Derivative of aralkyl amino acid compound and application thereof

Abstract

The invention provides a derivative of an aralkyl amino acid compound and application thereof. Specifically, the invention provides a compound as shown in a general formula (I), an isomer, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate of the compound, and application of the compound in preparation of medicines for treating type 2 diabetes and complications thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a derivative of an aralkyl amino acid compound and a use thereof. Background Art

[0002] Diabetes is a disease caused by multiple genetic disorders and currently affects a considerable portion of the world's population. It is divided into two types: (1) Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM), in which patients secrete very little or no insulin; and (2) Type 2 diabetes or non-insulin-dependent diabetes mellitus (NIDDM). The core problem of patients with type 2 diabetes is insulin resistance, which is the impairment of peripheral tissues such as muscle, liver, and adipose tissue in absorbing and metabolizing insulin-stimulated blood sugar, which in turn increases the burden on the pancreas to secrete insulin, ultimately leading to a progressive decline in pancreatic function or even loss. The treatment of type 2 diabetes usually includes lifestyle management and drug therapy. In addition to insulin, there are at least eight major categories of oral or injectable therapeutic drugs based on their therapeutic mechanisms, but the effective population and long-term efficacy of existing drugs are limited. Therefore, there is a constant need to develop new and more effective treatments for type 2 diabetes. Summary of the invention

[0003] The present invention discovers a class of arylalkyl amino acid compounds having excellent therapeutic effects on type 2 diabetes.

[0004] The present invention provides a compound represented by general formula (I), its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0005]

[0006] Among them, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , X 23 , X 24 , X 25 and X 26 are each independently selected from hydrogen or deuterium, and X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , X 23 , X 24 , X 25 or X 26 At least one of them is selected from deuterium.

[0007] In some embodiments, the pharmaceutically acceptable salts of the compound of formula (I) include alkali metal salts, alkaline earth metal salts, and ammonium salts.

[0008] In some preferred embodiments, the alkali metal salts include potassium salts and sodium salts.

[0009] In some more preferred embodiments, the alkali metal salt is a sodium salt.

[0010] In some embodiments, the pharmaceutically acceptable salt has a structure as shown in the general formula (II):

[0011]

[0012] Wherein, T is selected from sodium (Na), potassium (K), magnesium (Mg), calcium (Ca), and amine (NH4);

[0013] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , X 23 , X 24 , X 25 and X 26 The definition of is as mentioned above.

[0014] In some preferred embodiments, the general formula (II) has a structure as shown in the general formula (II'):

[0015]

[0016] Among them, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , X 23 , X 24 , X 25 and X 26 The definition of is as mentioned above.

[0017] In some embodiments, the compound represented by general formula (I) has one of the following structures:

[0018]

[0019]

[0020]

[0021]

[0022]

[0023]

[0024] In some embodiments, the compound represented by general formula (I) has one of the following structures:

[0025]

[0026] In some embodiments, the structure of formula (II) has one of the following structures:

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033] In some embodiments, the structure of formula (II) has one of the following structures:

[0034]

[0035] In the representative compounds of general formula (II) described above, K, Mg, Ca, or NH4 can be used to replace Na to form new compounds.

[0036] Any atom of the compound of the present invention, unless otherwise specified, refers to the isotope of its stable atom. Unless otherwise specified, when a site on the molecular structure is selected as "H" or "hydrogen", the site should be understood to have the natural abundance of hydrogen isotopes. Similarly, if not otherwise specified, when a site is selected as "D" or "deuterium", the site should be understood to have a deuterium isotope abundance of at least 3000 times its natural abundance (the natural abundance of deuterium isotopes is 0.015%), i.e., 45% deuterium atom enrichment. Preferably, the deuterium atom abundance of each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, at least 4500 times (67.5% deuterium atom enrichment). More preferably, at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).

[0037] The preparation of the compound of the general formula (I) and the compound of the salt form of the general formula (II) of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered in any way to limit the scope of the present invention. The compound of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of synthetic methods known in the art and the method of the present invention. The product obtained from each step of the reaction is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.

[0038] The following synthetic routes describe the preparation of the compounds of formula (I) and the compounds of general formula (II) in salt form of the present invention. The raw materials, reagents, catalysts, solvents, etc. used in the following synthetic routes can be prepared by methods well known to those skilled in the art of organic chemistry or can be commercially obtained. All final derivatives of the present invention can be prepared by the methods described in the synthetic routes or by analogous methods, which are well known to those skilled in the art of organic chemistry. All variables used in these synthetic routes are as defined above and below.

[0039] The definitions of the following variables are as described above, and the definitions of new variables are as described in this section. In addition, the compounds described in the general formula (I) and the intermediates involved can be purified by common separation methods, such as extraction, recrystallization and silica gel column chromatography. The 200-300 mesh silica gel and thin layer chromatography silica gel plates used are all produced by Qingdao Ocean Chemical Plant. The chemical reagents used are analytically pure or chemically pure commercial products of general reagents and are not further purified when used.

[0040] The present invention provides a method for preparing a compound represented by general formula (I) and a salt thereof represented by general formula (II), which comprises the following steps:

[0041]

[0042]

[0043] 1) The compound represented by formula (Ia) is reacted with the compound represented by formula (Ib) in a first solvent by a nucleophilic substitution reaction after being catalyzed by a first base to obtain the compound represented by formula (Ic);

[0044] 2) the compound represented by formula (Ic) and the compound represented by formula (Id) are reacted in a second solvent under the action of a second base to obtain a compound represented by formula (Ie);

[0045] 3) the compound represented by formula (Ie) and the compound represented by (If) undergo a substitution reaction under the action of a third base and in a third solvent to obtain a compound represented by formula (Ig);

[0046] 4) the compound represented by formula (Ig) is subjected to an ester hydrolysis reaction under the action of a fourth base to obtain a compound represented by formula (I);

[0047] 5) The compound represented by formula (I) is subjected to an acid-salting reaction under the action of a fifth base to obtain a compound represented by formula (II);

[0048] Among them, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , X 23 , X 24 , X 25 and X 26 The definition of is as mentioned above;

[0049] M is selected from bromine and iodine;

[0050] W is selected from methanesulfonyl (Ms), p-toluenesulfonyl (Ts), trifluoromethanesulfonyl (Tf);

[0051] T is selected from sodium (Na), potassium (K), magnesium (Mg), calcium (Ca), and amine (NH4).

[0052] In some embodiments, in step 1), the first solvent is selected from dichloromethane (DCM), 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), pyridine (Py), N-methylpyrrolidone (NMP) or a combination thereof.

[0053] In some embodiments, in step 1), the first base is selected from triethylamine (TEA), pyridine (Py), N,N'-dimethylethylenediamine (DIPEA), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3) or a combination thereof.

[0054] In some embodiments, in step 2), the second solvent is selected from dichloromethane (DCM), 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), pyridine (Py), N-methylpyrrolidone (NMP) or a combination thereof.

[0055] In some embodiments, in step 2), the first base is selected from triethylamine (TEA), pyridine (Py), N,N'-dimethylethylenediamine (DIPEA), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3) or a combination thereof.

[0056] In some embodiments, in step 3), the third base is selected from cesium carbonate (Cs2CO3), potassium carbonate (K2CO3) or a combination thereof.

[0057] In some embodiments, in step 3), the third solvent is selected from toluene, xylene, N,N'-dimethylformamide (DMF), pyridine (Py), N-methylpyrrolidone (NMP) or a combination thereof.

[0058] In some embodiments, in step 4), the fourth base is selected from lithium hydroxide (LiOH), lithium hydroxide (KOH), and sodium hydroxide (NaOH).

[0059] In some embodiments, in step 5), the fifth base is selected from sodium hydroxide (NaOH), lithium hydroxide (KOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), and different organic amines that can form salts.

[0060] The compounds provided by the present invention can all be prepared by the above general preparation method using one-to-one corresponding raw materials.

[0061] The present invention also provides a pharmaceutical composition, which contains the compound described in the first aspect, its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, and a pharmaceutically acceptable excipient or carrier.

[0062] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredients are known or will be apparent to those skilled in the art based on the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

[0063] The present invention also provides use of the compound described in the first aspect, its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition described in the second aspect in the preparation of drugs for treating diabetes and its complications.

[0064] In some embodiments, the disease is diabetes is type 2 diabetes.

[0065] Beneficial effects of the present invention:

[0066] The compounds of the present invention (such as representative compounds I-1 and II-1, I-2 and II-2, I-3 and II-3) have activation activity on the three subtypes of PPAR, which can increase insulin sensitivity, lower blood sugar and improve other metabolic syndromes, providing a new compound for the treatment of type 2 diabetes and its complications.

[0067] Technical terms of the present invention:

[0068] In the following description, certain specific details are set forth to provide a thorough understanding of different embodiments. However, it will be appreciated by those skilled in the art that the present invention can be implemented without these details. In other cases, known structures are not shown or described in detail to avoid making the description of the embodiments unclear unnecessarily. In addition, the titles provided herein are merely for convenience and are not intended to explain the scope or meaning of the invention for which protection is sought.

[0069] References throughout this specification to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described with respect to that embodiment is included in at least one embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Moreover, as used in this specification and the appended claims, the singular forms "a" and "an" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in a sense that includes "and / or" unless the context clearly dictates otherwise.

[0070] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent discovered by the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent.

[0071] The term "isomer" refers to any tautomer, stereoisomer, isotope isomer, enantiomer or diastereomer of any compound of the present invention. Among them, isotope isomers refer to different molecules that differ only in isotopes but have the same other structures. Specific implementation plan

[0072] Unless otherwise defined, all technical and scientific terms in the present invention have the same meaning as those commonly understood by those skilled in the art. Other various forms of modification, substitution or change may be made according to common technical knowledge and customary means in the art without departing from the above basic technical concept of the present invention.

[0073] The present invention is described in detail below by examples, but it is not intended to limit the present invention in any adverse way. The compounds of the present invention can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination thereof with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and improvements are made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention, and they should also be regarded as the protection scope of the present invention.

[0074] LC-MS analysis method:

[0075] Mass spectrometry conditions: instrument Thermo ISQ EC; ion source ESI (EA+EA-); source temperature 300°C; sheath gas pressure 50.0 psi; auxiliary gas pressure 5.0 psi; purge gas pressure 0.5 psi; vaporization chamber temperature 300°C.

[0076] Chromatographic conditions: instrument Thermo U3000; detector DAD-3000 (RS) (diode array detector); chromatographic column Pheromone Titank C18 3μm 4.6×50mm; flow rate 2.0mL / min, split; column temperature 35°C; mobile phase A contained 0.05% formic acid and 5% acetonitrile in water; mobile phase B contained 0.05% formic acid in acetonitrile; elution method was linear elution from 100% to 5% of phase A within 0 to 1.0min, and then 5% of phase A was maintained for 1.2min.

[0077] HPLC analysis method:

[0078] Instrument: Thermo U3000; detector: VWD-3×00(RS) (ultraviolet detector); wavelength: 254nm; chromatographic column: Shimadzu inertsil 3μm 4.6×150mm; flow rate: 0.8mL / min; column temperature: 35°C; mobile phase A: water containing 0.05% formic acid and 5% acetonitrile; mobile phase B: acetonitrile containing 0.05% formic acid; elution method: first maintain 100% phase A for 1.0min, then linearly elute phase A from 100% to 5% within 1.0-8.0min, and finally maintain 5% phase A for 4.0min.

[0079] 1 H-NMR analysis method:

[0080] 1H-NMR was measured at room temperature using a BRUKER AVANCE-400 MHz NMR spectrometer in DMSO-d6 or CDCl3 with TMS as the internal standard. Signal peaks were expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double of doublets), tt (double of triplets). The unit of coupling constant (J) is Hertz (Hz).

[0081] According to the above-described method, the present invention prepared representative compounds I-1, II-1, I-2, II-2, I-3, and II-3 (see Table 1), and detected and recorded their purities.

[0082] Table 1: Representative compounds

[0083]

[0084]

[0085] The present invention is further described below in conjunction with specific examples, but the protection scope of the present invention is not limited to these examples. The percentages described in the present invention are all weight percentages unless otherwise specified. The numerical ranges described in the specification, such as units of measurement, reaction conditions, physical states of compounds or percentages, are all for providing unambiguous written references. When implementing the present invention, those skilled in the art use temperatures, concentrations, quantities, carbon atoms, etc. outside this range or different from a single numerical value, and it is still possible to obtain the expected results. In addition, the raw materials in the following examples, if not otherwise specified, can all be commercially available, for example, can be purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., Jiangsu Aikang Biopharmaceutical R&D Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., and Hechun Biotechnology (Shanghai) Co., Ltd.

[0086] Example 1: Preparation of Compounds I-1 and II-1

[0087]

[0088] Step 1: Preparation of intermediate I-1c

[0089] Suspend KOH (2.11 g, 37.65 mmol, 6.0 eq) in ultra-dry DMF (15 mL), stir at room temperature for 10 min, add I-1a (1.10 g, 6.27 mmol, 1.0 eq), stir for 30 min, add I-1b (1.10 g, 8.78 mmol, 1.4 eq), and continue to stir the mixture for 16 h. Quench the reaction with water (150 mL) and extract twice with EA (150 mL). Combine the organic phases, wash three times with saturated brine (150 mL), dry over anhydrous Na2SO4, and concentrate. The crude product was purified by silica gel column chromatography (PE / EA (v / v) = 2 / 1) to obtain an off-white solid I-1c. (960.00 mg, yield 69.53%). LC-MS MS-ESI (m / z) 220.1 [M+H] + .

[0090] Step 2: Preparation of intermediate I-1e

[0091] I-1c (960.00 mg, 4.38 mmol, 1.0 eq) was dissolved in DCM (30 mL), TEA (1.33 g, 13.13 mmol, 3.0 eq) was added, cooled to -10 °C with an ice / salt bath, I-1d (1.00 g, 8.76 mmol, 2.0 eq) was added dropwise, and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (150 mL) and extracted twice with DCM (100 mL). The organic phases were combined and concentrated to give a light yellow solid I-1e. (1.29 g, yield 99.10%). LC-MS MS-ESI (m / z) 298.2 [M+H] + .

[0092] Step 3: Preparation of intermediate I-1g

[0093] I-1e (1.29 g, 4.34 mmol, 1.5 eq) was suspended in toluene (30 mL), and I-1f (1.14 g, 2.89 mmol, 1.0 eq) and Cs2CO3 (1.88 g, 5.78 mmol, 2.0 eq) were added. The resulting mixture was heated to 100 ° C, stirred for 6 h, and cooled to room temperature. The reaction was quenched with water (150 mL) and extracted twice with EA (150 mL). The organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (PE / EA (v / v) = 4 / 1 and 3 / 1) to obtain a yellow solid I-1g. (1.51 g, yield 87.86%). LC-MS MS-ESI (m / z) 595.3 [M+H] + .

[0094] Step 4: Preparation of Compound I-1

[0095] I-1g (1.51g, 2.54mmol, 1.0eq) was dissolved in THF (20mL), and a solution of LiOH·H2O (1.07g, 2.54mmol, 10.0eq) in H2O (20mL) was added, and the resulting mixture was stirred at room temperature for 16h. The reaction solution was concentrated to remove THF, and the residual aqueous phase was adjusted to pH 5-6 with 1M dilute hydrochloric acid and extracted twice with DCM (150mL). The organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH (v / v) = 40 / 1, 30 / 1, 20 / 1 and 10 / 1) to obtain a yellow solid I-1. (1.05g, yield 71.19%). LC-MS MS-ESI (m / z) 581.3 [M+H] + .

[0096] 1 H-NMR(400MHz,DMSO-d6)δppm 8.56(d,J=7.4Hz,1H),7.66-7.50(m,2H),7.39-7.23(m,4H),7.05(s,1H),7.03(s,1H),6.76(d,J=8.6Hz,1H),6.65(s,1H),6.63(s,1H),6.5 2(t,J=7.4Hz,1H),4.72(t,J=5.0Hz,2H),4.41-4.31(m,1H),4.29-4.20(m,2H),3.10(dd,J=13.8,5.0Hz,1H),2.94(dd,J=13.8,6.5Hz,1H).

[0097] Step 5: Preparation of Compound II-1

[0098] I-1 (174.20 mg, 0.30 mmol, 1.0 eq) was dissolved in THF (15 mL), 1 M NaOH solution (315.00 uL, 0.32 mmol, 1.05 eq) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain a yellow solid II-1 (180.00 mg, yield 99.56%). LC-MS MS-ESI (m / z) 581.4 [M+H] + .

[0099] 1H-NMR(400MHz,DMSO-d6)δppm 8.72(d,J=6.7Hz,1H),7.61-7.51(m,2H),7.35-7.17(m,4H),7.00(s,1 H),6.98(s,1H),6.64(d,J=8.6Hz,1H),6.60(s,1H),6.58(s,1H),6.38( t,J=7.4Hz,1H),4.73(t,J=5.3Hz,2H),4.24(t,J=5.3Hz,2H),3.86(q,5.7Hz,1H),3.04(dd,J=13.6,5.1Hz,1H),2.86(dd,J=13.6,5.8Hz,1H).

[0100] Example 2: Preparation of Compounds I-2 and II-2

[0101]

[0102]

[0103] Step 1: Preparation of intermediate I-2c

[0104] Off-white solid I-2c was prepared from KOH (1.86 g, 33.24 mmol, 6.0 eq), I-2a (925.57 mg, 5.54 mmol, 1.0 eq) and I-2b (1.00 g, 7.45 mmol, 1.4 eq) according to the similar steps of intermediate I-1c in the example. (770.00 mg, yield 64.56%). LC-MS MS-ESI (m / z) 216.4 [M+H] + .

[0105] Step 2: Preparation of intermediate I-2e

[0106] The light yellow solid I-2e was prepared from I-2c (770.00 mg, 3.58 mmol, 1.0 eq), TEA (1.08 g, 10.73 mmol, 3.0 eq) and I-1d (819.00 mg, 7.15 mmol, 2.0 eq) according to the similar steps in the intermediate I-1e in the example. (1.03 g, yield 98.07%). LC-MS MS-ESI (m / z) 294.1 [M+H] + . Step 3: Preparation of intermediate I-2g

[0107] Yellow solid I-2g was prepared from I-2e (1.03 g, 3.51 mmol, 1.5 eq), I-1f (920.70 mg, 2.34 mmol, 1.0 eq) and Cs2CO3 (1.52 g, 4.68 mmol, 2.0 eq) according to the similar steps in the intermediate I-1g of the example. (1.32 g, yield 95.34%). LC-MS MS-ESI (m / z) 591.4 [M+H] + .

[0108] Step 4: Preparation of Compound I-2

[0109] Yellow solid I-2 was prepared from I-2g (1.32g, 2.23mmol, 1.0eq) and LiOH·H2O (938.50mg, 22.35mmol, 10.0eq) according to the similar steps in Example I-1. (437.00mg, yield 33.98%). LC-MS MS-ESI (m / z) 577.2 [M+H] + .

[0110] 1 H-NMR(400MHz,DMSO-d6)δppm 8.55(d,J=7.5Hz,1H),8.13(s,1H),8.11(s,1H),7.63(s,1H),7.61(s,1H),7.60- 7.53(m,2H),7.46-7.39(m,2H),7.39-7.27(m,4H),7.14-7.22(m,2H),7.05(s,1H) ,7.03(s,1H),6.77(d,J=8.6Hz,1H),6.67(s,1H),6.64(s,1H),6.55(t,J=7.5Hz,1 H),4.50-4.31(m,1H),3.10(dd,J=13.9,5.1Hz,1H),2.95(dd,J=13.9,6.5Hz,1H).

[0111] Step 5: Preparation of Compound II-2

[0112] I-2 (173.00 mg, 0.30 mmol, 1.0 eq) was dissolved in THF (15 mL), 1 M NaOH solution (315.00 uL, 0.32 mmol, 1.05 eq) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain a yellow solid II-2 (164.00 mg, yield 91.32%). LC-MS MS-ESI (m / z) 577.2 [M+H] + .

[0113] 1 H-NMR(400MHz,DMSO-d6)δppm 8.72(d,J=6.7Hz,1H),8.13(s,1H),8.11(s,1H),7.64(s,1H),7.62(s,1H),7.60-7 .51(m,2H),7.46-7.38(m,2H),7.35-7.25(m,2H),7.23-7.14(m,4H),7.00(s,1H), 6.98(s,1H),6.64(d,J=8.6Hz,1H),6.60(s,1H),6.58(s,1H),6.38(t,J=7.4Hz,1H ),3.85(q,5.7Hz,1H),3.04(dd,J=13.6,5.1Hz,1H),2.85(dd,J=13.6,5.8Hz,1H).

[0114] Example 3: Preparation of Compounds I-3 and II-3

[0115]

[0116] Step 1: Preparation of intermediate I-3c

[0117] Off-white solid I-3c was prepared from KOH (1.86 g, 33.24 mmol, 6.0 eq), I-1a (971.16 mg, 5.54 mmol, 1.0 eq) and I-2b (1.00 g, 7.45 mmol, 1.4 eq) according to the similar steps in the intermediate I-1c in the example. (710.00 mg, yield 57.38%). LC-MS MS-ESI (m / z) 224.2 [M+H] + .

[0118] Step 2: Preparation of intermediate I-3e

[0119] The light yellow solid I-3e was prepared from I-3c (710.00 mg, 3.18 mmol, 1.0 eq), TEA (965.30 mg, 9.54 mmol, 3.0 eq) and I-1d (728.10 mg, 6.36 mmol, 2.0 eq) according to the similar steps in the intermediate I-1e in the example. (940.00 mg, yield 98.07%). LC-MS MS-ESI (m / z) 301.3 [M+H] + .

[0120] Step 3: Preparation of intermediate I-3g

[0121] Yellow solid I-3g was prepared from I-3e (940.00 mg, 3.12 mmol, 1.5 eq), I-1f (818.00 mg, 2.08 mmol, 1.0 eq) and Cs2CO3 (1.35 g, 4.16 mmol, 2.0 eq) according to the similar steps in the intermediate I-1g of the example. (1.14 g, yield 91.54%). LC-MS MS-ESI (m / z) 599.3 [M+H] + .

[0122] Step 4: Preparation of compound I-3

[0123] Yellow solid I-3 was prepared from I-3g (1.14g, 1.90mmol, 1.0eq) and LiOH·H2O (799.70mg, 19.04mmol, 10.0eq) according to the similar steps in Example I-1. (658.00mg, yield 59.23%). LC-MS MS-ESI (m / z) 585.3 [M+H] + .

[0124] 1 H-NMR(400MHz,DMSO-d6)δppm 8.54(d,J=7.6Hz,1H),7.64-7.54(m,2H),7.41-7.26(m,4H),7.05(s,1H),7.03(s,1H),6.78(d,J=8.5Hz,1H),6.67(s, 1H), 6.65 (s, 1H), 6.56 (t, J = 7.5Hz, 1H), 4.50-4.35 (m, 1H), 3.10 (dd, J = 13.9, 5.2Hz, 1H), 2.96 (dd, J = 13.9, 6.5Hz, 1H).

[0125] Step 5: Preparation of Compound II-3

[0126] I-3 (175.40 mg, 0.30 mmol, 1.0 eq) was dissolved in THF (15 mL), 1 M NaOH solution (315.00 uL, 0.32 mmol, 1.05 eq) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain a yellow solid II-3 (170.00 mg, yield 93.40%). LC-MS MS-ESI (m / z) 585.4 [M+H] + .

[0127] 1H-NMR(400MHz,DMSO-d6)δppm 8.73(d,J=6.7Hz,1H),7.60-7.51(m,2H),7.36-7.27(m,2H),7.26-7.16(m,2H),7.01(s,1H),6.98(s,1H),6.64(d,J=8.6Hz,1H), 6.60(s,1H),6.58(s,1H),6.38(t,J=7.4Hz,1H),3.86(q,5.7Hz,1H),3.04(dd,J=13.6,5.0Hz,1H),2.86(dd,J=13.8,6.0Hz,1H).

[0128] In vitro biological evaluation

[0129] Example A Activation of Human PPAR Receptors by Compounds of the Invention

[0130] The PPAR reporter gene model includes three subtypes of expression plasmids, RXR expression plasmid, reporter gene plasmid with luciferase, and GFP expression plasmid as a transfection internal reference. Human hepatocyte cell line L-02 was inoculated in a 96-well plate, with a number of 15,000 cells / well, and cultured at 37°C for 24 hours to make the cell fusion reach about 50% of the bottom area of ​​the well. Roche's FuGENE6 was used to transfer the corresponding expression plasmids into each well of cells (pHD luciferase reporter gene plasmid + PPARα expression plasmid + GFP expression plasmid for PPARα activity detection; pACOX luciferase reporter gene plasmid + PPARγ expression plasmid + RXR expression plasmid + GFP expression plasmid for PPARγ activity detection; pGL3-PPRE luciferase reporter gene plasmid + PPARδ expression plasmid + RXR expression plasmid + GFP expression plasmid for PPARδ activity detection).

[0131] 48 hours after transfection, test drugs of different final concentrations were added to each test well, and wells with an equivalent volume of DMSO were set up as solvent controls. Three replicate wells were set up for each treatment group.

[0132] 24 hours after drug addition, the cell culture medium was discarded, and the 96-well plate was inverted on absorbent paper to completely remove the culture medium. 80 μL of cell lysis solution (Promega, E153A) was added to each well. After standing at room temperature for 5 minutes, it was evenly pipetted with a pipette. 60 μL of cell lysis solution was transferred from each well to a white plate for detection (Corning, 3693).

[0133] First, use a fluorescence microplate reader to detect the fluorescence value of green fluorescent protein (GFP) in each well (wavelength 485-527nm) as an internal reference standard, then add 30μL of luciferase substrate (Promega, E151A) to each well, shake gently to mix, and then detect the fluorescence value at a wavelength of 562nm. The fluorescence value of the test drug is corrected with the internal reference GFP fluorescence value and compared with the corrected value of the solvent control to obtain a relative reporter gene activation intensity, and the half-activated activity (AC50) of the test drug is calculated by the activity at different concentrations.

[0134] The results show that the representative compounds of the present invention, I-1 and II-1, I-2 and II-2, I-3 and II-3, all have activation activity on the three subtypes of PPAR.

[0135] Industrial Applicability

[0136] The compounds provided by the invention all have agonist activity of three subtypes of PPAR and can be used for preparing medicines for treating diabetes, especially type 2 diabetes and its complications.

[0137] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound represented by general formula (I), its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate: in, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , X 23 , X 24 , X 25 and X 26 are each independently selected from hydrogen or deuterium, and X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , X 23 , X 24 , X 25 or X 26 At least one of them is selected from deuterium.

2. The compound according to claim 1, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Pharmaceutically acceptable salts of the compound of formula (I) include alkali metal salts, alkaline earth metal salts, and ammonium salts; The alkali metal salts include potassium salts and sodium salts; preferably sodium salts; The alkaline earth metal salts include calcium salts and magnesium salts; The isomer is selected from the group consisting of S configuration and R configuration.

3. The compound according to claim 1, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The pharmaceutically acceptable salt has a structure as shown in the general formula (II): Wherein, T is selected from Na, K, Mg, Ca, NH4; X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , X 23 , X 24 , X 25 and X 26 The definition as in claim 1.

4. The compound according to claim 3, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The general formula (II) has the structure shown in the general formula (II'): Among them, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , X 23 , X 24 , X 25 and X 26 The definition as in claim 1.

5. The compound according to claim 1, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein the compound of formula (I) has one of the following structures:

6. The compound according to claim 1, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein the compound of formula (I) has one of the following structures:

7. The compound according to claim 3, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein the general formula (II) has one of the following structures:

8. The compound according to claim 3, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein the general formula (II) has one of the following structures:

9. A pharmaceutical composition, characterized in that Contains the compound according to any one of claims 1 to 8, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, and a pharmaceutically acceptable excipient or carrier.

10. Use of the compound according to any one of claims 1 to 8, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating diabetes and its complications Preferably, the diabetes is type 2 diabetes.

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