CN103864737A - Phenyl C-glucoside derivative containing deoxyglucose structure as well as preparation method and application thereof - Google Patents

Phenyl C-glucoside derivative containing deoxyglucose structure as well as preparation method and application thereof Download PDF

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CN103864737A
CN103864737A CN201310213608.8A CN201310213608A CN103864737A CN 103864737 A CN103864737 A CN 103864737A CN 201310213608 A CN201310213608 A CN 201310213608A CN 103864737 A CN103864737 A CN 103864737A
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compound
hydroxyl
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reagent
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CN103864737B (en
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赵桂龙
王玉丽
魏群超
徐为人
邹美香
汤立达
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Guangzhou Lixin Pharmaceuticals Co ltd
Tianjin Institute of Pharmaceutical Research Co Ltd
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Priority to US14/652,225 priority patent/US9505734B2/en
Priority to EP13864482.8A priority patent/EP2933250B1/en
Priority to JP2015546829A priority patent/JP5944593B2/en
Priority to PCT/CN2013/088633 priority patent/WO2014094544A1/en
Priority to EP17176326.1A priority patent/EP3246324B1/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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    • C07—ORGANIC CHEMISTRY
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    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Abstract

The invention provides a phenyl C-glucoside derivative (compound as shown in a formula I) containing a deoxyglucose structure and a preparation method thereof, a pharmaceutical composition including the same and application of the phenyl C-glucoside derivative containing a deoxyglucose structure in preparation of medicines for treating diabetes mellitus. The definitions of the substituent groups R1-R7 are as shown in the specification, and the formula I is as shown in the specification.

Description

Contain phenyl C-glucoside derivative of deoxyglucose structure and its production and use
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Particularly, the present invention relates to 2 type sodium glucose of the medicative phenyl C-glucoside derivative that contains deoxyglucose structure of diabetes cotransport son (SGLT2) inhibitor and preparation method thereof and the pharmaceutical composition that contains them.
Background technology
Whole world diabetic subject nearly 1.7 hundred million left and right at present, wherein approximately most is II type (being non-insulin-depending type) diabetic subject.At present mainly contain N1,N1-Dimethylbiguanide class, sulfonylurea, insulin type, thiazolidinediones, alpha-glucosidase inhibitor class and dipeptidyl peptidase-iv inhibitor class medicine at the antidiabetic medicine of clinical use, these medicines have good therapeutic action, but there is safety issue in long-term treatment, as: liver toxicity, some drugs still has the problems such as body weight increase.And timely drug combination is also difficult to the glycemic control target that reaches desirable under many circumstances.Therefore be badly in need of having clinically the Remedies for diabetes of brand-new mechanism of action.
2 type sodium glucose (SGLT2) that cotransports is the novel targets of the treatment diabetes of discovered in recent years.SGLT2 is mainly distributed in kidney proximal tubule, and its effect is the glucose absorbing in urine, and returns it in blood, and that therefore suppresses SGLT2 just can reduce the concentration of glucose in blood, and this method has reduced glucose level from the past different approach.In the time that SGLT2 function is obstructed, in urine, will secrete more glucose, this will contribute to diabetic subject to keep correct glucose level.Because SGLT2 inhibitor stays out of glucose metabolism, therefore this class hypoglycemic drug is considered to have good security.
The compound that Chinese patent CN200610093189.9 discloses time array structure is as SGLT2 inhibitor:
Figure BDA00003282545700011
Wherein, A is O, S, NH or (CH 2) n, wherein, n=0-3.
The compound that Chinese patent CN200380110040.1 discloses time array structure is as SGLT2 inhibitor:
Figure BDA00003282545700021
Wherein, A is covalent linkage, O, S, NH or (CH 2) n, wherein, n=1-3.
The compound that Chinese patent CN200480006761.2 discloses time array structure is as SGLT2 inhibitor:
Figure BDA00003282545700022
Wherein, X is covalent linkage or low-grade alkylidene.
The invention discloses a class containing the phenyl C-glucoside analog derivative of deoxyglucose structure as novel SGLT2 inhibitor, these inhibitor can be for the preparation of the medicine of the medicine, particularly non insulin dependent diabetes for the treatment of diabetes.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, provide one to there is excellent activity, there is the compound of general formula I and acceptable prodrug ester pharmaceutically thereof.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for acceptable prodrug ester pharmaceutically thereof.
A further object of the present invention be to provide the compound that contains general formula I and pharmaceutically acceptable prodrug ester as effective constituent, and the pharmaceutical composition of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect diabetes in treatment.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides the compound with general formula I structure:
Figure BDA00003282545700031
Wherein, X is selected from O and S;
R 1, R 2, R 3and R 4independently selected from H and OH, and R 1, R 2, R 3and R 4in at least one be H;
R 5be selected from H, C 1-3alkyl ,-OCH 3with-OC 2h 5;
R 6be selected from halogen and C 1-3alkyl;
R 7be selected from
Figure BDA00003282545700032
wherein, R 8be selected from C 1-3alkyl, C 1-3alkoxyl group and
Figure BDA00003282545700033
r 9be selected from halogen and C 1-3alkyl;
Optionally, X, adjacent with X two carbon and-CH 2-O-forms five-ring; Or form unsubstituted carbon adjacent with glycosidic bond carbon on two carbon, phenyl ring of glycosidic bond and-CH 2-O-forms five-ring.
In some embodiments of the present invention, described in there is general formula I structure compound can comprise 15I-A and I-B, wherein, the general formula of described I-A is G1-G2,
G1 is selected from following two groups:
Figure BDA00003282545700034
G2 is selected from following five groups:
Figure BDA00003282545700035
Figure BDA00003282545700041
Described I-B has lower array structure:
Figure BDA00003282545700042
Wherein, X is selected from O and S;
R 1, R 2, R 3and R 4definition be selected from following 15 kinds of situations:
(1)R 1=H，R 2=OH，R 3=OH，R 4=OH；
(2)R 1=OH，R 2=H，R 3=OH，R 4=OH；
(3)R 1=OH，R 2=OH，R 3=H，R 4=OH；
(4)R 1=OH，R 2=OH，R 3=OH，R 4=H；
(5)R 1=H，R 2=H，R 3=OH，R 4=OH；
(6)R 1=H，R 2=OH，R 3=H，R 4=OH；
(7)R 1=H，R 2=OH，R 3=OH，R 4=H；
(8)R 1=OH，R 2=H，R 3=H，R 4=OH；
(9)R 1=OH，R 2=H，R 3=OH，R 4=H；
(10)R 1=OH，R 2=OH，R 3=H，R 4=H；
(11)R 1=H，R 2=H，R 3=H，R 4=OH；
(12)R 1=H，R 2=H，R 3=OH，R 4=H；
(13)R 1=H，R 2=OH，R 3=H，R 4=H；
(14)R 1=OH，R 2=H，R 3=H，R 4=H；
(15)R 1=H，R 2=H，R 3=H，R 4=H。
In a preferred embodiment of the invention, the compound of described general formula I structure has the one in lower array structure:
Figure BDA00003282545700043
Figure BDA00003282545700051
Figure BDA00003282545700061
Figure BDA00003282545700071
Figure BDA00003282545700081
In more preferred of the present invention, the compound of described general formula I structure has the one in lower array structure:
Figure BDA00003282545700091
Figure BDA00003282545700101
In most preferred embodiment of the present invention, the compound of described general formula I structure has the one in lower array structure:
Figure BDA00003282545700102
The present invention also provides the method for preparing the above-mentioned compound with general formula I structure, and described method comprises and adopt the phenyl C-glucoside of not deoxidation that has same structure with target product as raw material,
In the time of phenyl C-glucoside that target product is full deoxidation, the method comprises: the hydroxyl on sugar ring is all converted into iodine with iodination reagent, then reduction removes sugared iodine in ring, thereby obtains target product;
In the time that target product is the phenyl C-glucoside of part deoxidation, the method comprises the steps:
(1) hydroxyl protection: use hydroxyl protection reagent to protect hydroxyl to be retained on sugar ring;
(2) dehydroxylation: hydroxyl to be removed on sugar ring is converted into iodine with iodination reagent, then reduction, thereby hydroxyl to be removed described in removing; With
(3) deprotection: remove the hydroxy-protective group in above-mentioned steps gained compound, thereby obtain target product.
It should be noted that, in preparation method provided by the invention, only relate to the conversion of hydroxyl on sugar ring or derivatives thereof, do not relate to the variation of the other parts outside hydroxyl-removal in raw molecule.In the present invention, unless otherwise specified, when describing when certain reagent, the symbol "/" between compound represent " with " relation.
According to preparation method provided by the invention, wherein, to all ingredients using in preparation process, there is no particular limitation, as long as can make formula I compound of the present invention by described raw material according to step of the present invention, that is to say, as long as can make the hydroxyl that need to remove remove and not make the other parts outside hydroxyl-removal change.
According to preparation method provided by the invention, wherein, the phenyl C-glucoside of described not deoxidation refers to the R in compound of Formula I 1, R 2, R 3and R 4it is all the situation of OH.
According to preparation method provided by the invention, wherein, described iodination reagent can be I 2/ triphenylphosphine/imidazoles reagent (, I 2, triphenylphosphine and imidazoles three coupling reagent).The method that reduction removes sugared iodine in ring can or be used n-Bu for palladium catalyzed hydrogenation 3snH/AIBN reagent (wherein, AIBN is azo-bis-isobutyl cyanide) reduction.
Preparation in accordance with the present invention; wherein, described hydroxyl protection reagent can be selected from diacetyl oxide, Acetyl Chloride 98Min., t butyldimethylsilyl chloride (TBDMSCl), tert-butyl diphenyl silicon chlorides (TBDPSCl), Benzoyl chloride, to methyl benzoyl chloride, pivaloyl chloride, (dimethoxy methyl) benzene (PhCH (OMe) 2), phenylformic acid, 1,1,2, one or more in 2-tetramethoxy hexanaphthene/trimethyl orthoformate, chloroacetyl chloride and bromoacetyl chloride.
Because the hydroxyl reaction of different positions is active different, therefore, according to the position of hydroxyl to be retained, can adopt different hydroxyl protection reagent, and can take different protection processes.In actually operating; sometimes need to add some additional step outward in basic step step (1)-(3) Suo Shu; as sometimes needed protection-deprotection strategy by multistep by hydroxyl selective protection to be retained, protection-deprotection strategy object of implementing this multistep is to retain waiting and hydroxyl to be removed is distinguished.Following discloses of the present invention some typical examples for illustrate above-mentioned protection and deprotection skill (see following 1-D-6 to 1-D-2, the description of 3,4,6 synthetic schemes, and in embodiment to 1-D1-6 to 1-D1-2,3,4,6 more detailed description).
Preparation in accordance with the present invention, wherein, the reagent of selecting described deprotection steps to use according to used hydroxyl protection reagent, concrete selection scheme is conventionally known to one of skill in the art.For example, in the time using diacetyl oxide, Acetyl Chloride 98Min. or Benzoyl chloride etc. to carry out hydroxyl protection, deprotecting regent can be MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; In the time using TBDMSCl or TBDPSCl to carry out hydroxyl protection, deprotecting regent can be tetra-n-butyl Neutral ammonium fluoride or acetic acid; When using PhCH (OMe) 2while carrying out hydroxyl protection; under acidic conditions, carry out; described acid can be any in hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid and p-methyl benzenesulfonic acid; deprotecting regent can be also acid, example hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid and p-methyl benzenesulfonic acid.
For example, (1) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I to 6-position hydroxyl 1the hydroxyl of position), described preparation method can be: first use the reagent such as t butyldimethylsilyl chloride (TBDMSCl) that 6-position hydroxyl is converted into TBDMSO-, again with acetylation reagent by whole remaining hydroxyl acetylizes, then remove the TBDMS-of 6-position, treat thereby realized the protection that retains hydroxyl; With iodination reagent, 6-position hydroxyl is converted into I and also reduces, to remove 6-position hydroxyl; Last deacetylate, obtains removing the phenyl C-glucoside of 6-position hydroxyl.(specific examples of the present embodiment see below 1-D-6 building-up process)
(2) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I to 4-position hydroxyl 2the hydroxyl of position), described preparation method can be: first under acid catalysis, use PhCH (OMe) 2or phenyl aldehyde form benzal and 4-position and 6-position hydroxyl Cheng Huan, then with acetylation reagent by 2-position and 3 glycoloyl; Then slough benzal protecting group with acid treatment, then with Benzoyl chloride or pivaloyl chloride by primary alcohol group wherein (being 6-position hydroxyl) selective protection; With iodination reagent, 4-position hydroxyl is converted into I and also reduces, to remove 4-position hydroxyl; Last deacetylate and benzoyl or pivaloyl group protecting group, obtain removing the phenyl C-glucoside of 4-position hydroxyl.(building-up process that specific examples is shown in 1-D-4 of the present embodiment)
(3) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I to 3-position hydroxyl 3the hydroxyl of position), described preparation method can be: first under acid catalysis, use PhCH (OMe) 2or the phenyl aldehyde benzal and 4-position and the 6-position hydroxyl Cheng Huan that form, then 3-position hydroxyl is converted into TBDMSO-with reagent such as TBDMSCl, then with acetylation reagent by 2-position glycoloyl, then remove the TBDMS-of 3-position; With iodination reagent, 3-position hydroxyl is converted into I and also reduces, to remove 3-position hydroxyl; Last deacetylate and benzal protecting group, obtain removing the phenyl C-glucoside of 3-position hydroxyl.(building-up process that specific examples is shown in 1-D-3 of the present embodiment)
(4) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I to 2-position hydroxyl 4the hydroxyl of position), described preparation method can be: first under acid catalysis, use PhCH (OMe) 2or the phenyl aldehyde benzal and 4-position and the 6-position hydroxyl Cheng Huan that form, then with Benzoyl chloride etc. by primary alcohol group wherein (being 3-position hydroxyl) selective protection; With iodination reagent, 2-position hydroxyl is converted into I and also reduces, to remove 2-position hydroxyl; Finally slough benzoyl and benzal protecting group, obtain removing the phenyl C-glucoside of 2-position hydroxyl.(building-up process that specific examples is shown in 1-D-2 of the present embodiment)
(5) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 4-position and 6-position 1and R 2the hydroxyl of position), described preparation method can be: first under acid catalysis, use PhCH (OMe) 2or phenyl aldehyde form benzal and 4-position and 6-position hydroxyl Cheng Huan, then with acetylation reagent by whole remaining hydroxyl acetylizes, then remove the benzyl protecting group of 4-position and 6-position, thus realized treat reservation hydroxyl protection; With iodination reagent, the hydroxyl of 4-position and 6-position is converted into I and also reduces, to remove the hydroxyl of 4-position and 6-position; Last deacetylate, obtains removing the phenyl C-glucoside of 4-position and 6-position hydroxyl.(specific examples of the present embodiment is shown in 1-D-4,6 building-up process)
(6) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 3-position and 6-position 1and R 3the hydroxyl of position), described preparation method can be: first under acidic conditions, make raw material and 1,1,2,2-tetramethoxy hexanaphthene and trimethyl orthoformate reaction, obtain the protected product in 3-position and 4-position (acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid), with reagent such as TBDMSCl, 6-position hydroxyl is converted into TBDMSO-again, again with acetylation reagent by 2-position glycoloyl, then remove the protecting group of 3-position and 4-position and the protecting group of 6-position (acid used is selected from acetic acid or trifluoroacetic acid) with acid treatment; Again with reagent such as TBDMSCl, 6-position hydroxyl is converted into TBDMSO-, and with reagent such as TBDMSCl, 3-position hydroxyl is converted into TBDMSO-again, then with acetylation reagent by 4-position glycoloyl; Then slough the TBDMS-of 3-position and 6-position by tetra-n-butyl Neutral ammonium fluoride or acetic acid treatment; With iodination reagent, the hydroxyl of 3-position and 6-position is converted into I and also reduces, to remove the hydroxyl of 3-position and 6-position; Last deacetylate protecting group, obtains removing the phenyl C-glucoside of 3-position and 6-position hydroxyl.(specific examples of the present embodiment is shown in 1-D-3,6 building-up process)
(7) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 2-position and 6-position 1and R 4the hydroxyl of position), described preparation method can be: under acidic conditions, make raw material and 1,1,2,2-tetramethoxy hexanaphthene and trimethyl orthoformate reaction, obtain the protected product in 3-position and 4-position; With iodination reagent, the hydroxyl of 2-position and 6-position is converted into I and also reduces, to remove the hydroxyl of 2-position and 6-position; Finally remove the protecting group of 3-position and 4-position with acid treatment, obtain removing the phenyl C-glucoside of 2-position and 6-position hydroxyl.(specific examples of the present embodiment is shown in 1-D-2,6 building-up process)
(8) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 3-position and 4-position 2and R 3the hydroxyl of position), described preparation method can be: under acidic conditions, make raw material and 1,1,2,2-tetramethoxy hexanaphthene and trimethyl orthoformate reaction, obtain the protected product in 3-position and 4-position; Again with acetylation reagent by the glycoloyl of 2-position and 6-position; Remove again the protecting group of 3-position and 4-position with acid treatment; Then with iodination reagent, the hydroxyl of 3-position and 4-position is converted into I reduction, to remove the hydroxyl of 3-position and 4-position; Finally remove the ethanoyl of 2-position and 6-position, obtain removing the phenyl C-glucoside of 3-position and 4-position hydroxyl.(specific examples of the present embodiment is shown in 1-D-3,4 building-up process)
(9) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 2-position and 4-position 2and R 4the hydroxyl of position), described preparation method can be: under acidic conditions, make raw material and 1,1,2,2-tetramethoxy hexanaphthene and trimethyl orthoformate reaction, obtain the protected product in 3-position and 4-position; 6-position hydroxyl is carried out to selective protection with Benzoyl chloride; Remove again the protecting group of 3-position and 4-position with acid treatment; With Benzoyl chloride, 3-position hydroxyl is carried out to selective protection again; Then with iodination reagent, the hydroxyl of 2-position and 4-position is converted into I reduction, to remove the hydroxyl of 2-position and 4-position; Finally remove the benzoyl of 3-position and 6-position, obtain removing the phenyl C-glucoside of 2-position and 4-position hydroxyl.(specific examples of the present embodiment is shown in 1-D-2,4 building-up process)
(10) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 2-position and 3-position 1and R 4the hydroxyl of position), described preparation method can be: first under acid catalysis, use PhCH (OMe) 2or phenyl aldehyde form benzal and 4-position and 6-position hydroxyl Cheng Huan, then with iodination reagent by the hydroxyl of 2-position and 3-position be converted into I and reduce, to remove the hydroxyl of 2-position and 3-position; Finally remove the protecting group of 4-position and 6-position with acid treatment, obtain removing the phenyl C-glucoside of 2-position and 3-position hydroxyl.(specific examples of the present embodiment is shown in 1-D-2,3 building-up process)
(11) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 3-position, 4-position and 6-position 1, R 2and R 3the hydroxyl of position), described preparation method can be: first under acid catalysis, use PhCH (OMe) 2or the phenyl aldehyde benzal and 4-position and the 6-position hydroxyl Cheng Huan that form, then 3-position hydroxyl is converted into TBDMSO-with reagent such as TBDMSCl, then with acetylation reagent by 2-position glycoloyl; Then under acidic conditions, slough benzal and TBDMS-protecting group; With iodination reagent, the hydroxyl of 3-position, 4-position and 6-position is converted into I reduction again, to remove the hydroxyl of 3-position, 4-position and 6-position; Finally remove the ethanoyl of 2-position, obtain removing the phenyl C-glucoside of 3-position, 4-position and 6-position hydroxyl.(specific examples of the present embodiment is shown in 1-D-3,4,6 building-up process)
(12) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 2-position, 4-position and 6-position 1, R 2and R 4the hydroxyl of position), described preparation method can be: first under acid catalysis, use PhCH (OMe) 2or the phenyl aldehyde benzal and 4-position and the 6-position hydroxyl Cheng Huan that form, then 3-position hydroxyl is carried out to selective protection with Benzoyl chloride etc., then under acidic conditions, slough benzal; With iodination reagent, the hydroxyl of 2-position, 4-position and 6-position is converted into I and also reduces, to remove the hydroxyl of 2-position, 4-position and 6-position; Finally remove the benzoyl of 3-position, obtain removing the phenyl C-glucoside of 2-position, 4-position and 6-position hydroxyl.(specific examples of the present embodiment is shown in 1-D-2,4,6 building-up process)
(13) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 2-position, 3-position and 6-position 1, R 3and R 4the hydroxyl of position), described preparation method can be: first under acid catalysis, use PhCH (OMe) 2or benzal and 4-position and the 6-position hydroxyl Cheng Huan of phenyl aldehyde formation, then with chloroacetyl chloride or bromoacetyl chloride etc., 2-position and 3 hydroxyls are protected, then under acidic conditions, slough benzal; 6-position hydroxyl is converted into TBDMSO-with reagent such as TBDMSCl, then with acetylation reagent by 4-position glycoloyl; Under weak basic condition, slough 2-position and 3 s' protecting group, and slough the protecting group of 6-position by tetra-n-butyl Neutral ammonium fluoride or acetic acid treatment; With iodination reagent, the hydroxyl of 2-position, 3-position and 6-position is converted into I and also reduces, to remove the hydroxyl of 2-position, 3-position and 6-position; Finally remove the ethanoyl of 4-position, obtain removing the phenyl C-glucoside of 2-position, 3-position and 6-position hydroxyl.(specific examples of the present embodiment is shown in 1-D-2,3,6 building-up process)
(14) in certain embodiments, hydroxyl to be removed is that (that to be removed is R in general formula I for the hydroxyl of 2-position, 3-position and 4-position 2, R 3and R 4the hydroxyl of position), described preparation method can be: with Benzoyl chloride, methyl benzoyl chloride or pivaloyl chloride are protected 6-position hydroxyl; Then with iodination reagent, the hydroxyl of 2-position, 3-position and 4-position is converted into I reduction, to remove the hydroxyl of 2-position, 3-position and 4-position; Finally remove the protecting group of 6-position, obtain removing the phenyl C-glucoside of 2-position, 3-position and 4-position hydroxyl.Below (specific examples of the present embodiment is shown in 1-D-2,3,4 building-up process), will, take some preferred formula I structural compounds of the present invention as example, preparation method of the present invention be described in detail.
Can use following compounds to prepare the present invention and preferably have the compound of general formula I as raw material:
Figure BDA00003282545700161
Wherein, X is selected from O or S; G2 is selected from following group:
Figure BDA00003282545700162
General formula of the present invention is that the compound of I is when synthetic as raw material by S1-S3, synthesis step only relates to the conversion of hydroxyl on sugar ring and derivative thereof, do not relate to the variation of the part of other outside hydroxyl-removal in raw molecule, therefore in the time that raw material is S1-S3, we represent that take following general formula G S1-S3 sets forth the synthetic route of the compound to general formula of the present invention as I by S1-S3.
Figure BDA00003282545700171
Wherein, X is selected from O or S, Z 1-Z 3definition divide following situations:
(1) Z 1=G2, Z 2=Z 3=H: now G=S1;
(2) Z 1with Z 2become the ring as shown in S2, Z 3=H: now G=S2;
(3) Z 2with Z 3become the ring as shown in S3, Z 1for group as follows: now G=S3,
Figure BDA00003282545700172
Can be divided into following several situation by the synthetic representational compound of Formula I of raw material G:
Figure BDA00003282545700173
Raw material G uses the protection agent treated of 1 equivalent, is converted into G3, and this protection reagent is selected from TBDMSCl or TBDPSCl etc., corresponding PG 1be selected from TBDMS or TBDPS; G3 acetylize is converted into G4, and acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.; G4 removes protecting group PG through processing 1obtain G5, reagent is selected from tetra-n-butyl Neutral ammonium fluoride or acetic acid; G5 uses iodination reagent to be converted into G6, and reagent is I 2/ PPh 3/ imidazoles; G6 is converted to G7 under reductive condition, and condition is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide; Last G7 deacetylate obtains I-D-6, and condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-6 is the one of the compound with general formula I of the present invention.
Figure BDA00003282545700174
Raw material G reacts and is converted into G8 with suitable agent under acid catalysis, and agents useful for same is selected from PhCH (OMe) 2and phenyl aldehyde, acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid, p-methyl benzenesulfonic acid; G8 acetylize is converted into G9, and acetylation reagent is selected from diacetyl oxide, Acetyl Chloride 98Min.; G9 sloughs benzal protecting group with acid treatment and obtains G10, and acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid, p-methyl benzenesulfonic acid; G10 obtains G11, PG by Benzoyl chloride or pivaloyl chloride protecting group by primary alcohol group selective protection wherein 2be selected from benzoyl, pivaloyl group; G11 uses iodination reagent to be converted into G12, and reagent is I 2/ PPh 3/ imidazoles; G12 is converted to G13 under reductive condition, and condition is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide; Last G13 deacetylate obtains I-D-4, and condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-4 is the one of the compound with general formula I of the present invention.
Figure BDA00003282545700182
G8 obtains G14, PG with TBDMSCl or TBDPSCl protection 3be selected from TBDMS, TBDPS; G14 acetylize is converted into G15, and acetylation reagent is selected from diacetyl oxide, Acetyl Chloride 98Min.; G15 removes protecting group PG through processing 3obtain G16, reagent is tetra-n-butyl Neutral ammonium fluoride; G16 uses iodination reagent to be converted into G17, and reagent is I 2/ PPh 3/ imidazoles; G17 is converted to G18 under reductive condition, and condition is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide; G18 deacetylate obtains G19, and condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Last G19 sloughs benzal protecting group with acid treatment and obtains I-D-3, and acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-3 is the one of the compound with general formula I of the present invention.
Figure BDA00003282545700191
With Benzoyl chloride or to methyl benzoyl chloride, protection obtains compound G19, PG to compound G8 4be selected from benzoyl or to methyl benzoyl; G19 uses iodination reagent to be converted into G20, and reagent is I 2/ PPh 3/ imidazoles; G20 is converted to G21 under reductive condition, and condition is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide; G21 sloughs benzoyl or methyl benzoyl is obtained to G22, and condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Last G22 sloughs benzal protecting group with acid treatment and obtains I-D-2, and acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-2 is the one of the compound with general formula I of the present invention.
Figure BDA00003282545700192
Compound G8 acetylize is converted into G23, and acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.; Last G23 sloughs benzal protecting group with acid treatment and obtains G24, and acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid, p-methyl benzenesulfonic acid; G24 uses iodination reagent to be converted into G25, and reagent is I 2/ PPh 3/ imidazoles; G25 is converted to G26 under reductive condition, and condition is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide; G26 deacetylate obtains I-D-4, and 6, condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-4, the 6th, the one of the compound with general formula I of the present invention.
Compound G reacts with 1,1,2,2-tetramethoxy hexanaphthene and trimethyl orthoformate under acidic conditions, obtains G27, and acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid; G27 obtains G28, PG with TBDMSCl or TBDPSCl protection 5be selected from TBDMS or TBDPS; Compound G28 acetylize is converted into G29, and acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.; G29 removes protecting group through peracid treatment and obtains G30, and acid used is selected from acetic acid or trifluoroacetic acid; G30 obtains G31, PG with TBDMSCl or TBDPSCl protection 6be selected from TBDMS or TBDPS; G31 obtains G32, PG with TBDMSCl or TBDPSCl protection 7be selected from TBDMS or TBDPS; Compound G32 acetylize is converted into G33, and acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.; G33 sloughs PG 6and PG 7obtain G34, reagent is selected from tetra-n-butyl Neutral ammonium fluoride or acetic acid; G34 uses iodination reagent to be converted into G35, and reagent is I 2/ PPh 3/ imidazoles; G35 is converted to G36 under reductive condition, and condition is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide; Last G36 deacetylate obtains I-D-3, and 6, condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-3, the 6th, the one of the compound with general formula I of the present invention.
Figure BDA00003282545700211
Compound G27 uses iodination reagent to be converted into G37, and reagent is I 2/ PPh 3/ imidazoles; G37 is converted to G38 under reductive condition, and condition is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide; Last G38 sloughs protecting group and obtains I-D-2 under acidic conditions, and 6, acid used is selected from acetic acid or trifluoroacetic acid; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-2, the 6th, the one of the compound with general formula I of the present invention.
Figure BDA00003282545700212
Compound G27 acetylize is converted into G39, and acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.; G39 sloughs protecting group and obtains G40 under acidic conditions, and acid used is selected from acetic acid or trifluoroacetic acid; G40 uses iodination reagent to be converted into G41, and reagent is I 2/ PPh 3/ imidazoles; G41 is converted to G43 under reductive condition, and condition is selected from a) H 2, Pd/C, b) and H 2, Pd (OH) 2/ C and c) HCO 2nH 4, any of Pd/C; Last G43 deacetylate obtains I-D-3, and 4, condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-3, the 4th, the one of the compound with general formula I of the present invention.
Benzoyl chloride or pivaloyl chloride protection for compound G27 selectivity, obtain G44, PG 8be selected from benzoyl or pivaloyl group; G44 sloughs protecting group and obtains G45 under acidic conditions, and acid used is selected from acetic acid or trifluoroacetic acid; Benzoyl chloride or pivaloyl chloride protection for G45 selectivity, obtain G46, PG 9be selected from benzoyl or pivaloyl group; G46 uses iodination reagent to be converted into G47, and reagent is I 2/ PPh 3/ imidazoles; G47 is converted to G48 under reductive condition, and condition is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide; Last G48 sloughs PG 8and PG 9two protecting groups obtain I-D-2, and 4, condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-2, the 4th, the one of the compound with general formula I of the present invention.
Figure BDA00003282545700222
G8 uses iodination reagent to be converted into G49, and reagent is I 2/ PPh 3/ imidazoles; G49 is converted to G51 under reductive condition, and condition is selected from a) H 2, Pd/C, b) and H 2, Pd (OH) 2/ C and c) HCO 2nH 4, any of Pd/C; Last G51 sloughs protecting group and obtains I-D-2 under acidic conditions, and 3, acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-2, the 3rd, the one of the compound with general formula I of the present invention.
Figure BDA00003282545700223
Figure BDA00003282545700231
Compound G8 selectivity is used TBDMSCl, TIPSCl or TBDPSCl protection, obtains G52, PG 10be selected from TBDMS, TIPS or TBDPS; G52 acetylize is converted into G53, and acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.; G53 sloughs benzal and PG under acidic conditions 10obtain G54, acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid; G54 uses iodination reagent to be converted into G55, and reagent is I 2/ PPh 3/ imidazoles; G55 is converted to G57 under reductive condition, and condition is selected from a) H 2, Pd/C, b) and H 2, Pd (OH) 2/ C and c) HCO 2nH 4, any of Pd/C; Last G57 deacetylate obtains I-D-3, and 4,6, condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-3,4,6th, the one of the compound with general formula I of the present invention.
Figure BDA00003282545700232
Compound G19 sloughs benzal and obtains G58 under acidic conditions, and acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid; G58 uses iodination reagent to be converted into G59, and reagent is I 2/ PPh 3/ imidazoles; G59 is converted to G60 under reductive condition, and condition is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide; Last G60 sloughs protecting group PG 4obtain I-D-2,4,6, condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-2,4,6th, the one of the compound with general formula I of the present invention.
Figure BDA00003282545700241
Chloroacetyl chloride or bromoacetyl chloride protection for compound G8, obtain G61, PG 11be selected from chloracetyl or acetyl bromide; G61 sloughs benzal and obtains G62 under acidic conditions, and acid used is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, camphorsulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid; G62 obtains G63, PG with TBDMSCl or TBDPSCl protection 12be selected from TBDMS or TBDPS; G63 acetylize is converted into G64, and acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.; G64 processes under weak basic condition, obtains G65, and weak basic condition is selected from NaHCO 3/ EtOH, NaHCO 3/ MeOH, NaOAc/EtOH or NaOAc/MeOH; G65 sloughs protecting group PG by tetra-n-butyl Neutral ammonium fluoride or acetic acid treatment 12, obtain G66; G66 uses iodination reagent to be converted into G67, and reagent is I 2/ PPh 3/ imidazoles; G67 is converted to G69 under reductive condition, and condition is selected from a) H 2, Pd/C, b) and H 2, Pd (OH) 2/ C and c) HCO 2nH 4, any of Pd/C; Last G69 deacetylate obtains I-D-2, and 3,6, condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-2,3,6th, the one of the compound with general formula I of the present invention.
Figure BDA00003282545700242
Compound Benzoyl chloride for G, methyl benzoyl chloride or pivaloyl chloride protection are obtained to G70, PG 13be selected from benzoyl, to methyl benzoyl or pivaloyl group; G70 uses iodination reagent to be converted into G71, and reagent is I 2/ PPh 3/ imidazoles; G71 is converted to G73 under reductive condition, and condition is selected from a) H 2, Pd/C, b) and H 2, Pd (OH) 2/ C or c) HCO 2nH 4, Pd/C; Last G73 sloughs PG 13obtain I-D-2,3,4, condition is selected from MeONa/MeOH, NaOH/MeOH/H 2o, KOH/MeOH/H 2o, NaOH/EtOH/H 2o or KOH/EtOH/H 2o; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-2,3,4th, the one of the compound with general formula I of the present invention.
Figure BDA00003282545700251
Compound G uses iodination reagent to be converted into G74, and reagent is I 2/ PPh 3/ imidazoles; G74 successively uses two reductive conditions to process and finally obtains I-D-2, and 3,4,6, reductive condition 1 is selected from palladium catalyzed hydrogenation or n-Bu 3snH/AIBN, AIBN is azo-bis-isobutyl cyanide, reductive condition 2 is selected from a) H 2, Pd/C, b) and H 2, Pd (OH) 2/ C, c) HCO 2nH 4, any of Pd/C; Wherein, X is selected from O or S, Z 1-Z 3definition described above, I-D-2,3,4,6th, the one of the compound with general formula I of the present invention.
The present invention also provides the pharmaceutically acceptable prodrug ester of described formula I compound, comprises the ester that any one or more hydroxyls in molecule and ethanoyl, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. form.
The present invention also provides a kind of pharmaceutical composition, comprises compound or its pharmaceutically acceptable prodrug ester with general formula I structure of the present invention, and one or more pharmaceutically acceptable carriers, vehicle or thinner.Formula I compound of the present invention, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made the formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention, can accept auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle in described pharmacy or bromatology.
Composition of the present invention, can accept auxiliary material in described pharmacy or bromatology.Weighting agent is one or more the composition that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
The present invention also provides compound of Formula I or the purposes of its pharmaceutically acceptable prodrug ester in the medicine for the preparation of inhibition SGLT2 enzyme.The present invention also provides compound of Formula I or the purposes of its pharmaceutically acceptable prodrug ester in the medicine for the preparation for the treatment of diabetes.Compound of Formula I of the present invention has the restraining effect of SGLT2 enzyme, can be used as the medicine of effective constituent for the preparation of diabetes aspect.The activity of compound of Formula I of the present invention is drained modelling verification by glucose in urine.
The present invention also provides a kind of method for the treatment of diabetes, comprises compound or its pharmaceutically acceptable prodrug ester to patient's administration the present invention of this treatment of needs with general formula I structure.Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that take for example every day, within the scope of 1mg-500mg/ people, is divided into once or administration for several times.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the person's of being treated physical state, route of administration, age, body weight, individual reaction to medicine, the severity of symptom etc.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment is only for explanation, and not for limiting the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,6-dideoxy-D-Glucose (I-D1-6)
Figure BDA00003282545700261
A.
4.09g (10mmol) compound 1 is dissolved in the DMF that 30mL is dry, the cooling lower stirring of ice-water bath, add 2.72g (40mmol) imidazoles, then in 15 minutes, slowly drip 1.66g (11mmol) TBDMSCl (t butyldimethylsilyl chloride).After adding, compound of reaction at room temperature continues to stir 3 hours.150mL methylene dichloride dilution for reaction mixture, with the saturated common salt water washing of 50mL × 3, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 2, white foam shape solid. 1H?NMR(DMSO-d 6,400MHz),δ7.35(d,1H,J=8.0Hz),7.28(d,1H,J=2.0Hz),7.17(dd,1H,J=2.0Hz?and8.4Hz),7.05(d,2H,J=8.8Hz),6.79(d,2H,J=8.8Hz),4.92-4.95(m,2H),4.81(d,1H,J=6.0Hz),3.93-3.99(m,5H),3.85(d,1H,J=10.4Hz),3.66(dd,1H,J=5.2Hz?and11.6Hz),3.17-3.28(m,3H),3.02-3.08(m,1H),1.28(t,3H,J=7.0Hz),0.80(s,9H),-0.05(s,3H),-0.09(s,3H)。
B.
4.19g (8mmol) compound 2 is dissolved in 30mL pyridine, the cooling lower stirring of ice-water bath.Slowly drip 15mL acetic anhydride, then add again 0.1g DMAP (DMAP).After adding, reaction mixture at room temperature continues stirring and spends the night.Reaction mixture is poured in 200 mL frozen water, stirs, with 50mL × 3 dichloromethane extraction.Merge organic phase, use successively dilute hydrochloric acid and the water washing of 100mL saturated common salt of 50mL5%, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 3, white solid, fusing point 101-102 ° C. 1H?NMR(DMSO-d 6,400MHz),δ7.41(d,1H,J=8.0Hz),7.19-7.22(m,2H),7.03(d,2H,J=8.4Hz),6.80(d,2H,J=8.4Hz),5.30(t,1H,J=9.4Hz),5.06(t,1H,J=9.6Hz),4.83(t,1H,J=9.8Hz),4.61(d,1H,J=9.6Hz),3.90-4.00(m,4H),3.81-3.84(m,1H),3.60-3.71(m,2H),1.99(s,3H),1.90(s,3H),1.69(s,3H),1.28(t,3H,J=7.0Hz),0.82(s,9H),-0.03(s,3H),-0.08(s,3H)。
C.
3.90g (6mmol) compound 3 is dissolved in the aqueous acetic acid of 50mL90%, under 45 ° of C, stirs 5 hours, is then poured in 200mL frozen water, uses saturated NaHCO 3solution is adjusted to pH=7-8.With 50mL × 3 dichloromethane extraction.Merge organic phase, with the water washing of 100mL saturated common salt, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 4, white solid, fusing point 120-121 ° C. 1H?NMR(DMSO-d 6,400MHz),δ7.38-7.41(m,1H),7.26-7.30(m,1H),7.20(d,1H,J=7.6Hz),7.05(d,2H,J=8.4Hz),6.81(d,2H,J=8.8Hz),5.29(t,1H,J=9.6Hz),5.02(t,1H,J=9.6Hz),4.90(t,1H,J=9.6Hz),4.75(t,1H,J=5.8Hz),4.59(d,1H,J=9.6Hz),3.92-4.01(m,3H),3.74-3.78(m,1H),3.48-3.53(m,1H),3.39-3.43(m,1H),1.99(s,3H),1.91(s,3H),1.68(s,3H),1.28(t,3H,J=7.0Hz)。
D.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.67g (5mmol) compound 5, add under rear compound of reaction room temperature and stir and spend the night.200mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 5, white solid, fusing point 141-142 ° C. 1H?NMR(DMSO-d 6,400MHz),δ7.43(d,1H,J=8.4Hz),7.24(dd,1H,J=2.0Hz?and8.4Hz),7.20(d,1H,J=2.0Hz),7.06(d,2H,J=8.8Hz),6.82(d,2H,J=8.4Hz),5.35(t,1H,J=9.4Hz),4.92(t,1H,J=9.4Hz),4.86(t,1H,J=9.8Hz),4.71(d,1H,J=10.0Hz),3.92-4.01(m,4H),3.68-3.73(m,1H),3.49(dd,1H,J=2.8Hz?and11.2Hz),3.23-3.27(m,1H),2.02(s,3H),1.90(s,3H),1.69(s,3H),1.28(t,3H,J=7.0Hz)。
E.
1.93g (3mmol) compound 5,2.91g (10mmol) n-Bu 3snH and 0.49g (3mmol) AIBN is dissolved in the benzene that 20mL is dry, temperature rising reflux 3 hours under nitrogen atmosphere.Reaction mixture is cooling rear with the dilution of 100mL methylene dichloride, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 6, white foam shape solid. 1H?NMR(DMSO-d 6,400MHz),δ7.39(d,1H,J=8.0Hz),7.23-7.26(m,2H),7.04(d,2H,J=8.4Hz),6.81(d,2H,J=8.8Hz),5.26(t,1H,J=9.6Hz),4.94(t,1H,J=9.6Hz),4.83(t,1H,J=9.6Hz),4.57(d,1H,J=9.6Hz),3.92-4.01(m,4H),3.80-3.87(m,1H),2.02(s,3H),1.91(s,3H),1.67(s,3H),1.28(t,3H,J=6.8Hz),1.12(d,3H,J=6.0Hz)。 13C?NMR(DMSO-d 6,100MHz),δ169.55,169.49,168.41,156.91,138.35,136.52,132.82,130.92,130.16,129.50,129.25,126.57,114.27,77.52,73.25,73.01,72.95,72.65,62.85,37.37,20.42,20.26,19.98,17.33,14.60。
F.
In the dry anhydrous methanol of 10mL, add 0.2g sodium Metal 99.5, under room temperature nitrogen protection, stir, until sodium Metal 99.5 disappears.Then add 0.52g (1mmol) compound 6, under room temperature, continue to stir 3 hours.In reaction system, add 2g storng-acid cation exchange resin, under room temperature, stir and spend the night, until reaction mixture pH=7.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates obtaining is dry in the enterprising step of vacuum oil pump, obtains product I-D1-6, white foam shape solid. 1H?NMR(DMSO-d 6,400MHz),δ7.35(d,1H,J=8.0Hz),7.25(d,1H,J=2.0Hz),7.18(dd,1H,J=2.0Hz?and8.0Hz),7.08(d,2H,J=8.8Hz),6.82(d,2H,J=8.8Hz),4.96(d,1H,J=5.2Hz,D 2O-exchangable),4.91(d,1H,J=4.4Hz,D 2O-exchangable),4.80(d,1H,J=5.6Hz,D 2O-exchangable),3.92-4.01(m,5H),3.26-3.32(m,1H),3.18-3.25(m,1H),3.09-3.15(m,1H),2.89-2.95(m,1H),1.28(t,3H,J=7.0Hz),1.15(d,3H,J=6.0Hz)。 13C?NMR(DMSO-d 6,100MHz),δ156.85,139.65,137.82,131.83,131.16,130.58,129.52,128.65,127.14,114.26,80.71,77.98,75.77,75.51,74.81,62.84,37.56,18.19,14.63。HR-ESI-MS,calcd?for?C 21H 29ClNO 5,410.1734,found410.1730([M+NH 4] +)。
Embodiment 2
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-Isosorbide-5-Nitrae-dideoxy-D-Glucose (I-D1-4)
Figure BDA00003282545700291
A.
4.09g (10mmol) compound 1,1.83g (12mmol) phenyl aldehyde dimethylacetal and 0.1 gram of CAS (camphorsulfonic acid) are dissolved in the DMF that 30mL is dry, under nitrogen atmosphere 110 ° of C heated and stirred 3 hours.After reaction mixture is cooling, with the dilution of 150mL methylene dichloride, use successively sodium carbonate solution and the saturated common salt water washing of 20mL5%, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 7, white solid.Fusing point 176-178 ° C. 1H?NMR(DMSO-d 6,400MHz),δ7.45-7.47(m,2H),7.36-7.40(m,4H),7.28(d,1H,J=1.6Hz),7.21(dd,1H,J=2.0Hz?and8.4Hz),7.08(d,2H,J=8.8Hz),6.83(d,2H,J=8.4Hz),5.60(s,1H),5.31(d,1H,J=3.6Hz),5.13(d,1H,J=5.6Hz),4.16-4.22(m,2H),3.94-3.99(m,4H),3.65-3.70(m,1H),3.50-3.51(m,3H),3.24-3.28(m,1H),1.29(t,3H,J=6.8Hz)。
B.
3.98g (8mmol) compound 7 is dissolved in 30mL pyridine, the cooling lower stirring of ice-water bath.Slowly drip 15mL acetic anhydride, then add again 0.1g DMAP (DMAP).After adding, reaction mixture at room temperature continues stirring and spends the night.Reaction mixture is poured in 200mL frozen water, stirs, with 50mL × 3 dichloromethane extraction.Merge organic phase, use successively dilute hydrochloric acid and the water washing of 100mL saturated common salt of 50mL5%, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 8, white foam shape solid. 1H?NMR(DMSO-d 6,400MHz),δ7.36-7.42(m,6H),7.23-7.26(m,2H),7.04(d,2H,J=8.4Hz),6.82(d,2H,J=8.8Hz),5.66(s,1H),5.37(t,1H,J=9.4Hz),4.97(t,1H,J=9.6Hz),2.55(d,1H,J=9.6Hz),4.25-4.26(m,1H),3.93-4.02(m,5H),3.78-3.82(m,2H),1.96(s,3H),1.70(s,3H),1.29(t,3H,J=7.0Hz)。
C.
3.49g (6mmol) compound 8 and 0.5g CAS are dissolved in 30mL methyl alcohol, under room temperature, stir and spend the night.Compound of reaction, with the dilution of 100mL methylene dichloride, is used sodium carbonate solution and the saturated common salt water washing of 50mL2%, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 9, white foam shape solid. 1H?NMR(DMSO-d 6,400MHz),δ7.37-7.39(m,1H),7.25-7.27(m,2H),7.03(d,2H,J=8.4Hz),6.81(d,2H,J=8.8Hz),5.47(d,1H,J=5.6Hz,D 2O-exchangable),5.04(t,1H,J=9.2Hz),4.73(t,1H,J=9.6Hz),4.58(t,1H,J=5.8Hz,D 2O-exchangable),4.46(d,1H,J=9.6Hz),3.91-4.00(m,4H),3.71(dd,1H,J=5.2Hz?and10.8Hz),3.49-3.56(m,2H),3.43-3.47(m,1H),1.95(s,3H),1.62(s,3H),1.28(t,3H,J=7.0Hz)。
D.
2.46g (5mmol) compound 9 and 0.72g (0.55mmol) benzoyl cyanide are dissolved in the acetonitrile that 20mL is dry, under room temperature, stir.Slowly drip 0.21mL (0.15g, 1.5mmol) triethylamine with syringe.After adding, under compound of reaction room temperature, stir and spend the night.Reaction mixture is poured in 200mL frozen water, stirs, with using 50mL × 3 dichloromethane extraction.Merge organic phase, use successively dilute hydrochloric acid and the water washing of 100mL saturated common salt of 50mL1%, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 10, white foam shape solid. 1H?NMR(DMSO-d 6,400MHz),δ7.97-7.99(m,2H),7.66(t,1H,J=7.4Hz),7.53(t,2H,J=7.6Hz),7.37(d,1H,J=9.2Hz),7.20-7.21(m,2H),7.02(d,2H,J=8.8Hz),6.76(d,2H,J=8.4Hz),5.79(d,1H,J=6.0Hz,D 2O-exchangable),5.12(t,1H,J=9.4Hz),4.82(t,1H,J=9.8Hz),4.56-4.59(m,2H),4.42(dd,1H,J=5.2Hz?and12.0Hz),3.86-3.97(m,5H),3.71-3.77(m,1H),1.97(s,3H),1.67(s,3H),1.27(t,3H,J=7.0Hz)。
E.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.39g (4mmol) compound 10, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.200mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 11, white foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.92(d,2H,J=7.2Hz),7.66(t,1H,J=7.4Hz),7.52(t,2H,J=7.8Hz),7.44(d,1H,J=8.4Hz),7.25(dd,1H,J=2.0Hz?and8.4Hz),7.15(d,1H,J=2.0Hz),7.04(d,2H,J=8.8Hz),6.81(d,2H,J=8.4Hz),5.17(t,1H,J=9.6Hz),4.94(d,1H,J=3.6Hz),4.82(dd,1H,J=4.0Hz?and9.6Hz),4.65(d,1H,J=9.6Hz),4.42(dd,1H,J=6.8Hz?and11.2Hz),4.29(dd,1H,J=4.4Hz?and11.6Hz),3.91-4.01(m,4H),3.83(t,1H,J=5.4Hz),2.03(s,3H),1.72(s,3H),1.28(t,3H,J=6.8Hz)。
F.
1.41g (2mmol) compound 11 and 3mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 12, white solid.Fusing point 45-47 ° C. 1H?NMR(DMSO-d 6,400MHz),δ7.96(d,2H,J=7.6Hz),7.66(t,1H,J=7.2Hz),7.52(t,2H,J=7.4Hz),7.38(d,1H,J=8.0Hz),7.21-7.23(m,2H),7.03(d,2H,J=8.0Hz),6.78(d,2H,J=8.4Hz),5.14-5.21(m,1H),4.80(t,1H,J=9.4Hz),4.51(d,1H,J=9.6Hz),4.36-4.37(m,2H),4.14-4.17(m,1H),3.89-3.99(m,4H),2.21-2.24(m,1H),1.95(s,3H),1.69(s,3H),1.28(t,3H,J=6.8Hz)。 13C?NMR(DMSO-d 6,100MHz),δ169.64,168.67,165.46,156.89,138.25,136.98,133.40,132.64,130.91,130.06,129.48,129.39,129.20,129.14,128.77,126.47,114.25,77.75,73.35,72.58,71.03,65.98,62.84,37.38,32.48,20.61,20.09,14.59。
G.
0.58g (1mmol) compound 12 is dissolved in 10mL ethanol, stirs, and adds the NaOH solution of 1mL50%.Reaction mixture reflux 1 hour, is poured in water after cooling, regulates pH=3 with concentrated hydrochloric acid.With 50mL × 3 dichloromethane extraction, merge organic phase, use successively sodium carbonate solution and the saturated common salt water washing of 50mL5%, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling I-D1-4, white foam shape solid. 1H?NMR(DMSO-d 6,400MHz),δ7.35(d,1H,J=8.0Hz),7.28(d,1H,J=1.6Hz),7.20(dd,1H,J=1.8Hz?and8.2Hz),7.08(d,2H,J=8.4Hz),6.82(d,2H,J=8.8Hz),4.82(d,1H,J=4.8Hz),4.75(d,1H,J=5.6Hz),4.59(t,1H,J=5.8Hz),3.92-4.01(m,5H),3.46-3.51(m,2H),3.31-3.42(m,2H),2.99-3.05(m,1H),1.89(dd,1H,J=4.8Hz?and11.6Hz),1.23-1.30(m,4H)。 13C?NMR(DMSO-d 6,400MHz),156.84,139.83,137.72,131.76,131.16,130.76,129.51,128.58,127.31,114.25,80.97,76.57,76.24,71.97,64.04,62.83,37.57,36.28,14.62。
Embodiment 3
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,3-dideoxy-D-Glucose (I-D1-3)
Figure BDA00003282545700321
A.
4.97g (10mmol) compound 7 is dissolved in the DMF that 30mL is dry, the cooling lower stirring of ice-water bath, add 2.72g (40mmol) imidazoles, then in 15 minutes, slowly drip 1.66g (11mmol) TBDMSCl (t butyldimethylsilyl chloride).After adding, compound of reaction at room temperature continues to stir 3 hours.150mL methylene dichloride dilution for reaction mixture, with the saturated common salt water washing of 50mL × 3, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 13, white foam shape solid.ESI-MS,m/z=628([M+NH 4] +)。
B.
4.89g (8mmol) compound 13 is dissolved in 30mL pyridine, the cooling lower stirring of ice-water bath.Slowly drip 10mL acetic anhydride, then add again 0.1g DMAP (DMAP).After adding, reaction mixture at room temperature continues stirring and spends the night.Reaction mixture is poured in 200mL frozen water, stirs, with 50mL × 3 dichloromethane extraction.Merge organic phase, use successively dilute hydrochloric acid and the water washing of 100mL saturated common salt of 50mL5%, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 14, white foam shape solid.ESI-MS,m/z=670([M+NH 4] +)。
C.
3.92g (6mmol) compound 14 is dissolved in the THF that 40mL is dry, the cooling lower stirring of ice-water bath, add 0.37g (6mmol) Glacial acetic acid, more dropwise add 6mL (6mmol, the THF solution of 1M) TBAF (tetra-n-butyl Neutral ammonium fluoride) solution.Under compound of reaction room temperature, stir and spend the night, be poured in 200mL frozen water, stir, with 50mL × 3 dichloromethane extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 15, white foam shape solid.ESI-MS,m/z=561([M+Na] +)。
D.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.70g (5mmol) compound 15, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.200mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 16, white foam shape solid.ESI-MS,m/z=671([M+Na] +)。
E.
1.95g (3mmol) compound 16 and 3mL triethylamine are dissolved in 10mL THF, then add 0.3g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 17, white solid.ESI-MS,m/z=545([M+Na] +)。
F.
1.05g (2mmol) compound 17 is dissolved in 10mL ethanol, adds the NaOH solution of 1mL50%, and temperature rising reflux 1 hour, regulates pH=2 with concentrated hydrochloric acid after cool to room temperature, heats up and continues the half an hour of refluxing.Compound of reaction is poured in 100mL saturated aqueous common salt, stirs, and with 50mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling I-D1-3, white foam shape solid.ESI-MS,m/z=415([M+Na] +)。 1H?NMR(DMSO-d 6,400MHz),δ7.35(d,1H,J=8.4Hz),7.30(d,1H,J=1.6Hz),7.22(dd,1H,J=1.8Hz?and8.2Hz),7.08(d,2H,J=8.8Hz),6.81(d,2H,J=8.4Hz),4.82(d,1H,J=5.6Hz),4.73(d,1H,J=6.4Hz),4.38(t,1H,J=5.8Hz),3.92-4.01(m,4H),3.85(d,1H,J=9.2Hz),3.67-3.72(m,1H),3.27-3.45(m,3H),3.07-3.10(m,1H),2.20-2.25(m,1H),1.43(q,1H,J=11.5Hz),1.28(t,3H,J=6.8Hz)。 13C?NMR(DMSO-d 6,100MHz),δ156.83,139.91,137.66,131.78,131.17,130.73,129.48,128.55,127.18,114.24,83.29,82.92,69.20,64.67,62.83,61.22,42.81,37.60,14.62。
Embodiment 4
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,2-dideoxy-D-Glucose (I-D1-2)
Figure BDA00003282545700341
A.
4.97g (10mmol) compound 7 and 0.2g DMAP are dissolved in the pyridine that 20mL is dry, and the cooling lower stirring of ice-water bath dropwise adds 1.55g (11mmol) Benzoyl chloride.After adding, compound of reaction at room temperature continues stirring and spends the night.150mL methylene dichloride dilution for reaction mixture, uses the dilute hydrochloric acid of 100mL5% and the saturated common salt water washing of 50mL × 2, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 18, white foam shape solid.ESI-MS,m/z=623([M+Na] +)。
B.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 3.01g (5mmol) compound 18, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.200mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 19, white foam shape solid.ESI-MS,m/z=733([M+Na] +)。
C.
2.13g (3mmol) compound 19 and 3mL triethylamine are dissolved in 10mL THF, then add 0.3g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 20, white solid.ESI-MS,m/z=607([M+Na] +)。
D.
1.17g (2mmol) compound 20 is dissolved in 10mL ethanol, adds the NaOH solution of 1mL50%, and temperature rising reflux 1 hour, regulates pH=2 with concentrated hydrochloric acid after cool to room temperature, heats up and continues the half an hour of refluxing.Compound of reaction is poured in 100mL saturated aqueous common salt, stirs, and with 50mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling I-D1-2, white foam shape solid.ESI-MS,m/z=410([M+NH 4] +)。 1H?NMR(DMSO-d 6,400MHz),7.36(d,1H,J=8.4Hz),7.34(d,1H,J=1.6Hz),7.25(dd,1H,J=2.0Hz?and8.4Hz),7.07(d,2H,J=8.4Hz),6.82(d,2H,J=8.4Hz),4.88(d,1H,J=5.2Hz),4.83(d,1H,J=4.8Hz),4.38-4.43(m,2H),3.93-3.98(m,4H),3.69-3.74(m,1H),3.45-3.54(m,2H),3.16-3.20(m,1H),3.01-3.07(m,1H),1.98-2.02(m,1H),1.35(q,1H,J=12.0Hz),1.28(t,3H,J=7.0Hz)
Embodiment 5
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-Isosorbide-5-Nitrae, 6-tri-DDGs (I-D1-4,6)
Figure BDA00003282545700351
A.
4.97g (10mmol) compound 7 and 0.2g DMAP are dissolved in the pyridine that 30mL is dry, and the cooling lower stirring of ice-water bath, dropwise adds 10mL acetic anhydride.After adding, compound of reaction at room temperature continues stirring and spends the night.150mL methylene dichloride dilution for reaction mixture, uses the dilute hydrochloric acid of 100mL5% and the saturated common salt water washing of 50mL × 2, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 21, white foam shape solid.ESI-MS,m/z=603([M+Na] +)。
B.
4.65g (8mmol) compound 21 and 0.5g CAS are dissolved in 30mL methyl alcohol, under room temperature, stir and spend the night.Compound of reaction, with the dilution of 100mL methylene dichloride, is used sodium carbonate solution and the saturated common salt water washing of 50mL2%, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 22, white foam shape solid.ESI-MS,m/z=493([M+H] +)。
C.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.46g (5mmol) compound 22, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.200mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 23, white foam shape solid.ESI-MS,m/z=735([M+Na] +)。
D.
2.14g (3mmol) compound 23 and 2mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 24, white solid.ESI-MS,m/z=483([M+Na] +)。
E.
In the dry anhydrous methanol of 10mL, add 0.3g sodium Metal 99.5, under room temperature nitrogen protection, stir, until sodium Metal 99.5 disappears.Then add 0.46g (1mmol) compound 24, under room temperature, continue to stir 3 hours.In reaction system, add 3g storng-acid cation exchange resin, under room temperature, stir and spend the night, until reaction mixture pH=7.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates obtaining is dry in the enterprising step of vacuum oil pump, obtains product I-D1-4, and 6, white foam shape solid.ESI-MS,m/z=399([M+Na] +)。
Embodiment 6
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,3,6-tri-DDGs (I-D1-3,6)
Figure BDA00003282545700361
Figure BDA00003282545700371
A.
4.09g (10mmol) compound 1,3.06g (15mmol) 1,1,2,2-tetramethoxy hexanaphthene and 1mL trimethyl orthoformate are dissolved in the methyl alcohol that 40mL is dry, add 0.2g camphorsulfonic acid.Reaction mixture reflux is spent the night.After reaction mixture cool to room temperature, add 0.5g salt of wormwood, under room temperature, stir, until pH>7.Suction filtration, removes solid, and filtrate boils off solvent on Rotary Evaporators, and the direct column chromatography purification of resistates, obtains sterling 25, white solid.ESI-MS,m/z=571([M+Na] +)。
B.
4.39g (8mmol) compound 25 is dissolved in the DMF that 30mL is dry, the cooling lower stirring of ice-water bath, add 2.72g (40mmol) imidazoles, then in 15 minutes, slowly drip 2.75g (10mmol) TBDPSCl (tert-butyl diphenyl silicon chlorides).After adding, compound of reaction at room temperature continues to stir 3 hours.150mL methylene dichloride dilution for reaction mixture, with the saturated common salt water washing of 50mL × 3, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 26, white foam shape solid.ESI-MS,m/z=809([M+Na] +)。
C.
4.72g (6mmol) compound 26 and 0.2g DMAP are dissolved in the pyridine that 30mL is dry, and the cooling lower stirring of ice-water bath, dropwise adds 10mL acetic anhydride.After adding, compound of reaction at room temperature continues stirring and spends the night.150mL methylene dichloride dilution for reaction mixture, uses the dilute hydrochloric acid of 100mL5% and the saturated common salt water washing of 50mL × 2, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 27, white foam shape solid.ESI-MS,m/z=851([M+Na] +)。
D.
4.15g (5mmol) compound 27 is dissolved in the mixture of 10mL methylene dichloride and 10mL trifluoroacetic acid (TFA) composition, under room temperature, stirs and spends the night.Reaction mixture is poured in 100mL saturated aqueous common salt, stirs, and with 50mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 28, white foam shape solid.ESI-MS,m/z=473([M+Na] +)。
E.
1.80g (4mmol) compound 28 is dissolved in the DMF that 20mL is dry, the cooling lower stirring of ice-water bath, add 2.72g (40mmol) imidazoles, then in 15 minutes, slowly drip 1.37g (5mmol) TBDPSCl (tert-butyl diphenyl silicon chlorides).After adding, compound of reaction at room temperature continues to stir 3 hours.150mL methylene dichloride dilution for reaction mixture, with the saturated common salt water washing of 50mL × 3, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 29, white foam shape solid.ESI-MS,m/z=711([M+Na] +)。
F.
2.76g (4mmol) compound 29 is dissolved in the DMF that 20mL is dry, the cooling lower stirring of ice-water bath, add 2.72g (40mmol) imidazoles, then in 15 minutes, slowly drip 1.37g (5mmol) TBDPSCl (tert-butyl diphenyl silicon chlorides).After adding, compound of reaction at room temperature continues to stir 3 hours.150mL methylene dichloride dilution for reaction mixture, with the saturated common salt water washing of 50mL × 3, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 30, white foam shape solid.ESI-MS,m/z=949([M+Na] +)。
G.
2.78g (3mmol) compound 30 and 0.15g DMAP are dissolved in the pyridine that 20mL is dry, and the cooling lower stirring of ice-water bath, dropwise adds 8mL acetic anhydride.After adding, compound of reaction at room temperature continues stirring and spends the night.150mL methylene dichloride dilution for reaction mixture, uses the dilute hydrochloric acid of 100mL5% and the saturated common salt water washing of 50mL × 2, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 31, white foam shape solid.ESI-MS,m/z=991([M+Na] +)。
H.
2.42g (2.5mmol) compound 31 is dissolved in the aqueous acetic acid of 20mL90%, is warmed up to 60 ° of C, and stirring is spent the night.After reaction mixture is cooling, be poured in 100mL saturated aqueous common salt, use NaHCO 3saturated solution regulates pH=6-7, stirs, and with 50mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 32, white foam shape solid.ESI-MS,m/z=515([M+Na] +)。
I.
6.35g (25mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 6.56g (25mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 6.81g (100mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 0.99g (2mmol) compound 32, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 33, white foam shape solid.ESI-MS,m/z=735([M+Na] +)。
J.
0.93g (1.3mmol) compound 33 and 1mL triethylamine are dissolved in 5mL THF, then add 0.1g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 34, white solid.ESI-MS,m/z=478([M+NH 4] +)。
K.
In the dry anhydrous methanol of 5mL, add 0.1g sodium Metal 99.5, under room temperature nitrogen protection, stir, until sodium Metal 99.5 disappears.Then add 0.46g (1mmol) compound 34, under room temperature, continue to stir 3 hours.In reaction system, add 1g storng-acid cation exchange resin, under room temperature, stir and spend the night, until reaction mixture pH=7.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates obtaining is dry in the enterprising step of vacuum oil pump, obtains product I-D1-3, and 6, white foam shape solid.ESI-MS,m/z=399([M+Na] +)。
Embodiment 7
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,2,6-tri-DDGs (I-D1-2,6)
Figure BDA00003282545700391
A.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.75g (5mmol) compound 25, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 35, white foam shape solid.ESI-MS,m/z=791([M+Na] +)。
B.
1.54g (3mmol) compound 35 and 2mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 36, white solid.ESI-MS,m/z=539([M+Na] +)。
C.
0.52g (1mmol) compound 36 is dissolved in the mixture of 6mL methylene dichloride and 6mL trifluoroacetic acid (TFA) composition, under room temperature, stirs and spends the night.Reaction mixture is poured in 100mL saturated aqueous common salt, stirs, and with 50mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling I-D1-2, and 6, white foam shape solid.ESI-MS,m/z=393([M+NH 4] +)。
Embodiment 8
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,3,4-tri-DDGs (I-D1-3,4)
Figure BDA00003282545700401
A.
5.49g (10mmol) compound 25 and 0.30gDMAP are dissolved in the pyridine that 30mL is dry, and the cooling lower stirring of ice-water bath, dropwise adds 15mL acetic anhydride.After adding, compound of reaction at room temperature continues stirring and spends the night.150mL methylene dichloride dilution for reaction mixture, uses the dilute hydrochloric acid of 100mL5% and the saturated common salt water washing of 50mL × 2, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 37, white foam shape solid.ESI-MS,m/z=655([M+Na] +)。
B.
3.80g (6mmol) compound 37 is dissolved in the mixture of 10mL methylene dichloride and 10mL trifluoroacetic acid (TFA) composition, under room temperature, stirs and spends the night.Reaction mixture is poured in 100mL saturated aqueous common salt, stirs, and with 100mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 38, white foam shape solid.ESI-MS,m/z=493([M+H] +)。
C.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.46g (5mmol) compound 38, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 39, white foam shape solid.ESI-MS,m/z=735([M+Na] +)。
D.
2.14g (3mmol) compound 39 and 2mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 40, white foam shape solid.ESI-MS,m/z=483([M+Na] +)。
E.
In the dry anhydrous methanol of 5mL, add 0.1g sodium Metal 99.5, under room temperature nitrogen protection, stir, until sodium Metal 99.5 disappears.Then add 0.46g (1mmol) compound 40, under room temperature, continue to stir 3 hours.In reaction system, add 1g storng-acid cation exchange resin, under room temperature, stir and spend the night, until reaction mixture pH=7.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates obtaining is dry in the enterprising step of vacuum oil pump, obtains product I-D1-3, and 4, white foam shape solid.ESI-MS,m/z=394([M+NH 4] +)。
Embodiment 9
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,2,4-tri-DDGs (I-D1-2,4)
Figure BDA00003282545700411
Figure BDA00003282545700421
A.
5.49g (10mmol) compound 25 and 0.5g DMAP are dissolved in the pyridine that 20mL is dry, and the cooling lower stirring of ice-water bath dropwise adds 1.33g (11mmol) pivaloyl chloride.After adding, compound of reaction at room temperature continues stirring and spends the night.150mL methylene dichloride dilution for reaction mixture, uses the dilute hydrochloric acid of 100mL5% and the saturated common salt water washing of 50mL × 2, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 41, white foam shape solid.ESI-MS,m/z=655([M+Na] +)。
B.
5.07g (8mmol) compound 41 is dissolved in the mixture of 10mL methylene dichloride and 10mL trifluoroacetic acid (TFA) composition, under room temperature, stirs and spends the night.Reaction mixture is poured in 200mL saturated aqueous common salt, stirs, and with 100mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 42, white foam shape solid.ESI-MS,m/z=510([M+NH 4] +)。
C.
2.96g (6mmol) compound 42 and 0.3g DMAP are dissolved in the pyridine that 20mL is dry, and the cooling lower stirring of ice-water bath dropwise adds 0.96g (8mmol) pivaloyl chloride.After adding, compound of reaction at room temperature continues stirring and spends the night.150mL methylene dichloride dilution for reaction mixture, uses the dilute hydrochloric acid of 100mL5% and the saturated common salt water washing of 50mL × 2, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 43, white foam shape solid.ESI-MS,m/z=599([M+Na] +)。
D.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.89g (5mmol) compound 43, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 44, white foam shape solid.ESI-MS,m/z=797([M+H] +)。
E.
2.39g (3mmol) compound 44 and 2mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 45, white foam shape solid.ESI-MS,m/z=567([M+Na] +)。
F.
0.55 (1mmol) compound 45 is dissolved in 10mL methyl alcohol, stirs, and adds the NaOH solution of 1mL50%, temperature rising reflux half an hour.After compound of reaction is cooling, be poured in water, regulate pH=4 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL × 3.Merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling I-D1-2, and 4, white foam shape solid.ESI-MS,m/z=377([M+H] +)。
Embodiment 10
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,2,3-tri-DDGs (I-D1-2,3)
Figure BDA00003282545700431
A.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.48g (5mmol) compound 7, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 46, white foam shape solid.ESI-MS,m/z=734([M+NH 4] +)。
B.
1.43g (2mmol) compound 46 and 2mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 47, white foam shape solid.ESI-MS,m/z=487([M+Na] +)。
C.
0.46g (1mmol) compound 47 is dissolved in the 5mL methyl alcohol that contains 3 vitriol oils, under room temperature, stirs and spends the night.Reaction mixture is poured in 100mL saturated aqueous common salt, stirs, and with 100mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling I-D1-2, and 3, white foam shape solid.ESI-MS,m/z=394([M+NH 4] +)。
Embodiment 11
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,3,4,6-tetra-DDGs (I-D1-3,4,6)
Figure BDA00003282545700441
A.
6.53g (10mmol) compound 14 is dissolved in the aqueous acetic acid of 50mL90%, under 60 ° of C, stirs and spends the night, and is poured in 200mL frozen water after slightly cold, uses saturated NaHCO 3solution is adjusted to pH=7-8.With 50mL × 3 dichloromethane extraction.Merge organic phase, with the water washing of 100mL saturated common salt, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 48, white foam shape solid.ESI-MS,m/z=468([M+NH 4] +)。
B.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.25g (5mmol) compound 48, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 49, white foam shape solid.ESI-MS,m/z=803([M+Na] +)。
C.
1.56g (2mmol) compound 49 and 2mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 50, white foam shape solid.ESI-MS,m/z=425([M+Na] +)。
D.
In the dry anhydrous methanol of 5mL, add 0.1g sodium Metal 99.5, under room temperature nitrogen protection, stir, until sodium Metal 99.5 disappears.Then add 0.40g (1mmol) compound 50, under room temperature, continue to stir 3 hours.In reaction system, add 1g storng-acid cation exchange resin, under room temperature, stir and spend the night, until reaction mixture pH=7.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates obtaining is dry in the enterprising step of vacuum oil pump, obtains product I-D1-3, and 4,6, white foam shape solid.ESI-MS,m/z=378([M+NH 4] +)。
Embodiment 12
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,2,4,6-tetra-DDGs (I-D1-2,4,6)
A.
6.01g (10mmol) compound 18 is dissolved in the aqueous acetic acid of 50mL90%, under 60 ° of C, stirs and spends the night, and is poured in 200mL frozen water after slightly cold, uses saturated NaHCO 3solution is adjusted to pH=7-8.With 50mL × 3 dichloromethane extraction.Merge organic phase, with the water washing of 100mL saturated common salt, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 51, white foam shape solid.ESI-MS,m/z=535([M+Na] +)。
B.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 2.05g (4mmol) compound 51, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 52, white foam shape solid.ESI-MS,m/z=864([M+Na] +)。
C.
1.56g (2mmol) compound 52 and 2mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 53, white foam shape solid.ESI-MS,m/z=487([M+Na] +)。
D.
In the dry anhydrous methanol of 5mL, add 0.1g sodium Metal 99.5, under room temperature nitrogen protection, stir, until sodium Metal 99.5 disappears.Then add 0.47g (1mmol) compound 53, under room temperature, continue to stir 3 hours.In reaction system, add 1g storng-acid cation exchange resin, under room temperature, stir and spend the night, until reaction mixture pH=7.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates obtaining is dry in the enterprising step of vacuum oil pump, obtains product I-D1-2, and 4,6, white foam shape solid.ESI-MS,m/z=361([M+H] +)。
Embodiment 13
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,2,3,6-tetra-DDGs (I-D1-2,3,6)
Figure BDA00003282545700461
Figure BDA00003282545700471
A.
4.97g (10mmol) compound 7 and 6.07g (60mmol) triethylamine are dissolved in the methylene dichloride that 50mL is dry, the cooling lower stirring of ice-water bath.Slowly drip 3.39g (30mmol) chloroacetyl chloride.After dropwising, reaction mixture at room temperature stirs and spends the night.Reaction mixture is with 150mL methylene dichloride dilution, successively with saturated aqueous common salt, 2% dilute hydrochloric acid and saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 54, white foam shape solid.ESI-MS, m/z=671 and 673 ([M+Na] +).
B.
5.20g (8mmol) compound 54 is dissolved in the 40mL methyl alcohol that contains 5 vitriol oils, under room temperature, stirs and spends the night.Reaction mixture is poured in 200mL saturated aqueous common salt, stirs, and with 100mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 55, white foam shape solid.ESI-MS, m/z=578 and 580 ([M+NH 4] +).
C.
3.37g (6mmol) compound 55 is dissolved in the DMF that 20mL is dry, the cooling lower stirring of ice-water bath, add 2.72g (40mmol) imidazoles, then in 15 minutes, slowly drip 2.20g (8mmol) TBDPSCl (tert-butyl diphenyl silicon chlorides).After adding, compound of reaction at room temperature continues to stir 3 hours.150mL methylene dichloride dilution for reaction mixture, with the saturated common salt water washing of 50mL × 3, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 56, white foam shape solid.ESI-MS, m/z=821 and 823 ([M+Na] +).
D.
4.00g (5mmol) compound 56 and 0.30g DMAP are dissolved in the pyridine that 30mL is dry, and the cooling lower stirring of ice-water bath, dropwise adds 15mL acetic anhydride.After adding, compound of reaction at room temperature continues stirring and spends the night.150mL methylene dichloride dilution for reaction mixture, uses the dilute hydrochloric acid of 100mL5% and the saturated common salt water washing of 50mL × 2, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 57, white foam shape solid.ESI-MS, m/z=863 and 865 ([M+Na] +).
E.
3.37g (4mmol) compound 57 is dissolved in 30mL dehydrated alcohol, under room temperature, stirs, and adds 1.68g (20mmol) NaHCO 3solid, continues under room temperature to stir to spend the night.Reaction mixture is poured in 200mL saturated aqueous common salt, stirs, and with 100mL × 3 dichloromethane extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 58, white foam shape solid.ESI-MS,m/z=706([M+NH 4] +)。
F.
2.07g (3mmol) compound 58 is dissolved in the aqueous acetic acid of 20mL90%, under 60 ° of C, stirs and spends the night, and is poured in 200mL frozen water after slightly cold, uses saturated NaHCO 3solution is adjusted to pH=7-8.With 50mL × 3 dichloromethane extraction.Merge organic phase, with the water washing of 100mL saturated common salt, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 59, white foam shape solid.ESI-MS,m/z=473([M+Na] +)。
G.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 0.90g (2mmol) compound 59, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 60, white foam shape solid.ESI-MS,m/z=781([M+H] +)。
H.
1.17g (1.5mmol) compound 60 and 1mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 61, white foam shape solid.ESI-MS,m/z=425([M+Na] +)。
I.
In the dry anhydrous methanol of 5mL, add 0.1g sodium Metal 99.5, under room temperature nitrogen protection, stir, until sodium Metal 99.5 disappears.Then add 0.40g (1mmol) compound 61, under room temperature, continue to stir 3 hours.In reaction system, add 1g storng-acid cation exchange resin, under room temperature, stir and spend the night, until reaction mixture pH=7.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates obtaining is dry in the enterprising step of vacuum oil pump, obtains product I-D1-2, and 3,6, white foam shape solid.ESI-MS,?m/z=383([M+Na] +)。
Embodiment 14
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,2,3,4-tetra-DDGs (I-D1-2,3,4)
Figure BDA00003282545700491
A.
4.09g (10mmol) compound 1 and 0.5g DMAP are dissolved in the pyridine that 20mL is dry, and the cooling lower stirring of ice-water bath dropwise adds 1.33g (11mmol) pivaloyl chloride.After adding, compound of reaction at room temperature continues stirring and spends the night.150mL methylene dichloride dilution for reaction mixture, uses the dilute hydrochloric acid of 100mL5% and the saturated common salt water washing of 50mL × 2, anhydrous sodium sulfate drying successively.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 62, white foam shape solid.ESI-MS,m/z=515([M+Na] +)。
B.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 0.99g (2mmol) compound 62, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 63, white foam shape solid.ESI-MS,m/z=840([M+NH 4] +)。
C.
1.23g (1.5mmol) compound 63 and 1mL triethylamine are dissolved in 10mL THF, then add the Pd/C of 0.2g10%, and reaction mixture room temperature hydrogenation under the hydrogen pressure of 0.3MPa is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 64, white foam shape solid.ESI-MS,m/z=467([M+Na] +)。
D.
0.44 (1mmol) compound 65 is dissolved in 5mL methyl alcohol, stirs, and adds the NaOH solution of 0.5mL50%, temperature rising reflux half an hour.After compound of reaction is cooling, be poured in water, regulate pH=4 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL × 3.Merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling I-D1-2, and 3,4, white foam shape solid.ESI-MS,m/z=361([M+H] +)。
Embodiment 15
The preparation chloro-3-of (1S)-1-[4-(4-ethoxy benzyl) phenyl]-1,2,3,4,6-five DDGs (I-D1-2,3,4,6)
Figure BDA00003282545700501
A.
12.69g (50mmol) iodine is dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath slowly adds 13.11g (50mmol) triphenylphosphine, adds rear compound of reaction and continues to stir 10 minutes.Slowly add again 13.62g (200mmol) imidazoles, add rear continuation and stir one hour.In above-mentioned gained system, add 0.98g (2mmol) compound 1, add rear compound of reaction stirring and refluxing under nitrogen atmosphere and spend the night.100mL methylene dichloride dilution for reaction mixture, saturated common salt water washing, anhydrous sodium sulfate drying.Remove by filter siccative, filtrate boils off solvent on Rotary Evaporators, and the resistates obtaining, through silica gel column chromatography, obtains sterling 65, white foam shape solid.ESI-MS,m/z=870([M+Na] +)。
B.
0.85g (1.5mmol) compound 65 and 1mL triethylamine are dissolved in 10mL THF, then add 0.2g Pd (OH) 2, under reaction mixture room temperature, hydrogenation is spent the night.Compound of reaction suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling I-D1-2, and 3,4,6, white foam shape solid.ESI-MS,m/z=367([M+Na] +)。
Embodiment 16-106
Use the method for embodiment 1-15, prepared the following compound with general formula I structure.
Figure BDA00003282545700511
Figure BDA00003282545700521
Figure BDA00003282545700531
Figure BDA00003282545700541
Figure BDA00003282545700551
Figure BDA00003282545700561
Figure BDA00003282545700571
Figure BDA00003282545700581
Figure BDA00003282545700601
Embodiment 107
Figure BDA00003282545700602
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix softwood processed, sieve, wet granular processed, dry in 50-60 ° of C, by carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
Embodiment 108
Figure BDA00003282545700611
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix softwood processed, sieve, wet granular processed, dry in 50-60 ° of C, by carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
Embodiment 109
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix, softwood processed, sieves, and wet granular processed is dry in 50-60 ° of C, Magnesium Stearate and talcum powder are sieved in advance, then join in above-mentioned particle, encapsulated, to obtain final product.
Embodiment 110
Figure BDA00003282545700613
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix, softwood processed, sieves, and wet granular processed is dry in 50-60 ℃, Magnesium Stearate and talcum powder are sieved in advance, then join in above-mentioned particle, encapsulated, to obtain final product.
Embodiment 111
Figure BDA00003282545700614
In distilled water, first add distilled water and citric acid, stirring and dissolving and after, add sample, low-grade fever makes to dissolve again, and adjust pH is 4.0-5.0, add 0.2 gram of activated carbon, under room temperature, stir 20 minutes, filter filtrate, strength of solution is determined in middle detection, by 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes, obtains injection liquid.
Embodiment 112
Figure BDA00003282545700621
In distilled water, first add distilled water and citric acid, stirring and dissolving and after, add sample, low-grade fever makes to dissolve again, and adjust pH is 4.0-5.0, add 0.2 gram of activated carbon, under room temperature, stir 20 minutes, filter filtrate, strength of solution is determined in middle detection, by 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes, obtains injection liquid.
Embodiment 113
Figure BDA00003282545700622
Preparation technology: get water for injection 80mL, after adding main ingredient, N.F,USP MANNITOL, lactose, poloxamer and being stirred to dissolve, the Citric Acid that adds 1mol/L regulates PH to 7.0-9.0, mends and adds water to 100mL.Add 0.5g gac, under 30 ° of C, stir 20 minutes, de-charcoal, adopts filtering with microporous membrane degerming, filtrate is carried out packing by every 1ml, and pre-freeze is after 2 hours, freezing lower drying under reduced pressure 12 hours, to sample temperature after room temperature, dry 5 hours again, make white loose block, seal and get final product.
Embodiment 114
Figure BDA00003282545700623
Figure BDA00003282545700631
Preparation technology: main ingredient and auxiliary material are crossed respectively to 100 mesh sieves, fully mix, then take recipe quantity auxiliary material and fully mix with main ingredient.Add tackiness agent softwood processed, 14 mesh sieves are granulated again, and 55 ° of C are dry, and the whole grain of 12 mesh sieves is measured heavily packing of bag.
Embodiment 115
The high sugar of the high fat of normal SD rats was fed after one month, with the repeatedly abdominal injection modeling of streptozocin low dose (diabetes B model), and blood-sugar content before and after mensuration modeling.After modeling success, modeling rat is measured and body weight random packet (8/group) according to twenty-four-hour urine sugar, be respectively one group of blank group (giving equal-volume 0.5%CMC sodium solution) and some testing compound groups (6mg/kg).Fasting 16 hours before each group rat experiment.Gavage gives after experimental rat testing compound 0.5h, then gavage gives glucose (2g/kg).The urine of 0-12h time period after collection administration, with the urine sugar value of each time period of determination of glucose oxidase.The results are shown in following table 1.
The urine sugar value of each time period of determination of glucose oxidase for table 1
Figure BDA00003282545700632
Figure BDA00003282545700641
Figure BDA00003282545700651
Figure BDA00003282545700661
Above result shows, the compound with general formula I structure of the present invention has that to discharge ability than the compound glucose in urine that there is no deoxidation on corresponding sugar ring stronger.In the 6-of Compound I deoxidation series compound (seeing embodiment 1), the glucose in urine Excretion of the product I-D1-6 that embodiment 1 records is better than on two phenyl ring of its molecule right-hand member the analogue of other substituting groups combinations, and the substituting group combination optimum on two phenyl ring of the product I-D1-6 molecule right-hand member that the embodiment of the present invention 1 records be described.In the 4-deoxidation series compound of Compound I (seeing embodiment 2), the glucose in urine Excretion of the product I-D1-4 that embodiment 2 records is better than the analogue of other substituting groups combination on two phenyl ring of its molecule right-hand member, and the substituting group combination optimum on two phenyl ring of the product I-D1-4 molecule right-hand member that the embodiment of the present invention 2 records be described.In the 3-deoxidation series compound of Compound I (seeing embodiment 3), the glucose in urine Excretion of the product I-D1-3 that embodiment 3 records is better than the analogue of other substituting groups combination on two phenyl ring of its molecule right-hand member, and the substituting group combination optimum on two phenyl ring of the product I-D1-3 molecule right-hand member that the embodiment of the present invention 3 records be described.Equally, in the 2-deoxidation series compound of Compound I (seeing embodiment 4), the glucose in urine Excretion of the product I-D1-2 that embodiment 4 records is better than the analogue of other substituting groups combination on two phenyl ring of its molecule right-hand member, and the substituting group combination optimum on two phenyl ring of the product I-D1-2 molecule right-hand member that the embodiment of the present invention 4 records be described.
Embodiment 116
Mouse (18-20g), female, hero half and half, normally raised after 3 days, grouping (10 every group), fasting is after 12 hours, and gavage gives respectively the compound of single dose, dosage is 750mg/kg, observe to testing compound after behavior and death in one week.Situation is as shown in table 2 below.
Table 2 mouse give with testing compound after behavior and death condition in one week
Figure BDA00003282545700671
Figure BDA00003282545700681
Figure BDA00003282545700691
Above result shows, the compound with general formula I structure of the present invention has than not having the toxicity of compound of deoxidation less on corresponding sugar ring.
Embodiment 117
Some compound of the present invention and the related compound IC to SGLT2 and SGLT1 inhibition 50the similar method that value is recorded according to document is measured (Meng, W.et al, J.Med.Chem., 2008,51,1145-1149).Measurement result as shown in Listing 3.
The IC of some compound of table 3 to SGLT1 and SGLT2 50value
Above-mentioned IC 50measurement result show, on the molecule that the derivative that the 6-deoxidation polyglycoside molecule right-hand member take 1-D1-6 prepared in embodiment 1 as representative shown in above-mentioned contains oxyethyl group contains methoxyl group than correspondence position listed in table 3 and left side phenyl ring, correspondence position is the molecule of methyl: (1) is much better than aspect the inhibition of SGLT2; (2) to a little less than SGLT1 inhibition aspect many; (3) far better aspect the selectivity of SGLT1/SGLT2, illustrate that the substituting group combination on two phenyl ring of the product I-D1-6 molecule right-hand member that the embodiment of the present invention 1 records is optimum.

Claims (11)

1. there is compound or its pharmaceutically acceptable prodrug ester of general formula I structure:
Figure FDA00003282545600011
Wherein, X is selected from O and S;
R 1, R 2, R 3and R 4independently selected from H and OH, and R 1, R 2, R 3and R 4in at least one be H;
R 5be selected from H, C 1-3alkyl ,-OCH 3with-OC 2h 5;
R 6be selected from halogen and C 1-3alkyl;
R 7be selected from
Figure FDA00003282545600012
with
Figure FDA00003282545600013
wherein,
R 8be selected from C 1-3alkyl, C 1-3alkoxyl group and
Figure FDA00003282545600014
r 9be selected from halogen and C 1-3alkyl;
Optionally, X, adjacent with X two carbon and-CH 2-O-forms five-ring; Or form unsubstituted carbon adjacent with glycosidic bond carbon on two carbon, phenyl ring of glycosidic bond and-CH 2-O-forms five yuan of 15 ring.
2. compound or its pharmaceutically acceptable prodrug ester with general formula I structure according to claim 1, wherein, described in there is general formula I structure compound comprise I-A and I-B, wherein,
The general formula of described I-A is G1-G2, and wherein, G1 is selected from following two groups:
Figure FDA00003282545600015
Figure FDA00003282545600016
G2 is selected from following five groups:
Figure FDA00003282545600021
Figure FDA00003282545600022
Described I-B has lower array structure:
Figure FDA00003282545600023
Wherein, X is selected from O and S;
R 1, R 2, R 3and R 4definition be selected from following 15 kinds of situations:
(1)R 1=H,R 2=OH,R 3=OH,R 4=OH；
(2)R 1=OH,R 2=H,R 3=OH,R 4=OH；
(3)R 1=OH,R 2=OH,R 3=H,R 4=OH；
(4)R 1=OH,R 2=OH,R 3=OH,R 4=H；
(5)R 1=H,R 2=H,R 3=OH,R 4=OH；
(6)R 1=H,R 2=OH,R 3=H,R 4=OH；
(7)R 1=H,R 2=OH,R 3=OH,R 4=H；
(8)R 1=OH,R 2=H,R 3=H,R 4=OH；
(9)R 1=OH,R 2=H,R 3=OH,R 4=H；
(10)R 1=OH,R 2=OH,R 3=H,R 4=H；
(11)R 1=H,R 2=H,R 3=H,R 4=OH；
(12)R 1=H,R 2=H,R 3=OH,R 4=H；
(13)R 1=H,R 2=OH,R 3=H,R 4=H；
(14)R 1=OH,R 2=H,R 3=H,R 4=H；
(15)R 1=H,R 2=H,R 3=H,R 4=H。
3. compound or its pharmaceutically acceptable prodrug ester with general formula I structure according to claim 1 and 2, wherein, described in there is general formula I structure compound be the one in lower array structure:
Figure FDA00003282545600031
Figure FDA00003282545600041
Figure FDA00003282545600051
Figure FDA00003282545600061
4. according to the compound with general formula I structure described in any one in claims 1 to 3 or its pharmaceutically acceptable prodrug ester; wherein, described pharmaceutically acceptable prodrug ester comprises the ester that one or more hydroxyls in the compound molecule with general formula I structure and ethanoyl, pivaloyl group, phosphoryl, formamyl and/or alkoxyl formyl form.
5. prepare in claim 1 to 4 compound with general formula I structure described in any one or a method for its pharmaceutically acceptable prodrug ester, described method comprises and adopts the phenyl C-glucoside of not deoxidation that has same structure with target product as raw material,
In the time of phenyl C-glucoside that target product is full deoxidation, the method comprises: the hydroxyl on sugar ring is all converted into iodine with iodination reagent, then reduction removes sugared iodine in ring, thereby obtains target product;
In the time that target product is the phenyl C-glucoside of part deoxidation, the method comprises the steps:
(1) hydroxyl protection: use hydroxyl protection reagent to protect hydroxyl to be retained on sugar ring;
(2) dehydroxylation: hydroxyl to be removed on sugar ring is converted into iodine with iodination reagent, then reduction, thereby hydroxyl to be removed described in removing; With
(3) deprotection: remove the hydroxy-protective group in above-mentioned steps gained compound, thereby obtain target product.
6. method according to claim 5, wherein, described iodination reagent is I 2/ triphenylphosphine/imidazoles reagent.
7. according to the method described in claim 5 or 6, wherein, the method for the reduction in described step (2) is palladium catalyzed hydrogenation or uses n-Bu 3the reduction of SnH/AIBN reagent.
8. according to the method described in any one in claim 5 to 7; wherein, described hydroxyl protection reagent be selected from diacetyl oxide, Acetyl Chloride 98Min., t butyldimethylsilyl chloride (TBDMSCl), tert-butyl diphenyl silicon chlorides (TBDPSCl), Benzoyl chloride, to methyl benzoyl chloride, pivaloyl chloride, (dimethoxy methyl) benzene (PhCH (OMe) 2), phenylformic acid, 1,1,2, one or more in 2-tetramethoxy hexanaphthene/trimethyl orthoformate, chloroacetyl chloride and bromoacetyl chloride.
9. a pharmaceutical composition, comprises compound or its pharmaceutically acceptable prodrug ester with general formula I structure of the present invention, and one or more pharmaceutically acceptable carriers, vehicle or thinner.
10. the compound with general formula I structure described in any one or its pharmaceutically acceptable prodrug ester purposes in the medicine for the preparation of inhibition SGLT2 enzyme in claim 1 to 4.
The compound with general formula I structure in 11. claims 1 to 4 described in any one or its pharmaceutically acceptable prodrug ester purposes in the medicine for the preparation for the treatment of diabetes.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104098536A (en) * 2013-04-01 2014-10-15 天津药物研究院 Synthetic method of dideoxy C-glycosidic SGLT2 (sodium-dependent glucose cotransporter 2) inhibitor and intermediate product of preparation method
CN105294785A (en) * 2014-07-02 2016-02-03 上海阳帆医药科技有限公司 C-benzo five-membered heteroaromatic aryl glucoside derivative as well as preparation method and application thereof
US9340553B2 (en) 2014-05-19 2016-05-17 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
CN105732555A (en) * 2014-12-12 2016-07-06 天津药物研究院有限公司 Method for synthesizing 3-oxoglycoside SGLT2 inhibitor
CN106632222A (en) * 2015-11-04 2017-05-10 中国科学院大连化学物理研究所 Method for separating hydroxyl from polyhydric alcohol acetal formaldehyde through hydrogenation
CN108218928A (en) * 2016-12-13 2018-06-29 华润双鹤药业股份有限公司 Bicyclic derivatives of glucoside and its preparation method and application
CN112645915A (en) * 2021-01-13 2021-04-13 广州安岩仁医药科技有限公司 Synthetic method of SGLT2 inhibitor intermediate
CN115991702A (en) * 2021-12-09 2023-04-21 珠海市藤栢医药有限公司 Aryl C-glucoside derivative, preparation method and application thereof
WO2023104201A1 (en) * 2021-12-09 2023-06-15 珠海市藤栢医药有限公司 Aryl c-glucoside derivative, preparation method therefor and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092877A1 (en) * 2004-03-16 2005-10-06 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof
US20060009400A1 (en) * 2004-07-06 2006-01-12 Boehringer Ingelheim International Gmbh D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
US20070275907A1 (en) * 2006-05-23 2007-11-29 Yuanwei Chen Glucose transport inhibitors and methods of use
CN101103013A (en) * 2005-01-07 2008-01-09 大正制药株式会社 1-thio-D-glucitol derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092877A1 (en) * 2004-03-16 2005-10-06 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof
US20060009400A1 (en) * 2004-07-06 2006-01-12 Boehringer Ingelheim International Gmbh D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
CN101103013A (en) * 2005-01-07 2008-01-09 大正制药株式会社 1-thio-D-glucitol derivatives
US20070275907A1 (en) * 2006-05-23 2007-11-29 Yuanwei Chen Glucose transport inhibitors and methods of use

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
RALPH P. ROBINSON ET AL.: "C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization", 《BIOORG. MED. CHEM. LETT.》 *
RALPH P. ROBINSON ET AL.: "C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization", 《BIOORG. MED. CHEM. LETT.》, vol. 20, 21 January 2010 (2010-01-21), pages 1569 - 1572, XP026911306, DOI: doi:10.1016/j.bmcl.2010.01.075 *
万惠新 等.: "2 型糖尿病治疗靶点钠-葡萄糖共转运蛋白2 抑制剂研究进展", 《药学学报》 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104098536A (en) * 2013-04-01 2014-10-15 天津药物研究院 Synthetic method of dideoxy C-glycosidic SGLT2 (sodium-dependent glucose cotransporter 2) inhibitor and intermediate product of preparation method
US10039778B2 (en) 2014-05-19 2018-08-07 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US10813942B2 (en) 2014-05-19 2020-10-27 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US9617293B2 (en) 2014-05-19 2017-04-11 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US9340553B2 (en) 2014-05-19 2016-05-17 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US10376531B2 (en) 2014-05-19 2019-08-13 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
CN105294785A (en) * 2014-07-02 2016-02-03 上海阳帆医药科技有限公司 C-benzo five-membered heteroaromatic aryl glucoside derivative as well as preparation method and application thereof
CN105732555A (en) * 2014-12-12 2016-07-06 天津药物研究院有限公司 Method for synthesizing 3-oxoglycoside SGLT2 inhibitor
CN105732555B (en) * 2014-12-12 2018-05-01 天津药物研究院有限公司 A kind of method of synthesis 3- oxo glycoside SGLT2 inhibitors
CN106632222B (en) * 2015-11-04 2018-11-27 中国科学院大连化学物理研究所 A kind of polyalcohol formal adds the method for hydrogen dehydroxylation
CN106632222A (en) * 2015-11-04 2017-05-10 中国科学院大连化学物理研究所 Method for separating hydroxyl from polyhydric alcohol acetal formaldehyde through hydrogenation
CN108218928A (en) * 2016-12-13 2018-06-29 华润双鹤药业股份有限公司 Bicyclic derivatives of glucoside and its preparation method and application
CN108218928B (en) * 2016-12-13 2020-06-30 华润双鹤药业股份有限公司 Bicyclic derivatives of glucoside, preparation method and application thereof
CN112645915A (en) * 2021-01-13 2021-04-13 广州安岩仁医药科技有限公司 Synthetic method of SGLT2 inhibitor intermediate
CN115991702A (en) * 2021-12-09 2023-04-21 珠海市藤栢医药有限公司 Aryl C-glucoside derivative, preparation method and application thereof
WO2023104201A1 (en) * 2021-12-09 2023-06-15 珠海市藤栢医药有限公司 Aryl c-glucoside derivative, preparation method therefor and use thereof
CN115991702B (en) * 2021-12-09 2024-02-02 珠海市藤栢医药有限公司 Aryl C-glucoside derivative, preparation method and application thereof

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