CN111233820A

CN111233820A - Fingolimod derivative containing crown ether and di (2-methoxyethoxy) structure

Info

Publication number: CN111233820A
Application number: CN201811440376.9A
Authority: CN
Inventors: 姜海业; 马晓莉; 马忠民
Original assignee: Ruifulong Hangzhou Biomedical Co Ltd
Current assignee: Ruifulong Hangzhou Biomedical Co Ltd
Priority date: 2018-11-29
Filing date: 2018-11-29
Publication date: 2020-06-05
Anticipated expiration: 2038-11-29
Also published as: CN111233820B

Abstract

The invention designs and synthesizes a series of fingolimod derivatives containing crown ether or di (2-methoxyethoxy) structures by modifying the structure of an immunosuppressant fingolimod which is on the market and is used for treating multiple sclerosis. The hypoglycemic effect of the target compound was evaluated by in vivo animal experiments. The results show that the compounds including 1c-1e and Ic-Ie have certain effect of reducing blood sugar and have application prospect in preparing the medicines for treating diabetes.

Description

Fingolimod derivative containing crown ether and di (2-methoxyethoxy) structure

The invention relates to novel crown ether and bis (2-methoxyethoxy) structural fingolimod derivatives and application of the compounds in medicaments for treating diseases such as diabetes and the like.

Technical Field

The invention relates to a novel Fingolimod hydrochloride derivative with a crown ether or bis (2-methoxyethoxy) structure and a preparation method thereof, belonging to the technical field of drug synthesis. The invention provides a new choice for treating diabetes.

Technical Field

Fingolimod (Fingolimod) was originally studied as an immunosuppressant by professor of pharmacological datura of tokyo university, the natural amino acid structure extracted by taiwan taimen in cordyceps sinensis, but after further testing, the norwa pharmaceutical of switzerland took away the idea of immunosuppressant drugs used by transplanted patients, as it did not exceed the existing drugs. Interestingly, the company found that fingolimod had a strong effect in multiple sclerosis by testing thousands of patients, reducing the number of relapses, despite the fact that patients may develop vision problems, weakness and numbness. Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system. The disease is characterized by lesions in the brain or spinal cord, which produce symptoms due to loss of massive myelin sheath of varying size in the central nervous system. It is generally thought that the immune system mistakenly destroys myelin as a foreign substance. MS is caused by chronic infection of the virus, causing damage to the spinal sheath that insulates the nerves, resulting in erroneous nerve conduction in the nerve bundles of the brain and spinal cord.

In 2011 for 4 months, after more than 10 years of research, the U.S. food and drug administration has passed fingolimod as an oral drug for the treatment of multiple sclerosis. Multiple Sclerosis (MS) is an autoimmune disease characterized by demyelinating disease of the central nervous system white matter, known as "immotile cancer". The neuroimmune process possibly caused by the interaction of genetically susceptible individuals and environmental factors is one of the most important nervous system diseases because the incidence rate is high, the incidence rate of the common population is about 0.3 percent, the disease process is chronic, and the disease is prone to be suffered by young people.

Fingolimod (FTY720) has the chemical name of 2-amino-2- [2- (4-octylphenyl) ethyl]1, 3-propanediol hydrochloride, a compound discovered by Jifu pharmaceuticals, Inc., Japan, which is capable of prolonging the survival of animals in alloorgan transplant rejection tests in both rats and dogs, and exhibits significant immunosuppressive activity. Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and the like are main diseases which harm human health. The treatment of such diseases requires the reduction of the autoimmune response with immunosuppressive agents. But has long-term administration of immunosuppressionThe preparation has serious toxic and side effects, and can cause hypoimmunity of patients, and induce bacterial infection, cancer, heart disease, etc. At present, clinically, the types of selectable immunosuppressants are limited, and the toxicity of the drugs is high, so that the development of a novel immunosuppressant with high efficiency and low toxicity is an urgent requirement for drug research. Fingolimod (FTY720) is a prodrug, belongs to amino alcohol compounds, is a substrate of sphingosine kinase 2(SPHK2), and is phosphorylated by SPHK2 in vivo to generate active phosphate (S) -FTY720-P, S1P_{1，3，4，5}Full agonists of^[1，2]. (S) -FTY720-P can be activated by activating S1P₁The receptor induces the receptor to sink and plays a functional antagonistic role, and inhibits S1P₁Mediated lymphocyte migration, thereby facilitating T lymphocytes to stay in lymph nodes and triggering peripheral lymphocytes to have a homing effect so as to generate an immunosuppressive effect^[3，4]. In clinical research, the compound is found to activate S1P₃Receptors, which cause bradycardia side effects, greatly limit their use in treating immune diseases. By exploring for indications, FTY720 obtained FDA approved clinical for the treatment of multiple sclerosis 9 months 2010^[5，6]。

Researches in recent years show that fingolimod has potential application value in the field of diabetes treatment. Studies show that fingolimod can remarkably improve the regeneration capacity of islet cells of mice. One chinese patent application No. 201280037517.7 reports the potential utility of fingolimod in the treatment of diabetes.

How to find high selectivity S1PR₁The agonist becomes an immune disease treatment drug or a diabetes treatment drug with better curative effect, smaller toxic and side effect and wider application range, and becomes one of the hot spots of drug research.

We performed extensive analysis and summary of the structure of aminopropanediol by computer aided design software. The structure-activity relationship rule shows that the rigidity of a hydrophobic side chain is properly increased, and the pair S1P of the compound can be improved through conformation restriction₁Selectivity of the acceptor, thus introducing crown ether and bis (2-methoxyethoxy) structures into the hydrophobic side chain, simultaneously in crown ether and bisThe (2-methoxyethoxy) structure is connected with an aromatic heterocycle so as to improve the rigidity of a hydrophobic side chain; on the basis of keeping an aminopropanediol structure as a key pharmacophore, an ether group is introduced into a connecting chain to increase the interaction of hydrogen bonds between small molecules and a receptor, so that a compound with less toxic and side effects is obtained. The design concept of the target compound structure in the invention is shown as the following formula:

at present, the methods for synthesizing fingolimod hydrochloride reported at home and abroad include the following methods: US patent US5604229 (1997); US 5609226; US 2002/72635; chinese patent CN 1528738; chinese patent CN 201110026280; chinese patent CN 99102879; journal of Synthesis (Synthesis, 2000 (4): 505-; journal of organic chemistry (J.org.chem, 2000, 43 (15); 2946-2961); journal of Tetrahedron Letters (2011 (52): 5672-; journal of medical chemistry journal (J.Med.chem., 2000, 43 (15): 1211-1216); journal "synthetic communications" (Synlett, 2001 (9): 1411-; pharmaceutical science report 2014, 49 (6): 896-904; "Chinese herbal medicine" 2016, 47 (8): 1282-1288; china New drug journal 2006 (15): 802, a first step of; pharmaceutical and clinical studies 2011 (19): 182, 183, etc.

Disclosure of Invention

The invention aims to provide a series of fingolimod derivatives containing crown ether or bis (2-methoxyethoxy) structure.

In one aspect, the invention is directed to compounds having the following two general structural formulas and pharmaceutically acceptable salts thereof.

Characterized in that A is a 7 to 18 membered ring;

R₁、R₂、R₃the method comprises the following steps: hydrogen, halogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C_1-8Alkanoyl radical, C_1-8Alkoxycarbonyl, C_1-8Alkylsulfinyl radical, C_1-8Alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amino, carboxy, oxo, carbamoyl, C_1-8Alkoxy radical, C_2-8Alkenyloxy radical, C_2·8Alkynyloxy, C_1-8Alkylthio, N- (C)_1-8Alkyl) carbamoyl, N, N-di- (C)_1-8Alkyl), carbamoyl, C_1-8Alkanoyloxy radical, C_1-8Alkanoylamino group, C_2-8Alkynylamido, N- (C)_1-8Alkyl) sulfamoyl, N, N-di- (C)_1-8Alkyl) sulfamoyl;

m is an integer of 0 to 3;

x is N (R)₂NHCHR, O or S; wherein R is H or C_1-8An alkyl group; r is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl-C_1-3Alkyl, substituted or unsubstituted aryl-C_3-7A cycloalkyl group;

pharmaceutically acceptable salts of the above compounds; with the additional condition that: a is a 7-or 8-membered ring, then R₁Is not H, C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl radical, C_1-4Alkanoyl radical, C_1-4Alkoxy or-S (O) x (C)_1-4Alkyl), wherein X is 0-2, wherein said alkyl and said R₁Wherein the alkyl moiety is optionally substituted with 1 to 3 halogen atoms.

The invention provides a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.

The present invention provides a method of treating systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and the like, comprising administering to said patient a therapeutically effective amount of a compound of claim 1.

The invention uses computer aided design software to carry out deep analysis and summary on the structure of amino propanediol, and aims to realize the structural modificationSo as to obtain an immunosuppressant for treating multiple sclerosis or a fingolimod analogue with better anti-tumor effect. The structure-activity relationship rule shows that the rigidity and the hydrophilicity of a hydrophobic side chain are properly increased, and the pair S1P of the compound can be improved through conformation restriction₁Selectivity of acceptor crystal structure^[11]Fingolimod and S1P₁Binding mode of the receptor: the amino part of the ligand is used as a head and forms hydrogen bond with a part of amino acid residues of the receptor pocket to generate hydrogen bond action; the benzene ring part and alkyl side chain of the ligand produce weak hydrophobic bond effect with a part of amino acid residues of the receptor pocket. Therefore, by modifying the partial structure of the alkyl side chain, such as introducing crown ether and 2-methoxyethoxy, the hydrogen bond action between the drug and the receptor can be increased, so that the action strength and the selectivity of the compound on the receptor are improved. Secondly, on the basis of keeping the structure of the aminopropanediol as a key pharmacophore, the interaction between small molecules and receptors is hopefully increased to obtain a compound with stronger immunosuppressive activity and less toxic and side effects.

Takes o-diphenol as raw material, and carries out condensation ring closing, Friedel-crafts acylation reaction and S_N2 substitution reaction, carbonyl reduction, double Henry reaction, and finally catalytic hydrogenation to prepare the fingolimod analogue. The synthetic route for compound 1 is as follows:

the synthetic route for compound I is as follows:

Detailed Description

The present invention is directed to novel structural compounds represented by the following general formulae 1 and I.

The examples provided below are intended to better illustrate the invention. Unless otherwise indicated, all parts and percentages are by weight and temperatures are in degrees Celsius. The following abbreviations are used in the examples: DMF, N-dimethylformamide; DMSO, dimethyl sulfoxide; EtOAc, ethyl acetate; min., smallest; h, hours; SDS, sodium dodecyl sulfate, SDS-PAGE, sodium dodecyl sulfate-polyamide electrophoresis gel; rt, room temperature; TLC, thin layer chromatography.

All chemicals were purchased from commercial suppliers and used directly without further purification. Thin layer chromatography was performed using 250-nM silica gel plates. Thin layer chromatography was prepared using a silica gel GF254 plate from the ocean of Analte Qingdao. Flash column chromatography was performed using 40-63nM flash column silica gel, standard silica gel for column chromatography. NMR data were obtained using a QE-GE-Plus300 NMR spectrometer and Me₄Si as an internal standard (s represents a singlet, d represents a doublet, t represents a triplet, br represents a broad peak). Mass spectral data were made on a LCMS-2010(Shmadzu) mass spectrometer.

Example 1

Preparation of 1, 8-bis (p-toluenesulfonate) -3, 6-dioxaoctane (2)

Adding 16kg (400mol) of sodium hydroxide and 80L of water into a 400 reaction kettle for dissolving, then adding 18.8L (140mol) of triethylene glycol and 32L of tetrahydrofuran into the reaction kettle, cooling to below 5 ℃, dropwise adding 47.84kg (260mol) of solution of paratoluensulfonyl chloride and 50L of tetrahydrofuran, reacting for 2 hours at the temperature after dropwise adding, pouring into 240L of ice water, carrying out suction filtration, washing with a small amount of water, and drying to obtain 58.64kg of white crystalline powder with the yield of 91.4%. mp: 77-80 ℃, HPLC: 97 percent. TLC (1: 1 petroleum ether: ethyl acetate, 0.87 Rf).¹HNMR(CDCl₃): δ ppm: 7.78(d, 4H, J ═ 10.4Hz, phenyl ring by sulfonyl proton); 7.34(d, 4H, J ═ 11.6Hz, phenyl rings depend on methyl protons); 4.129(dd, 4H, J ═ 5.6Hz, near the sulfonyl glycol proton); 3.64(dd, 4H, J ═ 5.6Hz, away from sulfonyl glycol protons); 3.517(s, 4H, one intermediate ethylene glycol proton); 2.438(s, 6H, methyl proton on phenyl ring).

Example 2

Preparation of 3, 4-benzo-12-crown-4-benzene (3)

2.2kg (20mol) of catechol, 12.4kg (89.6mol) of potassium carbonate and 300L of DMF are mixed, stirred for about 30min, heated to 85-90 ℃, 8-di (p-toluenesulfonate) -3, 6-dioxyoctane is dropwise added to prepare 40L (9.17 kg (20mol) of DMF solution, the solution is dropwise added within 1.5-2 h, the solution is reacted for 30min, and the TLC check shows that the reaction is finished (a developing agent: petroleum ether: ethyl acetate is 1: 1, and Rf is 0.58). Sucking out about 40L of reaction liquid, repeating the operation for 3-5 times, performing suction filtration, evaporating DMF under reduced pressure, dissolving the residue with 240L of ethyl acetate, performing suction filtration, performing vacuum evaporation, and performing column chromatography on the residue with petroleum ether and ethyl acetate at a ratio of 1: 1. The solvent was recovered under reduced pressure and the solid was recrystallized from isopropanol 1: 2.5(W/V) to give 1.376kg of an off-white powder with a yield of 28%. mp: 73-76 ℃, HPLC: 96.4 percent.

UV(0.01mol/L HCl/CH₃OH)：λmax 215，257nm。

IR (KBr): ν 3620(C-OH), 2983(C-H), 1716(C ═ O), 1605, 1511(C ═ C), 1298, 1035(C-O), 1208, 1125 (ether C-O), 904, 762(C ═ C-H).

¹HNMR(CDCl₃): δ ppm: 6.66(dd, 2H, J ═ 2.4Hz, proton at the 3, 6 position of the phenyl ring); 6.71(dd, 2H, J ═ 2.8Hz, proton at 4, 5 positions of the phenyl ring); 3.78 to 4.23(dd, 12H, J ═ 4.8Hz, crown ether protons).

¹³CNMR(CDCl₃)：δppm：70.1，70.5，73.3，115.0，121.0，146.7。

MS(ESI)：m/z224.19。

Example 3

3. Preparation of 4-benzo-12-crown- α -chloroacetophenone (4)

3, 4-benzo-12-crown-4-benzene (18g, 80.3mmol) was dissolved in 200mL dry CH with ice cooling (0 deg.C)₂Cl₂In (1), chloroacetyl chloride (9.1g, 80.3mmol) was added, followed by slow addition of AlCl in portions₃(16.1g, 120.5mmol) of AlCl₃After all the solution is added, the temperature is naturally raised to the room temperature, and the stirring is continued for 2 hours. TLC (petroleum ether: ethyl acetate: 1: 0.52) detecting disappearance of raw material spot, pouring the reaction solution into ice-cold water hydrochloric acid for decomposition, separating organic layer, and using CH for water layer₂Cl₂Extracting for 3 times, mixing withWashing the organic layer with water to neutral, anhydrous Na₂SO₄Drying, filtering and concentrating to obtain crude light yellow solid 22.6 g. Suction filtration and ethanol recrystallization to obtain 19.2g of yellowish to yellow crystalline powder, yield 79%, mp: 92-95 ℃, HPLC: 98.2 percent. The product can also be directly used for the next reaction without separation and purification.

UV(0.01mol/LHCl/CH₃OH)：λmax 243，293nm。

IR (KBr): ν 2943(C-H), 1731(C ═ O), 1577, 1532(C ═ C,), 1207, 1122 (ether C-O), 902, 831(C ═ C-H).

¹HNMR(CDCl₃): δ ppm: 7.31(d, 1H, J ═ 2.6Hz, proton at the 6-position of the phenyl ring); 7.26(s, 1H, proton at the 2-position of the phenyl ring); 6.77(d, 1H, J ═ 2.6Hz, proton at the 5-position of the phenyl ring); 4.64(s, 2H, chloromethyl proton); 4.11-3.54(dd, 12H, J ═ 4.8Hz, crown ether protons).

¹³CNMR(CDCl₃)：δppm：46.4，70.1，70.5，73.3，114.9，121.0，129.3，146.6，151.1，191.2。

MS(ESI)：m/z302.6(M+1)。

Example 4

Preparation of 2-acetamido-2- [2- (3, 4-benzo-12-crown) -2-oxo-ethyl ] -1, 3-malonic acid diethyl ester (5)

Metallic sodium (1.8g, 78.2mmol) was added to 400mL of anhydrous ethanol until the metallic sodium was completely dissolved. A solution of diethyl acetylaminomalonate (DEAM) (17.7g, 81.5mmol) in ethanol and 0.6g (1.9mmol) of tetrabutylammonium bromide (TBAB) were added thereto under cooling in ice bath (0 ℃ C.), stirring was continued for 10min, a solution of 4(2.1g, 6.52mmol) in ether was added dropwise, the mixture was reacted for 1 hour in ice bath, and the reaction was continued for 4 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate, washed with water to neutrality, anhydrous Na₂SO₄Drying, filtering, concentrating, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate: 8: 1) to obtain light yellow solid. Recrystallization from ethyl acetate gave 1.29g, yield: 38.4%, mp: 198-201 ℃, HPLC: 99.1 percent. TLC (1: 1 petroleum ether: ethyl acetate, 0.33 Rf).

UV(0.01mol/L HCl/CH₃OH)：λmax 219，259nm。

IR (KBr): ν 3520, 3407(N-H), 3040(C ═ C-H), 2946(C-H), 2571(-NH), 1714(C ═ O), 1650 (amide I C ═ O), 1618 (amide II, N-H), 1513(C ═ C), 1351(C-N), 1301, 1073 (ester C-O), 1206, 1145 (ether C-O), 925, 831(C ═ C-H).

¹HNMR(d₆-DMSO): δ ppm: 8.0(br., 1H, amide proton); 7.34(d, 1H, J ═ 4.06Hz, proton at the 6-position of the phenyl ring); 7.29(s, 1H, proton at the 2-position of the phenyl ring); 6.74(d, 1H, J ═ 4.06Hz, proton at the 5-position of the phenyl ring); 4.25(q, 2H, J ═ 7.06Hz, methylene proton of ethyl); 4.05-3.54(dd, 12H, J ═ 4.04Hz, crown ether protons); 3.51(s, 2H, attached carbonyl methylene proton); 2.02(s, 3H, amidomethyl proton); 1.31(t, 6H, J ═ 7.06Hz, methyl proton of ethyl).

¹³CNMR(d₆-DMSO)：δppm：14.2，23.3，39.1，60.1，61.3，70.1，70.5，73.3，113.7，114.9，121.0，129.0，146.6，151.1，167.8，170.8，200.1。

MS(ESI)：m/z482.6(M+1)。

Example 5

Preparation of 2-acetamido-2- [2- (3, 4-benzo-12-crown) -ethyl ] -1, 3-malonic acid diethyl ester (6)

100mL of methylene chloride was sequentially added to a reaction flask, and 5(10.8g, 22.4mmol) and 9.9g (85.0mmol) of trimethylsilane were dissolved by stirring; the mixture was cooled to 0 ℃ in an ice bath, and a solution of 16.1g (85.0mmol) of titanium tetrachloride in 50mL of methylene chloride was added dropwise thereto, followed by stirring at room temperature for 9 hours. After TLC check, the reaction solution was poured into 100g of ice water, allowed to stand for layering, the aqueous layer was extracted with dichloromethane (2X 20mL), the organic phases were combined, washed with saturated sodium chloride (3X 100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from petroleum ether to give 8.0g of a white solid, yield: 76 percent. mp: and (3) carrying out HPLC (high performance liquid chromatography) at 78-81 ℃: 99.78 percent.

TLC (chloroform: methanol 8: 1, Rf 0.55)

UV(0.01mol/L HCl/CH₃OH)：λmax 220，247，313.5nm。

IR (KBr): ν 3311, 3164(N-H), 3036(C ═ C-H), 2918(C-H), 1696, 1660(C ═ O), 1615, 1499(C ═ C), 1476, 1448(N-H), 1292(C-N), 1124 (ether C-O), 909, 890(C ═ C-H).

¹HNMR(d₆-DMSO): δ ppm: 8.0(br., 1H, amide proton); 6.61(d, 1H, J ═ 4.06Hz, proton at the 5-position of the phenyl ring); 6.57(d, 1H, J ═ 4.06Hz, proton at the 6-position of the phenyl ring); 6.52(s, 1H, proton at 2-position of phenyl ring); 4.12(q, 2H, J ═ 7.06Hz, methylene proton of ethyl); 4.05-3.54(dd, 12H, J ═ 4.04Hz, crown ether protons); 2.58-2.55(t, 4H, J ═ 5.16Hz, methylene protons); 2.02(s, 3H, amidomethyl proton); 1.31(t, 6H, J ═ 7.06Hz, methyl proton of ethyl).

¹³CNMR(d₆-DMSO)：δppm：14.1，23.3，27.8，32.4，，61.2，61.3，70.1，70.5，73.3，112.9，115.1，120.4，130.9，144.0，146.8，167.8，170.8。

MS(ESI)：m/z484.6(M+1)。

Example 6

Preparation of 2-acetamido-2- [2- (3, 4-benzo-12-crown) -ethyl ] -1, 3-propanediol (7)

Sodium borohydride (8.5g, 0.22mol), 6(41.4g, 85.7mmol), anhydrous calcium chloride (25.0g, 0.22mol) and 520mL 77% ethanol were added sequentially to the reaction flask and stirred at room temperature for 9 h. After the completion of the reaction by TLC, 1mol/L hydrochloric acid (about 26ml) was added to adjust PH to 7, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from petroleum ether to obtain off-white 11.3g, yield 65%, mp: 128-131 ℃, HPLC: 99.58 percent. TLC (chloroform: methanol 8: 1, Rf 0.45).

UV(0.01mol/L HCl/CH₃OH)：λmax 215，245，328.5nm。

IR (KBr): ν 3630(O-H), 3311, 3164(N-H), 3036(C ═ C-H), 2918(C-H), 1696, 1660(C ═ O), 1615, 1499(C ═ C), 1476, 1448(N-H), 1292(C-N), 1124 (ether C-O), 1050(O-H), 909, 890(C ═ C-H).

¹HNMR(d₆-DMSO): δ ppm: 8.0(br., 1H, amide proton); 6.61(d, 1H, J ═ 4.06Hz, proton at the 5-position of the phenyl ring); 6.57(d, 1H, J ═ 4.06Hz, proton at the 6-position of the phenyl ring); 6.52(s, 1H, proton at 2-position of phenyl ring); 4.05-3.54(dd, 12H, J ═ 4.04Hz, crown ether protons); 3.71(s, 4H, hydroxymethyl protons); 2.58-1.88(t, 4H, J ═ 5.16Hz, methylene protons); 2.02(s, 3H, amidomethyl proton); 2.0(br., 2H, hydroxyl protons).

¹³CNMR(d₆-DMSO)：δppm：23.9，29.0，34.2，48.8，61.2，66.6，70.1，70.5，73.3，112.9，114.8，120.4，130.9，143.9，146.5，170.2。

MS(ESI)：m/z400.5(M+1)。

Example 7

Preparation of 2-amino-2- [2- (3, 4-benzo-12-crown) -ethyl ] -1, 3-propanediol hydrochloride (1)

Adding an aqueous solution (400ml) of lithium hydroxide hydrate (8.4g, 0.14mol) and a methanol solution (400ml) of 7(28.5g, 70.1mmol) into a reaction flask, heating and refluxing for 6h, then checking by TLC, after the reaction is finished, cooling to room temperature, precipitating a white solid, performing suction filtration, drying, dissolving in 500ml of absolute ethanol, introducing dry hydrogen chloride gas (or using a 30% ethanol solution of hydrogen chloride) at 25 ℃ to pH 1-2, concentrating under reduced pressure, and recrystallizing the residue with isopropanol to obtain a white solid 1(22.2g, yield 79%), mp: 146-148 ℃, HPLC: 99.78 percent. TLC (chloroform: methanol 8: 1, Rf 0.35). [ HPLC normalization method: chromatographic column diamonsil C₁₈Columns (4.6 mm. times.250 mm, 5 μm); mobile phase water (pH 3.0 with phosphoric acid) -methanol (1: 4): the detection wavelength is 220nm, the column temperature is 35 ℃, and the flow rate is 1.0ml/min]。

Elemental analysis: molecular formula C₁₇H₂₇NO₆Calculated HCl: c, 54.04; h, 7.47; n, 3.71; cl, 9.38; measured value: c, 54.08; h, 7.51; n, 3.68; cl, 9.40;

UV(0.01mol/L HCl/CH₃OH)：λmax 205，248，341nm。

IR(KBr)：ν3630(O-H)，3418(N-H)，3212(C＝C-H)，3119，3025(C＝C-H，N-C-H)，2913(C-H)，1637(C＝C，C-N)，1614，1566(C＝C，N-H)，1531，1512，1485，1448，1398(C＝C)，1361，1299(C-N)，1278，1167，1143，1113，1075，1050(O-H)，1045，1023(C-O-C)，8898，779(C＝C-H)，689，651(C＝C-H)。

¹HNMR(400MHz，d₆-DMSO)：δppm：¹HNMR(d₆-DMSO): δ ppm: 7.0(br., 3H, ammonia hydrochloride protons); 6.61(d, 1H, J ═ 4.06Hz, proton at the 5-position of the phenyl ring); 6.57(d, 1H, J ═ 4.06Hz, proton at the 6-position of the phenyl ring); 6.52(s, 1H, proton at 2-position of phenyl ring); 4.19(s, 4H, hydroxymethyl protons); 4.11-3.54(dd, 12H, J ═ 4.04Hz, crown ether protons); 2.55-2.28(t, 4H, J ═ 5.16Hz, methylene protons); 2.0(br., 2H, hydroxyl protons).

¹³CNMR(d₆-DMSO)：δppm：29.5，33.1，54.0，62.7，70.1，70.5，73.3，112.9，114.8，120.4，130.9，143.9，146.5。

MS(ESI)：m/z378.25(M+1)。

Example 8

Preparation of 3, 4-bis- (2-methoxyethoxy) -benzene (III)

Catechol (22.4g, 0.2mol), K₂CO₃(82.8g, 0.6mol), 2-chloroethyl methyl ether (45.4g, 0.48mol), potassium iodide (0.2g) and acetonitrile (200ml) were heated to reflux for 4h, the solvent was evaporated under reduced pressure, the residue was washed with water to neutrality, recrystallized from isopropanol, filtered, and the filter cake was dried under reduced pressure to give white powder II (32.9g, 94%), mp 50-51 deg.C (literature references)^[4]: the yield thereof was 93%, mp 50-51 ℃ C.

Example 9

3. Preparation of 4-bis- (2-methoxyethoxy) - α -chloroacetophenone (IV)

(III) (18.2g, 80.3mmol) was dissolved in 200mL dry CH with ice bath cooling (0 deg.C)₂Cl₂In (1), chloroacetyl chloride (9.1g, 80.3mmol) was added, followed by slow addition of AlCl in portions₃(16.1g, 120.5mmol) of AlCl₃After all the solution is added, the temperature is naturally raised to the room temperature, and the stirring is continued for 2 hours. TLC (petroleum ether: ethyl acetate: 1: 0.52) detecting disappearance of raw material spot, pouring the reaction solution into ice-cold water hydrochloric acid for decomposition, separating organic layer, and using CH for water layer₂Cl₂Extracting for 3 times, mixing organic layers, washing with water to neutral, and removing anhydrous Na₂SO₄Drying, filtering and concentrating to obtain 22.8g of crude off-white solid. Suction filtration and ethanol recrystallization to obtain 19.5g of off-white crystalline powder, yield 80%, mp: 90-93 deg.CHPLC: 98.2 percent. The product can also be directly used for the next reaction without separation and purification.

UV(0.01mol/LHCl/CH₃OH)：λmax 238，290nm。

¹HNMR(CDCl₃): δ ppm: 7.31(d, 1H, J ═ 2.6Hz, proton at the 6-position of the phenyl ring); 7.26(s, 1H, proton at the 2-position of the phenyl ring); 6.77(d, 1H, J ═ 2.6Hz, proton at the 5-position of the phenyl ring); 4.64(s, 2H, chloromethyl proton); 4.11-3.79(dd, 8H, J ═ 4.8Hz, methylene protons); 3.24(s, 6H, methyl proton).

¹³CNMR(CDCl₃)：δppm：46.4，59.3，，69.7，72.3，113.7，114.9，121.0，129.，0，146.6，151.1，191.2。

MS(ESI)：m/z303.2(M+1)。

Example 10

Preparation of diethyl 2-acetamido-2- [2- [3, 4-bis (2-methoxyethoxy) ] -2-oxo-ethyl ] -1, 3-malonate (V)

Metallic sodium (1.8g, 78.2mmol) was added to 400mL of anhydrous ethanol until the metallic sodium was completely dissolved. After cooling in ice bath (0 deg.C), a solution of diethyl acetylaminomalonate (DEAM) (17.7g, 81.5mmol) in ethanol and 0.6g (1.9mmol) of tetrabutylammonium bromide (TBAB) were added, followed by stirring for 10min, a solution of IV (2.2g, 7.2mmol) in ether was added dropwise, the mixture was reacted for 1h in ice bath, and the reaction was continued for 4h at room temperature. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate, washed with water to neutrality, anhydrous Na₂SO₄Drying, filtering, concentrating, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate: 8: 1) to obtain light yellow solid. Recrystallization from ethyl acetate gave 1.3g, yield: 38.5%, mp: 190-192 ℃, HPLC: 99.2 percent. TLC (1: 1 petroleum ether: ethyl acetate, 0.33 Rf).

UV(0.01mol/LHCl/CH₃OH)：λmax 214，256nm。

¹HNMR(d₆-DMSO): δ ppm: 8.0(br., 1H, amide proton); 7.34(d, 1H, J ═ 4.06Hz, proton at the 6-position of the phenyl ring); 7.29(s, 1H, proton at the 2-position of the phenyl ring); 6.74(d, 1H, J ═ 4.06Hz, proton at the 5-position of the phenyl ring); 4.12(q, 4H, J ═ 7.06Hz, methylene proton of ethyl); 4.11-3.79(dd, 8H, J ═ 4.04Hz, methylene proton of methoxyethyl); 3.24(s, 6H, methyl proton); 2.02(s, 3H, amidomethyl proton); 1.31(t, 6H, J ═ 7.06Hz, methyl proton of ethyl).

¹³CNMR(d₆-DMSO)：δppm：14.1，39.1，59.3，60.1，61.3，69.7，72.3，113.7，114.9，121.0，129.0，146.6，151.1，167.8，170.8，200.1。

MS(ESI)：m/z484.6(M+1)。

Example 11

Preparation of diethyl 2-acetamido-2- [2- [3, 4-bis (2-methoxyethoxy) ] -ethyl ] -1, 3-malonate (VI)

100mL of methylene chloride was sequentially added to a reaction flask, and V (10.9g, 22.4mmol) and 9.9g (85.0mmol) of trimethylsilane were dissolved by stirring; the mixture was cooled to 0 ℃ in an ice bath, and a solution of 16.1g (85.0mmol) of titanium tetrachloride in 50mL of methylene chloride was added dropwise thereto, followed by stirring at room temperature for 9 hours. After TLC check, the reaction solution was poured into 100g of ice water, allowed to stand for layering, the aqueous layer was extracted with dichloromethane (2X 20mL), the organic phases were combined, washed with saturated sodium chloride (3X 100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from petroleum ether to give 8.1g of a white solid, yield: 76 percent. mp: 80-83 ℃, HPLC: 99.38 percent. TLC (chloroform: methanol 8: 1, Rf 0.55)

UV(0.01mol/L HCl/CH₃OH)：λmax 222，249，312nm。

¹HNMR(d₆-DMSO): δ ppm: 8.0(br., 1H, amide proton); 6.61(d, 1H, J ═ 4.06Hz, proton at the 5-position of the phenyl ring); 6.57(d, 1H, J ═ 4.06Hz, proton at the 6-position of the phenyl ring); 6.52(s, 1H, proton at 2-position of phenyl ring); 4.12(q, 2H, J ═ 7.06Hz, methylene proton of ethyl); 4.11-3.79(dd, 8H, J ═ 4.04Hz, methylene proton of methoxyethyl); 3.24(s, 3H, methoxymethyl proton); 2.58-2.55(t, 4H, J ═ 5.16Hz, methylene protons); 2.02(s, 3H, amidomethyl proton); 1.30(t, 6H, J ═ 7.06Hz, methyl proton of ethyl).

¹³CNMR(d₆-DMSO)：δppm：14.1，27.8，32.4，59.3，61.2，61.3，69.7，72.3，112.9，115.1，120.4，130.9，144.0，146.8，167.8，170.8。

MS(ESI)：m/z470.4(M+1)。

Example 12

Preparation of 2-acetamido-2- [2- [3, 4-bis (2-methoxyethoxy) ] -ethyl ] -1, 3-propanediol (VII)

Sodium borohydride (8.5g, 0.22mol), VI (40.3g, 85.7mmol), anhydrous calcium chloride (25.0g, 0.22mol) and 520mL 77% ethanol were added sequentially to the reaction flask and stirred at room temperature for 9 h. After the completion of the reaction by TLC, 1mol/L hydrochloric acid (about 26ml) was added to adjust PH to 7, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from petroleum ether to obtain off-white 11.2g, yield 65%, mp: 135-137 ℃, HPLC: 99.58 percent. TLC (chloroform: methanol 8: 1, Rf 0.45).

UV(0.01mol/LHCl/CH₃OH)：λmax 213，241，326nm。

¹HNMR(d₆-DMSO): δ ppm: 8.0(br., 1H, amide proton); 6.61(d, 1H, J ═ 4.06Hz, proton at the 5-position of the phenyl ring); 6.57(d, 1H, J ═ 4.06Hz, proton at the 6-position of the phenyl ring); 6.52(s, 1H, proton at 2-position of phenyl ring); 4.11-3.79(dd, 12H, J ═ 4.04Hz, methylene proton of methoxyethyl); 3.71(s, 4H, hydroxymethyl proton); 3.24(s, 6H, methoxymethyl proton) 2.55-1.80(t, 4H, J ═ 5.16Hz, methylene proton); 2.02(s, 3H, amidomethyl proton); 2.0(br., 2H, hydroxyl protons).

¹³CNMR(d₆-DMSO)：δppm：23.9，29.0，34.2，59.3，66.6，69.7，72.3，112.9，114.8，120.4，130.9，143.9，146.5，170.2。

MS(ESI)：m/z386.41(M+1)。

Example 13

Preparation of 2-amino-2- [2- [3, 4-bis (2-methoxyethoxy) ] -ethyl ] -1, 3-propanediol hydrochloride (I)

Adding an aqueous solution (400ml) of lithium hydroxide hydrate (8.4g, 0.14mol) and a methanol solution (400ml) of VII (27.1g, 70.1mmol) into a reaction flask, heating and refluxing for 6h, then checking by TLC, after the reaction is finished, cooling to room temperature, precipitating a white solid, performing suction filtration, drying, dissolving in 500ml of absolute ethanol, introducing dry hydrogen chloride gas (or using a 30% ethanol solution of hydrogen chloride) at 25 ℃ to pH 1-2, concentrating under reduced pressure, and recrystallizing the residue with isopropanol to obtain a white solid I (21.6g, yield 79%), mp: 143-145 ℃, HPLC: 99.78 percent. TLC (chloroform: methanol 8: 1, Rf 0.35). [ HPLC normalization method: chromatographic column diamonsil C₁₈Columns (4.6 mm. times.250 mm, 5 μm); mobile phase water (pH 3.0 with phosphoric acid) -methanol (1: 4): the detection wavelength is 220nm, the column temperature is 35 ℃, and the flow rate is 1.0ml/min]。

Elemental analysis: molecular formula C₁₇H₂₉NO₆Calculated HCl: c, 53.75; h, 7.96; n, 3.69; cl, 9.33; measured value: c, 53.98; h, 7.81; n, 3.66; cl, 9.38;

UV(0.01mol/L HCl/CH₃OH)：λmax 203，245，338nm。

¹HNMR(400MHz，d₆-DMSO)：δppm：¹HNMR(d₆-DMSO): δ ppm: 7.0(br., 3H, ammonia hydrochloride protons); 6.61(d, 1H, J ═ 4.06Hz, proton at the 5-position of the phenyl ring); 6.57(d, 1H, J ═ 4.06Hz, proton at the 6-position of the phenyl ring); 6.52(s, 1H, proton at 2-position of phenyl ring); 4.19(s, 4H, hydroxymethyl protons); 4.11-3.79(dd, 8H, J ═ 4.04Hz, methylene proton of methoxyethyl); 3.24(s, 6H, methyl proton); 2.55-2.28(t, 4H, J ═ 5.16Hz, methylene protons); 2.0(br., 2H, hydroxyl protons).

¹³CNMR(d₆-DMSO)：δppm：29.5，33.1，54.0，59.3，62.7，69.7，72.3，112.9，114.8，120.4，130.9，143.9，146.5。

MS(ESI)：m/z380.18(M+1)。

Example 14

Biological characteristics: structure-activity relationship on immunosuppressive activity investigation

The target compounds 1a-1e, Ia-Ie were also subjected to an activity assay for reducing the number of lymphocytes in the peripheral circulation in vivo by steric hindrance in two batches, each of which was tested for a blank and a positive control, with the activity results shown in tables 1 and 2. The fingolimod derivatives containing crown ether and bis (2-methoxyethoxy) structures all show certain immunosuppressive activity, wherein the immunosuppressive activity of the compounds 1c, 1d and Ic-Ie is equivalent to that of a positive drug FTY 720. The structural characteristics of the compounds 1a-1e with crown ether connected with substituted benzene rings are analyzed, and the activity of ethyl as a substituent is better than that of methyl and hydrogen, and the activity of electron-donating group substitution is better than that of electron-withdrawing group. The structural characteristics of the compounds Ia to Ie of the bis (2-methoxyethoxy) structure are analyzed, and the activity when the hydrophobic chain ends are propyl groups is found to be superior to that of ethyl groups and methyl groups, and the activity of isopropyl groups is found to be superior to that of cyclopropyl groups and n-propyl groups. Taken together, the above analysis suggests that the length of hydrophobicity has an effect on activity, while the electrical and steric properties of the terminal substituents affect activity. The compound Ic-Ie with better immunosuppressive activity is selected to carry out an SD rat heart rate influence test, FTY720 is used as a positive control, and the activity results are shown in Table 3. The effect of the target compound on the rat heart rate is obviously reduced compared with FTY720, wherein the effect of the compound Ie on the rat heart rate is not obviously changed before and after the administration, and the compound has no side effect of bradycardia. The experimental results further verify that properly increasing the rigidity of the hydrophobic side chain is beneficial to increasing the compound pair S1P₁Receptor selectivity, a design basis for reducing bradycardia side effects.

Table 1 Effect of compounds 1a-1e on the lymph cells of peripheralblood of SD rats.

Δ％＝(the number of the lymph cells before administration-the lowestvalue or the number of the lymph cells after administration)/the number ofthe lymph cells before adminis-tration×100％

Table 2 Effect of compounds Ia-Ie on the lymph cells of peripheralblood of SD rats.

Δ％＝(the number of the lymph cells before administration-the lowestvalue or the number of the lymph cells after administration)/the number ofthe lymph cells before administration×100％

Example 15

Biological characteristics: blood sugar lowering effect

To determine the in vivo effects of 1e and Ib, pre-stage diabetic (six weeks of age, < 126mg/dL fasting blood glucose) and diabetic (8-9 weeks of age, < 430mg/dL fasting blood glucose) female db/db mice were fed daily for 29 weeks with 1e and Ib and tested by weekly fasting blood glucose. The results show that: fasting blood glucose levels remained normal (about 126mg/dL) in the 1e and Ib treated pre-diabetic db/db mice, became normal after six weeks 1e and Ib treatment in diabetic db/db mice (blood glucose ≧ 350mg/dL), while fasting blood glucose levels increased significantly in the untreated group by week eight and continued to increase over time to reach about 500mg/dL by week 12. In particular this well-controlled fasting blood glucose level continues to be maintained over time, although 1e and Ib use was completely discontinued after 29 weeks. Furthermore, body weight was significantly increased in the 1e and Ib treated groups compared to the untreated group.

The distribution of fasting plasma glucose further indicates: the fasting plasma glucose levels were normalized on average in db/db mice in all 1e and Ib treatment groups. Furthermore, blood insulin measurements indicated that: fasting serum insulin levels were significantly elevated in the 1e and Ib treatment groups. The data show that: 1e and Ib are effective in controlling blood glucose within the normal range by increasing insulin levels in db/db mice.

The glucose tolerance test shows that: there was a significant improvement in glucose tolerance in untreated mice versus db/db mice treated with 1e and Ib, while insulin sensitivity was not affected. Specifically, the initial fasting blood glucose level was 500mg/dL in the untreated group, but declined rapidly in the first hour after insulin administration; blood glucose levels in the treated and untreated groups were similar after 70 min. This is evidence of reversal of impaired glucose tolerance in db/db mice using 1e and Ib. The results show that: the use of 1e and Ib in db/db mice normalizes fasting glucose, resulting in the prevention and reversal of diabetes without affecting insulin sensitivity.

Claims

1. A series of compounds having the structure shown in formula 1 or formula I:

the above chemical formulas 1 and I, characterized in that:

a is a 7 to 18 membered ring;

R₁、R₂、R₃the method comprises the following steps: hydrogen, halogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C_1-8Alkanoyl radical, C_1-8Alkoxycarbonyl, C_1-8Alkylsulfinyl radical, C_1-8Alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amino, carboxy, oxo, carbamoyl, C_1-8Alkoxy radical, C_2-8Alkenyloxy radical, C_2-8Alkynyloxy, C_1-8Alkylthio, N- (C)_1-8Alkyl) carbamoyl, N, N-di- (C)_1-8Alkyl), carbamoyl, C_1-8Alkanoyloxy radical, C_1-8Alkanoylamino group, C_2-8Alkynylamido, N- (C)_1-8Alkyl) sulfamoyl, or N, N-di- (C)_1-8Alkyl) sulfamoyl;

m is an integer of 0 to 3;

x is N (R)₂NHCHR, O or S; wherein R is H or C_1-8An alkyl group;

r is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl-C_1-3Alkyl, substituted or unsubstituted aryl-C_3-7A cycloalkyl group;

with the additional condition that: a is a 7-or 8-membered ring, then R₁Is not H, C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl radical, C_1-4Alkanoyl radical, C_1-4Alkoxy or-S (O) x (C)_1-4Alkyl), wherein X is 0-2, wherein said alkyl and said R₁Wherein the alkyl moiety is optionally substituted with 1 to 3 halogen atoms.

2. A compound according to claim 1, characterized in that a further comprises 0-6 heteroatoms O, S and N.

3. Compounds according to claims 1, 2, characterized in that R₁Is hydrogen, halogen, C_1-8Alkyl radical, C_1-8Alkenyl radical, C_2-8Aryl, heteroaryl, heterocyclyl, (halo)_1-3(C_1-8) Alkyl, hydroxy (C)_1-8) Alkyl radical, C_1-4Alkoxy (C)_1-8) Alkyl, cyano (C)_1-8) Alkyl, amino (C)_1-8) Alkyl, aryl (C)_1-8) Alkyl, heteroaryl (C)_1-8) Alkyl, heterocyclyl (C)_1-8) An alkyl group; (halo)_1-3(C_2-8) Alkenyl, hydroxy (C)_2-8) Alkenyl radical, C_1-4Alkoxy (C)_2-8) Alkenyl, cyano (C)_2-8) Alkenyl, amino (C)_2-8) Alkenyl, aryl (C)_2-8) Alkenyl, heteroaryl (C)_2-8) Alkenyl, heterocyclyl (C)_2-8) Alkenyl, (halo)_1-3(C_2-8) Block based, hydroxy (C)_2-8) Alkynyl, C_1-4Alkoxy (C)_2·8) Alkynyl, cyano (C)_2-8) Alkynyl, amino (C)_2-8) Alkynyl, aryl (C)_2-8) Alkynyl, heteroaryl (C)_2-8) Alkynyl, heterocyclyl (C)_2-8) Alkynyl, C_1-8Alkanoyl, aryl (C)_1-8) Alkanoyl, heteroaryl (C)_1-8) Alkanoyl group, heterocyclic group (C)_1-8) Alkanoyl radical, (C)_1-8) Alkoxycarbonyl, aryl (C)_1-8) Alkoxycarbonyl, heteroaryl (C)_1-8) Alkoxycarbonyl, heterocyclyl (C)_1-8) Alkoxycarbonyl radical, C_1-8Alkylsulfinyl radical, C_1-8Alkanesulfonyl, arylsulfonyl, aryl (C)_1-8) Alkylsulfonyl, heteroaryl (C)_1-8) Alkanesulfonyl, heterocyclyl (C)_1-8) Alkylsulfonyl, aryl, heteroaryl, heterocyclyl, cyano, nitro, hydroxy, amino, carboxy, oxo, carbamoyl, C_1-8Alkoxy radical, C_2-8Alkenyloxy radical, C_2-8Alkynyloxy, C_1-8Alkylthio, N- (C)_1-8Alkyl) carbamoyl, N, N-di- (C)_1-8Alkyl) carbamoyl, C_1-8Alkanoyloxy radical, C_1-8Alkanoylamino group, C_3-8Alkynylamido, N (C)_1-8Alkyl) sulfamoyl and N, N-di- (C)_1-8Alkyl) sulfamoyl.

4. A compound according to claims 1, 2, 3, characterized in that R₁Amino group, amino group (C) as described in (1)_1-8) Alkyl, amino (C)_2-8) Alkenyl or amino (C)_2-8) The alkynyl group is freely substituted by two of the following groups; hydrogen, (C)_1-8) Alkyl radical, C_2-8Alkenyl radical, C_2-8An alkynyl group; and wherein R is₁Any aryl, heteroaryl or heterocyclyl group is optionally substituted with 1 to 3 substituents selected from: halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (C)_1-4) Alkyl radical (C)_2-4) Alkenyl, (C)_{2_4}) Alkynyl (C)_1-4) An alkoxy group.

5. A compound according to claims 1, 2, 3, 4, characterized in that R₁The method comprises the following steps: hydrogen, halogen, C_1-4Alkyl radical, C_1-4) Alkenyl radical, C_2-4Alkynyl, aryl, heteroaryl, heterocyclyl, (halo)_1-3(C_1-4) Alkyl, hydroxy (C)_1-4) Alkyl radical, C_1-4Alkoxy (C)_1-4) Alkyl, cyano (C)_1-4) Alkyl, amino (C)_1-4) Alkyl (in which the amino group is hydrogen or C)_1-4Alkyl-substituted), aryl (C)_1-4) Alkyl, heteroaryl (C)_1-4) Alkyl, heterocyclyl (C)_1-4) Alkyl, hydroxy, amino (by hydrogen or (C)_1-4Alkyl-substituted), carboxyl, C_1-4Alkoxy radical, C_1-4Alkylthio, and wherein R is₁Wherein any aryl, heteroaryl or heterocyclyl group optionally has 1 to 3 substituents selected from the group consisting of: halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (C)_1-4) Alkyl radical (C)_2-4) Alkenyl, (C)_2-4) Alkynyl (C)_1-4) An alkoxy group.

6. A compound according to claim 1, 2, 3, 4, 5, wherein said aryl or heteroaryl in R is each optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_1-8Alkynyl, cyano, nitro, hydroxy, amino, carboxyl, carbamoyl, C_1-8Alkoxy radical, C_2-8Alkenyloxy radical, C_2-8Alkynyloxy, C_1-8Alkylthio radical, C_1-8Alkylsulfinyl radical, C_1-8Alkanesulfonyl group, C_1-8Alkoxycarbonyl, N- (C)_1-8Alkyl) carbamoyl, N, N-di- (C)_1-8Alkyl) carbamoyl, (halo)_1-3(C_1-8) Alkyl group, (halo)_1-3(C_1-8) Alkoxy, hydroxy (C)_1-8) Alkyl radical, C_1-4Alkoxy (C)_1-8) Alkyl, cyano (C)_1-8) Alkyl, amino (C)_1-8) Alkyl, aryl (C)_1-8) Alkyl, heteroaryl (C)_1-8) Alkyl, heterocyclic (C)_1-8) Alkyl radical, C_2-8Alkanoyl radical, C_2-8Alkanoyloxy radical, C_2-8Alkanoylamino group, C_3-8Alkanoylamino group, C_3-8Alkynylamido, N- (C)_1-8Alkyl) sulfamoyl, N, N-di- (C)_1-8Alkyl) sulfamoyl, C_1-8Alkanesulfonamides, C_1-3An alkylene dioxy group; or selected from the group of formulae: -Y-R³Wherein Y may be selected from O, S, N (R)⁴)，SO，SO₂，CO，CON(R⁴)，N(R⁴)CO，SO₂N(R⁵)，N(R⁴)SO₂Wherein R is⁴Is hydrogen or (C)_1-4) Alkyl radical, R³Is halogen- (C)_1-8) Alkyl, hydroxy- (C)_1-8) Alkyl radical (C)_1-4) Alkoxy radical- (C_1-8) Alkyl, cyano- (C)_1-8) Alkyl, amino- (C)_1-8) Alkyl group, (C)_1-8) Alkylamino radical- (C)_1-8Alkyl or bis- [ (C)_1-8) Alkyl radical]Ammonia- (C)_1-8) Alkyl, aryl- (C)_1-8) Alkyl, heteroaryl- (C)_1-8) Alkyl, heterocyclyl or heterocyclyl- (C)_1-8) An alkyl group.

7. A compound according to claim 6, characterized in that amino or amino (C) in one substituent of R_1-8) The alkyl group is freely substituted by two of the following groups: hydrogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8An alkynyl group; and wherein any aryl, heteroaryl or heterocyclyl group on one substituent on R optionally has 1 to 3 of the following substituents: halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (C)_1-8) Alkyl group, (C)_2-8) Alkenyl, (C)_2-8) Alkynyl, C_1-8An alkoxy group.

8. The compound of claim 1, wherein said aryl or heteroaryl of R is optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cyano, nitro, hydroxy, amino (wherein amino is hydrogen or C)_1-4Alkyl-substituted), carboxyl, C_1-8Alkoxy radical, C_2-8Alkenyloxy radical, C_2-8Alkynyloxy, C_1-8Alkylthio, aryl (C)_1-8) Alkyl, heteroaryl (C)_1-8) Alkyl, heterocyclic (C)_1-8) Alkyl or C_1-3An alkylene dioxy group.

9. The compound of claim 1, wherein R is a saturated or unsaturated aryl, saturated or unsaturated heteroaryl.

10. The compound of claim 1, wherein R is substituted or unsubstituted phenyl.

11. A compound according to claim 1, wherein a is a 7 to 18 membered ring comprising 1-6O, S, N heteroatoms.

12. A compound according to claim 1, wherein a is a 9 to 15 membered ring comprising 2-5O, S, N heteroatoms.

13. A compound according to claim 1, characterized in that m is 0-2.

14. A compound according to claim 1, characterized in that X is N (R)₂R is H or C_1-4An alkyl group.

15. A compound according to claim 1, R₂、R₃The method comprises the following steps: hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C_1-8Alkanoyl radical, C_1-8Alkoxycarbonyl, C_1-8An alkylsulfinyl group.

16. The compound according to claim 1, characterized by comprising:

2-amino- (3-bromo-phenyl) - (7, 8, 10, 11-tetrahydro-6, 9, 12-trioxa-3, 4-cyclononano [ b ] phenethyl) -1, 3-propanediol (1 a);

2-amino- (3-bromophenyl) - (7, 8, 10, 11, 13, 14-hexaoxy-6, 9, 12, 15-tetraoxa-3, 4-cyclononano [ b ] phenylethyl) -1, 3-propanediol (1 b);

2-amino- (3-bromophenyl) - (2, 5, 8, 11, 14-pentaoxa-3, 4-cyclononano [ b ] phenylethyl) -1, 3-propanediol (1 c);

2-amino- (3-bromophenyl) - [9- (toluene-4-sulfinic acid) -8, 9, 10, 11-tetrahydro-7H-6, 12-dioxa-3, 4-cyclononano [ b ] phenethyl) -1, 3-propanediol (1 d);

2-amino- (3-bromophenyl) - (8, 9-benzo-7, 10-dihydro-6, 11-dioxa-3, 4-cycloocta [ b ] phenethyl) -1, 3-propanediol;

2-amino- (3-bromophenyl) - (8, 9-dihydro-7H-6, 10-dioxa-3, 4-cyclohepta [ b ] phenylethyl) -1, 3-propanediol;

2-amino- (3-chloro-4-fluorophenyl) - (7, 8, 10, 11, 13, 14-hexahydro-6, 9, 12, 15-tetraoxa-3, 4-cyclononano [ b ] phenethyl) -1, 3-propanediol;

2-amino- (3-chloro-4-fluorophenyl) - (2, 10-dioxo-6-thia-14, 16-diaza-tricyclo [9, 8, 0^13，18]Nineteen-1- (11), 12, 14, 16, 18-pentaeno [ b ]]Phenethyl) -1, 3-propanediol;

2-amino- (3-chlorophenyl) - (7, 8, 10, 11, 13, 14 hexahydro-6, 9, 12, 15-tetraoxa-3, 4-cyclononano [ b ] phenethyl) -1, 3-propanediol;

2-amino- (3-chlorophenyl) - (7, 8, 10, 11, 13, 14-hexahydro-6, 9, 12, 15-tetraoxa-3, 4-cyclodecano [ b ] phenethyl) -1, 3-propanediol;

2-amino- (3-ethynylbromophenyl) - (7, 8, 10, 11, 13, 14-hexahydro-6, 9, 12, 15-tetraoxa-3, 4-cyclodecno [ b ] phenylethyl) -1, 3-propanediol;

2-amino-2- [2- (3, 4-benzo-12-crown) -ethyl ] -1, 3-propanediol (1 e);

2-amino-2- [2- [3, 4-bis (2-hydroxyethoxy) ] -ethyl ] -1, 3-propanediol (Ia);

2-amino-2- [2- [3, 4-bis (2-methoxyethoxy) ] -ethyl ] -1, 3-propanediol (Ib);

2-amino-2- [2- [3, 4-bis (2-ethoxyethoxy) ] -ethyl ] -1, 3-propanediol (Ic);

2-amino-2- [2- [3, 4-bis (2-cyclopropylethoxy) ] -ethyl ] -1, 3-propanediol (Id)

2-amino-2- [2- [3, 4-bis (2-isopropylethoxy) ] -ethyl ] -1, 3-propanediol (Ie).

17. The compound of claim 1, wherein said pharmaceutically acceptable salt is an acidic/anionic salt or a basic/cationic salt.

18. A pharmaceutical formulation characterized by comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

19. The pharmaceutical formulation of claim 17, wherein the pharmaceutically acceptable carrier is: water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, alcohols, petrolatum, or mixtures thereof.

20. Use of compounds and formulations according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 for the preparation of a medicament for the treatment of diabetes.