CN102863417B - C-indican derivative - Google Patents

C-indican derivative Download PDF

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CN102863417B
CN102863417B CN201210236777.9A CN201210236777A CN102863417B CN 102863417 B CN102863417 B CN 102863417B CN 201210236777 A CN201210236777 A CN 201210236777A CN 102863417 B CN102863417 B CN 102863417B
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compound
base
chloro
methyl
glucose
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CN102863417A (en
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松山皓治
张蕙
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Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicine, and particularly relates to C-indican derivative as shown in general formula (I), the pharmaceutically acceptable salt of the C-indican derivative, the easily-hydrolyzed ester of the C-indican derivative, and the stereoisomer and the intermediate of the C-indican derivative. The invention specifically relates to the C-indican derivative taken as sodium-dependent glucose transporters (SGLT) inhibitor, the pharmaceutically acceptable salt of the C-indican derivative, the easily-hydrolyzed ester of the C-indican derivative, and the stereoisomer and the intermediate of the C-indican derivative. The C-indican derivative provided by the invention not only can be used for the diabetes mellitus such as the insulin dependent diabetes mellitus (I type diabetes mellitus), the non-insulin dependent diabetes mellitus (II type diabetes mellitus) and the like, but also can be used for the treatment and the prevention of various mellitus-related diseases such as the insulin-resistant disease and the fatness. R1, R2, R3, R4, R5, R6a, R6b, R6c, W, M, n and A are defined in the specification.

Description

C-glycosides derivatives
1, technical field
The invention belongs to medical art, relate to C-glycosides derivatives, the ester of its pharmacy acceptable salt, its facile hydrolysis, its steric isomer and intermediate.Be specifically related to the C-glycosides derivatives as white (SGLT) inhibitor of sodium glucose co-transporter 2, the ester of its pharmacy acceptable salt, its facile hydrolysis, its steric isomer and intermediate.C-glycosides derivatives of the present invention can be used in outside the diabetes such as diabetes (type i diabetes), non insulin dependent diabetes (type ii diabetes) as insulin-dependent, the treatment comprising insulin resistance disease and fat various diabetes related diseases can also be used for, and the prevention of these diseases.
2, background technology
Nearly 100,000,000 people in the whole world suffer from type ii diabetes, it is characterized in that because of the hyperglycemia caused by excessive hepatic glucose generation and periphery insulin resistance.Hyperglycemia is considered to the Major Risk Factors forming diabetic complication, and may be directly related with the impaired insulin secretion of late Type II diabetes.Therefore can expect that the normalizing of the blood sugar in type ii diabetes patient can improve the effect of Regular Insulin.Current existing diabetes medicament such as sulfonylurea, thiazolidinediones, N1,N1-Dimethylbiguanide and Regular Insulin have potential side effect, therefore need to develop new, safe and orally active antidiabetic medicine.
At kidney, glucose freely from glomerular filtration (about 180g/ days), but almost heavily can absorb at proximal convoluted tubule active transport.Wherein two the heavily absorptions of sodium-glucose transporter to glucose have played vital role, i.e. SGLT1 and SGLT2.And the effect of SGLT2 is particularly outstanding.SGLT2 is only at the transmembrane protein of the S1 section specifically expressing of proximal convoluted tubule, one of its topmost physiological action absorbs the sugared part flow through in uriniferous tubules blood, account for 90% of Reabsorption, SGLT2 transports with the ratio of sodium-glucose 1:1, SGLT-2 inhibitor can suppress blood sugar in the absorption of uriniferous tubules, and sugared part is discharged in a large number from urine.And SGLT1 mainly expresses at distal convoluted tubule, account for 10% of Reabsorption, SGLT1 and transport with the ratio of sodium-glucose 2:1.SGLT1 is have also discovered in addition in enteron aisle and its hetero-organization.These transhipment are played a role by Na+/ATP enzyme pump, and by glucose transporter 2(GLUT2) be transferred back in blood.What this showed most possibly to develop into drug target is SGLT2 transhipment, and being its absolute Reabsorption to glucose on the one hand, is that it is only expressed in kidney on the other hand.In the research to familial form ephrosis glucose in urine, also demonstrate that the feasibility of this approach.Familial ephrosis glucose in urine main manifestations is the glucose in urine (about 10-120g/ days) of non-quantitative, but patient's general status is good, does not find the disadvantageous long term negative effect of health.This optimum glucose in urine is mainly transported caused by sub-transgenation due to SGLT-2, and this shows optionally to suppress may to produce adverse consequences except induction glycosuria to the pharmacology of SGLT-2.And suppress SGLT-1, then can cause sugar-semi-lactosi malabsorption syndrome, dehydration can be caused.
Suppress the heavily absorption of kidney sugar to treat hyperglycemia by acting on SGLT-2 transhipment, the treatment for diabetes provides new approach.Although this approach can not directly act on the physiopathology of type ii diabetes, reduce blood sugar by the excretion increasing renal glucose sugar, the deficiency of net energy can be caused, promote weight loss and indirectly improve obesity symptom.Research finds that these medicines can share with existing ofhypoglycemic medicine or Regular Insulin, hypoglycemic risk occurs lower and have the effect of potential reduction body weight.Whether SGLT-2 inhibitor can occupy a tiny space in the pharmacological agent in type ii diabetes by final decision for the security of Long-term clinical experiment and validity.
Wherein, WO0127128, US2005209166 etc. patent document discloses a series of compound as SGLT-2 inhibitor.
3, summary of the invention
The present invention with develop excellent can being used for the treatment of and/or preventing the medicine of the diabetes of various Mammals (comprising the mankind) and the various diseases caused by diabetes for target by safety, invented and had the white 2(SGLT-2 of sodium glucose co-transporter 2) restraining effect and the C-glycosides derivatives of hypoglycemic activity.
Technical scheme of the present invention is as follows:
The ester of logical formula I, (II), the compound shown in (III), its pharmacy acceptable salt, its facile hydrolysis or its steric isomer:
Wherein, A ring is 3-14 unit cycloalkyl, and 6-14 unit aryl, has 1-4 and be selected from N, S, O, SO and/or SO 2the heterocyclic radical of heteroatomic 3-12 unit;
X, Y represent CH respectively 2, NH, O atom, S atom, SO and/or SO 2;
R 1represent hydrogen atom, C 1-6alkyl, C 3-14cycloalkyl, halogen ,-CN, alkynyl, C 2-6thiazolinyl ,-OH ,-OR 7;
R 2, R 3represent hydrogen atom respectively ,-OH ,-OR 7,-O-C 6-14aryl ,-OCH 2-C 6-14aryl, C 1-6alkyl, C 3-14cycloalkyl ,-CF 3,-OCHF 2,-OCF 3, halogen ,-CN ,-NR 8r 8a, carbonyl ,-COOR 7a,-COOH ,-COR 8b,-CH (OH) R 8c,-CH (OR 7f) R 8d,-CONR 8r 8a,-NHCOR 7b,-NHSO 2r 7c,-NHSO 2-C 6-14-C 6-14aryl, C 6-14aryl ,-SR 7d,-SOR 7e,-SO 2r 7f,-SO 2-C 6-14aryl, has 1-4 and is selected from N, S, O, SO and/or SO 2the heterocyclic radical of heteroatomic 5-10 unit;
R 4represent hydrogen atom respectively ,-OH ,-OR 7, C 1-6alkyl, C 3-14cycloalkyl ,-CF 3,-OCHF 2,-OCF 3, halogen ,-CN ,-NR 8r 8a, carbonyl ,-COOR 7a,-COOH ,-COR 8b,-CH (OH) R 8c,-CH (OR 7f) R 8d,-CONR 8r 8a,-NHCOR 7b,-NHSO 2r 7c,-SR 7d,-SOR 7e,-SO 2r 7f, there is 1-4 and be selected from N, S, O, SO and/or SO 2the heterocyclic radical of heteroatomic 3-12 unit;
R 7, R 7a, R 7b, R 7c, R 7d, R 7e, R 7frepresent hydrogen atom respectively, C 1-6alkyl, C 3-14cycloalkyl, or comprise by N, O, S, SO and/or SO 2heteroatoms substitute described alkyl, the cycloalkyl of 1-4 carbon atom;
R 8, R 8a, R 8b, R 8c, R 8drepresent hydrogen atom respectively, C 1-6alkyl, C 6-14aryl, C 1-6alkyl-C 6-14aryl or C 3-14cycloalkyl, or R 10and R 10abeing formed containing 1-4 together with the N that they connect is N, O, S, SO and/or SO 2the heterocyclic radical of heteroatomic 3-12 unit;
R 5, R 6a, R 6b, R 6crepresent hydrogen atom respectively, (C 1-18alkyl) carbonyl, (C 1-18alkyl) oxygen base carbonyl, C 6-14aryl carbonyl, or C 3-14aryl-(C 1-3alkyl) carbonyl;
M is 0,1,2 or 3;
N is 0,1,2 or 3;
W is chemical bond, NH, O, S, SO, SO 2or alkylidene group, described alkylidene group can be replaced by 1-4 substituting group further, and described substituting group comprises halogen, hydroxyl, C 1-4alkyl, C 1-4alkoxyl group, the C be optionally substituted by halogen 1-4alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can be replaced by 1-4 substituting group further, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, alkyl, C 1-6alkoxyl group, amino-sulfonyl, formamyl, the C replaced by halogen atom 1-4alkoxyl group, to be selected from the C that replaces of substituting group of halogen atom, hydroxyl, amino, carboxyl by 1 1-4alkyl.
Be preferably:
Wherein, A ring represents C 3-8there is 1-4 being selected from N, S, O, SO and/or SO of cycloalkyl or fractional saturation 2the heterocyclic radical of heteroatomic 3-12 unit;
X, Y represent CH respectively 2, NH, O atom or S atom;
R 1represent hydrogen atom, C 1-6alkyl, C 3-14cycloalkyl, halogen ,-CN, C 2-6alkynyl, C 2-6thiazolinyl ,-OH ,-OR 7;
R 2, R 3represent hydrogen atom respectively;
R 4represent hydrogen atom ,-OH ,-OR 7, C 1-6alkyl, C 3-8cycloalkyl ,-CF 3,-OCHF 2,-OCF 3, halogen ,-CN ,-NR 8r 8a, carbonyl ,-COOR 7a,-COOH ,-COR 8b,-CH (OH) R 8c,-CH (OR 7f) R 8d,-CONR 8r 8a,-NHCOR 7b,-NHSO 2r 7c,-SR 7d,-SOR 7e,-SO 2r 7f, saturated have 1-4 and be selected from N, S, O, SO and/or SO 2the heterocyclic radical of heteroatomic 3-12 unit;
R 7, R 7a, R 7b, R 7c, R 7d, R 7e, R 7frepresent C respectively 1-6alkyl, C 3-8cycloalkyl, comprises by N, O, S, SO and/or SO 2heteroatoms substitute the described C of 1-4 carbon atom 1-6alkyl, C 3-8cycloalkyl;
R 8, R 8a, R 8b, R 8c, R 8drepresent hydrogen atom respectively, C 1-6alkyl, C 6-14aryl, C 1-6alkyl-C 6-14aryl or C 3-8cycloalkyl, or R 10and R 10aformed together with the N that they connect again ring to be N, O, S, SO and/or SO containing 1-4 2the heterocyclic radical of heteroatomic 5-7 unit;
R 5, R 6a, R 6b, R 6crepresent hydrogen atom respectively;
M is 0,1 or 2;
N is 0,1 or 2;
W is alkylidene group, and described alkylidene group can be replaced by 1-4 substituting group further, and described substituting group comprises halogen, hydroxyl, C 1-4alkyl, C 1-4alkoxyl group, the C be optionally substituted by halogen 1-4alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can be replaced by 1-4 substituting group further, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, alkyl, C 1-6alkoxyl group, amino-sulfonyl, formamyl, the C replaced by halogen atom 1-4alkoxyl group, to be selected from the C that replaces of substituting group of halogen atom, hydroxyl, amino, carboxyl by 1 1-4alkyl.
Be preferably:
Wherein, A ring is C 3-8there is 1-2 being selected from N, S, O and/or SO of cycloalkyl or fractional saturation 2the heterocyclic radical of heteroatomic 3-7 unit;
X, Y represent CH respectively 2, NH, O atom or S atom;
R 1represent hydrogen atom, C 1-6alkyl, C 3-14cycloalkyl, halogen ,-CN, C 2-6alkynyl, C 2-6thiazolinyl ,-OH ,-OR 7;
R 2, R 3represent hydrogen atom respectively;
R 4represent hydrogen atom ,-OR 7, C 3-8cycloalkyl, halogen ,-CF 3,-OCHF 2,-OCF 3,-CN, saturated have 1-4 and be selected from N, S, O and/or SO 2the heterocyclic radical of heteroatomic 3-7 unit;
R 7represent C 1-6alkyl, C 3-8cycloalkyl, comprises by N, O, S, SO and/or SO 2heteroatoms substitute the described C of 1-4 carbon atom 1-6alkyl, C 3-8cycloalkyl;
R 5, R 6a, R 6b, R 6crepresent hydrogen atom respectively;
M is 0,1 or 2;
N is 0,1 or 2;
W is alkylidene group, and described alkylidene group can be replaced by 1-4 substituting group further, and described substituting group comprises halogen, hydroxyl, C 1-4alkyl, C 1-4alkoxyl group, the C be optionally substituted by halogen 1-4alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can be replaced by 1-4 substituting group further, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, C 1-6alkyl, C 1-6alkoxyl group, amino-sulfonyl, formamyl.
Be preferably:
Wherein, A ring is C 3-6cycloalkyl or fractional saturation there is the heterocyclic radical that 1-2 is selected from the heteroatomic 3-7 unit of S, O;
X, Y represent CH respectively 2, NH, O atom or S atom;
R 1represent halogen;
R 2, R 3, R 4represent hydrogen atom respectively;
R 5, R 6a, R 6b, R 6crepresent hydrogen atom respectively;
M is 0,1 or 2;
N is 0;
W is alkylidene group, and described alkylidene group can be replaced by 1-4 substituting group further, and described substituting group comprises halogen, hydroxyl, C 1-4alkyl, C 1-4alkoxyl group, the C be optionally substituted by halogen 1-4alkyl;
Wherein, described cycloalkyl, heterocyclic radical can be replaced by 1-4 substituting group further, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, C 1-6alkyl, C 1-6alkoxyl group, amino-sulfonyl, formamyl.
More preferably:
Wherein, A ring is cyclopropane base, tetramethylene base, pentamethylene base, tetrahydrofuran base, oxetanyl;
X, Y represent CH respectively 2, NH, O atom or S atom;
R 1represent hydrogen atom, alkyl, cycloalkyl, halogen ,-CN, alkynyl, thiazolinyl ,-OH ,-OR 7;
R 2, R 3, R 4represent hydrogen atom respectively;
R 5, R 6a, R 6b, R 6crepresent hydrogen atom respectively;
M is 0 or 1;
N is 0;
W is alkylidene group, and described alkylidene group can be replaced by 1-4 substituting group further, and described substituting group comprises halogen, hydroxyl, C 1-4alkyl, C 1-4alkoxyl group, the C be optionally substituted by halogen 1-4alkyl;
Wherein, described cyclopropane base, tetramethylene base, pentamethylene base, tetrahydrofuran base, oxetanyl can be replaced by 1-4 substituting group further, and described substituting group is selected from halogen atom, hydroxyl, amino, carboxyl, C 1-6alkyl, C 1-6alkoxyl group, amino-sulfonyl, formamyl.
More preferably:
Wherein, A ring is cyclopropane base, tetramethylene base, pentamethylene base, tetrahydrofuran base, oxetanyl;
X, Y represent CH respectively 2, NH, O atom or S atom;
R 1represent halogen;
R 2, R 3, R 4represent hydrogen atom respectively;
R 5, R 6a, R 6b, R 6crepresent hydrogen atom respectively;
M is 0 or 1;
N is 0;
W is methylene radical.
Particularly preferably compound is:
Detailed Description Of The Invention
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, atomic iodine, preferred fluorine atom and chlorine atom.
" alkyl " of the present invention refers to that the paraffin section containing 1-18 carbon atom removes the alkyl of the straight or branched that a hydrogen atom derives, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, 3-methyl butyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethyl-butyl, 2-ethyl-butyl, 1, 1, 2-thmethylpropyl, 1, 2, 2-thmethylpropyl, 1-ethyl-1-methyl-propyl and 1-Ethyl-2-Methyl propyl group.Preferred C 1-6alkyl, more preferably C 1-4alkyl, C 1-3alkyl, term " C 1-18alkyl ", " C 1-6alkyl ", " C 1-4alkyl ", " C 1-3alkyl " refer in above-mentioned example containing 1-18,1-6,1-4, a 1-3 carbon atom specific examples.
" alkylidene group " of the present invention refers to that abovementioned alkyl removes the derivative straight or branched alkane of a hydrogen atom, comprises-(CH 2) t-(t is the integer of 1-18), preferred t is the integer of 1-3, as methylene radical, ethylidene, propylidene etc.
" C of the present invention 2-6thiazolinyl " refer to that the carbonatoms containing double bond is the straight or branched of 2-6 or the thiazolinyl of ring-type, as vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl, 1-Ethyl-2-Methyl-2-propenyl, 1,3-butadiene, 1,3-pentadiene, Isosorbide-5-Nitrae-pentadiene, Isosorbide-5-Nitrae-hexadiene, cyclopentenyl, 1，3-cyclopentadiene base, cyclohexenyl, 1，4-cyclohexadiene base etc.
" C of the present invention 2-6alkynyl " refer to containing triple bond carbonatoms and be the alkynyl of the straight or branched of 3-6, as ethynyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1, 1-dimethyl-2-butyne base, 1, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2, 2-dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl etc.
" C of the present invention 1-6alkoxyl group " refer to term " C 1-6alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.
" C of the present invention 1-6alkyl-carbonyl " refer to term " C 1-6alkyl " group that is connected with other structures by carbonyl, as methyl carbonyl, ethylcarbonyl group, propyl group carbonyl, Isopropylcarbonyl, butyl carbonyl, butylcarbonyl, tert-butyl carbonyl, sec-butylcarbonyl group, pentylcarbonyl, neo-pentyl carbonyl, hexyl carbonyl etc.
" C of the present invention 1-6carbalkoxy " be term " C 1-6alkoxyl group " group that is connected with other structures by carbonyl, as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, butyloxycarbonyl, butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, secondary butoxy carbonyl, penta oxygen carbonyl, new penta oxygen carbonyl, own oxygen carbonyl etc.
" cycloalkyl " of the present invention refers to that the paraffin section of 3-14 carbon atom removes the derivative cyclic alkyl of a hydrogen atom, comprises 3-8 unit monocyclic cycloalkyl, 6-14 unit also ring cycloalkyl, the saturated volution of 7-12 unit's bridged ring base and 7-12 unit.Preferred C 3-8cycloalkyl, C 3-6cycloalkyl and C 5-6cycloalkyl.Term " C 3-14cycloalkyl ", " C 3-8cycloalkyl ", " C 3-6cycloalkyl ", " C 5-6cycloalkyl " be respectively in above-mentioned example containing 3-14,3-8,3-6, a 5-6 carbon atom specific examples.
3-8 unit monocyclic cycloalkyl, comprises the 3-8 saturated monocyclic cycloalkyl of unit and 3-8 unit fractional saturation monocyclic cycloalkyl.The saturated monocyclic cycloalkyl of 3-8 unit, refer to that this monocycle is all saturated carbocyclic ring, the example includes but not limited to: cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, methylcyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl etc.3-8 unit fractional saturation monocyclic cycloalkyl, refer to that this monocycle is the carbocyclic ring of fractional saturation, the example includes but are not limited to cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadiene base, cyclooctene base, 1,5-cyclooctadiene base etc.
And cyclic group, refer to and share by two or more ring texturees the 6-14 cyclic group that two adjacent carbon atoms are formed each other, comprise the saturated and cyclic group of 6-14 unit and 6-14 unit's fractional saturation and cyclic group.Preferred 6-12 unit also cyclic group, 6-10 unit also cyclic group.Saturated and the ring cycloalkyl of 6-14 unit, refer to that this and ring are all saturated carbocyclic ring, the example includes but not limited to: two rings [3.1.0] hexyl, two rings [4.1.0] heptane base, two rings [2.2.0] hexyl, two rings [3.2.0] heptane base, two rings [4.2.0] octyl, octahydro pentalene base, octahydro-1H-indenyl, decahydronaphthalene naphthyl, ten tetrahydrochysene phenanthryl etc.6-14 unit fractional saturation ring cycloalkyl, refers to this and in ring, at least one ring is the carbocyclic ring of fractional saturation, and the example includes but not limited to: oneself-2-thiazolinyl, dicyclo [4.1.0]-3-in heptan thiazolinyl, dicyclo [3.2.0]-3-in heptan thiazolinyl, pungent-3-thiazolinyl of dicyclo [4.2.0], 1,2 of dicyclo [3.1.0], 3,3a-tetrahydrochysene pentalene base, 2,3,3a, 4,7,7a-six hydrogen-1H-indenyl, 1,2,3,4,4a, 5,6, the octahydro naphthyl of 8a-, 1,2,4a, 5,6,8a-hexahydro-naphthyl, 1,2,3,4,5,6,7,8,9,10-decahydro phenanthryl etc.
" bridged ring base " of the present invention refers to that any two rings share the structure containing 5-12 carbon atom of the atom formation be neither directly connected, and " 5-12 unit bridged ring base " comprises the saturated bridged ring base of 5-12 unit, 5-12 unit fractional saturation bridged ring base.The saturated bridged ring base of 5-12 unit, the saturated bridged ring base of preferred 6-10 unit, includes but are not limited to dicyclo [2.1.1] hexane, dicyclo [2.2.1] heptane, dicyclo [2.2.2] octane, dicyclo [3.2.1] octane, dicyclo [3.3.1] nonane etc.7-12 unit fractional saturation bridged ring base, referring in this bridged ring to have has at least a ring to be undersaturated cyclic group, be preferably 6-10 unit fractional saturation bridged ring, specific examples includes but not limited to dicyclo [2.2.1]-5-in heptan alkene, dicyclo [3.2.1] oct-6-ene, dicyclopentadiene etc.
" volution base " of the present invention refers to that a class has at least two rings to share the 5-12 unit condensed cyclic structure of an atom formation.The saturated volution base of 5-12 unit, refer to that all rings in this volution base are saturated cyclic group, specific examples includes but are not limited to: spiral shell [3.3] heptane base, spiral shell [3.4] octyl, spiral shell [3.5] nonyl, spiral shell [4.4] nonyl, spiral shell [4.5] decyl, spiral shell [5.5] 11 (carbon) alkyl, spiral shell [4.6] 11 (carbon) alkyl, spiral shell [5.6] 12 (carbon) alkyl etc.5-12 unit fractional saturation volution base, refer in this volution base and have at least a ring to be undersaturated cyclic group, specific examples includes but are not limited to: spiral shell [3.4] oct-6-ene base, spiral shell [3.5]-6-in ninth of the ten Heavenly Stems thiazolinyl, spiral shell [4.4]-6-in ninth of the ten Heavenly Stems thiazolinyl, spiral shell [4.4] ninth of the ten Heavenly Stems-2,7-dialkylene, spiral shell [4.5] last of the ten Heavenly stems-6,8-dialkylene, spiral shell [5.5] 11 (carbon)-2-thiazolinyl, (Z)-spiral shell [4.6] 11 (carbon)-8-thiazolinyl, spiral shell [4.6] 11 (carbon)-2-thiazolinyl etc.Preferred 7-10 unit volution base, comprises " the saturated volution base of 7-10 unit " and " the unsaturated volution base of 7-10 unit ".
" C of the present invention 3-8cycloalkyloxy " refer to term " C 3-8cycloalkyl " group that is connected with other structures by Sauerstoffatom, as ring propoxy-, cyclobutoxy group, 1-methyl cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, ring octyloxy etc.
" aryl " of the present invention refers to that annular atoms is the cyclic aromatic groups of 6-14 unit carbon atom, comprises 6-8 unit's monocyclic aryl and 8-14 unit fused ring aryl.6-8 unit monocyclic aryl refers to whole undersaturated aryl, such as phenyl, cyclooctatetraenyl etc.8-14 unit fused ring aryl refers to and to be shared by two or more ring texturees that two adjacent carbon atoms are formed each other, a ring is had at least to be the cyclic group of whole undersaturated aromatic nucleus, comprise the whole unsaturated fused ring aryl of 8-14 unit, naphthyl, anthryl and phenanthryl etc., also comprise 8-14 unit fractional saturation fused ring aryl, the such as saturated monocyclic cycloalkyl of benzo 3-8 unit, benzo 3-8 unit fractional saturation monocyclic cycloalkyl, specific examples is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc.Term " C 6-14aryl " be the specific examples containing 6-14 carbon atom in above-mentioned example.
" heteroaryl " of the present invention its annular atoms, except carbon atom, also comprises 1-4 heteroatoms, and described " heteroatoms " includes but not limited to Sauerstoffatom, nitrogen-atoms and sulphur atom.Heteroaryl is by carbon or heterocyclic atom bonding.Comprise and there is mix aromatic nucleus and the saturated or undersaturated 1-4 of having of heteroatomic monocycle that 1-4 to be selected from N, S, O be selected from the heteroatomic fused heterocycle aryl of N, S, O.Bicyclic heteroaryl include but not limited to pyrryl, imidazolyl, pyrazolyl, 1,2,3-triazoles base, 1,2,4-triazolyl, pyridyl, furyl, thienyl, azoles base, different azoles base, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3- di azoly, 1,2,4- di azoly, 1,2,5- di azoly, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrazyl, triazolyl, 2H-1,2- piperazine base, 4H-1,2- piperazine base, 6H-1,2- piperazine base, 2H-1,3- piperazine base, 4H-1,3- piperazine base, 6H-1,3- piperazine base, 2H-1,4- piperazine base, 4H-1,4- piperazine base, different piperazine base, pyridazinyl, pyrimidyl and pyrazinyl etc.; Fused heterocycle aryl includes but not limited to benzofuryl, isobenzofuran-base, benzothienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, indolizine base, indazolyl, phthalazinyl, quinoxalinyl, quinazolyl, benzodiazine base, benzisoxa azoles base, benzo piperazine base, benzimidazolyl-, pyridopyridine base, pyrazolo [3,4-b] pyridyl, purine radicals, acridyl and xanthenyl etc.Term " 5-7 unit heteroaryl " refers to that in above-mentioned " heteroaryl ", annular atoms number is the specific examples of 5-7.
" heterocyclic radical " of the present invention refers to that described " heteroatoms " refers to nitrogen-atoms, Sauerstoffatom, sulphur atom etc. containing one or more heteroatomic 3-14 cyclic group.Comprise and there is 1-4 be selected from N, S, O and/or SO 2the single heterocyclic radical of heteroatomic 3-8 unit, 6-14 unit fused heterocycle base.Also comprise above mentioned heteroaryl and dihydro thereof and tetrahydro-analogue.Also comprise simultaneously and there is 1-4 be selected from N, S, O and/or SO 2heteroatomic and ring, volution, bridged ring.Preferred 5-10 unit heterocyclic radical, more preferably 5-7 unit heterocyclic radical.
Single heterocyclic radical, refers to the monocyclic heterocycles base containing 3-8 annular atoms (wherein at least containing a heteroatoms), comprises the unsaturated single heterocyclic radical of 3-8 unit, 3-8 unit fractional saturation list heterocyclic radical, the saturated single heterocyclic radical of 3-8 unit.The unsaturated single heterocyclic radical of preferred 5-7 unit, 5-7 unit fractional saturation list heterocyclic radical, the saturated single heterocyclic radical of 5-7 unit.The unsaturated single heterocyclic radical of 3-8 unit, what refer to aromaticity contains heteroatomic cyclic group, specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl group, oxazolyl, oxadiazoles base, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, 1, 4-Dioxin base, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 2, 4-triazinyl, 1, 3, 5-triazinyl, 1, 2, 4, 5-tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1, 3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc.3-8 unit fractional saturation list heterocyclic radical, refer to containing double bond, heteroatomic cyclic group, specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline bases, 3,4-dihydro-2H-pyranyls, 5,6-dihydro-4H-1,3-oxazinyl etc.The saturated single heterocyclic radical of 3-8 unit, refer to be all saturated bond containing heteroatomic cyclic group, specific examples includes but are not limited to: ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, 1,4-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc.
6-14 unit fused heterocycle base refer to and a non-common carbon atom in cyclic group, volution base, bridged ring base by N, S, O and/or SO 2heteroatoms substitute formed and heterocyclic radical, spiro heterocyclic radical, bridge heterocyclic radical.
And heterocyclic radical refer to containing 6-14 annular atoms (wherein at least containing a heteroatoms) by two or more ring texturees share each other two adjacent atoms couple together is formed and ring structure, comprise unsaturated and heterocyclic radical, the 6-14 unit's fractional saturation of 6-14 unit and the first saturated and heterocyclic radical of heterocyclic radical, 6-10.Unsaturated and the heterocyclic radical of 6-14 unit, refer to that whole rings is undersaturated condensed cyclic structure, the structure that single heterocyclic radical as unsaturated in benzo 3-8 unit is formed, the structure etc. that the 3-8 unsaturated single heterocyclic radical of unit the unsaturated single heterocyclic radical of 3-8 unit are formed, specific examples includes but not limited to: benzofuryl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl, thieno-[2, 3-b] thienyl, thieno-[3, 2-b] thienyl, benzo [b] thienyl, benzo [b] thiazolyl etc.6-14 unit fractional saturation heterocyclic radical, refer to the condensed cyclic structure at least containing a fractional saturation ring, as the structure that benzo 3-8 unit fractional saturation list heterocyclic radical is formed, the structure etc. that 3-8 unit's fractional saturation list heterocyclic radical 3-8 unit fractional saturation list heterocyclic radical are formed, specific examples includes but not limited to: 1, 3-dihydro benzo furyl, benzo [d] [1.3] dioxa cyclopentenyl, isoindoline base, chromanyl, 1, 2, 3, 4-Pyrrolidine also [3, 4-c] pyrryl, 2, 4, 6, 7-tetrahydro-pyrans [4, 3-c] pyrazolyl, 1, 4, 6, 7-tetrahydropyrans [4, 3-b] pyrryl, 4, 5, 6, 7-tetrahydro benzo [b] thienyl, 3, 4-dihydro-2H-benzo [b] [1, 4] thiazinyl, 2, 3-dihydrobenzo [b] [1, 4] Dioxins base, indolinyl, 1, 2, 3, 4-tetrahydric quinoline group, 3, 4-dihydro-2H-benzo [b] [1, 4] oxazinyl, chromanyl etc.Saturated and the heterocyclic radical of 6-10 unit, refer to that whole rings is saturated condensed cyclic structure, as the 3-8 saturated single heterocyclic radical of unit and the saturated single heterocyclic radical of 3-8 unit the structure that formed, specific examples includes but are not limited to: tetramethylene Pyrrolidine base, pentamethylene Pyrrolidine base, azetidine imidazolidyl, 3-oxabicyclo also [3.1.0] hexyl, hexahydro furyl [3,4-b] [1,4] Dioxins base, six hydrogen-2H-pentamethylene also [b] [Isosorbide-5-Nitrae] Dioxins base etc.
Bridge heterocyclic radical refers to the caged scaffold formed by 5-12 annular atoms (wherein at least containing a heteroatoms)." 5-12 unit bridge heterocycle " comprises the saturated bridge heterocyclic radical of 5-12 unit, 5-12 unit fractional saturation bridge heterocyclic radical.
The saturated bridge heterocyclic radical of 5-12 unit, refers to that all rings in this bridge heterocycle are saturated cyclic group, and be preferably the saturated bridge heterocyclic radical of 7-8 unit, specific examples includes but not limited to: 7-oxabicyclo bridge [2.2.1] heptane base, 7-amido dicyclo bridge [2.2.1] heptane base, 2,5-bis-amido dicyclo bridge [2.2.1] heptane base, 2-oxa--5-amido dicyclo bridge [2.2.1] heptane base, 2-amido dicyclo bridge [2.2.1] heptane base, 2-amido dicyclo bridge [2.2.2] octyl, 2-oxabicyclo bridge [2.2.2] octyl, 2-thia dicyclo bridge [2.2.2] octyl, dicyclo bridge [3.2.1] octyl, 8-amido dicyclo bridge [3.2.1] octyl, 1-amido dicyclo bridge [3.2.1] octyl, 3-amido dicyclo bridge [3.2.1] octyl, 6-amido dicyclo bridge [3.2.1] octyl, 3-oxa--8-amido dicyclo bridge [3.2.1] octyl, 4-oxa--1-amido dicyclo bridge [3.2.1] octyl, 3,8-bis-amido dicyclo bridge [3.2.1] octyl, 8-oxa--3-amido dicyclo bridge [3.2.1] octyl, 2-amido dicyclo bridge [3.2.1] octyl etc.
5-12 unit fractional saturation bridge heterocyclic radical, referring in this bridge heterocycle to have has at least a ring to be undersaturated cyclic group, be preferably 7-8 unit fractional saturation bridge heterocyclic radical, specific examples includes but not limited to: 3,8-diamines is mixed dicyclo bridge [3.2.1] oct-6-ene base, benzo 2-amido dicyclo bridge [2.2.2] octyl benzo 2-thia dicyclo bridge [2.2.2] octyl benzo 2-oxabicyclo bridge [2.2.2] octyl deng.
Spiro heterocyclic radical refers to the spirane structure formed by 5-12 annular atoms (wherein at least containing a heteroatoms).5-12 unit spiro heterocyclic radical comprises the saturated spiro heterocyclic radical of 5-12 unit, 5-12 unit fractional saturation spiro heterocyclic radical.
The saturated spiro heterocyclic radical of 5-12 unit, refer to that all rings in this spiroheterocyclic are saturated cyclic group, specific examples includes but are not limited to: 2-oxa-spiroheptane base, 6-oxaspiro [2.5] octyl, 4-oxa--7-amido spiral shell [2.5] octyl, 2-amido spiral shell [3.3] heptane base, 2-oxa--6-amido spiral shell [3.3] heptane base, 2-amido spiral shell [3.4] octyl, 6-oxa--2-amido spiral shell [3.4] octyl, 2-oxa--6-amido spiral shell [3.4] octyl, 2-oxaspiro [3.4] octyl, 5-oxaspiro [3.5] nonyl, 7-amido spiral shell [3.5] nonyl, 2-amido spiral shell [4.4] nonyl, 2-oxa--7-amido spiral shell [4.4] nonyl, 2-oxaspiro [4.4] nonyl, 1,7-dioxo spiro [4.4] nonyl, Isosorbide-5-Nitrae, 7-trioxa spiral shell [4.4] nonyl, 8-amido spiral shell [4.5] decyl, 6-oxa--9-amido spiral shell [4.5] decyl, 6-oxa--2-amido spiral shell [4.5] decyl, 3-amido spiral shell [5.5] 11 (carbon) alkyl, 1-oxa--9-amido spiral shell [5.5] 11 (carbon) alkyl, 3,9-bis-amido spiral shell [5.5] 11 (carbon) alkyl, 3-oxa--9-amido spiral shell [5.5] 11 (carbon) alkyl, 7,9-bis-amido spiral shell [4.6] 11 (carbon) alkyl etc.
5-12 unit fractional saturation spiro heterocyclic radical, refer in this spiroheterocyclic and have at least a ring to be undersaturated cyclic group, specific examples includes but are not limited to: 6-amido spiral shell [3.4] pungent-7-thiazolinyl, the pungent-7-thiazolinyl of 2-oxa--6-amido spiral shell [3.4], 7-amido spiral shell [3.5]-5-in ninth of the ten Heavenly Stems thiazolinyl, 2-amido spiral shell [4.4]-7-in ninth of the ten Heavenly Stems thiazolinyl, 8-amido spiral shell [4.5]-2-in last of the ten Heavenly stems thiazolinyl etc.
" N, O, S, SO and/or SO of the present invention 2heteroatoms substitute the cycloalkyl of 1-4 carbon atom " refer to 1-4 carbon atom in above-mentioned cycloalkyl (or CH, CH 2) by N, O, S, SO and/or SO 2heteroatoms substitute formed heterocyclic radical.
In the finger above-mentioned " heterocyclic radical " of term " 3-12 unit heterocyclic radical ", annular atoms number is the specific examples of 3-12.In the finger above-mentioned " heterocyclic radical " of term " 5-12 unit heterocyclic radical ", annular atoms number is the specific examples of 5-12.In the finger above-mentioned " heterocyclic radical " of term " 5-7 unit heterocyclic radical ", annular atoms number is the specific examples of 5-7.
It is of the present invention that " X, Y represent CH respectively 2, NH, O atom, S atom, SO and/or SO 2; " including but are not limited to following several situation: (1) X, Y is CH 2; (2) one is had in X, Y for NH, O atom, S atom, SO and/or SO 2; (3) in X, Y, any one is NH, O atom, S atom, SO and/or SO 2.
In the present invention A ring and the ring be connected thick with become and ring heterocycle, volution, spiroheterocyclic, bridged ring, bridge heterocycle.
The Preparation Method And Their Intermediate of compound described in the further claimed logical formula I of the present invention.
Above-claimed cpd of the present invention can adopt the method that describes in following flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to following methods.
When W is methylene radical, reaction scheme is:
Reactions steps:
The preparation of step 1 compound a
Raw material 1 and N-methylmorpholine are dissolved in THF; cool under nitrogen protection, slowly drip trimethylsilyl chloride, keep temperature; after to heat up stirring reaction; then stirring at room temperature reaction, cools after adding dilution with toluene, adds water and keeps temperature; the organic phase of reaction mixture is separated; use biphosphate sodium water solution respectively, water, saturated brine washs.Rotary evaporation obtains light yellow oil a.
The preparation of step 2 compound b
The dichloromethane solution of aluminum chloride is cooled to 0 DEG C, slowly adds raw material 3, keeps 0 DEG C to stir 1h, then the dichloromethane solution of raw material 2 is slowly dripped, detect to reacting end, reaction mixture is poured in frozen water, and with dichloromethane extraction three times, merge organic phase, use dilute hydrochloric acid respectively, water, NaOH (1N), saturated brine washs, Na 2sO 4drying, rotary evaporation organic phase, column chromatography obtains target compound b.
The preparation of step 3 compound c
Compound b is dissolved in trifluoroacetic acid, then triethyl silicane and boron trifluoride diethyl etherate is added, by reaction solution reflux, add saturated aqueous sodium carbonate after completion of the reaction and regulate pH=8, extraction into ethyl acetate obtains organic phase, and wash organic phase with saturated brine, vacuum-drying obtains crude Compound c.
The preparation of step 4 compound d
Compound c is dissolved in anhydrous THF; be cooled to-78 DEG C; nitrogen protection; after dripping n-BuLi, drip the hexane solution of compound a, keep stirring reaction; then reaction mixture saturated aqueous ammonium chloride cancellation; extraction into ethyl acetate water layer, the organic phase washed with water of merging and saturated brine washing, rotary evaporation obtains oily matter compound d.
The preparation of step 5 Verbindung
Compound d is dissolved in absolute methyl alcohol, adds the absolute methanol solution of methylsulfonic acid under cooling, slowly rise to stirring at room temperature, use saturated NaHCO after completion of the reaction 3solution regulates, and is extracted with ethyl acetate, the organic phases washed with water of merging, saturated common salt water washing, dry, revolves steaming and obtains Verbindung.
The preparation of step 6 compound f
By Verbindung, diisopropyl ethyl amine and DMAP are dissolved in THF, be cooled to zero degree, slowly add diacetyl oxide, stir, reaction mixture saturated sodium bicarbonate aqueous solution regulates, and be extracted with ethyl acetate, the organic phase washed with water of merging and saturated common salt water washing, dry, rotary evaporation concentrates, and column chromatography obtains compound f.
The preparation of step 7 compound g
Triethyl silicane or tri isopropyl silane and boron trifluoride diethyl etherate is added under being cooled by the acetonitrile solution of compound f, detect to reacting end, saturated sodium bicarbonate solution cancellation is reacted, and be extracted with ethyl acetate, the organic phase washed with water merged and saturated common salt water washing, drying, rotary evaporation concentrates, and recrystallization (normal hexane and ethyl acetate) obtains compound g.
The preparation of step 8 formula I ' compound
By in the mixing solutions of compound g tetrahydrofuran (THF) and methyl alcohol, the aqueous solution of a hydronium(ion) Lithium Oxide 98min is added under zero degree, reaction also slowly rises to room temperature, stir, detection reaction terminates, concentration of reaction solution, add dichloromethane extraction, by the organic phase washed with water of merging and saturated common salt water washing, dry, concentrate and obtain formula I ' compound.
In reaction scheme, R 1, R 2, R 3, R 4, R 5, R 6a, R 6b, R 6c, m, n and A as defined hereinabove.
The ester of the intermediate of compound in preparation process, its pharmacy acceptable salt, its facile hydrolysis shown in the further claimed logical formula I of the present invention or its steric isomer.
" pharmacy acceptable salt " of the above-mentioned arbitrary compound of the present invention comprises an alkali metal salt, as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt, as calcium salt, magnesium salts etc.; Other metal-salts, as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts, as ammonium salt; Organic alkali salt, as tertiary octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) aminomethane salt; Halogen acid salt, as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt, as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate, as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt, as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts, as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.
" ester of facile hydrolysis " of the above-mentioned arbitrary compound of the present invention refers to that those can be hydrolyzed the pharmaceutically acceptable ester generating parent compound in human body.It is evident that for those skilled in the art, the ester being easy to be hydrolyzed of the compounds of this invention can be formed at the free carboxy of this compound or hydroxyl place, can be obtained by ordinary method.
" steric isomer " of the above-mentioned arbitrary compound of the present invention comprises all differences to stereoisomerism, diastereo-isomerism and tautomeric form.When a key represents with a wedge, this to show that in three-dimensional this key will from paper out, and when a key is shade, this shows that this key will return in paper in three-dimensional.
The present invention is claimed further comprises arbitrary compound recited above, its pharmacy acceptable salt, the ester of its facile hydrolysis or the pharmaceutical composition of its steric isomer and other active pharmaceutical ingredients.
The present invention also comprises above-mentioned arbitrary compound, its pharmacy acceptable salt, the ester of its facile hydrolysis or its steric isomer, can be mixed with clinically by manner known in the art or pharmaceutically acceptable arbitrary formulation, with oral, parenteral, rectum or be applied to through modes such as lung administrations the patient needing this treatment.During for oral administration, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.When making oral preparations, suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc. can be added.During for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, the ordinary method in existing pharmacy field can be adopted to produce, during preparation injection, can not additives be added, also can add suitable additives according to the character of medicine.During for rectal administration, can be made into suppository etc.For through lung administration time, can be made into inhalation or sprays etc.
Present invention also offers the compounds of this invention and prepare the application treated and/or prevented in the medicine of diabetes.C-glycosides derivatives of the present invention can be used in outside the diabetes such as diabetes (type i diabetes), non insulin dependent diabetes (type ii diabetes) as insulin-dependent, the treatment comprising insulin resistance disease and fat various diabetes related diseases can also be used for, and the prevention of these diseases.
The compounds of this invention has following characteristics:
(1) the compounds of this invention is to the white 2(SGLT-2 of sodium glucose co-transporter 2) restraining effect and hypoglycemic activity remarkable, can being used for the treatment of and/or preventing the diabetes of various Mammals (comprising the mankind) and the various diseases caused by diabetes by safety;
(2) the compounds of this invention shows good physico-chemical property, and toxicity is low, few side effects;
(3) the compounds of this invention preparation technology is simple, and medicine purity is high, steady quality, is easy to carry out large-scale commercial production.
Set forth the compounds of this invention beneficial effect further below by way of pharmacological evaluation, but this should be interpreted as the compounds of this invention only has following beneficial effect.
Pharmacologically active in external, the body of experimental example the compounds of this invention
1, the in-vitro evaluation experiment of the compounds of this invention
In-vitro evaluation method of the present invention is that SGLT2 and the SGLT1 sequence of people is transfected into stably express on Chinese hamster ovary cell, by T suppression cell to [ 14c]-mark-R-methyl-D-glucopyranose glycosides (AMG) the dependent absorption of sodium, record 503nhibiting concentration IC 50.
Trial-product: part of compounds of the present invention, self-control, its chemical name and structural formula are as mentioned before.
Buffer?A(KRH-Na+)：120mM?NaCl，4.7mM?KCl，1.2mM?MgCl2，2.2mM?CaCl2，10mM?HEPES(PH?7.4with?1mM?Tris);
Buffer?A-(KRH-NMG)：120mM?NMG，4.7mM?KCl，1.2mM?MgCl2，2.2mM?CaCl2，10mM?HEPES(PH?7.4with?1mM?Tris);
Buffer?D：120mM?NaCl，4.7mM?KCl，1.2mM?MgCl2，2.2mM?CaCl2，10mM?HEPES，0.5mM?phlorizin(PH?7.4?with?1mM?Tris)。
Experimental technique: sequence stably express on Chinese hamster ovary celI of SGLT2 and SGLT1 of people, on 96 orifice plates, carry out cell cultures 12 hours, with KRH-Na+ (Buffer A) or KRH-NMG (Buffer A-) buffered soln 200 μ l/ hole, rinse 3 times.Again with the damping fluid 100 μ l/ hole added containing BufferA or BufferA-plus [14C]-AMG (10 μ Ci/mL), hatch 1 hour for 37 DEG C.Then, add ice-cold buffered soln (Buffer D) 100 μ l and stop test, clean 5 times.Add 100mM NaOH solution 20 μ l/ hole, 600rpm is centrifugal, 5 minutes, and Microscint 40 solution 80 μ l/ hole, and 600rpm is centrifugal, 5 minutes.Finally with scintillation counting technique MicroBeta Trilux (purchased from PerkinElmer company) detect [ 14c] radioactivity of-AMG, calculate 503nhibiting concentration IC 50.
Experimental result and conclusion:
The restraining effect evaluation result of table 1 the compounds of this invention is as follows:
It can thus be appreciated that the compounds of this invention has good restraining effect and good selectivity to SGLT2.
2, normal mice glucose in urine experiment
Trial-product: part of compounds of the present invention, self-control, its chemical name and structural formula are as mentioned before.
Experimental technique: glucose in urine experimental technique is for getting SPF level male Sprague-Dawley rat, in 6 week age, after animal fasting 15h, be divided into blank group, model group, positive drug group, test medicine group at random according to rat body weight, put into metabolic cage, feed water not feeding, collects 24h urine.Then oral administration (10mg/Kg) gives sugar (5g/kg) afterwards, then puts into metabolic cage, and administration is to supply food after sugared 1h, and free diet, collects 24h urine, record urine volume.By the centrifugal 15min of urine 3000rpm collected, remove residue, get supernatant, measure glucose in urine content wherein.Glucose in urine content is weight normalized with 200g.Data represent with means standard deviation, and income value analysis adopts one-way analysis of variance, and compare between group and adopt one-way analysis of variance Dunnett inspection, p<0.05 thinks to have statistical significance.
Table 2: the glucose in urine experimental result of compound:
In sum, the compounds of this invention shows good blood sugar reducing function.
4, embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.
embodiment 1 β-1 '-deoxidation-1 '-(the chloro-3-of 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose acetal the preparation of (compound 1)
The preparation of step 12,3,4,6-tetra-(trimethylsilyl ethers)-Gluconolactone
By raw material 1 (239g; 1.34mol) with N-methylmorpholine (1.18L; 10.73mol) be dissolved in THF (2.4L);-5 DEG C are cooled under nitrogen protection; slow dropping trimethylsilyl chloride (1022mL; 8.05mol); keep dripping process temperature and be no more than 5 DEG C; after be warming up to 35 DEG C stir 5h, then stirring at room temperature 15h, be cooled to 0-5 DEG C after adding dilution with toluene; then adding water keeps temperature to be no more than 10 DEG C; the organic phase of reaction mixture is separated, uses biphosphate sodium water solution respectively, water and saturated common salt water washing.Rotary evaporation obtains light yellow oil 2,3,4,6-tetra-(trimethylsilyl ethers)-Gluconolactone 593.2g, productive rate 92%.
The preparation of the chloro-3-of step 2 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-formyl radical) bromobenzene
By aluminum chloride (2.8g, dichloromethane solution (25mL) 21mmol) is cooled to 0 DEG C, slowly add compound (1a, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene (3.77g, 21.3mmol), 0 DEG C is kept to stir 1h, then slowly the bromo-Benzoyl chloride (6.9g of the chloro-5-of compound 2-is dripped, dichloromethane solution (15mL) 21.3mmol), detect to reacting end, reaction mixture is poured into (150mL) in frozen water, and with dichloromethane extraction (3 × 100mL), merge organic phase, use dilute hydrochloric acid (1N) respectively, water, NaOH (1N), saturated common salt water washing, anhydrous Na 2sO 4drying, rotary evaporation organic phase, column chromatography (n-hexane/ethyl acetate=1/20) obtains the chloro-3-of target compound 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-formyl radical) bromobenzene 7.03g, productive rate 80%.
The preparation of step 3 compound 4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) bromobenzene
By compound 4-chloro-3-(1a, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-formyl radical) bromobenzene (16.5g, 39.9mmol) be dissolved in (30mL) in trifluoroacetic acid, then triethyl silicane (7.86g is added, 67.6mmol) with boron trifluoride diethyl etherate (9.60g, 67.6mmol), reaction solution reflux 16h. is added saturated aqueous sodium carbonate and regulate pH=8, extraction into ethyl acetate obtains organic phase, and wash organic phase with saturated brine, vacuum-drying obtains the chloro-3-(1a of crude Compound 4-, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) bromobenzene 10.7g, productive rate 71%.
The preparation of step 4 compound 1 '-(the chloro-3-of 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose hemiacetal
By compound 4-chloro-3-(1a, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical)) bromobenzene (20.7g, 46mmol) be dissolved in anhydrous THF(150mL) in, be cooled to-78 DEG C, then n-BuLi (2.5M is slowly dripped under nitrogen protection, 18.4mL, 46mmol), after keeping stirring 3h, slowly compound 2 is dripped at-78 DEG C, 3, 4, the hexane solution (300mL) of 6-tetra-(trimethylsilyl ethers)-Gluconolactone, keep stirring 0.5h, then reaction mixture saturated aqueous ammonium chloride (100mL) cancellation, extraction into ethyl acetate water layer (3 × 100mL), the organic phase washed with water merged and saturated brine washing, rotary evaporation obtains the oily matter compound 1 '-(chloro-3-(1a of 4-, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose hemiacetal 18.2g, productive rate 82%.
Step 5 compound 1 '-O-methyl isophthalic acid ' preparation of-(the chloro-3-of 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose acetal
By the compound 1 '-(chloro-3-(1a of 4-, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose hemiacetal (4.86g, 10.0mmol) be dissolved in absolute methyl alcohol (10mL), be cooled to 0 DEG C, add anhydrous methanol (10mL) solution of methylsulfonic acid (0.4mL), slowly rise to stirring at room temperature 16h, use saturated NaHCO 3the aqueous solution regulates pH=8, and be extracted with ethyl acetate, the organic phases washed with water merged, saturated common salt water washing, dry, revolve steaming and obtain compound 1 '-O-methyl isophthalic acid '-(chloro-3-(1a of 4-, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical))-glucose acetal 4.95g, 100%.
Step 6 compound 1 '-O-methyl isophthalic acid '-(the chloro-3-of 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-2 ', the preparation of 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
By compound 1 '-O-methyl isophthalic acid '-(chloro-3-(1a of 4-, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose acetal (4.39g, 9.1mmol), diisopropyl ethyl amine (9.4g, 72.8mmol) be dissolved in THF (100mL) with DMAP (10mg), be cooled to zero degree, slowly add diacetyl oxide (7.43g, 72.8mmol), stir 0.5h, reaction mixture saturated sodium bicarbonate aqueous solution regulates pH=8, and be extracted with ethyl acetate (3 × 60mL), the organic phase washed with water (70mL) merged and saturated aqueous common salt (70mL) washing, dry, rotary evaporation concentrates, column chromatography obtains compound 1 '-O-methyl isophthalic acid '-(chloro-3-(1a of 4-, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal 3.93g, productive rate 65%.
Step 7 compound β-1 '-deoxidation-1 '-(the chloro-3-of 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-2 ', the preparation of 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
By compound 1 '-O-methyl isophthalic acid '-(chloro-3-(1a of 4-, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal (7.48g, acetonitrile solution (50mL) 16.0mmol) is cooled to 10 DEG C, add tri isopropyl silane (5.1g, 32mmol) with boron trifluoride diethyl etherate (6.8g, 48mmol), detect to reacting end, saturated sodium bicarbonate solution cancellation is reacted, and be extracted with ethyl acetate (3 × 100mL), the organic phase washed with water merged and saturated common salt water washing, dry, rotary evaporation concentrates, recrystallization (n-hexane/ethyl acetate=1/15, V/V) compound β-1 '-deoxidation-1 is obtained '-(chloro-3-(1a of 4-, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal 7.50g, productive rate 74%.
Step 8 compound β-1 '-deoxidation-1 ' preparation of-(the chloro-3-of 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose acetal
By compound β-1 '-deoxidation-1 '-(chloro-3-(1a of 4-, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal (10g, 15.7mmol) be dissolved in the mixing solutions of tetrahydrofuran (THF)-Ji (100mL) and methyl alcohol (100mL), a hydronium(ion) Lithium Oxide 98min (4.4g is added under zero degree, the aqueous solution (50mL) 104mmol), reaction solution slowly rises to room temperature, stir 14h, detection reaction terminates, concentration of reaction solution, add dichloromethane extraction, by the organic phase washed with water of merging and saturated common salt water washing, dry, concentrate and obtain compound β-1 '-deoxidation-1 '-(chloro-3-(1a of 4-, 2, 7, 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose acetal 5.93g, productive rate 81%.LC-MS(M+H) +:431.
embodiment 2 β-1 '-deoxidation-1 '-(the chloro-3-of 4-(3,3a, 4,9,9a-hexahydro naphthalene [2,3-c] furans-6-methylene radical) benzene)-glucose acetal (chemical combination thing 2) preparation
Reference example 1 obtains compound β-1 '-deoxidation-1 '-(the chloro-3-of 4-(3,3a, 4,9,9a-hexahydro naphthalene [2,3-c] furans-6-methylene radical) benzene)-glucose acetal.LC-MS(M+H) +:461.
embodiment 3 β-1 '-deoxidation-1 '-(the chloro-3-of 4-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) benzene) preparation of-glucose acetal (compound 3)
The chloro-3-((2 of step 1 4-, 3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins)-6-formyl radical) preparation of bromobenzene
By aluminum chloride (2.8g, dichloromethane solution (25mL) 21mmol) is cooled to 0 DEG C, slowly add compound phenyl ethyl ether (3.77g, 21.3mmol), 0 DEG C is kept to stir 1h, then slowly dripping the dichloromethane solution (15mL) of the bromo-Benzoyl chloride (6.9g, 21.3mmol) of the chloro-5-of compound 2-, detecting to reacting end, reaction mixture is poured into (150mL) in frozen water, and with dichloromethane extraction (3 × 100mL), merge organic phase, use dilute hydrochloric acid (1N) respectively, water, NaOH (1N), saturated common salt water washing, anhydrous Na 2sO 4drying, rotary evaporation organic phase, column chromatography (n-hexane/ethyl acetate=1/20) obtains the chloro-3-((2 of target compound 4-; 3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [E] [1; 4] Dioxins)-6-formyl radical) bromobenzene 7.03g, productive rate 80%.
Step 2 compound 4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) preparation of bromobenzene
By compound 4-chloro-3-((2, 3, 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1, 4] Dioxins)-6-formyl radical) bromobenzene (16.5g, 39.9mmol) be dissolved in (30mL) in trifluoroacetic acid, then triethyl silicon (7.86g is added, 67.6mmol), reaction solution reflux 16h. is added saturated aqueous sodium carbonate and regulate pH=8, extraction into ethyl acetate obtains organic phase, and wash organic phase with saturated brine, vacuum-drying obtains the chloro-3-((2 of crude Compound 4-, 3, 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1, 4] Dioxins) 6-methylene radical)) bromobenzene 10.6g, productive rate 71%.
Step 3 compound 1 '-(the chloro-3-((2 of 4-, 3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene) preparation of-glucose hemiacetal
By compound 4-chloro-3-((2, 3, 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1, 4] Dioxins) 6-methylene radical)) bromobenzene (20.7g, 46mmol) be dissolved in anhydrous THF(150mL) in, be cooled to-78 DEG C, then n-BuLi (2.5M is slowly dripped under nitrogen protection, 18.4mL, 46mmol), after keeping stirring 3h, slowly compound 2 is dripped at-78 DEG C, 3, 4, the hexane solution (300mL) of 6-tetra-(trimethylsilyl ethers)-Gluconolactone, keep stirring 0.5h, then reaction mixture saturated aqueous ammonium chloride (100mL) cancellation, extraction into ethyl acetate water layer (3 × 100mL), the organic phase washed with water merged and saturated brine washing, rotary evaporation obtains oily matter compound 1 '-(the chloro-3-((2 of 4-, 3, 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1, 4] Dioxins) 6-methylene radical) benzene)-glucose hemiacetal 18.2g, productive rate 82%.
Step 4 compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((2 of 4-, 3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene) preparation of-glucose acetal
By compound 1 '-(the chloro-3-((2 of 4-, 3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-glucose hemiacetal (4.82g, 10.0mmol) is dissolved in absolute methyl alcohol (10mL), be cooled to 0 DEG C, add anhydrous methanol (10mL) solution of methylsulfonic acid (0.4mL), slowly rise to stirring at room temperature 16h, use saturated NaHCO 3the aqueous solution regulates pH=8, and be extracted with ethyl acetate, the organic phases washed with water merged, saturated common salt water washing, dry, revolve steaming and obtain compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((2 of 4-, 3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1,4] Dioxins) 6-methylene radical))-glucose acetal 4.93g, 100%.
Step 5 compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((2 of 4-, 3,3a; 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-2 ', 3 '; the preparation of 4 ', 6 '-tetra-acetylated-glucose acetal
By compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((2 of 4-, 3, 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1, 4] Dioxins) 6-methylene radical) benzene)-glucose acetal (4.39g, 9.1mmol), diisopropyl ethyl amine (9.4g, 72.8mmol) be dissolved in THF (100mL) with DMAP (10mg), be cooled to zero degree, slowly add diacetyl oxide (7.43g, 72.8mmol), stir 0.5h, reaction mixture saturated sodium bicarbonate aqueous solution regulates pH=8, and be extracted with ethyl acetate (3 × 60mL), the organic phase washed with water (70mL) merged and saturated aqueous common salt (70mL) washing, dry, rotary evaporation concentrates, column chromatography obtains compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((2 of 4-, 3, 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1, 4] Dioxins) 6-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal 3.96g, productive rate 66%.
Step 6 compound β-1 '-deoxidation-1 '-(the chloro-3-((2 of 4-, 3,3a; 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) benzene)-2 ', 3 '; the preparation of 4 ', 6 '-tetra-acetylated-glucose acetal
By compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((1 of 4-, 3, 3a, 9a-tetrahydro benzo [b] furans [3, 4-e] [1, 4] Dioxins) 6-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal (7.48g, acetonitrile solution (50mL) 16.0mmol) is cooled to 10 DEG C, add triethyl silicon (5.1g, 32mmol) with boron trifluoride diethyl etherate (6.8g, 48mmol), detect to reacting end, saturated sodium bicarbonate solution cancellation is reacted, and be extracted with ethyl acetate (3 × 100mL), the organic phase washed with water merged and saturated common salt water washing, dry, rotary evaporation concentrates, recrystallization (n-hexane/ethyl acetate=1/15, V/V) compound β-1 '-deoxidation-1 is obtained '-(the chloro-3-((2 of 4-, 3, 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1, 4] Dioxins) 6-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal 7.48g, productive rate 74%.
Step 7 compound β-1 '-deoxidation-1 '-(the chloro-3-((2 of 4-, 3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene) preparation of-glucose acetal
By compound β-1 '-deoxidation-1 '-(the chloro-3-((2 of 4-, 3, 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1, 4] Dioxins) 6-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal (10g, 15.7mmol) be dissolved in the mixing solutions of tetrahydrofuran (THF) (100mL) and methyl alcohol (100mL), a hydronium(ion) Lithium Oxide 98min (4.4g is added under zero degree, the aqueous solution (50mL) 104mmol), reaction solution slowly rises to room temperature, stir 14h, detection reaction terminates, concentration of reaction solution, add dichloromethane extraction, by the organic phase washed with water of merging and saturated common salt water washing, dry, concentrate and obtain compound β-1 '-deoxidation-1 '-(the chloro-3-((2 of 4-, 3, 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1, 4] Dioxins) 6-methylene radical) benzene)-glucose acetal 5.91g, productive rate 80%. 1H?NMR(400MHz,MeOH-d 4):7.34(m,2H),7.28(m,1H),6.75(m,1H),6.69(m,2H),4.10(m,1H),3.96(m,2H),3.89(m,4H),3.68(m,1H),3.43(m,3H),2.13(m,2H),1.91(m,2H),1.67(m,2H)
LC-MS(M+H) +:463.
embodiment 4 β-1 '-deoxidation-1 '-(the chloro-3-of 4-(5a, 6,7,8,8a, 9-six hydrogen pentamethylene [e] pyridine [3,2-b] [Isosorbide-5-Nitrae] oxazines-6-methylene radical) benzene) preparation of-glucose acetal (compound 4)
The chloro-3-((1 of step 1 4-, 3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins)-6-formyl radical) preparation of bromobenzene
By aluminum chloride (2.8g, dichloromethane solution (25mL) 21mmol) is cooled to 0 DEG C, slowly add compound phenyl ethyl ether (3.77g, 21.3mmol), 0 DEG C is kept to stir 1h, then slowly dripping the dichloromethane solution (15mL) of the bromo-Benzoyl chloride (6.9g, 21.3mmol) of the chloro-5-of compound 2-, detecting to reacting end, reaction mixture is poured into (150mL) in frozen water, and with dichloromethane extraction (3 × 100mL), merge organic phase, use dilute hydrochloric acid (1N) respectively, water, NaOH (1N), saturated common salt water washing, anhydrous Na 2sO 4drying, rotary evaporation organic phase, column chromatography (n-hexane/ethyl acetate=1/20) obtains the chloro-3-((1 of target compound 4-; 3,3a, 9a-tetrahydro benzo [b] furyl [3; 4-e] [Isosorbide-5-Nitrae] Dioxins)-6-formyl radical) bromobenzene 7.03g, productive rate 80%.
Step 2 compound 4-chloro-3-((1,3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) preparation of bromobenzene
By compound 4-chloro-3-((1, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins)-6-formyl radical) bromobenzene (16.5g, 39.9mmol) be dissolved in (30mL) in trifluoroacetic acid, then triethyl silicane (7.86g is added, 67.6mmol), reaction solution reflux 16h. is added saturated aqueous sodium carbonate and regulate pH=8, extraction into ethyl acetate obtains organic phase, and wash organic phase with saturated brine, vacuum-drying obtains the chloro-3-((1 of crude Compound 4-, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins) 6-methylene radical)) bromobenzene 10.7g, productive rate 71%.
Step 3 compound 1 '-(the chloro-3-((1 of 4-, 3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene) preparation of-glucose hemiacetal
By compound 4-chloro-3-((1, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins) 6-methylene radical)) bromobenzene (20.7g, 46mmol) be dissolved in anhydrous THF(150mL) in, be cooled to-78 DEG C, then n-BuLi (2.5M is slowly dripped under nitrogen protection, 18.4mL, 46mmol), after keeping stirring 3h, slowly compound 2 is dripped at-78 DEG C, 3, 4, the hexane solution (300mL) of 6-tetra-(trimethylsilyl ethers)-Gluconolactone, keep stirring 0.5h, then reaction mixture saturated aqueous ammonium chloride (100mL) cancellation, extraction into ethyl acetate water layer (3 × 100mL), the organic phase washed with water merged and saturated brine washing, rotary evaporation obtains oily matter compound 1 '-(the chloro-3-((1 of 4-, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins) 6-methylene radical) benzene)-glucose hemiacetal 18.2g, productive rate 82%.
Step 4 compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((1 of 4-, 3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene) preparation of-glucose acetal
By compound 1 '-(the chloro-3-((1 of 4-, 3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [1,4] Dioxins) 6-methylene radical) benzene)-glucose hemiacetal (4.86g, 10.0mmol) be dissolved in absolute methyl alcohol (10mL), be cooled to 0 DEG C, add anhydrous methanol (10mL) solution of methylsulfonic acid (0.4mL), slowly rise to stirring at room temperature 16h, use saturated NaHCO 3the aqueous solution regulates pH=8, and be extracted with ethyl acetate, the organic phases washed with water of merging, saturated common salt water washing, dry, revolve steaming and obtain compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((1 of 4-, 3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical))-glucose acetal 4.95g, 100%.
Step 6 compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((1 of 4-, 3,3a; 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-2 '; the preparation of 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
By compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((1 of 4-, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins) 6-methylene radical) benzene)-glucose acetal (4.39g, 9.1mmol), diisopropyl ethyl amine (9.4g, 72.8mmol) be dissolved in THF (100mL) with DMAP (10mg), be cooled to zero degree, slowly add diacetyl oxide (7.43g, 72.8mmol), stir 0.5h, reaction mixture saturated sodium bicarbonate aqueous solution regulates pH=8, and be extracted with ethyl acetate (3 × 60mL), the organic phase washed with water (70mL) merged and saturated aqueous common salt (70mL) washing, dry, rotary evaporation concentrates, column chromatography obtains compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((1 of 4-, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins) 6-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal 3.93g, productive rate 65%.
Step 7 compound β-1 '-deoxidation-1 '-(the chloro-3-((1 of 4-, 3,3a; 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) benzene)-2 '; the preparation of 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
By compound 1 '-O-methyl isophthalic acid '-(the chloro-3-((1 of 4-, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins) 6-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal (7.48g, acetonitrile solution (50mL) 16.0mmol) is cooled to 10 DEG C, add triethyl silicon (5.1g, 32mmol) with boron trifluoride diethyl etherate (6.8g, 48mmol), detect to reacting end, saturated sodium bicarbonate solution cancellation is reacted, and be extracted with ethyl acetate (3 × 100mL), the organic phase washed with water merged and saturated common salt water washing, dry, rotary evaporation concentrates, recrystallization (n-hexane/ethyl acetate=1/15, V/V) compound β-1 '-deoxidation-1 is obtained '-(the chloro-3-((1 of 4-, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins) 6-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal 7.50g, productive rate 74%.
Step 8 compound β-1 '-deoxidation-1 '-(the chloro-3-((1 of 4-, 3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) benzene) preparation of-glucose acetal
By compound β-1 '-deoxidation-1 '-(the chloro-3-((1 of 4-, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins) 6-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal (10g, 15.7mmol) be dissolved in the mixing solutions of tetrahydrofuran base (100mL) and methyl alcohol (100mL), a hydronium(ion) Lithium Oxide 98min (4.4g is added under zero degree, the aqueous solution (50mL) 104mmol), reaction solution slowly rises to room temperature, stir 14h, detection reaction terminates, concentration of reaction solution, add dichloromethane extraction, by the organic phase washed with water of merging and saturated common salt water washing, dry, concentrate and obtain compound β-1 '-deoxidation-1 '-(the chloro-3-((1 of 4-, 3, 3a, 9a-tetrahydro benzo [b] furyl [3, 4-e] [1, 4] Dioxins)-6-methylene radical) benzene)-glucose acetal 5.93g, productive rate 81%. 1H?NMR(400MHz,CDCl 3):δ7.33(m,1H),7.17(m,2H),6.85(m,1H),6.74(m,2H),4.12-4.35(m,4H),3.89-4.12(m,3H),3.72-3.89(m,4H),3.57-3.72(m,2H),3.29-3.45(m,2H).
LC-MS(M+H) +:465.
embodiment 5 β-1 '-deoxidation-1 ' (the change of-(the chloro-3-of 4-(1 ', 3 '-dihydro spiral shell [cyclopentyl-1,2 '-indenes]-5-methylene radical) benzene)-glucose acetal compound 5) preparation
Reference example 3 obtains compound β-1 '-deoxidation-1 '-(the chloro-3-of 4-(1 ', 3 '-dihydro spiral shell [cyclopentyl-1,2 '-indenes]-5-methylene radical) benzene)-glucose acetal.LC-MS(M+H) +:459.
embodiment 6 β-1 '-deoxidation-1 '-(the chloro-3-of 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclobutyl spiral shell [b] naphthalene-4-methylene radical) benzene)-glucose acetal the preparation of (compound 6)
Reference example 3 obtains compound β-1 '-deoxidation-1 '-(the chloro-3-of 4-(1a, 2,7,7a-tetrahydrochysene-1H-cyclobutyl spiral shell [b] naphthalene-4-methylene radical) benzene)-glucose acetal.LC-MS(M+H) +:459.
embodiment 7 β-1 '-deoxidation-1 '-(the chloro-3-of 4-(1,3-dihydro spiral shell (indenes-2,3 '-oxetanylmethoxy-5-methylene radical) benzene)-glucose acetal the preparation of (compound 7)
Reference example 3 obtains compound β-1 '-deoxidation-1 '-(the chloro-3-of 4-(1,3-dihydro spiral shell (indenes-2,3 '-oxetanylmethoxy)-5-methylene radical) benzene)-glucose acetal.LC-MS(M+H) +:447.
embodiment 8 β-1 '-deoxidation-1 '-(the chloro-3-of 4-(1 ', 3 ', 4,5-tetrahydrochysene-2H-spiral shell (furans-3,2 '-indenes)-5-methylene radical) benzene)-glucose acetal the preparation of (compound 8)
Reference example 3 obtains compound β-1 '-deoxidation-1 '-(the chloro-3-of 4-(1 ', 3 ', 4,5-tetrahydrochysene-2H-spiral shell (furans-3,2 '-indenes)-5-methylene radical) benzene)-glucose acetal.LC-MS(M+H) +:461.
embodiment 9 β-1 '-deoxidation-1 '-(the chloro-3-of 4-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene)-Portugal the preparation of grape sugar acetal (compound 9)
The chloro-3-(4 ' of step 1 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-formyl radical) preparation of bromobenzene
By aluminum chloride (2.8g, dichloromethane solution (25mL) 21mmol) is cooled to 0 DEG C, slowly add compound phenyl ethyl ether (3.77g, 21.3mmol), 0 DEG C is kept to stir 1h, then slowly dripping the dichloromethane solution (15mL) of the bromo-Benzoyl chloride (6.9g, 21.3mmol) of the chloro-5-of compound 2-, detecting to reacting end, reaction mixture is poured into (150mL) in frozen water, and with dichloromethane extraction (3 × 100mL), merge organic phase, use dilute hydrochloric acid (1N) respectively, water, NaOH (1N), saturated common salt water washing, anhydrous Na 2sO 4drying, rotary evaporation organic phase, column chromatography (n-hexane/ethyl acetate=1/20) obtains the chloro-3-(4 ' of target compound 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-formyl radical) and bromobenzene 7.03g, productive rate 80%.
Step 2 compound 4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) preparation of bromobenzene
By compound 4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-formyl radical) bromobenzene (16.5g, 39.9mmol) be dissolved in (30mL) in trifluoroacetic acid, then triethyl silicon (7.86g is added, 67.6mmol), reaction solution reflux 16h. is added saturated aqueous sodium carbonate and regulate pH=8, extraction into ethyl acetate obtains organic phase, and wash organic phase with saturated brine, vacuum-drying obtains the chloro-3-(4 ' of crude Compound 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-methylene radical) bromobenzene 10.6g, productive rate 71%.
The preparation of step 3 compound 1 '-(the chloro-3-of 4-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene)-glucose hemiacetal
By compound 4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-methylene radical) benzene) bromobenzene (20.7g, 46mmol) be dissolved in anhydrous THF(150mL) in, be cooled to-78 DEG C, then n-BuLi (2.5M is slowly dripped under nitrogen protection, 18.4mL, 46mmol), after keeping stirring 3h, slowly compound 2 is dripped at-78 DEG C, 3, 4, the hexane solution (300mL) of 6-tetra-(trimethylsilyl ethers)-Gluconolactone, keep stirring 0.5h, then reaction mixture saturated aqueous ammonium chloride (100mL) cancellation, extraction into ethyl acetate water layer (3 × 100mL), the organic phase washed with water merged and saturated brine washing, rotary evaporation obtains oily matter compound 1 '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-methylene radical) benzene)-glucose hemiacetal 18.2g, productive rate 82%.
Step 4 compound 1 '-O-methyl isophthalic acid '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene) preparation of-glucose acetal
By compound 1 '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene)-glucose hemiacetal (4.82g, 10.0mmol) be dissolved in absolute methyl alcohol (10mL), be cooled to 0 DEG C, add anhydrous methanol (10mL) solution of methylsulfonic acid (0.4mL), slowly rise to stirring at room temperature 16h, use saturated NaHCO 3the aqueous solution regulates pH=8, and be extracted with ethyl acetate, the organic phases washed with water merged, saturated common salt water washing, dry, revolve steaming and obtain compound 1 '-O-methyl isophthalic acid '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone, 2,3 '-furans)-5-methylene radical) benzene)-glucose acetal 4.93g, 100%.
Step 5 compound 1 '-O-methyl isophthalic acid '-(the chloro-3-of 4-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2; 3 '-furans)-5-methylene radical) benzene)-2 '; the preparation of 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
By compound 1 '-O-methyl isophthalic acid '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-methylene radical) benzene)-glucose acetal (4.39g, 9.1mmol), diisopropyl ethyl amine (9.4g, 72.8mmol) be dissolved in THF (100mL) with DMAP (10mg), be cooled to zero degree, slowly add diacetyl oxide (7.43g, 72.8mmol), stir 0.5h, reaction mixture saturated sodium bicarbonate aqueous solution regulates pH=8, and be extracted with ethyl acetate (3 × 60mL), the organic phase washed with water (70mL) merged and saturated aqueous common salt (70mL) washing, dry, rotary evaporation concentrates, column chromatography obtains compound 1 '-O-methyl isophthalic acid '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal 3.96g, productive rate 66%.
Step 6 compound β-1 '-deoxidation-1 '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene)-2 ', the preparation of 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
By compound 1 '-O-methyl isophthalic acid '-(4-chloro-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal (7.48g, acetonitrile solution (50mL) 16.0mmol) is cooled to 10 DEG C, add triethyl silicon (5.1g, 32mmol) with boron trifluoride diethyl etherate (6.8g, 48mmol), detect to reacting end, saturated sodium bicarbonate solution cancellation is reacted, and be extracted with ethyl acetate (3 × 100mL), the organic phase washed with water merged and saturated common salt water washing, dry, rotary evaporation concentrates, recrystallization (n-hexane/ethyl acetate=1/15, V/V) compound β-1 '-deoxidation-1 is obtained '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal 7.48g, productive rate 74%.
Step 7 compound β-1 '-deoxidation-1 '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene) preparation of-glucose acetal
By compound β-1 '-deoxidation-1 '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal (10g, 15.7mmol) be dissolved in the mixing solutions of tetrahydrofuran (THF) (100mL) and methyl alcohol (100mL), a hydronium(ion) Lithium Oxide 98min (4.4g is added under zero degree, the aqueous solution (50mL) 104mmol), reaction solution slowly rises to room temperature, stir 14h, detection reaction terminates, concentration of reaction solution, add dichloromethane extraction, by the organic phase washed with water of merging and saturated common salt water washing, dry, concentrate and obtain compound β-1 '-deoxidation-1 '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2, 3 '-furans)-5-methylene radical) benzene)-glucose acetal 5.91g, productive rate 80%.
1H?NMR(400MHz,MeOH-d 4):7.34(m,2H),7.28(m,1H),7.01(m,1H),6.85(m,1H),6.60(m,1H),4.09(m,1H),4.03(m,5H),3.87(m,1H),3.70(m,2H),3.34-3.52(m,3H),3.29(m,1H),3.23(s,2H),2.29(m,1H),2.11(m,1H).
LC-MS(M+H) +:463.
embodiment 10 β-1 '-deoxidation-1 '-(the chloro-3-of 4-(4 ', 5 '-dihydro-2 ' H-spiral shell (benzo [d] [1,3] dioxole-2,3 '-furans)-5- methylene radical) benzene) preparation of-glucose acetal (compound 10)
Reference example 3 obtains compound β-1 '-deoxidation-1 '-(the chloro-3-(4 ' of 4-, 5 '-dihydro-2 ' H-spiral shell (benzo [d] [1,3] dioxole-2,3 '-furans)-5-methylene radical) benzene)-glucose acetal.LC-MS(M+H) +:465.
In addition, following compound is obtained with the racemic compound 1-10 that preparative HPLC gradient elution (C-18 pillar, eluent 5%-95% methanol/water) splits above-mentioned synthesis:

Claims (5)

1. logical compound shown in formula I or its pharmacy acceptable salt:
Wherein,
A ring is pentamethylene base or tetrahydrofuran base;
X, Y represent O atom respectively;
R 1represent halogen;
R 2, R 3, R 4represent hydrogen atom respectively;
R 5, R 6a, R 6b, R 6crepresent hydrogen atom respectively;
M is 0 or 1;
N is 0;
W is methylene radical.
2. compound as described below or its pharmacy acceptable salt:
3. compound as described below or its pharmacy acceptable salt:
4. comprising the pharmaceutical composition of compound described in the arbitrary claim of claim 1-3 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner, is pharmaceutically acceptable arbitrary formulation.
5. the compound as described in claim as arbitrary in claim 1-3 or its pharmacy acceptable salt are preparing the application treated and/or prevented in the medicine of diabetes.
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