CN111233820B - Fingolimod derivative containing crown ether and di (2-methoxyethoxy) structure - Google Patents
Fingolimod derivative containing crown ether and di (2-methoxyethoxy) structure Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
- C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
- C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
Abstract
The invention designs and synthesizes a series of fingolimod derivatives containing crown ether or di (2-methoxyethoxy) structures by modifying the structure of fingolimod which is an immunosuppressant 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
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, which damages the spinal sheath that insulates the nerves, resulting in erroneous nerve conduction in the nerve bundles of the brain and spinal cord.
After more than 10 years of research in 2011 in month 4, the U.S. food and drug administration 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 which is probably caused by the interaction of genetically susceptible individuals and environmental factors is one of the most important nervous system diseases because the incidence rate of the neuroimmune process is high, the incidence rate of the general population is about 0.3 percent, the neuroimmune process has a chronic course and is prone to be suffered by young people.
Fingolimod (FTY 720) 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. However, long-term administration of immunosuppressants can cause low immunity of patients, bacterial infection, cancer, heart disease, etc. in addition to serious toxic and side effects. 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 (FTY 720) is a prodrug, belongs to amino alcohol compounds, is a substrate of sphingosine kinase 2 (SPHK 2), 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 S1P 1 The receptor induces receptor invagination to exert functional antagonism and inhibit S1P 1 Mediated lymphocyte migration, thereby facilitating T lymphocyte stay in lymph node and triggering peripheral lymphocyteThe homing effect is generated to generate the immunosuppression effect [3，4] . In clinical research, the compound can stimulate S1P 3 Receptors, which cause bradycardia side effects, greatly limit their use in treating immune diseases. Through exploration for indications, FTY720 received FDA approval in 9 months 2010 for clinical use in treating multiple sclerosis [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 application value of fingolimod in the treatment of diabetes.
How to find the highly selective S1PR 1 The 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 used computer aided design software to carry out deep analysis and summarization on the structure of aminopropanediol. The prior structure-activity relationship law shows that the rigidity of a hydrophobic side chain is properly increased, and the S1P pair of the compound can be improved through conformational restriction 1 The selectivity of an acceptor is realized, so that crown ether and a bis (2-methoxyethoxy) structure are introduced into a hydrophobic side chain, and meanwhile, an aromatic heterocyclic ring is connected to the crown ether and the bis (2-methoxyethoxy) structure to improve the rigidity of the 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); US5609226; US2002/72635; chinese patent CN1528738; chinese patent CN201110026280; chinese patent CN99102879; journal of Synthesis (Synthesis, 2000 (4): 505-506 and 2006, (5): 753-755); journal of organic chemistry (J. Org. Chem,2000, 43 (15); 2946-2961); journal of Tetrahedron Letters (2011 (52): 5672-5675); journal of medical chemistry journal (j.med. Chem.,2000, 43 (15): 1211-1216); journal of synthetic communications (Synlett, 2001 (9): 1411-1414); 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, and the like.
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 as well as pharmaceutically acceptable salts thereof.
Wherein A is a 7 to 18 membered ring;
R 1 、R 2 、R 3 the method comprises the following steps: hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C 1-8 Alkanoyl radical, C 1-8 Alkoxycarbonyl group, C 1-8 Alkylsulfinyl radical, C 1-8 Alkylsulfonyl, arylsulfonyl, cyano, nitro, hydroxy, amino, carboxy, oxo, carbamoyl, C 1-8 Alkoxy radical, C 2-8 Alkenyloxy radical, C 2·8 Alkynyloxy, C 1-8 Alkylthio, N- (C) 1-8 Alkyl) carbamoyl, N, N-di- (C) 1-8 Alkyl), carbamoyl, C 1-8 Alkanoyloxy radical, C 1-8 Alkanoylamino group, C 2-8 Alkynylamido, N- (C) 1-8 Alkyl) sulfamoyl, N, N-di- (C) 1-8 Alkyl) ammoniaA sulfonyl group;
m is an integer of 0 to 3;
x is N (R) 2 NHCHR, O or S; wherein R is H or C 1-8 An alkyl group; r is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl-C 1-3 Alkyl, substituted or unsubstituted aryl-C 3-7 A cycloalkyl group;
pharmaceutically acceptable salts of the above compounds; with the additional condition that: a is a 7-or 8-membered ring, then R 1 Is not H, C 1-4 Alkyl radical, C 1-4 alkoxy-C 1-4 Alkyl radical, C 1-4 Alkanoyl radical, C 1-4 Alkoxy or-S (O) x (C) 1-4 Alkyl) where X is 0-2, wherein said alkyl and said R 1 Wherein 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, aiming at obtaining an immunosuppressant for treating multiple sclerosis or a fingolimod analogue with better anti-tumor effect by a structure modification method. The structure-activity relationship rule shows that the rigidity and the hydrophilicity of a hydrophobic side chain are properly increased, and the S1P pair of the compound can be improved through conformational restriction 1 Selectivity of acceptor crystal structure [11] Fingolimod and S1P 1 Binding 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 between the drug and the receptor can be increased, thereby improving the reactionThe strength and selectivity of action of the compounds on receptors. On the basis of keeping the structure of the aminopropanediol as a key pharmacophore, the interaction between small molecules and receptors is hoped to be 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 N 2 substitution reaction, carbonyl reduction, double Henry reaction, and finally obtaining the fingolimod analogue through catalytic hydrogenation. 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 compounds of the structures represented by the following general formulae 1 and I.
The examples provided below illustrate the invention better. 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, dimethylsulfoxide; 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 Analte Qingdao ocean. The flash column chromatography is performed with 40-63nM flash column silica gel, column chromatography using standard silica gel. The NMR data were obtained with a QE-GE-Plus300 NMR spectrometer and Me 4 Si 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 done on a LCMS-2010 (Shmadzu) mass spectrometer.
Example 1
Preparation of 1, 8-bis (p-toluenesulfonate) -3, 6-dioxaoctane (2)
Adding 16kg (400 mol) of sodium hydroxide and 80L of water into a 400 reaction kettle for dissolving, then adding 18.8L (140 mol) of triethylene glycol and 32L of tetrahydrofuran into the reaction kettle, cooling to below 5 ℃, dropwise adding 47.84kg (260 mol) 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 (petroleum ether: ethyl acetate = 1: 1, rf = 0.87). 1 HNMR(CDCl 3 ): δ ppm:7.78 (d, 4h, j =10.4hz, phenyl ring by sulfonyl proton); 7.34 (d, 4h, j =11.6hz, benzene ring by methyl proton); 4.129 (dd, 4h, j =5.6hz, close to the sulfonyl glycol proton); 3.64 (dd, 4h, j =5.6hz, away from the sulfonyl glycol proton); 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 (20 mol) of catechol, 12.4kg (89.6 mol) of potassium carbonate and 300L of DMF are mixed, stirred for about 30min, heated to 85-90 ℃, 8-bis (p-toluenesulfonate) -3, 6-dioxyoctane is added dropwise to prepare (2) 9.17kg (20 mol) of DMF solution 40L, the dropwise addition is completed within 1.5-2 h, the reaction is completed within 30min after the dropwise addition, and the TLC check reaction is completed (a developing agent: petroleum ether: ethyl acetate = 1: 1, rf = 0.58). About 40L of reaction solution is sucked out, the operations are repeated for 3-5 times, suction filtration is carried out, DMF is evaporated under reduced pressure, 240L of ethyl acetate is used for dissolving residues, suction filtration and reduced pressure evaporation are carried out, and the residues are subjected to column chromatography by using petroleum ether to ethyl acetate = 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/CH 3 OH)：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).
1 HNMR(CDCl 3 ): δ ppm:6.66 (dd, 2h, j =2.4hz, proton at 3,6 position of benzene ring); 6.71 (dd, 2h, j =2.8hz, proton at 4,5-position of benzene ring); 3.78-4.23 (dd, 12H, J =4.8Hz, crown ether proton).
13 CNMR(CDCl 3 )：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-alpha-chloroacetophenone (4)
3, 4-benzo-12-crown-4-benzene (18g, 80.3mmol) was dissolved in 200mL of dry CH under ice-cooling (0 ℃ C.) 2 Cl 2 To this, chloroacetyl chloride (9.1g, 80.3mmol) was added, followed by gradual addition of AlCl in portions 3 (16.1g, 120.5mmol) until AlCl is formed 3 After 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: 1, rf = 0.52) detecting disappearance of the material spot, pouring the reaction solution into ice-cold water hydrochloric acid to decompose, separating an organic layer, and using CH for an aqueous layer 2 Cl 2 Extracting for 3 times, mixing organic layers, washing with water to neutral, and removing anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain crude light yellow solid 22.6g. 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/CH 3 OH)：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).
1 HNMR(CDCl 3 )：δppm：7.31(d，1H，J =2.6Hz, proton 6 of the phenyl ring); 7.26 (s, 1H, proton at phenyl ring 2); 6.77 (d, 1h, j =2.6hz, proton at 5-position of benzene ring); 4.64 (s, 2H, chloromethyl protons); 4.11-3.54 (dd, 12h, j =4.8hz, crown ether proton).
13 CNMR(CDCl 3 )：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. After cooling in ice bath (0 ℃), an ethanol solution of diethyl acetylaminomalonate (DEAM) (17.7g, 81.5 mmol) and 0.6g (1.9 mmol) of tetrabutylammonium bromide (TBAB) were added thereto and stirred for 10min, and a solution of 4 (2.1g, 6.52mmol) in ether was added dropwise and reacted for 1h in ice bath and 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 Na 2 SO 4 Drying, filtering, concentrating, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a light yellow solid. Recrystallization from ethyl acetate gave 1.29g, yield: 38.4%, mp: 198-201 ℃, HPLC:99.1 percent. TLC (petroleum ether: ethyl acetate = 1: 1, rf = 0.33).
UV(0.01mol/L HCl/CH 3 OH)：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).
1 HNMR(d 6 -DMSO): δ ppm:8.0 (br., 1H, amide protons); 7.34 (d, 1h, j =4.06hz, proton at 6-position of benzene ring); 7.29 (s, 1H, proton at the 2-position of the phenyl ring); 6.74 (d, 1h, j =4.06hz, 5-position proton of benzene ring); 4.25 (q, 2h, j =7.06hz, methylene proton of ethyl); 4.05-3.54 (dd, 12h, j =4.04hz, crown ether proton); 3.51 (s, 2H, connecting carbonyl groups)Methylene protons); 2.02 (s, 3H, amidomethyl proton); 1.31 (t, 6H, J =7.06Hz, methyl proton of ethyl).
13 CNMR(d 6 -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 (85.0 mmol) of trimethylsilane were dissolved by stirring; after cooling to 0 ℃ in an ice bath, a solution of 16.1g (85.0 mmol) of titanium tetrachloride in 50mL of methylene chloride was added dropwise and stirring was continued at room temperature for 9h. 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 20 mL), the organic phases were combined, washed with saturated sodium chloride (3X 100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from petroleum ether to give 8.0g of a white solid, yield: and 76 percent. mp: 78-81 ℃, HPLC:99.78 percent.
TLC (chloroform: methanol = 8: 1, rf = 0.55)
UV(0.01mol/L HCl/CH 3 OH)：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).
1 HNMR(d 6 -DMSO): δ ppm:8.0 (br., 1H, amide proton); 6.61 (d, 1h, j =4.06hz, proton at 5-position of benzene ring); 6.57 (d, 1h, j =4.06hz, proton at 6-position of benzene ring); 6.52 (s, 1H, proton at phenyl ring 2); 4.12 (q, 2h, j =7.06hz, methylene proton of ethyl); 4.05-3.54 (dd, 12h, j =4.04hz, crown ether proton); 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).
13 CNMR(d 6 -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 of 77% ethanol were added in this order to a reaction flask and stirred at room temperature for 9 hours. TLC check, after the reaction was completed, PH =7 was adjusted with 1mol/L hydrochloric acid (about 26 ml), 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/CH 3 OH)：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).
1 HNMR(d 6 -DMSO): δ ppm:8.0 (br., 1H, amide protons); 6.61 (d, 1h, j =4.06hz, proton at 5-position of benzene ring); 6.57 (d, 1h, j =4.06hz, 6-position proton of benzene ring); 6.52 (s, 1H, proton at the 2-position of the phenyl ring); 4.05-3.54 (dd, 12h, j =4.04hz, crown ether proton); 3.71 (s, 4H, hydroxymethyl proton); 2.58-1.88 (t, 4h, j =5.16hz, methylene protons); 2.02 (s, 3H, amidomethyl proton); 2.0 (br., 2H, hydroxyl proton).
13 CNMR(d 6 -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)
An aqueous solution (400 ml) of lithium hydroxide hydrate (8.4g, 0.14mol) and a methanol solution (400 ml) of 7 (28.5g, 70.1mmol) were added to a reaction flask, and after heating and refluxing for 6 hours, TLC inspection was carried out, after completion of the reaction, cooling to room temperature, a white solid was precipitated, suction-filtered, dried and dissolved in 500ml of anhydrous ethanol, dried hydrogen chloride gas (or 30% ethanol solution of hydrogen chloride) was introduced at 25 ℃ to pH =1-2, concentrated under reduced pressure, and the residue was recrystallized from isopropanol to give 1 (22.2 g, yield 79%), mp: 146-148 ℃, HPLC:99.78 percent. TLC (chloroform: methanol = 8: 1, rf = 0.35). [ HPLC normalization method: chromatographic column DiamonsilC 18 Columns (4.6 mm. Times.250mm, 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 C 17 H 27 NO 6 Calculated 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/CH 3 OH)：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)。
1 HNMR(400MHz，d 6 -DMSO)：δppm： 1 HNMR(d 6 -DMSO): δ ppm:7.0 (br., 3H, ammonium hydrochloride protons); 6.61 (d, 1h, j =4.06hz, 5-position proton of benzene ring); 6.57 (d, 1h, j =4.06hz, proton at 6-position of benzene ring); 6.52 (s, 1H, proton at the 2-position of the phenyl ring); 4.19 (s, 4H, hydroxymethyl proton); 4.11-3.54 (dd, 12h, j =4.04hz, crown ether proton); 2.55-2.28 (t, 4h, j =5.16hz, methylene protons); 2.0 (br., 2H, hydroxyl proton).
13 CNMR(d 6 -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), K 2 CO 3 (82.8g, 0.6 mol), 2-chloroethyl methyl ether (45.4g, 0.48mol), potassium iodide (0.2 g) and acetonitrile (200 ml) were heated to reflux reaction for 4h, the solvent was distilled off 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 ℃ (literature references) [4] : the yield is 93 percent, and mp 50-51 ℃ is adopted.
Example 9
3. Preparation of 4-bis- (2-methoxyethoxy) - α -chloroacetophenone (IV)
(III) (18.2 g,80.3 mmol) was dissolved in 200mL dry CH with ice cooling (0 ℃ C.) 2 Cl 2 To this, chloroacetyl chloride (9.1g, 80.3mmol) was added, followed by gradual addition of AlCl in portions 3 (16.1g, 120.5mmol) until AlCl is obtained 3 After 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: 1, rf = 0.52) detecting disappearance of the material spot, pouring the reaction solution into ice-cold water hydrochloric acid to decompose, separating an organic layer, and using CH for an aqueous layer 2 Cl 2 Extracting for 3 times, mixing organic layers, washing with water to neutral, and removing anhydrous Na 2 SO 4 Drying, 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 ℃, HPLC:98.2 percent. The product can also be directly used for the next reaction without separation and purification.
UV(0.01mol/LHCl/CH 3 OH)：λmax 238，290nm。
1 HNMR(CDCl 3 ): δ ppm:7.31 (d, 1h, j =2.6hz, 6-position proton of benzene ring); 7.26 (s, 1H, proton at the 2-position of the phenyl ring); 6.77 (d, 1h, j =2.6hz, proton at 5-position of benzene ring); 4.64 (s, 2H, chloromethyl protons); 4.11-3.79 (dd, 8h, j =4.8hz, methylene proton); 3.24 (s, 6H, methyl proton).
13 CNMR(CDCl 3 )：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 2-acetamido-2- [2- [3, 4-bis (2-methoxyethoxy) ] -2-oxo-ethyl ] -1, 3-malonic acid diethyl ester (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 (1.9 mmol) of tetrabutylammonium bromide (TBAB) were added, followed by stirring for 10min, a solution of IV (2.2g, 7.2mmol) in diethyl 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, and then with anhydrous Na 2 SO 4 Drying, filtering, concentrating, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a light yellow solid. Recrystallization from ethyl acetate gave 1.3g, yield: 38.5%, mp: 190-192 ℃, HPLC:99.2 percent. TLC (petroleum ether: ethyl acetate = 1: 1, rf = 0.33).
UV(0.01mol/LHCl/CH 3 OH)：λmax 214，256nm。
1 HNMR(d 6 -DMSO): δ ppm:8.0 (br., 1H, amide proton); 7.34 (d, 1h, j =4.06hz, proton at 6-position of benzene ring); 7.29 (s, 1H, proton at the 2-position of the phenyl ring); 6.74 (d, 1h, j =4.06hz, proton at 5-position of benzene 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).
13 CNMR(d 6 -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 2-acetamido-2- [2- [3, 4-bis (2-methoxyethoxy) ] -ethyl ] -1, 3-malonic acid diethyl ester (VI)
100mL of methylene chloride was sequentially added to a reaction flask, and V (10.9g, 22.4mmol) and 9.9g (85.0 mmol) of trimethylsilane were dissolved by stirring; the mixture was cooled to 0 ℃ in an ice bath, and a solution of 16.1g (85.0 mmol) 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 20 mL), the organic phases were combined, washed with saturated sodium chloride (3X 100 mL), 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/CH 3 OH)：λmax 222，249，312nm。
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).
1 HNMR(d 6 -DMSO): δ ppm:8.0 (br., 1H, amide proton); 6.61 (d, 1h, j =4.06hz, 5-position proton of benzene ring); 6.57 (d, 1h, j =4.06hz, proton at 6-position of benzene ring); 6.52 (s, 1H, proton at the 2-position of the 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).
13 CNMR(d 6 -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 of 77% ethanol were sequentially added to a reaction flask, and the mixture was stirred at room temperature for 9 hours. After the reaction was completed by TLC, 1mol/L hydrochloric acid (about 26 ml) was used to adjust PH =7, and 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/CH 3 OH)：λmax 213，241，326nm。
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).
1 HNMR(d 6 -DMSO): δ ppm:8.0 (br., 1H, amide protons); 6.61 (d, 1h, j =4.06hz, 5-position proton of benzene ring); 6.57 (d, 1h, j =4.06hz, proton at 6-position of benzene ring); 6.52 (s, 1H, proton at the 2-position of the 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 protons) 2.55-1.80 (t, 4H, j =5.16hz, methylene protons); 2.02 (s, 3H, amidomethyl proton); 2.0 (br., 2H, hydroxyl proton).
13 CNMR(d 6 -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 aqueous solution (400 ml) of lithium hydroxide hydrate (8.4g, 0.14mol) and methanol solution (400 ml) 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 white solid, filtering, drying, dissolving in 500ml absolute ethyl alcohol, introducing dry hydrogen chloride gas (or using 30% ethanol solution of hydrogen chloride) at 25 ℃ to pH =1-2, concentrating under reduced pressure, and remainingThe material was recrystallized from isopropanol to give I as a white solid (21.6 g, 79% yield), mp: 143-145 ℃, HPLC:99.78 percent. TLC (chloroform: methanol = 8: 1, rf = 0.35). [ HPLC normalization method: chromatographic column diamonsil C 18 Columns (4.6 mm. Times.250mm, 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 C 17 H 29 NO 6 Calculated 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/CH 3 OH)：λmax 203，245，338nm。
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)。
1 HNMR(400MHz，d 6 -DMSO)：δppm： 1 HNMR(d 6 -DMSO): δ ppm:7.0 (br., 3H, ammonium hydrochloride protons); 6.61 (d, 1h, j =4.06hz, proton at 5-position of benzene ring); 6.57 (d, 1h, j =4.06hz, 6-position proton of benzene ring); 6.52 (s, 1H, proton at phenyl ring 2); 4.19 (s, 4H, hydroxymethyl proton); 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 proton).
13 CNMR(d 6 -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 for investigating immunosuppressive activity
Steric hindrance of the target compounds 1a-1e and Ia-Ie in two batches also reduces the peripheral circulation system in vivoLymphocyte number activity assay blank and positive control were tested for each batch and the activity results are 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 the substituted benzene ring are analyzed, and the fact that the activity of the substituent group of ethyl is better than that of methyl and hydrogen and the activity of electron-donating group substitution is better than that of electron-withdrawing group is found. The structural characteristics of the compounds Ia to Ie with the bis (2-methoxyethoxy) structure are analyzed, and the activity of propyl at the end of a hydrophobic chain is better than that of ethyl and methyl, and the activity of isopropyl is better than that of cyclopropyl and n-propyl. 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 result further verifies that the proper improvement of the rigidity of the hydrophobic side chain is beneficial to the improvement of S1P pair of the compound 1 Receptor selectivity, a design basis for reducing bradycardia side effects.
Table 1 Effect of compounds 1a-1e on the lymph cells of peripheral blood of SD rats.
Δ％＝(the number of the lymph cells before administration-the lowest value or the number of the lymph cells after administration)/the number of the lymph cells before adminis-tration×100％
Table 2 Effect of compounds Ia-Ie on the lymph cells of peripheral blood of SD rats.
Δ％＝(the number of the lymph cells before administration-the lowest value or the number of the lymph cells after administration)/the number of the lymph cells before administration×100％
Example 15
Biological characteristics: blood sugar lowering effect
To determine the in vivo effects of 1e and Ib, female db/db mice with advanced diabetes (six weeks of age, < 126mg/dL fasting plasma glucose) and diabetes (8-9 weeks of age, =430 mg/dL) were fed daily for 29 weeks with 1e and Ib, and tested by weekly fasting plasma glucose. The results show that: fasting blood glucose levels remained normal (about 126 mg/dL) in 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 ≧ 350 mg/dL), while fasting blood glucose levels increased significantly in the untreated group by the eighth week 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 can effectively control blood glucose within the normal range by increasing insulin levels in db/db mice.
The glucose tolerance test shows that: there was a marked 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 (4)
1. A compound having the structure shown by the following structural formula:
2. a pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
3. The pharmaceutical formulation of claim 2, wherein the pharmaceutically acceptable carrier is: water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, alcohols, petrolatum, or mixtures thereof.
4. Use of a compound according to claim 1 or a pharmaceutical formulation according to claim 2 or 3 in the manufacture of a medicament for the treatment of diabetes.
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| WO1993015041A1 (en) * | 1992-02-03 | 1993-08-05 | Fujisawa Pharmaceutical Co., Ltd. | Ethanolamine derivatives having sympathomimetic and anti-pollakiuria activities |
| CN101010276A (en) * | 2004-07-26 | 2007-08-01 | 中外制药株式会社 | Novel cyclohexane derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes |
| CN104292115A (en) * | 2013-07-19 | 2015-01-21 | 烟台大学 | New synthetic method of fingolimod hydrochloride |
| CN105384745A (en) * | 2015-07-27 | 2016-03-09 | 北京师范大学 | Crown ether cyclic quinazoline compound, preparation method therefor and application thereof in preparing tumor therapy and imaging drug |
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| WO1993015041A1 (en) * | 1992-02-03 | 1993-08-05 | Fujisawa Pharmaceutical Co., Ltd. | Ethanolamine derivatives having sympathomimetic and anti-pollakiuria activities |
| CN101010276A (en) * | 2004-07-26 | 2007-08-01 | 中外制药株式会社 | Novel cyclohexane derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes |
| CN104292115A (en) * | 2013-07-19 | 2015-01-21 | 烟台大学 | New synthetic method of fingolimod hydrochloride |
| CN105384745A (en) * | 2015-07-27 | 2016-03-09 | 北京师范大学 | Crown ether cyclic quinazoline compound, preparation method therefor and application thereof in preparing tumor therapy and imaging drug |
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