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CN111057059A - Benzodithiepyrrole compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents

Benzodithiepyrrole compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDF

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CN111057059A
CN111057059A CN201911166962.3A CN201911166962A CN111057059A CN 111057059 A CN111057059 A CN 111057059A CN 201911166962 A CN201911166962 A CN 201911166962A CN 111057059 A CN111057059 A CN 111057059A
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benzoditetrahydropyrrole
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acyl
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CN111057059B (en
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马艳芳
曾少高
巫培山
石燕丽
宋浩军
曹宏宝
伍俊林
刘琳
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Institute Of Testing And Analysis Guangdong Academy Of Sciences Guangzhou Analysis And Testing Center China
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Abstract

The invention discloses a benzoditetrahydropyrrole compound or a pharmaceutically acceptable compound thereofSalt, and a preparation method and application thereof. The benzoditetrahydropyrrole compound has a structure shown in a formula I, has a very good selective inhibition effect on DPP-IV through in vitro and in vivo experiments, hardly influences the activity of DPP-VIII and DPP-IX while effectively inhibiting the activity of DPP-IV, has a low potassium ion channel inhibition rate, and is expected to have low toxicity after being developed into a medicament. Compared with the marketed once-a-week oral drug of augustine, the benzoditetrahydropyrrole compound has equivalent or higher bioavailability, and is expected to achieve the treatment effect of being orally taken for a long time after being developed, so that the convenience and compliance of patients are greatly improved. And the preparation method is simple, the raw materials are easy to obtain, and the method is suitable for industrial large-scale production.

Description

Benzodithiepyrrole compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a benzoditetrahydropyrrole compound or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
Diabetes mellitus is caused by blood sugar rise due to absolute or relative insufficiency of insulin, so that serious complications are caused, and finally patients are disabled or killed, diabetes mellitus is clinically classified into type I and type II, type I diabetes mellitus is caused by blood sugar rise due to damage of islet β -cells and lack of insulin secretion, and the patients only depend on exogenous insulin, type II diabetes mellitus is caused by hyperglycemia due to relative insufficiency of insulin secretion or incomplete insulin action, and the incidence rate of the hyperglycemia accounts for more than 90% of all diabetes mellitus patients, and current pharmaceutical research is mainly directed to type 2 diabetes mellitus (T2 DM).
The insulin secretion of pancreatic islets β -cells is the main means for treating T2DM, but the conventional hypoglycemic drugs, such as insulin sensitizer (such as biguanides, thiazolidinediones and the like) and insulin secretagogue (such as sulfonylurea and non-sulfonylurea drugs) and the like, often cause hypoglycemia, weight gain, cardiovascular pathological reaction and β -cell death and other side effects during treatment, so how to reduce complications and adverse side effects is the main direction for treating T2 DM.
Glucagon-like peptidase-1 (GLP-1) is an endogenous hormone that is secreted by L cells in the small intestine to stimulate insulin secretion in response to postprandial elevation in blood glucose. Thus, GLP-1 secretion is closely related to the amount of blood glucose ingested. The GLP-1-based treatment scheme can effectively control blood sugar without increasing weight, and adverse reactions such as hypoglycemia and the like are avoided. GLP-1 is used as a substrate of dipeptidyl peptidase-IV (DPP-IV), has short half-life and is rapidly cut and inactivated by DPP-IV within 1-2 minutes after secretion. The research shows that DPP-IV has constant cleavage sites to the substrate, and is proline or alanine at the penultimate N-terminal position. If the activity of DPP-IV is inhibited, the content of GLP-1 in vivo can be indirectly increased, thereby causing a series of physiology in vivo, stimulating the secretion of insulin and achieving the aim of treating T2 DM.
The DPP-IV inhibitor is a new oral antidiabetic drug, can prevent the rapid degradation of incretin hormone, improves the GLP-1 level after meals, has small toxic and side effects and obvious drug effect, has small risk of hypoglycemia no matter single administration or combined administration, is a safe and effective drug so far, and has become a new choice for treating T2 DM.
At present, the research of DPP-IV inhibitor has made a major breakthrough, and the marketed drugs include Sitagliptin from Merck, Vildagliptin from Nowa, Saxagliptin from BaishiGuibao, Alogliptin from Wutian, and Linagliptin from Boerger Invitrogen, and meanwhile, dozens of varieties are in clinical research stage. Trelagliptin from Wutian, marketed in Japan at 3.2015, is a long-acting DPP-IV inhibitor administered orally once a week, whereas the market for the same DPP-4 inhibitor requires once daily administration. Meanwhile, merck corporation is also developing a long-acting DPP-4 inhibitor Omarigliptin, which is shown to be orally administered once a week, and which is now successful in clinical trials and approved for marketing in japanese applications. The medication advantages of the long-acting DPP-IV inhibitor undoubtedly provide more convenient treatment options for diabetic patients, and the long-acting DPP-IV inhibitor is expected to greatly improve the convenience and compliance of the patients and becomes a new direction for researching the DPP-IV inhibitor.
However, both of these drugs may not be marketed to the FDA and in european applications for safety reasons. Therefore, in the art, it is desired to develop more drugs capable of effectively and safely controlling blood glucose for a long period of time, and based on this, the present invention has been completed.
Disclosure of Invention
The invention aims to provide a benzoditetrahydropyrrole compound or pharmaceutically acceptable salt and application thereof. The compound is an effective DPP-IV inhibitor, can effectively reduce blood sugar, does not cause risks such as weight gain and hypoglycemia, and can achieve the treatment effect of controlling blood sugar for a long time.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the invention provides a benzoditetrahydropyrrole compound or a pharmaceutically acceptable salt thereof, wherein the benzoditetrahydropyrrole compound has a structure shown in formula I:
Figure BDA0002287714080000031
wherein R is1Selected from hydrogen, hydroxyl, C1-C6 straight chain or branched chain saturated or unsaturated alkyl, C3-C7 cyclic alkyl, 4-7 membered heterocyclic group, C1-C6 alkyl acyl, C1-C6 alkyl sulfonyl, C1-C6 alkyl sulfinyl, C3-C7 cyclic amino acyl, 5-7 membered heterocyclic amino acyl, aryl, benzyl, aryl acyl methylene, 5-7 membered heteroaromaticA group, a 5-to 7-membered heteroarylmethylene group, a 5-to 7-membered heteroarylacyl group or a 5-to 7-membered heteroarylacylmethylene group;
R2and R3Independently selected from hydrogen, halogen, amino, cyano, nitro, C1-C6 straight chain or branched chain saturated or unsaturated alkyl, C3-C7 cyclic alkyl, 4-7 membered heterocyclic group, C1-C4 alkyl acyl, C3-C7 cyclic amino acyl, 5-7 membered heterocyclic amino acyl, aryl, benzyl, aryl acyl methylene, 5-7 membered heteroaryl methylene, 5-7 membered heteroaryl acyl or 5-7 membered heteroaryl acyl methylene.
Preferably, the benzoditetrahydropyrrole compound has a structure shown in a formula II:
Figure BDA0002287714080000032
wherein R is1Having the ranges indicated above;
in the present invention, R1～R3Wherein the C1-C6 linear or branched chain saturated or unsaturated alkyl, C1-C4 alkylacyl, C3-C7 cycloalkyl, C1-C6 alkylacyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, aryl, benzyl, arylacyl, arylacylmethylene, 5-7 membered heteroaryl, 5-7 membered heteroarylmethylene, 5-7 membered heteroarylacyl or 5-7 membered heteroarylacylmethylene has hydrogen on carbon thereof substituted by one or more R11Substituted; the R is11Selected from halogen, carbonyl, hydroxyl, amino, nitro, sulfhydryl, cyano, C1-C3 alkylsulfo or C1-C3 alkoxy; r1～R3Wherein hydrogen on nitrogen of the 4-to 7-membered heterocyclic group or hydrogen on nitrogen of the 5-to 7-membered heterocyclic aminoacyl group is substituted with one or more R12Substituted; the R is12Selected from C1-C6 alkyl, C1-C6 alkanoyl or C1-C3 alkylsulfo.
When R is2And R3Selected from hydrogen, halogen, amino, cyano, nitro, C1-C6 straight chain or branched chain saturated or unsaturated alkyl, C3-C7 cyclic alkyl, 4-7 membered heterocyclic group, C1-C4 alkyl acyl, C3-C7 cyclic amino acyl, 5-7 membered heterocyclic amineAcyl, aryl, benzyl, arylacyl, arylacylmethylene, 5-to 7-membered heteroaryl, 5-to 7-membered heteroarylmethylene, 5-to 7-membered heteroarylacyl, or 5-to 7-membered heteroarylacylmethylene; preferably, R1Selected from hydrogen, C1-C6 straight chain or branched chain saturated or unsaturated alkyl, C3-C7 cyclic alkyl, C1-C6 alkyl acyl, C1-C6 alkyl sulfonyl, benzyl, aryl acyl methylene, 5-7 membered heteroaryl methylene or 5-7 membered heteroaryl acyl.
Preferably, the benzoditetrahydropyrrole compound is selected from any one of the following compounds:
Figure BDA0002287714080000041
the invention includes the compounds of formula I-II in free form, as well as in the form of pharmaceutically acceptable salts thereof.
Preferably, the pharmaceutically acceptable salt of the benzoditetrahydropyrrole compound is an acid addition salt or a base addition salt of the benzoditetrahydropyrrole compound.
When the compounds of the present invention are in the form of a free base, acid addition salts of the compounds of the present invention can be prepared by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
Preferably, the acid addition salts of benzoditetrahydropyrrole compounds include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, phosphate, sulphate, nitrate, ethanesulphonate, toluenesulphonate, benzenesulphonate, acetate, maleate, tartrate, succinate, citrate, benzoate, ascorbate, salicylate, malonate, adipate, hexanoate, arginate, fumarate, nicotinate, phthalate and oxalate.
When the benzoditetrahydropyrrole compounds of the present invention have a free acid form, base addition salts of the compounds of the present invention may be prepared by reacting the free acid form with a pharmaceutically acceptable inorganic or organic base.
Preferably, the base addition salt of the benzoditetrahydropyrrole compound includes, but is not limited to, lithium salt, sodium salt, potassium salt, barium salt, calcium salt, magnesium salt, aluminum salt, ferric salt, ferrous salt, copper salt, zinc salt of the thienopyrimidone compound, and salt of the thienopyrimidone compound with morpholine, diethylamine, triethylamine, isopropylamine, trimethylamine, lysine or histidine.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The term "alkanoyl" refers to a substituent of the RCO class, wherein R represents alkyl.
The term "arylacyl" refers to an ArCO-like substituent, wherein Ar represents an aryl group.
The term "alkylsulfonyl" refers to RSO2The substituent is shown in the specification, wherein R represents alkyl.
The term "arylsulfonyl" refers to ArSO2A substituent group, wherein Ar represents an aryl group.
The term "arylacylmethylene" refers to ArCOCH2A substituent group, wherein Ar represents an aryl group.
The term "heteroarylacylmethylene" refers to ArCOCH2A substituent group of the formula (I), wherein Ar represents heteroaryl.
The term "heteroarylmethylene" refers to ArCH2A substituent group of the formula (I), wherein Ar represents heteroaryl.
The term "cyclic aminoacyl" refers to
Figure BDA0002287714080000061
The term "heterocyclic aminoacyl" refers to
Figure BDA0002287714080000062
X represents a heteroatom N, O, S.
In the present invention, the C1-C6 linear or branched saturated or unsaturated hydrocarbon group means a linear or branched saturated or unsaturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms; the C3-C7 cyclic hydrocarbon group refers to a cyclic hydrocarbon group containing 3, 4, 5, 6 or 7 carbon atoms, and the 4-7-membered heterocyclic group refers to a 4-membered, 5-membered, 6-membered or 7-membered heterocyclic group; the C1-C4 alkylacyl refers to an alkylacyl group having 1, 2, 3 or 4 carbon atoms, the C3-C7 cycloalkylacylamino refers to a cycloalkylacylamino group having 3, 4, 5, 6 or 7 carbon atoms, the 5-to 7-membered heterocycloaminoacyl refers to a 5-, 6-or 7-membered heterocycloaminoacyl, and similarly, the 5-to 7-membered heteroaryl, 5-to 7-membered heteroarylmethylene, 5-to 7-membered heteroarylacyl and 5-to 7-membered heteroarylacylmethylene refer to the same 5-to 7-membered, 6-or 7-membered group.
In another aspect, the present invention provides a method for preparing the benzoditetrahydropyrrole compound or the pharmaceutically acceptable salt thereof as described above, wherein the synthetic route of the preparation method is as follows (mainly comprising the steps (1) to (5)):
Figure BDA0002287714080000071
wherein: r1、R2、R3As defined above for the compounds of formula I.
In the step (1), R is2、R3Reacting the substituted tetrabromomethylbenzene with trifluoroacetamide to obtain a compound A;
in the step (2), hydrolyzing the compound A in strong alkali to obtain a compound B;
in the step (3), the compound B and 2- (2 ', 5' -difluorophenyl) -3-amino-5-hydropyrone (intermediate C) are hydrolyzed under alkaline condition (base) to obtain a compound D;
in the step (4), the compound D and X-R are reacted1(X ═ I, Br, Cl, OTs, OMs, OTf) to give compound E;
in the step (5), removing the Boc protecting group from the compound E to obtain a compound I with a general formula;
the specific synthesis steps are as follows:
in the step (1), R is2、R3Substituted tetrabromomethylbenzene in tetrahydrofuranAdding 4 equivalents of trifluoroacetamide into organic solvents such as pyran, slowly adding 6 equivalents of sodium hydrogen (60 wt% in oil) at-5 ℃, stirring for more than 30 minutes at 0-room temperature, then heating to reflux and stirring for more than 3 hours, extracting after TLC detection of no raw material, washing with water, drying, evaporating the solvent under reduced pressure, and purifying the concentrate by column chromatography to obtain a compound A;
in the step (2), the compound A is suspended and dissolved in water/methanol, 10 equivalents of sodium hydroxide is slowly added at room temperature, the mixture is heated to reflux and stirred for about two hours, TLC detects that no raw material exists, the mixture is cooled and decompressed to remove the methanol, solid is separated out, filtered, filter cake is washed by water, and the mixture is dried by pumping to obtain a compound B;
in the step (3), dissolving the compound B in N, N-dimethylacetamide, adding equivalent benzenesulfonic acid, adding equivalent 2- (2 ', 5' -difluorophenyl) -3-amino-5-hydropyranone (intermediate C), slowly adding 1.1 equivalent sodium triacetoxyborohydride at 10 ℃, keeping the temperature and stirring for 10 to 20 hours, after TLC detection reaction is finished, adding water, extracting with ethyl acetate for three times, combining organic phases, washing the organic phase with water and saturated salt water successively, drying, concentrating, and purifying the obtained concentrate by column chromatography to obtain a compound D;
dissolving the compound D in DMF, adding 1.1 equivalent of alkali, dropwise adding halogenated hydrocarbon or alkyl (aryl) acyl halide or alkyl (aryl) sulfonyl halide at the temperature of between 10 ℃ below zero and room temperature, stirring for 2 to 6 hours at the temperature of between room temperature and 100 ℃, cooling to room temperature after the reaction is finished, adding water, extracting for three times by using ethyl acetate, combining organic phases, washing the organic phases by using water and saturated salt water in turn, drying, concentrating, and purifying the obtained concentrate by using column chromatography to obtain a compound E;
and (5) dissolving the compound E in methanol, dropwise adding a saturated hydrogen chloride methanol solution at room temperature, stirring at room temperature overnight, after TLC detection reaction is finished, evaporating under reduced pressure to remove excessive methanol and hydrogen chloride, dissolving the solid in methanol, adding excessive sodium bicarbonate, stirring for more than 2 hours, filtering to remove the solid, evaporating under reduced pressure to remove the solvent from the filtrate, and purifying the obtained concentrate by column chromatography to obtain the benzoditetrahydropyrrole compound shown as the general formula I.
In the preparation method, the drying in each step is performed for about 30 minutes by using anhydrous magnesium sulfate or anhydrous sodium sulfate as a drying agent. The concentration is carried out by evaporating the solvent to dryness by atmospheric distillation, reduced pressure distillation or rotary evaporation method.
In the above preparation method, the base in step (4) may be an inorganic base selected from at least one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, sodium hydroxide, lithium hydroxide and potassium hydroxide, or an organic base selected from at least one of triethylamine, pyridine, Diazabicyclo (DBU) and N, N-Diisopropylethylamine (DIPEA); the organic solvent in the step (1) is selected from at least one of Tetrahydrofuran (THF), Dichloromethane (DCM), Ethyl Acetate (EA), acetonitrile, acetone, 1, 4-dioxane, alcohols, diethyl ether, toluene, N-Dimethylformamide (DMF), N-Dimethylformamide (DMA), ethylene glycol dimethyl ether and dimethyl sulfoxide (DMSO); the halogenating agent in step (4) may be halogen or N-halogenated succinimide (NXS, X ═ I, Br, Cl).
In another aspect, the present invention provides a pharmaceutical composition comprising the benzoditetrahydropyrrole compound or the pharmaceutically acceptable salt thereof as described above as an active ingredient, and a pharmaceutically acceptable carrier.
In the present invention, the pharmaceutically acceptable carrier, which may be in liquid, semi-liquid or solid form, is formulated in a manner suitable for the route of administration used, can be used for in vivo therapy and is biocompatible. The pharmaceutical composition may be administered in the following manner: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, etc. forms.
Oral compositions may be solid, gel or liquid. Examples of solid formulations include, but are not limited to, tablets, capsules, granules, and bulk powders. These formulations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents and the like. Examples of binders include, but are not limited to, microcrystalline cellulose, glucose solutions, acacia mucilage, gelatin solutions, sucrose and starch pastes; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silicon dioxide; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, and carboxymethylcellulose.
The compositions of the present invention are administered parenterally, typically by injection, including subcutaneous, intramuscular, or intravenous injection. Injectables can be prepared in any conventional form, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or emulsions. Examples of pharmaceutically acceptable carriers that may be used in the injections of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents, and other pharmaceutically acceptable materials. Examples of aqueous carriers include sodium chloride injection, ringer's injection, isotonic glucose injection, sterile water injection, dextrose and lactated ringer's injection; examples of non-aqueous carriers include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, and the like; examples of isotonic agents include sodium chloride and glucose; buffers include phosphates and citrates.
The compositions of the present invention may also be prepared as sterile lyophilized powders for injection, by dissolving the compound in a buffered solution of sodium phosphate containing dextrose or other suitable excipient, followed by sterile filtration of the solution under standard conditions known to those skilled in the art, followed by lyophilization to provide the desired formulation.
In another aspect, the invention provides the use of the benzoditetrahydropyrrole compound or the pharmaceutically acceptable salt thereof as described above in the preparation of a DPP-IV inhibitor.
In another aspect, the present invention provides the use of a benzoditetrahydropyrrole compound as described above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and prevention of diseases benefiting from DPP-IV inhibition.
Preferably, the disease benefiting from DPP-IV inhibition is selected from type ii diabetes, diabetic dyslipidemia, Impaired Glucose Tolerance (IGT) disorders, impaired fasting plasma glucose (IFG) disorders, metabolic acidosis, ketosis, appetite regulation, obesity, various cancers, neurological disorders or immune system disorders, preferably type ii diabetes or obesity.
Compared with the prior art, the invention has the following beneficial effects:
(1) the benzoditetrahydropyrrole compound or the pharmaceutically acceptable salt thereof has a novel chemical structure, has a very good selective inhibition effect on DPP-IV through in vitro and in vivo experiments, hardly influences the activity of DPP-VIII and DPP-IX while effectively inhibiting the activity of DPP-IV, has a low potassium ion channel inhibition rate, and can be expected to have low toxicity after the compound is developed into a medicament.
(2) Preliminary pharmacodynamic studies show that the benzoditetrahydropyrrole compound has higher in vitro activity and equivalent or higher bioavailability compared with the marketed once-a-week oral drug of augustine (MK-3102), and the compound is expected to achieve the treatment effect of being orally taken for a long time after being developed, so that the convenience and compliance of patients are greatly improved. Preliminary drug effect and drug metabolism researches show that the DPP-IV inhibitor has the efficacy of inhibiting DPP-IV for a longer time in vivo, and is expected to be developed into a DPP-IV inhibitor with longer time.
(3) The preparation method of the benzoditetrahydropyrrole compound has the characteristics of simple process, easily obtained raw materials and suitability for industrial large-scale production.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
In the examples below, the analytical data of the samples were determined by the following instruments: the nuclear magnetic resonance is measured by a Bruker AMX-400 nuclear magnetic resonance instrument, TMS (tetramethylsilane) is taken as an internal standard, the unit of chemical shift is ppm, and the unit of coupling constant is Hz; mass spectra were determined by an Agilent1200/MSD mass spectrometer.
Silica gel 200-300 mesh for column chromatography (produced by Qingdao ocean factory); the TLC silica gel plate is an HSGF-254 thin-layer chromatography prefabricated plate produced by a cigarette bench chemical plant; the boiling range of petroleum ether is 60-90 ℃; an ultraviolet lamp and an iodine cylinder are adopted for color development.
The starting materials, reaction reagents and the like used in the following examples are commercially available products unless otherwise specified. Reagents and solvents used in the experiment are all processed according to the specific conditions of the reaction.
The abbreviations used in the present invention are the same as those commonly used in the art and have the following meanings:
DCM: dichloromethane, DIEA: n, N-diisopropylethylamine, DMA: n, N-dimethylacetamide, DME: ethylene glycol dimethyl ether, DMF: n, N-dimethylformamide, EA: ethyl acetate, NBS: n-bromosuccinimide, PE: petroleum ether, TEA: triethylamine, THF: tetrahydrofuran, GP-AMC: glycine-proline-7-amino-4-trifluoromethylcoumarin.
Example 1Synthesis of Compound 1
Figure BDA0002287714080000121
The synthetic route is as follows:
Figure BDA0002287714080000122
synthesis of Compounds 1-1:
tetrabromomethylbenzene (9.0g,20mmol) is dissolved in 200mL tetrahydrofuran, trifluoroacetamide (9.0g,80mmol) is added, sodium hydrogen (4.8g,120mmol,60 wt% in oil) is slowly added at 0 ℃, the temperature is gradually increased to room temperature and stirred for 30 minutes, then the temperature is increased to reflux and stirred for 3 hours, after TLC detection of no raw material, 300mL ethyl acetate is added into reaction liquid for dilution, an organic phase is washed once by 200mL water and saturated saline solution in sequence, then dried by anhydrous magnesium sulfate, filtered, and subjected to reduced pressure evaporation to remove a solvent from a filtrate, and an obtained concentrate is purified by column chromatography (200-300-mesh silica gel, the eluent is petroleum ether/ethyl acetate, the volume ratio is 4:1) to obtain 6.0g of a white solid (compound 1-1), and the yield is 85%;
MS:353.1[M+H+]。
synthesis of Compounds 1-2:
suspending and dissolving the compound 1-1(5.3g,15mmol) in 100mL of water/methanol mixed solvent with the volume ratio of 1:1, slowly adding sodium hydroxide (6.0g,150mmol) at room temperature, heating to reflux, stirring for about 2 hours, performing TLC detection on the mixture without raw materials, cooling, performing reduced pressure evaporation to remove methanol, separating out a solid, filtering, washing a filter cake with water, and performing suction drying to obtain 2.0g of a mud yellow solid (the compound 1-2), wherein the yield is 82%;
1H-NMR(400MHz，DMSO-d6):δ7.08(2H,s),4.00(8H,s)；MS:161.2[M+H+]。
synthesis of Compounds 1-3:
dissolving the compound 1-2(1.9g,12mmol) in 10mL of N, N-dimethylacetamide, sequentially adding phenylmethanesulfonic acid (1.9g,12mmol) and 2- (2 ', 5' -difluorophenyl) -3-amino-5-hydropyranone (3.9g,12mmol) at room temperature, slowly adding sodium triacetoxyborohydride (2.8g,13mmol) at 10 ℃, keeping the temperature and stirring for 20 hours, after TLC detection reaction is finished, adding 30mL of water, extracting with ethyl acetate for three times (50 mL. times.3), combining organic phases, washing the organic phases with equal volume of water for three times, washing with saturated saline water once, drying with anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained concentrate with 200-mesh 300-mesh silica gel, dichloromethane/methanol as eluent and volume ratio of 15:1), 3.0g of a yellow solid (Compound 1-3) was obtained in 53% yield;
MS:472.2[M+H+]。
synthesis of Compounds 1-4:
dissolving the compound 1-3(2.36g,5.0mmol) in 10mL DMF, adding triethylamine (0.55g,5.5mmol), dropwise adding methanesulfonyl chloride (0.63g,5.5mmol) at 0 ℃, gradually heating to room temperature and stirring for 2 hours, after TLC detection reaction is finished, adding 30mL of water, extracting with ethyl acetate three times (50mL multiplied by 3), washing the organic phase with water of the same volume three times in sequence, washing with saturated saline solution once, drying with anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained concentrate with column chromatography (200-mesh silica gel with 300 meshes, the eluent is dichloromethane/methanol, the volume ratio is 20:1) to obtain 2.2g of white solid (compound 1-4), and the yield is 81%;
MS:550.2[M+H+]。
synthesis of compound 1:
dissolving the compound 1-4(1.6g,3mmol) in 20mL of methanol, slowly adding an equal volume of saturated hydrogen chloride methanol solution at room temperature, stirring overnight at room temperature, after TLC detection reaction is finished, evaporating excessive methanol and hydrogen chloride under reduced pressure, dissolving the solid with methanol, adding sodium bicarbonate to adjust the pH value to 8, stirring for more than 2 hours, filtering to remove the solid, evaporating the solvent from the filtrate under reduced pressure, purifying the obtained concentrate with column chromatography (200-mesh 300-mesh silica gel, the eluent is dichloromethane/methanol, the volume ratio is 10:1) to obtain 1.2g of light yellow solid (compound 1), and the yield is 88%;
1H-NMR(400MHz，CDCl3):δ7.15-7.14(1H,m),7.10(2H,s),7.07-6.96(1H,m),7.07-6.96 (1H,m),4.67(4H,s),4.29-4.21(2H,m),4.03-3.96(4H,dd,J＝4.0Hz,16.0Hz),3.75-3.72(2H,br), 3.64-3.40(2H,t,J＝10.4Hz),2.95-2.88(1H,m),2.86(3H,s),2.50-2.47(1H,m),1.86-1.83(2H, m)；MS:450.1[M+H+]。
example 2Synthesis of Compound 2
Figure BDA0002287714080000141
Taking the intermediate 1-3 (compound 1-3) as a raw material, replacing the raw material methanesulfonyl chloride in example 1 with trifluoromethanesulfonyl chloride, synthesizing a compound 2 by referring to the synthesis method of the last two steps in example 1, wherein the yield of the last two steps is 62%; MS 504.1[ M + H + ].
Example 3Synthesis of Compound 3
Figure BDA0002287714080000142
Taking the intermediate 1-3 as a raw material, replacing the raw material methanesulfonyl chloride in example 1 with raw material isopropyl sulfonyl chloride, synthesizing a compound 3 with reference to the synthesis method of the last two steps in example 1, wherein the yield of the last two steps is 65%; MS:477.1[ M + H + ].
Example 4Synthesis of Compound 4
Figure BDA0002287714080000151
Taking the intermediate 1-3 as a raw material, replacing the raw material methanesulfonyl chloride in example 1 with the raw material cyclopropylsulfonyl chloride, and synthesizing a compound 4 with a yield of 67% in the last two steps with reference to the synthesis method of the last two steps in example 1; MS:476.1[ M + H + ].
Example 5Synthesis of Compound 5
Figure BDA0002287714080000152
Taking the intermediate 1-3 as a raw material, replacing the raw material methanesulfonyl chloride in example 1 with the raw material p-toluenesulfonyl chloride, synthesizing a compound 5 with a yield of 67% in the last two steps with reference to the synthesis method of the last two steps in example 1; MS 526.2[ M + H ]+]。
Example 6Synthesis of Compound 6
Figure BDA0002287714080000153
Taking the intermediate 1-3 as a raw material, replacing the raw material methanesulfonyl chloride in example 1 with raw material methyl iodide, and synthesizing a compound 6 with a yield of 58% in the last two steps by referring to the synthesis method of the last two steps in example 1; MS 386.2[ M + H ]+]。
Example 7Synthesis of Compound 7
Figure BDA0002287714080000154
The intermediate 1-3 is taken as a raw material, the raw material of the methane sulfonyl chloride in the example 1 is replaced by the raw material of the trifluoroiodomethane, and the synthesis method of the last two steps in the reference example 1 is synthesizedCompound 7 is formed, and the yield of the last two steps is 51 percent; MS 440.1[ M + H ]+]。
Example 8Synthesis of Compound 8
Figure BDA0002287714080000161
Taking the intermediate 1-3 as a raw material, replacing the raw material methanesulfonyl chloride in example 1 with the raw material p-fluorobenzyl bromide, and synthesizing a compound 8 by referring to the synthesis method of the last two steps in example 1, wherein the yield of the last two steps is 64%; MS 480.2[ M + H ]+]。
Example 9Synthesis of Compound 9
Figure BDA0002287714080000162
Taking the intermediate 1-3 as a raw material, replacing the raw material methanesulfonyl chloride in example 1 with raw material acetyl chloride, and synthesizing a compound 9 with a yield of 66% in the last two steps by referring to the synthesis method of the last two steps in example 1; MS 414.2[ M + H ]+]。
Example 10Synthesis of Compound 10
Figure BDA0002287714080000163
Taking the intermediate 1-3 as a raw material, replacing the raw material methanesulfonyl chloride in example 1 with the raw material trifluoroacetyl chloride, and synthesizing a compound 10 by referring to the synthesis method of the last two steps in example 1, wherein the yield of the last two steps is 64%; MS 468.1[ M + H ]+]。
Example 11Synthesis of Compound 11
Figure BDA0002287714080000171
Taking the intermediate 1-3 as a raw material, replacing the raw material methanesulfonyl chloride in example 1 with the raw material thiophene-1-formyl chloride, synthesizing a compound 11 by referring to the synthesis method of the last two steps in example 1, wherein the yield of the last two steps is 60%; MS 482.1[ M + H ]+]。
Example 12Synthesis of Compound 12
Figure BDA0002287714080000172
Taking the intermediate 1-3 as a raw material, substituting the raw material p-fluorobenzoyl chloride for the raw material methanesulfonyl chloride in example 1, and synthesizing a compound 12 by referring to the synthesis method of the last two steps in example 1, wherein the yield of the last two steps is 61%; MS 494.2[ M + H+]。
Example 13Synthesis of Compound 13
Figure BDA0002287714080000173
Compound 13 was synthesized with the total yield of 24% by referring to the synthesis method of example 1, substituting raw materials of tetrabromomethylbenzene and methanesulfonyl chloride in example 1 with raw materials of 1, 4-difluorotetrabromomethylbenzene and iodomethane, respectively; MS 422.2[ M + H ]+]。
Example 14Synthesis of Compound 14
Figure BDA0002287714080000174
Compound 14 was synthesized with the total yield of 21% by referring to the synthesis method of example 1, substituting raw materials of tetrabromomethylbenzene and methanesulfonyl chloride in example 1 with raw materials of 1, 4-dichlorotetrabromomethylbenzene and methyl iodide, respectively; MS 454.1[ M + H ]+]。
Example 15Synthesis of Compound 15
Figure BDA0002287714080000181
Raw materials of 1, 4-dibromo tetrabromomethylbenzene and methyl iodide are respectively used for replacing the raw materials of tetrabromomethylbenzene and methanesulfonyl chloride in example 1, and a compound 15 is synthesized with the total yield of 20% by referring to the synthesis method of example 1; MS 544.0[ M + H ]+]。
Example 16In vitro Activity assay
The inventionThe DPP-IV inhibition ratio of the compounds 1-15 can be DPP-IV-GloTMHomogeneous phase luminescence detection system (DPP-IV-Glo) of proteolytic enzymeTMProtease Assay, Promega cat # G8350).
The system comprises a DPP-IV substrate Gly-Pro-aminoluciferin and a buffer solution system for luciferase activity detection, and the detection principle is as follows: DPPIV-GloTMCleavage by DPP-IV activates the luciferase reaction, producing a "glow-type" type luminescent signal, which is then used in Turner VeritasTMThe activity of DPP-IV can be represented by detecting a luminescent signal by a microplate luminometer.
Purpose of the experiment: the inhibitory activity and selective inhibitory effect of the compounds 1 to 15 of the present invention on DPP-IV enzyme were determined.
Experimental materials: DPP-IV enzyme, DPP-VIII enzyme, DPP-IX enzyme, GP-AMC (BioMol), black 96 pore plates and a super enzyme labeling instrument; DPP-IV and DPP-VIII assay buffers: 100mmol/L Tris/HCl buffer, pH8.0,0.1 mg/mLBSA; assay buffer for DPP-IX: 100mmol/L Tris/HCl buffer, pH 7.4,0.1mg/mL BSA.
The experimental method comprises the following steps:
a. determination of the enzymatic activity:
GP-AMC was diluted in the respective buffer at a concentration of 100. mu. mol/L, 25. mu.L per well; and (3) performing enzyme gradient dilution, wherein the initial concentrations are DPP-VIII and DPP-IX: 0.01 μ g/μ L, DPP-IV: 0.01 mU/microliter, diluting by 5 times, and mixing well, wherein each well contains 25 microliter; measuring the dynamic change of the fluorescence value at 37 ℃ and 360/460nm for 30 minutes; the enzyme concentration at which the absorbance linearly increases and S/B is not less than 5 is used.
b. And (3) inhibitor activity determination:
all enzymes, inhibitors, GP-AMC were formulated in assay buffer, with no compound control and no enzyme control. Preparing enzyme solution according to the using concentration of the enzyme, wherein each hole is 25 mu L; gradient dilution inhibitor (10-fold or 5-fold dilution), 25 μ L per well, and mixing; adding 50 mu L of diluted GP-AMC solution, and mixing evenly; the reaction was carried out at 37 ℃ for 20 minutes, and the fluorescence was measured at 360/460 nm.
c. And (3) data analysis: analysis was performed using GraphPad-Prism software.
The experimental results are as follows: the data for the inhibitory activity of compounds 1-15 of the present invention against three enzymes are shown in table 1 below.
TABLE 1 in vitro Activity and selectivity data
Figure BDA0002287714080000191
Figure BDA0002287714080000201
The experimental results show that: compared with the reference drug of alogliptin, the compound has very good selective inhibition effect on DPP-IV, and the inhibition rate of the compound on DPP-IV is equal to or better than that of the reference drug. The data in the table also show that the compound has little influence on the activity of DPP-VIII and DPP-IX while effectively inhibiting the activity of DPP-IV, and the toxicity of the compound is expected to be lower after the compound is developed into a medicament.
Example 17Inhibition of hERG in vitro
Experimental materials: tested compounds 1 and 6, hERG/HEK293 stable cell lines (purchased from King of St. Biotech, Inc., Nanjing).
The experimental method comprises the following steps: dissolving the compound 1 or the compound 6 in a proper amount of DMSO (dimethyl sulfoxide) to prepare 100mM stock solution, wherein the solution is clear and transparent; subpackaging the stock solution at-70 deg.C for use. During the experiment, the stock solution is diluted by an extracellular fluid gradient to be the detection concentration. HEK293 cells stably expressing the hERG channel were cultured in 35mm dishes at 37 ℃/5% CO2The incubator was left for at least 24 hours and then used for the experiment. One culture dish was removed for each experiment, washed twice with extracellular fluid, and placed on the stage of an inverted microscope. The whole-cell patch clamp experiment is carried out at room temperature, and the tip resistance of the used borosilicate glass microelectrode is 3-5M omega. After a whole cell recording mode is formed, clamping the membrane potential at minus 80mV, giving a depolarization voltage stimulus of plus 50mV to the cell every 30s, repolarizing to minus 50mV after lasting for 2s, and lasting for 3s, thus leading out the hERG tail current. Before depolarization voltage stimulation, 50ms and 50mV repolarization voltage is given to the cells, and the current recorded at the voltage is used as the calculation hEBaseline of RG tail current. Only cells that meet the criteria for recording will be used for detection of the test compound. Before the compound was added, the hERG tail current was stably recorded in the extracellular fluid for at least 3 minutes. When the change of hERG tail current amplitude is smaller than that after perfusion administration<At 5%, the drug effect is considered to reach steady state. If the current does not reach steady state within 6 minutes, the concentration compound detection is also ended.
The results of the experiment are shown in table 2 below.
TABLE 2 inhibition of hERG channel (%)
Name of Compound 30 μ M inhibition (%)
Compound 1 2.96
Compound 6 15.85
The experimental results show that the compound 1 and the compound 6 have weak inhibition on hERG, and the compound of the invention can be predicted to have no cardiotoxicity after being used for preparing the medicine.
Example 18Evaluation of rat pharmacokinetics
Animals: SD male rats (5-7 weeks old, sex: male, body weight 200-.
The method comprises the following steps: fasted overnight. On the day of experiment, 3 SD rats were gavaged with 5 mg/kg of gastric lavage-1The compound, 15min, 30min, 45min, 1h, 2h, 4h, 8h, 12h and 24h before and after administration, respectively, was collected from the jugular vein at 0.20mL and placed in an EDTA tube. After blood sample collection, internal standard (verapamil, 5.00ng/mL and glibenclamide, 50.0 ng-mL) of acetonitrile, vortexed vigorously and centrifuged at 13000rpm for 10 min. Taking the supernatant to carry out LC-MS/MS detection.
As a result: pharmacokinetic parameters were calculated using a non-compartmental model in Pharsight Phoenix 6.3 and the results are shown in table 3.
TABLE 3 rat pharmacokinetic evaluation results
Figure BDA0002287714080000211
Figure BDA0002287714080000221
And (4) conclusion: compared with the positive control drug of the augustine, the compound of the invention has higher maximum blood concentration and exposure amount on rats, longer half-life period and long-acting hypoglycemic potential.
The applicant states that the benzoditetrahydropyrrole compounds or pharmaceutically acceptable salts thereof, and the preparation method and application thereof are illustrated by the above examples, but the invention is not limited by the above examples, i.e. the invention is not limited by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims (10)

1. A benzoditetrahydropyrrole compound or a pharmaceutically acceptable salt thereof, wherein the benzoditetrahydropyrrole compound has a structure shown in formula I:
Figure FDA0002287714070000011
wherein R is1Selected from hydrogen, hydroxyl, C1-C6 straight chain or branched chain saturated or unsaturated alkyl, C3-C7 cyclic alkyl, 4-7 membered heterocyclic group, C1-C6 alkyl acyl, C1-C6 alkyl sulfonylC1-C6 alkylsulfinyl, C3-C7 cycloaminoacyl, 5-to 7-membered heterocycloaminoacyl, aryl, benzyl, arylacyl, arylacylmethylene, 5-to 7-membered heteroaryl, 5-to 7-membered heteroarylmethylene, 5-to 7-membered heteroarylacyl or 5-to 7-membered heteroarylacylmethylene;
R2and R3Independently selected from hydrogen, halogen, amino, cyano, nitro, C1-C6 straight chain or branched chain saturated or unsaturated alkyl, C3-C7 cyclic alkyl, 4-7 membered heterocyclic group, C1-C4 alkyl acyl, C3-C7 cyclic amino acyl, 5-7 membered heterocyclic amino acyl, aryl, benzyl, aryl acyl methylene, 5-7 membered heteroaryl methylene, 5-7 membered heteroaryl acyl or 5-7 membered heteroaryl acyl methylene.
2. The benzoditetrahydropyrrole compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the benzoditetrahydropyrrole compound has a structure represented by formula II:
Figure FDA0002287714070000012
wherein R is1Having the scope as defined in claim 1.
3. The benzoditetrahydropyrrole compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is1～R3Wherein the C1-C6 linear or branched chain saturated or unsaturated alkyl, C1-C4 alkylacyl, C3-C7 cycloalkyl, C1-C6 alkylacyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, aryl, benzyl, arylacyl, arylacylmethylene, 5-7 membered heteroaryl, 5-7 membered heteroarylmethylene, 5-7 membered heteroarylacyl or 5-7 membered heteroarylacylmethylene has hydrogen on carbon thereof substituted by one or more R11Substituted; the R is11Selected from halogen, carbonyl, hydroxyl, amino, nitro, sulfhydryl, cyano, C1-C3 alkylsulfo or C1-C3 alkoxy; r1～R3As described inHydrogen on nitrogen of 4-7 membered heterocyclic group or hydrogen on nitrogen of 5-7 membered heterocyclic aminoacyl group is substituted with one or more R12Substituted; the R is12Selected from C1-C6 alkyl, C1-C6 alkanoyl or C1-C3 alkylsulfo.
4. The benzoditetrahydropyrrole compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is2And R3Selected from hydrogen, halogen, amino, cyano, nitro, C1-C6 straight chain or branched chain saturated or unsaturated alkyl, C3-C7 cyclic alkyl, 4-7 membered heterocyclic group, C1-C4 alkyl acyl, C3-C7 cyclic amino acyl, 5-7 membered heterocyclic amino acyl, aryl, benzyl, aryl acyl methylene, 5-7 membered heteroaryl methylene, 5-7 membered heteroaryl acyl or 5-7 membered heteroaryl acyl methylene;
R1selected from hydrogen, C1-C6 straight chain or branched chain saturated or unsaturated alkyl, C3-C7 cyclic alkyl, C1-C6 alkyl acyl, C1-C6 alkyl sulfonyl, benzyl, aryl acyl methylene, 5-7 membered heteroaryl methylene or 5-7 membered heteroaryl acyl.
5. The benzoditetrahydropyrrole compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the benzoditetrahydropyrrole compound is selected from any one of the following compounds:
Figure FDA0002287714070000021
Figure FDA0002287714070000031
6. the benzoditetrahydropyrrole compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the pharmaceutically acceptable salt of the benzoditetrahydropyrrole compound is an acid addition salt or a base addition salt of the benzoditetrahydropyrrole compound;
the acid addition salt is selected from at least one of hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate, ethanesulfonate, toluenesulfonate, benzenesulfonate, acetate, maleate, tartrate, succinate, citrate, benzoate, ascorbate, salicylate, malonate, adipate, hexanoate, arginine, fumarate, nicotinate, phthalate and oxalate; the alkali addition salt is selected from lithium salt, sodium salt, potassium salt, barium salt, calcium salt, magnesium salt, aluminum salt, ferric salt, ferrous salt, copper salt and zinc salt of benzoditetrahydropyrrole compounds, and at least one of salts of benzoditetrahydropyrrole compounds and morpholine, diethylamine, triethylamine, isopropylamine, trimethylamine, lysine or histidine.
7. A process for the preparation of benzoditetrahydropyrrole compounds according to any one of claims 1 to 6, wherein said benzoditetrahydropyrrole compounds are synthesized by the following scheme:
Figure FDA0002287714070000041
wherein: r1、R2、R3As defined in formula I in claim 1;
in the step (1), R is2、R3Reacting the substituted tetrabromomethylbenzene with trifluoroacetamide to obtain a compound A;
in the step (2), hydrolyzing the compound A in strong alkali to obtain a compound B;
in the step (3), the compound B and the 2- (2 ', 5' -difluorophenyl) -3-amino-5-hydropyropyranone intermediate C are hydrolyzed under alkaline conditions to obtain a compound D;
in the step (4), the compound D and X-R are reacted1Reacting, wherein X is I, Br, Cl, OTs, OMs or OTf to obtain a compound E;
in the step (5), the compound E is subjected to removal of Boc protecting group, so as to obtain the benzoditetrahydropyrrole compound shown in the general formula I in claim 1.
8. The method according to claim 7, wherein the organic solvent in the step (1) is at least one selected from the group consisting of tetrahydrofuran, dichloromethane, ethyl acetate, acetonitrile, acetone, 1, 4-dioxane, alcohols, diethyl ether, toluene, N-dimethylformamide, N-dimethylformamide, ethylene glycol dimethyl ether and dimethyl sulfoxide.
9. A pharmaceutical composition comprising the benzoditetrahydropyrrole compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
10. Use of benzoditetrahydropyrrole compounds or pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 6 for the preparation of a DPP-IV inhibitor for the preparation of a medicament for the treatment of a metabolic disease, such as type ii diabetes, diabetic dyslipidemia, impaired glucose tolerance, fasting plasma glucose-loss, metabolic acidosis, ketosis, appetite regulation, obesity, various cancers, neurological disorders or immune system disorders.
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WO1999009032A1 (en) * 1997-08-13 1999-02-25 Merck & Co., Inc. Carbapenems with naphthosultam derivative linked via methylene
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