CN110330452A - Nafoxidine alkanes compound or its pharmaceutically acceptable salt and its preparation method and application - Google Patents
Nafoxidine alkanes compound or its pharmaceutically acceptable salt and its preparation method and application Download PDFInfo
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses nafoxidine alkanes compounds, preparation method and the usage, specifically disclose a kind of nafoxidine alkanes compound (I), pharmacological testing proves, nafoxidine alkanes compound of the invention has stronger inhibitory activity to sphingosine kinase 1 (SphK1), and part of compounds has certain inhibiting effect to tumour.Such compound and its pharmaceutical formulation can be used for preparing a series of drug for treating cancers, diseases associated with inflammation, such as colon cancer, lung cancer, breast cancer, liver cancer, gastric cancer, adenocarcinoma of lung, melanoma, the cancer of the esophagus；The diseases associated with inflammation includes inflammatory bowel disease, hepatitis, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis or multiple sclerosis.Formula (I)
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of nafoxidine alkanes compound, preparation method simultaneously wrap
Containing its pharmaceutical preparation and its medical usage.
Background technique
Sphingomyelins is one of ingredient of cell membrane, metabolite ceramide (ceramide, Cer), sphingol
(sphingosine, Sp) and sphingosine-1-phosphate (sphingosine-1-phosphate, S1P) regulating cell be proliferated,
It is played an important role in migration and apoptosis.Cer and Sp can inhibit cell growth, promote Apoptosis, and S1P then promotes cell raw
Long, inhibition Apoptosis.Sphingosine kinase (sphingosinekinase, SphK) is regulation above-mentioned substance dynamic in the cell
The important rate-limiting enzyme and cell Proliferation and the signal of interest molecule of survival of balance.
Discovery has two kinds of isomers of SphK1 and SphK2 in mammalian tissues at present.SphK1 is primarily present in cell
In matter, major function be phosphorylation Sp generate S1P, and then regulating cell be proliferated, migrate, infecting, breaking up and cell it is procedural
The multiple biological functions such as apoptosis are important in SphK1-S1P-S1P receptor (SphK1-S1P-S1PRs) signal path to swash
Enzyme.SphK1 high expression can not only stimulating cellular growth, and malignant transformation of cells can be led to, therefore SphK1 gene also has
The characteristic of oncogene.SphK1 is in glioma, colon and rectum carcinoma, lung cancer, oophoroma, breast cancer, gastric cancer, cervical carcinoma, kidney
Etc. expression high in a variety of cancer cells, activity height directly decides the destiny of cancer cell.The activity of SphK1 is suppressed to be made carefully
Cer and Sp level intracellular increases, and S1P level reduces, and then inhibits cell growth or promote Apoptosis, and therefore, SphK1 is
The ideal targets for the treatment of of cancer.In recent years, SphK1-S1P-S1PRs signal path and its tumour, autoimmune pathologies,
Effect in a variety of diseases such as inflammation, atherosclerosis, the nervous system disease is gradually elucidated with, targets the drug of SphK1
Design, developmental research also become one of hot spot of drug research.
Since the disease incidence of cancer and diseases associated with inflammation is in raised trend year by year, pathomechanism is extremely complex, therefore,
It was found that the SphK1 inhibitor of structure diversity is extremely urgent to alleviate cancer and inflammatory bowel disease.Researcher is based on this research
Thinking has found the compound containing tetrahydro pyrrolidine, has preferable selectivity and antiproliferation to SphK1.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of nafoxidine alkanes compound and its pharmaceutically acceptable salt,
Preparation method, pharmaceutical composition and its answering in preparation prevention and/or treatment disease relevant to Sphk1 dysfunction
With.
To solve technical problem of the invention, the invention provides the following technical scheme:
The first aspect of technical solution of the present invention is to provide such as logical formula (I) compound represented or its is pharmaceutically acceptable
Salt:
Wherein, R is
-C16H33,-C14H29,-C12H25,
Preferably, above compound or its pharmaceutically acceptable salt, the R are
It is furthermore preferred that above compound or its pharmaceutically acceptable salt, the R are
It is further preferred that above compound or its pharmaceutically acceptable salt, the R areStill more preferably, above compound or its pharmaceutically acceptable salt, it is described
R is
Any of the above-described compound pharmaceutically acceptable salt of the present invention is acylate or inorganic acid salt, wherein organic acid packet
Include acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, succinic acid, tartaric acid, citric acid, fumaric acid；Inorganic acid includes
Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid.
The second aspect of technical solution of the present invention is to provide the preparation method of compound described in first aspect, and of the invention is logical
Formula (I) compound can be prepared with following methods:
R'=-C13H27,-C11H23,-C9H19,
R=-C16H33,-C14H29,-C12H25,
Compound II is dissolved in methylene chloride, under nitrogen protection, corresponding alkene, Grubbs is added2nd, heat back
Stream reaction 7h is disappeared with TLC detection reaction raw materials；Reaction solution is cooled to room temperature and passes through short silicagel column and filters, and is washed with EtOAc
It is de-, obtain crude compound (III)；Crude compound (III) is dissolved in acetonitrile, cesium carbonate, benzene are added under nitrogen protection
Thiophenol, 50 DEG C of reaction 3h are disappeared with TLC detection reaction raw materials；Reaction solution is cooled to room temperature and passes through short silicagel column and filters, and uses
Dichloromethane eluent obtains crude compound (IV)；Crude compound (IV) is dissolved in methanol, 20% hydroxide palladium carbon is added
(30wt%), 10% palladium carbon (10wt%), reacts for 24 hours under hydrogen atmosphere, and reaction solution is filtered with diatomite, is spin-dried for solvent, obtains
Crude compound (V)；Crude compound (V) is dissolved in acetonitrile/water (volume ratio 1:4), ammonium ceric nitrate, room temperature reaction is added
3h, reaction solution directly with silica gel column chromatography separation (eluant, eluent is methanol/ethanol-methylene chloride-ammonium hydroxide -6:12:77:5), obtain mesh
Mark compound.
Compound II structure is described as follows:
The third aspect of technical solution of the present invention is to provide its medicine of the pharmaceutical composition comprising compound described in first aspect
The pharmaceutical composition of acceptable salt and one or more pharmaceutical carriers and/or diluent on, clinically or pharmaceutically may be used
Any dosage form received, preferably oral preparation or injection.Wherein contain a effective amount of logical formula (I) compound represented of physiology
0.01g~10g, can for 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.04g, 0.05g, 0.1g, 0.125g,
0.2g、0.25g、0.3g、 0.4g、0.5g、0.6g、0.75g、1g、1.25g、1.5g、1.75g、2g、2.5g、3g、4g、5g、
6g, 7g, 8g, 9g, 10g etc..
Any compound of the present invention, its pharmaceutically acceptable salt, can be applied in a manner of oral and extra-parenteral administration etc.
Need the patient of this treatment.
When for parenteral administration, injection can be made into.When injection is made, the routine in existing pharmaceutical field can be used
Method production, can be selected aqueous solvent or non-aqueous solvent.Most common aqueous solvent is water for injection, it is also possible to 0.9% chlorine
Change sodium solution or other suitable aqueous solutions；Common non-aqueous solvent is vegetable oil, predominantly injection soybean oil, other
There are also the aqueous solutions of ethyl alcohol, propylene glycol, polyethylene glycol etc..When preparing injection, additives can be added without, it can also be according to drug
Property suitable additives are added, as osmotic pressure regulator, pH adjusting agent, solubilizer, filler, antioxidant, bacteriostatic agent,
Emulsifier, suspending agent etc..When for taking orally, conventional solid pharmaceutical preparation, such as tablet, capsule, pill, granule can be made into；
It may be made as oral liquid, such as oral solution, oral suspensions, syrup.When oral preparation is made, it can be added
Suitable filler, adhesive, disintegrating agent, lubricant etc..
Compound of the present invention can add pharmaceutically acceptable carrier and common pharmaceutical formulation, such as piece is made
Fragrance, sweetener, liquid or solid filler or diluent can be added in agent, capsule, pulvis, syrup, liquor, suspending agent, injection
Etc. common medicinal supplementary materials.
The administration mode of compound of the present invention clinically can be using modes such as oral, injections.
Dosage used in the compound of the present invention clinic is 0.01-1000mg/ days, can also be according to the weight of the state of an illness or dosage form
Difference deviates this range.
The fourth aspect of technical solution of the present invention is to provide comprising described in compound described in first aspect and the third aspect
Application of the pharmaceutical composition in the drug of preparation prevention or the relevant disease for the treatment of SphK1 dysfunction.Wherein, it is described with
The relevant disease of SphK1 dysfunction includes cancer, diseases associated with inflammation.The cancer include colon cancer, lung cancer, breast cancer,
Liver cancer, gastric cancer, adenocarcinoma of lung, melanoma, the cancer of the esophagus；The diseases associated with inflammation includes inflammatory bowel disease, hepatitis, asthma, slow
Property obstructive lung disease, rheumatoid arthritis or multiple sclerosis.
Advantageous effects:
It is an advantage of the current invention that the compound has stronger selectivity and inhibiting effect to SphK1, such chemical combination
Object and its pharmaceutical formulation can be used for treating a series of diseases caused by SphK1 dysfunction, such as colon cancer, liver cancer, inflammation
Property enteropathy, hepatitis, asthma, hair property sclerosis etc..In addition, preparation method provided by the invention, which has, does not need intermediate separation,
The features such as reaction condition is mild, easy to operate.
Specific embodiment
Next With reference to embodiment the present invention will be further explained, more so as to those skilled in the art
Understand the present invention, but the present invention is not limited with this.
Compound II (0.186mmol) is dissolved in methylene chloride (6mL), under nitrogen protection, alkene is added
(0.744 mmol), Grubbs2nd(0.037mmol), heating reflux reaction 7h are disappeared with TLC detection raw material.Reaction solution is cooling
It filters to room temperature and by short silicagel column, is eluted with EtOAc, obtain crude compound (III).Gained crude product (III) is dissolved in
In acetonitrile (6mL), cesium carbonate (0.372mmol) is added under nitrogen protection, benzenethiol (0.28mmol), 50 DEG C of reaction 3h, with
TLC detects raw material and disappears.Reaction solution is cooled to room temperature and passes through short short silicagel column filtering, with dichloromethane eluent, obtains chemical combination
Object crude product (IV).Gained crude product (IV) is dissolved in methanol (6mL), 20% hydroxide palladium carbon (30wt%), 10% palladium is added
Carbon (10wt%), reacts for 24 hours under hydrogen atmosphere, and reaction solution is filtered through diatomite, is spin-dried for solvent, obtains crude compound (V).It will
Gained crude product (V) is dissolved in acetonitrile/water (1:4), is added ammonium ceric nitrate (0.372mmol), and 3h is reacted at room temperature.Reaction solution is direct
With silica gel column chromatography separation (eluant, eluent is methanol/ethanol-methylene chloride-ammonium hydroxide -6:12:77:5), P series tetrahydro pyrrolidine is obtained
Class target compound,
Embodiment 1
The synthesis of the preparation (P1) of (2R, 3S, 4S) -4- amino -2- tetradecyl pyrrolidine -3- alcohol
Compound II (0.186mmol) is dissolved in methylene chloride (6mL), under nitrogen protection, 1- tridecylene is added
(0.744mmol), Grubbs2nd(0.037mmol), heating reflux reaction 7h, with TLC detection raw material disappearance (ethyl acetate-two
Chloromethanes-petroleum ether 3:2:5).Reaction solution is cooled to room temperature and passes through short silicagel column and filters, and is eluted with EtOAc, obtains crude product.It will
Gained crude product is dissolved in acetonitrile (6mL), cesium carbonate (0.372mmol) is added under nitrogen protection, benzenethiol (0.28
Mmol), 50 DEG C of reaction 3h disappear (methanol dichloromethane 7:93) with TLC detection raw material.Reaction solution is cooled to room temperature and passes through
Short short silicagel column filtering, with dichloromethane eluent, obtains crude product.Gained crude product is dissolved in methanol (6mL), 20% hydrogen is added
It aoxidizes palladium carbon (30wt%), 10% palladium carbon (10wt%) is reacted for 24 hours under hydrogen atmosphere, and reaction solution is filtered through diatomite, is spin-dried for
Solvent obtains crude product.Gained crude product is dissolved in acetonitrile/water (1:4), is added ammonium ceric nitrate (0.372mmol), room temperature reaction
3h.Reaction solution must directly be changed with silica gel column chromatography separation (eluant, eluent is methanol/ethanol-methylene chloride-ammonium hydroxide -6:12:77:5)
Close object P1.White solid, yield: 25%, 1H NMR(CDCl3,400MHz) δ
(ppm): 3.48 (t, J=5.6Hz, 1H), 3.29-3.43 (m, 2H), 2.82 (q, J=5.6Hz, 1H), 2.60 (dq, J=
11.6,6.0,5.5Hz, 1H), 1.84 (brs, 4H), 1.54-1.63 (m, 1H), 1.25 (s, 25H), 0.88 (t, J=6.7Hz,
3H).13C NMR(CDCl3,100MHz)δ(ppm):75.72,65.00,53.15,51.73,34.02,31.85,29.55,
29.58(2C), 29.62(4C),29.48,29.29,26.75,22.61,14.00.IR(KBr,cm-1):3348,3242,
2918,2850,1558,1469, 1458,1377,1350,1118,1080,1028,956,908,894,869,825,
719.HRMS(ESI):m/z calcd for C18H38N2O(M+H)+:299.3062.found:299.3047.
The preparation method is the same as that of Example 1 by compound P2-P17 in embodiment 2-17, and difference is to try using different alkene
Agent synthesis, specifically olefin feedstock used in each embodiment is on the books in corresponding embodiment:
Embodiment 2
The preparation (P2) of (2R, 3S, 4S) -4- amino -2- dodecyl pyrrolidine -3- alcohol
Olefinic reactants used are 1- hendecene.Product is white solid, yield: 36%, 1H NMR(CD3OD,600MHz)δ(ppm):3.62–3.66(m,1H),3.22(q,J
=6.7Hz, 1H), 3.17 (dd, J=11.0,6.7Hz, 1H), 2.90 (q, J=5.8Hz, 1H), 2.62 (dd, J=11.0,
7.4Hz, 1H), 1.58-1.65 (m, 1H), 1.24-1.51 (m, 21H), 0.92 (t, J=7.0Hz, 3H)13C NMR(CD3OD,
150MHz)δ(ppm):75.93,64.58,53.38, 50.68,33.65,31.69,29.44,29.42,29.40,29.38,
29.36,39.30,29.10,26.66,22.36,13.07.IR(KBr, cm-1):3350,3244,2920,2850,2667,
2546,1641,1591,1467,1377,1352,1311,1116,1080,1029, 954,906,871,823,719cm-1；
HRMS(ESI):m/z calcd for C16H34N2O(M+H)+:271.2749.found: 271.2629.
Embodiment 3
(2R, 3S, 4S) -4- amino -2- hexadecyl pyrrolidine -3- alcohol (P3)
Olefinic reactants used are 1-tetradecylene.Product is white solid, yield: 30%, 1H NMR(CD3OD,600MHz)δ(ppm):3.55–3.58(m,1H),3.15(q,J
=6.7Hz, 1H), 3.09 (dd, J=11.2,6.7Hz, 1H), 2.84 (q, J=6.3Hz, 1H), 2.56 (dd, J=11.2,
7.5Hz, 1H), 1.48-1.55 (m, 1H), 1.11-1.40 (m, 29H), 0.80 (t, J=7.0Hz, 3H)13C NMR(CDCl3,
150MHz)δ(ppm):75.66,65.09, 53.01,51.91,33.98,31.90,29.59,29.63(2C),29.67(6C),
29.52,29.33,26.79,22.66,14.07.IR (KBr,cm-1):3350,3240,2956,2918,2850,1558,
1469,1458,1261,1101,1083,1028,954,914, 883,852,804,765,719.HRMS(ESI):m/z
calcd for C20H42N2O(M+H)+:327.3375.found: 327.3231.
Embodiment 4
The preparation (P4) of (2R, 3S, 4S) -4- amino -2- [9- (cyclohexyl) nonyl] pyrrolidines -3- alcohol
Olefinic reactants used are ((octyl- 7- alkene -1- oxygroup) methyl) hexamethylene.Product is sticky oil, yield: 29%, 1H NMR(CDCl3, 400MHz) and δ (ppm): 3.52 (t, J=5.3Hz, 1H), 3.36
(h, J=7.3Hz, 4H), 3.19 (d, J=6.6Hz, 2H), 2.82-2.90 (m, 1H), 2.63 (dd, J=9.7,6.2Hz,
1H), 2.41 (brs, 4H), 1.12-1.79 (m, 25H), 0.90 (q, J=10.9,10.1Hz, 2H)13C NMR(CDCl3,
100MHz)δ(ppm):76.83, 75.81,71.13,65.53,53.29,53.00,38.04,34.42,30.18(2C),
29.74(2C),29.55,29.51,29.48,26.90, 26.69,26.17,25.90(2C).IR(KBr,cm-1):3427
(br),3248,2924,2850,2792,2665,1463,1448, 1409,1375,1122,927,910,891,844,815,
723.HRMS(ESI):m/z calcd for C20H40N2O2(M+H)+: 341.3168.found:341.3419.
Embodiment 5
The preparation (P5) of (2R, 3S, 4S) -4- amino -2- [10- (cyclohexyl) decyl] pyrrolidines -3- alcohol
Olefinic reactants used are ((nonyl- 8- alkene -1- oxygroup) methyl) hexamethylene.Product is sticky oil, yield: 17%, 1H NMR(CD3OD, 400MHz) δ (ppm): 3.63 (t, J=5.4Hz, 1H), 3.39
(t, J=6.5Hz, 2H), 3.12-3.24 (m, 4H), 2.89 (q, J=5.9Hz, 1H), 2.61 (dd, J=10.7,7.2Hz,
1H), 1.50-1.79 (m, 10H), 1.19-1.45 (m, 21H), 0.94 (q, J=10.5,9.0Hz, 2H)13C NMR(CD3OD,
100MHz)δ(ppm): 76.48,75.83,70.75,64.60,53.31,50.58,37.93,33.51,29.83(2C),
29.42,29.34(2C),29.29,29.27, 29.17,26.64,26.37,26.89,25.62(2C).IR(KBr,cm-1):
3338,3253,2924,2850,2792,1558,1541, 1454,1373,1124,964,916,887,815,721.HRMS
(ESI):m/zcalcd for C21H42N2O2(M+H)+: 355.3325.found:355.3316.
Embodiment 6
The preparation (P6) of (2R, 3S, 4S) -4- amino -2- [11- (cyclohexyl) undecyl] pyrrolidines -3- alcohol
Olefinic reactants used are ((last of the ten Heavenly stems -9- alkene -1- oxygroup) methyl) hexamethylene.Product is sticky oil, yield: 23%, 1H NMR(CDCl3, 400MHz) and δ (ppm): 3.52 (t, J=5.3Hz, 1H), 3.36
(h, J=6.7Hz, 4H), 3.19 (d, J=6.6Hz, 2H), 2.86 (d, J=5.2Hz, 1H), 2.63 (dd, J=9.6,
6.1Hz, 1H), 2.31 (brs, 4H), 1.10-1.81 (m, 29H), 0.90 (q, J=10.9,10.1Hz, 2H)13C NMR
(CDCl3,100MHz)δ (ppm):76.83,75.80,71.15,65.54,53.26,52.97,38.05,34.40,30.18
(2C),29.75(2C),29.59(2C), 29.56,29.55,29.50,26.91,26.69,26.18,25.91(2C).IR
(KBr,cm-1):3348,3244,2922,2850,2792, 1558,1541,1465,1448,1406,1375,1124,1014,
954,889,821,721.HRMS(ESI):m/z calcd for C22H44N2O2(M+H)+:369.3481.found:
369.3477.
Embodiment 7
The preparation (P7) of (2R, 3S, 4S) -4- amino -2- (10- isobutyl group decane) pyrrolidines -3- alcohol
Olefinic reactants used are 9-isobutoxies-1- alkene.Product is sticky oil, yield: 26%, 1H NMR(CD3OD, 600MHz) δ (ppm): 3.87 (t, J=5.3Hz, 1H), 3.52
(q, J=6.6Hz, 1H), 3.39 (dt, J=18.7,6.7Hz, 3H), 3.20 (dd, J=12.6,6.9Hz, 3H), 2.93 (dd,
J=11.8,7.1Hz, 1H), 1.77-1.89 (m, 1H), 1.69 (dt, J=15.3,7.8Hz, 1H), 1.54 (dt, J=14.4,
7.2Hz, 3H), 1.16-1.49 (m, 18H), 0.90 (d, J=6.7Hz, 6H)13C NMR(CD3OD,150MHz)δ(ppm):
77.51,74.02,70.07,64.72, 51.99,31.43,29.36,29.32,29.23,29.18,29.15,29.13,
28.19,26.32,25.91,18.37(2C).IR(KBr, cm-1):3246,3070,2927,2852,1635,1558,1521,
1419,1114,1041,1008,968,945,873,831,819, 721.HRMS(ESI):m/z calcd for C18H38N2O2
(M+H)+:315.3012.found:315.3000.
Embodiment 8
The preparation (P8) of (2R, 3S, 4S) -4- amino -2- [9- (benzyl oxygroup) nonyl] pyrrolidines -3- alcohol
Olefinic reactants used are ((octyl- 7- alkene -1- oxygroup) methyl) benzene.Product is white solid, yield: 37%, 1H NMR(CDCl3,400MHz)δ(ppm):7.23–7.41(m,5H),4.50(s,
2H), 3.48 (dt, J=21.9,6.1Hz, 3H), 3.33 (h, J=6.9Hz, 2H), 2.85 (q, J=5.8Hz, 1H), 2.61
(dq, J=11.7,6.5,5.7Hz, 1H), 2.31 (brs, 4H), 1.06-1.68 (m, 16H)13C NMR(CDCl3,100MHz)
δ(ppm):138.71,128.33 (2C),127.61(2C),127.45,75.84,72.85,70.53,66.51,53.30,
53.06,34.47,29.77,29.74,29.53, 29.50,29.46,26.90,26.18.IR(KBr,cm-1):3346,3242,
2924,2850,2659,2536,1585,1496,1454, 1363,1311,1114,1074,1035,964,921,910,875,
825,734,698,634,609.HRMS(ESI):m/z calcd for C20H34N2O2(M+H)+:335.2699.found:
335.2696.
Embodiment 9
The preparation (P9) of (2R, 3S, 4S) -4- amino -2- [10- (1- phenyl ethoxy) decyl] pyrrolidines -3- alcohol
Olefinic reactants used are the chloro- 4- of 1- (1- (nonyl- 8- alkene -1- oxygroup) ethyl) benzene.Product is white solid, yield:
34%, 1H NMR(CD3OD, 400MHz) δ (ppm): 7.28 (dp, J=21.3,
7.2Hz, 5H), 4.40 (q, J=6.5Hz, 1H), 3.63 (t, J=5.3Hz, 1H), 3.30 (dt, J=13.4,7.6Hz, 3H),
3.18 (ddd, J=17.6,11.9,6.6Hz, 2H), 2.89 (q, J=5.8Hz, 1H), 2.60 (dd, J=10.6,7.1Hz,
1H),1.08–1.66(m,24H).13C NMR(CD3OD,100MHz)δ(ppm):143.88,128.07(2C),127.10,
125.82(2C),77.94,75.91,68.37, 64.59,53.38,50.72,33.68,29.55,29.45,29.32,
29.30,29.29,29.15,26.66,25.90,23.15.IR(KBr, cm-1):3344,3267,3028,2926,2852,
1647,1558,1541,1456,1406,1369,1280,1207,1105,815, 759,700,611,559.HRMS(ESI):
m/z calcd for C22H38N2O2(M+H)+:363.3012.found:363.2998.
Embodiment 10
The preparation of (2R, 3S, 4S) -4- amino -2- { 10- [1- (4- fluorophenyl) ethyoxyl] decyl } pyrrolidines -3- alcohol
(P10)
Olefinic reactants used are the fluoro- 4- of 1- (1- (nonyl- 8- alkene -1- oxygroup) ethyl) benzene.Product is white solid, yield:
38%, 1H NMR(CDCl3, 400MHz) and δ (ppm): 7.27 (t, J=6.7Hz, 2H),
7.02 (t, J=8.6Hz, 2H), 4.36 (q, J=6.3Hz, 1H), 3.52 (t, J=4.8Hz, 1H), 3.35 (dq, J=16.2,
6.7Hz, 2H), 3.25 (p, J=9.0,7.6Hz, 2H), 2.80-2.89 (m, 1H), 2.56-2.69 (m, 1H), 1.03-1.71
(m,25H).13C NMR (CDCl3, 100MHz) and δ (ppm): 162.03 (d, J=243.0Hz), 140.03,127.65 (d, J=
7.0Hz, 2C), 115.14 (d, J=21.0Hz, 2C), 77.18,75.81,68.73,65.53,53.29,53.01,34.44,
29.91,29.75,29.55,29.54(2C), 29.43,26.90,26.17,24.20.IR(KBr,cm-1):3400(br),
3253,2926,2854,1645,1606,1560,1510, 1456,1369,1340,1224,1103,1016,887,837,
725,640,580.HRMS(ESI):m/z calcd for C22H37FN2O2(M+H)+:381.2917.found:381.2761.
Embodiment 11
The preparation (P11) of (2R, 3S, 4S) -4- amino -2- { 10- [1- (4- fluorophenyl) oxygroup] decyl } pyrrolidines -3- alcohol
Olefinic reactants used are the fluoro- 1- of the chloro- 4- of 2- ((nonyl- 8- alkene -1- oxygroup) methyl) benzene.Product is white solid, is produced
Rate: 26%； 1H NMR(CD3OD,400MHz)δ(ppm):7.29–7.38(m,2H),
7.05 (t, J=8.7Hz, 2H), 4.46 (s, 2H), 3.63 (t, J=5.3Hz, 1H), 3.47 (t, J=6.5Hz, 2H), 3.18
(ddd, J=17.5,12.0,6.7Hz, 2H), 2.89 (q, J=5.8Hz, 1H), 2.61 (dd, J=10.7,7.2Hz, 1H),
1.20–1.67(m,22H).13C NMR(CD3OD, 100MHz) δ (ppm): 162.32 (d, J=242.0Hz), 134.50,
129.35 (d, J=8.0Hz, 2C), 114.63 (d, J=21.0Hz, 2C), 75.85,71.71,70.08,64.60,53.33,
50.62, 33.58,29.41,29.35,29.31,29.27,29.26,29.14,26.63,25.88.IR(KBr,cm-1):
3348,3242,2922,2850,2791,2659, 2528,1514,1465,1363,1298,1240,1120,1016,966,
921,879,821,767,721,634,567.HRMS(ESI):m/z calcd for C21H35FN2O2(M+H)+:
367.2761.found:367.2761.
Embodiment 12
(2R, 3S, 4S) -4- amino -2- { 10- [(the fluoro- 4- methylbenzyl of 2,3,5,6- tetra-) oxygroup] decyl } pyrrolidines -3-
The preparation (P12) of alcohol
Olefinic reactants used are the fluoro- 3- methyl -6- of 1,2,4,5- tetra- ((nonyl- 8- alkene -1- oxygroup) methyl) benzene.Product is white
Color solid, yield: 33%, 1H NMR(CD3OD,600MHz)δ(ppm):4.59(s,
2H), 3.67 (t, J=5.4 Hz, 1H), 3.49 (t, J=6.5Hz, 2H), 3.26 (q, J=6.7Hz, 1H), 3.19 (dd, J=
11.2,6.7Hz, 1H), 2.91-2.97 (m, 1H), 2.66 (dd, J=11.3,7.5Hz, 1H), 2.28 (s, 3H), 1.59
(ddt, J=27.5,14.0,7.6Hz, 3H), 1.22-1.49 (m, 19H)13C NMR(CDCl3,100MHz)δ(ppm):
(146.20,145.92,143.86,143.56,116.25 t, J=19.0Hz, 1C), 113.64 (t, J=18.0Hz, 1C),
75.81,70.90,65.54,59.74,53.31,52.99, 34.43,29.74,29.55,29.52(3C),29.37,26.89,
25.99,7.61.IR(KBr,cm-1):3350,3244,2920,2850, 2686,2538,1633,1581,1487,1409,
1367,1284,1109,1072,1031,956,923,875,837,752,719, 667,597.HRMS(ESI):m/z calcd
for C22H34F4N2O2(M+H)+:435.2635.found:435.2453.
Embodiment 13
The system of (2R, 3S, 4S) -4- amino -2- { 10- { [4- (trifluoromethyl) benzyl] oxygroup } decyl } pyrrolidines -3- alcohol
Standby (P13)
Olefinic reactants used are 1- ((nonyl- 8- alkene -1- oxygroup) methyl) -4- (trifluoromethyl) benzene.Product is white solid,
Yield: 35%, 1H NMR(CDCl3, 400MHz) and δ (ppm): 7.60 (d, J=
8.0Hz, 2H), 7.45 (d, J=7.9Hz, 2H), 4.55 (s, 2H), 3.50 (dt, J=19.5,6.0Hz, 3H), 3.30-3.43
(m, 2H), 2.87 (d, J=5.3Hz, 1H), 2.64 (dd, J=9.7,6.1Hz, 1H), 2.40 (brs, 4H), 1.11-1.68
(m,18H).13C NMR(CDCl3, 100 MHz) and δ (ppm): 142.90,129.60 (d, J=32.0Hz), 127.46 (2C),
125.26 (q, J=3.8Hz, 2C), 122.85,75.76,72.02,70.93,65.52,53.14,52.94,34.33,29.73
(2C),29.56,29.54(2C),29.46,26.89,26.17. IR(KBr,cm-1):3350,3240,2926,2850,1622,
1558,1469,1406,1340,1165,1124,1066,1018, 970,921,879,823,758,646,594.HRMS
(ESI):m/z calcd for C22H35F3N2O2(M+H)+:417.2729. found:417.2721.
Embodiment 14
The system of (2R, 3S, 4S) -4- amino -2- { 10- [(2,4- dimethoxy-benzyl) oxygroup] decyl } pyrrolidines -3- alcohol
Standby (P14)
Olefinic reactants used are 2,4- dimethoxy -1- ((nonyl- 8- alkene -1- oxygroup) methyl) benzene.Product is white solid,
Yield: 19%, 1H NMR(CD3OD, 600MHz) δ (ppm): 7.09 (d, J=
8.3Hz, 1H), 6.42 (d, J=2.3Hz, 1H), 6.38 (dd, J=8.3,2.3Hz, 1H), 4.33 (s, 2H), 3.70 (s,
3H), 3.69 (s, 3H), 3.54-3.57 (m, 1H), 3.36 (t, J=6.6Hz, 2H), 3.14 (q, J=6.7Hz, 1H), 3.08
(dd, J=11.2,6.7Hz, 1H), 2.82 (q, J=6.1Hz, 1H), 2.54 (dd, J=11.2,7.5Hz, 1H), 1.44-
1.54(m,3H),1.15–1.40(m,19H).13C NMR (CD3OD,150MHz)δ(ppm):161.01,158.72,130.32,
118.56,103.89,97.80,75.63,69.79,67.08, 64.62,54.46,54.37,53.16,50.31,33.30,
29.36,29.31,29.27,29.25,29.23,29.11,26.58,25.82.IR (KBr,cm-1):3433(br),3269,
2926,2850,1618,1510,1259,1209,1138,1093,970,920,869,829, 790,719,634,565.HRMS
(ESI):m/z calcd for C23H40N2O4(M+H)+:409.3066.found:409.2900.
Embodiment 15
The preparation (P15) of (2R, 3S, 4S) -4- amino -2- (10- hydroxydecyl) pyrrolidines -3- alcohol
Olefinic reactants used are 2- ((nonyl- 8- alkene -1- base oxygroup) methyl) naphthalene.Product is white solid, yield: 28%, 1H NMR(CDCl3, 400MHz) and δ (ppm): 3.59 (t, J=6.6Hz, 3H), 3.20-
3.31 (m, 2H), 3.12 (brs, 5H), 2.90 (q, J=6.6,5.9Hz, 1H), 2.62 (dd, J=10.1,6.7Hz, 1H),
1.08–1.65(m,18H). 13C NMR(CDCl3,100MHz)δ(ppm):75.74,65.00,62.49,53.18,51.84,
34.03,32.52,29.50,29.38, 29.31,29.29,29.26,26.66,25.63.IR(KBr,cm-1):3342,3248,
2922,2850,2659,2528,1649,1558, 1467,1431,1354,1321,1109,1062,1020,966,920,
877,831,786,719,634,570,513.HRMS (ESI):m/z calcd for C14H30N2O2(M+H)+:
259.2386.found:259.2380.
Embodiment 16
4- { { { 10-[(2R, 3S, 4S)-4- amino-3- hydroxyl pyrrolidine-2- base] decyl } oxygroup } methyl } benzonitrile (P16)
Olefinic reactants used are 4- ((nonyl- 8- alkene -1- oxygroup) methyl) benzonitrile.Product is white solid, yield:
26%, 1H NMR(CD3OD, 600MHz) δ (ppm): 7.22 (d, J=8.0Hz, 2H),
7.16 (d, J=7.9 Hz, 2H), 4.45 (s, 2H), 3.64 (dd, J=6.0,4.9Hz, 1H), 3.47 (t, J=6.6Hz, 2H),
3.14-3.24 (m, 2H), 2.90 (dt, J=7.2,5.5Hz, 1H), 2.62 (dd, J=11.0,7.4Hz, 1H), 1.56-1.64
(m,3H),1.26–1.51(m, 15H).13C NMR(CD3OD,150MHz)δ(ppm):137.03,135.34,128.56(2C),
127.59(2C),75.89, 72.34,69.87,64.59,50.65,33.61,29.41,29.33,29.31,29.27,
29.25,29.13,26.63,25.86,19.83.IR (KBr,cm-1):3348,3242,2920,2850,2657,2520,
1720,1587,1516,1465,1367,1114,1020,960, 920,877,833,800,754,719,682,655,632,
567.HRMS(ESI):m/z calcd for C22H35N3O2(M+Na)+: 396.6080.found:396.6080.
Embodiment 17
The system of (2R, 3S, 4S) -4- amino -2- { 10- [(tetrahydro -2H- pyrans -4- base) oxygroup] decyl } pyrrolidines -3- alcohol
Standby (P17)
Olefinic reactants used are 4- (nonyl- 8- alkene -1- oxygroup) tetrahydro -2H- pyrans.Product is white solid, yield:
37%, 1H NMR(CD3OD,600MHz)δ(ppm):3.50–3.54(m,1H),3.32
(t, J=6.6Hz, 2H), 3.19 (d, J=7.1Hz, 2H), 3.03-3.13 (m, 2H), 2.78 (q, J=5.8Hz, 1H), 2.50
(dd, J=11.0,7.5Hz, 1H), 2.03 (dq, J=14.9,7.5Hz, 1H), 1.60-1.67 (m, 2H), 1.49 (dddd, J
=27.3,20.0,10.1,4.9Hz, 7H), 1.18-1.39 (m, 15H), 1.15 (dq, J=14.2,7.2Hz, 2H)13C NMR
(CD3OD,150MHz)δ(ppm): 75.93,75.20,70.69,64.58,53.39,50.70,39.31,33.66,29.44,
29.35,29.34,29.29,29.28,29.24, 29.18(2C),26.66,25.90,25.00(2C).IR(KBr,cm-1):
3336,3255,2920,2850,2796,2546,1558, 1469,1373,1116,1078,1008,964,914,875,813,
759,719,665,634.HRMS(ESI):m/z calcd for C14H30N2O2(M+H)+:357.3117.found:
357.3000.
The partial pharmacologic of the compounds of this invention is tested and result is as follows:
Experimental example 1: the compounds of this invention detects the inhibiting effect of SphK1 and SphK2
Experimental method: compound P1-P17 is configured to the mother liquor of 10mM with DMSO first, ultrasound accelerates dissolution, rear to use
DMSO and kinase buffer liquid carry out gradient dilution, guarantee the final concentration of DMSO less than 1%.On the ELISA Plate of white, every hole adds
The drug of 1uL, is then added the mixing of 10 μ LAKT1 enzymes (hole 100ng/), then plus 5 μ L Crosstide substrate, it is rear that 34 μ L are added
Analysis buffer (pH7.4,40mMTris, 10mM MgCl2, 0.1mg/mL BSA, 1mM DTT, 10 μM of ATP), it mixes,
It is incubated at 30 DEG C 40 minutes, ATP is then added and detects 50 μ L of liquid, reacted at room temperature 5 minutes, detecting chemistry in microplate reader immediately
Numerical value is substituted into following formula, calculates percent activity by luminous signal:
%activity=[(Lu drug-Lu background)/(Lu enzyme-Lu background)] × 100%
It is handled with GraphpadPrism5 software, calculates the IC of compound50Value.
Experimental result
1, results of preliminary screening
1 compound P1-P17 of table (10 μM) is to SphK1 and SphK2 inhibiting rate
Preliminary the selection result shows that compound P3, P4, P5, P7, P17 all have one to SphK1 when concentration is 10 μM
Fixed inhibitory effect, wherein the inhibiting rate of compound P17 is up to 95%.All compounds of primary dcreening operation hardly have SphK2
Inhibiting effect, the tested results explanation, part of compounds have preferable selectivity to SphK1.Continue to choose compound P3,
The IC of P4, P5, P7, P17 progress SphK1 and SphK250Value test.
2, the IC of compound P3, P4, P5, P7, P17 to SphK1 and SphK250Value
The IC of table 2 compound P3, P4, P5, P7, P17 to SphK1 and SphK250Value
The IC of compound P3, P4, P5, P7, P17 to SphK1 and SphK250Value shows the IC of compound P350Value is greater than 10
μM, P4, P5, the IC of P7, P1750Value is respectively less than 10 μM, is the desirable compounds for go deep into pharmacological research.Particularly, P17
IC50Value is 0.8 μM, and SphK2/SphK1 is higher than 125, be the best SphK1 antagonist of presently found known selectivity it
One.
Experimental example 2: the compounds of this invention antitumor activity
2.1. experimental material
Compound P1-P17 is dissolved with dimethyl sulfoxide (DMSO, final concentration 0.4%) respectively, with containing 15% fetal calf serum
RPMI-1640 culture medium is configured to that 1mg/mL is spare, and the used time is diluted to required concentration.Human lung adenocarcinoma (A549), human colon carcinoma
(LOVO), human melanoma cell (A375), human liver cancer (HepG2) and human esophagus cancer (TE-1) cell line, purchase is in China
Academy of sciences's cell bank is placed in 37 DEG C, 5% CO using DMEM (HighGlucose) culture medium for containing 15% fetal calf serum2Training
Support culture in case.
The experiment of 2.2 anti-tumor activities
2.2.1 MTT preparation method
The MTT solution of 5mg/mL is prepared: being weighed MTT powder 500.0mg, is dissolved in the 100mLPBS of temperature, with 0.22 μm of hole
The filtering with microporous membrane of diameter obtains filtrate, and low dose is sub-packed in the EP pipe after high pressure sterilization, is placed in freezing at -20 DEG C and is protected from light guarantor
It deposits.
2.2.2 cell culture and experimental method
The cryopreservation tube for preserving tumour cell is removed from liquid nitrogen, is put into rapidly in 37 DEG C of insulating boxs, is kept stirred, directly
To thawing.It behind 75% alcohol wipe cryopreservation tube lid edge, draws cell suspension and is transferred in 10mL centrifuge tube, add 5mL culture
Base.Low-speed centrifugal (25 DEG C, 3000r/min, 5min) abandons supernatant, adds culture medium to repeat eccentric cleaning primary.Add appropriate culture
After base dilution, cell is dispelled with suction pipe, suspension is made, be transferred in culture bottle, be placed in 37 DEG C, 5%CO2It is trained in cell incubator
It supports.Next day replaces culture solution, is placed in 37 DEG C, 5%CO2Continue to cultivate in cell incubator.
Human lung adenocarcinoma (A549), human colon carcinoma (LOVO), human melanoma cell (A375), human liver cancer (HepG2) and people
The cancer of the esophagus (TE-1) cell is attached cell, according to tumor cell growth rates, will be in the attached tumor of logarithmic growth phase
Cell washing is digested through 0.25% EDTA pancreatin, and adjustment cell number is 1 × 105/ mL is inoculated in 96 orifice plates, every 100 μ of hole
L, in CO at 37 DEG C2Culture, is administered afterwards for 24 hours in incubator.Various concentration drug (compound P1-P17) is added in administration group, each medicine
5 dosage groups are arranged in object, and respectively 100.00,10.00,1.00,0.10,0.01 μM/L, each concentration sets three multiple holes.Setting
Blank control, DMSO (0.8%) solvent control and cis-platinum positive control.In 37 DEG C of CO2In incubator after culture 48h, MTT is used
Method measures OD value, calculates cell inhibitory rate.
2.2.3 cell IC50The calculating of value
Human lung adenocarcinoma (A549), human colon carcinoma (LOVO), human melanoma cell (A375), human liver cancer (HepG2) and people
After the cancer of the esophagus (TE-1) cell culture 48h, terminates, 10 μ L0.5%MTT solution are then added in each hole and are placed in CO2Culture
In case, after 4h, the liquid in each hole is removed, is then separately added into the DMSO solution of 0.2mL again, low frequency sufficiently shakes on shaking table
It swings, the first a ceremonial jade-ladle, used in libation for crystallizing bluish violet sufficiently dissolves, and is placed in microplate reader, and OD value is recorded at 490nm wavelength, calculates various concentration
Three parallel holes average value OD value, according to the cell inhibitory rate of each test medicine under mean value calculation various concentration
And IC50Value (is shown in Table 3).
Inhibiting rate (%)=[1- test sample OD value/negative control group OD value] × 100%
2.2.4 result judges
New Chinese medicine preclinical study guideline shows natural products IC50Think there is certain inhibition when≤30 μm of ol/mL
Effect；Synthetic drug IC50Think there is certain inhibiting effect when≤10 μm of ol/mL.
The IC of 3 compound inhibiting tumor cell of table proliferation50Value
2.3 results and discussion
Anti-tumour cell proliferative activity shows 2,3, the 4 three substituted-tetrahydro pyrrolidines of majority of this project synthesis
Through IC measured by MTT50Value is substantially at 3 μM or so, wherein compound P1, P2, P6, P12, P16 are to human lung adenocarcinoma (A549), people
The IC of colon cancer (LOVO), human liver cancer (HepG2)50It is worth smaller, the IC of P9, P13 to human lung adenocarcinoma (A549)50Value is smaller,
The IC of P3, P11 to human liver cancer (HepG2)50Value is smaller, and the active phase all with positive control drug cis-platinum (cisplatin)
When.These compounds are that the development and utilization of corresponding anticancer drug is laid a good foundation.
Claims (10)
1. compound shown in logical formula (I) or its pharmaceutically acceptable salt,
R are as follows:
-C16H33,-C14H29,-C12H25,
2. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the R is-C12H25,-
C16H33,
3. compound as claimed in claim 2 or its pharmaceutically acceptable salt, which is characterized in that the R is-C16H33,
4. compound as claimed in claim 3 or its pharmaceutically acceptable salt, which is characterized in that the R is
5. compound as claimed in claim 3 or its pharmaceutically acceptable salt, which is characterized in that the R is
6. the preparation method of compound described in claim 1-5 any claim or its pharmaceutically acceptable salt, including
Following steps:
Compound II is dissolved in methylene chloride, under nitrogen protection, alkene, Grubbs is added2nd, heating reflux reaction 7h,
It is disappeared with TLC detection reaction raw materials；Reaction solution is cooled to room temperature and passes through short silicagel column and filters, and is eluted with EtOAc, obtains compound
Crude product (III)；Crude compound (III) is dissolved in acetonitrile, cesium carbonate is added under nitrogen protection, benzenethiol, 50 DEG C anti-
3h is answered, is disappeared with TLC detection reaction raw materials；Reaction solution is cooled to room temperature and passes through short silicagel column and filters, with dichloromethane eluent,
It obtains crude compound (IV)；Crude compound (IV) is dissolved in methanol, 20% hydroxide palladium carbon of addition, 10% palladium carbon, in
It is reacted under hydrogen atmosphere for 24 hours, reaction solution is filtered with diatomite, is spin-dried for solvent, obtains crude compound (V)；By crude compound (V)
It is dissolved in acetonitrile/water, ammonium ceric nitrate is added, react at room temperature 3h, reaction solution is directly separated with silica gel column chromatography, obtains target chemical combination
Object.
7. a kind of pharmaceutical composition, which is characterized in that the compound containing any one of claim 1-6 or its is pharmaceutically acceptable
Salt and pharmaceutically acceptable carrier or excipient.
8. the pharmaceutical composition of the compound of any one of claim 1-6 or its pharmaceutically acceptable salt or claim 7 exists
Application in the drug of preparation prevention and/or treatment disease relevant to SphK1 dysfunction.
9. application according to claim 8, which is characterized in that the disease relevant to SphK1 dysfunction include cancer,
Diseases associated with inflammation.
10. application according to claim 9, which is characterized in that the cancer include colon cancer, lung cancer, breast cancer, liver cancer,
Gastric cancer, adenocarcinoma of lung, melanoma, the cancer of the esophagus；The diseases associated with inflammation includes inflammatory bowel disease, hepatitis, asthma, chronic obstruction
Property tuberculosis, rheumatoid arthritis or multiple sclerosis.
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| CN111484435A (en) * | 2019-06-12 | 2020-08-04 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | Tetrahydropyrrolidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
| CN114436925A (en) * | 2022-01-14 | 2022-05-06 | 河北大学 | M-diphenyl phenol ether compound and its preparation method and use |
| WO2022262350A1 (en) * | 2021-06-15 | 2022-12-22 | 山东第一医科大学(山东省医学科学院) | Substituted diaryl compound, and preparation method therefor and use thereof |
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| CN110256321B (en) * | 2019-06-12 | 2021-05-28 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | Preparation method and application of (2R,3S,4S) -4-amino-2-tetradecyl pyrrolidine-3-alcohol |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111484435A (en) * | 2019-06-12 | 2020-08-04 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | Tetrahydropyrrolidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
| CN111574421A (en) * | 2019-06-12 | 2020-08-25 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | 2,3, 4-trisubstituted pyrrolidine compound and preparation method and application thereof |
| CN111484435B (en) * | 2019-06-12 | 2021-04-02 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | Tetrahydropyrrolidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
| WO2022262350A1 (en) * | 2021-06-15 | 2022-12-22 | 山东第一医科大学(山东省医学科学院) | Substituted diaryl compound, and preparation method therefor and use thereof |
| CN114436925A (en) * | 2022-01-14 | 2022-05-06 | 河北大学 | M-diphenyl phenol ether compound and its preparation method and use |
| CN114436925B (en) * | 2022-01-14 | 2023-08-15 | 河北大学 | M-diphenol ether compound, preparation method and application thereof |
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| CN111484435B (en) | 2021-04-02 |
| CN111484435A (en) | 2020-08-04 |
| CN111574421A (en) | 2020-08-25 |
| CN111574421B (en) | 2021-04-16 |
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