Compounds having glycosidase inhibitory activity, salts and hydrates thereof, and uses thereof

Abstract

The present invention relates to a compound capable of inhibiting glycosidase and its salt or hydrate, and discloses a compound with the structure shown below. 0 is hydrogen or a C1-C20 straight or branched alkyl group; R 1 , R 2 , R 3 , R 4 , R 5 Each is independently selected from hydrogen, fluorine, chlorine, bromine, nitro, phenyl or C1-C20 straight or branched alkyl; n is an integer of 0-20; * represents a chiral carbon atom. The compound and its salt or hydrate have good glycosidase inhibition, especially excellent β-glucosidase inhibition, especially excellent selectivity and inhibitory effect on β-glucosidase derived from human lysosomes. Thus, it can be used to prevent or treat Gaucher's disease and / or Parkinson's syndrome.

Description

Technical Field

[0001] The present invention relates to a compound capable of inhibiting glycosidase and a salt and a hydrate thereof. Background Art

[0002] Gaucher disease (GD) is a progressive lysosomal storage disorder caused by a defect in acid β-glucosidase (GCase) in the lysosome, which leads to a decrease in its activity. It is characterized by the accumulation of glycosphingolipid ceramide in macrophage lysosomes, leading to multi-organ system dysfunction [Brady RO. Gaucher's disease: past, present and future. Baillieres Clin. Haematol. 10(4), 621–634(1997)].

[0003] Currently, the treatments for Gaucher disease mainly include the following methods: 1) enzyme replacement therapy (ERT therapy); 2) substrate reduction therapy (SRT therapy); 3) pharmacological chaperone therapy (PCT therapy).

[0004] Among them, ERT therapy is relatively expensive (RMB 700,000-1.5 million per person per year). The principle of SRT therapy is to find a glucosylceramide synthase inhibitor that can reduce the biosynthesis of glucosylceramide (GlcCer). The drug NB-DNJ (miglustat, Zavesca) is already on the market [Cox T, Lachmann R, Hollak C et al. Noveloral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355 (9214), 1481–1485 (2000)], but it has strong side effects, such as tremor or severe gastrointestinal side effects.

[0005] PCT therapy is a method developed in recent years to treat lysosomal diseases. It is based on reversible competitive inhibitors. It can selectively bind and stabilize the mutant β-glucosidase through the quality control mechanism of the endoplasmic reticulum before the abnormal enzyme is transferred to the lysosome through small molecule chaperones, thereby affecting the folding state of the abnormal enzyme and restoring the activity of the β-glucosidase. Chaperone molecules are usually derived from β-glucosidase inhibitors. Therefore, highly selective β-glucosidase inhibitors have the effect of treating Gaucher's disease.

[0006] On the other hand, a large number of clinical, genetic and pathological studies in recent years have confirmed that β-glucosidase deficiency is a major risk factor for Parkinson's disease [Avenali, M.; Blandini, F.; Cerri, S. Front Aging Neurosci 2020, 12, 97.], which means that β-glucosidase is also an effective therapeutic target for Parkinson's disease drug discovery [Sidransky E. Gaucher disease and parkinsonism. Mol. Genet. Metab. 84 (4), 302–304 (2005)]. Highly selective β-glucosidase inhibitors can also play a good therapeutic effect in the prevention and treatment of Parkinson's syndrome. Summary of the invention

[0007] The object of the present invention is to provide a compound and a salt or hydrate thereof, which has good glycosidase inhibitory effect, especially excellent β-glucosidase inhibitory effect, especially excellent selectivity and inhibitory effect on β-glucosidase derived from human lysosomes, and can be used to prevent or treat Gaucher's disease and / or Parkinson's syndrome.

[0008] In order to achieve the above object, the present invention provides a compound as shown in Formula I:

[0009]

[0010] Wherein, R0 is hydrogen or a C1-C20 straight or branched alkyl group;

[0011] R1, R2, R3, R4, and R5 are each independently selected from hydrogen, fluorine, chlorine, bromine, nitro, phenyl, or a C1-C20 straight or branched alkyl group;

[0012] n is an integer from 0 to 20;

[0013] * indicates a chiral carbon atom.

[0014] Preferably, R0 is hydrogen or a C1-C10 linear or branched alkyl group.

[0015] Preferably, R1, R2, R3, R4 and R5 are each independently selected from hydrogen, fluorine, chlorine, bromine, nitro, phenyl or a C1-C6 linear or branched alkyl group.

[0016] Preferably, n is an integer of 0-4.

[0017] Preferably, the stereo configuration of carbon at positions 2, 3, and 4 of the compound represented by formula I is 2S, 3R, 4S or 2R, 3S, 4R.

[0018] Preferably, R0 is hydrogen.

[0019] Preferably, R1, R2, R3, R4, R5 are each independently selected from hydrogen, fluorine, methyl or phenyl.

[0020] Preferably, not all of R1, R2, R3, R4, and R5 are hydrogen.

[0021] Preferably, n is an integer of 0-3.

[0022] Preferably, the structure of the compound represented by formula I is any one of the following structures:

[0023]

[0024] The second aspect of the present invention provides a salt or hydrate of the compound described in the first aspect of the present invention.

[0025] Preferably, the salt is a pharmaceutically acceptable salt of the compound described in the first aspect of the present invention.

[0026] Preferably, the salt is one or more of hydrochloride, sulfonate, trifluoroacetate, carbonate, nitrate, phosphate, folate, and acetate; more preferably, the salt is hydrochloride.

[0027] Preferably, the structure of the salt is any one of the following structures:

[0028]

[0029] The third aspect of the present invention provides a glycosidase inhibitor, wherein the glycosidase inhibitor contains the compound according to the first aspect of the present invention and / or the salt or hydrate according to the second aspect of the present invention as an active ingredient.

[0030] Preferably, the glycosidase inhibitor is used to inhibit one or more of α-glucosidase, β-glucosidase, α-galactosidase, β-galactosidase, α-mannosidase, β-mannosidase, α,α-trehalase, α-L-rhamnosidase, amyloglucosidase and β-glucuronidase.

[0031] Preferably, the glycosidase inhibitor is used to inhibit β-glucosidase.

[0032] More preferably, the glycosidase inhibitor is used to inhibit human lysosomal-derived β-glucosidase.

[0033] The fourth aspect of the present invention provides a use of the compound described in the first aspect of the present invention and / or the salt or hydrate described in the second aspect of the present invention in preventing or treating Gaucher's disease and / or Parkinson's syndrome.

[0034] The compound provided by the present invention has a simple preparation method and can effectively and highly selectively inhibit β-glucosidase, especially β-glucosidase derived from human lysosomes, so it can be used to prevent or treat Gaucher's disease and Parkinson's syndrome. DETAILED DESCRIPTION

[0035] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0036] The first aspect of the present invention provides a compound, the structure of which is shown in Formula I:

[0037]

[0038] Wherein, R0 is hydrogen or a C1-C20 straight chain or branched alkyl group; R1, R2, R3, R4, and R5 are each independently selected from hydrogen, fluorine, chlorine, bromine, nitro, phenyl, or a C1-C20 straight chain or branched alkyl group; n is an integer of 0-20, and * represents a chiral carbon atom.

[0039] In the present invention, examples of the C1-C20 straight-chain or branched alkyl group include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, isohexyl, isoheptyl, 2-methylhexyl, 2-ethylhexyl, 1-methylheptyl, 2-methylheptyl, isooctyl, isononyl, 3,5,5-trimethylhexyl, 2,6-dimethyl-4-heptyl, isodecyl, isoundecyl, isododecyl, isotridecyl, isotetradecyl, isopentadecyl, isohexadecyl, isoheptadecyl, isooctadecyl, isononadecyl, isoeicosyl, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-oeicosyl.

[0040] In the present invention, preferably, R0 is hydrogen or a C1-C10 straight or branched alkyl group; more preferably, it is hydrogen.

[0041] In the present invention, preferably, R1, R2, R3, R4, and R5 are each independently selected from hydrogen, fluorine, chlorine, bromine, nitro, phenyl, or a C1-C6 straight-chain or branched alkyl group; more preferably, R1, R2, R3, R4, and R5 are each independently selected from hydrogen, fluorine, methyl, or phenyl.

[0042] Furthermore, according to the present invention, preferably, not all of R1, R2, R3, R4 and R5 are hydrogen.

[0043] In the present invention, the n can be, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, without particular limitation.

[0044] Preferably, n is 0, 1, 2, 3 or 4; more preferably, n is 0, 1, 2 or 3.

[0045] According to the present invention, the stereo configuration of carbon at positions 2, 3, and 4 of the compound represented by formula I is preferably 2S, 3R, 4S or 2R, 3S, 4R.

[0046] In the present invention, preferably, the structure of the compound represented by formula I is any one of the following structures:

[0047]

[0048] Wherein Me is methyl and F is fluorine.

[0049] When the compound represented by Formula I is any one of the structures represented by Formulas D1-D4 and L1-L4, it has excellent β-glucosidase inhibition and extremely high β-glucosidase selectivity (especially β-glucosidase derived from human lysosomes), and is therefore very suitable for use as an active ingredient of a β-glucosidase inhibitor.

[0050] According to the first aspect of the present invention, when R0 is hydrogen, the compound represented by formula I can be prepared by an addition reaction between a nitrone compound and an organic metal reagent and a reduction deprotection reaction and an ion exchange method, and the preparation method may include the following steps:

[0051] 1) The nitrone compound shown in formula II is subjected to addition reaction with an organometallic reagent RMgX to generate a first intermediate shown in formula III:

[0052]

[0053] 2) subjecting the first intermediate represented by formula III obtained in step 1) to a deprotection reaction to generate a compound represented by formula IV:

[0054]

[0055] 3) The second intermediate represented by formula IV obtained in step 2) is subjected to a neutralization reaction with aqueous ammonia to obtain a compound represented by formula I:

[0056]

[0057] In step 1), in formula II, R6 is a hydroxyl protecting group.

[0058] Preferably, R6 is benzyl.

[0059] The nitrone compound represented by formula II can be prepared by conventional methods in the art, or obtained through commercial channels, without particular limitation.

[0060] For example, the preparation method of the nitrone compound in formula II, in which R6 is benzyl, can be carried out according to the method provided in the literature [Cicchi, S.; Hold, I.; Brandi, AJ Org. Chem. 1993, 58, 5274.].

[0061] In the present invention, X in the RMgX is a halogen (F, Cl, Br, I); R in the RMgX is Wherein R1, R2, R3, R4, R5 and n are the same as those of Formula I and can be specifically selected according to the compound of Formula I to be prepared.

[0062] In step 1), the amount of the compound represented by formula II and the organometallic reagent RMgX can vary within a wide range without particular limitation. For example, the molar ratio of the compound represented by formula II to the organometallic reagent RMgX can be 1:1-20; preferably 1:1-10; more preferably 1:1-2.

[0063] According to the present invention, the reaction in step 1) can be carried out in an anhydrous aprotic solvent, and the anhydrous aprotic solvent can be, for example, one or more of tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene and dichloromethane; preferably anhydrous tetrahydrofuran.

[0064] In the present invention, the volume ratio of the compound represented by formula II to the anhydrous aprotic solvent can be 1:5-50; preferably 1:10-20.

[0065] According to the present invention, the reaction conditions A may include: a reaction temperature of 0-45°C, and a reaction time of 1-60 min. Preferably, the reaction conditions A include: a reaction temperature of 0-20°C, and a reaction time of 20-40 min.

[0066] Step 1) After the reaction is carried out, a saturated NH4Cl aqueous solution can be added for quenching, and then the organic phases are combined after extraction with ethyl acetate, and then the organic phases are dried over anhydrous MgSO4, and the magnesium sulfate is removed by filtration. Then, the solvent can be removed by concentration under reduced pressure, and then purified by column chromatography (for example, the volume ratio of petroleum ether to ethyl acetate during column chromatography can be 10:1), thereby obtaining the compound shown in Formula III.

[0067] According to the first aspect of the present invention, in step 2), the hydrogen source is not particularly limited, and can be, for example, selected from hydrogen and / or ammonium formate, etc., preferably hydrogen.

[0068] In step 2), the catalyst is not particularly limited and can be a conventional choice in the art. For example, the catalyst can be selected from one or more of 10% Pd / C (Pd / C with a Pd content of 10% by weight), palladium black, palladium hydroxide, palladium acetate, palladium chloride, platinum oxide and platinum black, etc.; preferably 10% Pd / C.

[0069] In the present invention, the reaction in step 2) can be carried out in a solvent, and the solvent is not particularly limited, for example, it can be one or more of methanol, toluene, dichloromethane and water, preferably methanol.

[0070] According to the present invention, the amount of the solvent, hydrochloric acid and catalyst used in step 2) can vary within a wide range as long as the reaction can proceed smoothly. For example, relative to 1g of the compound represented by formula III, the amount of the solvent can be 10-200mL; the amount of hydrochloric acid can be 1-100mL (hydrochloric acid concentration is 12mol / L); the amount of the catalyst can be 0.01-0.1mg.

[0071] Preferably, relative to 1 g of the compound represented by formula III, the amount of the solvent used is 50-150 mL; the amount of the hydrochloric acid used is 5-20 mL; and the amount of the catalyst used is 0.03-0.08 mg.

[0072] In addition, in step 2), the amount of the hydrogen source relative to the compound represented by formula III can also vary within a large range. For example, relative to 1 mol of the compound represented by formula III, the amount of the hydrogen source can be 10-100 mol; preferably 50-100 mol.

[0073] In the present invention, the reaction conditions B may include: a reaction temperature of 0-45°C, and a reaction time of 6-48h; preferably, the reaction conditions B include: a reaction temperature of 10-30°C, and a reaction time of 8-20h.

[0074] Step 2) After the reaction, the resulting mixture is filtered to remove the catalyst, washed with methanol and concentrated in vacuo to obtain the compound represented by formula IV.

[0075] According to the present invention, in step 3), the product obtained in step 2) can be neutralized to prepare the compound described in the first aspect of the present application.

[0076] Specifically, the compound represented by Formula IV can be reacted with concentrated aqueous ammonia (eg, 13 mol / L). At this time, the amount of the concentrated aqueous ammonia used can be 10-50 mL, preferably 10-30 mL, relative to 1 g of the compound represented by Formula IV.

[0077] After the above neutralization reaction, the obtained reaction product is evaporated to dryness and passed through an acidic resin column to prepare the compound represented by formula I.

[0078] In addition, according to the first aspect of the present invention, when R0 is a C1-C20 straight-chain or branched alkyl group, the corresponding compound of formula I can be further prepared on the basis of the compound of formula I in which R0 is hydrogen.

[0079] Specifically, the compound shown in Formula I in which R0 is hydrogen and the aldehyde corresponding to the straight-chain or branched alkyl group of C1-C20 can be prepared by a condensation reduction reaction in a methanol solvent in the presence of acetic acid, a catalyst (for example, a Pd / C catalyst) and hydrogen. The specific reaction is shown below (the reaction can be carried out according to the method described in the literature [Yang, LF; Shimadate, Y.; Kato, A.; Li, YX; Jia, YM; Fleet, GWJ; Yu, CYOrg Biomol Chem 2020, 18, 999.] and patent CN110128315A).

[0080]

[0081] The second aspect of the present invention provides a salt or hydrate of the compound described in the first aspect of the present invention.

[0082] According to the present invention, the salt of the compound described in the first aspect of the present invention is not particularly limited, and is preferably a pharmaceutically acceptable salt of the compound described in the first aspect of the present invention.

[0083] As a pharmaceutically acceptable salt of the compound, for example, it can be one or more of the hydrochloride, sulfonate, trifluoroacetate, carbonate, nitrate, phosphate, folate and acetate of the compound; preferably, the salt is one or more of the hydrochloride, sulfonate and trifluoroacetate; more preferably, the salt is the hydrochloride.

[0084] In the present invention, preferably, the structure of the salt described in the second aspect of the present invention is any one of the following structures:

[0085]

[0086] Wherein Me represents methyl, and F represents fluorine.

[0087] The third aspect of the present invention provides a glycosidase inhibitor, wherein the glycosidase inhibitor contains the compound according to the first aspect of the present invention and / or the salt or hydrate according to the second aspect of the present invention as an active ingredient.

[0088] According to the third aspect of the present invention, the glycosidase inhibitor can be used to inhibit one or more of α-glucosidase, β-glucosidase, α-galactosidase, β-galactosidase, α-mannosidase, β-mannosidase, α,α-trehalase, α-L-rhamnosidase, amyloglucosidase and β-glucuronidase.

[0089] In addition, in the present invention, the glycosidase inhibitor has very excellent inhibitory activity against β-glucosidase, especially against β-glucosidase derived from human lysosomes, and at the same time shows very high selectivity for β-glucosidase derived from human lysosomes.

[0090] The fourth aspect of the present invention provides a use of the compound described in the first aspect of the present invention and / or the salt or hydrate described in the second aspect of the present invention in preventing or treating Gaucher's disease and / or Parkinson's syndrome.

[0091] In the present invention, the prevention or treatment of Gaucher's disease and / or Parkinson's syndrome is achieved by using the compound described in the first aspect of the present invention or the salt or hydrate described in the second aspect of the present invention as a small molecule chaperone to repair β-glucosidase.

[0092] According to the fourth aspect of the present invention, when the compound or its salt or its hydrate is used to prevent or treat Gaucher's disease and / or Parkinson's syndrome, the compound or its salt or its hydrate can be prepared into a medicine, and one or more pharmaceutically acceptable carriers can be added to the medicine. For example, the carrier can include one or more of various diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers and lubricants commonly used in the pharmaceutical field, without particular limitation.

[0093] According to the present invention, when the compound or its salt or hydrate thereof is prepared into a medicine for preventing or treating Gaucher's disease and / or Parkinson's syndrome, the medicine can be prepared into various conventional forms in the art such as injection, tablet, powder, granule, capsule, oral solution, ointment and cream, without special limitation.

[0094] In addition, according to the fourth aspect of the present invention, when the compound or its salt or hydrate thereof is used to prevent or treat Gaucher's disease and / or Parkinson's syndrome, it can be administered by various routes, including but not limited to oral, inhalation, rectal, transdermal, intramucosal administration, and subcutaneous, intramuscular or intravenous injection.

[0095] The present invention will be described in detail below through examples.

[0096] In the following preparation examples and test examples, unless otherwise specified, the methods described are conventional methods in the art, and the reagents used are reagents obtained from commercial sources.

[0097] The following preparation examples are shown in formula II It was prepared according to the method provided in the literature [Cicchi, S.; Hold, I.; Brandi, AJ Org. Chem. 1993, 58, 5274.].

[0098] Preparation Example 1

[0099] Preparation of D1-1

[0100]

[0101] 1) Dissolve 1.5 g (5.1 mmol) of the compound represented by formula II-D in 20 mL of anhydrous tetrahydrofuran, introduce argon gas for protection and cool the reaction solution to 0°C, add 5 mL of RMgBr (p-fluorophenylmagnesium bromide, 1.6 mol / L) was added dropwise to the above reaction solution and reacted at 0°C for 30 min;

[0102] 2) The reaction was quenched with 5 mL of saturated NH4Cl aqueous solution, and then extracted with ethyl acetate three times (10 mL of ethyl acetate each time), the organic phases were combined, dried over anhydrous MgSO4 and filtered, and then concentrated under reduced pressure to remove the solvent to obtain a crude product, which was then subjected to column chromatography (using petroleum ether and ethyl acetate in a volume ratio of 10:1 for column chromatography) to obtain a compound represented by formula III-D1-1;

[0103] The data of the H NMR spectrum of the compound represented by Formula III-D1-1 are as follows: 1H NMR (400MHz, CDCl3) δ (ppm) 7.43–7.26 (m, 8H), 7.26–7.21 (m, 2H), 7.13–6.98 (m, 4H),4.56(d,J=11.9Hz,1H,-OCH2Ph),4.46(d,J=11.9Hz,1H,-OCH2Ph),4.34(s, 2H,-OCH2Ph), 4.01 (d, J=6.6Hz, 1H, H3), 3.86 (d, J=7.2Hz, 1H, H2), 3.75 (d, J=7. 4Hz,1H,H4),3.52(d,J=10.6Hz,1H,H1),3.17(dd,J1=6.8Hz,J2=10.5Hz,1H,H1);

[0104] 3) 100 mg of the compound represented by formula III-1 was dissolved in 10 mL of methanol, 1 mL of 12 mol / L hydrochloric acid and 5 mg of Pd / C catalyst (Pd content was 10 wt%) were added, and then the air in the reaction device was replaced with argon three times and then hydrogen was introduced, and the reaction was carried out for 12 hours;

[0105] 4) The reaction product obtained in step 3) was filtered to remove the catalyst, and the filter cake was washed three times with methanol (3 mL of methanol each time), and then the organic phases were combined and concentrated under reduced pressure to obtain the compound shown in D1-1.

[0106] The nuclear magnetic resonance hydrogen spectrum measurement data of the compound shown in D1-1 is: 1 H NMR (400MHz, CD3OD) δ (ppm) 7.61 (t, J = 7.5Hz, 2H), 7.14 (t, J = 7.8Hz, 2H), 4.40 (s, 1H, H2 ), 4.31 (d, J = 9.0Hz, 2H, H3, H4), 3.56 (d, J = 10.1Hz, 1H, H1), 3.40 (d, J = 10.9Hz, 1H, H1).

[0107] Preparation Example 2

[0108] Preparation of L1-1

[0109]

[0110] The method described in Preparation Example 1 is followed, except that in step 1), the compound represented by formula II-L is used for preparation.

[0111] The compound of formula III-L-1 was obtained, and the data of H NMR spectrum were as follows: 1H NMR (400MHz, CDCl3) δ (ppm) 7.43–7.26 (m, 8H), 7.26–7.20 (m, 2H), 7.13–6.98 (m, 4H), 4.56 (d, J = 11.8Hz 1H,-OCH2Ph),4.46(d,J=11.9Hz,1H,-OCH2Ph),4.34(s,2H,-OCH2Ph),4.01(d,J=6.6Hz,1H,H3),3.87(d,J= 7.2Hz,1H,H2),3.75(d,J=7.4Hz,1H,H4)3.52(d,J=10.6Hz,1H,H1),3.17(dd,J1=6.8Hz,J2=10.5Hz,1H,H1);

[0112] The nuclear magnetic resonance hydrogen spectrum measurement data of the compound represented by L1-1 prepared in this way is: 1 HNMR (400MHz, CD3OD) δ (ppm) 7.58 (s, 2H), 7.16 (t, J = 8.4Hz, 2H), 4.39 (s, 1H, H3), 4. 30 (d, J = 10.3Hz, 2H, H2, H4), 3.54 (d, J = 11.5Hz, 1H, H1), 3.38 (d, J = 11.8Hz, 1H, H1).

[0113] Preparation Example 3

[0114] Preparation of D2-1

[0115]

[0116] The method described in Preparation Example 1 was followed, except that

[0117] The RMgBr used in step 1) is 1,1'-biphenyl magnesium bromide,

[0118] The compound represented by formula III-D2-1 was obtained, and the data of H NMR spectrum were as follows: 1H NMR(500MHz, CDCl3)δ(ppm)7.65–7.26(m,15H),7.26–7.21(m,2H),7.16–7.09(m,2H ),4.60(d,J=11.9Hz,1H,-OCH2Ph),4.51(d,J=11.9Hz,1H,-OCH2Ph),4.39(ABq,J=1 1.8Hz,2H,-OCH2Ph),4.06(d,J=6.7Hz,1H,H3),3.98(d,J=7.1Hz,1H,H2),3.84(d,J =7.4Hz, 1H, H4), 3.62 (d, J = 10.6Hz, 1H, H1), 3.34 (dd, J1 = 7.0Hz, J2 = 10.5Hz, 1H, H1).

[0119] The nuclear magnetic resonance hydrogen spectrum measurement data of the compound D2-1 prepared in this way is: 1 HNMR(500MHz,CD3OD)δ(ppm)7.78–7.72(m,2H),7.71–7.63(m,4H),7.50–7.44(m,2H),7.42–7.36(m,1H),4.48 –4.45(m,1H,H2),4.42(s,1H,H3),4.38–4.34(m,2H,H1,H4),3.69–3.60(m,1H,H1),3.47(d,J=11.8Hz,1H,H1).

[0120] Preparation Example 4

[0121] Preparation of L2-1

[0122]

[0123] The method described in Preparation Example 3 is followed, except that in step 1), the compound represented by formula II-L is used for preparation.

[0124] The compound represented by formula III-L2-1 was obtained, and the data of H NMR spectrum were as follows: 1H NMR(500MHz, CDCl3)δ(ppm)7.65–7.26(m,15H),7.26–7.21(m,2H),7.16–7.09(m,2H ),4.59(d,J=11.9Hz,1H,-OCH2Ph),4.50(d,J=11.9Hz,1H,-OCH2Ph),4.39(ABq,J=1 1.8Hz,2H,-OCH2Ph),4.05(d,J=6.6Hz,1H,H3),3.97(d,J=7.2Hz,1H,H2),3.84(d,J =7.4Hz, 1H, H4), 3.59 (d, J = 10.7Hz, 1H, H1), 3.23 (dd, J1 = 6.9Hz, J2 = 10.6Hz, 1H, H1);

[0125] The nuclear magnetic resonance hydrogen spectrum measurement data of the compound represented by formula L2-1 prepared in this way is: 1 HNMR(500MHz,CD3OD)δ(ppm)7.76(d,J=8.3Hz,2H),7.71–7.63(m,4H),7.48(t,J=7.4Hz,2H),7.39(t,J=7.4Hz,1H),4.48(d,J= 4.0Hz,1H,H2),4.44–4.41(m,1H,H3),4.38–4.34(m,2H,H1,H4),3.64(dd,J=4.1Hz,11.9Hz,1H,H1),3.47(d,J=13.4Hz,1H,H1).

[0126] Preparation Example 5

[0127] Preparation of D3-1

[0128]

[0129] The method described in Preparation Example 1 was followed, except that

[0130] The RMgBr used in step 1) is 3-phenylpropylmagnesium bromide,

[0131] The compound represented by formula III-D3-1 was obtained, and the data of H NMR spectrum were as follows: 1H NMR (400MHz, CDCl3) δ (ppm) 7.39–7.26 (m, 10H), 7.26–7.10 (m, 5H,), 4.54 (d, J = 12Hz, 1H ,-OCH2Ph),4.51–4.40(m,3H,-OCH2Ph),3.95(d,J=5.7Hz,1H,H2),3.66(d,J=5.9Hz,1H ,H3),3.43(d,J=11.1Hz,1H,H1),3.08(dd,J1=6.0Hz,J2=10.9Hz,1H,H1),2.82(q,J=6. 3Hz,1H,H4),2.62(t,J=7.6Hz,2H,H7),1.89–1.69(m,3H,H5,H6),1.69–1.56(m,1H,H5);

[0132] The nuclear magnetic resonance hydrogen spectrum measurement data of the compound D3-1 prepared in this way is: 1 HNMR(500MHz,CD3OD)δ(ppm)7.31–7.11(m,5H),4.18(s,1H,H2),3.97(s,1H,H3),3.48–3.36( m, 2H, H1, H4), 3.29 (d, J = 11.8Hz, 1H, H1), 2.69 (t, J = 7.4Hz, 2H, H7), 1.94–1.74 (m, 4H, H5, H6).

[0133] Preparation Example 6

[0134] Preparation of L3-1

[0135]

[0136] The method described in Preparation Example 5 is followed, except that in step 1), the compound represented by Formula II-L is used for preparation.

[0137] Thus, the compound represented by formula III-L3-1 is obtained, and the data of H NMR spectrum are as follows: 1HNMR (400MHz, CDCl3) δ (ppm) 7.39–7.261 (m, 10H), 7.259–7.10 (m, 5H), 4.57 (d, J = 12.0Hz, 1H, - OCH2Ph),4.51–4.39(m,3H,-OCH2Ph),3.95(d,J=4.6Hz,1H,H2),3.66(d,J=5.6Hz,1H,H3),3.4 1(d,J=11.2Hz,1H,H1),3.08(dd,J1=6.1Hz,J2=11.0Hz,1H,H1),2.85(q,J=6.6Hz,1H,H4),2.6 6–2.57(m,2H,H7),1.89–1.79(m,1H,H5,),1.75(quin,J=7.5Hz,2H,H6),1.69–1.56(m,1H,H5);

[0138] The H NMR spectrum of the prepared compound L3-1 is as follows: 1 H NMR(500MHz,CD3OD)δ(ppm)7.34–7.14(m,5H),4.19(s,1H,H2),3.98(s,1H,H3),3.48–3.36(m ,2H,H1,H4),3.28(d,J=11.8Hz,1H,H1),2.71(t,J=7.0Hz,2H,H7),1.99–1.74(m,4H,H5,H6).

[0139] Preparation Example 7

[0140] Preparation of D4-1

[0141]

[0142] The method described in Preparation Example 1 was followed, except that

[0143] The RMgBr used in step 1) is p-tolylmagnesium bromide,

[0144] The compound represented by formula III-D4-1 was obtained, and the data of H NMR spectrum were as follows: 1H NMR(500MHz, CDCl3)δ(ppm)7.38–7.26(m,8H),7.26–7.07(m,7H),4.60–4.52(m,1H,-OCH2Ph),4.49–4.43(m,1H,-OCH2Ph),4.39–4.26(m,2H,-OCH2 Ph),4.03–4.98(m,1H,H3),3.95–3.90(m,1H,H2),3.76–3.70(m,1H,H4), 3.57–3.51(m,1H,H1),3.20–3.14(m,1H,H1),2.36(d,J=3.8Hz,3H,-CH3);

[0145] The nuclear magnetic resonance hydrogen spectrum measurement data of the compound D4-1 prepared in this way is: 1 HNMR(500MHz,CD3OD)δ(ppm)7.09(d,J=7.4Hz,2H),6.87(d,J=7.3Hz,2H),3.99(s,1H,H2),3.96(s ,1H,H3),3.92(s,1H,H4),3.19(d,J=9.1Hz,1H,H1),3.01(d,J=11.5Hz,1H,H1),1.95(s,1H,-CH3).

[0146] Preparation Example 8

[0147] Preparation of L4-1

[0148]

[0149] The method described in Preparation Example 7 is followed, except that in step 1), the compound represented by Formula II-L is used for preparation.

[0150] The H NMR spectrum of the compound represented by Formula III-L4-1 is as follows: 1 H NMR (500MHz, CDCl3) δ (ppm) 7.38–7.26 (m, 8H), 7.26–7.07 (m, 7H), 4.55 (d, J = 11 .9Hz,1H,-OCH2Ph),4.46(d,J=11.9Hz,1H,-OCH2Ph),4.36(ABq,J1=11.7Hz,2H, -OCH2Ph),4.01(d,J=6.0Hz,1H,H3),3.91(d,J=7.3Hz,1H,H2),3.73(d,J=7.4H z,1H,H4),3.54(d,J=10.6Hz,1H,H1),3.19–3.12(m,1H,H1),2.35(s,3H,-CH3);

[0151] The nuclear magnetic resonance hydrogen spectrum measurement data of the compound shown in L4-1 is: 1 H NMR(500MHz,CD3OD)δ(ppm)7.30(d,J=6.9Hz,2H),7.10(d,J=7.3Hz,2H),4.20(s,1H,H2),4.17(s, 1H, H3), 4.14 (s, 1H, H4), 3.40 (d, J = 11.2Hz, 1H, H1), 3.23 (d, J = 11.5Hz, 1H, H1), 2.18 (s, 1H, -CH3).

[0152] Test Case

[0153] The substrate 4-nitrophenolpyranoside and various enzymes used in this test example were purchased from Sigma-Aldrich.

[0154] Activity assays were performed in sodium citrate / phosphate buffer (50 m mol / L) at 37°C using 4-nitrophenolpyranoside as the substrate at the optimal activity pH for each enzyme.

[0155] The substrate, enzyme solution (0.1-0.5 mg / mL) and inhibitor (compounds D1-1, L1-1, D2-1, L2-1, D3-1, L3-1, D4-1 and L4-1 prepared in Preparation Example 1-8) were incubated at 37°C for 30 minutes, and then the reaction was started in a UV-visible spectrophotometer to test its absorption of 400 nM wavelength light.

[0156] Data analysis was performed using the GraFit program (see Leatherbarrow, RJ Grafit 4.0; Erithacus Software: Staines, UK, 1998).

[0157] The results are shown in Tables 1 and 2.

[0158] In Table 1 and Table 2, IC 50 The percentage in brackets indicates the inhibitor concentration when the inhibition rate of the enzyme is 50%; the percentage in brackets indicates the inhibition rate of the enzyme when the inhibitor concentration is 1000 μmol / L.

[0159] Table 1

[0160]

[0161] Table 2

[0162]

[0163] It can be seen from the data in Tables 1 and 2 that the compounds of the present invention have a good inhibitory effect on glycosidase, especially exhibiting good inhibitory activity on β-glucosidase.

[0164] Among β-glucosidase, the compound of the present invention shows very strong inhibitory activity against β-glucosidase derived from human lysosomes, and also has high selectivity.

[0165] In addition, when the carbon 2 of the compound represented by Formula I of the present invention is connected to a biphenyl group (ie, compounds D2 and L2), its inhibitory activity against human lysosomal-derived β-glucosidase is more significant.

[0166] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A compound, wherein The structure of the compound is any one of the following structures:

2. A salt of the compound according to claim 1.

3. The salt of the compound according to claim 2, wherein The salt of the compound is a pharmaceutically acceptable salt of the compound.

4. The salt of the compound according to claim 3, wherein The salt of the compound is one or more of hydrochloride, sulfonate, trifluoroacetate, carbonate, nitrate, phosphate, folate and acetate.

5. The salt of the compound according to claim 4, wherein The salt of the compound is the hydrochloride.

6. The salt of the compound according to claim 2, wherein The structure of the salt of the compound is any one of the following structures:

7. A glycosidase inhibitor, characterized in that The glycosidase inhibitor contains the compound according to claim 1 and / or the salt of the compound according to any one of claims 2 to 6 as an active ingredient.

8. The glycosidase inhibitor according to claim 7, wherein The glycosidase inhibitor is used to inhibit one or more of α-glucosidase, β-glucosidase, α-galactosidase, β-galactosidase, α-mannosidase, β-mannosidase, α,α-trehalase, α-L-rhamnosidase, amyloglucosidase and β-glucuronidase.

9. The glycosidase inhibitor according to claim 8, wherein The glycosidase inhibitor is used to inhibit β-glucosidase.

10. The glycosidase inhibitor according to claim 9, wherein The glycosidase inhibitor is used for inhibiting β-glucosidase derived from human lysosome.

11. Use of the compound according to claim 1 and / or the salt of the compound according to any one of claims 2 to 6 in the preparation of a medicament for preventing or treating Gaucher's disease and / or Parkinson's syndrome.

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