CN102863417B - C-indican derivative - Google Patents

C-indican derivative Download PDF

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

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

Description

c-glycoside derivatives
1. Field of the invention
The invention belongs to the technical field of medicines, and relates to a C-glucoside derivative, a pharmaceutically acceptable salt thereof, an easily-hydrolyzed ester thereof, a stereoisomer thereof and an intermediate. In particular to a C-glucoside derivative used as a sodium-glucose cotransporter (SGLT) inhibitor, a pharmaceutically acceptable salt thereof, an easily hydrolyzed ester thereof, a stereoisomer thereof and an intermediate. The C-glycoside derivative of the present invention can be used for diabetes such as insulin-dependent diabetes (type I diabetes), non-insulin-dependent diabetes (type II diabetes), and the like, and can also be used for the treatment of various diabetes-related diseases including insulin-resistant diseases and obesity, and the prevention of these diseases.
2. Background of the invention
Approximately 1 million people worldwide suffer from type II diabetes, which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance. Hyperglycemia is considered to be a major risk factor for developing diabetic complications and may be directly associated with impaired insulin secretion in late stage type II diabetes. Normalization of blood glucose in type II diabetic patients can therefore be expected to improve the action of insulin. Currently available diabetes drugs such as sulfonylureas, thiazolidinediones, metformin and insulin have potential side effects, and thus there is a need to develop new, safe and orally effective antidiabetic drugs.
In the kidney, glucose can freely filter from the glomerulus (about 180 g/day), but is almost actively transported in the proximal convoluted tubule and reabsorbed. Two of the sodium-glucose transporters play an important role in glucose reabsorption, namely SGLT1 and SGLT 2. The function of SGLT2 is particularly prominent. SGLT2 is a transmembrane protein specifically expressed only in the S1 segment of the proximal convoluted tubule, and one of the most important physiological effects is the absorption of sugars in the blood flowing through the renal tubules, accounting for 90% of the absorption, SGLT2 is expressed as sodium-glucose 1: 1, and the SGLT-2 inhibitor inhibits the absorption of blood sugar into the renal tubules, resulting in the excretion of a large amount of sugar from urine. While SGLT1 is expressed predominantly in the distal convoluted tubule, accounting for 10% of the reabsorption, SGLT1 is expressed as sodium-glucose 2: a ratio of 1. SGLT1 is also found in the intestinal tract and other tissues. These transporters function via the Na +/ATPase pump and are transported back into the blood via the glucose transporter 2 (GLUT 2). This indicates that the SGLT2 transporter, which is most likely to be the target for drug action, is on the one hand its absolute reabsorption of glucose and on the other hand it is only expressed in the kidney. The feasibility of the pathway is also proved in the research of the urine glucose of the familial nephropathy. Familial nephropathy urinary glucose is predominantly expressed as variable amounts of urinary sugar (about 10-120 g/day), but patients are generally in good condition and no long term adverse health effects are found. This benign urinary sugar is mainly due to mutations in the SGLT-2 transporter, suggesting that selective pharmacological inhibition of SGLT-2 may not have adverse consequences other than the induction of diabetes. Inhibition of SGLT-1, on the other hand, causes sugar-galactose malabsorption syndrome, which may lead to dehydration.
The medicine treats hyperglycemia by acting on SGLT-2 transporters to inhibit the reabsorption of renal sugar, and provides a new way for treating diabetes. Although this pathway does not directly act on the pathophysiology of type II diabetes, lowering blood glucose by increasing renal glucose excretion causes a net energy deficit, promotes weight loss and indirectly ameliorates obesity symptoms. The research finds that the medicines can be combined with the existing hypoglycemic medicines or insulin, have lower risk of generating hypoglycemia and have the potential weight-reducing effect. The safety and efficacy of long-term clinical trials will ultimately determine whether SGLT-2 inhibitors can play a seat in drug therapy in type II diabetes.
Among them, patent documents such as WO0127128, US2005209166 and the like disclose a series of compounds as SGLT-2 inhibitors.
3. Summary of the invention
The present invention has been made in view of the development of an excellent and safe drug for the treatment and/or prevention of diabetes mellitus in various mammals (including humans) and various diseases caused by diabetes mellitus, and has an object to provide a C-glycoside derivative having an inhibitory activity against sodium-glucose cotransporter 2 (SGLT-2) and a hypoglycemic activity.
The technical scheme of the invention is as follows:
a compound represented by general formula (I), (II), (III), a pharmaceutically acceptable salt thereof, an easily hydrolysable ester thereof, or a stereoisomer thereof:
wherein ring A is 3-14 membered cycloalkyl, 6-14 membered aryl, having 1-4 substituents selected from N, S, O, SO and/or SO23-12 membered heterocyclic group of the heteroatom(s);
x, Y each represents CH2NH, O atom, S atom, SO and/or SO2；
R1Represents a hydrogen atom, C1-6Alkyl radical, C3-14Cycloalkyl, halogen, -CN, alkynyl, C2-6Alkenyl, -OH, -OR7；
R2，R3Each represents a hydrogen atom, -OH, -OR7，-O-C6-14Aryl, -OCH2-C6-14Aryl radical, C1-6Alkyl radical, C3-14Cycloalkyl, -CF3，-OCHF2，-OCF3Halogen, -CN, -NR8R8aCarbonyl group, -COOR7a，-COOH，-COR8b，-CH(OH)R8c，-CH(OR7f)R8d，-CONR8R8a，-NHCOR7b，-NHSO2R7c，-NHSO2-C6-14-C6-14Aryl radical, C6-14Aryl, -SR7d，-SOR7e，-SO2R7f，-SO2-C6-14Aryl having 1-4 substituents selected from N, S, O, SO and/or SO2A 5-10 membered heterocyclic group of the heteroatom of (a);
R4each represents a hydrogen atom, -OH, -OR7，C1-6Alkyl radical, C3-14Cycloalkyl, -CF3，-OCHF2，-OCF3Halogen, -CN, -NR8R8aCarbonyl group, -COOR7a，-COOH，-COR8b，-CH(OH)R8c，-CH(OR7f)R8d，-CONR8R8a，-NHCOR7b，-NHSO2R7c，-SR7d，-SOR7e，-SO2R7fHaving 1-4 substituents selected from N, S, O, SO and/or SO23-12 membered heterocyclic group of the heteroatom(s);
R7，R7a，R7b，R7c，R7d，R7e，R7feach represents a hydrogen atom, C1-6Alkyl radical, C3-14Cycloalkyl radicals, or containing radicals N, O, S, SO and/or SO2Said alkyl, cycloalkyl substituted with a heteroatom of (a) 1 to 4 carbon atoms;
R8，R8a，R8b，R8c，R8deach represents a hydrogen atom, C1-6Alkyl radical, C6-14Aryl radical, C1-6alkyl-C6-14Aryl or C3-14Cycloalkyl, or R10And R10aTogether with the N to which they are attached form a compound containing 1-4 groups of N, O, S, SO and/or SO2A 3-12 membered heterocyclic group of a heteroatom;
R5，R6a，R6b，R6ceach represents a hydrogen atom, (C)1-18Alkyl) carbonyl (C)1-18Alkyl) oxycarbonyl, C6-14Arylcarbonyl, or C3-14Aryl radical- (C)1-3Alkyl) carbonyl;
m is 0,1,2 or 3;
n is 0,1,2 or 3;
w is a bond, NH, O, S, SO2Or alkylene, said alkylene can be further substituted with 1-4 substituents, said substituents including halogen, hydroxy，C1-4Alkyl radical, C1-4Alkoxy, C substituted by halogen1-4An alkyl group;
wherein, the alkyl, the cycloalkyl, the aryl and the heterocyclic radical can be further substituted by 1 to 4 substituents, and the substituents comprise halogen atoms, hydroxyl, amino, carboxyl, alkyl and C1-6Alkoxy, aminosulfonyl, carbamoyl, C substituted by halogen atoms1-4Alkoxy, C substituted by 1 substituent selected from halogen atom, hydroxyl, amino, carboxyl1-4An alkyl group.
Preferably:
wherein ring A represents C3-8Cycloalkyl or partially saturated having 1-4 substituents selected from N, S, O, SO and/or SO23-12 membered heterocyclic group of the heteroatom(s);
x, Y each represents CH2NH, O atom or S atom;
R1represents a hydrogen atom, C1-6Alkyl radical, C3-14Cycloalkyl, halogen, -CN, C2-6Alkynyl, C2-6Alkenyl, -OH, -OR7；
R2，R3Each represents a hydrogen atom;
R4represents a hydrogen atom, -OH, -OR7，C1-6Alkyl radical, C3-8Cycloalkyl, -CF3，-OCHF2，-OCF3Halogen, -CN, -NR8R8aCarbonyl group, -COOR7a，-COOH，-COR8b，-CH(OH)R8c，-CH(OR7f)R8d，-CONR8R8a，-NHCOR7b，-NHSO2R7c，-SR7d，-SOR7e，-SO2R7fSaturated with 1-4 substituents selected from N, S, O, SO and/or SO23-12 membered heterocyclic group of the heteroatom(s);
R7，R7a，R7b，R7c，R7d，R7e，R7feach represents C1-6Alkyl radical, C3-8Cycloalkyl radicals containing radicals N, O, S, SO and/or SO2Said C having 1 to 4 carbon atoms replaced by a heteroatom of (A)1-6Alkyl radical, C3-8A cycloalkyl group;
R8，R8a，R8b，R8c，R8deach represents a hydrogen atom, C1-6Alkyl radical, C6-14Aryl radical, C1-6alkyl-C6-14Aryl or C3-8Cycloalkyl, or R10And R10aTogether with the N to which they are attached form a recyclable ring containing from 1 to 4 of N, O, S, SO and/or SO2A 5-7 membered heterocyclic group of a heteroatom;
R5，R6a，R6b，R6ceach represents a hydrogen atom;
m is 0,1 or 2;
n is 0,1 or 2;
w is alkylene which may be further substituted with 1 to 4 substituents including halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy, C substituted by halogen1-4An alkyl group;
wherein, the alkyl, the cycloalkyl, the aryl and the heterocyclic radical can be further substituted by 1 to 4 substituents, and the substituents comprise halogen atoms, hydroxyl, amino, carboxyl, alkyl and C1-6Alkoxy, aminosulfonyl, carbamoyl, C substituted by halogen atoms1-4Alkoxy, C substituted by 1 substituent selected from halogen atom, hydroxyl, amino, carboxyl1-4An alkyl group.
Preferably:
wherein ring A is C3-8Cycloalkyl or partially saturated having 1-2 substituents selected from N, S, O and/or SO23-7 membered heterocyclic group of the heteroatom(s);
x, Y each represents CH2NH, O atomOr an S atom;
R1represents a hydrogen atom, C1-6Alkyl radical, C3-14Cycloalkyl, halogen, -CN, C2-6Alkynyl, C2-6Alkenyl, -OH, -OR7；
R2，R3Each represents a hydrogen atom;
R4represents a hydrogen atom, -OR7，C3-8Cycloalkyl, halogen, -CF3，-OCHF2，-OCF3-CN, saturated with 1-4 substituents selected from N, S, O and/or SO23-7 membered heterocyclic group of the heteroatom(s);
R7represents C1-6Alkyl radical, C3-8Cycloalkyl radicals containing radicals N, O, S, SO and/or SO2Said C having 1 to 4 carbon atoms replaced by a heteroatom of (A)1-6Alkyl radical, C3-8A cycloalkyl group;
R5，R6a，R6b，R6ceach represents a hydrogen atom;
m is 0,1 or 2;
n is 0,1 or 2;
w is alkylene which may be further substituted with 1 to 4 substituents including halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy, C substituted by halogen1-4An alkyl group;
wherein, the alkyl, the cycloalkyl, the aryl and the heterocyclic radical can be further substituted by 1 to 4 substituents, and the substituents comprise halogen atoms, hydroxyl, amino, carboxyl and C1-6Alkyl radical, C1-6Alkoxy, aminosulfonyl, carbamoyl.
Preferably:
wherein ring A is C3-6Cycloalkyl or a partially saturated 3-7 membered heterocyclyl having 1-2 heteroatoms selected from S, O;
x, Y each represents CH2NH, O atom or S atom;
R1represents halogen;
R2，R3，R4each represents a hydrogen atom;
R5，R6a，R6b，R6ceach represents a hydrogen atom;
m is 0,1 or 2;
n is 0;
w is alkylene which may be further substituted with 1 to 4 substituents including halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy, C substituted by halogen1-4An alkyl group;
wherein, the cycloalkyl and the heterocyclic radical can be further substituted by 1 to 4 substituents, and the substituents comprise halogen atoms, hydroxyl, amino, carboxyl and C1-6Alkyl radical, C1-6Alkoxy, aminosulfonyl, carbamoyl.
More preferably:
wherein, the A ring is cyclopropyl, cyclobutane, cyclopentyl, tetrahydrofuranyl, oxetanyl;
x, Y each represents CH2NH, O atom or S atom;
R1represents a hydrogen atom, an alkyl group, a cycloalkyl group, a halogen, -CN, an alkynyl group, an alkenyl group, -OH, -OR7；
R2，R3，R4Each represents a hydrogen atom;
R5，R6a，R6b，R6ceach represents a hydrogen atom;
m is 0 or 1;
n is 0;
w is alkylene which may be further substituted with 1 to 4 substituents including halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy, C substituted by halogen1-4An alkyl group;
wherein said cyclopropane group, cyclobutane group, cyclopentane group, tetrahydrofuran group, and oxetane group may be further substituted with 1 to 4 substituents selected from halogen atom, hydroxyl group, amino group, carboxyl group, C1-6Alkyl radical, C1-6Alkoxy, aminosulfonyl, carbamoyl.
More preferably:
wherein, the A ring is cyclopropyl, cyclobutane, cyclopentyl, tetrahydrofuranyl, oxetanyl;
x, Y each represents CH2NH, O atom or S atom;
R1represents halogen;
R2，R3，R4each represents a hydrogen atom;
R5，R6a，R6b，R6ceach represents a hydrogen atom;
m is 0 or 1;
n is 0;
w is methylene.
Particularly preferred compounds are:
Detailed Description
The "halogen atom" in the present invention includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and preferably a fluorine atom and a chlorine atom.
The "alkyl group" as referred to herein means a straight-chain or branched alkyl group derived from an alkane having 1 to 18 carbon atoms in which one hydrogen atom has been removed from the alkane moiety, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Preferably C1-6Alkyl, more preferably C1-4Alkyl radical, C1-3Alkyl radical, the term "C1-18Alkyl group "," C1-6Alkyl group "," C1-4Alkyl group "," C1-3Alkyl "refers to the specific examples of the above examples containing 1 to 18, 1 to 6, 1 to 4, 1 to 3 carbon atoms.
The "alkylene group" in the present invention means a straight-chain or branched alkane derived from the above alkyl group by removing one hydrogen atom, and includes- (CH)2)t- (t is an integer of 1 to 18), preferably t is an integer of 1 to 3, such as methylene, ethylene, propylene and the like.
"C" according to the invention2-6The "alkenyl group" means a straight-chain or branched or cyclic alkenyl group having 2 to 6 carbon atoms and containing a double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenylA phenyl group, a 1-methyl-2-propenyl group, a 2-methyl-2-propenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-methyl-1-butenyl group, a 2-methyl-1-butenyl group, a 3-methyl-1-butenyl group, a 1-methyl-2-butenyl group, a 2-methyl-2-butenyl group, a 3-methyl-2-butenyl group, a 1-methyl-3-butenyl group, a 2-methyl-3-butenyl group, a 3-methyl-3-butenyl group, a 1, 1-dimethyl-2-propenyl group, a 1, 2-dimethyl-1-propenyl group, a 3-, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 1-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 2-pentenyl, 4-methyl-4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 2, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2-methyl-butenyl, 3-methyl-butenyl, 2-methyl-propenyl, 2, 1-ethyl-2-methyl-1-propenyl group, 1-ethyl-2-methyl-2-propenyl group, 1, 3-butadiene group, 1, 3-pentadiene, 1, 4-hexadiene, cyclopentenyl group, 1, 3-cyclopentadienyl group, cyclohexenyl group, 1, 4-cyclohexadienyl group and the like.
"C" according to the invention2-6Alkynyl "means a straight-chain or branched alkynyl group having 3 to 6 carbon atoms and having a triple bond, such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-Dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1-dimethyl-2-butynyl, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 4-methyl-4-pentynyl, 1-dimethyl-2-butynyl, 1, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl, and the like.
Said "C" of the present invention1-6Alkoxy "means the term" C1-6Alkyl "a group attached to another structure through an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, and the like.
Said "C" of the present invention1-6Alkylcarbonyl "refers to the term" C1-6Alkyl "a group attached to another structure through a carbonyl group, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, and the like.
Said "C" of the present invention1-6Alkoxycarbonyl "is the term" C1-6Alkoxy "a group bonded to another structure through a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.
The "cycloalkyl" as referred to herein means a cyclic alkyl group derived from an alkane moiety of 3 to 14 carbon atoms by removing one hydrogen atom, and includes a 3-8 membered monocyclic cycloalkyl group, a 6-14 membered fused cyclic alkyl group, a 7-12 membered bridged cyclic group and a 7-12 membered saturated spirocyclic group. Preferably C3-8Cycloalkyl radical, C3-6Cycloalkyl and C5-6A cycloalkyl group. The term "C3-14Cycloalkyl group "," C3-8Cycloalkyl group "," C3-6Cycloalkyl group "," C5-6Cycloalkyl "is a specific example containing 3 to 14, 3 to 8, 3 to 6, and 5 to 6 carbon atoms in the above examples, respectively.
3-8 membered monocyclic cycloalkyl groups, including 3-8 membered saturated monocyclic cycloalkyl groups and 3-8 membered partially saturated monocyclic cycloalkyl groups. 3-8 membered saturated monocyclic cycloalkyl, meaning that the monocyclic ring is fully saturated carbocyclic, examples of which include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, dimethylcyclohexane, etc. 3-8 membered partially saturated monocyclic cycloalkyl, meaning that the monocyclic ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, 1, 5-cyclooctadienyl, and the like.
And a fused cyclic group means a 6-14 membered cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other, and includes a 6-14 membered saturated fused cyclic group and a 6-14 membered partially saturated fused cyclic group. 6-to 12-membered fused ring group, 6-to 10-membered fused ring group are preferred. 6-14 membered saturated fused cycloalkyl, meaning that the fused ring is a fully saturated carbocyclic ring, examples of which include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl and the like. A 6-14 membered partially saturated fused cycloalkyl group, meaning that at least one ring in the fused ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to: bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3,3 a-tetrahydropentalenyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9, 10-decahydrophenanthryl and the like.
The "bridged cyclic group" as used herein refers to a structure containing 5 to 12 carbon atoms in which any two rings share two atoms not directly connected to each other, and the "5 to 12-membered bridged cyclic group" includes a 5 to 12-membered saturated bridged cyclic group and a 5 to 12-membered partially saturated bridged cyclic group. 5-12 membered saturated bridged ring group, preferably 6-10 membered saturated bridged ring group, including but not limited to bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.1] octane, bicyclo [3.3.1] nonane, etc. The 7-to 12-membered partially saturated bridged ring group means a cyclic group in which at least one ring is unsaturated, preferably a 6-to 10-membered partially saturated bridged ring, and specific examples include, but are not limited to, bicyclo [2.2.1] hept-5-ene, bicyclo [3.2.1] oct-6-ene, dicyclopentadiene and the like.
The "spiro ring group" in the invention refers to a 5-12 membered fused ring structure formed by at least two rings sharing one atom. 5-12 membered saturated spiro ring group means that all rings in the spiro ring group are saturated cyclic groups, specific examples include but are not limited to: spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [5.5] undecanyl, spiro [4.6] undecanyl, spiro [5.6] dodecanyl and the like. 5-12 membered partially saturated spiro ring group means a cyclic group in which at least one ring of the spiro ring group is unsaturated, and specific examples include, but are not limited to: spiro [3.4] oct-6-enyl, spiro [3.5] non-6-enyl, spiro [4.4] non-2, 7-dienyl, spiro [4.5] dec-6, 8-dienyl, spiro [5.5] undec) -2-enyl, (Z) -spiro [4.6] undec) -8-enyl, spiro [4.6] undec) -2-enyl and the like. Preferred are 7-to 10-membered spiro ring groups, including "7-to 10-membered saturated spiro ring groups" and "7-to 10-membered unsaturated spiro ring groups".
"C" according to the invention3-8Cycloalkoxy "refers to the term" C3-8Cycloalkyl "a group attached to another structure through an oxygen atom, such as cyclopropyloxy, cyclobutyloxy, 1-methylcyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.
The "aryl" in the invention refers to a cyclic aromatic group with 6-14 carbon atoms as ring atoms, and comprises 6-8 membered monocyclic aryl and 8-14 membered fused ring aryl. 6-8 membered monocyclic aryl means allUnsaturated aryl groups such as phenyl, cyclooctatetraenyl and the like. The 8-to 14-membered fused ring aryl group means a cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other and having at least one ring being an all unsaturated aromatic ring, and includes 8-to 14-membered all unsaturated fused ring aryl, naphthyl, anthryl, phenanthryl and the like, and also includes 8-to 14-membered partially saturated fused ring aryl groups such as benzo 3-to 8-membered saturated monocyclic cycloalkyl, benzo 3-to 8-membered partially saturated monocyclic cycloalkyl, and specific examples thereof are 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like. The term "C6-14Aryl "is a specific example of the above examples having 6 to 14 carbon atoms.
The "heteroaryl" of the present invention includes 1 to 4 heteroatoms in addition to carbon atoms in its ring atoms, and includes, but is not limited to, oxygen atoms, nitrogen atoms, and sulfur atoms. Heteroaryl groups may be bonded through carbon or a heterocyclic atom. Including monocyclic heteroaromatic rings having 1-4 heteroatoms selected from N, S, O and saturated or unsaturated fused heterocyclic aromatic groups having 1-4 heteroatoms selected from N, S, O. Monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, furyl, thienyl,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2,3-Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2,5-Oxadiazolyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, tetrazolyl,Triazolyl, 2H-1,2-Oxazinyl, 4H-1,2-Oxazinyl, 6H-1,2-Oxazinyl, 2H-1,3-Oxazinyl, 4H-1,3-Oxazinyl, 6H-1,3-Oxazinyl, 2H-1,4-Oxazinyl, 4H-1,4-Oxazinyl radical, iso-isomerOxazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like; fused heterocyclic aryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, indolizinyl, indazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzisoxazolyl, benzothienyl, and the likeAzolyl, benzoAzinyl, benzimidazolyl, pyridopyridyl, pyrazolo[3,4-b]Pyridyl, purinyl, acridinyl, xanthenyl and the like. The term "5-7 membered heteroaryl" refers to a specific example of the above-mentioned "heteroaryl" having 5 to 7 ring atoms.
The "heterocyclic group" in the present invention means a 3-to 14-membered cyclic group containing one or more hetero atoms, and the "hetero atom" means a nitrogen atom, an oxygen atom, a sulfur atom or the like. Comprises a mixture of at least one compound having 1 to 4 substituents selected from N, S, O and/or SO23-to 8-membered heteromonocyclic group and 6-to 14-membered fused heterocyclic group of (a). Also included are the heteroaryl groups mentioned above and their dihydro and tetrahydro analogs. Also includes having 1-4 selected from N, S, O and/or SO2Fused, spiro, bridged rings of heteroatoms of (a). Preferably 5-10 membered heterocyclic group, more preferably 5-7 membered heterocyclic group.
Monoheterocyclyl means monocyclic heterocyclyl containing 3 to 8 ring atoms (wherein at least one heteroatom is present), including 3 to 8 membered unsaturated heteromonocyclic group, 3 to 8 membered partially saturated heteromonocyclic group, 3 to 8 membered saturated heteromonocyclic group. Preference is given to 5-7-membered unsaturated heteromonocyclic groups, 5-7-membered partially saturated heteromonocyclic groups, 5-7-membered saturated heteromonocyclic groups. 3-8 membered unsaturated Monoheterocyclyl, which means an aromatic heteroatom-containing cyclic group, specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 1, 4-dioxadienyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, oxepitrienyl, oxacycloheptatrienyl, oxatriazinyl, and the like, Thiepinatrienyl, azepinatrienyl, 1, 3-diazacycloheptatrienyl, azepintetraenyl, and the like. 3-8 membered partially saturated monoheterocyclyl means a cyclic group containing a double bond, a heteroatom, and specific examples include, but are not limited to, 2, 5-dihydrothienyl, 4, 5-dihydropyrazolyl, 3, 4-dihydro-2H-pyranyl, 5, 6-dihydro-4H-1, 3-oxazinyl, and the like. 3-8 membered saturated monoheterocyclyl, refers to heteroatom-containing cyclic groups that are all saturated bonds, specific examples include, but are not limited to: aziridinyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1, 4-dioxanyl, 1, 3-dithianyl, morpholinyl, piperazinyl, and the like.
6-14 membered fused heterocyclyl means an aromatic fused ring group, spiro ring group, bridged ring group in which one of the carbon atoms not shared is N, S, O and/or SO2The heteroatom(s) in place of the heterocyclo, spiroheterocyclyl, bridged heterocyclyl groups formed.
Heterocyclyl means a fused ring structure containing 6 to 14 ring atoms (wherein at least one heteroatom is contained) and formed by two or more ring structures sharing two adjacent atoms to each other, and includes 6 to 14-membered unsaturated fused heterocyclyl, 6 to 14-membered partially saturated fused heterocyclyl, 6 to 10-membered saturated fused heterocyclyl. 6-14 membered unsaturated heterocyclo means that all rings are unsaturated fused ring structures such as structures formed by benzo 3-8 membered unsaturated heteromonocyclic group, structures formed by 3-8 membered unsaturated heteromonocyclic group and 3-8 membered unsaturated heteromonocyclic group, and the like, and specific examples include, but are not limited to: benzofuranyl, benzisofuranyl, benzothienyl, indolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, benzpyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, thieno [2,3-b ] thienyl, thieno [3,2-b ] thienyl, benzo [ b ] thiazolyl, and the like. The 6-14 membered partially saturated and heterocyclic group means a condensed ring structure containing at least one partially saturated ring, such as a structure formed by a benzo 3-8 membered partially saturated heteromonocyclic group, a structure formed by a 3-8 membered partially saturated heteromonocyclic group and a 3-8 membered partially saturated heteromonocyclic group, and the like, and specific examples include, but are not limited to: 1, 3-dihydrobenzofuranyl, benzo [ d ] [1.3] dioxolyl, isoindolinyl, chromanyl, 1,2,3, 4-tetrahydropyrrolo [3,4-c ] pyrrolyl, 2,4,6, 7-tetrahydropyran [4,3-c ] pyrazolyl, 1,4,6, 7-tetrahydropyran [4,3-b ] pyrrolyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, 3, 4-dihydro-2H-benzo [ b ] [1,4] thiazinyl, 2, 3-dihydrobenzo [ b ] [1,4] dioxinyl, indolinyl, 1,2,3, 4-tetrahydroquinolyl, 3, 4-dihydro-2H-benzo [ b ] [1,4] oxazinyl, chromanyl, and the like. 6-to 10-membered saturated and heterocyclic group means a fused ring structure in which all rings are saturated, such as a structure formed by a 3-to 8-membered saturated heteromonocyclic group and a 3-to 8-membered saturated heteromonocyclic group, and specific examples include, but are not limited to: cyclobutane four pyrrolidine base, cyclopentane four pyrrolidine base, azetidine imidazole alkyl, 3-oxabicyclo [3.1.0] hexyl, six hydrogen furan [3,4-b ] [1,4] two oxa-base, six hydrogen-2H-cyclopentane [ b ] [1,4] two oxa-base etc..
Bridged heterocyclic groups refer to bridged ring structures formed by 5 to 12 ring atoms, which contain at least one heteroatom. "5-12 membered bridged heterocyclic ring" includes 5-12 membered saturated bridged heterocyclic group, 5-12 membered partially saturated bridged heterocyclic group.
5-12 membered saturated bridged heterocyclyl, meaning that all rings in the bridged heterocyclyl are saturated cyclic groups, preferably 7-8 membered saturated bridged heterocyclyl, specific examples include but are not limited to: 7-oxabicyclo [2.2.1] heptanyl, 7-aminobicyclo [2.2.1] heptanyl, 2, 5-diaminobicyclo [2.2.1] heptanyl, 2-oxa-5-aminobicyclo [2.2.1] heptanyl, 2-aminobicyclo [2.2.2] octanyl, 2-oxabicyclo [2.2.2] octanyl, 2-thiabicyclo [2.2.2] octanyl, bicyclo [3.2.1] octanyl, 8-aminobicyclo [3.2.1] octanyl, 1-aminobicyclo [3.2.1] octanyl, 3-aminobicyclo [3.2.1] octanyl, 6-aminobicyclo [3.2.1] octanyl, 3-oxa-8-aminobicyclo [3.2.1] octanyl, 4-oxabicyclo [3.2.1] octanyl, 3, 8-diaminobicyclo [3.2.1] octane group, 8-oxa-3-aminobicyclo [3.2.1] octane group, 2-aminobicyclo [3.2.1] octane group, and the like.
5-12 membered partially saturated bridged heterocyclyl means that there is a cyclic group in the bridged heterocyclyl in which at least one ring is unsaturated, preferably 7-8 membered partially saturated bridged heterocyclyl, specific examples include, but are not limited to: 3, 8-diamine heterobicyclic bridges [3.2.1]Oct-6-alkenyl, benzo 2-amino-bicyclo [2.2.2] bridges]Octyl radicalBenzo 2-thiabicyclo [2.2.2] bridges]Octyl radicalBenzo 2-oxabicyclo [2.2.2] bridges]Octyl radicalAnd the like.
Spiroheterocyclyl means a spirocyclic structure formed by 5 to 12 ring atoms containing at least one heteroatom. The 5-12 membered spiroheterocyclic group includes a 5-12 membered saturated spiroheterocyclic group, a 5-12 membered partially saturated spiroheterocyclic group.
5-12 membered saturated spiroheterocyclyl, meaning that all rings in the spiroheterocyclyl are saturated cyclic groups, specific examples include, but are not limited to: 2-oxaspiro [3.3] heptyl group, 6-oxaspiro [2.5] octyl group, 4-oxa-7-aminospiro [2.5] octyl group, 2-aminospiro [3.3] heptyl group, 2-oxa-6-aminospiro [3.3] heptyl group, 2-aminospiro [3.4] octyl group, 6-oxa-2-aminospiro [3.4] octyl group, 2-oxa-6-aminospiro [3.4] octyl group, 2-oxaspiro [3.4] octyl group, 5-oxaspiro [3.5] nonyl group, 7-aminospiro [3.5] nonyl group, 2-aminospiro [4.4] nonyl group, 2-oxa-7-aminospiro [4.4] nonyl group, 2-oxaspiro [4.4] nonyl group, 1, 7-dioxaspiro [4.4] nonyl group, 1,4, 7-trioxaspiro [4.4] nonanyl group, 8-aminospiro [4.5] decanyl group, 6-oxa-9-aminospiro [4.5] decanyl group, 6-oxa-2-aminospiro [4.5] decanyl group, 3-aminospiro [5.5] undecanyl group, 1-oxa-9-aminospiro [5.5] undecanyl group, 3, 9-diaminospiro [5.5] undecanyl group, 3-oxa-9-aminospiro [5.5] undecanyl group, 7, 9-diaminospiro [4.6] undecanyl group and the like.
5-12 membered partially saturated spiroheterocyclic group means a cyclic group in which at least one ring of the spiroheterocyclic group is unsaturated, and specific examples include, but are not limited to: 6-aminospiro [3.4] oct-7-enyl, 2-oxa-6-aminospiro [3.4] oct-7-enyl, 7-aminospiro [3.5] non-5-enyl, 2-aminospiro [4.4] non-7-enyl, 8-aminospiro [4.5] dec-2-enyl and the like.
N, O, S, SO and/or SO as defined in the invention2The "cycloalkyl group having 1 to 4 carbon atoms substituted with the hetero atom(s)" means 1 to 4 carbon atoms (or CH, CH) in the above-mentioned cycloalkyl group2) Is N, O, S, SO and/or SO2The heteroatom(s) replaces the heterocyclic group formed.
The term "3-to 12-membered heterocyclic group" means a specific example of the above-mentioned "heterocyclic group" having 3 to 12 ring atoms. The term "5-to 12-membered heterocyclic group" means a specific example of the above-mentioned "heterocyclic group" having 5 to 12 ring atoms. The term "5-to 7-membered heterocyclic group" means a specific example of the above-mentioned "heterocyclic group" having 5 to 7 ring atoms.
The "X, Y represents CH respectively2NH, O atom, S atom, SO and/or SO2(ii) a "includes but is not limited to the following cases: (1) x, Y are all CH2(ii) a (2) X, Y one of them is NH, O, S, SO and/or SO2(ii) a (3) X, Y is NH, O, S, SO and/or SO2。
In the invention, the ring A and the connected ring are fused to form a fused ring, a fused heterocycle, a spiro heterocycle, a bridged ring and a bridged heterocycle.
The invention further claims a preparation method of the compound shown in the general formula (I) and an intermediate thereof.
The above compounds of the present invention can be synthesized using the methods described in the schemes below and/or other techniques known to those of ordinary skill in the art, but are not limited to the methods below.
When W is methylene, the reaction scheme is:
the reaction steps are as follows:
step 1 preparation of Compound a
Dissolving raw material 1 and N-methylmorpholine in THF, cooling under the protection of nitrogen, slowly adding trimethyl silicon chloride dropwise, keeping the temperature, heating and stirring for reaction after the temperature is kept, then stirring for reaction at room temperature, adding toluene for dilution, cooling, adding water for keeping the temperature, separating out an organic phase of a reaction mixture, and washing with sodium dihydrogen phosphate aqueous solution, water and saturated saline respectively. Rotary evaporation gave a pale yellow oil a.
Step 2 preparation of Compound b
Cooling the dichloromethane solution of aluminum trichloride to 0 deg.C, slowly adding raw material 3, stirring at 0 deg.C for 1h, slowly adding dichloromethane solution of raw material 2 dropwise, detecting until the reaction is finished, pouring the reaction mixture into ice water, extracting with dichloromethane for three times, combining organic phases, washing with dilute hydrochloric acid, water, NaOH (1N), saturated saline water, and Na2SO4Drying, rotary evaporating organic phase, and column chromatography to obtain target compound b.
Step 3 preparation of Compound c
Dissolving the compound b in trifluoroacetic acid, adding triethylsilane and boron trifluoride diethyl etherate, heating and refluxing the reaction solution, adding saturated sodium carbonate aqueous solution after the reaction is finished to adjust the pH to be =8, extracting with ethyl acetate to obtain an organic phase, washing the organic phase with saturated saline water, and drying in vacuum to obtain a crude compound c.
Step 4 preparation of Compound d
Dissolving the compound c in anhydrous THF, cooling to-78 ℃, carrying out nitrogen protection, dropwise adding n-BuLi, dropwise adding an n-hexane solution of the compound a, keeping stirring for reaction, quenching a reaction mixture by using a saturated ammonium chloride aqueous solution, extracting an aqueous layer by using ethyl acetate, washing combined organic phases by using water and saturated saline, and carrying out rotary evaporation to obtain an oily compound d.
Step 5 preparation of Compound e
Dissolving compound d in absolute methanol, adding anhydrous methanol solution of methanesulfonic acid while cooling, slowly raising to room temperatureStirring the mixture warm, and reacting the mixture with saturated NaHCO3The solution was adjusted and extracted with ethyl acetate and the combined organic phases washed with water, brine, dried and rotary evaporated to give compound e.
Step 6 preparation of Compound f
Dissolving the compound e, diisopropylethylamine and DMAP in THF, cooling to zero degree, slowly adding acetic anhydride, stirring, regulating reaction mixture with saturated aqueous solution of sodium bicarbonate, extracting with ethyl acetate, washing combined organic phases with water and saturated brine, drying, rotary evaporation and concentration, and carrying out column chromatography to obtain the compound f.
Step 7 preparation of Compound g
And (3) adding triethylsilane or triisopropylsilane and boron trifluoride diethyl etherate into the acetonitrile solution of the compound f under cooling, detecting until the reaction is finished, quenching the reaction by using a saturated sodium bicarbonate solution, extracting by using ethyl acetate, washing combined organic phases by using water and saturated saline, drying, carrying out rotary evaporation concentration, and recrystallizing (normal hexane and ethyl acetate) to obtain a compound g.
Step 8 preparation of Compounds of formula I
Adding a compound g of tetrahydrofuran and methanol into a mixed solution of the compound g of lithium hydroxide monohydrate at zero temperature, slowly raising the temperature of the reaction to room temperature, stirring, detecting the end of the reaction, concentrating the reaction solution, adding dichloromethane for extraction, washing the combined organic phase with water and saturated saline, drying and concentrating to obtain the compound shown in the formula I'.
In the reaction scheme, R1、R2、R3、R4、R5、R6a、R6b、R6cM, n and A are as defined above.
The invention further claims intermediates of the compounds shown in the general formula (I) in the preparation process, pharmaceutically acceptable salts, easily hydrolysable esters or stereoisomers thereof.
"pharmaceutically acceptable salts" of any of the above compounds of the invention include alkali metal salts, such as sodium, potassium, lithium, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts such as ammonium salts; organic base salts such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris (hydroxymethyl) aminomethane salt; hydrohalic acid salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide and the like; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate and the like; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and the like; aryl sulfonates such as benzenesulfonate, p-benzenesulfonate and the like; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.; amino acid salts such as glycinate, trimethylglycinate, arginate, ornithine, glutamate, aspartate and the like.
"readily hydrolyzable esters" of any of the above compounds of the present invention are those pharmaceutically acceptable esters which hydrolyze in vivo to form the parent compound. It will be apparent to those skilled in the art that readily hydrolyzable esters of the compounds of the present invention may be formed at the free carboxyl or hydroxyl group of the compound and may be prepared by conventional methods.
"stereoisomers" of any of the above compounds of the invention include all epimeric, diastereomeric and tautomeric forms. When a key is represented by a wedge, this indicates that the key will come out of the paper in three dimensions, and when a key is shaded, this indicates that the key will come back into the paper in three dimensions.
The present invention further claims a pharmaceutical composition comprising any of the above-mentioned compounds, pharmaceutically acceptable salts thereof, easily hydrolysable esters thereof or stereoisomers thereof together with other pharmaceutically active ingredients.
The invention also includes any compound, its pharmaceutically acceptable salt, its easily hydrolysable ester or its stereoisomer, which can be prepared into any clinically or pharmaceutically acceptable dosage form by the known method in the field, and can be applied to the patients needing the treatment by oral, parenteral, rectal or pulmonary administration. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray.
The invention also provides application of the compound in preparing a medicament for treating and/or preventing diabetes. The C-glycoside derivative of the present invention can be used for diabetes such as insulin-dependent diabetes (type I diabetes), non-insulin-dependent diabetes (type II diabetes), and the like, and can also be used for the treatment of various diabetes-related diseases including insulin-resistant diseases and obesity, and the prevention of these diseases.
The compound of the invention has the following characteristics:
(1) the compound has obvious inhibition effect and hypoglycemic effect on sodium-glucose cotransporter 2 (SGLT-2), and can be safely used for treating and/or preventing diabetes of various mammals (including human beings) and various diseases caused by the diabetes;
(2) the compound of the invention has better physicochemical property, low toxicity and less side effect;
(3) the compound of the invention has simple preparation process, high medicine purity and stable quality, and is easy to carry out large-scale industrial production.
The advantageous effects of the compounds of the present invention are further illustrated below by pharmacological experiments, but this should not be construed as the compounds of the present invention having only the following advantageous effects.
Experimental examples in vitro and in vivo pharmacological Activity of the Compounds of the invention
1. In vitro evaluation experiments of Compounds of the invention
The in vitro evaluation method of the invention is to transfect human SGLT2 and SGLT1 sequences onto Chinese hamster ovary cells for stable expression, and to inhibit the cell pair [14C-sodium-dependent absorption of the marker-R-methyl-D-glucopyranoside (AMG), determination of the semi-inhibitory concentration IC50。
And (3) testing the sample: the chemical name and the structural formula of the partial compound are as described in the specification.
Buffer A(KRH-Na+)：120mM NaCl，4.7mM KCl，1.2mM MgCl2，2.2mM CaCl2，10mMHEPES(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)。
The experimental method comprises the following steps: the human SGLT2 and SGLT1 sequences were stably expressed in CHO cells by culturing the cells in 96-well plates for 12 hours, washing 3 times with 200. mu.l/well of KRH-Na + (Buffer A) or KRH-NMG (Buffer A-) Buffer solution. Then adding the mixture containing BufferA or BufferA-plus [14C ]]AMG (10. mu. Ci/mL) in 100. mu.l/well buffer, incubated at 37 ℃ for 1 hour. Then, ice is addedThe test was stopped with 100. mu.l of pre-cooled Buffer solution (Buffer D) and washed 5 times. Add 100mM NaOH solution 20. mu.l/well, centrifuge at 600rpm, 5 minutes, and Microscint 40 solution 80. mu.l/well, centrifuge at 600rpm, 5 minutes. Finally, the value was detected by scintillation counting using a Microbeta Trilux (available from PerkinElmer Co., Ltd.)14C]Radioactivity of AMG, calculation of the semi-inhibitory concentration IC50。
Experimental results and conclusions:
table 1 evaluation results of the inhibitory effect of the compounds of the present invention are as follows:
therefore, the compound has better inhibition effect and selectivity on SGLT 2.
2. Urine glucose test in Normal mice
And (3) testing the sample: the chemical name and the structural formula of the partial compound are as described in the specification.
The experimental method comprises the following steps: the urine glucose test method comprises the steps of taking SPF male Sprague-Dawley rats with the age of 6 weeks, after fasting animals for 15 hours, randomly dividing the animals into a blank control group, a model group, a positive drug group and a tested drug group according to the weight of the rats, putting the animals into a metabolism cage, feeding water or not, and collecting 24 hours of urine. Then, sugar (5g/Kg) was administered after oral administration (10 mg/Kg), and then placed in a metabolism cage, and after 1 hour of sugar administration, food was supplied, diet was freed, 24 hours of urine was collected, and the amount of urine was recorded. Centrifuging the collected urine at 3000rpm for 15min, removing residue, collecting supernatant, and measuring urine sugar content. Urine glucose content was normalized to 200g body weight. Data are presented as mean ± standard deviation, with single-factor analysis of variance used for analysis of values, and Dunnett's test for comparison between groups, with p <0.05 considered statistically significant.
Table 2: results of urine glucose test for compounds:
in conclusion, the compound of the invention shows better hypoglycemic effect.
4. Detailed description of the preferred embodiments
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.
Example 1 beta-1 '-deoxy-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ]]Naphthalene-4-methylene) benzene) -glucose acetal Preparation of (Compound 1)
Step 12, 3,4, 6-tetra (trimethylsilyl ether) -gluconolactone preparation
Dissolving raw material 1(239g,1.34mol) and N-methylmorpholine (1.18L,10.73mol) in THF (2.4L), cooling to-5 ℃ under the protection of nitrogen, slowly adding trimethyl silicon chloride (1022mL,8.05mol) dropwise, keeping the temperature of the dropwise adding process not to exceed 5 ℃, heating to 35 ℃ after finishing the dropwise adding process, stirring for 5 hours, then stirring for 15 hours at room temperature, adding toluene for dilution, cooling to 0-5 ℃, then adding water for keeping the temperature not to exceed 10 ℃, separating out an organic phase of the reaction mixture, and washing with sodium dihydrogen phosphate aqueous solution, water and saturated common salt water respectively. Rotary evaporation gave 593.2g of 2,3,4, 6-tetrakis (trimethylsilyl ether) -gluconolactone as a pale yellow oil in 92% yield.
Step preparation of 24-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalene-4-formyl) bromobenzene
A solution of aluminum trichloride (2.8g,21mmol) in dichloromethane (25mL) was cooled to 0 deg.C and compound (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] was added slowly]Naphthalene-4-methylene) benzene (3.77g,21.3mmol), stirred at 0 ℃ for 1h, then a solution of compound 2-chloro-5-bromo-benzoyl chloride (6.9g,21.3mmol) in dichloromethane (15 mL) was slowly added dropwise, detection was carried out until the reaction was complete, the reaction mixture was poured into ice water (150 mL) and extracted with dichloromethane (3X 100mL), the organic phases were combined, washed with dilute hydrochloric acid (1N), water, NaOH (1N), saturated brine, anhydrous Na2SO4Drying, rotary evaporating organic phase, and performing column chromatography (n-hexane/ethyl acetate = 1/20) to obtain the target compound 4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b [ -b ]]Naphthalene-4-formyl) bromobenzene 7.03g, yield 80%.
Step 3 preparation of the Compound 4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalene-4-methylene) bromobenzene
The compound 4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalene-4-formyl) bromobenzene (16.5g,39.9mmol) was dissolved in trifluoroacetic acid (30 mL), then triethylsilane (7.86g,67.6mmol) and boron trifluoride diethyl ether (9.60g,67.6mmol) were added, the reaction solution was heated under reflux for 16H, saturated aqueous sodium carbonate solution was added to adjust pH =8, ethyl acetate was extracted to give an organic phase, and the organic phase was washed with saturated brine and dried under vacuum to give crude compound 4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalene-4-methylene) bromobenzene 10.7g in 71% yield.
Step 4 preparation of the Compound 1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalene-4-methylene) benzene) -glucose hemiacetal
The compound 4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalene-4-methylene)) bromobenzene (20.7g,46mmol) was dissolved in anhydrous THF (150 mL), cooled to-78 deg.C, then n-BuLi (2.5M,18.4mL,46mmol) was slowly added dropwise under nitrogen protection, stirring was maintained for 3H, then a solution of the compound 2,3,4, 6-tetrakis (trimethylsilylether) -gluconolactone in n-hexane (300 mL) was slowly added dropwise at-78 deg.C, stirring was maintained for 0.5H, the reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (100mL), the aqueous layer was extracted with ethyl acetate (3X 100mL), the combined organic phases were washed with water and saturated brine, rotary evaporation was carried out to give the compound 1' - (4-chloro-3- (1 a), 2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalene-4-methylene) benzene) -glucose hemiacetal 18.2g, 82% yield.
Step 5 preparation of the Compound 1 '-O-methyl-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalene-4-methylene) benzene) -glucal acetal
The compound 1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b)]Naphthalene-4-methylene) benzene) -glucose hemiacetal (4.86g,10.0mmol) was dissolved in absolute methanol (10 mL), cooled to 0 deg.C, added methanesulfonic acid (0.4 mL) in absolute methanol (10 mL), slowly warmed to room temperature and stirred for 16h with saturated NaHCO3Adjusting pH of the aqueous solution to =8, extracting with ethyl acetate, washing the combined organic phases with water, washing with saturated brine, drying, and rotary evaporating to obtain the compound 1 '-O-methyl-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b)]Naphthalene-4-methylene)) -glucose acetal 4.95g, 100%.
Step 6 preparation of the Compound 1 '-O-methyl-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalen-4-ylidene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal
The compound 1 '-O-methyl-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalen-4-ylidene) benzene) -glucose acetal (4.39g,9.1mmol), diisopropylethylamine (9.4g,72.8mmol) and DMAP (10mg) were dissolved in THF (100mL), cooled to zero, acetic anhydride (7.43g,72.8mmol) was slowly added, stirred for 0.5H, the reaction mixture was adjusted to pH =8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 × 60mL), the combined organic phases were washed with water (70mL) and saturated brine (70mL), dried, concentrated by rotary evaporation, column chromatographed to give the compound 1 '-O-methyl-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalen-4-ylidene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal 3.93g, 65% yield.
Step 7 preparation of the compound beta-1 '-deoxy-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalen-4-ylidene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal
A solution of the compound 1 '-O-methyl-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalen-4-ylidene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal (7.48g,16.0mmol) in acetonitrile (50mL) was cooled to 10 deg.C, triisopropylsilane (5.1g,32mmol) and boron trifluoride diethyl ether (6.8g,48mmol) were added, detection was complete, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3X 100mL), the combined organic phases were washed with water and saturated brine, dried, concentrated by rotary evaporation, and recrystallized (n-hexane/ethyl acetate =1/15, V/V) to give the compound β -1 '-deoxy-1' - (4-chloro-3- (1) and a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalen-4-ylidene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal 7.50g, 74% yield.
Step 8 preparation of beta-1 '-deoxy-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] naphthalene-4-methylene) benzene) -glucal, compound
The compound beta-1 '-deoxy-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ]]Naphthalene-4-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal (10g,15.7mmol) was dissolved in a mixed solution of tetrahydrofuran-base (100mL) and methanol (100mL), an aqueous solution (50mL) of lithium hydroxide monohydrate (4.4g,104mmol) was added at zero temperature, the reaction solution was slowly warmed to room temperature, stirred for 14H, detection of reaction completion, the reaction solution was concentrated, dichloromethane was added for extraction, the combined organic phases were washed with water and saturated brine, dried, and concentrated to give the compound β -1 '-deoxy-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclopropyl [ b ] b]Naphthalene-4-methylene) benzene) -glucose acetal 5.93g, 81% yield. LC-MS (M + H)+:431.
Example 2 beta-1 '-deoxy-1' - (4-chloro-3- (3,3a,4,9,9 a-hexahydronaphthalene [2, 3-c)]Furan-6-methylene) benzene) -glucose acetal (compound Preparation of object 2)
The compound beta-1 '-deoxy-1' - (4-chloro-3- (3,3a,4,9,9 a-hexahydronaphthalene [2, 3-c) was obtained in reference example 1]Furan-6-methylene) benzene) -glucose acetal. LC-MS (M + H)+:461.
Example 3 beta-1 '-deoxy-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ]]Cyclopentyl [ e ]][1，4]Dioxin) -6-methylene) Preparation of benzene) -glucose Acetal (Compound 3)
Step preparation of 14-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) -6-formyl) bromobenzene
A solution of aluminium trichloride (2.8g,21mmol) in dichloromethane (25mL) was cooled to 0 deg.C, the compound phenetole (3.77g,21.3mmol) was slowly added, stirring was maintained at 0 deg.C for 1h, then a solution of the compound 2-chloro-5-bromo-benzoyl chloride (6.9g,21.3mmol) in dichloromethane (15 mL) was slowly added dropwise, detection was made until the reaction was complete, the reaction mixture was poured into ice water (150 mL) and extracted with dichloromethane (3X 100mL), the organic phases were combined, washed with dilute hydrochloric acid (1N), water, NaOH (1N), saturated brine, anhydrous Na2SO4Drying, rotary evaporating organic phase, and performing column chromatography (n-hexane/ethyl acetate = 1/20) to obtain target compound 4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b)]Cyclopentyl [ E][1,4]Dioxin) -6-formyl) bromobenzene 7.03g, yield 80%.
Step 2 preparation of the Compound 4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) -6-methylene) bromobenzene
The compound 4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxin) -6-formyl) bromobenzene (16.5g,39.9mmol) was dissolved in trifluoroacetic acid (30 mL), then triethylsilane (7.86g,67.6mmol) was added, the reaction liquid was heated under reflux for 16H, a saturated aqueous solution of sodium carbonate was added to adjust pH =8, the organic phase was extracted with ethyl acetate, washed with saturated brine, and dried in vacuo to give the crude compound 4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxin) 6-methylene)) bromobenzene 10.6g, in 71% yield.
Step 3 preparation of 1 '- (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) 6-methylene) benzene) -glucose hemiacetal, compound 1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine)
The compound 4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxin) 6-methylene)) bromobenzene (20.7g,46mmol) was dissolved in anhydrous THF (150 mL), cooled to-78 deg.C under nitrogen protection and then n-BuLi (2.5M,18.4mL,46mmol) was slowly added dropwise, after stirring for 3H, a solution of the compound 2,3,4, 6-tetrakis (trimethylsilyl ether) -gluconolactone in n-hexane (300 mL) was slowly added dropwise at-78 deg.C, stirring was maintained for 0.5H, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution (100mL), the aqueous layer was extracted with ethyl acetate (3X 100mL), the combined organic phases were washed with water and saturated brine, rotary evaporation was carried out to give the compound 1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) 6-methylene) benzene) -glucose hemiacetal 18.2g, 82% yield.
Preparation of step 4 Compound 1 '-O-methyl-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) 6-methylene) benzene) -glucal
Mixing a compound 1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b)]Cyclopentyl [ e ]][1,4]Dioxin) 6-methylene) benzene) -glucose hemiacetal (4.82g,10.0mmol) was dissolved in absolute methanol (10 mL), cooled to 0 deg.C, and methanesulfonic acid (0.4 mL) in absolute methanol (1)0mL) solution, slowly warmed to room temperature and stirred for 16h, with saturated NaHCO3Adjusting pH =8 with aqueous solution, extracting with ethyl acetate, washing the combined organic phases with water, washing with saturated brine, drying, and rotary evaporating to obtain compound 1 '-O-methyl-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b)]Cyclopentyl [ e ]][1,4]Dioxin) 6-methylene)) -glucose acetal 4.93g, 100%.
Step 5 preparation of Compound 1 '-O-methyl-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal
The compound 1 '-O-methyl-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) 6-methylene) benzene) -glucose acetal (4.39g,9.1mmol), diisopropylethylamine (9.4g,72.8mmol) and DMAP (10mg) were dissolved in THF (100mL), cooled to zero, acetic anhydride (7.43g,72.8mmol) was slowly added, stirred for 0.5H, the reaction mixture was adjusted to pH =8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 × 60mL), the combined organic phases were washed with water (70mL) and saturated brine (70mL), dried, concentrated by rotary evaporation to give the compound 1 '-O-methyl-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal 3.96g, 66% yield.
Step 6 preparation of Compound beta-1 '-deoxy-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) -6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal
A solution of the compound 1 '-O-methyl-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furan [3,4-e ] [1,4] dioxine) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal (7.48g,16.0mmol) in acetonitrile (50mL) was cooled to 10 ℃, triethylsilicon (5.1g,32mmol) and boron trifluoride diethyl etherate (6.8g,48mmol) were added, detection was carried out until the reaction was complete, the reaction was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (3X 100mL), the combined organic phases were washed with water and saturated brine, dried, concentrated by rotary evaporation, and recrystallized (n-hexane/ethyl acetate =1/15, V/V) to give the compound β -1 '-deoxy-1' - (4-chloro- 3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxine) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal 7.48g, yield 74%.
Preparation of step 7 compound beta-1 '-deoxy-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] cyclopentyl [ e ] [1,4] dioxin) 6-methylene) benzene) -glucal
The compound beta-1 '-deoxy-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b)]Cyclopentyl [ e ]][1,4]Dioxin) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal (10g,15.7mmol) is dissolved in a mixed solution of tetrahydrofuran (100mL) and methanol (100mL), an aqueous solution (50mL) of lithium hydroxide monohydrate (4.4g,104mmol) is added at zero temperature, the reaction solution slowly rises to room temperature, stirring is carried out for 14H, detection is carried out for reaction completion, the reaction solution is concentrated, dichloromethane is added for extraction, the combined organic phase is washed with water and saturated common salt water, drying and concentration are carried out to obtain a compound beta-1 '-deoxy-1' - (4-chloro-3- ((2,3,3a,9 a-tetrahydro-1H-benzo [ b ] b]Cyclopentyl [ e ]][1,4]Dioxin) 6-methylene) benzene) -glucose acetal 5.91g, yield 80%.1H NMR(400MHz,MeOH-d4):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.
Example 4 beta-1 '-deoxy-1' - (4-chloro-3- (5a,6,7,8,8a, 9-hexahydrocyclopentane [ e ]]Pyridine [3,2-b ]][1,4]Oxazine-6-methylene) Preparation of benzene) -glucose Acetal (Compound 4)
Step 14 preparation of chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) -6-formyl) bromobenzene
A solution of aluminium trichloride (2.8g,21mmol) in dichloromethane (25mL) was cooled to 0 deg.C, the compound phenetole (3.77g,21.3mmol) was slowly added, stirring was maintained at 0 deg.C for 1h, then a solution of the compound 2-chloro-5-bromo-benzoyl chloride (6.9g,21.3mmol) in dichloromethane (15 mL) was slowly added dropwise, detection was made until the reaction was complete, the reaction mixture was poured into ice water (150 mL) and extracted with dichloromethane (3X 100mL), the organic phases were combined, washed with dilute hydrochloric acid (1N), water, NaOH (1N), saturated brine, anhydrous Na2SO4Drying, rotary evaporating organic phase, and performing column chromatography (n-hexane/ethyl acetate = 1/20) to obtain target compound 4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b)]Furyl [3,4-e ]][1,4]Dioxin) -6-formyl) bromobenzene 7.03g, yield 80%.
Step 2 preparation of 4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furyl [3,4-e ] [1,4] dioxin) -6-methylene) bromobenzene as compound
The compound 4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxin) -6-formyl) bromobenzene (16.5g,39.9mmol) was dissolved in trifluoroacetic acid (30 mL), triethylsilane (7.86g,67.6mmol) was then added, the reaction solution was heated under reflux for 16h, a saturated aqueous solution of sodium carbonate was added to adjust pH =8, the organic phase was extracted with ethyl acetate, washed with saturated brine, and dried in vacuo to give the crude compound 4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxin) 6-methylene)) bromobenzene 10.7g, in 71% yield.
Step 3 preparation of 1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) 6-methylene) benzene) -glucose hemiacetal, compound
The compound 4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) 6-methylene)) bromobenzene (20.7g,46mmol) was dissolved in anhydrous THF (150 mL), cooled to-78 ℃, then n-BuLi (2.5M,18.4mL,46mmol) was slowly added dropwise under nitrogen protection, after stirring for 3h, a solution of compound 2,3,4, 6-tetrakis (trimethylsilyl ether) -gluconolactone in n-hexane (300 mL) was slowly added dropwise at-78 ℃, stirring was maintained for 0.5h, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution (100mL), the aqueous layer was extracted with ethyl acetate (3 × 100mL), the combined organic phases were washed with water and saturated brine, rotary evaporation was carried out to give compound 1' - (4-chloro-3- ((1,3,3a,9 a-Tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) 6-methylene) benzene) -glucose hemiacetal 18.2g, 82% yield.
Preparation of step 4 Compound 1 '-O-methyl-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) 6-methylene) benzene) -glucal
The compound1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b)]Furyl [3,4-e ]][1,4]Dioxin) 6-methylene) benzene) -glucose hemiacetal (4.86g,10.0mmol) was dissolved in absolute methanol (10 mL), cooled to 0 deg.C, added methanesulfonic acid (0.4 mL) in absolute methanol (10 mL), slowly warmed to room temperature and stirred for 16h with saturated NaHCO3Adjusting pH =8 with water solution, extracting with ethyl acetate, washing the combined organic phases with water, washing with saturated brine, drying, and rotary evaporating to obtain compound 1 '-O-methyl-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b)]Furyl [3,4-e ]][1,4]Dioxin) 6-methylene)) -glucose acetal 4.95g, 100%.
Step 6 preparation of Compound 1 '-O-methyl-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal
The compound 1 '-O-methyl-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) 6-methylene) benzene) -glucose acetal (4.39g,9.1mmol), diisopropylethylamine (9.4g,72.8mmol) and DMAP (10mg) were dissolved in THF (100mL), cooled to zero, acetic anhydride (7.43g,72.8mmol) was slowly added, stirred for 0.5h, the reaction mixture was adjusted to pH =8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 × 60mL), the combined organic phases were washed with water (70mL) and saturated brine (70mL), dried, concentrated by rotary evaporation to give the compound 1 '-O-methyl-1' - (4-chloro-3- ((1,3,3a,9 a-Tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal 3.93g, yield 65%.
Preparation of step 7 Compound beta-1 '-deoxy-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) -6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal
A solution (50mL) of the compound 1 '-O-methyl-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal (7.48g,16.0mmol) in acetonitrile was cooled to 10 ℃, triethylsilicon (5.1g,32mmol) and boron trifluoride diethyl etherate (6.8g,48mmol) were added, and upon completion of the reaction, the reaction was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (3X 100mL), the combined organic phases were washed with water and saturated brine, dried, concentrated by rotary evaporation, and recrystallized (n-hexane/ethyl acetate =1/15, V/V) to give the compound β -1 '-deoxy-1' - (4-chloro- 3- ((1,3,3a,9 a-Tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal 7.50g, yield 74%.
Step 8 preparation of beta-1 '-deoxy-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] furanyl [3,4-e ] [1,4] dioxine) -6-methylene) benzene) -glucal, a compound of step 8
The compound beta-1 '-deoxy-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b)]Furyl [3,4-e ]][1,4]Dioxin) 6-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal (10g,15.7mmol) is dissolved in a mixed solution of tetrahydrofuranyl (100mL) and methanol (100mL), an aqueous solution (50mL) of lithium hydroxide monohydrate (4.4g,104mmol) is added at zero temperature, the reaction solution is slowly warmed to room temperature and stirred for 14h, detection of reaction completion is carried out, the reaction solution is concentrated, dichloromethane is added for extraction, the combined organic phase is washed with water and saturated common salt water, drying and concentration are carried out to obtain the compound beta-1 '-deoxy-1' - (4-chloro-3- ((1,3,3a,9 a-tetrahydrobenzo [ b ] b]Furyl [3,4-e ]][1,4]Dioxin) -6-methylene) benzene) -glucose acetal 5.93g, 81% yield.1H NMR(400MHz,CDCl3):7.33(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.
Example 5 beta-1 ' -deoxy-1 ' - (4-chloro-3- (1 ', 3 ' -dihydrospiro [ cyclopentyl-1, 2 ' -indene)]-5-methylene) benzene) -glucose acetalization Preparation of Compound 5)
Reference example 3 gave the compound β -1 ' -deoxy-1 ' - (4-chloro-3- (1 ', 3 ' -dihydrospiro [ cyclopentyl-1, 2 ' -indene)]-5-methylene) benzene) -glucose acetal. LC-MS (M + H)+:459.
Example 6 beta-1 '-deoxy-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclobutylspiro [ b ]]Naphthalene-4-methylene) benzene) -glucose acetal Preparation of (Compound 6)
Reference example 3 gave the compound β -1 '-deoxy-1' - (4-chloro-3- (1a,2,7,7 a-tetrahydro-1H-cyclobutylspiro [ b ]]Naphthalene-4-methylene) benzene) -glucose acetal. LC-MS (M + H)+:459.
Example 7 beta-1 ' -deoxy-1 ' - (4-chloro-3- (1, 3-dihydrospiro (indene-2, 3 ' -oxetanyl-5-methylidene) benzene) -glucose acetal Preparation of (Compound 7)
Reference example 3 gave the compound β -1 ' -deoxy-1 ' - (4-chloro-3- (1, 3-dihydrospiro (indene-2, 3 ' -oxetanyl) -5-methylene) benzene) -glucose acetal. LC-MS (M + H)+:447.
Example 8 beta-1 ' -deoxy-1 ' - (4-chloro-3- (1 ', 3 ', 4, 5-tetrahydro-2H-spiro (furan-3, 2 ' -indene) -5-methylene) benzene) -glucose acetal Preparation of (Compound 8)
Reference example 3 gave the compound β -1 ' -deoxy-1 ' - (4-chloro-3- (1 ', 3 ', 4, 5-tetrahydro-2H-spiro (furan-3, 2 ' -indene) -5-methylene) benzene) -glucose acetal. LC-MS (M + H)+:461.
Example 9 beta-1 '-deoxy-1' - (4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) benzene) -dextran Preparation of glucoacetal (Compound 9)
Step preparation of 14-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-formyl) bromobenzene
A solution of aluminum trichloride (2.8g,21mmol) in dichloromethane (25mL) was cooled to 0 deg.C, the compound phenetole (3.77g,21.3mmol) was added slowly, the mixture was stirred at 0 deg.C for 1h, and then the compound 2-chloro-5-bromo-was added slowly dropwise-benzoyl chloride (6.9g,21.3mmol) in dichloromethane (15 mL), detection until the reaction is complete, pouring the reaction mixture into ice water (150 mL) and extraction with dichloromethane (3 × 100mL), combining the organic phases, washing with dilute hydrochloric acid (1N), water, NaOH (1N), saturated brine, anhydrous Na, respectively2SO4Drying and rotary evaporation of the organic phase followed by column chromatography (n-hexane/ethyl acetate = 1/20) gave 7.03g of the title compound, 4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-formyl) bromobenzene in 80% yield.
Step 2 preparation of the Compound 4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) bromobenzene
The compound 4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-formyl) bromobenzene (16.5g,39.9mmol) was dissolved in trifluoroacetic acid (30 mL), then triethylsilane (7.86g,67.6mmol) was added, the reaction was heated under reflux for 16H, saturated aqueous sodium carbonate was added to adjust pH =8, ethyl acetate was extracted to obtain an organic phase, and the organic phase was washed with saturated brine and dried under vacuum to obtain crude compound 4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) bromobenzene 10.6g with 71% yield.
Step 3 preparation of the Compound 1 ' - (4-chloro-3- (4 ', 5 ' -dihydro-2 ' H, 3H-spiro (benzofuran-2, 3 ' -furan) -5-methylene) benzene) -glucose hemiacetal
The compound 4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) benzene) bromobenzene (20.7g,46mmol) was dissolved in anhydrous THF (150 mL), cooled to-78 deg.C under nitrogen protection and then n-BuLi (2.5M,18.4mL,46mmol) was slowly added dropwise, after stirring for 3H, a solution of the compound 2,3,4, 6-tetrakis (trimethylsilyl ether) -gluconolactone in n-hexane (300 mL) was slowly added dropwise at-78 deg.C, stirring was maintained for 0.5H, the reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (100mL), the aqueous layer was extracted with ethyl acetate (3X 100mL), the combined organic phases were washed with water and saturated brine, and rotary evaporated to give the compound 1 '- (4-chloro-3- (4', 18.2g of 5 ' -dihydro-2 ' H, 3H-spiro (benzofuran-2, 3 ' -furan) -5-methylene) benzene) -glucose hemiacetal in 82% yield.
Step 4 preparation of the Compound 1 '-O-methyl-1' - (4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) benzene) -glucal acetal
The compound 1 ' - (4-chloro-3- (4 ', 5 ' -dihydro-2 ' H, 3H-spiro (benzofuran-2, 3 ' -furan) -5-methylene) benzene) -glucose hemiacetal (4.82g,10.0mmol) was dissolved in absolute anhydrous methanol (10 mL), cooled to 0 deg.C, added a solution of methanesulfonic acid (0.4 mL) in anhydrous methanol (10 mL), slowly warmed to room temperature and stirred for 16H, with saturated NaHCO3The aqueous solution was adjusted to pH =8 and extracted with ethyl acetate, the combined organic phases were washed with water, brine, dried and rotary evaporated to give the compound 1 '-O-methyl-1' - (4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran, 2, 3' -furan) -5-methylene) benzene) -glucose acetal 4.93g, 100%.
Step 5 preparation of the compound 1 '-O-methyl-1' - (4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal
The compound 1 ' -O-methyl-1 ' - (4-chloro-3- (4 ', 5 ' -dihydro-2 ' H, 3H-spiro (benzofuran-2, 3 ' -furan) -5-methylene) benzene) -glucose acetal (4.39g,9.1mmol), diisopropylethylamine (9.4g,72.8mmol) and DMAP (10mg) were dissolved in THF (100mL), cooled to zero, acetic anhydride (7.43g,72.8mmol) was slowly added, stirred for 0.5H, the reaction mixture was adjusted to pH =8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 × 60mL), the combined organic phases were washed with water (70mL) and saturated brine (70mL), dried, concentrated by rotary evaporation, and column chromatographed to give the compound 1 ' -O-methyl-1 ' - (4-chloro-3- (4 ', 3.96g of 5 ' -dihydro-2 ' H, 3H-spiro (benzofuran-2, 3 ' -furan) -5-methylene) benzene) -2 ', 3 ', 4 ', 6 ' -tetraacetyl-glucal, yield 66%.
Step 6 preparation of the compound β -1 '-deoxy-1' - (4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucal
A solution of the compound 1 '-O-methyl-1' - (4-chloro- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal (7.48g,16.0mmol) in acetonitrile (50mL) was cooled to 10 deg.C, triethylsilane (5.1g,32mmol) and boron trifluoride diethyl ether (6.8g,48mmol) were added, detection was complete, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3X 100mL), the combined organic phases were washed with water and saturated brine, dried, concentrated by rotary evaporation, and recrystallized (n-hexane/ethyl acetate =1/15, V/V) to give the compound β -1 '-deoxy-1' - (4-chloro- 3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) benzene) -2 ', 3', 4 ', 6' -tetraacetyl-glucose acetal 7.48g, 74% yield.
Preparation of step 7 Compound beta-1 '-deoxy-1' - (4-chloro-3- (4 ', 5' -dihydro-2 'H, 3H-spiro (benzofuran-2, 3' -furan) -5-methylene) benzene) -glucal acetal
Dissolving the compound beta-1 ' -deoxy-1 ' - (4-chloro-3- (4 ', 5 ' -dihydro-2 ' H, 3H-spiro (benzofuran-2, 3 ' -furan) -5-methylene) benzene) -2 ', 3 ', 4 ', 6 ' -tetraacetyl-glucose acetal (10g,15.7mmol) in a mixed solution of tetrahydrofuran (100mL) and methanol (100mL), adding an aqueous solution (50mL) of lithium hydroxide monohydrate (4.4g,104mmol) at zero temperature, slowly raising the temperature of the reaction solution to room temperature, stirring for 14H, detecting the end of the reaction, concentrating the reaction solution, adding dichloromethane for extraction, washing the combined organic phases with water and saturated common salt solution, drying, and concentrating to obtain the compound beta-1 ' -deoxy-1 ' - (4-chloro-3- (4 ', 5 ' -dihydro-2 ' H, 3H-spiro (benzofuran-2, 3 ' -furan) -5-methylene) benzene) -glucose acetal 5.91g, yield 80%.
1H NMR(400MHz,MeOH-d4):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.
Example 10 beta-1 ' -deoxy-1 ' - (4-chloro-3- (4 ', 5 ' -dihydro-2 ' H-spiro (benzo [ d ])][1,3]Dioxole-2, 3' -furan) -5- Preparation of methylene) benzene) -glucose Acetal (Compound 10)
Reference example 3 gave the compound β -1 ' -deoxy-1 ' - (4-chloro-3- (4 ', 5 ' -dihydro-2 ' H-spiro (benzo [ d ]][1,3]Dioxol-2, 3' -furan) -5-methylene) benzene) -glucose acetal. LC-MS (M + H)+:465.
In addition, resolution of the racemic compounds 1-10 synthesized above using preparative HPLC gradient elution (C-18 column, eluent 5% -95% methanol/water) gave the following compounds:

Claims (5)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
the A ring is cyclopentyl or tetrahydrofuryl;
x, Y represent O atoms;
R1represents halogen;
R2，R3，R4each represents a hydrogen atom;
R5，R6a，R6b，R6ceach represents a hydrogen atom;
m is 0 or 1;
n is 0;
w is methylene.
2. A compound, or a pharmaceutically acceptable salt thereof, as described below:
3. a compound, or a pharmaceutically acceptable salt thereof, as described below:
4. a pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers and/or diluents, in any pharmaceutically acceptable dosage form.
5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prophylaxis of diabetes.
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CN1950389A (en) * 2004-03-04 2007-04-18 橘生药品工业株式会社 Nitrogenous fused-ring derivatives, medicinal compositions containing the derivatives, and use thereof as drugs
CN101534815A (en) * 2006-11-09 2009-09-16 贝林格尔.英格海姆国际有限公司 Combination therapy with SGLT-2 inhibitors and their pharmaceutical compositions
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