CN102863417A - C-indican derivative - Google Patents

C-indican derivative Download PDF

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CN102863417A
CN102863417A CN2012102367779A CN201210236777A CN102863417A CN 102863417 A CN102863417 A CN 102863417A CN 2012102367779 A CN2012102367779 A CN 2012102367779A CN 201210236777 A CN201210236777 A CN 201210236777A CN 102863417 A CN102863417 A CN 102863417A
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alkyl
cycloalkyl
atom
halogen
aryl
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CN102863417B (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

The C-glycosides derivatives
1, technical field
The invention belongs to medical technical field, relate to the 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) such as insulin-dependent, non insulin dependent diabetes (type ii diabetes), can also be used for comprising the treatment of insulin resistance disease and the various diabetes relative diseases of obesity, 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 due to excessive Hepatic glucose production and the periphery insulin resistance.Hyperglycemia is considered to form the Major Risk Factors of diabetic complication, and may with late period type ii diabetes insulin secretion impaired directly related.Therefore can expect that the normalizing of the blood sugar among the type ii diabetes patient can improve the effect of Regular Insulin.Present existing diabetes medicament such as sulfonylurea, thiazolidinediones, N1,N1-Dimethylbiguanide and Regular Insulin have potential side effect, so the needs exploitation is new, safe and orally active antidiabetic medicine.
At kidney, glucose can be freely from glomerular filtration (approximately 180g/ days), but almost heavily absorb at the proximal convoluted tubule active transport.Wherein two sodium-glucose transporters have been brought into play vital role to the heavily absorption of glucose, i.e. SGLT1 and SGLT2.And the effect of SGLT2 is particularly outstanding.SGLT2 is only at the transmembrane protein of the S1 of proximal convoluted tubule section specifically expressing, one of its topmost physiological action is to absorb sugar part of flowing through in the uriniferous tubules blood, account for 90% of Reabsorption, SGLT2 transports with the ratio of sodium-glucose 1:1, the SGLT-2 inhibitor can suppress blood sugar in the absorption of uriniferous tubules, makes sugar part in a large number discharge from urine.And SGLT1 mainly expresses at distal convoluted tubule, accounts for 10% of Reabsorption, and SGLT1 is with the ratio transhipment of sodium-glucose 2:1.In enteron aisle and its hetero-organization, also found SGLT1 in addition.These transhipment play a role by Na+/ATP enzyme pump, and by glucose transporter 2(GLUT2) be transferred back in the blood.This shows that what most possibly develop into drug target is SGLT2 transhipment, be on the one hand it to the absolute Reabsorption of glucose, be that it only is expressed in kidney on the other hand.In the research to familial form ephrosis glucose in urine, also confirmed the feasibility of this approach.Familial ephrosis glucose in urine main manifestations is the glucose in urine (approximately 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 mainly be since SGLT-2 transhipment subbase because of due to the sudden change, this shows that optionally the pharmacology to SGLT-2 suppresses that it(?) may not can except inducing glycosuria produce adverse consequences.And suppress SGLT-1, and then can cause sugar-semi-lactosi malabsorption syndrome, can cause dehydration.
Suppress the heavily absorption of kidney sugar by acting on SGLT-2 transhipment and treat hyperglycemia, for the treatment of diabetes provides new approach.Although this approach can not directly act on the physiopathology of type ii diabetes, come lowering blood glucose by the drainage that increases kidney glucose, can cause the deficiency of net energy, 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 the effect of potential reduction body weight arranged.Whether the SGLT-2 inhibitor can occupy a tiny space in the pharmacological agent in type ii diabetes with final decision for the security of Long-term clinical experiment and validity.
Wherein, WO0127128, the patent documentations such as US2005209166 disclose a series of compounds as the SGLT-2 inhibitor.
3, summary of the invention
The present invention take develop good can by safety be used for the treatment of and/or prevent the diabetes of various Mammalss (comprising the mankind) and by the medicine of the caused various diseases of diabetes as target, invented have 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:
Ester or its steric isomer of the compound shown in logical formula I, (II), (III), its pharmacy acceptable salt, its facile hydrolysis:
Figure BDA00001866357500021
Wherein, the A ring is 3-14 unit cycloalkyl, and 6-14 unit aryl has 1-4 and is selected from N, S, O, SO and/or SO 2The heterocyclic radical of heteroatomic 3-12 unit;
X, Y represent respectively CH 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 respectively hydrogen atom ,-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 respectively hydrogen atom ,-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, 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 respectively hydrogen atom, 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 respectively hydrogen atom, C 1-6Alkyl, C 6-14Aryl, C 1-6Alkyl-C 6-14Aryl or C 3-14Cycloalkyl, or R 10And R 10aThe N that connects with them forms and contains 1-4 and be N, O, S, SO and/or SO 2The heterocyclic radical of heteroatomic 3-12 unit;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom, (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 2Perhaps alkylidene group, described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can further be replaced by 1-4 substituting group, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl, the C that is replaced by halogen atom 1-4Alkoxyl group, the C that is replaced by 1 substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl 1-4Alkyl.
Be preferably:
Wherein, the A ring represents C 3-8The 1-4 that has of cycloalkyl or fractional saturation is selected from N, S, O, SO and/or SO 2The heterocyclic radical of heteroatomic 3-12 unit;
X, Y represent respectively CH 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 respectively hydrogen atom;
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 respectively 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 8, R 8a, R 8b, R 8c, R 8dRepresent respectively hydrogen atom, C 1-6Alkyl, C 6-14Aryl, C 1-6Alkyl-C 6-14Aryl or C 3-8Cycloalkyl, or R 10And R 10aThe N that connects with them forms to encircle again and contains 1-4 and be N, O, S, SO and/or SO 2The heterocyclic radical of heteroatomic 5-7 unit;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom;
M is 0,1 or 2;
N is 0,1 or 2;
W is alkylidene group, and described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can further be replaced by 1-4 substituting group, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl, the C that is replaced by halogen atom 1-4Alkoxyl group, the C that is replaced by 1 substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl 1-4Alkyl.
Be preferably:
Wherein, the A ring is C 3-8The 1-2 that has of cycloalkyl or fractional saturation is selected from N, S, O and/or SO 2The heterocyclic radical of heteroatomic 3-7 unit;
X, Y represent respectively CH 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 respectively hydrogen atom;
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 respectively hydrogen atom;
M is 0,1 or 2;
N is 0,1 or 2;
W is alkylidene group, and described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can further be replaced by 1-4 substituting group, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, C 1-6Alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl.
Be preferably:
Wherein, the A ring is C 3-6Cycloalkyl or fractional saturation have a heterocyclic radical that 1-2 is selected from the heteroatomic 3-7 unit of S, O;
X, Y represent respectively CH 2, NH, O atom or S atom;
R 1Represent halogen;
R 2, R 3, R 4Represent respectively hydrogen atom;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom;
M is 0,1 or 2;
N is 0;
W is alkylidene group, and described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described cycloalkyl, heterocyclic radical can further be replaced by 1-4 substituting group, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, C 1-6Alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl.
More preferably:
Wherein, the A ring is cyclopropane base, tetramethylene base, pentamethylene base, tetrahydrofuran base, oxetanyl;
X, Y represent respectively CH 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 respectively hydrogen atom;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom;
M is 0 or 1;
N is 0;
W is alkylidene group, and described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described cyclopropane base, the tetramethylene base, the pentamethylene base, tetrahydrofuran base, oxetanyl can further be replaced by 1-4 substituting group, 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, the A ring is cyclopropane base, tetramethylene base, pentamethylene base, tetrahydrofuran base, oxetanyl;
X, Y represent respectively CH 2, NH, O atom or S atom;
R 1Represent halogen;
R 2, R 3, R 4Represent respectively hydrogen atom;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom;
M is 0 or 1;
N is 0;
W is methylene radical.
Particularly preferably compound is:
Figure BDA00001866357500051
Figure BDA00001866357500061
Figure BDA00001866357500071
Detailed Description Of The Invention
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom, preferred fluorine atom and chlorine atom.
The paraffin section that " alkyl " of the present invention refers to contain 1-18 carbon atom is removed the alkyl of the derivative straight or branched of a hydrogen atom, such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, the 3-methyl butyl, 1, the 1-dimethyl propyl, 1, the 2-dimethyl propyl, neo-pentyl, the 1-ethyl propyl, n-hexyl, isohexyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 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 to the specific examples that contains 1-18,1-6,1-4, a 1-3 carbon atom in the above-mentioned example.
" alkylidene group " of the present invention refers to the derivative straight or branched alkane of hydrogen atom of abovementioned alkyl removal, comprises-(CH 2) t-(t is the integer of 1-18), preferred t is the integer of 1-3, such as methylene radical, ethylidene, propylidene etc.
" C of the present invention 2-6Thiazolinyl " carbonatoms that refers to contain two keys is the straight or branched of 2-6 or the thiazolinyl of ring-type; such as vinyl; the 1-propenyl; the 2-propenyl; the 1-methyl ethylene; the 1-butylene base, crotyl, the 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, the 1-pentenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, 1-methyl isophthalic acid-butenyl, the 2-methyl-1-butene thiazolinyl, the 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, the 1-hexenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, the 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, the 1-methyl-3-pentenyl, the 2-methyl-3-pentenyl, the 3-methyl-3-pentenyl, the 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, the 3-divinyl, 1, the 3-pentadiene, 1, the 4-pentadiene, 1, the 4-hexadiene, cyclopentenyl, 1, the 3-cyclopentadienyl, cyclohexenyl, 1，4-cyclohexadiene base etc.
" C of the present invention 2-6Alkynyl " carbonatoms that refers to contain triple bond is the alkynyl of the straight or branched of 3-6; such as ethynyl; 2-propynyl; the 2-butyne base; the 3-butynyl; 1-methyl-2-propynyl, the valerylene base, the 3-pentynyl, the 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, such 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, such as methyl carbonyl, ethyl carbonyl, propyl group carbonyl, sec.-propyl carbonyl, butyl carbonyl, isobutyl-carbonyl, tertiary butyl carbonyl, sec-butyl carbonyl, amyl group carbonyl, 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, such as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, isopropyl oxygen carbonyl, 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 the derivative cyclic alkyl of hydrogen atom of paraffin section removal of 3-14 carbon atom, comprises 3-8 unit monocyclic cycloalkyl, 6-14 unit and encircles cycloalkyl, 7-12 unit's bridged ring base and the first saturated volution of 7-12.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 the specific examples that contains 3-14,3-8,3-6, a 5-6 carbon atom in the above-mentioned example.
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 whole saturated carbocyclic rings, 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, dimethyl tetramethylene base, methylcyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyl cyclohexane base 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 share each other two the formed 6-14 of adjacent carbon atom unit cyclic groups by two or more ring texturees, comprise 6-14 first saturated and cyclic group and 6-14 unit's fractional saturation and cyclic group.Preferred 6-12 unit and cyclic group, 6-10 unit and cyclic group.The first saturated and ring cycloalkyl of 6-14, refer to that this and ring are whole saturated carbocyclic rings, the example includes but not limited to: two ring [3.1.0] hexyls, two ring [4.1.0] heptane bases, two ring [2.2.0] hexyls, two ring [3.2.0] heptane bases, two encircle [4.2.0] octyls, octahydro pentalene base, octahydro-1H-indenyl, naphthane base, ten tetrahydrochysene phenanthryl etc.6-14 unit fractional saturation is also encircled cycloalkyl, refers to that at least one ring is the carbocyclic ring of fractional saturation in this and the ring, and the example includes but not limited to: dicyclo [3.1.0] is own-2-thiazolinyl, dicyclo [4.1.0] heptan-3-thiazolinyl, dicyclo [3.2.0] heptan-3-thiazolinyl, dicyclo [4.2.0] suffering-3-thiazolinyl, 1,2,3,3a-tetrahydrochysene pentalene base, 2,3,3a, 4,7,7a-, six hydrogen-1H-indenyl, 1,2,3,4,4a, 5,6,8a-octalin base, 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 that contains 5-12 carbon atom of the atom formation that neither directly links to each other, 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, refer to have in this bridged ring that to have a ring at least be undersaturated cyclic group, be preferably 6-10 unit fractional saturation bridged ring, specific examples includes but not limited to dicyclo [2.2.1] heptan-5-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 ring structure that an atom forms.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: spiroheptane 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 to that having a ring in this volution base at least is undersaturated cyclic group, specific examples includes but are not limited to: spiral shell [3.4] oct-6-ene base, spiral shell [3.5] ninth of the ten Heavenly Stems-6-thiazolinyl, spiral shell [4.4] ninth of the ten Heavenly Stems-6-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-thiazolinyls, (Z)-spiral shell [4.6] 11 (carbon)-8-thiazolinyls, spiral shell [4.6] 11 (carbon)-2-thiazolinyls etc.The first volution base of preferred 7-10 comprises that " the saturated volution base of 7-10 unit " reaches " 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, such 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 ring-type aromatic group 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.It is formed that 8-14 unit fused ring aryl refers to share each other two adjacent carbon atoms by two or more ring texturees, having a ring at least is 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 for example saturated monocyclic cycloalkyl of benzo 3-8 unit, benzo 3-8 unit fractional saturation monocyclic cycloalkyl, specific examples is such as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc.Term " C 6-14Aryl " for containing the specific examples of 6-14 carbon atom in the above-mentioned example.
" heteroaryl " of the present invention its annular atoms also comprises 1-4 heteroatoms except carbon atom, described " heteroatoms " includes but not limited to Sauerstoffatom, nitrogen-atoms and sulphur atom.Heteroaryl can pass through carbon or heterocyclic atom bonding.Comprise and have 1-4 the assorted aromatic nucleus of heteroatomic monocycle and the saturated or undersaturated 1-4 of having heteroatomic fused heterocycle aryl that is selected from N, S, O that is selected from N, S, O.Bicyclic heteroaryl includes but not limited to pyrryl, imidazolyl, pyrazolyl, 1,2,3-triazoles base, 1,2,4-triazolyl, pyridyl, furyl, thienyl,
Figure BDA00001866357500101
Azoles base, different
Figure BDA00001866357500102
Azoles base, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-
Figure BDA00001866357500103
Di azoly, 1,2,4-
Figure BDA00001866357500104
Di azoly, 1,2,5-
Figure BDA00001866357500105
Di azoly, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrazyl, Triazolyl, 2H-1,2- Piperazine base, 4H-1,2-
Figure BDA00001866357500108
Piperazine base, 6H-1,2- Piperazine base, 2H-1,3-
Figure BDA000018663575001010
Piperazine base, 4H-1,3-
Figure BDA000018663575001011
Piperazine base, 6H-1,3-
Figure BDA000018663575001012
Piperazine base, 2H-1,4-
Figure BDA000018663575001013
Piperazine base, 4H-1,4-
Figure BDA000018663575001014
Piperazine base, different Piperazine base, pyridazinyl, pyrimidyl and pyrazinyl etc.; The 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
Figure BDA000018663575001016
Azoles base, benzo
Figure BDA000018663575001017
Piperazine base, benzimidazolyl-, pyridopyridine base, pyrazolo [3,4-b] pyridyl, purine radicals, acridyl and xanthenyl etc.Term " 5-7 unit heteroaryl " refers to that the annular atoms number is the specific examples of 5-7 in above-mentioned " heteroaryl ".
" heterocyclic radical " of the present invention refers to contain the first cyclic group of one or more heteroatomic 3-14, and described " heteroatoms " refers to nitrogen-atoms, Sauerstoffatom, sulphur atom etc.Comprise that having 1-4 is 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.Comprise also that simultaneously having 1-4 is selected from N, S, O and/or SO 2Heteroatomic and ring, volution, bridged ring.The first heterocyclic radical of preferred 5-10, more preferably 5-7 unit heterocyclic radical.
Single heterocyclic radical refers to contain 3-8 the annular atoms monocyclic heterocycles base of (wherein containing at least a heteroatoms), comprises the unsaturated single heterocyclic radical of 3-8 unit, the single heterocyclic radical of 3-8 unit fractional saturation, 3-8 unit saturated mono heterocyclic radical.The unsaturated single heterocyclic radical of preferred 5-7 unit, the single heterocyclic radical of 5-7 unit fractional saturation, 5-7 unit saturated mono heterocyclic radical.The unsaturated single heterocyclic radical of 3-8 unit, refer to heteroatomic cyclic group of containing of aromaticity, specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl group, oxazolyl, the oxadiazoles base, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, 1,4-Dioxin base, 2H-1, the 2-oxazinyl, 4H-1, the 2-oxazinyl, 6H-1, the 2-oxazinyl, 4H-1, the 3-oxazinyl, 6H-1, the 3-oxazinyl, 4H-1, the 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2, the 4-triazinyl, the 1,3,5-triazines base, 1,2,4,5-tetrazine base, the oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1,3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc.The single heterocyclic radical of 3-8 unit fractional saturation refers to contain two keys, heteroatomic cyclic group, and specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-oxazinyl etc.3-8 unit saturated mono heterocyclic radical, refer to all to be heteroatomic cyclic group of containing of saturated bond, 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 refers to and cyclic group, volution base, bridged ring base in a non-shared carbon atom by N, S, O and/or SO 2Heteroatoms substitute formed and heterocyclic radical, spiro heterocyclic radical, bridge heterocyclic radical.
And heterocyclic radical refer to contain 6-14 annular atoms (wherein containing at least a heteroatoms) by two or more ring texturees share each other two adjacent atoms couple together forms and ring structure, comprise 6-14 unit unsaturated and heterocyclic radical, 6-14 unit's fractional saturation and heterocyclic radical, the first saturated and heterocyclic radical of 6-10.Unsaturated and the heterocyclic radical of 6-14 unit, refer to that whole rings is undersaturated condensed ring structure, structure such as the unsaturated single heterocyclic radical formation of benzo 3-8 unit, the structure that the unsaturated single heterocyclic radical of the 3-8 unsaturated single heterocyclic radical of unit and 3-8 unit forms etc., specific examples includes but not limited to: benzofuryl, the benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, the benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, the 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 and heterocyclic radical refer to contain at least the condensed ring structure of a fractional saturation ring, the structure that forms such as the benzo 3-8 unit single heterocyclic radical of fractional saturation, the structure that the single heterocyclic radical of 3-8 unit fractional saturation and the 3-8 unit single heterocyclic radical of fractional saturation form etc., specific examples includes but not limited to: 1,3-dihydro benzo furyl, benzo [d] [1.3] dioxa cyclopentenyl, the isoindoline base, chromanyl, 1,2,3,4-Pyrrolidine is [3,4-c] pyrryl also, 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] [Isosorbide-5-Nitrae] Dioxins base, indolinyl, 1,2,3, the 4-tetrahydric quinoline group, 3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazinyl, chromanyl etc.Saturated and the heterocyclic radical of 6-10 unit, refer to that whole rings is saturated condensed ring structure, such as 3-8 unit's saturated mono heterocyclic radical and the formed structure of 3-8 unit's saturated mono heterocyclic radical, specific examples includes but are not limited to: tetramethylene and Pyrrolidine base, pentamethylene and Pyrrolidine base, azetidine and imidazolidyl, 3-oxabicyclo be [3.1.0] hexyl, hexahydro furyl [3 also, 4-b] [1,4] Dioxins base, six hydrogen-2H-pentamethylene [b] [Isosorbide-5-Nitrae] Dioxins base etc. also.
The bridge heterocyclic radical refers to the caged scaffold that formed by 5-12 annular atoms (wherein containing at least 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, refer to that all rings in this bridge heterocycle are saturated cyclic group, 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-two amido dicyclo bridge [2.2.1] heptane bases, 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-, two amido dicyclo bridge [3.2.1] octyls, 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, refer to have in this bridge heterocycle that to have a ring at least be undersaturated cyclic group, be preferably 7-8 unit fractional saturation bridge heterocyclic radical, specific examples includes but not limited to: 3,8-diamines mix 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
Figure BDA00001866357500123
Deng.
Spiro heterocyclic radical refers to the spirane structure that formed by 5-12 annular atoms (wherein containing at least 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 spiroheptane base, 2-oxa--6-amido spiroheptane 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, 1,4,7-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-two amido spiral shells [5.5] 11 (carbon) alkyl, 3-oxa--9-amido spiral shell [5.5] 11 (carbon) alkyl, 7,9-, two amido spiral shells [4.6], 11 (carbon) alkyl etc.
5-12 unit fractional saturation spiro heterocyclic radical, refer to that having a ring in this spiroheterocyclic at least is undersaturated cyclic group, specific examples includes but are not limited to: 6-amido spiral shell [3.4] suffering-7-thiazolinyl, 2-oxa--6-amido spiral shell [3.4] suffering-7-thiazolinyl, 7-amido spiral shell [3.5] ninth of the ten Heavenly Stems-5-thiazolinyl, 2-amido spiral shell [4.4] ninth of the ten Heavenly Stems-7-thiazolinyl, 8-amido spiral shell [4.5] last of the ten Heavenly stems-2-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 (or CH, CH in the above-mentioned cycloalkyl 2) by N, O, S, SO and/or SO 2Heteroatoms substitute formed heterocyclic radical.
The annular atoms number is the specific examples of 3-12 in the finger above-mentioned " heterocyclic radical " of term " 3-12 unit heterocyclic radical ".The annular atoms number is the specific examples of 5-12 in the finger above-mentioned " heterocyclic radical " of term " 5-12 unit heterocyclic radical ".The annular atoms number is the specific examples of 5-7 in the finger above-mentioned " heterocyclic radical " of term " 5-7 unit heterocyclic radical ".
It is of the present invention that " X, Y represent respectively CH 2, NH, O atom, S atom, SO and/or SO 2" including but are not limited to following several situation: (1) X, Y are CH 2(2) there is one to be NH, O atom, S atom, SO and/or SO among X, the Y 2(3) any is NH among X, the Y, O atom, S atom, SO and/or SO 2
Among the present invention A ring and the ring that is connected thick with become and encircle and heterocycle, volution, spiroheterocyclic, bridged ring, bridge heterocycle.
The present invention is the Preparation Method And Their Intermediate of the described compound of claimed logical formula I further.
Above-claimed cpd of the present invention can adopt method and/or other technology known to persons of ordinary skill in the art of describing in the following flow process to synthesize, but is not limited only to following methods.
When W was methylene radical, reaction scheme was:
Figure BDA00001866357500131
Reactions steps:
The preparation of step 1 compound a
Raw material 1 and N-methylmorpholine are dissolved among the THF; cool off under the nitrogen protection, slowly drip the trimethylammonium silicon chlorides, keep temperature; complete rear intensification stirring reaction; then stirring at room reaction is cooled off after the adding dilution with toluene, adds entry and keeps temperature; the organic phase of reaction mixture is separated; use respectively the biphosphate sodium water solution, water, saturated brine washing.Rotary evaporation obtains light yellow oil a.
The preparation of step 2 compound b
The dichloromethane solution of aluminum chloride is cooled to 0 ℃, slowly adds raw material 3, keeps 0 ℃ to stir 1h, then slowly drip the dichloromethane solution of raw material 2, detect to reaction and finish, reaction mixture is poured in the frozen water, and with dichloromethane extraction three times, merge organic phase, use respectively dilute hydrochloric acid, water, NaOH (1N), the saturated brine washing, Na 2SO 4Drying, the rotary evaporation organic phase, column chromatography obtains target compound b.
The preparation of step 3 compound c
Compound b is dissolved in the trifluoroacetic acid, then add triethyl silicane and boron trifluoride diethyl etherate, with the reaction solution reflux, react complete rear adding saturated aqueous sodium carbonate and regulate pH=8, ethyl acetate extraction obtains organic phase, and wash organic phase with saturated brine, vacuum-drying obtains the crude product compound c.
The preparation of step 4 compound d
Compound c is dissolved among the anhydrous THF; be cooled to-78 ℃; nitrogen protection; after dripping n-BuLi, drip the hexane solution of compound a, keep stirring reaction; then reaction mixture saturated aqueous ammonium chloride cancellation; the ethyl acetate extraction water layer, the organic phase water of merging and saturated brine washing, rotary evaporation obtains the oily matter compound d.
The preparation of step 5 Verbindung
Compound d is dissolved in the absolute anhydrous methanol, and the lower absolute methanol solution that adds methylsulfonic acid of cooling slowly rises to stirring at room, reacts the complete rear saturated NaHCO that uses 3Solution is regulated, and uses ethyl acetate extraction, and the organic phase of merging washes with water, the saturated common salt water washing, and drying is revolved steaming and is obtained Verbindung.
The preparation of step 6 compound f
With Verbindung, diisopropyl ethyl amine and DMAP are dissolved in THF, be cooled to zero degree, slowly add diacetyl oxide, stir, reaction mixture is regulated with saturated sodium bicarbonate aqueous solution, and use ethyl acetate extraction, the organic phase water of merging and saturated common salt water washing, drying, rotary evaporation is concentrated, and column chromatography obtains compound f.
The preparation of step 7 compound g
With lower triethyl silicane or tri isopropyl silane and the boron trifluoride diethyl etherate of adding of the acetonitrile solution cooling of compound f, detect to the reaction end, saturated sodium bicarbonate solution cancellation reaction, and use ethyl acetate extraction, the organic phase water and the saturated common salt water washing that merge, drying, rotary evaporation is concentrated, and recrystallization (normal hexane and ethyl acetate) obtains compound g.
Step 8 formula I ' preparation of compound
In the mixing solutions with compound g tetrahydrofuran (THF) and methyl alcohol, the aqueous solution that adds a hydronium(ion) oxidation lithium under the zero degree, reaction also slowly rises to room temperature, stir, detection reaction finishes, concentration of reaction solution, add dichloromethane extraction, with organic phase water and the saturated common salt water washing that merges, drying, the concentrated formula I that obtains ' compound.
In the reaction scheme, R 1, R 2, R 3, R 4, R 5, R 6a, R 6b, R 6c, m, n and A such as preamble define.
The present invention is ester or its steric isomer of the intermediate of compound shown in the claimed logical formula I in preparation process, its pharmacy acceptable salt, its facile hydrolysis further.
" pharmacy acceptable salt " of the above-mentioned arbitrary compound of the present invention comprises an alkali metal salt, such as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt is such as calcium salt, magnesium salts etc.; Other metal-salts are such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts is such as ammonium salt; Organic alkali salt, such as uncle's octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethyl amine 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) amido methane salt; Halogen acid salt is such as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt is such as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate is such as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate is such as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt is such as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts is such 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 that generates parent compound in human body.It is evident that for those skilled in the art, the ester that is easy to be hydrolyzed of the compounds of this invention can form at free carboxy or the hydroxyl place of this compound, can make by ordinary method.
" steric isomer " of the above-mentioned arbitrary compound of the present invention comprises that all are poor to stereoisomerism, diastereo-isomerism and tautomeric form.When a key represented with a wedge, this showed that on three-dimensional this key will be from paper out, and when a key was shade, this showed that this key will return in the paper on three-dimensional.
The present invention is the claimed ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis or the pharmaceutical composition of its steric isomer and other active pharmaceutical ingredients of comprising further.
The present invention also comprises ester or its steric isomer of above-mentioned arbitrary compound, its pharmacy acceptable salt, its facile hydrolysis, can be mixed with clinically or pharmaceutically acceptable arbitrary formulation with manner known in the art, be applied to the patient who needs this treatment with oral, parenteral, rectum or through modes such as lung administrations.When being used for oral administration, can be made into conventional solid preparation, such as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, such as oral solution, oral suspensions, syrup etc.When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.When being used for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, can adopt the ordinary method production in the existing pharmacy field, during the preparation injection, can not add additives, also can add suitable additives according to the character of medicine.When being used for rectal administration, can be made into suppository etc.Be used for when the lung administration, can be made into inhalation or sprays etc.
The present invention also provides the compounds of this invention to treat and/or prevent application in the medicine of diabetes in preparation.C-glycosides derivatives of the present invention can be used in outside the diabetes such as diabetes (type i diabetes) such as insulin-dependent, non insulin dependent diabetes (type ii diabetes), can also be used for comprising the treatment of insulin resistance disease and the various diabetes relative diseases of obesity, 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 Mammalss (comprising the mankind) and by the caused various diseases of diabetes by safety;
(2) the compounds of this invention shows preferably 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.
Below further set forth the compounds of this invention beneficial effect by pharmacological evaluation, but this should be interpreted as that the compounds of this invention only has following beneficial effect.
External, the interior pharmacologically active of body of experimental example the compounds of this invention
1, the in-vitro evaluation of the compounds of this invention experiment
In-vitro evaluation method of the present invention is that people's SGLT2 and SGLT1 sequence are transfected into stably express on the Chinese hamster ovary cell, by suppress cell to [ 14C]-the dependent absorption of sodium of mark-R-methyl D-glucopyranoside (AMG), 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: people's SGLT2 and the sequence of SGLT1 stably express on Chinese hamster ovary celI, to carry out cell cultures 12 hours at 96 orifice plates, with KRH-Na+ (Buffer A) or KRH-NMG (Buffer A-) buffered soln 200 μ l/ holes, wash 3 times.Contain BufferA or BufferA-plus[14C with adding again]-the damping fluid 100 μ l/ holes of AMG (10 μ Ci/mL), hatched 1 hour for 37 ℃.Then, add ice-cold buffered soln (Buffer D) 100 μ l and stop test, clean 5 times.Add 100mM NaOH solution 20 μ l/ holes, 600rpm is centrifugal, and 5 minutes, and Microscint 40 solution 80 μ l/ holes, 600rpm is centrifugal, 5 minutes.At last with scintillation counting technique with MicroBeta Trilux (available 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:
Hence one can see that, and the compounds of this invention is to the preferably restraining effect and preferably selectivity of having of 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: the glucose in urine experimental technique is for getting SPF level male Sprague-Dawley rat, in 6 ages in week, behind animal fasting 15h, be divided at random blank group, model group, positive drug group, tested medicine group, put into metabolic cage according to rat body weight, the not feeding that feeds water is collected the 24h urine.Then give sugar (5g/kg) behind the oral administration (10mg/Kg), put into metabolic cage again, administration is to supply food behind the sugared 1h, and free diet is collected the 24h urine, record urine amount.The centrifugal 15min of urine 3000rpm with collecting removes residue, gets supernatant, measures glucose in urine content wherein.Glucose in urine content is with the 200g weight standard.Data represent with means standard deviation, and one-way analysis of variance is adopted in the income value analysis, relatively adopt one-way analysis of variance Dunnett check between group, and p＜0.05 thinks to have statistical significance.
Table 2: the glucose in urine experimental result of compound:
Figure BDA00001866357500171
In sum, the compounds of this invention shows preferably blood sugar reducing function.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.
Embodiment 1 β-1 '-deoxidation-1 '-(4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose acetal The preparation of (compound 1)
Figure BDA00001866357500172
Step 12,3,4, the preparation of 6-four (trimethylsilyl ethers)-Gluconolactone
Figure BDA00001866357500173
With raw material 1 (239g; 1.34mol) and N-methylmorpholine (1.18L; 10.73mol) be dissolved among the THF (2.4L); be cooled to-5 ℃ under the nitrogen protection; slowly drip trimethylammonium silicon chlorides (1022mL; 8.05mol); keep dripping process temperature and be no more than 5 ℃; be warming up to 35 ℃ after complete and stir 5h, then stirring at room 15h is cooled to 0-5 ℃ after the adding dilution with toluene; then adding entry keeps temperature to be no more than 10 ℃; the organic phase of reaction mixture is separated, used respectively the biphosphate sodium water solution, water and saturated common salt water washing.Rotary evaporation obtains light yellow oil 2,3,4,6-four (trimethylsilyl ethers)-Gluconolactone 593.2g, productive rate 92%.
The preparation of step 2 4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-formyl radical) bromobenzene
With aluminum chloride (2.8g, dichloromethane solution 21mmol) (25mL) is cooled to 0 ℃, slowly add compound (1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene (3.77g, 21.3mmol), keep 0 ℃ to stir 1h, then slowly drip compound 2-chloro-5-bromo-Benzoyl chloride (6.9g, 21.3mmol) dichloromethane solution (15mL), detect to reaction and finish, pour reaction mixture in the frozen water (150mL), and with dichloromethane extraction (3 * 100mL), merge organic phase, use respectively dilute hydrochloric acid (1N), water, NaOH (1N), the saturated common salt water washing, anhydrous Na 2SO 4Drying, the rotary evaporation organic phase, column chromatography (n-hexane/ethyl acetate=1/20) obtains target compound 4-chloro-3-(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
Figure BDA00001866357500181
With 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 the trifluoroacetic acid; then add triethyl silicane (7.86g, 67.6mmol) and boron trifluoride diethyl etherate (9.60g, 67.6mmol); reaction solution reflux 16h. is added saturated aqueous sodium carbonate regulate pH=8; ethyl acetate extraction obtains organic phase, and washs organic phase with saturated brine, and vacuum-drying obtains crude product compound 4-chloro-3-(1a; 2; 7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) bromobenzene 10.7g, productive rate 71%.
The preparation of step 4 compound 1 '-(4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose hemiacetal
Figure BDA00001866357500182
With 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 ℃; then slowly drip n-BuLi (2.5M, 18.4mL, 46mmol) under the nitrogen protection; after keeping stirring 3h; at-78 ℃ of lower compounds 2,3,4 that slowly drip; the hexane solution (300mL) of 6-four (trimethylsilyl ethers)-Gluconolactone; keep stirring 0.5h, then reaction mixture saturated aqueous ammonium chloride (100mL) cancellation, ethyl acetate extraction water layer (3 * 100mL); the organic phase water that merges and saturated brine washing; rotary evaporation obtains oily matter compound 1 '-(4-chloro-3-(1a, 2,7; 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-and glucose hemiacetal 18.2g, productive rate 82%.
Step 5 compound 1 '-O-methyl isophthalic acid '-preparation of (4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose acetal
Figure BDA00001866357500183
With compound 1 '-(4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose hemiacetal (4.86g, 10.0mmol) be dissolved in the absolute anhydrous methanol (10mL), be cooled to 0 ℃, add anhydrous methanol (10mL) solution of methylsulfonic acid (0.4mL), slowly rise to stirring at room 16h, use saturated NaHCO 3The aqueous solution is regulated pH=8, and use ethyl acetate extraction, the organic phase that merges washes with water, the saturated common salt water washing, drying is revolved steaming and is obtained compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical))-and glucose acetal 4.95g, 100%.
Step 6 compound 1 '-O-methyl isophthalic acid '-preparation of (4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
With compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-(1a; 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) and DMAP (10mg) are dissolved in THF (100mL), are cooled to zero degree; slowly add diacetyl oxide (7.43g; 72.8mmol), stirring 0.5h, reaction mixture is regulated pH=8 with saturated sodium bicarbonate aqueous solution; and with ethyl acetate extraction (3 * 60mL); the organic phase water (70mL) that merges and saturated aqueous common salt (70mL) washing, drying, rotary evaporation is concentrated; column chromatography obtains compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-(1a; 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%.
The preparation of step 7 compound β-1 '-deoxidation-1 '-(4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
Figure BDA00001866357500192
With compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-(1a; 2; 7; 7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-2 ', 3 ', 4 '; 6 '-tetra-acetylated-glucose acetal (7.48g; 16.0mmol) acetonitrile solution (50mL) be cooled to 10 ℃, add tri isopropyl silane (5.1g, 32mmol) and boron trifluoride diethyl etherate (6.8g; 48mmol); detect to reaction and finish, saturated sodium bicarbonate solution cancellation reaction, and with ethyl acetate extraction (3 * 100mL); the organic phase water and the saturated common salt water washing that merge; drying, rotary evaporation is concentrated, recrystallization (n-hexane/ethyl acetate=1/15; V/V) obtain compound β-1 '-deoxidation-1 '-(4-chloro-3-(1a; 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%.
The preparation of step 8 compound β-1 '-deoxidation-1 '-(4-chloro-3-(1a, 2,7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-glucose acetal
Figure BDA00001866357500193
With compound β-1 '-deoxidation-1 '-(4-chloro-3-(1a; 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), add the aqueous solution (50mL) of a hydronium(ion) oxidation lithium (4.4g, 104mmol) under the zero degree; reaction solution slowly rises to room temperature; stir 14h, detection reaction finishes, concentration of reaction solution; add dichloromethane extraction; with organic phase water and the saturated common salt water washing that merges, drying, concentrated compound β-1 '-deoxidation-1 '-(the 4-chloro-3-(1a that obtains; 2; 7,7a-tetrahydrochysene-1H-cyclopropyl [b] naphthalene-4-methylene radical) benzene)-and glucose acetal 5.93g, productive rate 81%.LC-MS(M+H) +:431.
Embodiment 2 β-1 '-deoxidation-1 '-(4-chloro-3-(3,3a, 4,9,9a-hexahydro naphthalene [2,3-c] furans-6-methylene radical) benzene)-glucose acetal (chemical combination Thing 2) preparation
Figure BDA00001866357500201
Reference example 1 obtains compound β-1 '-deoxidation-1 '-(4-chloro-3-(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 '-(4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) Benzene)-preparation of glucose acetal (compound 3)
Figure BDA00001866357500202
Step 1 4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins)-the 6-formyl radical) preparation of bromobenzene
With aluminum chloride (2.8g, dichloromethane solution 21mmol) (25mL) is cooled to 0 ℃, slowly add compound phenyl ethyl ether (3.77g, 21.3mmol), keep 0 ℃ to stir 1h, then slowly drip the dichloromethane solution (15mL) of compound 2-chloro-5-bromo-Benzoyl chloride (6.9g, 21.3mmol), detect to the reaction end, pour reaction mixture in the frozen water (150mL), and with dichloromethane extraction (3 * 100mL), merge organic phase, use respectively dilute hydrochloric acid (1N), water, NaOH (1N), saturated common salt water washing, anhydrous Na 2SO 4Drying, the rotary evaporation organic phase, column chromatography (n-hexane/ethyl acetate=1/20) obtains target compound 4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [E] [Isosorbide-5-Nitrae] 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)-the 6-methylene radical) preparation of bromobenzene
Figure BDA00001866357500204
With compound 4-chloro-3-((2; 3; 3a; 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1; 4] Dioxins)-and the 6-formyl radical) bromobenzene (16.5g, 39.9mmol) is dissolved in (30mL) in the trifluoroacetic acid, then adds triethyl silicon (7.86g; 67.6mmol); reaction solution reflux 16h. is added saturated aqueous sodium carbonate regulate pH=8, ethyl acetate extraction obtains organic phase, and washs organic phase with saturated brine; vacuum-drying obtains crude product compound 4-chloro-3-((2; 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 '-(4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-preparation of glucose hemiacetal
Figure BDA00001866357500211
With compound 4-chloro-3-((2; 3; 3a; 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1; 4] Dioxins) 6-methylene radical)) bromobenzene (20.7g, 46mmol) is dissolved in anhydrous THF(150mL) in, be cooled to-78 ℃; then slowly drip n-BuLi (2.5M under the nitrogen protection; 18.4mL, 46mmol), after keeping stirring 3h; at-78 ℃ of lower compounds 2 that slowly drip; the hexane solution (300mL) of 3,4,6-four (trimethylsilyl ethers)-Gluconolactone; keep stirring 0.5h; then reaction mixture saturated aqueous ammonium chloride (100mL) cancellation, and the ethyl acetate extraction water layer (3 * 100mL), the organic phase water of merging and saturated brine washing; rotary evaporation obtains oily matter compound 1 '-(4-chloro-3-((2; 3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1; 4] Dioxins) 6-methylene radical) benzene)-and glucose hemiacetal 18.2g, productive rate 82%.
Step 4 compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-preparation of glucose acetal
With compound 1 '-(4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-glucose hemiacetal (4.82g, 10.0mmol) is dissolved in the absolute anhydrous methanol (10mL), be cooled to 0 ℃, add anhydrous methanol (10mL) solution of methylsulfonic acid (0.4mL), slowly rise to stirring at room 16h, use saturated NaHCO 3The aqueous solution is regulated pH=8, and use ethyl acetate extraction, the organic phase that merges washes saturated common salt water washing, drying with water, revolve to steam and obtain compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [1,4] Dioxins) 6-methylene radical))-and glucose acetal 4.93g, 100%.
Step 5 compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene) preparation of-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
With compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((2; 3; 3a; 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-glucose acetal (4.39g, 9.1mmol); diisopropyl ethyl amine (9.4g; 72.8mmol) and DMAP (10mg) be dissolved in THF (100mL), be cooled to zero degree, slowly add diacetyl oxide (7.43g; 72.8mmol); stir 0.5h, reaction mixture is regulated pH=8 with saturated sodium bicarbonate aqueous solution, and with ethyl acetate extraction (3 * 60mL); the organic phase water (70mL) that merges and saturated aqueous common salt (70mL) washing; drying, rotary evaporation is concentrated, column chromatography obtains compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((2; 3; 3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) the 6-methylene radical) benzene)-2 '; 3 '; 4 ', 6 '-tetra-acetylated-glucose acetal 3.96g, productive rate 66%.
Step 6 compound β-1 '-deoxidation-1 '-(4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) benzene) preparation of-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
Figure BDA00001866357500222
With compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((1,3,3a; 9a-tetrahydro benzo [b] furans [3; 4-e] [Isosorbide-5-Nitrae] Dioxins) the 6-methylene radical) benzene)-2 ', 3 '; 4 '; the acetonitrile solution (50mL) of 6 '-tetra-acetylated-glucose acetal (7.48g, 16.0mmol) is cooled to 10 ℃, adds triethyl silicon (5.1g; 32mmol) and boron trifluoride diethyl etherate (6.8g; 48mmol), detect to the reaction end saturated sodium bicarbonate solution cancellation reaction; and with ethyl acetate extraction (3 * 100mL); the organic phase water and the saturated common salt water washing that merge, drying, rotary evaporation is concentrated; recrystallization (n-hexane/ethyl acetate=1/15; V/V) obtain compound β-1 '-deoxidation-1 '-(4-chloro-3-((2,3,3a; 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 '-(4-chloro-3-((2,3,3a, 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-preparation of glucose acetal
Figure BDA00001866357500223
With compound β-1 '-deoxidation-1 '-(4-chloro-3-((2; 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); add the aqueous solution (50mL) of a hydronium(ion) oxidation lithium (4.4g, 104mmol) under the zero degree, reaction solution slowly rises to room temperature; stir 14h; detection reaction finishes, and concentration of reaction solution adds dichloromethane extraction; with organic phase water and the saturated common salt water washing that merges; drying, concentrated compound β-1 '-deoxidation-1 '-(4-chloro-3-((2,3 that obtain; 3a; 9a-tetrahydrochysene-1H-benzo [b] cyclopentyl [e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-and 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 '-(4-chloro-3-(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)
Figure BDA00001866357500231
Step 1 4-chloro-3-((1,3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins)-the 6-formyl radical) preparation of bromobenzene
Figure BDA00001866357500232
With aluminum chloride (2.8g, dichloromethane solution 21mmol) (25mL) is cooled to 0 ℃, slowly add compound phenyl ethyl ether (3.77g, 21.3mmol), keep 0 ℃ to stir 1h, then slowly drip the dichloromethane solution (15mL) of compound 2-chloro-5-bromo-Benzoyl chloride (6.9g, 21.3mmol), detect to the reaction end, pour reaction mixture in the frozen water (150mL), and with dichloromethane extraction (3 * 100mL), merge organic phase, use respectively dilute hydrochloric acid (1N), water, NaOH (1N), saturated common salt water washing, anhydrous Na 2SO 4Drying, the rotary evaporation organic phase, column chromatography (n-hexane/ethyl acetate=1/20) obtains target compound 4-chloro-3-((1,3,3a, 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)-the 6-methylene radical) preparation of bromobenzene
With compound 4-chloro-3-((1; 3; 3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [1; 4] Dioxins)-and the 6-formyl radical) bromobenzene (16.5g; 39.9mmol) be dissolved in (30mL) in the trifluoroacetic acid, then add triethyl silicane (7.86g, 67.6mmol); reaction solution reflux 16h. is added saturated aqueous sodium carbonate regulate pH=8; ethyl acetate extraction obtains organic phase, and washs organic phase with saturated brine, and vacuum-drying obtains crude product compound 4-chloro-3-((1; 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 '-(4-chloro-3-((1,3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-preparation of glucose hemiacetal
Figure BDA00001866357500241
With 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 ℃, then slowly drip n-BuLi (2.5M under the nitrogen protection; 18.4mL; 46mmol), after keeping stirring 3h, at-78 ℃ of lower compounds 2 that slowly drip; 3; the hexane solution (300mL) of 4,6-four (trimethylsilyl ethers)-Gluconolactone keeps stirring 0.5h; then reaction mixture saturated aqueous ammonium chloride (100mL) cancellation; the ethyl acetate extraction water layer (3 * 100mL), the organic phase water of merging and saturated brine washing, rotary evaporation obtains oily matter compound 1 '-(4-chloro-3-((1; 3; 3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [1; 4] Dioxins) 6-methylene radical) benzene)-and glucose hemiacetal 18.2g, productive rate 82%.
Step 4 compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((1,3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-preparation of glucose acetal
Figure BDA00001866357500242
With compound 1 '-(4-chloro-3-((1,3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [1,4] Dioxins) 6-methylene radical) benzene)-glucose hemiacetal (4.86g, 10.0mmol) be dissolved in the absolute anhydrous methanol (10mL), be cooled to 0 ℃, add anhydrous methanol (10mL) solution of methylsulfonic acid (0.4mL), slowly rise to stirring at room 16h, use saturated NaHCO 3The aqueous solution is regulated pH=8, and use ethyl acetate extraction, the organic phase of merging washes with water, the saturated common salt water washing, dry, revolve to steam and obtain compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((1,3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) the 6-methylene radical))-glucose acetal 4.95g, 100%.
Step 6 compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((1,3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene) preparation of-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
Figure BDA00001866357500243
With compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((1; 3,3a, 9a-tetrahydro benzo [b] furyl [3; 4-e] [1; 4] Dioxins) 6-methylene radical) benzene)-and glucose acetal (4.39g, 9.1mmol), diisopropyl ethyl amine (9.4g; 72.8mmol) and DMAP (10mg) be dissolved in THF (100mL); be cooled to zero degree, slowly add diacetyl oxide (7.43g, 72.8mmol); stir 0.5h; reaction mixture is regulated pH=8 with saturated sodium bicarbonate aqueous solution, and (3 * 60mL), the organic phase water (70mL) of merging and saturated aqueous common salt (70mL) wash with ethyl acetate extraction; dry; rotary evaporation is concentrated, and column chromatography obtains compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((1,3; 3a; 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] 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 '-(4-chloro-3-((1,3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) benzene) preparation of-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
Figure BDA00001866357500251
With compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-((1,3,3a; 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-2 '; 3 '; the acetonitrile solution (50mL) of 4 ', 6 '-tetra-acetylated-glucose acetal (7.48g, 16.0mmol) is cooled to 10 ℃; add triethyl silicon (5.1g; 32mmol) and boron trifluoride diethyl etherate (6.8g, 48mmol), detect to reaction and finish; saturated sodium bicarbonate solution cancellation reaction; and with ethyl acetate extraction (3 * 100mL), the organic phase water of merging and saturated common salt water washing, drying; rotary evaporation is concentrated; (n-hexane/ethyl acetate=1/15 V/V) obtains compound β-1 '-deoxidation-1 '-(4-chloro-3-((1,3 to recrystallization; 3a; 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] 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 '-(4-chloro-3-((1,3,3a, 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins)-6-methylene radical) benzene)-preparation of glucose acetal
Figure BDA00001866357500252
With compound β-1 '-deoxidation-1 '-(4-chloro-3-((1; 3; 3a; 9a-tetrahydro benzo [b] furyl [3,4-e] [Isosorbide-5-Nitrae] Dioxins) 6-methylene radical) benzene)-2 '; 3 '; 4 ', 6 '-tetra-acetylated-glucose acetal (10g, 15.7mmol) is dissolved in the mixing solutions of tetrahydrofuran base (100mL) and methyl alcohol (100mL); add a hydronium(ion) oxidation lithium (4.4g under the zero degree; aqueous solution 104mmol) (50mL), reaction solution slowly rises to room temperature, stirs 14h; detection reaction finishes; concentration of reaction solution adds dichloromethane extraction, with organic phase water and the saturated common salt water washing that merges; dry; concentrated compound β-1 '-deoxidation-1 '-(4-chloro-3-((1,3, the 3a that obtains; 9a-tetrahydro benzo [b] furyl [3; 4-e] [Isosorbide-5-Nitrae] Dioxins)-the 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 '-(4-chloro-3-(1 ', 3 '-the dihydro spiral shell [cyclopentyl-1,2 '-indenes]-the 5-methylene radical) benzene)-(change of glucose acetal Compound 5) preparation
Figure BDA00001866357500261
Reference example 3 obtain compound β-1 '-deoxidation-1 '-(4-chloro-3-(1 ', 3 '-dihydro spiral shell [cyclopentyl-1,2 '-indenes]-5-methylene radical) benzene)-the glucose acetal.LC-MS(M+H) +:459.
Embodiment 6 β-1 '-deoxidation-1 '-(4-chloro-3-(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 '-(4-chloro-3-(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 '-(4-chloro-3-(1,3-dihydro spiral shell (indenes-2,3 '-oxa-cyclobutyl-5-methylene radical) benzene)-the glucose acetal The preparation of (compound 7)
Figure BDA00001866357500263
Reference example 3 obtains compound β-1 '-deoxidation-1 '-(4-chloro-3-(1,3-dihydro spiral shell (indenes-2,3 '-oxa-cyclobutyl)-5-methylene radical) benzene)-glucose acetal.LC-MS(M+H) +:447.
Embodiment 8 β-1 '-deoxidation-1 '-(4-chloro-3-(1 ', 3 ', 4,5-tetrahydrochysene-2H-spiral shell (furans-3,2 '-indenes)-the 5-methylene radical) benzene)-the glucose acetal The preparation of (compound 8)
Figure BDA00001866357500264
Reference example 3 obtain compound β-1 '-deoxidation-1 '-(4-chloro-3-(1 ', 3 ', 4,5-tetrahydrochysene-2H-spiral shell (furans-3,2 '-indenes)-5-methylene radical) benzene)-the glucose acetal.LC-MS(M+H) +:461.
Embodiment 9 β-1 '-deoxidation-1 '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H, the 3H-spiral shell (cumarone-2,3 '-furans)-the 5-methylene radical) benzene)-Portugal The preparation of grape sugar acetals (compound 9)
Step 1 4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-formyl radical) preparation of bromobenzene
Figure BDA00001866357500272
With aluminum chloride (2.8g, dichloromethane solution 21mmol) (25mL) is cooled to 0 ℃, slowly add compound phenyl ethyl ether (3.77g, 21.3mmol), keep 0 ℃ to stir 1h, then slowly drip the dichloromethane solution (15mL) of compound 2-chloro-5-bromo-Benzoyl chloride (6.9g, 21.3mmol), detect to the reaction end, pour reaction mixture in the frozen water (150mL), and with dichloromethane extraction (3 * 100mL), merge organic phase, use respectively dilute hydrochloric acid (1N), water, NaOH (1N), saturated common salt water washing, anhydrous Na 2SO 4Drying, the rotary evaporation organic phase, column chromatography (n-hexane/ethyl acetate=1/20) obtains target compound 4-chloro-3-(4 ', 5 '-dihydro-2 ' H, the 3H-spiral shell (cumarone-2,3 '-furans)-the 5-formyl radical) 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
Figure BDA00001866357500273
With compound 4-chloro-3-(4 '; 5 '-dihydro-2 ' H; 3H-spiral shell (cumarone-2; 3 '-furans)-the 5-formyl radical) bromobenzene (16.5g; 39.9mmol) be dissolved in (30mL) in the trifluoroacetic acid; then add triethyl silicon (7.86g; 67.6mmol), reaction solution reflux 16h. being added saturated aqueous sodium carbonate regulate pH=8, ethyl acetate extraction obtains organic phase; and wash organic phase with saturated brine; vacuum-drying obtains crude product compound 4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2; 3 '-furans)-the 5-methylene radical) bromobenzene 10.6g, productive rate 71%.
Step 3 compound 1 '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene)-preparation of glucose hemiacetal
Figure BDA00001866357500274
With compound 4-chloro-3-(4 '; 5 '-dihydro-2 ' H; 3H-spiral shell (cumarone-2; 3 '-furans)-the 5-methylene radical) benzene) bromobenzene (20.7g; 46mmol) be dissolved in anhydrous THF(150mL) in; be cooled to-78 ℃; then slowly drip n-BuLi (2.5M, 18.4mL, 46mmol) under the nitrogen protection; after keeping stirring 3h; at-78 ℃ of lower compounds 2,3,4 that slowly drip; the hexane solution (300mL) of 6-four (trimethylsilyl ethers)-Gluconolactone; keep stirring 0.5h, then reaction mixture saturated aqueous ammonium chloride (100mL) cancellation, ethyl acetate extraction water layer (3 * 100mL); the organic phase water that merges and saturated brine washing; rotary evaporation obtain oily matter compound 1 '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2; 3 '-furans)-the 5-methylene radical) benzene)-glucose hemiacetal 18.2g, productive rate 82%.
Step 4 compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene)-preparation of glucose acetal
With compound 1 '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-the 5-methylene radical) benzene)-glucose hemiacetal (4.82g, 10.0mmol) be dissolved in the absolute anhydrous methanol (10mL), be cooled to 0 ℃, add anhydrous methanol (10mL) solution of methylsulfonic acid (0.4mL), slowly rise to stirring at room 16h, use saturated NaHCO 3The aqueous solution is regulated pH=8, and use ethyl acetate extraction, the organic phase that merges washes saturated common salt water washing, drying with water, revolve to steam and obtain compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone, 2,3 '-furans)-the 5-methylene radical) benzene)-glucose acetal 4.93g, 100%.
Step 5 compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene) preparation of-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
Figure BDA00001866357500282
With compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-(4 '; 5 '-dihydro-2 ' H; 3H-spiral shell (cumarone-2; 3 '-furans)-the 5-methylene radical) benzene)-glucose acetal (4.39g; 9.1mmol); diisopropyl ethyl amine (9.4g, 72.8mmol) and DMAP (10mg) are dissolved in THF (100mL), are cooled to zero degree; slowly add diacetyl oxide (7.43g; 72.8mmol), stirring 0.5h, reaction mixture is regulated pH=8 with saturated sodium bicarbonate aqueous solution; and with ethyl acetate extraction (3 * 60mL); the organic phase water (70mL) that merges and saturated aqueous common salt (70mL) washing, drying, rotary evaporation is concentrated; column chromatography obtains compound 1 '-O-methyl isophthalic acid '-(4-chloro-3-(4 '; 5 '-dihydro-2 ' H, the 3H-spiral shell (cumarone-2,3 '-furans)-the 5-methylene radical) benzene)-2 '; 3 '; 4 ', 6 '-tetra-acetylated-glucose acetal 3.96g, productive rate 66%.
Step 6 compound β-1 '-deoxidation-1 '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene) preparation of-2 ', 3 ', 4 ', 6 '-tetra-acetylated-glucose acetal
Figure BDA00001866357500283
With compound 1 '-O-methyl isophthalic acid '-(the 4-chloro-(4 '; 5 '-dihydro-2 ' H; 3H-spiral shell (cumarone-2; 3 '-furans)-the 5-methylene radical) benzene)-2 ', 3 ', 4 '; 6 '-tetra-acetylated-glucose acetal (7.48g; 16.0mmol) acetonitrile solution (50mL) be cooled to 10 ℃, add triethyl silicon (5.1g, 32mmol) and boron trifluoride diethyl etherate (6.8g; 48mmol); detect to reaction and finish, saturated sodium bicarbonate solution cancellation reaction, and with ethyl acetate extraction (3 * 100mL); the organic phase water and the saturated common salt water washing that merge; drying, rotary evaporation is concentrated, recrystallization (n-hexane/ethyl acetate=1/15; V/V) obtain compound β-1 '-deoxidation-1 '-(4-chloro-3-(4 '; 5 '-dihydro-2 ' H, the 3H-spiral shell (cumarone-2,3 '-furans)-the 5-methylene radical) benzene)-2 '; 3 '; 4 ', 6 '-tetra-acetylated-glucose acetal 7.48g, productive rate 74%.
Step 7 compound β-1 '-deoxidation-1 '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H, 3H-spiral shell (cumarone-2,3 '-furans)-5-methylene radical) benzene)-preparation of glucose acetal
With compound β-1 '-deoxidation-1 '-(4-chloro-3-(4 '; 5 '-dihydro-2 ' H; 3H-spiral shell (cumarone-2; 3 '-furans)-the 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), add the aqueous solution (50mL) of a hydronium(ion) oxidation lithium (4.4g, 104mmol) under the zero degree; reaction solution slowly rises to room temperature; stir 14h, detection reaction finishes, concentration of reaction solution; add dichloromethane extraction; with organic phase water and the saturated common salt water washing that merges, drying, concentrated compound β-1 '-deoxidation-1 '-(the 4-chloro-3-(4 ' that obtains; 5 '-dihydro-2 ' H; the 3H-spiral shell (cumarone-2,3 '-furans)-the 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 '-(4-chloro-3-(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 obtain compound β-1 '-deoxidation-1 '-(4-chloro-3-(4 ', 5 '-dihydro-2 ' H-spiral shell (benzo [d] [1,3] dioxole-2,3 '-furans)-5-methylene radical) benzene)-the glucose acetal.LC-MS(M+H) +:465.
In addition, split above-mentioned synthetic racemic compound 1-10 with preparative HPLC gradient elution (C-18 pillar, eluent 5%-95% methanol/water) and obtain following compound:
Figure BDA00001866357500301

Claims (10)

1. the ester or its steric isomer that lead to the compound shown in the formula I, its pharmacy acceptable salt, its facile hydrolysis:
Figure FDA00001866357400011
Wherein,
The A ring is 3-14 unit cycloalkyl, and 6-14 unit aryl has 1-4 and is selected from N, S, O, SO and/or SO 2The heterocyclic radical of heteroatomic 3-12 unit;
X, Y represent respectively CH 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 respectively hydrogen atom ,-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 respectively hydrogen atom ,-OH ,-OR 7, C 1-6Alkyl, C 3-14Cycloalkyl ,-CF 3,-OCHFX ,-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, 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 respectively hydrogen atom, 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 respectively hydrogen atom, C 1-6Alkyl, C 6-14Aryl, C 1-6Alkyl-C 6-14Aryl or C 3-14Cycloalkyl, or R 10And R 10aThe N that connects with them forms and contains 1-4 and be N, O, S, SO and/or SO 2The heterocyclic radical of heteroatomic 3-12 unit;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom, (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 2Perhaps alkylidene group, described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can further be replaced by 1-4 substituting group, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl, the C that is replaced by halogen atom 1-4Alkoxyl group, the C that is replaced by 1 substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl 1-4Alkyl.
2. the ester or its steric isomer that lead to the compound shown in formula II, (III), its pharmacy acceptable salt, its facile hydrolysis:
Figure FDA00001866357400021
Wherein,
The A ring is 3-14 unit cycloalkyl, and 6-14 unit aryl has 1-4 and is selected from N, S, O, SO and/or SO 2The heterocyclic radical of heteroatomic 3-12 unit;
X, Y represent respectively CH 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 respectively hydrogen atom ,-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 respectively hydrogen atom ,-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, 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 respectively hydrogen atom, 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 respectively hydrogen atom, C 1-6Alkyl, C 6-14Aryl, C 1-6Alkyl-C 6-14Aryl or C 3-14Cycloalkyl, or R 10And R 10aThe N that connects with them forms and contains 1-4 and be N, O, S, SO and/or SO 2The heterocyclic radical of heteroatomic 3-12 unit;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom, (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 2Perhaps alkylidene group, described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can further be replaced by 1-4 substituting group, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl, the C that is replaced by halogen atom 1-4Alkoxyl group, the C that is replaced by 1 substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl 1-4Alkyl.
3. the ester of compound as claimed in claim 1 or 2, its pharmacy acceptable salt, its facile hydrolysis or its steric isomer:
Wherein,
The A ring represents C 3-8Cycloalkyl or have 1-4 and be selected from N, S, O, SO and/or SO 2The heterocyclic radical of heteroatomic 3-12 unit;
X, Y represent respectively CH 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 respectively hydrogen atom;
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, 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 respectively 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 8, R 8a, R 8b, R 8c, R 8dRepresent respectively hydrogen atom, C 1-6Alkyl, C 6-14Aryl, C 1-6Alkyl-C 6-14Aryl or C 3-8Cycloalkyl, or R 10And R 10aThe N that connects with them forms to encircle again and contains 1-4 and be N, O, S, SO and/or SO 2The heterocyclic radical of heteroatomic 5-7 unit;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom;
M is 0,1 or 2;
N is 0,1 or 2;
W is alkylidene group, and described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can further be replaced by 1-4 substituting group, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl, the C that is replaced by halogen atom 1-4Alkoxyl group, the C that is replaced by 1 substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl 1-4Alkyl.
4. the ester of compound as claimed in claim 3, its pharmacy acceptable salt, its facile hydrolysis or its steric isomer:
Wherein,
The A ring is C 3-8Cycloalkyl or have 1-2 and be selected from N, S, O and/or SO 2The heterocyclic radical of heteroatomic 3-7 unit;
X, Y represent respectively CH 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 respectively hydrogen atom;
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 respectively hydrogen atom;
M is 0,1 or 2;
N is 0,1 or 2;
W is alkylidene group, and described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described alkyl, cycloalkyl, aryl, heterocyclic radical can further be replaced by 1-4 substituting group, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, C 1-6Alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl.
5. the ester of compound as claimed in claim 4, its pharmacy acceptable salt, its facile hydrolysis or its steric isomer:
Wherein,
The A ring is C 3-6Cycloalkyl or have the heterocyclic radical that 1-2 is selected from the heteroatomic 3-7 unit of S, O;
X, Y represent respectively CH 2, NH, O atom or S atom;
R 1Represent halogen;
R 2, R 3, R 4Represent respectively hydrogen atom;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom;
M is 0,1 or 2;
N is 0;
W is alkylidene group, and described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described cycloalkyl, heterocyclic radical can further be replaced by 1-4 substituting group, and described substituting group comprises halogen atom, hydroxyl, amino, carboxyl, C 1-6Alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl.
6. the ester of compound as claimed in claim 5, its pharmacy acceptable salt, its facile hydrolysis or its steric isomer:
Wherein,
The A ring is cyclopropane base, tetramethylene base, pentamethylene base, tetrahydrofuran base, oxetanyl;
X, Y represent respectively CH 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 respectively hydrogen atom;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom;
M is 0 or 1;
N is 0;
W is alkylidene group, and described alkylidene group can further be replaced by 1-4 substituting group, and described substituting group comprises halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group, the C that is replaced by halogen 1-4Alkyl;
Wherein, described cyclopropane base, the tetramethylene base, the pentamethylene base, tetrahydrofuran base, oxetanyl can further be replaced by 1-4 substituting group, and described substituting group is selected from halogen atom, hydroxyl, amino, carboxyl, C 1-6Alkyl, C 1-6Alkoxyl group, amino-sulfonyl, formamyl.
7. the ester of compound as claimed in claim 6, its pharmacy acceptable salt, its facile hydrolysis or its steric isomer:
Wherein,
The A ring is cyclopropane base, tetramethylene base, pentamethylene base, tetrahydrofuran base, oxetanyl;
X, Y represent respectively CH 2, NH, O atom or S atom;
R 1Represent halogen;
R 2, R 3, R 4Represent respectively hydrogen atom;
R 5, R 6a, R 6b, R 6cRepresent respectively hydrogen atom;
M is 0 or 1;
N is 0;
W is methylene radical.
8. the ester of compound as claimed in claim 1 or 2, its pharmacy acceptable salt, its facile hydrolysis or its steric isomer:
Figure FDA00001866357400051
Figure FDA00001866357400061
Figure FDA00001866357400071
9. comprise the ester of the described compound of the arbitrary claim of claim 1-8, its pharmacy acceptable salt, its facile hydrolysis or the pharmaceutical composition of its steric isomer and one or more pharmaceutical carriers and/or thinner, be pharmaceutically acceptable arbitrary formulation.
10. treat and/or prevent application in the medicine of diabetes such as the ester of the described compound of the arbitrary claim of claim 1-8, its pharmacy acceptable salt, its facile hydrolysis or its steric isomer in preparation.
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