^, ^) -3- acetamidos -2- [(- 1,-acetoxyl group -2,-diethylin -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- methyl formates, (2 chi ^, ^) -3- acetamidos -2- [(- 1,-acetoxyl group -2,-diethylin -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- methyl formates,
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-diethylin -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2 chi ^, ^) -3- acetamidos -2- [(5) -1,-hydroxyl -2,-amino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-isopropylamine base -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-azanol base -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid
    (2R, ^S 3- acetamidos -2- [(5 1,-hydroxyl -2,-cyclohexylamino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2R, ^S 3- acetamidos -2- [(- 1,-hydroxyl -2,-cyclohexyl amido -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (^ 3- acetamidos -2- [(5) -1,-hydroxyl -2,-amino -2,-oxygen ethyl] -4- guanidine radicals -3, the 4- dihydropyran -6- formic acid of 2 chi 3,
    (2R, ^S 3- acetamidos -2- [0)-l,-hydroxyl -2,-isopropylamine amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-two（Ethoxy）Amido -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid, (2R, ^S 3- acetamidos -2- [C)-l,-hydroxyl -2,-two（Ethoxy）Amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-ethoxy amido -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2¾^, ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-ethoxy amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2R, 3R, 4S) -3- acetamidos -2- [(5)-Γ-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- methyl formates,
    (2R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2R, ^S)-3- acetamidos-2- [(5 1 ,-hydroxyl-2,-(tetrahydrochysene-2,4,5- trihydroxies-6- (methylol)-2-pyrans-3- bases amino)-2,-oxygen ethyl]-4- amino-3,4- dihydropyran-6- formic acid and (2R, ^S 3- acetamidos-2- [(5 1 ,-hydroxyl-2 ,-(tetrahydrochysene-2,4,5- trihydroxies-6- (methylol)-2-pyrans-3- bases amino)-2 ,-oxygen ethyl]-4- guanidine radicals-3,4- dihydropyran-6- formic acid.
    6th, shown in formula (I) according to claim 5 N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, it is characterised in that it is selected from：
    (the chi ^ of 2 chi 3) -3- acetamidos -2- [(- 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2R, ^S) -3- acetamidos -2- [(- 1,-hydroxyl -2,-dimethylamino -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2 chi ^, ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-diethylin -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid, (2/ R, 4) -3- acetamidos -2- [(5 Γ-hydroxyl -2,-diethylin -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2 chi ^, ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-cyclopentamine base -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (ZR, ^) -3- acetamidos -2- [0)-l,-hydroxyl -2,-two（Ethoxy）Amido -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (the chi ^ of 2 chi 3) -3- acetamidos -2- [(- 1,-hydroxyl -2,-two（Ethoxy）Amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2^ chi ^) -3- acetamidos -2- [(- 1,-hydroxyl -2,-ethoxy amido -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2 R, 4 3- acetamidos -2- [(5 1,-hydroxyl -2,-ethoxy amido -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    (2R R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- amino -3,4- dihydropyran -6- formic acid,
    (2i R, ^S 3- acetamidos -2- [(5) -1,-hydroxyl -2,-morpholinyl -2,-oxygen ethyl] -4- guanidine radicals -3,4- dihydropyran -6- formic acid,
    Chi ^, ^^- acetamido ^-,-hydroxyl-Tetrahydrochysene ^- trihydroxies methylol)-2-pyrans-3- bases amino)-2,-oxygen ethyl]-4- amino-3,4- dihydropyran-6- formic acid and (2 R, ^S 3- acetamidos-2- [(5 1,-hydroxyl-2,-(tetrahydrochysene-2,4,5- trihydroxies-6- (methylol)-2/7- pyrans-3- bases amino)-2,-oxygen ethyl]-4- guanidine radicals-3,4- dihydropyran-6- formic acid.
    7th, described in claim 1 N-acetyl-neuraminate class compound shown in formula (I) or the preparation method of their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, characterized in that, using any one in following methods：
    (1) as R in logical formula (I) compound1For OH, R2It is not H, R3For N3, R4For COOR5, and R5When being not H, i.e. formula (la) compound is prepared by the cracking of formula (Π) compound oxidation；If desired, being then deprotected；The R of formula (Π) compound2And R4Substitution Base defines same general formula compound:
    (II) (la)
    Oxicracking is completed by Liang Walk：Mono- Walk react with periodate；Bis- Walk reagent is chlorite；
    (2) as R in logical formula (I) compound1For OR5Or SR5When, i.e. formula (Ic) compound passes through the R in corresponding general formula compound1Represent OH formula (lb) compound and by R5The oxygen-containing or sulfur-containing compound of substitution is prepared by condensation reaction；
    (lb) (lc) (R1=OR5,SR5、
    (3) as R in logical formula (I) compound1For NR5R6、 N(OR5) R6 or N (NR5R6) R6When, i.e. formula (id) compound passes through the R in corresponding general formula compound1Represent OH formula
    (lb) compound and-R6、 -(OR5)R6Or-(NR5R6)R6Substituted nitrogen-containing compound reacts to prepare；Carboxyl is activated before being reacted with amine；Aminating reaction is completed in organic solvent；
    (lb) (Id) (R1=NR5R6,N(OR5)R6, N(NR5R6)R6、
    (4) as R in formula (i) compound3For When, i.e. formula (if) compound passes through the R led to accordingly in formula (I) compound3Represent N3Formula (Ie) compound with by R11And R12Substituted acetylene compound reacts to prepare；Prepare and carried out under catalyst, catalysis process bag Include cuprous ion catalysis;
    (le) (If)
    (5) as R in logical formula (I) compound3During for N, i.e. formula (Ig) compound passes through the R in corresponding general formula compound3Represent N3Formula (le) compound prepared by the reduction reaction of azido；
    (le) (ig)
    (6) as R in logical formula (I) compound3For NR7R8When, i.e. formula (Ih) compound, the R from logical formula (I) compound3For N formula (Ig) compound by with by R7And R8Substituted compound reacts to prepare；
    (7) as R in logical formula (I) compound3For NHC (=NR14)NR15R16When, i.e. formula (Ii) compound, from the R in general formula compound3For NR7R8Formula (lh) compound pass through guanidine radicals Change reaction to prepare；When R is NHC (=NH) NH in logical formula (I) compound2When, i.e. formula (Ik) compound passes through the R in logical formula (I) compound3For NH2Formula (Ig) compound and guanylpyrazole or its salt or derivatives reaction or by the R in general formula compound3Prepared for the NHCN compound of intermediate formula 00；
    (8) as R in logical formula (I) compound3Represent N3, R4For CONR5R6When, i.e. formula (Im) compound passes through the R led to accordingly in formula (I) compound3Represent N3, R4For COOR5, and R5It is not that H logical formula (II) compound is obtained with the basic salt reaction of azanol or derivatives thereof；
    (9) R in formula (I) compound is led to3For NR7R8Formula (Ih) compound or logical formula (I) compound in R3For NHC (=NR14)NR15R16Formula (Ii) compound from the R in general formula compound3Represent N3, R4For CONR5R6Formula (Im) compound by with the above method（5) similar azido restoring method is reduced, and then Jin mono- Walk react to prepare；Or
    (10) other compounds of formula can be prepared by mutually being converted by the functional group between formula different compounds 1.；Wherein R2Prepared for H compound by not being H compound； R7And R8Corresponding R is not passed through for H compound7And/or R8Prepared for H compound； R4For COOR5、 CONR5R6Or CON (OR5)R6Compound and R4Mutually converted for COOH compound.
    8th, shown in formula (I) according to claim 7 N-acetyl-neuraminate class compound or the preparation method of their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, it is characterized in that, when preparing formula (la) compound, oxicracking mono- Walk are to use periodate, are completed in water-containing organic solvent；Bis- Walk are to use chlorite, there are the buffer including alkali metal or alkali earth metal phosphate, are completed in water-containing organic solvent. 9th, shown in formula (I) according to claim 7 N-acetyl-neuraminate class compound or the preparation method of their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, it is characterized in that, when preparing formula (Id) compound, the method that carboxyl is activated before being reacted with amine includes changing into phenyl-pentafluoride epoxide；Aminating reaction is completed in ether.
    10th, formula according to claim 7 1. shown N-acetyl-neuraminate class compound or the preparation method of their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates, it is characterized in that, when preparing formula (Ig) compound, the reducing condition is Lindlar catalysts, and hydrogen or formic acid provide reactive hydrogen.
    11st, the 1. purposes of shown N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates in the medicine of neuraminidase inhibitor is prepared of the formula in claim 16.
    12nd, the 1. purposes of shown N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates in the medicine for suppressing virus is prepared of the formula in claim 16.
    13rd, purposes according to claim 12, it is characterised in that the virus includes influenza virus.
    14th, the 1. purposes of shown N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates in the medicine of prevention and treatment viral disease and its infection is prepared of the formula in claim 16.
    15th, a kind of formula for being used to suppress in the pharmaceutical composition of neuraminidase, one or more claims 16 of the said composition comprising therapeutically effective amount 1. shown N-acetyl-neuraminate class compound or their any prodrug forms, their officinal salt or pharmaceutical acceptable solvates and one or more pharmaceutical acceptable carrier or diluent.
CN201080003065.1A 2009-01-23 2010-01-25 N-acetylneuraminic acid compounds, pharmaceutical composition, preparation method and uses thereof Expired - Fee Related CN102232069B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201080003065.1A CN102232069B (en) 2009-01-23 2010-01-25 N-acetylneuraminic acid compounds, pharmaceutical composition, preparation method and uses thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN200910045818.4 2009-01-23
CN200910045818A CN101787008A (en) 2009-01-23 2009-01-23 N-acetyl neuraminic acid compounds, medicine compositions thereof and preparation methods and purposes thereof
CN201080003065.1A CN102232069B (en) 2009-01-23 2010-01-25 N-acetylneuraminic acid compounds, pharmaceutical composition, preparation method and uses thereof
PCT/CN2010/000115 WO2010083732A1 (en) 2009-01-23 2010-01-25 N-acetylneuraminic acid compounds, pharmaceutical composition, preparation method and uses thereof

Publications (2)

Publication Number Publication Date
CN102232069A true CN102232069A (en) 2011-11-02
CN102232069B CN102232069B (en) 2015-01-07

Family

ID=42355533

Family Applications (2)

Application Number Title Priority Date Filing Date
CN200910045818A Pending CN101787008A (en) 2009-01-23 2009-01-23 N-acetyl neuraminic acid compounds, medicine compositions thereof and preparation methods and purposes thereof
CN201080003065.1A Expired - Fee Related CN102232069B (en) 2009-01-23 2010-01-25 N-acetylneuraminic acid compounds, pharmaceutical composition, preparation method and uses thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN200910045818A Pending CN101787008A (en) 2009-01-23 2009-01-23 N-acetyl neuraminic acid compounds, medicine compositions thereof and preparation methods and purposes thereof

Country Status (2)

Country Link
CN (2) CN101787008A (en)
WO (1) WO2010083732A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104418876A (en) * 2013-09-09 2015-03-18 中国科学院上海有机化学研究所 Zanamivir, intermediates thereof and synthesis methods of zanamiviri and intermediates thereof

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104561194A (en) * 2013-10-16 2015-04-29 南京工业大学 Application of N-acetylneuraminic acid aldolase for catalyzing and synthetizing N-acetylneuraminic acid
NL2013420B1 (en) * 2014-09-05 2016-09-27 Univ Griffith Antiviral agents and uses thereof.
CN109678749B (en) * 2019-01-04 2021-09-28 中国科学院烟台海岸带研究所 Cyclonerane type sesquiterpene amide and preparation and application thereof
CN109503414B (en) * 2019-01-04 2021-09-24 中国科学院烟台海岸带研究所 Nitrogenous ring nerolidine type sesquiterpene derivative and preparation and application thereof
CN109503535B (en) * 2019-01-04 2021-09-28 中国科学院烟台海岸带研究所 Bicyclic ring nerolidine type sesquiterpene derivative and preparation and application thereof
CN109503428B (en) * 2019-01-04 2021-09-28 中国科学院烟台海岸带研究所 Cyclonerane hydroxamic acid derivative and preparation and application thereof
CN109503413B (en) * 2019-01-04 2021-09-28 中国科学院烟台海岸带研究所 Monocyclic ring nerolidine type sesquiterpene derivative and preparation and application thereof
CN109627192B (en) * 2019-01-04 2020-12-29 中国科学院烟台海岸带研究所 Cyclonerane type sesquiterpene derivative and preparation and application thereof
CN110003041B (en) * 2019-04-26 2021-09-28 中国科学院烟台海岸带研究所 Cyclonerane acylated derivative and preparation and application thereof
CN109956883B (en) * 2019-04-26 2021-09-28 中国科学院烟台海岸带研究所 Acetylated nitrogenous ring nerolidine type sesquiterpene derivative and preparation and application thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9516276D0 (en) * 1995-08-08 1995-10-11 Biota Scient Management Chemical compounds
TWI291462B (en) * 2000-04-25 2007-12-21 Daiichi Sankyo Co Ltd Hydrate crystal of neuraminic acid compound

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104418876A (en) * 2013-09-09 2015-03-18 中国科学院上海有机化学研究所 Zanamivir, intermediates thereof and synthesis methods of zanamiviri and intermediates thereof
CN104418876B (en) * 2013-09-09 2019-05-17 中国科学院上海有机化学研究所 The intermediate and its synthetic method of zanamivir and La Na meter Wei

Also Published As

Publication number Publication date
CN102232069B (en) 2015-01-07
CN101787008A (en) 2010-07-28
WO2010083732A1 (en) 2010-07-29

Similar Documents

Publication Publication Date Title
CN102232069A (en) N-acetylneuraminic acid compounds, pharmaceutical composition, preparation method and uses thereof
EP2997019B1 (en) Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
JP3836436B2 (en) Heterocyclic compounds and antitumor agents containing the same as active ingredients
CN112341435B (en) Immunomodulator
IL237048A (en) Fused bicyclic sulfamoyl derivatives and the use thereof as medicaments for the treatment of hepatitis b
HU228987B1 (en) Aryl-substituted propanolamine derivatives, methods for their production, medicaments containing said compounds and their use
WO2017192929A1 (en) SUBSTITUTED PYRROLO[1,2-α]TRIAZINES AND RELATED COMPOUNDS AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS
DE60126143T2 (en) GUANIDINE AND AMIDINE COMPOUNDS, AND THEIR USE AS FACTOR XA INHIBITORS
CN101679355B (en) Benzimidazole cannabinoid agonists
CZ366697A3 (en) Derivatives of 6-carboxamidodihydropyran
KR100704009B1 (en) 6-Alkylamino-2-methyl-2'-N-methyl substituted sulfonamidomethyl-2H-1-benzopyran derivatives as anti-inflammatory inhibitors
WO1998047887A1 (en) Novel epoxysuccinamide derivatives or salts thereof
JP4233262B2 (en) Carbasugar amine derivatives and glycosidase inhibitors using the same
CN107987054B (en) CDK2 inhibitor
DE60222459T2 (en) 2- (3-SULFONYLAMINO-2-OXOPYRROLIDIN-1-YL) PROPANAMIDES AS FACTOR XA INHIBITORS
CN113336735B (en) Urolithin compound, preparation method, pharmaceutical composition and application
TWI782523B (en) Compounds as RET kinase inhibitors and their applications
CN103360315A (en) Heterocyclic aryloxyacetyl hydrazone derivative and its preparation method and application thereof
CN112079785B (en) Novel anti-influenza virus oseltamivir derivative, and preparation method and application thereof
CN111670191B (en) Crystal form of pyridone derivative, preparation method and application
CN109810115B (en) Isoflavone compound and preparation method and application thereof
CN103420985A (en) Dabigatran derivative used as prodrug, and preparation method and application thereof
JPH05221938A (en) Substituted aminopropane, preparation thereof and use thereof
CN112661801A (en) Nucleoside analogue and deuteron thereof, and preparation method and application thereof
CN114920663B (en) Biphenyl oseltamivir derivative and preparation method and application thereof

Legal Events

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

Granted publication date: 20150107

Termination date: 20160125

EXPY Termination of patent right or utility model