CN101787008A - N-acetyl neuraminic acid compounds, medicine compositions thereof and preparation methods and purposes thereof - Google Patents

N-acetyl neuraminic acid compounds, medicine compositions thereof and preparation methods and purposes thereof Download PDF

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CN101787008A
CN101787008A CN200910045818A CN200910045818A CN101787008A CN 101787008 A CN101787008 A CN 101787008A CN 200910045818 A CN200910045818 A CN 200910045818A CN 200910045818 A CN200910045818 A CN 200910045818A CN 101787008 A CN101787008 A CN 101787008A
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dihydropyrane
acetamido
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赵庆杰
李剑峰
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
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Bioinformatics & Molecular Des
Shanghai Institute of Materia Medica of CAS
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Abstract

The invention discloses N-acetyl neuraminic acid compounds shown as the following general formula, medicine compositions thereof and preparation methods and purposes thereof. The compounds can inhibite surface neuraminidase of influenza viruses, thereby resisting the influenza viruses, in particular treating the infections of the influenza viruses resistant to other influenza-resistant medicaments, such as Zanamivir, Oseltamivir and the like.

Description

N-acetyl neuraminic acid compounds, its pharmaceutical composition and its production and use
Technical field
The present invention relates to N-acetyl neuraminic acid compounds, its pharmaceutical composition and its production and use.These compounds can suppress the virus surface neuraminidase, thereby can be applicable to the treatment of relative disease.
Background technology
Neuraminidase is present in the surface of virus particle such as many influenza viruses, parainfluenza virus, mumps virus.
Because the α-ketoside bond cleavage between its terminal neuraminic acid of energy catalysis and adjacent glycosyl is separated, acceptor is destroyed, virosome is dissociated, thereby increases the weight of infection symptoms.Therefore, by suppressing the activity of neuraminidase, can block the surface that progeny virus breaks away from cells infected, thereby prevent secondary infection.So, it is generally acknowledged that having the active material of the neuraminidase of inhibition can be used for treatment or flu-prevention.
Most of known neuraminidase inhibitors are analogues of neuraminic acid, as 2-deoxidation-2, and 3-two dehydrogenations-N-n acetylneuraminic acid n (DANA) and its derivative.Described the derivative of a series of DANA in the International Patent Application WO 91/16320, they all have certain inhibition activity to neuraminidase with external in vivo.During other DANA derivative is disclosed in and asks in the international monopolies such as WO98/06712, WO97/06157, WO01/81331.Zanamivir is exactly the neuraminidase inhibitor of first listing, yet, because this compound polarity is very big, its oral administration biaavailability very low (2-3%), can not oral administration, need make sprays, by the nasal cavity inhalation-type drug administration, bring very big inconvenience for patient's medication, also increased the production cost of preparation.On the other hand, influenza virus for example zanamivir, its Wei of department difficult to understand etc. easily produce resistance to marketed drug.
Therefore, it is extremely urgent to seek the anti-influenza virus medicament that new active compound and then exploitation make new advances.Seeking new influenza virus being had in the process of inhibiting active compound, the inventor has found the N-acetyl neuraminic acid compounds with tangible anti-influenza virus activity of a class formation novelty.
Summary of the invention
Therefore, main purpose of the present invention provides the novel inhibition virus of a class, particularly suppresses the N-acetyl neuraminic acid compounds of influenza virus or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing.
A further object of the present invention provides this N-acetyl neuraminic acid compounds or their any prodrug forms, their pharmacologically acceptable salt or the preparation method of acceptable solvent thing.
An also purpose of the present invention provides a kind of anti-viral pharmaceutical compositions of effective inhibition neuraminidase.
Another purpose of the present invention provides above-mentioned N-acetyl neuraminic acid compounds or their any prodrug forms, their pharmacologically acceptable salt or the purposes of acceptable solvent thing and pharmaceutical composition, described N-acetyl neuraminic acid compounds or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing and its pharmaceutical composition can suppress neuraminidase effectively, thereby be neuraminidase inhibitor, the virus disease that can be applicable to be correlated with and the treatment of infection thereof.
According to an aspect of the present invention, the invention provides the N-acetyl neuraminic acid compounds shown in the following general formula (I) or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing:
Figure G2009100458184D0000021
Wherein:
R 1Represent OR 5, SR 5, NR 5R 6, N (OR 5) R 6Or N (NR 5R 6) R 6
R 2Represent H, C 1-20Alkyl, C 1-5The C that alkoxyl group replaces 1-5Alkyl, COR 5Or CONR 5R 6
R 3Represent N 3, NR 7R 8, NHC (=NR 9) NR 5R 10, N=PPh 3Or
Figure G2009100458184D0000022
R 4Represent COOR 5, CONR 5R 6Or CON (OR 5) R 6
R 5Represent H, C 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, pentafluorophenyl group, aryl, CONR 14R 15, COOR 14, COR 14Or by the C of one or more following groups replacements 1-10Alkyl: NR 14R 15, NR 14COR 15, CO 2R 14, OR 14, C 3-8Cycloalkyl and aryl;
R 6Represent H, C 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, aryl, COR 14Or by the C of one or more following groups replacements 1-10Alkyl: NR 14R 14, COR 14, C 3-8Cycloalkyl, CN, N 3, OR 14And aryl;
Perhaps R 5And R 6The nitrogen-atoms that links to each other with them constitutes ring texture jointly, and this ring texture can be saturated or unsaturated, and can contain the heteroatoms among one or more N of being selected from, O and the S, and this ring texture can also be not necessarily by halogen, C 1-10Alkyl, C 1-C10Alkoxyl group, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, CF 3, CN or NO 2Replace;
R 7And R 8Represent H, CN, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or C 2-6Hydrocarbon chain, not necessarily contain a NR in this hydrocarbon chain 11Group, this hydrocarbon chain not necessarily are selected from oxo base (carbonyl) and C by 1～4 1-6The group of alkyl replaces, and this C 1-6Alkyl is not necessarily replaced by hydroxyl or aryl;
R 9And R 10Represent H, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, NR 14R 15, OR 14, CN or NO 2
R 11And R 12Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 1-10Alkoxyl group, COOR 5, CONR 14R 15Or aryl; Perhaps not necessarily by hydroxyl, amino, amido, COOR 5Or C 1-6The C that alkoxyl group replaces 1-10Alkyl;
R 14And R 15Represent H, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl or aryl;
Wherein, described aryl is meant aromatic carbocyclic ring or heterocyclic group, and not necessarily is substituted.When described aryl was substituted, suitable substituents comprised C 1-4Alkyl, C 1-4Alkoxyl group, halogen, nitro, trifluoromethyl, amino, C 1-4Amino, phenyl and phenmethyl that alkyl replaces.Suitable is that described aryl is replaced by 1～3 above-mentioned substituting group.
Herein, alkyl comprises the saturated alkyl of straight or branched.
Herein, thiazolinyl is meant alkyl straight or branched, that contain one or more carbon-to-carbon double bonds.
Herein, alkynyl is meant alkyl straight or branched, that contain one or more carbon-to-carbon triple bonds.
Therefore in above-mentioned definition, the compound of general formula (I) can contain one or more chiral centres, can have steric isomer, i.e. enantiomer or diastereomer, or its mixture.Compound of the present invention can be the single steric isomer of general formula (I) compound or the mixture of each steric isomer.Can be by routine techniques with diastereomeric separation, for example, the non-enantiomer mixture of general formula (I) compound or its suitable salt or derivatives thereof is separated by fractional crystallization or chromatogram (comprising HPLC).Also can separate with chiral column during fractionation, perhaps diastereomeric salt fractional crystallization by forming with optically active acid or alkali reaction by corresponding optically pure intermediate preparation or by splitting the single enantiomer of preparation general formula (I).
The pharmacy acceptable salt of compound is meant shown in the general formula of the present invention (I), according to chemically conventional salifiable method, the salt that compound shown in the general formula (I) and suitable acid or alkali form, the example of for example suitable acid comprises spirit of salt, Hydrogen bromide, sulfuric acid, perchloric acid, fumaric acid, toxilic acid, phosphoric acid, oxyacetic acid, lactic acid, Whitfield's ointment, succsinic acid, tosic acid, tartrate, acetate, trifluoroacetic acid, citric acid, methylsulfonic acid, formic acid, phenylformic acid, propanedioic acid, naphthalene-2-sulfonic acid and Phenylsulfonic acid, other acid such as oxalic acid, though itself be not pharmaceutically acceptable, but can be used for preparing the salt as intermediate, described intermediate is used to prepare The compounds of this invention and pharmaceutically acceptable acid salt thereof; With the salt of alkali formation, for example basic metal (as sodium) of compound shown in the general formula (I), alkaline-earth metal (as magnesium), ammonium or NR 4+(wherein R is C 1-4Alkyl) salt.
Preferably, in formula (I) compound:
R 1Represent OR 5, NR 5R 6Or N (OR 5) R 6
R 2Represent H, COR 5Or CONR 5R 6
R 3Represent NR 7R 8, NHC (=NR 9) NR 5R 10Or
Figure G2009100458184D0000031
It is the α configuration;
R 4Represent COOR 5, CONR 5R 6Or CON (OR 5) R 6
R 5And R 6Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl or aryl; Perhaps by OR 14, C 3-8The C that cycloalkyl or aryl replace 1-10Alkyl;
Perhaps R 5And R 6The nitrogen-atoms that links to each other with them constitutes ring texture jointly, and this ring texture can be saturated or unsaturated, and can contain the heteroatoms among one or more N of being selected from, O and the S, and this ring texture can also be not necessarily by halogen, C 1-10Alkyl, C 1-C 10Alkoxyl group, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl substituted;
R 7And R 8Represent H, CN, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or C 2-6Hydrocarbon chain, not necessarily contain a NR in this hydrocarbon chain 11Group, this hydrocarbon chain not necessarily are selected from oxo base (carbonyl) and C by 1～4 1-6The group of alkyl replaces, and this C 1-6Alkyl is not necessarily replaced by hydroxyl or aryl;
R 9And R 10Represent H, C independently of one another 1-6Alkyl, NR 14R 15, OR 14, CN or NO 2
R 11And R 12Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, COOR 5Or aryl; Perhaps not necessarily by hydroxyl, amino, amido, COOR 5Or C 1-6The C that alkoxyl group replaces 1-10Alkyl;
R 14And R 15Represent H, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl or aryl;
Wherein, the definition of described aryl is the same.
More preferably, in formula (I) compound:
R 1Represent NR 5R 6Or N (OR 5) R 6
R 2Represent H or COR 5
R 3Be the α configuration;
R 3Represent NR 7R 8Or NHC (=NR 9) NR 5R 10
R 4Represent COOR 5Or CON (OR 5) R 6
R 5And R 6Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl; Perhaps R 5And R 6The nitrogen-atoms that links to each other with them constitutes ring texture jointly, and this ring texture can be saturated or unsaturated, and can contain the heteroatoms among one or more N of being selected from, O and the S, and this ring texture can also be not necessarily by C 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl substituted;
R 7And R 8Represent H, CN, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or C 2-6Hydrocarbon chain, not necessarily contain a NR in this hydrocarbon chain 11Group, this hydrocarbon chain not necessarily are selected from oxo base (carbonyl) and C by 1 or 2 1-6The group of alkyl replaces, and this C 1-6Alkyl is not necessarily replaced by hydroxyl or aryl, and described aryl comprises phenyl, naphthyl, pyridyl, imidazolyl and thienyl, and not necessarily is substituted; When described aryl was substituted, described substituting group comprised C 1-4Alkyl, C 1-4Alkoxyl group, nitro, amino, phenyl and phenmethyl; And described substituted aryl has 1～3 above-mentioned substituting group;
R 9And R 10Represent H, C independently of one another 1-6Alkyl, NH 2, OH, CN or NO 2
R 11And R 12Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl or COOR 5
Further preferred again compound is as shown in the formula shown in (I):
R 1Represent NR 5R 6
R 2Represent H;
R 3Represent NH 2Or NHC (=NH) NH 2, it is the α configuration;
R 4Represent COOR 5
R 5And R 6Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl; Perhaps R 5And R 6The nitrogen-atoms that links to each other with them constitutes ring texture jointly, and this ring texture can be saturated or unsaturated, and can contain the heteroatoms among one or more N of being selected from, O and the S, and this ring texture can also be not necessarily by C 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl substituted.
The particularly preferred particular compound of the present invention comprises:
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 22 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid (embodiment 23 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 24 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid (embodiment 25 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-methyl-formiate (embodiment 27 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 28 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid (embodiment 30 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 31 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-methyl-formiate (embodiment 32 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-methyl-formiate (embodiment 34 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid (embodiment 35 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 36 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid (embodiment 37 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-amino-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 42 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-isopropylamine base-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 43 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-azanol base-2 '-oxygen ethyl }-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 44 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclohexylamino-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 45 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclohexyl amido-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (embodiment 47 compounds),
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-amino-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid (embodiment 48 compounds) and
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-Isopropylamine amido-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid (embodiment 49 compounds).
The further particularly preferred particular compound of the present invention comprises:
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid,
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid,
(2R, 3R, 4s)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid,
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid and
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid.
According to a further aspect in the invention, the invention provides the N-acetyl neuraminic acid compounds shown in the general formula (I) or their any prodrug forms, their pharmacologically acceptable salt or the preparation method of acceptable solvent thing, this method comprises any of following method:
(1) R in general formula (I) compound 1Be OH, R 2Be not H, R 3Be N 3, R 4Be COOR 5, and R 5When being not H, i.e. general formula (Ia) compound, can pass through general formula (II) compound (Carbohydrate Research, 2008,343,14,2459-2462.) oxicracking prepares, and if desired, carries out deprotection subsequently, the R of general formula (II) compound 2And R 4Substituting group defines same general formula (I) compound:
Figure G2009100458184D0000071
Oxicracking is suitably finished by two steps.Suitable is that the first step adopts periodate to finish, as uses sodium periodate, suitably is to finish in suitable solvent, as water-containing organic solvent, and aqueous methanol for example.The suitable agent that is used for second step of oxicracking can be a chlorite, as Textone, suitably be to have buffer reagent, as basic metal or alkali earth metal phosphate, as potassium primary phosphate, and in water-containing organic solvent, as the aqueous mixture of pure and mild hydrocarbon, the aqueous mixture of the trimethyl carbinol and tetrahydrobenzene for example.
(2) R in general formula (I) compound 1Be OR 5Or SR 5The time, promptly general formula (Ic) compound can pass through corresponding general formula (Ib) compound (R in general formula (I) compound 1Represent OH) and by R 5Replace contain oxygen or sulfocompound prepares by condensation reaction:
(3) R in general formula (I) compound 1Be NR 5R 6, N (OR 5) R 6Or N (NR 5R 6) R 6The time, promptly general formula (Id) compound can pass through corresponding general formula (Ib) compound (R in general formula (I) compound 1Represent OH) with-R 5R 6,-(OR 5) R 6Or-(NR 5R 6) R 6The nitrogenous compound that replaces reacts and prepares.Suitable is that carboxyl was activated before reacting with amine.Suitable activation method is clearly for those skilled in the art, and comprises and for example change into penta fluoro benzene oxygen base.Amination reaction can be finished in suitable organic solvent easily, as in ether, for example in THF.
Figure G2009100458184D0000081
(4) R in general formula (I) compound 3For
Figure G2009100458184D0000082
The time, promptly general formula (If) compound can pass through corresponding general formula (Ie) compound (R in general formula (I) compound 3Represent N 3) and by R 11And R 12The acetylene compound that replaces reacts and prepares.Suitable is that preparation need be carried out under catalyst.Suitable catalysis process is clearly for those skilled in the art, as cuprous ion catalysis.
Figure G2009100458184D0000083
(5) R in general formula (I) compound 3Be NH 2The time, promptly general formula (Ig) compound can pass through corresponding general formula (Ie) compound (R in general formula (I) compound 3Represent N 3) prepare by the reduction reaction of azido-:
Figure G2009100458184D0000084
Can adopt any known method that triazo-compound is transformed into amine to finish reduction reaction.Appropriate means is described in following examples, and for example among the open WO93/12105 of international patent application and the WO95/00503 description is arranged all.Suitable is that use Lindlar catalyst, hydrogen or formic acid etc. can provide the compound bearing active hydrogen reduction to finish reaction.
(6) R in general formula (I) compound 3Be NR 7R 8The time, i.e. general formula (Ih) compound can be from general formula (Ig) compound (R general formula (I) compound 3Be NH 2) by with by R 7And R 8The compound that replaces reacts and prepares, for example with containing R 7And R 8Substituent halogenide, acid anhydrides, acyl halide derivative etc. react through the N of routine functionalization and prepare, but are not limited thereto.Suitable preparation method is clearly for those skilled in the art.
Figure G2009100458184D0000091
(7) R in general formula (I) compound 3Be NHC (=NR 14) NR 15R 16The time, i.e. general formula (Ii) compound can be from general formula (Ih) compound (R general formula (I) compound 3Be NR 7R 8) prepare by the guanidine glycosylation reaction.The suitable introducing guanidine radicals and the method for derivative thereof are clearly for those skilled in the art.Especially work as R in general formula (I) compound 3Be NHC (=NH) NH 2The time, promptly general formula (Ik) compound for example passes through general formula (Ig) compound (R in general formula (I) compound 3Be NH 2) and amidino groups pyrazoles or its salt or derivative (preferred amidino groups pyrazoles) reaction or process intermediate formula (Ij) compound (R in general formula (I) compound 3Be NHCN) prepare.
(8) R in general formula (I) compound 3Represent N 3, R 4Be CONR 5R 6The time, promptly general formula (Im) compound can pass through corresponding general formula (Il) compound (R in general formula (I) compound 3Represent N 3, R 4Be COOR 5, and R 5For H) obtain with the subsalt reaction of azanol or derivatives thereof.Suitable method for transformation is clearly for those skilled in the art, and comprises and for example use NH 2OH/KOH.
Figure G2009100458184D0000092
(9) general formula (Ih) compound (R wherein 3Be NR 7R 8) or general formula (Ii) compound (R wherein 3Be NHC (=NR 14) NR 15R 16) can also be from general formula (Im) compound (R general formula (I) compound 3Represent N 3, R 4Be CONR 5R 6) by reducing with the similar azido-method of reducing of aforesaid method (5), further reaction prepares then.Suitable preparation method is clearly for those skilled in the art.
(10) transform other compound that can prepare general formula (I) mutually by the functional group between the different compounds of general formula (I).For example, R wherein 2For the compound of H can be by not preparing for the compound of H; R 7And R 8The compound that is not H can pass through corresponding R 7And/or R 8For the compound of H prepares; R 4Be COOR 5, CONR 5R 6Or CON (OR 5) R 6Compound can with R 4For the compound of COOH transforms mutually.
It will be understood by those skilled in the art that in order to prevent side reaction, the one or more sensitive groups in any stage of aforesaid method may need protection molecule; Arbitrary suitable later stages at reaction sequence can be removed the protectiveness group.
The protectiveness group that is used to prepare general formula (I) compound can use traditional method.For example referring to " Greene ' s protectivegroups in organic synthesis ", Peter G M.Wuts and Theodora W.Greene (A John Wiley ﹠amp; Sons, Inc., 2007).
Traditional amido protecting group can comprise: aralkyl for example, as benzyl, diphenyl methyl or trityl group; And acyl group, as N-benzyloxycarbonyl or tert-butoxycarbonyl.
Hydroxyl can be by following radical protection: as aralkyl, as benzyl, diphenyl methyl or trityl group; Acyl group is as ethanoyl; Silicon protectiveness group is as trimethyl silyl, perhaps as tetrahydrofuran derivatives.
The carboxylic acid group can suitably protect becomes methyl esters or phenylbenzene methyl esters.
Available traditional method is removed any protectiveness group of existence.
When needs with salt, when for example the isolated in form of acid salt went out The compounds of this invention, this can finish by the free alkali of handling general formula (I) with suitable acid (preferably using the acid of equivalent).
According to another aspect of the invention, pharmaceutical composition of the present invention contains the N-acetyl neuraminic acid compounds shown in one or more above-mentioned general formulas (I) for the treatment of significant quantity or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing, and one or more pharmaceutically acceptable carrier or thinner.
In accordance with a further aspect of the present invention, general formula (I) compound can be used as prodrug forms and uses, thereby improves bioavailability or improve the physico-chemical property of this compounds.R in general formula (I) compound for example 4Represent COOR 5(R 5For H) compound also can be used as R 4Represent the prodrug forms of the compound of COOH.The polarity of compound reduces, and helps patient's oral administration.
N-acetyl neuraminic acid compounds of the present invention or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing and its pharmaceutical composition can suppress neuraminidase effectively, thereby can be applicable to the treatment of relative disease.
Embodiment
The following example has further been explained the synthetic of compound of the present invention and intermediate thereof, but does not limit the scope of the invention.
1H NMR finishes on Mercury-400 nuclear magnetic resonance spectrometer (Varian company), 1The observing frequency of H NMR is 300MHz or 400MHz.Conventional abbreviation is as follows: s, and unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet.Mass spectroscopy is finished on MAT-95 type mass spectrograph (Thermo Finnigan company), ionization mode EI 70V, 200 ℃ of source temperature, LR resolving power 1000.High resolution mass spectrum is by Finnigan MAT, Bruker Daltonics FTMS-7 type Instrument measuring.
Embodiment 1 (S)-[(2R, 3R, 4S)-3-acetamido-4-azido--6-(methoxycarbonyl-3,4-dihydropyrane-2 ']-the 2-acetoxy acid
Figure G2009100458184D0000111
7-O-ethanoyl-N-ethanoyl-2,4-dideoxy-2,3-dehydrogenation-4 α-azido--D-neuraminic acid methyl esters (1.6g, and 4.3mmol) (Carbohydrate Research, 2008,343,12,2459-2462.) be dissolved in CH 3OH and H 2In the mixing solutions of O (48mL and 16mL), add NaIO 4(1.84g, 8.6mmol 2.0eq.), behind the stirring at room 30min, filter, and concentrating under reduced pressure gets white solid.White solid is dissolved among the t-BuOH (27mL), adds tetrahydrobenzene (2.7mL), and then in system, add NaClO 2(2.87g), KH 2PO 4The water of (2.87g) (18.5mL) solution.Solution by colourless become bright orange-yellow, behind the stirring at room 2h, stopped reaction.In reaction soln, add ethyl acetate (50mL) and H 2O (100mL), separatory discards ethyl acetate layer, and water layer with ethyl acetate extraction (75mL * 5), merges organic phase, anhydrous MgSO after regulating pH=1～2 with 6M HCl solution 4After the drying, filter, concentrating under reduced pressure gets the title compound 1.765g of white solid, productive rate: 100%.
1H NMR (300MHz, DMSO): δ 8.19 (1H, d, J=9.3Hz, NH), 5.89 (1H, d, J=2.5Hz, 3-H), 5.22 (1H, d, J=2.1Hz, 7-H), 4.56 (1H, dd, J=2.1Hz, J=10.9Hz, 6-H), 4.43 (1H, dd, J=2.3Hz, J=9.4Hz, 4-H), 4.07 (1H, d, J=10.5Hz, 5-H), 3.71 (3H, s, CH 3), 2.05 (3H, s, OAc), 1.79 (3H, s, NAc); HRMS (ESI): m/z calculated value: C 13H 16N 4O 8[M+H] +357.1. measured value: 356.3.
Embodiment 2 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-penta fluoro benzene oxygen base-2 '-oxygen ethyl]-4-azido--3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000112
With embodiment 1 compound (855mg 2.4mmol) is dissolved among the DMF (8mL), add again pyridine (0.2mL, 2.5mmol, 1.1eq.) and CF 3COOC 6F 5(1.11mL, 0.63g/mL, 2.5mmol, 1.1eq.), and behind the stirring at room 2h, stopped reaction.In reaction solution, add ethyl acetate (32mL), use 1M HCl (30mL * 3), saturated NaHCO successively 3(30mL * 3), saturated NaCl solution (30mL * 1) are washed anhydrous MgSO 4After the drying, filter, being evaporated to has solid to separate out just, drips sherwood oil and makes crystallization get title compound 523mg, productive rate: 42%.
1H?NMR(300MHz，CDCl 3)：δ6.05(1H，d，J＝2.6Hz，3-H)，5.78(1H，d，J＝2.7Hz，7-H)，5.61(1H，d，J＝8.7Hz，NH)，4.99(1H，dd，J＝2.6Hz，J＝10.4Hz，6-H)，4.47(1H，dd，J＝2.7Hz，J＝9.2Hz，4-H)，4.09(1H，dd，J＝9.1Hz，J＝19.0Hz，5-H)，3.81(3H，s，CH 3)，2.27(3H，s，OAc)，2.06(3H，s，NAc)；LRMS(ESI)：m/z[M+H] +＝544.9。
Embodiment 3 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 ,-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl]-4-azido--3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000121
With embodiment 1 compound (35mg, 0.1mmol) and 1-ethyl-3-(3-dimethylamine propyl) carbodiimide (EDCI) (21mg, 0.11mmol) be dissolved among the THF (0.5mL), adding I-hydroxybenzotriazole (HOBt) under the frozen water cooling conditions (15mg, 0.11mmol), behind the stirring at room 10min, the aqueous solution (the 12 μ L that add methylamine, 0.11mmol), the TLC demonstration reacts completely stopped reaction behind the 2.5h.Be evaporated to dried, column chromatography for separation (CH 2Cl 2: CH 3OH=60: 1 (v/v)) the title compound 27mg of white solid, productive rate: 75%.
1H?NMR(400MHz，CDCl 3)：δ7.26(1H，d，J＝8.9Hz，NHCO)，6.49(1H，d，J＝4.7Hz，NH)，5.91(1H，d，J＝2.2Hz，3-H)，5.40(1H，d，J＝1.7Hz，7-H)，4.49(1H，dd，J＝1.8Hz，J＝8.7Hz，6-H)，4.35(1H，dd，J＝9.4Hz，J＝9.8Hz，5-H)，4.26(1H，dd，J＝2.4Hz，J＝6.7Hz，4-H)，3.77(3H，s，CH 3)，2.87(1H，d，NHCH 3)，2.22(3H，s，OAc)，1.97(3H，s，NAc)； 13C?NMR(400MHz，CDCl 3)：20.82(OCOCH 3)，23.00(NHCOCH 3)，26.26(NHCH 3)，48.45(C-5)，52.53(OCH 3)，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＝O)，169.84(C＝O)，170.61(C＝O)。
Embodiment 4 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-azido--3,4-dihydropyrane-6-methyl-formiate
According to the method identical, adopt ethamine to replace methylamine to prepare title compound with embodiment 3; Productive rate: 67%.
1H NMR (300MHz, CDCl 3): δ 6.53 (1H, d, J=9.4Hz, NH), 6.32 (1H, m, NH), 5.95 (1H, d, J=2.4Hz, 3-H), 5.42 (1H, d, J=1.9Hz, 7-H), 4.53 (1H, dd, J=2.1Hz, J=10.4Hz, 6-H), 4.33 (1H, dd, J=9.4Hz, J=19.1Hz, 5-H), 4.25 (1H, dd, J=2.5Hz, J=8.9Hz, 4-H), 3.78 (3H, s, CH 3), 3.49 (1H, m, CH), 3.22 (1H, m, CH), 2.24 (3H, s, OAc), 1.98 (3H, s, NAc), 1.20 (3H, t, J=7.1Hz, CH 3); HRMS (ESI): m/z calculated value: C 15H 22N 5O 7[M+H] +384.1519, measured value: 384.1535.
Embodiment 5 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-amino-2 '-oxygen ethyl]-4-azido--3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000131
With embodiment 2 compounds (369mg 0.73mmol) is dissolved among the THF (15mL), slowly add ammonia methyl alcohol (0.2mL, 0.87mmol, 1.2eq.), behind the stirring at room 30min, stopped reaction.Behind the concentrating under reduced pressure, column chromatography for separation (EtOAc: sherwood oil=1: 1 (v/v)) get title compound 206mg, productive rate: 80%.
1H?NMR(300MHz，CDCl 3)：δ6.59(1H，s，NH)，6.49(1H，s，NH)，6.06(1H，d，J＝6.6Hz，NH)，5.96(1H，s，3-H)，5.44(1H，s，7-H)，4.56(1H，d，J＝5.1Hz，6-H)，4.28(1H，s，4-H?and5-H)，3.79(3H，s，CH 3)，2.23(3H，s，OAc)，1.98(3H，s，NAc)；LRMS(ESI)：m/z[M+Na] +＝378.0。
Embodiment 6 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl]-4-azido--3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000132
According to the method identical, adopt dimethyl amine to replace ammonia methyl alcohol to prepare title compound with embodiment 5; Productive rate: 86%.
1H NMR (300MHz, CDCl 3): δ 6.24 (1H, d, J=6.8Hz, NH), 6.05 (1H, d, J=3.6Hz, 7-H), 5.87 (1H, d, J=2.1Hz, 3-H), 4.74 (1H, t, J=6.5Hz, 4-H), 4.58 (1H, dd, J=3.7Hz, J=6.3Hz, 6-H), 4.12 (1H, dd, J=7.1Hz, J=14.4Hz, 5-H), 3.81 (3H, s, CH 3), 3.13 (3H, s, CH 3), 2.99 (3H, s, CH 3), 2.15 (3H, s, OAc), 1.99 (3H, s, NAc); HRMS (EI): m/z calculated value: C 15H 22N 5O 7[M+H] +384.1519; Measured value: 384.1527.
Embodiment 7 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-azido--3,4-dihydropyrane-6-methyl-formiate
According to the method identical, adopt diethylamide to replace ammonia methyl alcohol to prepare title compound with embodiment 5; Productive rate: 90%.
1H?NMR(300MHz，CDCl 3)：δ6.29(1H，d，J＝7.5Hz，NH)，6.05(1H，d，J＝3.6Hz，3-H)，5.87(1H，d，J＝6.3Hz，7-H)，4.75(1H，t，J＝6.3Hz，6-H)，4.56(1H，dd，J＝3.6Hz，J＝6.3Hz，4-H)，4.03(1H，dt，J＝6.9Hz，J＝13.8Hz，5-H)，3.80(3H，s，CH 3)，3.37(4H，m，2CH 2)，2.15(3H，s，OAc)，1.99(3H，s，NAc)，1.15(6H，m，2CH 3)；LRMS(EI)：m/z[M+H] +＝412.0。
Embodiment 8 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-azanol base-2 '-oxygen ethyl]-4-azido--3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000141
With embodiment 2 compound (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-penta fluoro benzene oxygen base-2 '-oxygen ethyl]-4-azido--3,4-dihydropyrane-6-methyl-formiate (200mg, 0.04mmol) be dissolved among the THF (5mL), add oxammonium hydrochloride (30mg, 0.043mmol, 1.1eq.) and diisopropylethylamine (DIPEA) (7.5 μ L, 0.043mmol, 1.1eq.), behind the stirring at room 30min, stopped reaction.Behind the concentrating under reduced pressure, column chromatography for separation (EtOAc) gets title compound 131mg, productive rate: 92%.
1H?NMR(300MHz，D 2O)：δ6.20(1H，d，J＝2.8Hz，3-H)，5.57(1H，d，J＝2.2Hz，7-H)，4.66(1H，t，J＝2.1Hz，J＝10.5Hz，6-H)，4.51(1H，dd，J＝2.9Hz，J＝9.6Hz，4-H)，4.29(1H，t，J＝9.9Hz，5-H)，3.89(3H，s，CH 3)，2.28(3H，s，OAc)，2.09(3H，s，NAc)；LRMS(ESI)：m/z[M+Na] +＝478.1。
Embodiment 9 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-azido--3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000142
According to the method identical, adopt cyclopentamine to replace ammonia methyl alcohol to prepare title compound with embodiment 5; Productive rate: 98%.
1H?NMR(300MHz，CDCl 3)：δ6.78(1H，d，J＝8.3Hz，NH)，5.99(1H，d，J＝3.0Hz，3-H)，5.56(1H，d，J＝4.4Hz，7-H)，4.66(1H，dd，J＝4.8Hz，J＝9.1Hz，6-H)，4.56(1H，dd，J＝2.8Hz，J＝7.8Hz，4-H)，4.11(1H，dt，J＝8.5Hz，J＝16.5Hz，5-H)，3.69(4H，m，2CH 2)，3.79(3H，s，CH 3)，2.16(3H，s，OAc)，1.99(3H，s，NAc)，1.92(4H，m，2CH 2)；LRMS(ESI)：m/z[M+H] +＝410.0。
Embodiment 10 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl]-4-azido--N-hydroxyl-3,4-dihydropyrane-6-methane amide
Figure G2009100458184D0000151
(100mg 0.26mmol) is dissolved in CH with embodiment 6 compounds 3Among the OH (5mL), add NH 2OH/KOH/CH 3(1.0mL, 0.72mmol), behind the stirring at room 10min, the TLC demonstration reacts completely OH solution, adds Glacial acetic acid regulation system pH=6.5.Get the title compound reaction solution, can be not treated, be directly used in the next step.
HRMS (ESI): m/z calculated value: C 12H 18N 6O 6Na[M+Na] +365.1186, measured value: 365.1181.
Embodiment 11 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-amino-N-hydroxyl-3,4-dihydropyrane-6-methane amide
Figure G2009100458184D0000152
Add Lindlar (10mg) catalyzer in the reaction soln of embodiment 10, behind the room temperature normal pressure hydrogenation reaction 48h, the TLC demonstration reacts completely, and stopped reaction adds Glacial acetic acid regulation system pH=6.5 to reaction system.Behind diatomite filtration, reversed-phase silica gel column chromatography separate title compound 16mg, productive rate: 20%.
1H NMR (300MHz, D 2O): δ 5.76 (1H, d, J=2.3Hz, 3-H), 4.56 (1H, dd, J=2.0Hz, J=9.8Hz, 6-H), 4.37 (1H, t, J=9.5Hz, 5-H), 4.31 (1H, dd, J=2.2Hz, J=9.6Hz, 4-H), 3.14 (3H, s, CH 3), 3.05 (3H, s, CH 3), 2.15 (3H, s, NAc); HRMS (ESI): m/z calculated value: C 12H 20N 4O 6Na[M+Na] +339.1281, measured value: 339.1266.
Embodiment 12 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-methylol-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000153
With embodiment 3 compound (60mg, 0.16mmol) be dissolved in aqueous ethanolic solution (0.5mL), add propiolic alcohol (11 μ L, 0.16mmol), SODIUM ASCORBATE (the 0.38mL that adds new preparation again, 30%mmol, 25mg/mL), the cupric sulfate pentahydrate aqueous solution (0.21mL, 5%mmol, 0.4mg/mL), under the lucifuge condition, stirring at room 18h removes solvent under reduced pressure.With ethyl acetate: methyl alcohol=25: 1 (v/v) is eluent, and column chromatography for separation gets title compound (48mg, 70%).
1H NMR (400MHz, CDCl 3): δ 7.72 (1H, s, CH), 7.44 (1H, d, J=9.2Hz, NH), 6.42 (1H, d, J=4.1Hz, NH), 6.03 (1H, d, J=2.1Hz, 3-H), 5.71 (1H, dd, J=2.5Hz, J=10.6Hz, 4-H), 5.61 (1H, s, 7-H), 4.85 (1H, d, J=1.3Hz, J=10.7Hz, 6-H), 4.77 (2H, s, CH 2), 4.56 (1H, dt, J=10.5Hz, J=20.1Hz, 5-H), 3.79 (3H, s, CH 3), 2.91 (3H, d, J=4.8Hz, CH 3), 2.18 (3H, s, OAc), 1.80 (3H, s, NHAc); HRMS (EI) m/z calculated value: C 17H 23N 5O 8[M] +425.1547, measured value: 425.1512.
Embodiment 13 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-methylol-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid
With embodiment 12 compounds (20mg 0.04mmol) is dissolved in the methyl alcohol (0.4mL), add then NaOH methanol solution (0.17mL, 0.16mmol, 24mg/mL).Behind the stirring at room 2h, the TLC demonstration reacts completely, and adds Dowex50W * 8 (H then +), regulation system pH is 7.After the filtration, concentrating under reduced pressure gets title compound (16mg, 92%).
1H NMR (400MHz, DMSO): δ 8.27 (1H, d, J=8.8Hz, NH), 7.90 (1H, s, CH), 7.79 (1H, d, J=4.8Hz, NH), 5.81 (1H, d, J=2.3Hz, 3-H), 5.57 (1H, dd, J=1.9Hz, J=9.7Hz, 4-H), 4.51 (2H, m, 6-H and 7-H), 4.47 (2H, s, CH 2), 4.29 (1H, dt, J=10.2Hz, J=18.1Hz, 5-H), 2.62 (2H, d, J=3.7Hz, CH 3), 1.75 (3H, s, NHAc); HRMS (ESI): [M+H] +=369.9; HRMS (EI) m/z calculated value: C 14H 21N 5O 7Na[M+Na] +392.1182, measured value: 392.1170.
Embodiment 14 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-methoxycarbonyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000162
According to the method identical, adopt the propynoic acid methyl esters to replace propiolic alcohol to prepare title compound with embodiment 12; Productive rate: 72%.
1H NMR (400MHz, CDCl 3): δ 8.26 (1H, s, CH), 7.30 (1H, t, J=9.6Hz, NH), 6.43 (1H, d, J=4.9Hz, NH), 6.04 (1H, d, J=2.2Hz, 3-H), 5.80 (1H, dd, J=2.3Hz, J=10.0Hz, 4-H), 5.57 (1H, d, J=1.6Hz, 7-H), 4.90 (1H, dd, J=1.7Hz, J=10.8Hz, 6-H), 4.57 (1H, dt, J=9.7Hz, J=19.8Hz, 5-H), 3.93 (3H, s, CH 3), 3.80 (3H, s, CH 3), 2.92 (3H, d, J=4.8Hz, CH 3), 2.19 (3H, s, OAc), 1.83 (3H, s, NHAc); HRMS (EI) m/z calculated value: C 18H 24N 5O 9[M+H] +454.0574, measured value: 454.1603.
Embodiment 15 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-carboxyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid
According to the method identical, be that raw material prepares title compound with embodiment 14 compounds with embodiment 13; Productive rate: 92%.
1H NMR (400MHz, DMSO): δ 8.63 (1H, s, CH), 7.82 (1H, m, NH), 5.91 (1H, d, J=2.3Hz, 3-H), 5.60 (1H, dd, J=1.9Hz, J=9.8Hz, 4-H), 4.58 (1H, d, J=11.3Hz, 6-H), 4.33 (1H, m, 5-H), 4.09 (1H, s, 7-H), 2.64 (5H, d, J=3.6Hz, CH 3), 1.74 (3H, s, NHAc); HRMS (ESI) m/z calculated value: C 14H 17N 5O 8Na[M+Na] +406.0975, measured value: 406.0991.
Embodiment 16 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000172
According to the method identical, adopt phenylacetylene to replace propiolic alcohol to prepare title compound with embodiment 12; Productive rate: 61%.
1H NMR (400MHz, CDCl 3): δ 7.92 (1H, s, CH), 7.82 (2H, d, J=7.3Hz, PhH), 7.43 (2H, t, J=7.3Hz, PhH), 7.34 (1H, t, J=7.3Hz, PhH), 6.98 (1H, d, J=9.7Hz, NH), 6.37 (1H, d, J=5.5Hz, NH), 6.09 (1H, d, J=2.4Hz, 3-H), 5.79 (1H, dd, J=2.6Hz, J=10.1Hz, 4-H), 5.61 (1H, d, J=1.5Hz, 7-H), 4.88 (1H, dd, J=1.9Hz, J=10.6Hz, 6-H), 4.66 (1H, dt, J=9.9Hz, J=20.0Hz, 5-H), 3.81 (3H, s, CH 3), 2.93 (3H, d, J=5.1Hz, CH 3), 2.22 (3H, s, OAc), 1.82 (3H, s, NHAc); HRMS (EI) m/z calculated value: C 22H 26N 5O 7[M+H] +472.1832, measured value: 472.1809.
Embodiment 17 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000181
According to the method identical, be that raw material prepares title compound with embodiment 16 compounds with embodiment 13; Productive rate: 90%.
1H NMR (400MHz, DMSO): δ 8.59 (1H, s, CH), 8.25 (1H, d, J=8.7Hz, NH), 7.85 (2H, d, J=7.8Hz, PhH), 7.80 (1H, d, J=4.8Hz, NH), 7.42 (2H, t, J=7.5Hz, PhH), 7.31 (1H, t, J=7.5Hz, PhH), 5.90 (1H, d, J=2.0Hz, 3-H), 5.61 (1H, d, J=10.0Hz, 4-H), 4.59 (1H, d, J=11.1Hz, 6-H), 4.31 (1H, dt, J=10.0Hz, J=20.5Hz, 5-H), 4.08 (1H, s, 7-H), 2.64 (3H, d, J=3.7Hz, CH 3), 1.74 (3H, s, NHAc); HRMS (ESI): [M+H] +=415.9; HRMS (EI) m/z calculated value: C 19H 21N 5O 6Na[M+Na] +438.1390, measured value: 438.1367.
Embodiment 18 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-methoxycarbonyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate
According to the method identical with embodiment 12, be raw material with embodiment 9 compounds, adopt the propynoic acid methyl esters to replace propiolic alcohol to prepare title compound; Productive rate: 55%.
1H NMR (400MHz, DMSO): δ 8.86 (1H, s, CH), 6.08 (1H, d, J=2.7Hz, 3-H), 5.61 (1H, dd, J=2.3Hz, J=9.6Hz, 6-H), 5.31 (1H, d, J=2.4Hz, 7-H), 4.74 (1H, dd, J=2.7Hz, J=10.3Hz, 4-H), 4.39 (1H, t, J=10.0Hz, 5-H), 3.87 (1H, m, CH), 3.83 (3H, m, CH 3), 3.74 (3H, m, CH 3), 3.31 (3H, m, CH 2+ CH), 2.04 (3H, s, OAc), 1.87 (4H, m, 2CH 2), 1.66 (3H, s, NHAc); HRMS (ESI): [M] +=494.0,516.1; HRMS (ESI) m/z calculated value: C 21H 27N 5O 9Na[M-H] +516.1706, measured value: 516.1714.
Embodiment 19 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-carboxyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000191
According to the method identical, be that raw material prepares title compound with embodiment 18 compounds with embodiment 13; Productive rate: 76%.
1H NMR (400MHz, DMSO): δ 8.62 (1H, s, CH), 5.87 (1H, d, J=2.1Hz, 3-H), 5.60 (1H, d, J=2.2Hz, J=9.5Hz, 6-H), 4.56 (1H, dd, J=2.4Hz, J=10.3Hz, 4-H), 4.33 (1H, d, J=2.1Hz, 7-H), 4.24 (1H, t, J=9.8Hz, 5-H), 3.74 (1H, m, CH), 3.30 (3H, m, CH 2+ CH), 1.80 (4H, m, 2CH 2), 1.71 (3H, s, NHAc); HRMS (ESI): [M+H] +=424.0,445.9; HRMS (ESI) m/z calculated value: C 17H 21N 5O 8Na[M+Na] +446.1288, measured value: 446.1266.
Embodiment 20 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000192
According to the method identical with embodiment 12, be raw material with embodiment 9 compounds, adopt cyclopropyl acethlene to replace propiolic alcohol to prepare title compound; Productive rate: 38%.
1H?NMR(400MHz，DMSO)：δ7.83(1H，s，CH)，5.97(1H，d，J＝2.4Hz，3-H)，5.47(1H，dd，J＝2.6Hz，J＝9.5Hz，6-H)，5.25(1H，d，J＝2.8Hz，7-H)，4.68(1H，dd，J＝2.5Hz，J＝9.9Hz，4-H)，4.27(1H，t，J＝10.0Hz，5-H)，3.82(1H，m，CH)，3.71(3H，m，CH 3)，3.27(3H，m，CH 2+CH)，2.03(3H，s，OAc)，1.85(4H，m，2CH 2)，1.68(3H，s，NHAc)，0.86(2H，m，CH 2)，0.67(2H，m，CH 2)；HRMS(ESI)：[M] +＝498.2，510.1。
Embodiment 21 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000201
According to the method identical, be that raw material prepares title compound with embodiment 20 compounds with embodiment 13; Productive rate: 90%.
1H NMR (400MHz, CDCl 3): δ 7.79 (1H, s, CH), 5.83 (1H, d, J=2.5Hz, 3-H), 5.51 (1H, d, J=2.3Hz, J=9.3Hz, 6-H), 4.55 (1H, dd, J=2.5Hz, J=10.2Hz, 4-H), 4.29 (1H, d, J=2.5Hz, 7-H), 4.13 (1H, t, J=9.9Hz, 5-H), 3.75 (1H, m, CH), 3.25 (3H, m, CH 2+ CH), 1.83 (4H, m, 2CH 2), 1.73 (3H, s, NHAc), 0.86 (2H, m, CH 2), 0.67 (2H, m, CH 2); HRMS (ESI): [M+H] +=420.0,442.1; HRMS (ESI) m/z calculated value: C 19H 25N 5O 6Na[M] +442.1703, measured value: 442.1705.
Embodiment 22 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000202
(78mg 0.21mmol) is dissolved in 0.3mL H with embodiment 3 compounds 2Among the O, add 1, (7.0eq.), behind the stirring at room 2h, the TLC demonstration reacts completely 8-diazacyclo [5,4,0] hendecene-7 (DBU) for 0.22mL, 1.47mmol.After reaction system adds Lindlar catalyzer (8mg), feed H 2Behind the reaction 24h, the TLC demonstration reacts completely stopped reaction.Remove by filter insolubles, spent ion exchange resin separate title compound 42mg, productive rate: 70%.
1H?NMR(300MHz，D 2O)：δ5.71(1H，d，J＝2.6Hz，3-H)，4.53(1H，d，J＝10.9Hz，6-H)，4.42(1H，s，7-H)，4.34(1H，t，J＝9.9Hz，5-H)，4.15(1H，dd，J＝1.4Hz，J＝9.2Hz，4-H)，2.87(3H，s，CH 3)，2.12(3H，s，NAc)；MS(ESI)：m/z(％)＝287.1(100)[M+H +].LRMS(ESI)：m/z[M+Na] +＝288.0。
Embodiment 23 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000203
(10mg 0.035mmol) is dissolved in 0.3mL H with embodiment 22 compounds 2Among the O, add amidino groups pyrazoles mono-hydrochloric salts (7.6mg, 0.042mmol, 1.5eq) and imidazoles (11.8mg, 0.17mmol 5.0eq.), behind the stirring 24h, add 4 Et 3N, after continuing to stir 12h, the TLC demonstration reacts completely.Part material is removed in the separation of reaction solution spent ion exchange resin, separated (eluent: water) get title compound 8.4mg, productive rate 74% with reversed-phase silica gel column chromatography again.
1H?NMR(400MHz，D 2O)：δ5.64(1H，d，J＝2.5Hz，3-H)，4.54(1H，dd，J＝1.9Hz，J＝10.4Hz，6-H)，4.46(1H，dd，J＝2.4Hz，J＝6.8Hz，4-H)，4.39(1H，dd，J＝2.0Hz，J＝4.5Hz，7-H)，4.26(1H，t，J＝10.1Hz，5-H)，2.84(3H，s，CH 3)，2.04(3H，s，NAc)；LRMS(ESI)：m/z[M+H] +＝330.1。
Embodiment 24 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000211
According to the method identical, be that raw material prepares title compound with embodiment 6 compounds with embodiment 22; Productive rate: 70%.
1H NMR (300MHz, D 2O): δ 5.74 (1H, d, J=2.1Hz, 3-H), 4.90 (1H, d, J=2.1Hz, 7-H), 4.54 (1H, dd, J=2.1Hz, J=9.6Hz, 6-H), 4.35 (1H, t, J=9.6Hz, 5-H), 4.28 (1H, dd, J=2.4Hz, J=9.3Hz, 4-H), 3.12 (3H, s, CH 3), 3.03 (3H, s, CH 3), 2.13 (3H, s, NAc); HRMS (EI): m/z calculated value: C 12H 19N 3O 6Na[M+Na] +324.1172, measured value: 324.1163.
Embodiment 25 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000212
According to the method identical, be that raw material prepares title compound with embodiment 24 compounds with embodiment 23; Productive rate: 74%.
1H NMR (300MHz, D 2O): δ 5.72 (1H, d, J=3.2Hz, 3-H), 4.55 (1H, dd, J=4.2Hz, J=8.2Hz, 6-H), 4.42 (1H, dd, J=3.0Hz, J=7.8Hz, 4-H), 4.21 (1H, t, J=7.9Hz, 5-H), 3.13 (3H, s, CH 3), 3.00 (3H, s, CH 3), 2.06 (3H, s, NAc); 13C NMR (400MHz, D 2O): δ 19.03,33.14, and 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 value: C 13H 21N 5O 6[M+H] +344.1570, measured value: 344.1577.
Embodiment 26 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-triphenylphosphine imido grpup-3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000221
(30mg 0.07mmol) is dissolved among the THF (2.0mL), adds PPh with embodiment 4 compounds 3(1.05eq.), behind the stirring at room 18h, concentrating under reduced pressure gets oily matter for 20mg, 0.07mmol.Preparation plate (CH 2Cl 2: CH 3OH=30: 1 (v/v)) separate title compound 15mg, productive rate: 30%.
1H?NMR(300MHz，CDCl 3)：δ8.20(1H，d，J＝7.8Hz，NH)，7.73(18H，m，18PhH)，6.56(1H，m，NH)，5.45(1H，d，J＝1.5Hz，7-H)，5.40(1H，d，J＝2.1Hz，3-H)，4.98(1H，dd，J＝1.5Hz，J＝10.2Hz，6-H)，4.82(1H，m，4-H)，4.14(1H，dt，J＝10.5Hz，J＝17.7Hz，5-H)，3.67(3H，s，CH 3)，3.39(1H，m，CH)，3.18(1H，m，CH)，2.23(3H，s，OAc)，1.76(3H，s，NAc)，1.12(3H，t，J＝7.2Hz，CH 3)；LRMS(ESI)：m/z[M+H] +＝618.3。
Embodiment 27 (2R, 3R, S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000222
(30mg 0.07mmol) is dissolved among the THF (2.0mL), adds PPh with embodiment 4 compounds 3(1.05eq.), behind the stirring at room 18h, concentrating under reduced pressure gets oily matter for 20mg, 0.07mmol.Preparation plate (CH 2Cl 2: CH 3OH=10: 1 (v/v)) separate title compound 24mg, productive rate: 50%.
1H?NMR(300MHz，CDCl 3)：δ5.87(1H，d，J＝2.5Hz，3-H)，5.08(1H，d，J＝1.8Hz，7-H)，4.30(1H，dd，J＝1.6Hz，J＝10.4Hz，6-H)，3.76(1H，t，J＝9.9Hz，5-H)，3.68(3H，s，CH 3)，3.40(1H，m，4-H)，3.24(1H，m，CH)，2.99(1H，m，CH)，2.11(3H，s，OAc)，1.79(3H，s，NAc)，1.03(3H，t，J＝7.1Hz，CH 3)；LRMS(ESI)：m/z[M+Na] +＝380.1。
Embodiment 28 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000223
With embodiment 26 compound (15mg, 0.024mmol) be dissolved in the mixing solutions of methyl alcohol (0.75mL) and water (0.75mL), add KOH (0.3mL), behind the stirring at room 16h, with the hydrochloric acid conditioning solution pH=6-7 of 2mol/L, get the title compound of light yellow solid behind the concentrating under reduced pressure.Can be not purified, be directly used in the next step.
LRMS(ESI)：m/z[M-H] +＝300.1。
Embodiment 29 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-[2 ', 3 '-two tertbutyloxycarbonyl guanidine radicals]-3,4-dihydropyrane-6-formic acid
Embodiment 28 compounds are dissolved in the mixing solutions of methyl alcohol (0.2mL) and THF (0.2mL), add N then, and N '-two tertbutyloxycarbonyl amidino groups pyrazoles (10.4mg, 0.04mmol), behind the stirring at room 24h, concentrating under reduced pressure, preparation plate (CH 2Cl 2: CH 3OH=6: 1 (v/v)) separate title compound 10mg, productive rate: 76%.
LRMS(ESI)：m/z[M+Na] +＝566.1。
Embodiment 30 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000232
(10mg 0.02mmol) is dissolved in CH with embodiment 29 compounds 2Cl 2(0.2mL), add CF then 3COOH (0.1mL), behind the stirring at room 2h, be evaporated to dried, ion exchange resin separate the title compound 6mg of white solid, productive rate: 96%.
1H?NMR(300MHz，D 2O)：δ5.65(1H，d，J＝2.4Hz，3-H)，4.55(1H，dd，J＝2.1Hz，J＝10.5Hz，6-H)，4.48(1H，dd，J＝2.4Hz，J＝12.0Hz，4-H)，4.39(1H，d，J＝2.1Hz，7-H)，4.28(1H，dt，J＝7.8Hz，J＝17.7Hz，5-H)，3.33(4H，dt，J＝7.2Hz，J＝14.4Hz，CH 2)，2.07(3H，s，NAc)，1.17(6H，t，J＝7.2Hz，CH 3)。
Embodiment 31 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000241
According to the method identical, be that raw material prepares target compound with the compound of embodiment 7 with embodiment 22; Productive rate: 93%.
1H?NMR(300MHz，D 2O)：δ5.73(1H，d，J＝1.8Hz，3-H)，4.74(1H，d，J＝3.0Hz，7-H)，4.47(1H，dd，J＝2.7Hz，J＝9.0Hz，6-H)，4.23(1H，dt，J＝9.6Hz，J＝18.6Hz，5-H)，4.20(1H，dd，J＝2.1Hz，J＝10.5Hz，4-H)，3.43(4H，m，2CH 2)，2.10(3H，s，NAc)，1.23(3H，t，J＝7.2Hz，CH 3)，1.15(3H，t，J＝7.2Hz，CH 3)；LRMS(ESI)：m/z[M+H] +＝330.0。
Embodiment 32 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000242
(10mg 0.02mmol) is dissolved in THF (0.5mL) and H with embodiment 7 compounds 2O (4.4 μ L, 0.2mmol, 10eq.) in, add PPh 3(7mg, 0.02mmol), behind the stirring at room 48h, stopped reaction.Behind the concentrating under reduced pressure, preparation plate (CH 2Cl 2: CH 3OH=6/1 (v/v)) gets title compound 4mg, productive rate: 43%.
1H?NMR(300MHz，CDCl 3)：δ6.94(1H，d，J＝8.7Hz，NH)，6.05(1H，d，J＝3.0Hz，3-H)，5.80(1H，d，J＝4.5Hz，7-H)，4.57(1H，dd，J＝4.8Hz，J＝8.4Hz，6-H)，3.97(1H，dt，J＝8.4Hz，J＝16.5Hz，5-H)，3.78(3H，s，CH 3)，3.73(2H，m，CH?and?4-H)，3.35(3H，m，CH?and?CH 2)，2.19(3H，s，OAc)，1.99(3H，s，NAc)，1.13(6H，t，J＝6.9Hz，2CH 3)；LRMS(ESI)：m/z[M+Na] +＝408.3。
Embodiment 33 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-[2 ', 3 '-two tertbutyloxycarbonyl guanidine radicals]-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000243
(60mg 0.16mmol) is dissolved in the anhydrous methanol (2mL) N with embodiment 32 compounds 2Protection drips N, N '-two tertbutyloxycarbonyl amidino groups pyrazoles (60mg, THF 0.19mmol) (2mL) solution down.Behind the stirring at room 48h, revolve most solvent, directly prepare plate (CH 2Cl 2: CH 3OH=10: 1 (v/v)) separate, get the title compound 78mg of white solid, productive rate: 80%.
1H?NMR(300MHz，CDCl 3)：δ11.40(1H，s，NH)，8.52(1H，d，J＝8.3Hz，NH)，6.66(1H，d，J＝8.5Hz，NH)，5.92(1H，d，J＝2.3Hz，3-H)，5.65(1H，d，J＝4.2Hz，7-H)，5.21(1H，dd，J＝2.2Hz，J＝10.3Hz，4-H)，4.55(1H，dd，J＝4.3Hz，J＝10.7Hz，6-H)，4.25(1H，dt，J＝9.9Hz，J＝18.8Hz，5-H)，3.84(3H，s，CH 3)，3.36(4H，m，2CH 2)，2.23(3H，s，OAc)，1.91(3H，s，NAc)，1.52(9H，s，3CH 3)，1.51(9H，s，3CH 3)，1.16(3H，t，J＝6.9Hz，CH 3)；LRMS(ESI)：m/z[M+H] +＝628.1。
Embodiment 34 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-methyl-formiate
Figure G2009100458184D0000251
(4mg 0.03mmol) is dissolved in anhydrous CH with embodiment 33 compounds 2Cl 2(0.5mL), N 2Protection adds CF down 3COOH (0.2mL) solution.Behind the stirring at room 5h, revolve most solvent, get title compound 3mg, can be directly used in the next step.
LRMS(ESI)：m/z[M+H] +＝372.2。
Embodiment 35 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000252
With embodiment 34 compounds (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-guanidine radicals-3, (3mg 0.01mmol) is dissolved in H to 4-dihydropyrane-6-methyl-formiate 2In the aqueous solution of O (0.2mL) and 1M NaOH (2 μ L), behind the stirring at room 15h, stopped reaction.Zeo-karb separate title compound 2mg, productive rate: 73%.
1H?NMR(300MHz，D 2O)：δ5.79(1H，d，J＝3.3Hz，3-H)，4.80(1H，d，J＝5.7Hz，7-H)，4.61(1H，t，J＝6.0Hz，6-H)，4.43(1H，dd，J＝3.3Hz，J＝6.6Hz，4-H)，4.23(1H，dt，J＝9.0Hz，J＝15.9Hz，5-H)，3.49(4H，m，CH 2)，2.11(3H，s，NAc)，1.29(6H，t，J＝7.2Hz，2CH 3)；LRMS(ESI)：m/z[M+H] +＝372.2。
Embodiment 36 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000261
According to the method identical, be that raw material prepares title compound with embodiment 9 compounds with embodiment 22; Productive rate: 90%.
1H?NMR(400MHz，D 2O)：δ5.74(1H，d，J＝3.0Hz，3-H)，4.70(1H，d，J＝2.5Hz，7-H)，4.52(1H，t，J＝2.7Hz，J＝10.2Hz，6-H)，4.34(1H，t，J＝9.4Hz，5-H)，4.27(1H，dd，J＝2.2Hz，J＝9.4Hz，4-H)，3.58(4H，m，2CH 2)，2.12(3H，s，NAc)，1.97(4H，m，2CH 2)；LR-ESI-MS：[M+Na] +＝350.1。
Embodiment 37 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid
Figure G2009100458184D0000262
According to the method identical, be that raw material prepares title compound with embodiment 36 compounds with embodiment 23; Productive rate: 80%.
1H?NMR(300MHz，D 2O)：δ5.73(1H，d，J＝3.0Hz，3-H)，4.67(1H，d，J＝4.5Hz，7-H)，4.55(1H，dd，J＝4.5Hz，J＝8.4Hz，6-H)，4.43(1H，dd，J＝3.0Hz，J＝7.5Hz，5-H)，4.237(1H，t，J＝8.1Hz，5-H)，3.69(1H，m，CH)，3.51(3H，m，CH+CH 2)，2.06(3H，s，NAc)，1.95(4H，m，2CH 2)；HRMS(ESI)：[M+H] +＝370.2。
Embodiment 38～41
According to the method identical,, prepare embodiment 38～41 compounds respectively with embodiment 2 compounds and different amine reactions with embodiment 5.
Figure G2009100458184D0000263
Figure G2009100458184D0000271
Figure G2009100458184D0000281
Embodiment 42～47
Method according to identical with embodiment 31 correspondingly prepares embodiment 42～47 compounds by embodiment 5,38,8,39～41 respectively.
Figure G2009100458184D0000282
Figure G2009100458184D0000291
Embodiment 48～52
Method according to identical with embodiment 23 correspondingly prepares embodiment 48～52 compounds by embodiment 42～46 respectively.
Embodiment 53～87
Preparation method according to identical with embodiment 12 correspondingly prepares embodiment 53～87 compounds.
Figure G2009100458184D0000311
Figure G2009100458184D0000312
Figure G2009100458184D0000321
Embodiment The name and 1H-NMR, MS data
??53 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-(1 "-hydroxyethyl)-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.63(1H，s，CH)，7.01(1H，t，J＝6.8Hz，NH)，??6.37(1H，d，J＝4.6Hz，NH)，6.04(1H，d，J＝2.3Hz，3-H)，5.69(1H，m，CH)，??5.58(1H，d，J＝1.6Hz，7-H)，5.06(1H，t，J＝6.8Hz，4-H)，4.82(1H，dd，J＝??3.6Hz，J＝10.9Hz，6-H)，4.53(1H，dt，J＝10.2Hz，J＝20.5Hz，5-H)，3.80(3??H，s，CH 3)，2.92(3H，d，J＝4.9Hz，CH 3)，2.18(3H，s，OAc)，1.80(3H，s，??NHAc)，1.58(3H，dd，J＝2.7，6.6Hz，CH 3); HRMS (EI): m/z calculated value: C 18H 25N 5O 8Na[M+Na] +462.1601, measured value: 462.1611.
??54 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-hydroxypropyl-1,2, the 3-triazole-]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.51(1H，s，CH)，7.38(1H，t，J＝9.8Hz，NH)，??6.42(1H，d，J＝5.0Hz，NH)，6.04(1H，d，J＝2.4Hz，3-H)，5.65(1H，dd，J＝??2.4Hz，J＝10.1Hz，4-H)，5.59(1H，d，J＝2.0Hz，7-H)，4.80(1H，dd，J＝2.1??Hz，J＝10.7Hz，6-H)，4.58(1H，dt，J＝10.4Hz，J＝19.4Hz，5-H)，3.79(3H，s，??CH 3)，3.64(2H，m，CH 2)，2.91(3H，d，J＝4.9Hz，CH 3)，2.82(2H，t，J＝7.4
??Hz，CH 2)，2.18(3H，s，OAc)，1.93(2H，q，J＝7.0Hz，J＝13.5Hz，CH 2), 1.77 (3H, s, NHAc); HRMS (EI): m/z calculated value: C 18H 25N 5O 8[M] +453.1860, measured value: 453.1877.
Embodiment The name and 1H-NMR, MS data
??55 1-[(2R, 3R, 4S)-and 3-acetamido-2-((S)-1 '-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl)-6-methoxycarbonyl-3,4-dihydropyrane-4]-1,2,3-triazole-4,5-dioctyl phthalate methyl esters 1H?NMR(300MHz，CDCl 3)：δ6.72(2H，d，J＝9.3Hz，NH)，6.38(1H，d，J＝??4.5Hz，NH)，6.08(1H，d，J＝2.4Hz，3-H)，6.00(1H，dd，J＝2.7Hz，J＝9.6Hz，??4-H)，5.45(1H，d，J＝9.0Hz，7-H)，4.95(1H，dd，J＝1.5Hz，J＝10.8Hz，6-H)，??4.60(1H，dt，J＝9.6Hz，J＝19.8Hz，5-H)，3.97(3H，s，CH 3)，3.94(3H，s，??CH 3)，3.79(3H，s，CH 3)，2.92(3H，d，J＝4.8Hz，CH 3)，2.17(3H，s，OAc)，1.84??(3H，s，NHAc)；HRMS(ESI)：m/z[M+Na] +＝534.3.
??56 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-cyclopropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.37(1H，s，CH)，7.20(1H，t，J＝9.3Hz，NH)，??6.49(1H，d，J＝4.9Hz，NH)，5.99(1H，d，J＝2.4Hz，3-H)，5.64(1H，dd，J＝??2.3Hz，J＝10.1Hz，4-H)，5.57(1H，d，J＝1.6Hz，7-H)，4.80(1H，dd，J＝1.8??Hz，J＝10.5Hz，6-H)，4.59(1H，dt，J＝10.2Hz，J＝20.5Hz，5-H)，3.78(3H，s，??CH 3)，2.90(3H，d，J＝6.8Hz，CH 3)，2.20(3H，s，OAc)，1.92(1H，m，CH)，1.78??(3H，s，NHAc)，0.94(1H，m，CH 2)，0.84(1H，m，CH 2); HRMS (EI): m/z calculated value: C 19H 26N 5O 7[M+H] +436.1832, measured value: 436.1823.
Embodiment The name and 1H-NMR, MS data
??57 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.88(1H，s，CH)，7.61(1H，d，J＝9.6Hz，NH)，??7.33(1H，t，J＝1.8Hz，PhH)，7.18(2H，t，J＝7.9Hz，PhH)，7.08(1H，t，J＝6.6??Hz，PhH)，6.66(1H，dd，J＝1.5Hz，J＝8.1Hz，PhH)，6.40(1H，d，J＝5.0Hz，??NH)，6.06(1H，d，J＝2.2Hz，3-H)，5.78(1H，dd，J＝2.1Hz，J＝9.9Hz，4-H)，??5.64(1H，d，J＝1.6Hz，7-H)，4.87(1H，dd，J＝1.8Hz，J＝10.6Hz，6-H)，4.66??(1H，dt，J＝9.7Hz，J＝19.8Hz，5-H)，3.80(3H，s，CH 3)，2.92(3H，d，J＝4.8??Hz，CH 3), 2.19 (3H, s, OAc), 1.76 (3H, s, NHAc); HRMS (EI): m/z calculated value: C 22H 26N 6O 7[M] +486.1863, measured value: 486.1876.
??58 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-methylol-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.69(1H，s，CH)，7.07(1H，d，J＝7.1Hz，NH)，??6.11(1H，d，J＝2.4Hz，3-H)，6.01(1H，d，J＝7.5Hz，4-H)，5.78(1H，d，J＝??3.9Hz，7-H)，4.99(1H，dd，J＝4.2Hz，J＝9.9Hz，6-H)，4.76(2H，s，CH 2)，4.21??(1H，d，J＝8.1Hz，5-H)，3.80(3H，s，CH 3)，3.18(3H，s，CH 3)，2.97(3H，s，??CH 3), 2.13 (3H, s, OAc), 1.90 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 18H 25N 5O 8Na[M+Na] +462.1601, measured value: 462.1597.
Embodiment The name and 1H-NMR, MS data
??59 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-(1 "-hydroxyethyl)-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.61(1H，s，CH)，6.95(1H，d，J＝8.1Hz，NH)，??6.12(1H，m，3-H)，6.01(1H，m，4-H)，5.78(1H，d，J＝4.1Hz，7-H)，5.04(1H，??m，CH)，4.98(1H，m，CH)，4.20(1H，m，5-H)，3.80(3H，s，CH 3)，3.18(3H，s，??CH 3)，2.97(3H，s，CH 3)，2.13(3H，s，OAc)，1.89(3H，s，NHAc)，1.57(3H，m，??CH 3).
??60 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-hydroxypropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.49(1H，s，CH)，6.87(1H，d，J＝7.9Hz，NH)，
??6.13(1H，d，J＝2.7Hz，3-H)，6.01(1H，dd，J＝2.6Hz，J＝9.4Hz，4-H)，5.79??(1H，d，J＝4.2Hz，7-H)，4.93(1H，dd，J＝4.2Hz，J＝9.7Hz，6-H)，4.27(1H，??dd，J＝8.4Hz，5-H)，3.80(3H，s，CH 3)，3.18(2H，d，J＝5.5Hz，CH 2)，3.18(3??H，s，CH 3)，2.97(3H，s，CH 3)，2.82(2H，t，J＝7.3Hz，CH 2)，2.13(3H，s，OAc)，??1.92(2H，t，J＝6.2Hz，CH 2), 1.89 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 20H 29N 5O 8Na[M+Na] +490.1914, measured value: 490.1902.
Embodiment The name and 1H-NMR, MS data
??61 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-methoxycarbonyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ8.17(1H，s，CH)，6.92(1H，d，J＝7.5Hz，NH)，??6.19(1H，dd，J＝2.4Hz，J＝9.2Hz，4-H)，6.10(1H，d，J＝2.7Hz，3-H)，5.79??(1H，d，J＝3.7Hz，7-H)，5.07(1H，dd，J＝3.7Hz，J＝10.0Hz，6-H)，4.11(1H，??dt，J＝9.6Hz，J＝17.0Hz，5-H)，3.93(3H，s，CH 3)，3.81(3H，s，CH 3)，3.20(3??H，s，CH 3)，2.98(3H，s，CH 3), 2.14 (3H, s, OAc), 1.95 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 19H 25N 5O 9Na[M+Na] +490.1550, measured value: 490.1562.
??62 1-[(2R, 3R, 4S)-and 3-acetamido-2-((S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl)-6-methoxycarbonyl-3,4-dihydropyrane-4]-1,2,3-triazole-4,5-dioctyl phthalate methyl esters 1H?NMR(400MHz，CDCl 3)：δ6.50(1H，dd，J＝2.4Hz，J＝9.5Hz，4-H)，6.47??(1H，d，J＝6.8Hz，NH)，6.13(1H，d，J＝2.4Hz，3-H)，5.77(1H，d，J＝3.5Hz，??7-H)，5.10(1H，dd，J＝3.5Hz，J＝10.3Hz，6-H)，4.03(1H，m，5-H)，3.99(3H，??s，CH 3)，3.96(3H，s，CH 3)，3.80(3H，s，CH 3)，3.23(3H，s，CH 3)，2.99(3H，s，??CH 3), 2.11 (3H, s, OAc), 1.91 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 21H 27N 5O 11Na[M+Na] +548.1605, measured value: 549.1604.
Embodiment The name and 1H-NMR, MS data
??63 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-cyclopropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(300MHz，CDCl 3)：δ7.36(1H，s，CH)，6.57(1H，d，J＝7.8Hz，NH)，??6.12(1H，d，J＝2.7Hz，3-H)，5.96(1H，dd，J＝2.7Hz，J＝9.0Hz，4-H)，5.80??(1H，d，J＝4.2Hz，7-H)，4.94(1H，dd，J＝6.9Hz，J＝12.0Hz，6-H)，4.27(1H，??dt，J＝9.3Hz，J＝17.1Hz，5-H)，3.81(3H，s，CH 3)，3.17(2H，s，CH 3)，2.96(3??H，s，CH 3)，2.14(3H，s，OAc)，1.94(1H，m，CH)，1.91(3H，s，NHAc)，0.95(2??H，m，CH 2)，0.82(2H，m，CH 2); HRMS (EI): m/z calculated value: C 20H 27N 5O 7[M] +449.1910, measured value: 449.1929.
??64 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-phenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.92(1H，s，CH)，7.80(2H，dd，J＝1.4Hz，J＝??8.6Hz，PhH)，7.37(4H，m，PhH)，6.95(1H，d，J＝8.1Hz，NH)，6.18(1H，d，J??＝2.6Hz，3-H)，6.06(1H，dd，J＝2.6Hz，J＝9.2Hz，4-H)，5.79(1H，d，J＝4.0??Hz，7-H)，4.98(1H，dd，J＝4.1Hz，J＝9.7Hz，6-H)，4.37(1H，dt，J＝9.7Hz，J??＝17.6Hz，5-H)，3.81(3H，s，CH 3)，3.18(3H，s，CH 3)，2.96(3H，s，CH 3), 2.14 (3H, s, OAc), 1.90 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 23H 27N 5O 7Na??[M+Na] +508.1808, measured value: 508.1788.
Embodiment The name and 1H-NMR, MS data
??65 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.86(1H，s，CH)，7.17(3H，m，PhH)，6.84(1H，??d，J＝7.8Hz，PhH)，6.67(1H，d，J＝7.8Hz，NH)，6.17(1H，d，J＝2.6Hz，3-H)，??6.05(1H，dd，J＝2.7Hz，J＝9.1Hz，4-H)，5.82(1H，d，J＝4.3Hz，7-H)，5.00??(1H，dd，J＝4.1Hz，J＝9.3Hz，6-H)，4.27(1H，dt，J＝9.4Hz，J＝17.2Hz，??5-H)，3.81(3H，s，CH 3)，3.16(3H，s，CH 3)，2.95(3H，s，CH 3)，2.13(3H，s，
OAc), 1.91 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 23H 28N 6O 7Na??[M+Na] +523.1917, measured value: 523.1932.
??66 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-methylol-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.83(1H，s，J＝9.9Hz，NH)，7.73(1H，s，CH)，??6.45(1H，t，J＝5.5Hz，NH)，6.04(1H，d，J＝2.2Hz，3-H)，5.71(1H，dd，J＝??2.4Hz，J＝9.8Hz，4-H)，5.59(1H，d，J＝1.7Hz，7-H)，4.85(1H，dd，J＝1.8??Hz，J＝10.8Hz，6-H)，4.03(1H，dt，J＝9.9Hz，J＝20.2Hz，5-H)，4.09(1H，s，??OH)，3.78(3H，s，CH 3)，3.53(1H，m，CH)，3.23(1H，m，CH)，2.16(3H，s，??OAc)，1.77(3H，s，NHAc)，1.22(3H，t，J＝7.0Hz，CH 3); HRMS (EI) m/z calculated value: C 18H 25N 5O 8[M] +439.1703, measured value: 439.1698.
Embodiment The name and 1H-NMR, MS data
??67 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-(1 "-hydroxyethyl)-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate HRMS (EI) m/z calculated value: C 19H 27N 5O 8[M] +453.1859, measured value: 453.1852.
??68 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-hydroxypropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.50(1H，s，CH)，7.48(1H，d，J＝9.5Hz，NH)，??6.36(1H，t，J＝5.9Hz，NH)，6.04(1H，d，J＝2.2Hz，3-H)，5.64(1H，dd，J＝??2.2Hz，J＝9.9Hz，4-H)，5.59(1H，d，J＝1.8Hz，7-H)，4.80(1H，dd，J＝1.8??Hz，J＝10.6Hz，6-H)，4.60(1H，dt，J＝7.5Hz，J＝15.3Hz，5-H)，3.78(3H，s，??CH 3)，3.64(2H，m，CH 2)，3.55(1H，m，CH)，3.23(1H，m，CH)，2.82(2H，t，J??＝7.3Hz，CH 2)，2.19(3H，s，OAc)，1.93(2H，f，J＝6.6Hz，J＝13.2Hz，CH 2)，??1.75(3H，s，NHAc)，1.22(3H，t，J＝7.3Hz，CH 3); HRMS (EI) m/z calculated value: C 20H 29N 5O 8[M] +467.2016, measured value: 467.1997.
Embodiment The name and 1H-NMR, MS data
??69 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-methoxycarbonyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(300MHz，CDCl 3)：δ8.24(1H，s，CH)，7.02(1H，d，J＝9.6Hz，NH)，??6.34(1H，t，J＝6.3Hz，NH)，6.04(1H，d，J＝2.4Hz，3-H)，5.78(1H，dd，J＝??2.4Hz，J＝10.2Hz，4-H)，5.56(1H，d，J＝1.8Hz，7-H)，4.90(1H，dd，J＝1.8??Hz，J＝10.8Hz，6-H)，4.56(1H，dt，J＝9.9Hz，J＝20.1Hz，5-H)，3.94(3H，s，??CH 3)，3.80(3H，s，CH 3)，3.55(1H，m，CH)，3.27(1H，m，CH)，2.20(3H，s，??OAc)，1.83(3H，s，NHAc)，1.23(1H，t，J＝7.2Hz，CH 3); HRMS (EI) m/z calculated value: C 19H 26N 5O 9[M+H] +468.1731, measured value: 468.1725.
??70 1-[(2R, 3R, 4S)-and 3-acetamido-2-((S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl)-6-methoxycarbonyl-3,4-dihydropyrane-4]-1,2,3-triazole-4,5-dioctyl phthalate methyl esters 1H?NMR(300MHz，CDCl 3)：δ6.61(1H，d，J＝9.6Hz，NH)，6.33(1H，t，J＝??6.9Hz，NH)，6.09(1H，d，J＝2.7Hz，3-H)，6.00(1H，dd，J＝2.4Hz，J＝9.6Hz，??4-H)，5.44(1H，d，J＝1.5Hz，7-H)，4.96(1H，dd，J＝1.5Hz，J＝10.8Hz，6-H)，??4.59(1H，dt，J＝9.6Hz，J＝19.8Hz，5-H)，3.98(3H，s，CH 3)，3.95(3H，s，??CH 3)，3.79(3H，s，CH 3)，3.55(1H，m，CH)，3.26(1H，m，CH)，2.18(3H，s，??OAc)，1.84(3H，s，NHAc)，1.22(3H，t，J＝7.2Hz，CH 3); HRMS (EI) m/z calculated value: C 21H2 8N 5O 11[M+H] +526.1785, measured value: 526.1787.
Embodiment The name and 1H-NMR, MS data
??71 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-cyclopropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(300MHz，CDCl 3)：δ7.37(1H，s，CH)，7.32(1H，d，J＝9.9Hz，NH)，??6.31(1H，t，J＝6.0Hz，NH)，6.00(1H，d，J＝2.7Hz，3-H)，5.63(1H，dd，J＝??2.4Hz，J＝10.2Hz，4-H)，5.57(1H，d，J＝1.5Hz，7-H)，4.79(1H，dd，J＝1.8??Hz，J＝10.8Hz，6-H)，4.59(1H，dt，J＝9.9Hz，J＝20.1Hz，5-H)，3.77(3H，s，
??CH 3)，3.53(1H，m，CH)，3.22(1H，m，CH)，2.21(3H，s，OAc)，1.92(1H，m，??CH)，1.76(3H，s，NHAc)，1.22(3H，t，J＝7.2Hz，CH 3)，0.87(4H，m，2CH 2); HRMS (EI) m/z calculated value: C 20H 28N 5O 7[M+H] +450.1989, measured value: 450.2001.
Embodiment The name and 1H-NMR, MS data
??72 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-phenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(300MHz，CDCl 3)：δ7.90(1H，s，CH)，7.82(2H，d，J＝6.9Hz，PhH)，??7.43(2H，t，J＝7.2Hz，PhH)，7.34(1H，t，J＝7.5Hz，PhH)，6.96(1H，d，J＝??9.6Hz，NH)，6.31(1H，t，J＝7.5Hz，NH)，6.10(1H，d，J＝2.4Hz，3-H)，5.77??(1H，dd，J＝2.4Hz，J＝10.2Hz，4-H)，5.60(1H，d，J＝1.8Hz，7-H)，4.87(1H，??dd，J＝1.8Hz，J＝10.8Hz，6-H)，4.69(1H，dt，J＝9.9Hz，J＝20.1Hz，5-H)，??3.80(3H，s，CH 3)，3.57(1H，m，CH)，3.26(1H，m，CH)，2.23(3H，s，OAc)，??1.81(3H，s，NHAc)，1.24(3H，t，J＝7.2Hz，CH 3); HRMS (EI): m/z calculated value: C 23H 28N 5O 7[M+H] +486.1989, measured value: 486.1984.
Embodiment The name and 1H-NMR, MS data
??73 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(300MHz，CDCl 3)：δ7.86(1H，s，CH)，7.56(1H，d，J＝9.9Hz，NH)，??7.34(1H，s，PhH)，7.18(1H，t，J＝7.8Hz，PhH)，7.08(1H，d，J＝7.8Hz，PhH)，??6.66(1H，d，J＝9.3Hz，NH)，631(1H，t，J＝5.7Hz，NH)，6.06(1H，d，J＝2.1??Hz，3-H)，5.77(1H，dd，J＝2.4Hz，J＝10.8Hz，4-H)，5.64(1H，d，J＝1.5Hz，??7-H)，4.86(1H，dd，J＝1.5Hz，J＝10.5Hz，6-H)，4.67(1H，dt，J＝10.2Hz，J＝??20.4Hz，5-H)，3.79(3H，s，CH 3)，3.57(1H，m，CH)，3.25(1H，m，CH)，2.21(3??H，s，OAc)，1.75(3H，s，NHAc)，1.23(3H，t，J＝6.6Hz，CH 3); HRMS (ESI): m/z calculated value: C 23H 28N 6O 7[M] +500.2020, measured value: 500.2019.
??74 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-methylol-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，DMSO-d6)：δ8.23(1H，d，J＝9.1Hz，NH)，7.96(1H，s，??CH)，6.00(1H，d，J＝2.2Hz，3-H)，5.55(1H，dd，J＝2.7Hz，J＝9.5Hz，6-H)，??5.28(1H，d，J＝2.9Hz，7-H)，4.69(1H，dd，J＝2.4Hz，J＝9.8Hz，4-H)，4.49??(2H，m，CH 2)，4.36(1H，dt，J＝9.5Hz，J＝16.8Hz，5-H)，3.84(1H，m，CH)，??3.73(3H，s，CH 3)，3.23(3H，m，CH 2+CH)，2.05(3H，s，OAc)，1.87(4H，m，??2CH 2)，1.69(3H，s，NHAc)；HRMS(ESI)：m/z[M+H] +＝466.0.
Embodiment The name and 1H-NMR, MS data
??75 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-(1 "-hydroxyethyl)-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.64(1H，d，J＝2.6Hz，CH)，?7.46(1H，d，J＝??8.5Hz，NH)，6.09(1H，d，J＝2.0Hz，3-H)，5.92(1H，d，J＝9.7Hz，6-H)，5.58??(1H，d，J＝2.1Hz，7-H)，5.04(1H，m，CH)，4.92(1H，dd，J＝3.2Hz，J＝10.4??Hz，4-H)，4.41(1H，dd，J＝10.6Hz，J＝20.7Hz，5-H)，4.00(1H，m，CH)，3.79??(3H，m，CH 3)，3.52(3H，m，CH 2and?CH)，2.14(3H，s，OAc)，1.94(4H，m，??2CH 2)，1.84(3H，s，NHAc)，1.57(3H，dd，J＝3.0Hz，J＝6.3Hz，CH 3); HRMS (EI): m/z calculated value: C 21H 29N 5O 8[M] +479.2016, measured value: 479.2032.
??76 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-hydroxypropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，DMSO-d6)：δ8.20(1H，d，J＝9.1Hz，NH)，7.85(1H，s，??CH)，6.02(1H，d，J＝2.8Hz，3-H)，5.49(1H，dd，J＝2.7Hz，J＝9.9Hz，6-H)，??5.28(1H，d，J＝2.7Hz，7-H)，4.69(1H，dd，J＝2.6Hz，J＝10.1Hz，4-H)，4.31??(1H，dt，J＝9.5Hz，J＝19.2Hz，5-H)，3.84(1H，m，CH)，3.73(3H，m，CH 3)，??3.26(3H，m，CH 2and?CH)，2.62(2H，t，J＝7.3Hz，CH 2)，2.05(3H，s，OAc)，??1.86(4H，m，2CH 2)，1.71(2H，dt，J＝6.4Hz，J＝14.3Hz，CH 2)，1.68(3H，s，??NHAc)；HRMS(ESI)：m/z[M+Na] +＝516.2.
Embodiment The name and 1H-NMR, MS data
??77 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-phenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，DMSO-d6)：δ8.64(1H，s，CH)，7.84(1H，d，J＝6.9Hz，??PhH)，7.42(2H，t，J＝7.6Hz，PhH)，7.31(2H，t，J＝7.6Hz，PhH)，6.09(1H，d，??J＝2.7Hz，3-H)，5.60(1H，dd，J＝2.5Hz，J＝9.9Hz，6-H)，5.29(1H，d，J＝2.6??Hz，7-H)，4.74(1H，dd，J＝2.6Hz，J＝10.6Hz，4-H)，4.37(1H，t，J＝10.3Hz，??5-H)，3.86(1H，m，CH)，3.73(3H，s，CH 3)，3.31(3H，m，CH 2and?CH)，2.03(3??H，s，OAc)，1.84(4H，m，2CH 2), 1.78 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 25H 29N 5O 7Na[M+Na] +534.1965, measured value: 534.1990.
??78 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，DMSO-d6)：δ7.87(1H，s，CH)，7.17(3H，m，PhH)，6.66??(1H，d，J＝7.6Hz，PhH)，6.14(1H，d，J＝2.6Hz，3-H)，6.03(1H，d，J＝9.8Hz，??6-H)，5.63(1H，d，J＝3.6Hz，7-H)，4.96(1H，dd，J＝3.3Hz，J＝9.6Hz，4-H)，??4.46(1H，dt，J＝9.5Hz，J＝17.5Hz，5-H)，3.95(1H，m，CH)，3.80(3H，s，??CH 3)，3.50(3H，m，CH 2and?CH)，2.15(3H，s，OAc)，1.88(4H，m，2CH 2), 1.86 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 25H 30N 6O 7Na[M+Na] +549.2074, measured value: 549.2051.
Embodiment The name and 1H-NMR, MS data
??79 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-[4 '-methylol-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR?(400MHz，CDCl 3)：δ7.69(1H，s，CH)，7.28(1H，d，J＝8.0Hz，NH)，??6.09(1H，d，J＝2.2Hz，3-H)，5.99(1H，d，J＝9.2Hz，4-H)，5.75(1H，d，J＝??3.7Hz，7-H)，5.04(1H，dd，J＝3.7Hz，J＝9.9Hz，6-H)，4.73(2H，s，CH 2)，4.23??(1H，dt，J＝9.2Hz，J＝17.6Hz，5-H)，3.78(3H，s，CH 3)，3.47(4H，m，2CH 2)，??2.12(3H，s，OAc)，1.90(3H，s，NHAc)，1.21(3H，t，J＝6.8Hz，CH 3)，1.13(3??H，t，J＝6.8Hz，CH 3); HRMS (ESI): m/z calculated value: C 20H 29N 5O 8Na[M+Na] +490.1914, measured value: 490.1916.
??80 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-[4 '-(1 "-hydroxyethyl)-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.60(1H，s，CH)，6.95(1H，d，J＝7.7Hz，NH)，??6.10(1H，d，J＝2.6Hz，3-H)，6.01(1H，dd，J＝2.2Hz，J＝9.2Hz，4-H)，5.77??(1H，d，J＝3.7Hz，7-H)，5.02(2H，m，CH?and?6-H)，4.19(1H，m，5-H)，3.79(3??H，s，CH 3)，3.46(4H，m，2CH 2)，2.14(3H，s，OAc)，1.90(3H，s，NHAc)，1.57??(1H，dd，J＝4.0Hz，J＝6.4Hz，4-H)，1.21(3H，t，J＝7.2Hz，CH 3)，1.13(3H，t，??J＝7.2Hz，CH 3); HRMS (ESI): m/z calculated value: C 21H 31N 5O 8Na[M+Na] +504.2070, measured value: 504.2056.
Embodiment The name and 1H-NMR, MS data
??81 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-[4 '-hydroxypropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.50(1H，s，CH)，7.19(1H，d，J＝8.4Hz，NH)，??6.10(1H，d，J＝2.2Hz，3-H)，5.89(1H，dd，J＝2.2Hz，J＝9.5Hz，4-H)，5.74??(1H，d，J＝4.0Hz，7-H)，4.95(1H，dd，J＝3.7Hz，J＝9.9Hz，6-H)，4.36(1H，??dt，J＝9.2Hz，J＝18.4Hz，5-H)，3.78(3H，s，CH 3)，3.65(3H，m，CH?and?CH 2)，??3.40(3H，m，CH?and?CH 2)，2.81(2H，t，J＝7.2Hz，CH 2)，2.11(3H，s，OAc)，??1.91(2H，t，J＝6.4Hz，CH 2)，1.85(3H，s，NHAc)，1.19(3H，t，J＝7.2Hz，??CH 3)，1.13(3H，t，J＝6.8Hz，CH 3); HRMS (ESI): m/z calculated value: C 22H 33N 5O 8Na??[M+Na] +518.2227, measured value: 518.2222.
??82 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-[4 '-methoxycarbonyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate
?? 1H?NMR(300MHz，CDCl 3)：δ8.14(1H，s，CH)，7.23(1H，d，J＝8.1Hz，NH)，??6.13(1H，dd，J＝2.4Hz，J＝9.6Hz，4-H)，6.13(1H，d，J＝2.7Hz，3-H)，5.74??(1H，d，J＝3.6Hz，7-H)，5.13(1H，dd，J＝3.6Hz，J＝9.9Hz，6-H)，4.17(1H，??dt，J＝9.6Hz，J＝17.4Hz，5-H)，3.92(3H，s，CH 3)，3.80(3H，s，CH 3)，3.43(4??H，m，2CH 2)，2.14(3H，s，OAc)，1.96(3H，s，NHAc)，1.22(3H，t，J＝7.2Hz，??CH 3)，1.13(3H，t，J＝7.2Hz，CH 3)；HRMS(ESI)：m/z[M+H] +＝496.4.
Embodiment The name and 1H-NMR, MS data
??83 1-[(2R, 3R, 4S)-and 3-acetamido-2-((S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl)-6-methoxycarbonyl-3,4-dihydropyrane-4]-1,2,3-triazole-4,5-dioctyl phthalate methyl esters 1H?NMR(300MHz，CDCl 3)：δ6.83(1H，d，J＝7.2Hz，NH)，6.43(1H，dd，J＝??2.4Hz，J＝9.6Hz，4-H)，6.08(1H，d，J＝2.1Hz，3-H)，5.71(1H，d，J＝3.0Hz，??7-H)，5.17(1H，dd，J＝3.0Hz，J＝10.5Hz，6-H)，4.09(1H，dt，J＝9.9Hz，J＝??17.1Hz，5-H)，3.97(3H，s，CH 3)，3.93(3H，s，CH 3)，3.78(3H，s，CH 3)，3.44(4??H，m，2CH 2)，2.10(3H，s，OAc)，1.92(3H，s，NHAc)，1.24(3H，t，J＝7.5Hz，??CH 3)，(3H，t，J＝6.9Hz，CH 3)；HRMS(ESI)：m/z[M+Na] +＝576.3.
??84 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-[4 '-cyclopropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(300MHz，CDCl 3)：δ7.50(1H，s，C-H)，7.32(1H，s，NH)，6.06(1H，??s，C-H)，5.92(1H，s，C-H)，5.75(1H，s，C-H)，4.99(1H，s，C-H)，4.42(1H，s，??C-H)，3.76(3H，s，CH 3)，3.42(4H，m，2CH 2)，2.09(3H，s，OAc)，1.90(3H，s，??NHAc)，1.22(3H，t，J＝6.9Hz，CH 3)，1.13(3H，s，CH 3)，.0.99(4H，d，J＝6.9??Hz，CH 2)，0.99(4H，s，CH 2)；HRMS(ESI)：m/z[M+H] +＝478.3.
Embodiment The name and 1H-NMR, MS data
??85 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-[4 '-phenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.95(1H，s，CH)，7.77(1H，d，J＝6.9Hz，NH)，??7.40(5H，m，PhH)，6.17(1H，s，C-H)，6.05(1H，d，J＝8.7Hz，C-H)，6.07(1H，??d，J＝8.4Hz，4-H)，5.80(1H，s，C-H)，5.05(1H，s，C-H)，4.40(1H，s，C-H)，??3.81(3H，s，CH 3)，3.45(4H，m，2CH 2)，2.13(3H，s，OAc)，1.94(3H，s，??NHAc)，1.23(3H，t，J＝6.9Hz，CH 3)，1.12(3H，t，J＝6.6Hz，CH 3)；??HRMS(ESI)：m/z[M+H] +＝514.4.
??86 (2R, 3R, 4R)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(400MHz，CDCl 3)：δ7.83(1H，s，CH)，7.18(2H，t，J＝7.7Hz，NH??and?PhH)，7.11(1H，d，J＝7.3Hz，PhH)，6.67(1H，t，J＝7.7Hz，PhH)，6.17(1??H，d，J＝1.5Hz，3-H)，6.07(1H，d，J＝8.4Hz，4-H)，5.82(1H，d，J＝4.4Hz，??7-H)，5.02(1H，dd，J＝4.8Hz，J＝9.5Hz，6-H)，4.21(1H，dt，J＝8.4Hz，J＝??16.8Hz，5-H)，3.81(3H，s，CH 3)，3.41(4H，m，2CH 2)，2.15(3H，s，OAc)，1.92??(3H，s，NHAc)，1.21(3H，t，J＝6.8Hz，CH 3)，1.10(3H，t，J＝13.6Hz，CH 3); HRMS (ESI): m/z calculated value: C 25H 32N 6O 7Na[M+Na] +551.2230, measured value: 551.2217.
Embodiment The name and 1H-NMR, MS data
??87 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-azanol base-2 '-oxygen ethyl]-4-[4 '-methoxycarbonyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-methyl-formiate 1H?NMR(300MHz，DMSO-d6)：δ10.91(1H，d，J＝1.5Hz，OH)，9.08(1H，d，??J＝1.5Hz，NH)，8.87(1H，s，CH)，8.14(1H，d，J＝9.6Hz，NH)，6.06(1H，d，J??＝2.4Hz，3-H)，5.59(1H，dd，J＝2.4Hz，J＝9.9Hz，4-H)，5.32(1H，d，J＝1.8??Hz，7-H)，4.79(1H，dd，J＝1.8Hz，J＝10.8Hz，6-H)，4.33(1H，dt，J＝9.9Hz，??J＝20.1Hz，5-H)，3.83(3H，s，CH 3)，3.74(3H，s，CH 3)，1.99(3H，s，OAc)，??1.62(3H，s，NHAc)；HRMS(ESI)：m/z[M+Na] +＝478.1
Embodiment 88～111
Method according to identical with embodiment 13 correspondingly prepares embodiment 88～111 compounds.
Figure G2009100458184D0000391
Figure G2009100458184D0000392
Figure G2009100458184D0000401
Embodiment The name and 1H-NMR, MS data
??88 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-(1 "-hydroxyethyl)-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ7.75(1H，d，J＝3.2Hz，CH)，5.50(1H，d，J＝??9.2Hz，CH)，5.43(1H，s，CH)，4.79(1H，m，CH)，4.34(1H，d，J＝11.2Hz，CH)，??4.18(1H，m，CH)，2.65(1H，d，J＝4.0Hz，CH)，1.76(3H，s，NHAc)，1.37(3H，m，??CH 3); HRMS (ESI): m/z calculated value: C 15H 21N 5O 7Na[M+Na] +406.1339, measured value: 406.1345.
??89 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-hydroxypropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ7.78(1H，s，CH)，5.83(1H，d，J＝2.5Hz，3-H)，??5.51(1H，dd，J＝2.5Hz，J＝9.7Hz，4-H)，4.53(1H，d，J＝11.1Hz，6-H)，4.24(1??H，dt，J＝10.6Hz，J＝21.0Hz，5-H)，4.04(1H，s，7-H)，2.61(5H，m，CH 3+CH 2)，??1.73(3H，s，NHAc)，1.69(2H，q，J＝8.0Hz，J＝15.1Hz，CH 2); HRMS (ESI): m/z calculated value: C 16H 23N 5O 7Na[M+Na] +420.1495, measured value: 420.1514.
Embodiment The name and 1H-NMR, MS data
??90 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-cyclopropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ7.79(1H，s，CH)，5.81(1H，d，J＝2.4Hz，3-H)，??5.51(1H，dd，J＝2.0Hz，J＝7.2Hz，4-H)，4.55(1H，d，J＝10.8Hz，6-H)，4.22(1??H，m，5-H)，4.05(1H，d，J＝4.0Hz，7-H)，2.64(3H，d，J＝3.6Hz，CH 3)，1.92(1H，??m，CH)，1.76(3H，s，NHAc)，1.17(3H，m，CH 3)，0.88(2H，m，CH 2)，0.69(2H，m，??CH 2); HRMS (ESI): m/z calculated value: C 16H 20N 5O 62Na[M-H+2Na] +424.1209, measured value: 424.1232.
??91 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ8.28(1H，s，CH)，7.03(4H，m，PhH)，6.51(1H，??d，J＝7.6Hz，NH)，5.51(2H，d，J＝4.5Hz，3-H?and?7-H)，4.46(1H，m，CH)，4.29??(1H，m，CH)，4.05(1H，m，CH)，2.65(3H，d，J＝3.6Hz，CH 3), 1.74 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 19H 22N 6O 6Na[M+Na] +453.1499, measured value: 453.1515.
Embodiment The name and 1H-NMR, MS data
??92 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-methylol-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ7.92(1H，s，CH)，5.80(1H，s，3-H)，5.61(1H，??d，J＝9.5Hz，4-H)，4.60(1H，d，J＝9.5Hz)，4.51(1H，d，J＝6.1Hz)，4.49(2H，s，??CH 2)，4.17(1H，t，J＝9.5Hz，5-H)，3.03(3H，s，CH 3)，2.88(3H，s，CH 3), 1.99 (3 H, s, NHAc); HRMS (ESI): m/z calculated value: C 15H 21N 5O 7Na[M+Na] +406.1339, measure
Value: 406.1330.
??93 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-(1 "-hydroxyethyl)-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ7.87(1H，d，J＝4.8Hz，CH)，5.88(1H，s，3-H)，??5.59(1H，s，4-H)，4.80(1H，m，6-H)，4.61(1H，m，7-H)，4.50(2H，s，CH 2)，4.17??(1H，t，J＝5.9Hz，5-H)，3.02(3H，s，CH 3)，2.86(3H，s，CH 3)，1.77(3H，s，??NHAc)，1.39(3H，d，J＝6.2Hz，CH 3); HRMS (ESI): m/z calculated value: C 16H 23N 5O 7Na??[M+Na] +420.1495, measured value: 420.1503.
Embodiment The name and 1H-NMR, MS data
??94 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-hydroxypropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ7.79(1H，s，CH)，5.72(1H，s，3-H)，5.56(1H，??d，J＝9.2Hz，4-H)，4.57(2H，t，6-H?and?7-H)，4.13(1H，t，J＝9.5Hz，5-H)，3.40(2??H，m，CH 2)，3.02(3H，s，CH 3)，2.88(3H，s，CH 3)，2.61(2H，t，J＝7.3Hz，CH 2)，??1.76(3H，s，NHAc)，1.69(2H，t，J＝6.2Hz，CH 2); HRMS (ESI): m/z calculated value: C 17H 25N 5O 7Na[M+Na] +434.1652, measured value: 434.1662.
??95 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-carboxyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，CDCl 3)：δ8.64(1H，s，CH)，5.91(1H，d，J＝2.1Hz，3-H)，??5.61(1H，dd，J＝2.0Hz，J＝9.4Hz，4-H)，4.60(1H，dd，J＝2.2Hz，J＝9.6Hz，??6-H)，4.50(1H，s，7-H)，4.20(1H，t，J＝10.0Hz，5-H)，3.02(3H，s，CH 3)，2.84(3??H，s，CH 3), 1.72 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 15H 19N 5O 8Na??[M+Na] +420.1131, measured value: 420.1121.
??96 1-[(2R, 3R, 4S)-3-acetamido-2-(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl)-6-carboxyl-3,4-dihydropyrane-4]-1,2,3-triazole-4,5-dioctyl phthalate 1H?NMR(400MHz，DMSO-d6)：δ6.61(1H，d，J＝8.8Hz，NH)，5.92(1H，d，J＝??2.1Hz，3-H)，4.65(1H，d，J＝10.0Hz，4-H)，4.51(1H，m，6-H?and?7-H)，4.34(1H，??m，5-H)，3.03(3H，s，CH 3)，2.86(3H，s，CH 3), 1.65 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 21H 27N 5O 11Na 2[M+2Na] +486.0849, measured value: 486.0862.
Embodiment The name and 1H-NMR, MS data
??97 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-cyclopropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ7.82(1H，s，CH)，5.84(1H，s，3-H)，5.55(1H，??d，J＝8.1Hz，4-H)，4.62(2H，t，J＝1.5Hz，J＝8.1Hz，6-H)，4.50(2H，d，J＝1.1??Hz，7-H)，4.11(1H，t，J＝9.9Hz，5-H)，3.03(2H，m，CH 3)，2.87(3H，s，CH 3)，1.92??(1H，m，CH)，1.76(3H，s，NHAc)，0.88(2H，d，J＝8.4Hz，CH 2)，0.70(2H，s，??CH 2); HRMS (ESI): m/z calculated value: C 17H 23N 5O 6Na[M+Na] +416.1546, measured value: 416.1500.
??98 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-phenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR?(400MHz，DMSO-d6)：δ8.68(1H，s，CH)，7.92(2H，d，J＝7.2Hz，??PhH)，7.44(2H，t，J＝7.2Hz，PhH)，7.32(1H，t，J＝7.6Hz，PhH)，6.03(1H，d，J＝??4.8Hz，3-H)，5.67(1H，dd，J＝2.8Hz，J＝10.4Hz，4-H)，5.48(1H，t，J＝3.6Hz，??7-H)，4.66(1H，dd，J＝2.0Hz，J＝10.4Hz，6-H)，4.20(1H，dt，J＝10.4Hz，J＝??18.0Hz，5-H)，3.11(3H，s，CH 3)，3.05(3H，s，CH 3), 1.76 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 20H 23N 5O 6Na[M+Na] +452.1546, measured value: 452.1537.
??99 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid
Embodiment The name and 1H-NMR, MS data
?? 1H?NMR(400MHz，DMSO-d6)：δ8.41(1H，s，CH)，7.05(5H，m，PhH+2NH)，??6.52(2H，m，PhH+NH)，5.94(1H，d，J＝2.6Hz，3-H)，5.64(1H，dd，J＝2.2Hz，J??＝9.5Hz，4-H)，4.65(1H，dd，J＝2.1Hz，J＝10.1Hz，6-H)，4.51(1H，d，J＝2.4??Hz，7-H)，4.21(1H，t，J＝9.5Hz，5-H)，3.04(3H，s，CH 3)，2.85(3H，s，CH 3), 1.76 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 20H 24N 6O 6Na[M+Na] +467.1655, measured value: 467.1668.
??100 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-methylol-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid HRMS (ESI): [M+Na] +＝406.1.
??101 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-(1 "-hydroxyethyl)-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid HRMS (ESI): [M+H] +＝398.2；
Embodiment The name and 1H-NMR, MS data
??102 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-hydroxypropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1HNMR(300MHz，DMSO-d6)：δ8.23(1H，d，J＝8.7Hz，NH)，7.80(1H，s，CH)，??7.68(1H，m，NH)，5.97(1H，d，J＝5.4Hz，7-H)，5.84(1H，d，J＝2.4Hz，3-H)，??5.54(1H，dd，J＝2.4Hz，J＝9.9Hz，4-H)，5.43(1H，t，J＝5.4Hz，5-H)，4.53(1H，??m，6-H)，4.25(2H，m，CH 2)，3.16(2H，m，CH 2)，2.65(2H，dt，J＝8.7Hz，J＝16.2??Hz，CH 2)，1.76(3H，s，NHAc)，1.72(2H，t，J＝7.8Hz，CH 2)，1.04(3H，m，CH 3)；??HRMS(ESI)：[M+H] +＝412.3.
??103 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-cyclopropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(300MHz，DMSO-d6)：δ8.21(1H，d，J＝8.7Hz，NH)，7.79(1H，s，CH)，??7.69(1H，m，NH)，5.96(1H，d，J＝5.4Hz，7-H)，5.80(1H，d，J＝2.4Hz，3-H)，??5.53(1H，dd，J＝2.7Hz，J＝9.9Hz，4-H)，5.37(1H，t，J＝5.1Hz，5-H)，4.51(1H，??m，6-H)，3.14(2H，m，CH 2)，1.94(1H，m，CH)，1.88(3H，s，NHAc)，1.04(3H，m，??CH 3)，0.88(2H，m，CH 2)，0.69(2H，m，CH 2)；HRMS(ESI)：m/z[M+H] +＝394.2.
??104 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-phenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid HRMS (ESI): [M+H] +＝430.2.
Embodiment The name and 1H-NMR, MS data
??105 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid HRMS (ESI): [M+H] +＝445.2.
??106 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-methylol-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ8.24(1H，d，J＝8.8Hz，OH)，7.87(1H，s，CH)，??5.96(1H，d，J＝5.7Hz，OH).5.84(1H，d，J＝2.7Hz，3-H)，5.57(1H，dd，J＝2.7??Hz，J＝9.5Hz，4-H)，4.55(1H，dd，J＝2.4Hz，J＝9.9Hz，6-H)，4.47(2H，s，CH 2)，??4.31(1H，d，J＝3.0Hz，7-H)，4.21(1H，t，J＝9.4Hz，J＝19.4Hz，5-H)，3.57(4H，??m，2CH 2)，1.76(4H，m，2CH 2), 1.73 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 17H 23N 5O 7Na[M+Na] +432.1495, measured value: 432.1490.
??107 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-(1 "-hydroxyethyl)-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，CDCl 3)：δ7.64(1H，d，J＝2.6Hz，CH)，5.87(1H，d，J＝2.0??Hz，3-H)，5.57(1H，d，J＝9.0Hz，6-H)，4.80(1H，d，J＝2.4Hz，7-H)，4.56(1H，??m，CH)，4.32(1H，dd，J＝3.0Hz，J＝10.1Hz，4-H)，4.18(1H，dd，J＝10.0Hz，J＝??18.7Hz，5-H)，3.62(4H，m，2CH 2)，1.78(4H，m，2CH 2)，1.75(3H，s，NHAc)，1.38??(3H，d，J＝6.5Hz，CH 3); HRMS (ESI): m/z calculated value: C 18H 25N 5O 7Na[M+Na] +
446.1652, measured value: 446.1627.
Embodiment The name and 1H-NMR, MS data
??108 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-hydroxypropyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ7.76(1H，s，CH)，5.55(1H，s，3-H)，4.52(1H，??d，J＝10.0Hz，6-H)，4.36(2H，m，4-H?and?7-H)，4.10(1H，t，J＝9.8Hz，5-H)，3.76??(1H，m，CH)，3.60(3H，m，CH?and?CH 2)，2.56(2H，t，J＝7.2Hz，CH 2)，1.80(4H，??m，2CH 2)，1.73(3H，s，NHAc)，1.63(2H，t，J＝6.3Hz，CH 2); HRMS (ESI): m/z calculated value: C 19H 27N 5O 7Na[M+Na] +460.1808, measured value: 460.1812.
??109 1-[(2R, 3R, 4S)-3-acetamido-2-(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl)-6-carboxyl-3,4-dihydropyrane-4]-1,2,3-triazole-4,5-dioctyl phthalate 1H?NMR(400MHz，DMSO-d6)：δ6.78(1H，m，CH)，5.98(1H，d，J＝1.9Hz，??3-H)，4.61(1H，m，CH)，4.46(1H，m，CH)，4.34(1H，m，CH)，3.75(4H，m，??2CH 2)，1.80(4H，m，2CH 2), 1.66 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 18H 22N 5O 10[M] +468.1367, measured value: 468.1340.
Embodiment The name and 1H-NMR, MS data
??110 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-phenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ8.62(1H，s，CH)，7.92(2H，t，J＝7.3Hz，PhH)，??7.43(2H，t，J＝7.6Hz，PhH)，7.32(1H，t，J＝7.2Hz，PhH)，5.69(1H，s，3-H)，??5.41(1H，s，6-H)，4.63(1H，s，4-H)，4.48(1H，s，5-H)，4.32(1H，d，J＝7.8Hz，??5-H)，4.24(1H，m，CH)，3.71(3H，m，CH 2and?CH)，1.84(4H，m，2CH 2), 1.74 (3 H, s, NHAc); HRMS (ESI): m/z calculated value: C 22H 25N 5O 6Na[M+Na] +478.1703, measured value: 478.1722.
??111 (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-[4 '-(3 "-aminophenyl-1,2,3-triazole-1]-3,4-dihydropyrane-6-formic acid 1H?NMR(400MHz，DMSO-d6)：δ8.42(1H，s，CH)，7.08(3H，m，PhH)，6.54(1H，??m，PhH)，5.95(1H，d，J＝2.6Hz，3-H)，5.63(1H，dd，J＝2.3Hz，J＝9.4Hz，6-H)，??4.62(1H，dd，J＝2.8Hz，J＝10.2Hz，4-H)，4.35(1H，d，J＝2.7Hz，7-H)，4.27(1??H，t，J＝9.8Hz，5-H)，3.79(1H，m，CH)，3.28(3H，m，CH 2and?CH)，1.76(4H，m，??2CH 2), 1.74 (3H, s, NHAc); HRMS (ESI): m/z calculated value: C 22H 26N 6O 6Na[M+Na]+493.1812, measured value: 493.1815.
The neuraminidase of The compounds of this invention suppresses determination of activity:
Reference literature (Bioorg. ﹠amp; Med Chem.Lett 2007,17,1655-1658) method has been measured the inhibition activity of general formula of the present invention (I) compound to influenza virus H3N2.Measurement result such as following table:
Figure G2009100458184D0000431
As seen from the above table, compound of the present invention has the inhibition activity to influenza virus, and the structure of this compounds is different with zanamivir, can be used for the treatment to the drug-fast influenza virus of zanamivir, and the reduction of compound polarity, helps oral administration.Thus, the invention provides the highly active N-acetyl neuraminic acid compounds of a class, this compounds and pharmaceutical composition thereof can be used for resisiting influenza virus, and be special, can be used for the treatment to drug-fast influenza infections of other Tamiflu such as zanamivir, its Weis of department difficult to understand.

Claims (15)

1. the N-acetyl neuraminic acid compounds shown in the following general formula (I) or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing:
Figure F2009100458184C0000011
Wherein:
R 1Represent OR 5, SR 5, NR 5R 6, N (OR 5) R 6Or N (NR 5R 6) R 6
R 2Represent H, C 1-20Alkyl, C 1-5The C that alkoxyl group replaces 1-5Alkyl, COR 5Or CONR 5R 6
R 3Represent N 3, NR 7R 8, NHC (=NR 9) NR 5R 10, N=PPh 3Or
R 4Represent COOR 5, CONR 5R 6Or CON (OR 5) R 6
R 5Represent H, C 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, pentafluorophenyl group, aryl, CONR 14R 15, COOR 14, COR 14Or by the C of one or more following groups replacements 1-10Alkyl: NR 14R 15, NR 14COR 15, CO 2R 14, OR 14, C 3-8Cycloalkyl and aryl;
R 6Represent H, C 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, aryl, COR 14Or by the C of one or more following groups replacements 1-10Alkyl: NR 14R 14, COR 14, C 3-8Cycloalkyl, CN, N 3, OR 14And aryl;
Perhaps R 5And R 6The nitrogen-atoms that links to each other with them constitutes ring texture jointly, and this ring texture is saturated or unsaturated, and contains the heteroatoms among one or more N of being selected from, O and the S, and this ring texture is not necessarily by halogen, C 1-10Alkyl, C 1-C 10Alkoxyl group, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, CF 3, CN or NO 2Replace;
R 7And R 8Represent H, CN, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or C 2-6Hydrocarbon chain, not necessarily contain a NR in this hydrocarbon chain 11Group, this hydrocarbon chain not necessarily is selected from oxo base and C by 1～4 1-6The group of alkyl replaces, and this C 1-6Alkyl is not necessarily replaced by hydroxyl or aryl;
R 9And R 10Represent H, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, NR 14R 15, OR 14, CN or NO 2
R 11And R 12Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 1-10Alkoxyl group, COOR 5, CONR 14R 15Or aryl; Perhaps not necessarily by hydroxyl, amino, amido, COOR 5Or C 1-6The C that alkoxyl group replaces 1-10Alkyl;
R 14And R 15Represent H, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl or aryl;
Wherein, described aryl is meant aromatic carbocyclic ring or heterocyclic group, and not necessarily is substituted; When described aryl was substituted, substituting group comprised C 1-4Alkyl, C 1-4Alkoxyl group, halogen, nitro, trifluoromethyl, amino, C 1-4Amino, phenyl and phenmethyl that alkyl replaces; Described aryl is replaced by 1～3 above-mentioned substituting group.
2. the N-acetyl neuraminic acid compounds shown in the formula according to claim 1 (I) or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing is characterized in that, wherein,
R 1Represent OR 5, NR 5R 6Or N (OR 5) R 6
R 2Represent H, COR 5Or CONR 5R 6
R 3Represent NR 7R 8, NHC (=NR 9) NR 5R 10Or It is the α configuration;
R 4Represent COOR 5, CONR 5R 6Or CON (OR 5) R 6
R 5And R 6Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl, C 2-10Alkynyl or aryl; Perhaps by OR 14, C 3-8The C that cycloalkyl or aryl replace 1-10Alkyl;
Perhaps R 5And R 6The nitrogen-atoms that links to each other with them constitutes ring texture jointly, and this ring texture is saturated or unsaturated, and contains the heteroatoms among one or more N of being selected from, O and the S, and this ring texture is not necessarily by halogen, C 1-10Alkyl, C 1-C 10Alkoxyl group, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl substituted;
R 7And R 8Represent H, CN, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or C 2-6Hydrocarbon chain, not necessarily contain a NR in this hydrocarbon chain 11Group, this hydrocarbon chain not necessarily is selected from oxo base and C by 1～4 1-6The group of alkyl replaces, and this C 1-6Alkyl is not necessarily replaced by hydroxyl or aryl;
R 9And R 10Represent H, C independently of one another 1-6Alkyl, NR 14R 15, OR 14, CN or NO 2
R 11And R 12Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, COOR 5Or aryl; Perhaps not necessarily by hydroxyl, amino, amido, COOR 5Or C 1-6The C that alkoxyl group replaces 1-10Alkyl;
R 14And R 15Represent H, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl or aryl;
The definition of described aryl is identical with claim 1.
3. the N-acetyl neuraminic acid compounds shown in the formula according to claim 2 (I) or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing is characterized in that, wherein,
R 1Represent NR 5R 6Or N (OR 5) R 6
R 2Represent H or COR 5
R 3Be the α configuration;
R 3Represent NR 7R 8Or NHC (=NR 9) NR 5R 10
R 4Represent COOR 5Or CON (OR 5) R 6
R 5And R 6Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl; Perhaps R 5And R 6The nitrogen-atoms that links to each other with them constitutes ring texture jointly, and this ring texture is saturated or unsaturated, and contains the heteroatoms among one or more N of being selected from, O and the S, and this ring texture is not necessarily by C 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl substituted;
R 7And R 8Represent H, CN, C independently of one another 1-6Alkyl, C 3-8Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or C 2-6Hydrocarbon chain, not necessarily contain a NR in this hydrocarbon chain 11Group, this hydrocarbon chain not necessarily is selected from oxo base and C by 1 or 2 1-6The group of alkyl replaces, and this C 1-6Alkyl is not necessarily replaced by hydroxyl or aryl; Described aryl comprises phenyl, naphthyl, pyridyl, imidazolyl and thienyl, and not necessarily is substituted; When described aryl was substituted, described substituting group comprised C 1-4Alkyl, C 1-4Alkoxyl group, nitro, amino, phenyl and phenmethyl; And described substituted aryl has 1～3 above-mentioned substituting group;
R 9And R 10Represent H, C independently of one another 1-6Alkyl, NH 2, OH, CN or NO 2
R 11And R 12Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl or COOR 5
4. the N-acetyl neuraminic acid compounds shown in the formula according to claim 3 (I) or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing is characterized in that, wherein,
R 1Represent NR 5R 6
R 2Represent H;
R 3Represent NH 2Or NHC (=NH) NH 2, it is the α configuration;
R 4Represent COOR 5
R 5And R 6Represent H, C independently of one another 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl; Perhaps R 5And R 6The nitrogen-atoms that links to each other with them constitutes ring texture jointly, and this ring texture is saturated or unsaturated, and contains the heteroatoms among one or more N of being selected from, O and the S, and this ring texture is not necessarily by C 1-10Alkyl, C 3-8Cycloalkyl, C 2-10Thiazolinyl or C 2-10Alkynyl substituted.
5. the N-acetyl neuraminic acid compounds shown in the formula according to claim 1 (I) or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing is characterized in that it is selected from:
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-methylamino-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-ethylamino--2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-methyl-formiate;
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-ethylamino--2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-methyl-formiate;
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-acetoxyl group-2 '-diethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-methyl-formiate,
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-amino-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-isopropylamine base-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-azanol base-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclohexylamino-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclohexyl amido-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid;
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-amino-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid and (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-Isopropylamine amido-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid.
6. the N-acetyl neuraminic acid compounds shown in the formula according to claim 5 (I) or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing is characterized in that it is selected from:
(2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-dimethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-amino-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-diethylin-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid, (2R, 3R, 4S)-the 3-acetamido-2-[(S)-1 '-hydroxyl-2 '-cyclopentamine base-2 '-oxygen ethyl]-4-guanidine radicals-3,4-dihydropyrane-6-formic acid.
7. the N-acetyl neuraminic acid compounds shown in the described formula of claim 1 (I) or their any prodrug forms, their pharmacologically acceptable salt or the preparation method of acceptable solvent thing is characterized in that, adopt in the following method any one:
(1) R in general formula (I) compound 1Be OH, R 2Be not H, R 3Be N 3, R 4Be COOR 5, and R 5When being not H, promptly general formula (Ia) compound prepares by the cracking of general formula (II) compound oxidation; If desired, carry out deprotection subsequently; The R of general formula (II) compound 2And R 4Substituting group defines same general formula (I) compound:
Figure F2009100458184C0000051
Oxicracking was finished by two steps: the first step and periodate reaction; The reagent in second step is chlorite;
(2) R in general formula (I) compound 1Be OR 5Or SR 5The time, i.e. general formula (Ic) compound is by the R in corresponding general formula (I) compound 1Represent general formula (Ib) compound of OH with by R 5Replace contain oxygen or sulfocompound prepares by condensation reaction;
(3) R in general formula (I) compound 1Be NR 5R 6, N (OR 5) R 6Or N (NR 5R 6) R 6The time, i.e. general formula (Id) compound is by the R in corresponding general formula (I) compound 1General formula (Ib) compound of representing OH and-R 5R 6,-(OR 5) R 6Or-(NR 5R 6) R 6The nitrogenous compound that replaces reacts and prepares; Carboxyl was activated before reacting with amine; Amination reaction is finished in organic solvent;
Figure F2009100458184C0000053
(4) R in general formula (I) compound 3For
Figure F2009100458184C0000054
The time, i.e. general formula (If) compound is by the R in corresponding general formula (I) compound 3Represent N 3General formula (Ie) compound with by R 11And R 12The acetylene compound that replaces reacts and prepares; Preparation is carried out under catalyst, and catalysis process comprises cuprous ion catalysis;
Figure F2009100458184C0000055
(5) R in general formula (I) compound 3Be NH 2The time, i.e. general formula (Ig) compound is by the R in corresponding general formula (I) compound 3Represent N 3The reduction reaction of general formula (Ie) compound by azido-prepare;
Figure F2009100458184C0000061
(6) R in general formula (I) compound 3Be NR 7R 8The time, i.e. general formula (Ih) compound, the R from general formula (I) compound 3Be NH 2General formula (Ig) compound by with by R 7And R 8The compound that replaces reacts and prepares;
Figure F2009100458184C0000062
(7) R in general formula (I) compound 3Be NHC (=NR 14) NR 15R 16The time, i.e. general formula (Ii) compound, the R from general formula (I) compound 3Be NR 7R 8General formula (Ih) compound prepare by the guanidine glycosylation reaction; R in general formula (I) compound 3Be NHC (=NH) NH 2The time, i.e. general formula (Ik) compound is by the R in general formula (I) compound 3Be NH 2General formula (Ig) compound and amidino groups pyrazoles or its salt or derivatives reaction or through the R in general formula (I) compound 3For intermediate formula (Ij) compound of NHCN prepares;
(8) R in general formula (I) compound 3Represent N 3, R 4Be CONR 5R 6The time, i.e. general formula (Im) compound is by the R in corresponding general formula (I) compound 3Represent N 3, R 4Be COOR 5, and R 5The subsalt reaction for the general formula of H (Il) compound and azanol or derivatives thereof does not obtain;
Figure F2009100458184C0000063
(9) R in general formula (I) compound 3Be NR 7R 8General formula (Ih) compound or general formula (I) compound in R 3Be NHC (=NR 14) NR 15R 16The R of general formula (Ii) compound from general formula (I) compound 3Represent N 3, R 4Be CONR 5R 6General formula (Im) compound by with similarly azido-method of reducing reduction of aforesaid method (5), further reaction prepares then; Or
(10) transform other compound that can prepare general formula (I) mutually by the functional group between the different compounds of general formula (I); R wherein 2For the compound of H by not preparing for the compound of H; R 7And R 8The compound that is not H is by corresponding R 7And/or R 8For the compound of H prepares; R 4Be COOR 5, CONR 5R 6Or CON (OR 5) R 6Compound and R 4For the compound of COOH transforms mutually.
8. the N-acetyl neuraminic acid compounds shown in the formula according to claim 7 (I) or their any prodrug forms, their pharmacologically acceptable salt or the preparation method of acceptable solvent thing, it is characterized in that, when preparation general formula (Ia) compound, the first step of oxicracking is to adopt periodate, finishes in water-containing organic solvent; Second step was to adopt chlorite, had the buffer reagent that comprises basic metal or alkali earth metal phosphate, finished in water-containing organic solvent.
9. the N-acetyl neuraminic acid compounds shown in the formula according to claim 7 (I) or their any prodrug forms, their pharmacologically acceptable salt or the preparation method of acceptable solvent thing, it is characterized in that, when preparation general formula (Id) compound, carboxyl with the amine reaction before carry out the activatory method and comprise and change into penta fluoro benzene oxygen base; Amination reaction is finished in ether.
10. the N-acetyl neuraminic acid compounds shown in the formula according to claim 7 (I) or their any prodrug forms, their pharmacologically acceptable salt or the preparation method of acceptable solvent thing, it is characterized in that, when preparation general formula (Ig) compound, described reductive condition is the Lindlar catalyst, and hydrogen or formic acid provide active hydrogen.
11. the N-acetyl neuraminic acid compounds shown in the formula in the claim 1～6 (I) or their any prodrug forms, their pharmacologically acceptable salt or the purposes of acceptable solvent thing in the medicine of preparation neuraminidase inhibitor.
12. the N-acetyl neuraminic acid compounds shown in the formula in the claim 1～6 (I) or their any prodrug forms, their pharmacologically acceptable salt or the purposes of acceptable solvent thing in the medicine of preparation inhibition virus.
13. purposes according to claim 12 is characterized in that, described virus comprises influenza virus.
14. the N-acetyl neuraminic acid compounds shown in the formula in the claim 1～6 (I) or their any prodrug forms, their pharmacologically acceptable salt or the purposes of acceptable solvent thing in the medicine of preparation prevention and treatment virus disease and infection thereof.
15. a pharmaceutical composition that is used to suppress neuraminidase, said composition comprise the N-acetyl neuraminic acid compounds shown in the formula (I) in one or more claims 1～6 for the treatment of significant quantity or their any prodrug forms, their pharmacologically acceptable salt or acceptable solvent thing and one or more pharmaceutically acceptable carrier or thinner.
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