CN101503399A - C-aryl glucoside SGLT2 inhibitor - Google Patents
C-aryl glucoside SGLT2 inhibitor Download PDFInfo
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- CN101503399A CN101503399A CNA2008101766807A CN200810176680A CN101503399A CN 101503399 A CN101503399 A CN 101503399A CN A2008101766807 A CNA2008101766807 A CN A2008101766807A CN 200810176680 A CN200810176680 A CN 200810176680A CN 101503399 A CN101503399 A CN 101503399A
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Abstract
The invention relates to a C-aryl glucoside derivative indicated by a general formula I, as well as a usage and a composition thereof. The C-aryl glucoside derivative has a good effect in inhibiting SGLT. The composition can be separately used or used together with other antidiabetic medicine or other therapeutic agent and can be used for preventing or curing diabetes and other relevant diseases.
Description
Technical field
The invention belongs to field of pharmacology, relate to class C-aryl glucoside derivative or its isomer, racemic modification, precursor or a pharmacy acceptable salt, and their purposes and composition.
Background technology
According to the data that the World Health Organization announces, nearly 1.5 hundred million people in the whole world suffer from diabetes.Type i diabetes (IDDM) and type ii diabetes (NIDDM) are two types the most basic in the diabetes, the former pathogenic characteristic is that pancreas can not excreting insulin, and the latter's pathogenic characteristic is the Regular Insulin relative deficiency due to the slow and insulin resistant of insulin secretion.Type ii diabetes is the most general one type, and nearly 90% diabetic subject belongs to this type.Hyperglycemia is considered to form the primary hazard factor of diabetic complication.The major complications of diabetes comprises retinal diseases, cardiovascular disorder, kidney disease, DPN, ulcer and foot pathology etc.
Type i diabetes generally adopts insulinize, though type ii diabetes can and be taken exercise and regulate by diet, pharmacological agent is normally requisite.The treatment type ii diabetes is except using Regular Insulin at present, also has some other alternative antidiabetic medicine, such as biguanides (reducing glycogen output and increase susceptibility), sulfonylurea and meglitinide (stimulating the generation of Regular Insulin), alpha-glucosidase inhibitor (reduction postprandial blood sugar) and thiazolidinediones (increasing susceptibility) to Regular Insulin to Regular Insulin.These Side effects of pharmaceutical drugs mainly comprise lactic acidosis (biguanides), hypoglycemia (sulfonylurea), oedema and weight increase (thiazolidinediones).Therefore wish to develop that make new advances, safe and orally active antidiabetic medicine,, and avoid occurring the relevant potential side effect of these medicines with additional existing therapy.
Kidney glucose transport system is a very promising target spot that can be used for therapeutic intervention diabetes and metabolism disorder thereof.The glucose transport of cell is finished by the glucose transporter (GLUTs) and the sodium dependent glucose transporter (SGLT) of facilitation diffusion.SGLT1 mainly is distributed in the brush border of small intestine, and SGLT2 is distributed in kidney cortex proximal tubule.Glucose heavily absorbing in kidney 90% betides in the epithelial cell of initial S1 section of kidney cortex proximal tubule, and SGLT2 is likely and is responsible for this re-absorbed main translocator.Nearest research prompting, thus the drainage that suppresses the SGLT increase glucose in urine of kidney is effective means (Arakawa K etc., Br J Pharmacol 132:578-86,2001 of treatment hyperglycemia; OkuA etc., Diabetes48:1794-1800,1999).Discover that thereby the SGLT2 transgenation that occurs in familial kidney glucose in urine patient causes sugar to be discharged from urine and makes glucose level normalizing, and the disorderly symptom relevant with other of renal function disappeared also.Therefore, can suppress SGLT particularly the compound of SGLT2 be very promising candidate antidiabetic medicine.
Although had at present at the compound that suppresses SGLT, yet also there are defectives such as activity is on the low side, effect is not enough in these compounds, so this area awaits to develop more effective compound.
Summary of the invention
The object of the present invention is to provide a class for suppressing SGLT very effective C-aryl glucoside derivative or its isomer, racemic modification, precursor or pharmacy acceptable salt, their purposes and pharmaceutical composition.
In a first aspect of the present invention, provide compound shown in a kind of general formula I or its isomer, racemic modification, precursor or pharmacy acceptable salt:
Wherein:
R
1Be selected from cyano group, aminocarbonyl, (C
1-3-alkylamino) carbonyl, two (C
1-3-alkyl) aminocarbonyl, C
3-7-cycloalkyl or C
5-7-cycloalkenyl group,
Wherein, described alkyl does not have and replaces or through fluorine list or polysubstituted, and described cycloalkyl, cycloalkenyl group do not have and replace or through being selected from fluorine, chlorine, hydroxyl, C
1-3-alkyl, C
1-3-alkoxyl group, C
1-3-alkane carbonyl oxygen base, amino, C
1-3-alkylamino or C
1-3The group list of-alkane carbonyl amino or polysubstituted, and
In described cycloalkyl, the cycloalkenyl group, one or two methylene radical does not have and replaces or through being selected from O, S, CO, SO, SO
2, NR
5Group replace;
R
2Be selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano group, nitro, C
1-6-alkyl, C
1-6-alkoxyl group, C
1-4-alkoxy-C
1-4-alkyl, C
1-4-alkoxy-C
1-4-alkoxyl group, C
2-6-alkene-1-base, C
2-4-thiazolinyl-C
1-4-alkyl, C
2-4-thiazolinyl-C
1-4-alkoxyl group, C
2-4-thiazolinyl oxygen-C
1-4-alkyl, C
2-4-thiazolinyl oxygen-C
2-4-alkoxyl group, C
2-6-alkynes-1-base, C
2-4-alkynyl-C
1-4-alkyl, C
2-4-alkynyloxy-C
1-4-alkyl, C
2-4-alkynyl-C
1-4-alkoxyl group, C
2-4-alkynyloxy-C
1-4-alkoxyl group, C
3-7-cycloalkyl, C
3-7-cycloalkyl-C
1-4-alkyl, C
3-7-cycloalkyloxy-C
1-4-alkyl, C
3-7-cycloalkyloxy, C
3-7-cycloalkyl-C
1-4-alkoxyl group, C
3-7-cycloalkyloxy-C
1-4-alkoxyl group, C
3-7-cycloalkenyl group, C
3-7-cycloalkenyl group-C
1-4-alkyl, C
3-7-cyclenes oxygen base-C
1-4-alkyl, C
3-7-cyclenes oxygen base, C
3-7-cycloalkenyl group-C
1-4-alkoxyl group, C
3-7-cyclenes oxygen base-C
1-4-alkoxyl group, aryl, heteroaryl, C
1-4-alkyl carbonyl, aromatic carbonyl, assorted aromatic carbonyl, aminocarbonyl, C
1-4-alkane aminocarbonyl, two-(C
1-3-alkyl) aminocarbonyl, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, piperazine-1-base carbonyl, 4-(C
1-4-alkyl) piperazine-1-base carbonyl, fragrant aminocarbonyl, assorted fragrant aminocarbonyl, C
1-4-carbalkoxy, aryl-C
1-3-carbalkoxy, heteroaryl-C
1-3-carbalkoxy, amino, C
1-4-alkylamino, two-(C
1-3-alkyl) amino, C
2-4-thiazolinyl-C
1-4-alkylamino, C
2-4-alkynyl-C
1-4-alkylamino, C
3-7-cycloalkyl-C
1-4-alkylamino, C
3-7-cycloalkenyl group-C
1-4-alkylamino, tetramethyleneimine-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4-base, piperazine-1-base, 4-(C
1-3-alkyl)-piperazine-1-base, C
1-4-alkane carbonyl amino, fragrant carbonyl amino, assorted fragrant carbonyl amino, C
3-7-cycloalkyloxy, C
5-7-cyclenes oxygen base, aryloxy, heteroaryloxy, C
1-4-alkyl sulfinyl, C
1-4-alkane alkylsulfonyl, C
3-7-cycloalkylthio, C
3-7-cycloalkanes sulfinyl, C
3-7-cycloalkanes alkylsulfonyl, C
3-7-cyclenes sulfenyl, C
3-7-cyclenes sulfinyl, C
3-7-cyclenes alkylsulfonyl, arylthio, fragrant sulfinyl, arylsulfonyl, heteroarylthio, assorted fragrant sulfinyl or assorted arylsulfonyl;
Wherein,
Described thiazolinyl, alkynyl do not have and replace or through identical or different fluorine, chlorine, hydroxyl, cyano group, nitro, C
3-7-cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, C
1-4-alkylthio, arylthio or heteroarylthio list or polysubstituted, and
Described alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, cycloalkenyl group, cyclenes oxygen base do not have and replace or through being selected from fluorine, chlorine, cyano group, hydroxyl, sulfydryl, C
1-3-alkoxyl group, C
1-3The group list of-alkyl or polysubstituted; And
In described cycloalkyl, cycloalkyloxy, cycloalkenyl group, cyclenes oxygen base, one or two methylene radical does not have and replaces or through being selected from O, S, CO, SO, SO
2Or NR
5Group replace;
R
3Be selected from hydrogen, fluorine, chlorine, bromine, cyano group, nitro, hydroxyl, C
1-6-alkyl, C
1-6-alkoxyl group, C
3-7-cycloalkyl, C
3-7-cycloalkyloxy or C
2-6-alkynyl,
Wherein, described alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy or alkynyl do not have and replace or through being selected from fluorine, chlorine, cyano group, hydroxyl, sulfydryl, C
1-3-alkoxyl group, C
1-3The group list of-alkyl or polysubstituted;
R
4Be selected from hydroxyl, hydrogen, fluorine, chlorine, bromine, cyano group, C
1-6-alkyl, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-7-cycloalkyl, C
5-7-cycloalkenyl group, amino, C
1-4-alkylamino, two-(C
1-3-alkyl) amino, C
1-4-alkane carbonyl amino, C
1-4-alkane sulfonamido, C
1-4-alkane sulfonamido, C
1-6-alkoxyl group, C
3-7-cycloalkyloxy, C
2-6-alkene oxygen base, C
2-6-alkynyloxy group, C
1-6-alkane carbonyl oxygen base, C
1-4-alkane sulfinyl oxygen base, C
1-4-alkane sulfonyloxy, sulfydryl, C
1-4-alkylthio, arylthio, arylamino, fragrant sulfonamido, aryl-sulphonamidic base, aryloxy, aryl sulfinyl oxygen base or aryl-sulfonyl oxygen,
Wherein, described alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group do not have and replace or through fluorine list or polysubstituted, or through being selected from chlorine, cyano group, hydroxyl, sulfydryl, C
1-3-alkoxyl group, C
1-3The group list of-alkyl or polysubstituted, and
In described cycloalkyl, the cycloalkenyl group, one or two methylene radical does not have and replaces or through being selected from O, S, CO, SO, SO
2, NR
5Group replace;
R
5Be selected from hydrogen, C
1-4-alkyl, C
1-4-alkyl carbonyl, C
1-4-alkyl sulfinyl or C
1-4-alkane alkylsulfonyl;
A is selected from O, S, SO, SO
2, NH or (CH
2)
n, wherein n is selected from 1,2 or 3;
In described group, aryl is selected from phenyl or naphthyl, and it is the group list of group or polysubstituted under identical or different being selected from independently: fluorine, chlorine, bromine, iodine, C
1-3-alkyl, the methyl, the C that replace through 1 to 3 fluorine atom
1-3-alkoxyl group, the methoxyl group or the cyano group that replace through 1 to 3 fluorine atom;
In described group, heteroaryl is selected from furyl, pyrryl, thienyl, pyridyl, indyl, benzofuryl, benzimidazole thiophanate phenyl, quinolyl, isoquinolyl, tetrazyl, or be selected from pyrryl, furyl, thienyl, pyridyl and wherein 1 or 2 methyne replace through nitrogen-atoms, or be selected from indyl, benzofuryl, benzimidazole thiophanate phenyl, quinolyl, isoquinolyl and wherein 1 to 3 methyne replace through nitrogen-atoms;
And described heteroaryl does not have replacement or the group list of organizing or polysubstituted under identical or different being selected from: fluorine, chlorine, bromine, iodine, C
1-3-alkyl, the methyl, the C that replace through 1 to 3 fluorine atom
1-3-alkoxyl group, the methoxyl group or the cyano group that replace through 1 to 3 fluorine atom.
In another preference, R
1Be selected from: C
3-7-cycloalkyl, C
5-7-cycloalkenyl group, cyano group, aminocarbonyl.Preferred, R
1It is cyclopropyl.
In another preference, R
4The methyl that is selected from hydroxyl, hydrogen, fluorine, chlorine, bromine, cyano group, methyl, ethyl, cyclopropyl, ethynyl, methoxyl group, oxyethyl group or replaces through 1 to 3 fluorine atom.
In another preference, R
2Be selected from: hydrogen, fluorine, chlorine, bromine, cyano group, nitro, hydroxyl, methyl, ethyl, cyclopropyl, ethynyl, methoxyl group, oxyethyl group, the methyl that replaces through 1 to 3 fluorine atom or the methoxyl group that replaces through 1 to 3 fluorine atom.
In another preference, R
3Be selected from: hydrogen, fluorine, chlorine, bromine, cyano group, nitro, hydroxyl, methyl, ethyl, cyclopropyl, ethynyl, methoxyl group, oxyethyl group, the methyl that replaces through 1 to 3 fluorine atom or the methoxyl group that replaces through 1 to 3 fluorine atom.
In another preference, A is selected from O, S or CH
2
In another preference, described compound is selected from:
Or
In another preference, described pharmacy acceptable salt is: the salt that compound shown in the general formula I and mineral acid or organic acid (comprising amino acid) produce.
In a second aspect of the present invention, the purposes of the arbitrary described compound in front is provided, be used to prepare the composition of treatment or prevent diabetes and relative disease.
In another preference, described composition also can suppress Na-dependent glucose transporter (SGLT).
In another preference, described inhibition Na-dependent glucose transporter is SGLT2.
In another preference, described composition also is used for prevention or treatment Mammals diabetes and diabetes relative disease.
In another preference, described diabetes relative disease comprises: retinopathy, neuropathy, ephrosis, retardance wound healing, insulin resistance, glucose homeostasis are impaired, hyperglycemia, hyperinsulinemia, the acid of hyperlipidemia fat or glycerine level, obesity, hyperlipidaemia, X syndromes, hypertension, atherosclerosis.
In a third aspect of the present invention, provide a kind of can treatment or the composition of prevent diabetes and relative disease, described composition comprises:
The arbitrary described compound in the front of significant quantity or its isomer, racemic modification, precursor or pharmacy acceptable salt or their mixture, and one or more bromatologies or pharmaceutically acceptable carrier or vehicle.
In another preference, described compound or its isomer, racemic modification, precursor or pharmacy acceptable salt or their mixture can suppress the composition of Na-dependent glucose transporter.
In another preference, also can comprise in the described composition: the antidiabetic medicine of non-Na-dependent glucose transporter inhibitor, diabetic complication medicine, anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine and/or blood lipid-lowering medicine.
In another preference, described antidiabetic medicine is selected from following one or more: N1,N1-Dimethylbiguanide, Glyburide, glimepiride, Glipizide, gliclazide, Glipyride, pioglitazone, troglitazone, Rosiglitazone, acarbose, miglitol, the sick urea of chlorine sulphur, nateglinide, repaglinide, Regular Insulin, AC2993, AJ9677, AR-HO39242, GI-262570, Isaglitazone, JTT-501, KAD1129, KRP297, LY315902, NN-2344, NVP-DPP-728A, R-119702 or YM-440.
On the other hand, also provide the method for a kind of treatment or prevent diabetes and relative disease, described method comprises: the arbitrary described compound in the front of the object significant quantity that needs.
Others of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Embodiment
The inventor is through long term studies and test, find that unexpectedly a class C-aryl glucoside derivative (formula I compound) has good effect in inhibiting SGLT, thereby can significantly promote the discharge of glucose in urine in the mammalian body, very effective for prevention or treatment diabetes and diabetic complication, finished the present invention on this basis.
Term used herein " alkyl " refers to aliphatic hydrocarbon group saturated, straight or branched.Described " alkoxyl group " refers to oxygen containing alkyl.For example, alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl." thiazolinyl " refers to contain the straight or branched alkyl of at least one carbon-carbon double bond and at least 2 carbon atoms (preferably 2-6 carbon atom); " alkynyl " refers to contain the straight chain and the branched hydrocarbyl of at least one carbon carbon triple bond and at least 2 carbon atoms (preferably 2-6 carbon atom).
Term used herein " halogen " refers to F, Cl, Br or I, particularly F, Cl or Br.
Term used herein " alkoxyl group " refers to oxygen containing alkyl, for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy etc.
Term used herein " alkyl carbonyl " refers to the alkyl that contains carbonyl, for example first carbonyl, B carbonyl, third carbonyl, positive fourth carbonyl, isobutyl carbonyl etc.
Term used herein " cycloalkyl " refers to the naphthene group with 3 to 7 carbon atoms, as cyclopropyl, cyclopentyl, cyclohexyl and suberyl etc.
The definition of term used herein " cycloalkenyl group " is as " cycloalkyl ", and contains at least one undersaturated carbon-carbon double bond.
Term used herein " aryl " refers to aromatic systems, can be monocycle or originally condensed or many aromatic rings of linking together, thereby at least a portion is condensed or the ring that connects forms conjugated virtue system.Aromatic yl group comprises (but being not restricted to): phenyl, naphthyl.
Term used herein " heterocycle " refers to stable 4-7 unit's monocycle or stable many rings heterocycle, this heterocycle can be saturated, part is undersaturated or undersaturated, and by carbon atom be selected from a following 1-4 heteroatoms and constitute: N, O and S atom.N and S atom can be oxidized.Heterocycle also can comprise any many rings, and wherein arbitrary above-mentioned heterocycle can condense in aromatic ring.
Term used herein " heteroaryl " is meant the heterocyclic aryl.
Term used herein " isomer " comprising: conformer, optical isomer (as enantiomer and diastereomer), geometrical isomer (as cis-trans-isomer).
Compound
The present invention at first provides a kind of compound shown in structural formula (I):
Wherein, R
1, R
2, R
3, R
4Definition with claim 1.
As optimal way of the present invention, R
1Be selected from: C
3-7-cycloalkyl, C
5-7-cycloalkenyl group, cyano group, aminocarbonyl.For example, R
1Be cyclopropyl, aminocarbonyl or cyano group.Preferred, R
1Be cyclopropyl or hydroxyl cyclopropyl.
As optimal way of the present invention, R
2Be selected from: hydrogen, fluorine, chlorine, bromine, cyano group, nitro, hydroxyl, methyl, ethyl, cyclopropyl, ethynyl, methoxyl group, oxyethyl group, the methyl that replaces through 1 to 3 fluorine atom or the methoxyl group that replaces through 1 to 3 fluorine atom.Preferred, R
2Be H.
As optimal way of the present invention, R
3Be selected from: hydrogen, fluorine, chlorine, bromine, cyano group, nitro, hydroxyl, methyl, ethyl, cyclopropyl, ethynyl, methoxyl group, oxyethyl group, the methyl that replaces through 1 to 3 fluorine atom or the methoxyl group that replaces through 1 to 3 fluorine atom.Preferred, R
3Be Cl.
As optimal way of the present invention, R
4The methyl that is selected from hydroxyl, hydrogen, fluorine, chlorine, bromine, cyano group, methyl, ethyl, cyclopropyl, ethynyl, methoxyl group, oxyethyl group or replaces through 1 to 3 fluorine atom.R for example
4Be hydroxyl or F.Preferred, R
4Be hydroxyl or fluorine.
Some preferred compounds of the present invention are for example:
The present invention also comprises isomer, racemic modification, pharmacy acceptable salt, hydrate or the precursor of above-claimed cpd.
Described " pharmacy acceptable salt " is meant the salt that reactions such as formula I compound and mineral acid, organic acid, basic metal or alkaline-earth metal generate.These salt include, but is not limited to: the salt that (1) and following mineral acid form: example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid; (2) salt that forms with following organic acid is as acetate, lactic acid, citric acid, succsinic acid, fumaric acid, gluconic acid, M-nitro benzoic acid, methanesulfonic, ethane sulfonic acid, Phenylsulfonic acid, tosic acid, oxalic acid, Succinic Acid, tartrate, toxilic acid or arginine.Other salt comprises the salt that forms with basic metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium), ammonium salt or water miscible amine salt (as N-methylglucosamine salt), rudimentary alkanol ammonium salt and other pharmaceutically acceptable amine salt are (such as methylamine salt, ethylamine salt, propylamine salt, dimethyl amine salt, trismethylamine salt, diethyl amine salt, triethyl amine salt, tert-butylamine salt, ethylenediamine salt, oxyethylamine salt, dihydroxy ethylamine salt, three oxyethylamine salt, or the form of " prodrug " of other routine and the amine salt that forms by morpholine, piperazine, Methionin respectively).Compound has one or more asymmetric centers.So these compounds can be used as racemic mixture, independent enantiomer, independent diastereomer, non-enantiomer mixture, cis or trans-isomer(ide) existence.
Described " precursor of compound " refers to after taking with appropriate means, and the precursor of this compound carries out metabolism or chemical reaction and is transformed into a kind of compound of structural formula I in the patient body, or the compound of chemical structural formula I salt or the solution formed.The precursor of compound is including, but not limited to forms such as the carboxylicesters of described compound, carbonic ether, phosphoric acid ester, nitric ether, sulfuric ester, sulfone ester, sulfoxide esters, aminocompound, carbaminate, azo-compound, phosphamide, glucoside, ether, acetals.
The preparation of compound
Those skilled in the art should understand, after the structure of cicada The compounds of this invention, can be by multiple method well known in the art, utilize known raw material, obtain compound of the present invention, such as chemosynthesis or the method extracted from plant, these methods all comprise in the present invention.Unless otherwise indicated or the preparation method is provided, prepare the used raw material of compound of the present invention or its intermediate and all be known in the art maybe can be by commercially available.
As optimal way of the present invention, can prepare compound of the present invention by following reaction process and description.
Flow process 1
Shown in flow process 1, at-78 ℃, formula V compound is handled in the mixed solvent of tetrahydrofuran (THF)/toluene with n-Butyl Lithium or tert-butyl lithium, adds lactone VI then, question response back fully adds methanesulfonic or dilute hydrochloric acid or tosic acid and methyl alcohol, and stirring spends the night obtains formula VII compound.The preparation reference literature R.Benhaddous of lactone VI, S.Czemecki etc., Carbohydr.Res., 1994,260,243-250.
At-30 ℃, with silane such as Et
3SiH or (iPr)
3SiH and Lewis acid are as BF
3.OEt
2In the mixed solvent of methylene dichloride/acetonitrile, handle formula VII compound, can preparation formula VIII compound.
At room temperature, in solvent such as methylene dichloride, handle formula VIII compound with pyridine or diisopropyl ethyl amine and acetic anhydride, can preparation formula IX compound.
Flow process 2
Shown in flow process 2, formula V compound can be by using silane such as Et
3SiH or (iPr)
3SiH handles formula IV compound in trifluoroacetic acid.
Formula IV compound can pass through conventional Friedel-Crafts prepared in reaction by formula II compound and formula III compound.
Flow process 3
Shown in flow process 3, work as R
1During for hydrogen, in solvent such as methylene dichloride, handle formula IXa compound with aluminum chloride and Acetyl Chloride 98Min. (AcCl), can preparation formula X compound.
In tetrahydrofuran solution, handle formula X compound with sodium borohydride and methyl alcohol, can preparation formula XI compound.
At 120 ℃, in toluene, handle formula XI compound with a hydration tosic acid, can obtain formula XII compound.
Handle formula XII compound with trifluoroacetic acid, zinc ethyl and methylene iodide, can preparation formula XIIIa compound.
In the mixed solvent of 2:3:1 tetrahydrofuran (THF)/methanol, handle formula XIIIa compound with a hydronium(ion) oxidation lithium, can preparation formula XIVa compound.
Various synthetic compounds can further be further purified by modes such as column chromatography, high performance liquid chromatography or crystallizations.Synthetic chemistry is transformed, protection functional group methodology (protect or go and protect) is helpful to synthetic application compound, and be technology commonly known in the art, as R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3
RdEd., all have among the John Wiley and Sons (1999) openly.
Purposes
New discovery based on the inventor, the invention provides the purposes of the compound shown in the formula I or its isomer, racemic modification, precursor or pharmacy acceptable salt, be used for the composition that preparation suppresses Na-dependent glucose transporter (SGLT), described inhibition Na-dependent glucose transporter is SGLT2 particularly; Perhaps, be used to prepare the composition of prevention or treatment Mammals diabetes or diabetes associated conditions; Perhaps, be used to prepare the composition that promotes that glucose in urine is discharged; Perhaps, be used to prepare the composition of prevention or treatment carbohydrate metabolism imbalance relative disease.
Described diabetes comprise: type i diabetes or type ii diabetes.
Described diabetes associated conditions includes, but is not limited to: retinopathy, neuropathy, ephrosis, retardance wound healing, insulin resistance, glucose homeostasis are impaired, impaired glucose tolerance, hyperglycemia, hyperinsulinemia, the acid of hyperlipidemia fat or glycerine level (comprising hypertriglyceridemia), obesity, hyperlipidaemia, fatty liver, hyperuricemia, X syndromes (claiming metabolic syndrome again), hypertension, atherosclerosis, gout, hypercholesterolemia.The common feature of these illnesss all is that sugar, fat and/or proteinic metabolism are not normal.
Composition
As used herein, term " composition of the present invention " includes, but is not limited to: pharmaceutical composition, dietary supplement, Halth-care composition, as long as they contain formula I compound of the present invention (C-aryl glucoside derivative), as for suppressing effectively activeconstituents of SGLT (particularly SGLT2), or as for prevention or treatment Mammals diabetes or the effective activeconstituents of diabetic complication.
The present invention also provides a kind of composition, contains: (a) compound shown in the formula I of significant quantity or its isomer, racemic modification, precursor or pharmacy acceptable salt or their mixture; (b) bromatology or pharmaceutically acceptable carrier or vehicle.
Among the present invention, term " contains " the various compositions of expression and can be applied to together in mixture of the present invention or the composition.Therefore, term " mainly by ... form " and " by ... composition " be included in during term " contains ".
Among the present invention, " bromatology or pharmaceutically acceptable " composition is to be applicable to people and/or animal and not have the material that excessive bad side reaction (as toxicity, stimulation and transformation reactions) promptly has rational benefit/risk ratio.
Among the present invention, " pharmaceutically acceptable carrier " or " acceptable carrier on the bromatology " is acceptable solvent, suspension agent or the vehicle pharmaceutically or on the food that is used for compound of the present invention, its isomer, racemic modification, precursor or pharmacy acceptable salt or their mixture are sent to the animal or human.Carrier can be a liquid or solid.
The formulation of composition of the present invention can be diversified, all is fine so long as can make activeconstituents arrive the intravital formulation of Mammals effectively.Such as being selected from: tablet, capsule, powder, particle, syrup, solution, suspension or aerosol.Wherein this compounds may reside in suitable solid or liquid support or the diluent.
Described compound or composition can be by oral and intravenously, intramuscular or administrations such as subcutaneous.From being easy to prepare the position with administration, preferred pharmaceutical composition is a solid-state composition, and especially tablet and solid are filled or the capsule of liquid filling.The oral administration of pharmaceutical composition is preferred.And can be with following form oral administration: agent, capsule, dispersible powder, particle or suspension (containing 0.05-5% suspension agent according to appointment), syrup (containing 10-50% sugar according to appointment) and elixir (containing 20-50% ethanol according to appointment), perhaps carry out the parenteral administration with sterile injectable solution or form of suspension (containing the 0.05-5% suspension agent of having an appointment in the medium waiting to ooze).For example, these pharmaceutical preparations can contain and the about 1-50% of carrier blended (weight), are about the activeconstituents of 2-40% (weight) usually.
The medicament forms that is adapted to inject comprises: aseptic aqueous solution or dispersion liquid and aseptic powder (being used for preparing aseptic injectable solution or dispersion liquid) temporarily.In all situations, these forms must be aseptic and must be that fluid is discharged fluid to be easy to syringe.Under manufacturing and condition of storage must be stable, and must be able to prevent the pollution effect of microorganism (as bacterium and fungi).Carrier can be solvent or dispersion medium, wherein contains just like water, alcohol (as glycerine, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetables oil.
As optimal way of the present invention, described composition contains compound, its isomer, racemic modification, precursor or pharmacy acceptable salt or their mixture shown in the formula I of 1-200 weight part; And the pharmaceutically acceptable carrier or the vehicle of 10-5000 weight part.Preferably, described composition contains compound, its isomer, racemic modification, precursor or pharmacy acceptable salt or their mixture shown in the formula I of 5-150 weight part; And the pharmaceutically acceptable carrier or the vehicle of 30-2000 weight part.
Compound of the present invention or its composition also can be stored in the disinfector that is suitable for injecting or instils.In pharmaceutical composition of the present invention, activeconstituents accounts for the 1-50% (preferably 2-40%, more preferably 3-30%) of gross weight usually, and all the other are materials such as pharmaceutically acceptable carrier and other additive.
The present invention also provides the method for a kind of SGLT of inhibition and/or prevention or treatment diabetes or diabetic complication, and described method comprises: the described compound of the object significant quantity that needs.
Effective application dosage of used activeconstituents can change with the severity of the pattern of used compound, administration and disease to be treated.Yet, when compound of the present invention every day gives with the dosage of about 0.01-500mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 1-3 time every day, or with the slowly-releasing form administration.For most of large mammal, the total dose of every day is about 0.5-6000mg, preferably is about 10-1000mg.Be applicable to dosage form for oral administration, comprise and the solid-state or intimately mixed active compound of liquid carrier.Can regulate this dosage replys so that optimal treatment to be provided.For example, by an urgent demand of treatment situation, but give the dosage that several times separate every day, or dosage is reduced pari passu.
Composition of the present invention can also with other one or more for preventing and treating diabetes or diabetes associated conditions effective substance combined utilization.For example, also can contain in the described composition: the medicine that is selected from following one or more: antidiabetic medicine, fat-reducing medicament, slimming medicine, antihypertensive drug, Antiatherosclerosis medicine or anticoagulation medicine.When two kinds or two or more medication combined administration, generally have and be better than individually dosed respectively effect.
Usually, the part by weight of compound of the present invention and these auxiliary medicaments is at 1:100-100:1; Preferable at 1:50-50:1; Better for 1:10-10:1; For example can be 1:5-5:1 or 1:2-2:1 or 1:1-1:1 etc.
Major advantage of the present invention is:
Found the new purposes of compound shown in the formula I aspect treatment diabetes and diabetes associated conditions unexpectedly, it can have fabulous prospect in medicine by suppressing SGLT, promoting that ejecting of glucose in urine brought into play the good curing effect in the mammalian body.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
The preparation of embodiment 1 midbody compound
1. prepare (2-chloro-5-bromo-phenyl)-(phenyl)-ketone
Under the room temperature, with 41mL (477mmol) oxalyl chloride and 0.64mL N, dinethylformamide joins 100g (425mmol) 2-chloro-5-bromo-benzoic acid and is dissolved in the dichloromethane solution of 300mL.This mixing solutions at room temperature stirs and spends the night, and all volatile components are removed in underpressure distillation then.The solid residue of gained is dissolved in the 100mL methylene dichloride again, and this solution is cooled to-5 ℃, and adds 76mL (850mmol) benzene.Add 62.4g (468mmol) aluminum chloride then in batches.Reaction mixture stirred 10 minutes at-3 ℃, slowly rose to room temperature then, and at room temperature continued to stir 1 hour.This reaction mixture is poured in the beaker that fills ice, separated organic phase, the water dichloromethane extraction of 100mL * 3.The organic phase that merges is washed once with the dilute hydrochloric acid solution of 150mL 1M, with the 100mL washing once, washes once with the sodium hydroxide solution of 150mL1M, at last with the washing of 150mL saturated common salt once.Use anhydrous sodium sulfate drying then, underpressure distillation removes to desolvate and obtains oily matter, and this oily matter is not purified to be directly used in next step reaction.
Get crude product 124.2g (yield theoretical value 99%).
1H NMR(400MHz，CDCl3)δ 7.80(dd，J＝8.0，1.0Hz，2H)，7.63(t，J＝7.4Hz，1H)，7.56(dd，J＝8.4，2.4Hz，1H)，7.51-7.46(m，3H)，7.33(d，J＝8.4Hz，1H)；
LC-MS(ESI)：m/z＝295/297/299(Br+Cl)[M+H]
+。
2. prepare 1-chloro-2-benzyl-4-bromobenzene
The solution that 124.2g (420mmol) (2-chloro-5-bromo-phenyl)-(phenyl)-ketone is dissolved in the 210mL trifluoroacetic acid is cooled to 0 ℃, adds 147mL (924mmol) triethyl silicane, slowly drips the 1.9mL trifluoromethane sulfonic acid then in this mixture.Finish and remove ice bath, temperature of reaction rises to 50 ℃ and stirred 6 hours under this temperature, be cooled to stirred overnight at room temperature then.Volatile matter is removed in underpressure distillation, adds saturated sodium bicarbonate solution then while stirring until being alkalescence in this residual mixture.In this mixture, add ethyl acetate, separate organic phase, water ethyl acetate extraction 3 times.Organic phase difference water that merges and saturated common salt water washing are once used anhydrous sodium sulfate drying then.Desolventize 40 ℃ of following underpressure distillation, remove high boiling substance triethyl silicon ether 120 ℃ of following underpressure distillation then.The colorless oil that obtains is not purified to be directly used in next step reaction.
Get crude product 116g (yield theoretical value 98%).
1H NMR(400MHz，CDCl3)δ 7.33-7.23(m，6H)，7.18(d，J＝6.8Hz，2H)，4.06(s，2H)。
3. prepare 2,3,4,6-four-O-(TMS)-D-Glucopyranose ketone
With 27g (0.152mol) D-glucose-1, the 270mL tetrahydrofuran solution of 5-lactone and 134mL (1.39mol) N-methylmorpholine is cooled to-5 ℃.Drip 116mL (0.916mol) trimethylchlorosilane then, the temperature of control reaction soln is no more than 5 ℃.Reaction soln was risen to stirring at room 1 hour, rise to 35 ℃ then and stirred 5 hours, and then at room temperature stir and spend the night.After in reaction flask, adding 400mL toluene,, drip 790mL water inwards, make temperature be no more than 10 ℃ with the ice bath cooling.Separate organic phase, and use saturated sodium dihydrogen phosphate respectively, water and saturated common salt water washing are once.Underpressure distillation removes desolvates, resistates be dissolved in the toluene of 50mL and once more underpressure distillation remove and desolvate, repeat once so again.
Get product 50g (yield theoretical value 71%, purity is about 98%).
GC-MS(ESI)：m/z＝467[M+H]
+。
4. prepare 1-chloro-2-benzyl-4-(1-methoxyl group-D-Glucopyranose-1-yl)-benzene
17.5mL anhydrous tetrahydro furan/toluene (2:1) solution of 2g (7.1mmol) 1-chloro-2-benzyl-4-bromobenzene is cooled to-78 ℃ under argon atmospher.The hexane solution that slowly adds the n-Butyl Lithium of 3mL 2.5M (7.5mmol) in this solution adds the back and continues to stir 30 minutes at-78 ℃.In this reaction soln, slowly drip the 3.59g (7.7mmol) 2,3,4 that is cooled to-78 ℃, the 17.5mL anhydrous toluene solution of 6-four-O-(TMS)-D-Glucopyranose ketone by feed hopper then.Reaction solution after 50 minutes, drips the 16mL methanol solution of 1.7g (17.7mmol) methanesulfonic-78 ℃ of stirrings inwards under this temperature.Add recession and rose to stirring at room 22 hours except that refrigerating unit.With saturated sodium bicarbonate solution cancellation reaction, organic solvent is removed in underpressure distillation then.The residual aqueous solution is with ethyl acetate extraction 3 times, and the organic phase of merging is used anhydrous sodium sulfate drying after with saturated common salt water washing once.Underpressure distillation removes desolvates, and the residue that obtains is not purified to be directly used in next step reaction.
Get crude product 1.68g (yield theoretical value 60%).
LC-MS(ESI)：m/z＝363/365(Cl)[M-MeOH+H]
+，412/414(Cl)[M+NH
4]
+，439/441(Cl)[M+HCO
2]
-。
5. prepare 1-chloro-2-benzyl-4-(β-D-Glucopyranose-1-yl)-benzene
The solution that the above-mentioned 1.65g that obtains (4.2mmol) 1-chloro-2-benzyl-4-(1-methoxyl group-D-Glucopyranose-1-yl)-benzene and 1.47mL triethyl silicane (9.2mmol) is dissolved in 18mL methylene dichloride/acetonitrile (1:1) is cooled to-30 ℃ under argon atmospher.In this mixture, slowly drip 0.79mL (6.2mmol) boron trifluoride ether solution., react after 4 hours-30 ℃ of stirrings with the saturated sodium bicarbonate cancellation.Reaction mixture is with ethyl acetate extraction 3 times, the organic phase of merging with saturated common salt water washing 1 time after anhydrous sodium sulfate drying.Underpressure distillation removes and desolvates, and the residue that obtains is through silica gel purification (5:1 petrol ether/ethyl acetate-100% ethyl acetate).
Get product 1.36g (yield theoretical value 89%).
1H NMR(400MHz，CDCl3)δ 7.38-7.36(m，2H)，7.32-7.15(m，6H)，4.15(d，J＝15.4Hz，1H)，4.11(d，J＝9.6Hz，1H)，4.09(d，J＝15.4Hz，1H)，3.89(d，J＝12.0Hz，1H)，3.72-3.68(m，1H)，3.49-3.40(m，3H)，3.3(t，J＝9.2Hz，1H)；
LC-MS(ESI)：m/z＝365/367(Cl)[M+H]
+，382/384(Cl)[M+NH
4]
+，409/411(Cl)[M+HCO
2]
-。
6. prepare 1-chloro-2-benzyl-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene
In the 15mL dichloromethane solution of 1.09g (3mmol) 1-chloro-2-benzyl-4-(β-D-Glucopyranose-1-yl)-benzene, add 2.4mL (30mmol) pyridine and 2.8mL (30mmol) acetic anhydride successively, add 36.5mg (0.3mmol) N at last, N-dimethyl amine pyridine.After this reaction soln at room temperature stirs 2 hours, add the dilution of 50mL methylene dichloride.Solution after the dilution is with 1M hydrochloric acid soln washing 2 times, uses anhydrous sodium sulfate drying after the saturated common salt water washing 1 time.Underpressure distillation removes desolvates, and the residue that obtains is not purified to be directly used in next step reaction.
Get crude product 1.2g (yield theoretical value 75%).
LC-MS(ESI)：m/z＝533/535(Cl)[M+H]
+，550/552(Cl)[M+NH
4]
+。
7. prepare 1-chloro-2-(4-ethanoyl benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene
With the above-mentioned 1.1g that obtains (2.1mmol) 1-chloro-2-benzyl-4-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-the 10mL dichloromethane solution of benzene and 0.88mL (12.4mmol) Acetyl Chloride 98Min. cools off with ice bath, adds 413mg (3.1mmol) aluminum chloride then inwards in batches.Reaction solution rises to stirring at room after about 3 hours, again with adding 964mg (7.2mmol) aluminum chloride after the ice bath cooling.Continuation stirring reaction in 70 minutes finishes after rising to room temperature.Reaction solution is poured cancellation in the frozen water into, mixed solution dichloromethane extraction 3 times, and the organic phase of the merging dilute hydrochloric acid solution of 1M, water, the sodium hydroxide solution of 1M, saturated aqueous common salt is respectively washed once.Use anhydrous sodium sulfate drying then, underpressure distillation removes desolvates, and the residue that obtains is not purified to be directly used in next step reaction.
Get crude product 1.1g (yield theoretical value 93%).
1H NMR(400MHz，CDCl3)δ 7.90(d，J＝8.0Hz，2H)，7.39(d，J＝8.4Hz，1H)，7.26(d，J＝8.4Hz，2H)，7.22(dd，J＝8.4，2.2Hz，1H)，7.17(d，J＝2.0Hz，1H)，5.31(t，J＝9.4Hz，1H)，5.22(t，J＝9.8Hz，1H)，5.09(t，J＝9.4Hz，1H)，4.35(d，J＝10.0Hz，1H)，4.29(dd，J＝12.4，4.8Hz，1H)，4.18-4.13(m，3H)，3.85-3.81(m，1H)，2.60(s，3H)，2.09(s，3H)，2.07(s，3H)，2.01(s，3H)，1.75(s，3H)；
LC-MS(ESI)：m/z＝575/577(Cl)[M+H]
+，619/621(Cl)[M+HCO
2]
-。
8. prepare 1-chloro-2-[4-(2-hydroxyethyl)-benzyl]-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene
With the above-mentioned 240mg that obtains (0.42mmol) 1-chloro-2-(4-ethanoyl benzyl)-4-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-the 2.5mL tetrahydrofuran solution of benzene and 39mg (1.03mmol) sodium borohydride cools off with ice bath, slowly drips 0.1mL methyl alcohol in this mixture.Add the back and after 2 hours, drip saturated ammonium chloride solution cancellation reaction at 0～5 ℃ of stir about.Reaction mixture is with ethyl acetate extraction 3 times, after anhydrous sodium sulfate drying, underpressure distillation removes and desolvates the organic phase of merging with saturated common salt water washing 1 time, and the residue that obtains is not purified to be directly used in next step reaction.
Get crude product 235mg (yield theoretical value 98%).
LC-MS(ESI)：m/z＝594/596(Cl)[M+NH
4]
+，621/623(Cl)[M+HCO
2]
-。
9. prepare 1-chloro-2-(4-vinyl benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene
With the above-mentioned 235mg that obtains (0.41mmol) 1-chloro-2-[4-(2-hydroxyethyl)-benzyl]-4-(2; 3; 4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-the 5mL toluene solution of benzene and 7.7mg (0.04mmol) hydration tosic acid refluxed 70 minutes at 120 ℃.Concentrating under reduced pressure, the residue that obtains thin-layer silicon offset plate purifying (4:1 petrol ether/ethyl acetate).
Get product 193mg (yield theoretical value 85%).
LC-MS(ESI)：m/z＝559/521(Cl)[M+H]
+，576/578(Cl)[M+NH
4]
+。
10. prepare 1-chloro-2-(4-cyclopropyl benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene
The hexane solution of 0.7mL1M (0.7mmol) zinc ethyl is dissolved in the 0.5mL methylene dichloride, and this solution is cooled to 0 ℃ in argon atmospher.The 0.3mL dichloromethane solution of slow Dropwise 5 0uL (0.67mmol) trifluoroacetic acid in this solution.After 30 minutes, add the 0.3mL dichloromethane solution of 56uL (0.69mmol) methylene iodide at 0 ℃ of stir about.Continue to stir after 30 minutes, add the 0.8mL dichloromethane solution of 114mg (0.2mmol) 1-chloro-2-(4-vinyl benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene.At room temperature stirred after adding 24 hours, and added saturated sodium bicarbonate solution cancellation reaction.Reaction mixture is with dichloromethane extraction 3 times, after anhydrous sodium sulfate drying, underpressure distillation removes and desolvates the organic phase of merging with the saturated common salt water washing, and the residue that obtains is not purified to be directly used in next step reaction.
Get crude product 105mg (yield theoretical value 90%).
LC-MS(ESI)：m/z＝573/575(Cl)[M+H]
+，590/592(Cl)[M+NH
4]
+。
11. preparation 1-chloro-2-(4-carboxyl benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene
With the above-mentioned 103mg that obtains (0.18mmol) 1-chloro-2-(4-ethanoyl benzyl)-4-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene; 3.2mg the mixture of the 1mL acetate of 50% (0.0089mmol) manganous nitrate and 2.6mg (0.0089mmol) Cobaltous nitrate hexahydrate, under the 1atm oxygen atmosphere 100 ℃ of stir abouts 6.5 hours.Reaction solution concentrates the back and adds ethyl acetate, washes with water then 2 times, and saturated sodium bicarbonate is washed 1 time, and saturated common salt washing 1 time is after anhydrous sodium sulfate drying, and underpressure distillation removes and desolvates, and the residue that obtains is not purified to be directly used in next step reaction.
Get crude product: 103mg (yield theoretical value 100%).
LC-MS(ESI)：m/z＝577/579(Cl)[M+H]
+，575/577(Cl)[M-H]
-。
12. preparation 1-chloro-2-(4-carboxyl benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene
With the above-mentioned 83mg that obtains (0.14mmol) 1-chloro-2-(4-carboxyl benzyl)-4-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-solution of the 2mL 2:3:1 tetrahydrofuran (THF)/methanol of benzene and 9.3mg (0.22mmol) hydronium(ion) oxidation lithium at room temperature stirs and spends the night; concentrate then; use ethyl acetate extraction 3 times after adding entry; the organic phase that merges is washed 1 time after anhydrous sodium sulfate drying with saturated ammonium chloride; underpressure distillation removes desolvates, and the residue that obtains is not purified to be directly used in next step reaction.
Get crude product: 53mg (yield theoretical value 90%).
LC-MS(ESI)：m/z＝409/411(Cl)[M+H]
+，407/409(Cl)[M-H]
-。
13. preparation 1-chloro-2-(4-methoxycarbonyl benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene
After the 1mL methanol solution of the above-mentioned 53mg that obtains (0.13mmol) 1-chloro-2-(4-carboxyl benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene and 38mg (0.32mmol) thionyl chloride refluxed 140 minutes, use the saturated sodium bicarbonate solution cancellation.Concentrating under reduced pressure is removed volatile solvent, ethyl acetate extraction 3 times of remaining water layer, the organic phase that merges is washed 1 time after anhydrous sodium sulfate drying with saturated sodium-chloride, underpressure distillation removes and desolvates, and the residue that obtains is with preparing thin layer plate separation and purification (the 10:1 ethyl acetate/methanol is made developping agent).
Get product: 16mg (yield theoretical value 29%).
LC-MS(ESI)：m/z＝423/425(Cl)[M+H]
+，467/469(Cl)[M+HCO
2]
-。
14. preparation 1-chloro-2-(4-aminocarbonyl benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene
To the above-mentioned 103mg that obtains (0.18mmol) 1-chloro-2-(4-carboxyl benzyl)-4-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-drip the N of catalytic amount in the 1mL dichloromethane solution of benzene and 0.14mL (1.6mmol) oxalyl chloride; dinethylformamide, this reaction solution at room temperature stirred 5 hours.All volatile components are removed in underpressure distillation.The solid residue of gained is dissolved in the 2mL methylene dichloride again, and is cooled to-78 ℃.In this solution, add 1mL liquefied ammonia, slowly rise to stirred overnight at room temperature then.Concentrating under reduced pressure, the solid residue that obtains is not purified to be directly used in next step reaction.
Get crude product: 87mg (yield theoretical value 84%).
LC-MS(ESI)：m/z＝576/578(Cl)[M+H]
+，620/622(Cl)[M+HCO
2]
-.
15.1-chloro-2-(4-cyano group benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene
0.5mL N, dinethylformamide are cooled to 0 ℃ under argon atmospher, drip 33uL (0.45mmol) thionyl chloride then.Behind the stir about 10 minutes, in reaction solution, drip the 1.1mL N of 86mg (0.15mmol) 1-chloro-2-(4-aminocarbonyl benzyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-benzene, the solution of dinethylformamide.Add the back and continue to stir 7.5 hours, then with saturated sodium bicarbonate solution cancellation reaction at 0 ℃.Mixture is with ethyl acetate extraction 3 times, and water and saturated aqueous common salt are respectively washed 1 time after anhydrous sodium sulfate drying then, and underpressure distillation removes and desolvates, and the solid residue that obtains is not purified to be directly used in next step reaction.
Get crude product: 82mg (yield theoretical value 95%).
LC-MS(ESI)：m/z＝575/577(Cl)[M+NH
4]
+，602/604(Cl)[M+HCO
2]
-。
The preparation of embodiment 2 end products
1. prepare 1-chloro-2-(4-cyclopropyl benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene (compd A)
With the above-mentioned 105mg that obtains (0.18mmol) 1-chloro-2-(4-cyclopropyl benzyl)-4-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-solution of the 1mL 2:3:1 tetrahydrofuran (THF)/methanol of benzene and 4.7mg (0.11mmol) hydronium(ion) oxidation lithium at room temperature stirred 2 hours; concentrate then, the residue that obtains is with preparing the HPLC purifying.
Get product: 38mg (yield theoretical value 51%).
1H NMR(400MHz，CDCl3)δ 7.33(d，J＝8.0Hz，1H)，7.31(d，J＝2.0Hz，1H)，7.26(dd，J＝8.4，2.4Hz，1H)，7.05(d，J＝8.0Hz，2H)，6.94(d，J＝8.0Hz，2H)，4.08(d，J＝9.2Hz，1H)，4.06(d，J＝14.8Hz，1H)，4.00(d，J＝14.8Hz，1H)，3.86(dd，J＝12.0，1.6Hz，1H)，3.68(dd，J＝11.6，5.2Hz，1H)，3.47-3.37(m，3H)，3.28(t，J＝8.4Hz，1H)，1.85-1.80(m，1H)，0.92-0.87(m，2H)，0.62-0.58(m，2H)；
LC-MS(ESI)：m/z＝405/407(Cl)[M+H]
+，422/424(Cl)[M+NH
4]
+，449/451(Cl)[M+HCO
2]
-。
2. prepare 1-chloro-2-(4-cyclopropyl benzyl)-4-(6-deoxidation-6-fluoro-beta-D-Glucopyranose-1-yl)-benzene (compd B)
25mg (0.062mmol) 1-chloro-2-(4-cyclopropyl benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene is dissolved in the 1mL methylene dichloride, and this solution is cooled to-78 ℃ in argon atmospher.In this solution, drip 49uL diethylaminosulfurtrifluoride (0.37mmol) then, allow this reaction mixture slowly rise to room temperature and stir and spend the night.The saturated sodium bicarbonate solution cancellation use in reaction, uses ethyl acetate extraction then 3 times, after anhydrous sodium sulfate drying, underpressure distillation removes and desolvates the organic phase of merging with saturated common salt washing 1 time, and the residue that obtains is with preparing the HPLC purifying.
Get product: 10.5mg (yield theoretical value 42%).
1H NMR(400MHz，CDCl3)δ 7.35(d，J＝8.0Hz，1H)，7.27-7.22(m，2H)，7.05(d，J＝8.0Hz，2H)，6.95(d，J＝8.0Hz，2H)，4.69-4.63(m，1H)，4.57-4.51(m，1H)，4.09(d，J＝9.2Hz，1H)，4.06(d，J＝14.8Hz，1H)，4.00(d，J＝14.8Hz，1H)，3.53-3.43(m，3H)，3.28-3.24(m，1H)，1.86-1.82(m，1H)，0.92-0.88(m，2H)，0.63-0.59(m，2H)；
LC-MS(ESI)：m/z＝424/426(Cl)[M+NH
4]
+，451/453(Cl)[M+HCO
2]
-。
3.1-chloro-2-(4-aminocarbonyl benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene (Compound C)
With the above-mentioned 34mg that obtains (0.059mmol) 1-chloro-2-(4-aminocarbonyl benzyl)-4-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-solution of the 0.5mL 2:3:1 tetrahydrofuran (THF)/methanol of benzene and 2.3mg (0.055mmol) hydronium(ion) oxidation lithium at room temperature stirred 3 hours; concentrate then, the residue that obtains is with preparing the HPLC purifying.
Get product: 9.6mg (yield theoretical value 40%).
1H NMR(400MHz，CDCl3)δ 7.79(d，J＝8.8Hz，2H)，7.40(d，J＝1.2Hz，1H)，7.38(d，J＝8.4Hz，1H)，7.33(dd，J＝8.4，1.6Hz，1H)，7.31(d，J＝8.0Hz，2H)，4.21(d，J＝15.6Hz，1H)，4.16(d，J＝15.6Hz，1H)，4.13(d，J＝9.6Hz，1H)，3.89(dd，J＝12.4，2.0Hz，1H)，3.73-3.69(m，1H)，3.49-3.39(m，3H)，3.29(t，J＝8.4Hz，1H)；
LC-MS(ESI)：m/z＝408/410(Cl)[M+H]
+，406/408(Cl)[M-H]
-，452/454(Cl)[M+HCO
2]
-。
4.1-chloro-2-(4-cyano group benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene (Compound D)
With the above-mentioned 90mg that obtains (0.16mmol) 1-chloro-2-(4-cyano group benzyl)-4-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-solution of the 1mL 2:3:1 tetrahydrofuran (THF)/methanol of benzene and 4.7mg (0.11mmol) hydronium(ion) oxidation lithium at room temperature stirred 4 hours; concentrate then, the residue that obtains is with preparing the HPLC purifying.
Get product: 28mg (yield theoretical value 45%).
1H NMR(400MHz，CDCl3)δ 7.63(d，J＝8.0Hz，2H)，7.42(d，J＝2.0Hz，1H)，7.39(d，J＝8.0Hz，3H)，7.35(dd，J＝8.0，2.0Hz，1H)，4.23(d，J＝15.4Hz，1H)，4.19(d，J＝15.4Hz，1H)，4.14(d，J＝9.6Hz，1H)，3.89(d，J＝12.8Hz，1H)，3.71(dd，J＝12.0，5.2Hz，1H)，3.50-3.40(m，3H)，3.29(t，J＝8.4Hz，1H)；
LC-MS(ESI)：m/z＝390/392(Cl)[M+H]
+，407/409(Cl)[M+NH
4]
+，434/436(Cl)[M+HCO
2]
-。
5.1-chloro-2-[4-(1-hydroxyl cyclopropyl)] benzyl-4-(β-D-Glucopyranose-1-yl)-benzene (compd E)
16mg (0.038mmol) 1-chloro-2-(4-methoxycarbonyl benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene and 34uL (0.11mmol) tetraisopropoxy titanium are dissolved in the tetrahydrofuran (THF) of 0.5mL, and this solution is cooled to 0 ℃ in argon atmospher.In solution, drip the freshly prepd ethylmagnesium bromide of 0.3mL (1M is dissolved in the tetrahydrofuran (THF)) then.Finish, mixed solution is used the saturated ammonium chloride solution cancellation then 0 ℃ of following stir about 6 hours.Reaction mixture is with ethyl acetate extraction 3 times, after anhydrous sodium sulfate drying, underpressure distillation removes and desolvates the organic phase of merging with saturated common salt washing 1 time, and the residue that obtains is with preparation HPLC purifying.
Get product: 4.2mg (yield theoretical value 26%).
1H NMR(400MHz，CDCl3)δ 7.34(d，J＝8.8Hz，1H)，7.33(d，1H)，7.27(dd，J＝8.2，2.2Hz，1H)，7.19(d，J＝8.2Hz，2H)，7.12(d，J＝8.2Hz，2H)，4.10(d，J＝15.6Hz，1H)，4.08(d，J＝9.6Hz，1H)，4.04(d，J＝15.6Hz，1H)，3.86(dd，J＝12.8，1.6Hz，1H)，3.68(dd，J＝11.6，5.2Hz，1H)，3.47-3.36(m，3H)，3.28(t，J＝8.8Hz，1H)，1.14-1.11(m，2H)，0.96-0.93(m，2H)；
LC-MS(ESI)：m/z＝421/423(Cl)[M+H]
+，438/440(Cl)[M+NH
4]
+，465/467(Cl)[M+HCO
2]
-。
The external SGLT restraining effect test of embodiment 3 compounds
The preparation of people SGLT2 expression vector
With full length cDNA clone (available from GenScript company) (having put Hind III and the Not I site) subclone of expressing human SGLT2 at the cDNA two ends between the Hind III and Not I site of pEAK15 expression vector (U.S. Theracos company).The clone who contains target gene determines with the method for digestion with restriction enzyme.
The preparation of people SGLT2 stably transfected cell line
Utilize restriction enzyme NsiI digestion to contain the plasmid of people SGLT2, make it linearizing, linear DNA is carried out purifying with agarose gel electrophoresis.Change the DNA behind the purifying over to HEK293 cell (U.S. Theracos company) with transfection reagent Lipofectamine 2000 (Invitrogen company).With the cell after the transfection in containing the DMEM substratum of 10% foetal calf serum in 37 ℃, 5% CO
2Cultivate after 24 hours under the condition, adding purine mycin (Invitrogen company) in identical growth medium continues to cultivate for 2 weeks, will be through the cell inoculation in 96 new orifice plates (cell in every hole) that has the tetracycline resistance after the screening, in the substratum that contains the purinase element, cultivate, grow to converging state until cell.Cell clone with tetracycline resistance is by the active methyl-α of reflection SGLT2-D-[U-
14C] further screening (experimental technique has detailed description hereinafter) of pyranoside picked-up test.The cell clone that selection has highest signal to noise ratio is used for follow-up methyl-α-D-[U-
14C] pyranoside picked-up test.
The preparation of people SGLT1 express cell
PDream 2.1 expression vectors that contain total length people SGLT1 cDNA are purchased the company in GenScript.Plasmid increases in bacillus coli DH 5 alpha, and this strain culturing is in the Luria-Bertani that contains penbritin (LB) substratum.With QIAGEN Plasmid Midi test kit (QIAGEN company) extracting plasmid.With Lipofectamine 2000 transfection reagents, change people SGLT1 expression vector plasmid over to COS-7 cell (available from American type culture collection) according to the method for operational manual.Transfectional cell in the DMEM that contains 10% DMSO in-80 ℃ of preservations.
Methyl-α-D-[U-
14C] pyranoside picked-up test
Before the test, the cell of expressing SGLT1 and SGLT2 respectively is inoculated in 96 hole ScintiPlate liquid sudden strain of a muscle plates (PerkinElmer company) with the DMEM that contains 10% FBS, and (every hole adds 100 μ L nutrient solutions, contains 1 * 10
5Individual cell), and in 37 ℃, 5% CO
2Cultivated 48 hours under the condition.Cell contains sodium damping fluid (137mM NaCl, 5.4mM KCl, 2.8mM CaCl with 150 μ L
2, 1.2mM MgCl
2, 10mM Tutofusin tris/N-2-hydroxyethyl piperazine-N '-ethane sulfonic acid [Tris/Hepes], pH7.2) or do not have sodium damping fluid (137mM N-methyl-glycosamine, 5.4mM KCl, a 2.8mM CaCl
2, 1.2mM MgCl
2, 10mM Tris/Hepes pH7.2) washes twice.Testing compound is dissolved in contains 25% human plasma and 40 μ Ci/mL methyl-α-D-[U-
14C] the containing sodium or do not have in the sodium damping fluid of pyranoside (Amersham Biosciences/GE Healthcare), be prepared into the testing compound solution of a series of suitable concns.The every hole of 96 orifice plates adds 50 μ L testing compound solutions, shaking culture 2 hours (SGLT1 analysis) or 1.5 hours (SGLT2 analysis).(137mM N-methylglucosamine, 10mM Tris/Hepes pH7.2) washes twice to cell, uses TopCount liquid scintillation counter (Perkin Elmer company) to methyl-α-D-[U-with 150 μ L cleaning buffer solutions
14C] pyranoside picked-up carrying out quantitative analysis.Sodium dependency pyranoside intake is with containing the sodium damping fluid and handles the intake obtain and deduct no sodium damping fluid and handle the difference of the intake that obtains (three answer the mean values in holes).
Table 1 compound external activity test result
| Compound number | SGLT2 IC 50(nM) | SGLT1 IC 50(nM) | Selectivity (IC 50-SGLT1/IC 50-SGLT2) |
| DAPAGLIFLOZIN (BMS-512148) | 7 | 885 | 126 |
| Compd A | 2 | 614 | 307 |
Annotate: the data of the DAPAGLIFLOZIN (BMS-512148) that ADA (ADA) annual meeting in 2007 is announced are SGLT2 IC50=1.0nM, SGLT1 IC50=1600nM, and compound is 1600 to the selectivity of SGLT2 and SGLT1.For activity that can more objective compound of reaction, the inventor has added in test 25% human plasma (seeing test portion for details), with the intravital environment of anthropomorphic dummy.
Wherein, Compound D APAGLIFLOZIN (BMS-512148, CAS number: 461432-26-8) be a kind of C-aryl glucoside SGLT2 inhibitor.Its structure and relevant information are as follows:
Therefore as seen, in the test system that has added 25% human plasma, the external activity of the compd A of the present invention and selectivity of SGLT2 and SGLT1 significantly is better than reference compound DAPAGLIFLOZIN (BMS-512148) has the effect of good inhibition Na-dependent glucose transporter (SGLT2).
The glucose in urine of embodiment 4 compounds is discharged test
1. the rat glucose in urine of compound is discharged test
Irritate stomach by the compound (being respectively DAPAGLIFLOZIN (BMS-512148) and compd A) of body weight 1mg/kg amount after the fasting overnight of healthy male SD rat (5 every group), after the administration 1 hour, the glucose solution that orally give body weight 2g/kg measures.Urine is collected to detect in the urine glucose concn and to write down the urine amount in 4 hours and 24 hours after administration.Multiply by the uri-meter calculation with glucose in urine concentration and obtain the glucose in urine output.
2. the Beagle dog glucose in urine of compound is discharged test
Compound by body weight 0.03mg/kg amount after healthy adult Beagle dog (3 the every group) fasting overnight is irritated stomach (being respectively DAPAGLIFLOZIN (BMS-512148) and compd A), and after the administration 1 hour, orally give was by the glucose solution of body weight 2g/kg amount.After administration, collected urine in 8 hours and 24 hours respectively to detect in the urine glucose concn and to write down the urine amount.Multiply by the uri-meter calculation with glucose in urine concentration and obtain the glucose in urine output.
Table 2 compound glucose in urine is discharged test-results
| Compound number | 0-24 hour row's sugar of healthy male SD rat amount | 0-24 hour row's sugar of healthy adult Beagle dog amount |
| DAPAGLIFLOZIN (BMS-512148) | 2.05g | 12.42g |
| Compd A | 2.68g | 18.68g |
By The above results as seen, the drug effect of compd A significantly is better than reference compound DAPAGLIFLOZIN (BMS-512148).Compare with DAPAGLIFLOZIN (BMS-512148), compd A makes row's sugar amount of SD rat high more than 30%, makes row's sugar amount of Beagle dog high more than 50%.
Embodiment 5 compositions
1. the compd A tablet 1
Weighing: compd A 20g, lactose 85g, Microcrystalline Cellulose 75g, W-Gum 12g, sodium starch glycolate 6g, Magnesium Stearate 2g.Make 1000 after the mixing altogether.
The method for making of method for making such as conventional tablet.
2. the compd A tablet 2
Weighing: compound A-13 0g; Lactose 80g, Microcrystalline Cellulose 70g, W-Gum 12g, sodium starch glycolate 6g, Magnesium Stearate 2g.Make 1000 after the mixing altogether.
3. the compd A tablet 3
Weighing: compd A 20g; N1,N1-Dimethylbiguanide 20g; Lactose 80g, Microcrystalline Cellulose 60g, W-Gum 12g, sodium starch glycolate 6g, Magnesium Stearate 2g.Make 1000 after the mixing altogether.
Empirical tests, above-mentioned three kinds of compositions all have good promotion dog glucose in urine to discharge effect.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (14)
1. compound or its isomer, racemic modification, precursor or pharmacy acceptable salt shown in the general formula I:
Wherein:
R
1Be selected from cyano group, aminocarbonyl, (C
1-3-alkylamino) carbonyl, two (C
1-3-alkyl) aminocarbonyl, C
3-7-cycloalkyl or C
5-7-cycloalkenyl group,
Wherein, described alkyl does not have and replaces or through fluorine list or polysubstituted, and described cycloalkyl, cycloalkenyl group do not have and replace or through being selected from fluorine, chlorine, hydroxyl, C
1-3-alkyl, C
1-3-alkoxyl group, C
1-3-alkane carbonyl oxygen base, amino, C
1-3-alkylamino or C
1-3The group list of-alkane carbonyl amino or polysubstituted, and
In described cycloalkyl, the cycloalkenyl group, one or two methylene radical does not have and replaces or through being selected from O, S, CO, SO, SO
2, NR
5Group replace;
R
2Be selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano group, nitro, C
1-6-alkyl, C
1-6-alkoxyl group, C
1-4-alkoxy-C
1-4-alkyl, C
1-4-alkoxy-C
1-4-alkoxyl group, C
2-6-alkene-1-base, C
2-4-thiazolinyl-C
1-4-alkyl, C
2-4-thiazolinyl-C
1-4-alkoxyl group, C
2-4-thiazolinyl oxygen-C
1-4-alkyl, C
2-4-thiazolinyl oxygen-C
2-4-alkoxyl group, C
2-6-alkynes-1-base, C
2-4-alkynyl-C
1-4-alkyl, C
2-4-alkynyloxy-C
1-4-alkyl, C
2-4-alkynyl-C
1-4-alkoxyl group, C
2-4-alkynyloxy-C
1-4-alkoxyl group, C
3-7-cycloalkyl, C
3-7-cycloalkyl-C
1-4-alkyl, C
3-7-cycloalkyloxy-C
1-4-alkyl, C
3-7-cycloalkyloxy, C
3-7-cycloalkyl-C
1-4-alkoxyl group, C
3-7-cycloalkyloxy-C
1-4-alkoxyl group, C
3-7-cycloalkenyl group, C
3-7-cycloalkenyl group-C
1-4-alkyl, C
3-7-cyclenes oxygen base-C
1-4-alkyl, C
3-7-cyclenes oxygen base, C
3-7-cycloalkenyl group-C
1-4-alkoxyl group, C
3-7-cyclenes oxygen base-C
1-4-alkoxyl group, aryl, heteroaryl, C
1-4-alkyl carbonyl, aromatic carbonyl, assorted aromatic carbonyl, aminocarbonyl, C
1-4-alkane aminocarbonyl, two-(C
1-3-alkyl) aminocarbonyl, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, piperazine-1-base carbonyl, 4-(C
1-4-alkyl) piperazine-1-base carbonyl, fragrant aminocarbonyl, assorted fragrant aminocarbonyl, C
1-4-carbalkoxy, aryl-C
1-3-carbalkoxy, heteroaryl-C
1-3-carbalkoxy, amino, C
1-4-alkylamino, two-(C
1-3-alkyl) amino, C
2-4-thiazolinyl-C
1-4-alkylamino, C
2-4-alkynyl-C
1-4-alkylamino, C
3-7-cycloalkyl-C
1-4-alkylamino, C
3-7-cycloalkenyl group-C
1-4-alkylamino, tetramethyleneimine-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4-base, piperazine-1-base, 4-(C
1-3-alkyl)-piperazine-1-base, C
1-4-alkane carbonyl amino, fragrant carbonyl amino, assorted fragrant carbonyl amino, C
3-7-cycloalkyloxy, C
5-7-cyclenes oxygen base, aryloxy, heteroaryloxy, C
1-4-alkyl sulfinyl, C
1-4-alkane alkylsulfonyl, C
3-7-cycloalkylthio, C
3-7-cycloalkanes sulfinyl, C
3-7-cycloalkanes alkylsulfonyl, C
3-7-cyclenes sulfenyl, C
3-7-cyclenes sulfinyl, C
3-7-cyclenes alkylsulfonyl, arylthio, fragrant sulfinyl, arylsulfonyl, heteroarylthio, assorted fragrant sulfinyl or assorted arylsulfonyl;
Wherein,
Described thiazolinyl, alkynyl do not have and replace or through identical or different fluorine, chlorine, hydroxyl, cyano group, nitro, C
3-7-cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, C
1-4-alkylthio, arylthio or heteroarylthio list or polysubstituted, and
Described alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, cycloalkenyl group, cyclenes oxygen base do not have and replace or through being selected from fluorine, chlorine, cyano group, hydroxyl, sulfydryl, C
1-3-alkoxyl group, C
1-3The group list of-alkyl or polysubstituted; And
In described cycloalkyl, cycloalkyloxy, cycloalkenyl group, cyclenes oxygen base, one or two methylene radical does not have and replaces or through being selected from O, S, CO, SO, SO
2Or NR
5Group replace;
R
3Be selected from hydrogen, fluorine, chlorine, bromine, cyano group, nitro, hydroxyl, C
1-6-alkyl, C
1-6-alkoxyl group, C
3-7-cycloalkyl, C
3-7-cycloalkyloxy or C
2-6-alkynyl,
Wherein, described alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy or alkynyl do not have and replace or through being selected from fluorine, chlorine, cyano group, hydroxyl, sulfydryl, C
1-3-alkoxyl group, C
1-3The group list of-alkyl or polysubstituted;
R
4Be selected from hydroxyl, hydrogen, fluorine, chlorine, bromine, cyano group, C
1-6-alkyl, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-7-cycloalkyl, C
5-7-cycloalkenyl group, amino, C
1-4-alkylamino, two-(C
1-3-alkyl) amino, C
1-4-alkane carbonyl amino, C
1-4-alkane sulfonamido, C
1-4-alkane sulfonamido, C
1-6-alkoxyl group, C
3-7-cycloalkyloxy, C
2-6-alkene oxygen base, C
2-6-alkynyloxy group, C
1-6-alkane carbonyl oxygen base, C
1-4-alkane sulfinyl oxygen base, C
1-4-alkane sulfonyloxy, sulfydryl, C
1-4-alkylthio, arylthio, arylamino, fragrant sulfonamido, aryl-sulphonamidic base, aryloxy, aryl sulfinyl oxygen base or aryl-sulfonyl oxygen,
Wherein, described alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group do not have and replace or through fluorine list or polysubstituted, or through being selected from chlorine, cyano group, hydroxyl, sulfydryl, C
1-3-alkoxyl group, C
1-3The group list of-alkyl or polysubstituted, and
In described cycloalkyl, the cycloalkenyl group, one or two methylene radical does not have and replaces or through being selected from O, S, CO, SO, SO
2, NR
5Group replace;
R
5Be selected from hydrogen, C
1-4-alkyl, C
1-4-alkyl carbonyl, C
1-4-alkyl sulfinyl or C
1-4-alkane alkylsulfonyl;
A is selected from O, S, SO, SO
2, NH or (CH
2)
n, wherein n is selected from 1,2 or 3;
In described group, aryl is selected from phenyl or naphthyl, and it is the group list of group or polysubstituted under identical or different being selected from independently: fluorine, chlorine, bromine, iodine, C
1-3-alkyl, the methyl, the C that replace through 1 to 3 fluorine atom
1-3-alkoxyl group, the methoxyl group or the cyano group that replace through 1 to 3 fluorine atom;
In described group, heteroaryl is selected from furyl, pyrryl, thienyl, pyridyl, indyl, benzofuryl, benzimidazole thiophanate phenyl, quinolyl, isoquinolyl, tetrazyl, or be selected from pyrryl, furyl, thienyl, pyridyl and wherein 1 or 2 methyne replace through nitrogen-atoms, or be selected from indyl, benzofuryl, benzimidazole thiophanate phenyl, quinolyl, isoquinolyl and wherein 1 to 3 methyne replace through nitrogen-atoms;
And described heteroaryl does not have replacement or the group list of organizing or polysubstituted under identical or different being selected from: fluorine, chlorine, bromine, iodine, C
1-3-alkyl, the methyl, the C that replace through 1 to 3 fluorine atom
1-3-alkoxyl group, the methoxyl group or the cyano group that replace through 1 to 3 fluorine atom.
2. compound as claimed in claim 1 is characterized in that, A is O, S or CH
2
3. compound as claimed in claim 1 is characterized in that R
1Be selected from: C
3-7-cycloalkyl, C
5-7-cycloalkenyl group, cyano group, aminocarbonyl.
4. compound as claimed in claim 3 is characterized in that R
1It is cyclopropyl.
5. compound as claimed in claim 1 is characterized in that R
4Methyl that is selected from hydroxyl, hydrogen, fluorine, chlorine, bromine, cyano group, methyl, ethyl, cyclopropyl, ethynyl, methoxyl group, oxyethyl group, replaces through 1 to 3 fluorine atom or the methoxyl group that replaces through 1 to 3 fluorine atom.
6. compound as claimed in claim 1 is characterized in that R
2Be selected from: hydrogen, fluorine, chlorine, bromine, cyano group, nitro, hydroxyl, methyl, ethyl, cyclopropyl, ethynyl, methoxyl group, oxyethyl group, the methyl that replaces through 1 to 3 fluorine atom or the methoxyl group that replaces through 1 to 3 fluorine atom.
7. compound as claimed in claim 1 is characterized in that R
3Be selected from: hydrogen, fluorine, chlorine, bromine, cyano group, nitro, hydroxyl, methyl, ethyl, cyclopropyl, ethynyl, methoxyl group, oxyethyl group, the methyl that replaces through 1 to 3 fluorine atom or the methoxyl group that replaces through 1 to 3 fluorine atom.
8. compound as claimed in claim 1 is characterized in that, described compound is selected from:
Or
9. compound as claimed in claim 1 is characterized in that, described pharmacy acceptable salt is: the salt that compound shown in the general formula I and mineral acid or organic acid produce.
10. the purposes of the arbitrary described compound of claim 1-9 is characterized in that, is used to prepare the composition of treatment or prevent diabetes and relative disease.
11. purposes as claimed in claim 10, it is characterized in that the diabetes relative disease comprises: retinopathy, neuropathy, ephrosis, retardance wound healing, insulin resistance, glucose homeostasis are impaired, hyperglycemia, hyperinsulinemia, the acid of hyperlipidemia fat or glycerine level, obesity, hyperlipidaemia, X syndromes, hypertension, atherosclerosis.
12. one kind can treatment or the composition of prevent diabetes and relative disease, it is characterized in that described composition comprises:
Arbitrary described compound or its isomer, racemic modification, precursor or pharmacy acceptable salt or their mixture among the claim 1-9 of significant quantity, and
One or more bromatologies or pharmaceutically acceptable carrier or vehicle.
13. composition as claimed in claim 12 is characterized in that, wherein also can comprise:
The antidiabetic medicine of non-Na-dependent glucose transporter inhibitor, diabetic complication medicine, anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine and/or blood lipid-lowering medicine.
14. pharmaceutical composition as claimed in claim 13, it is characterized in that described antidiabetic medicine is selected from following one or more: N1,N1-Dimethylbiguanide, Glyburide, glimepiride, Glipizide, gliclazide, Glipyride, pioglitazone, troglitazone, Rosiglitazone, acarbose, miglitol, the sick urea of chlorine sulphur, nateglinide, repaglinide, Regular Insulin, AC2993, AJ9677, AR-H039242, GI-262570, Isaglitazone, JTT-501, KAD1129, KRP297, LY315902, NN-2344, NVP-DPP-728A, R-119702 or YM-440.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| PH12000002657B1 (en) * | 1999-10-12 | 2006-02-21 | Bristol Myers Squibb Co | C-aryl glucoside SGLT2 inhibitors |
| US6515117B2 (en) * | 1999-10-12 | 2003-02-04 | Bristol-Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
| DE102004012676A1 (en) * | 2004-03-16 | 2005-10-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New glucopyranosyl-substituted benzene derivatives are sodium-dependent glucose cotransporter inhibitors, useful for treating e.g. metabolic disorders (type 1 and type 2 diabetes mellitus or metabolic acidosis) |
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