Compound targeting prostate specific membrane antigen as well as preparation method and application thereof

Abstract

The invention relates to a compound targeting prostate specific membrane antigen as well as a preparation method and application thereof. The compound provided by the invention has a wide application prospect in the aspects of diagnosis and treatment of diseases with high expression of prostate specific membrane antigen (PSMA). The preparation method of the compound provided by the invention has the advantages of simplicity, high efficiency and short preparation time, the marking condition of radiolabeling is simple, and the radiochemical yield is high.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a compound targeting prostate-specific membrane antigen and a preparation method and application thereof. Background Art

[0003] Prostate-specific membrane antigen (PSMA), also known as type II glutamate carboxypeptidase, is expressed 100 to 1000 times higher in prostate cancer than in normal tissues, and its expression level is directly related to the disease state. Immunohistochemical analysis shows that PSMA expression can be detected in 94% of prostate cancer samples. Due to the specific expression of PSMA in prostate cancer cells, it has become an important target for the diagnosis and treatment of prostate cancer.

[0004] In 2021, the U.S. Food and Drug Administration (FDA) approved the PSMA-targeted diagnostic drug Pylarify for positron emission tomography (PET) of PSMA-positive lesions in prostate cancer patients. With the approval of Pylarify, some men with prostate cancer will have more access to PSMA-targeted PET imaging, which can help doctors better assess their patients' condition. PSMA-1007 is another PSMA-targeted imaging agent in use. Although its effect is better than Pylarify, it still has the disadvantages of complex labeling conditions, time-consuming preparation, and low radiochemical yield. Summary of the invention

[0005] In order to solve the problems of the prior art, the present invention provides a class of compounds targeting prostate-specific membrane antigen and a preparation method and application thereof.

[0006] The specific technical solutions of the present invention are as follows:

[0007] A compound targeting prostate-specific membrane antigen has a structure as shown in formula (I):

[0008]

[0009] In formula (I):

[0010] X is C 0-10 An alkylene group, wherein the alkylene group may contain heteroatoms;

[0011] R1 is selected from hydrogen, cyano, nitro, C1-C 10 Alkyl, C1-C 10 alkoxy, halogen, carboxyl, ester, hydroxyl or fluorosulfonate;

[0012] R2 is selected from hydrogen, cyano, nitro, C1-C 10 Alkyl, C1-C10 alkoxy, halogen, carboxyl, ester, hydroxyl or fluorosulfonate;

[0013] Ar is an aromatic ring.

[0014] Further,

[0015] In formula (I):

[0016] X is C 0-6 The alkylene group, wherein the heteroatom is O and / or N;

[0017] R1 is selected from hydrogen, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, carboxyl, ester, hydroxyl or fluorosulfonate;

[0018] R2 is selected from hydrogen, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, carboxyl, ester, hydroxyl or fluorosulfonate;

[0019] Ar is selected from phenylene, naphthylene, pyridylene, furylene, thiazolylene or pyrazolylene.

[0020] Further,

[0021] In formula (I):

[0022] X is C 0-2 An alkylene group, wherein the heteroatom is N;

[0023] R1 is selected from H, OMe or CN;

[0024] R2 is selected from H, OMe or CN;

[0025] Ar is selected from phenylene, naphthylene or pyridylene.

[0026] Further, formula (I) is selected from the compounds shown in the following formula ah:

[0027]

[0028] Furthermore, the fluorine atom of the fluorosulfonate in the structural formula (I) is selected from 19 F or 18 F.

[0029] The present invention also discloses a method for preparing the above-mentioned compound, which is prepared by the following steps:

[0030]

[0031] The first step is to dissolve the compound represented by formula (II) or formula (III) in an organic solvent, add a condensing agent, an auxiliary condensing agent, and an organic base, stir at a certain temperature for a certain time, and separate and purify to obtain a compound represented by formula (IV);

[0032] In the second step, the compound represented by formula (IV) is mixed with an acid and stirred at a certain temperature for a certain period of time, and the compound represented by formula (I) is obtained by separation and purification.

[0033] Further, the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, and N,N-dimethylformamide, preferably dichloromethane;

[0034] The condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (hereinafter referred to as EDCI), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as HATU), 1-propylphosphoric acid cyclic anhydride (hereinafter referred to as T3P), preferably HATU;

[0035] The auxiliary condensing agent is selected from N-hydroxy-7-azabenzotriazole (hereinafter referred to as HOAt) and 1-hydroxybenzotriazole (hereinafter referred to as HOBt), preferably HOAt;

[0036] The organic base is selected from triethylamine (hereinafter referred to as TEA) and N,N-diisopropylethylamine (hereinafter referred to as DIPEA), preferably TEA;

[0037] The first step reaction temperature is -20 to 50 degrees Celsius, and the reaction time is 1 to 24 hours;

[0038] The preferred reaction temperature is 0 to 25 degrees Celsius and the reaction time is 8 to 12 hours;

[0039] The acid is selected from trifluoroacetic acid, hydrogen chloride-organic solution, hydrogen bromide-organic solution;

[0040] Trifluoroacetic acid is preferred;

[0041] The reaction temperature of the second step is 0 to 60 degrees Celsius and the reaction time is 2 to 20 hours;

[0042] The preferred reaction temperature is 20 to 25 degrees Celsius and the reaction time is 6 to 16 hours.

[0043] The present invention also discloses a pharmaceutical composition, comprising the fluorosulfonate compound or a pharmaceutically acceptable salt of the fluorosulfonate compound as described above, and a pharmaceutically acceptable carrier, diluent, excipient or auxiliary material.

[0044] The present invention also discloses the use of the above-mentioned compound or the above-mentioned pharmaceutical composition in the preparation of a diagnostic or therapeutic drug, a medicament or a kit for a disease with high expression of prostate surface membrane antigen.

[0045] Furthermore, the disease with high expression of prostate surface membrane antigen is specifically selected from prostate cancer and / or its metastatic lesions.

[0046] Advantages and effects of the present invention:

[0047] 1) Existing 18 The F labeling method has harsh conditions, low efficiency, and many by-products, while the compounds disclosed in the present invention can be rapidly and efficiently 18 F labeling, mild reaction conditions, is a 18 A revolutionary improvement in the F labeling method; traditional 18 The F labeling method generally requires a reaction at 100°C for 10-20 minutes, and also requires protection and deprotection processes. There are many by-products, most of which require HPLC separation and purification;

[0048] 2) The present invention relates to 18 The F-labeled compounds all contain a core OSO2F group (which, when labeled, is converted into radioactive OSO2 18 F), which can specifically target PSMA protein and perform PET imaging on PSMA-highly expressed tumors; the F isotope exchange method adopted in this method can achieve a yield of more than 90% at 80°C for 5 minutes, without the need for deprotection, with few by-products, and a simple solid phase extraction method can obtain the final product, greatly shortening the total time for drug preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 is the HPLC spectrum of compound a;

[0050] Figure 2 is the HPLC spectrum of compound b;

[0051] Figure 3 is the HPLC spectrum of compound c;

[0052] Figure 4 is the HPLC spectrum of compound d;

[0053] Figure 5 is the HPLC spectrum of compound f;

[0054] Figure 6 is the HPLC spectrum of compound h;

[0055] Figure 7 This is a typical PET / CT imaging image of compound a in a prostate cancer model;

[0056] Figure 8 This is a typical PET / CT imaging image of compound b in a prostate cancer model;

[0057] Fig. 9 This is a typical PET / CT imaging image of compound c in a prostate cancer model;

[0058] Fig.10 This is a typical PET / CT imaging image of compound d in a prostate cancer model;

[0059] Fig.11 This is a typical PET / CT imaging image of compound f in a prostate cancer model;

[0060] Fig.12 This is a typical PET / CT imaging image of compound h in a prostate cancer model;

[0061] Fig.13 This is the affinity diagram of compound a and PSMA protein;

[0062] Fig.14 This is the affinity diagram of compound b and PSMA protein;

[0063] Fig.15 This is the affinity diagram of compound c and PSMA protein;

[0064] Fig.16 is the affinity diagram of compound d and PSMA protein;

[0065] Fig.17 This is the affinity diagram of compound e and PSMA protein;

[0066] Fig.18 This is the affinity diagram of compound f and PSMA protein;

[0067] Fig.19 This is the affinity diagram of compound g and PSMA protein;

[0068] Fig. 20 This is the affinity diagram of compound h and PSMA protein. DETAILED DESCRIPTION

[0069] The present invention will be further described in detail below by way of examples, but these examples do not limit the present invention in any way.

[0070] Example 1

[0071] Preparation of compound a

[0072]

[0073] Dissolve 0.5 mmol of compound II in 6 ml of anhydrous dichloromethane, add 4-((fluorosulfonyl)oxy)benzoic acid (0.43 mmol), HATU (202.4 mg, 0.53 mmol), HOAt (72.4 mg, 0.53 mmol) and DIPEA (185 μL, 1.06 mmol) under ice-water bath conditions. Naturally warm to room temperature and stir overnight. Add 30 mL of dichloromethane to dilute, wash with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, dry and concentrate the organic layer, and separate on a preparative plate to obtain compound IVa.

[0074] IVa obtained above was dissolved in 8 ml of trifluoroacetic acid and stirred at room temperature overnight. The next day, the trifluoroacetic acid was removed by concentration under reduced pressure, and 8 ml of trifluoroacetic acid was added and stirred for 4 hours. The trifluoroacetic acid was removed by concentration under reduced pressure, and 10 ml of dichloromethane was added to dissolve it, and the mixture was concentrated under reduced pressure again. This was repeated 4 times to obtain compound a.

[0075] The structural characterization data of compound a are as follows:

[0076] 1H NMR(600MHz,DMSO-d6)δ12.29(s,3H),8.72(d,J=7.4Hz,1H),8.53(d,J=8.4Hz,1H),8.41(t,J=5.9Hz,1H),8.13(d,J=7.8Hz,1H),8.09(t,J=5.5Hz,1H),8.05(d,J=8.7Hz,2H),7.82(d,J=7.9Hz,1H),7.80-7.77(m,3H),7.74(d,J=8.1Hz,2H),7.70(d,J=8.7Hz,2H),7.50(d,J=8.8Hz,1H),7.46-7.38(m,2H),7.27(d,J=8.1Hz,2H),6.32(d,J=8.2Hz,1H),6.29(d,J=8.1Hz,1H),4.78-4.72(m,1H),4.47-4.41(m,1H),4.30(d,J=5.5Hz,2H),4.29-4.26(m,1H),4.13-4.08(m,1H),4.06-4.01(m,1H),3.24(dd,J=13.5,4.4Hz,2H),3.18-3.14(m,1H),3.14-3.06(m,2H),3.04-2.97(m,1H),2.39-2.32(m,2H),2.31-2.18(m,4H),2.10-2.02(m,1H),1.99-1.89(m,3H),1.84-1.76(m,1H),1.75-1.67(m,1H),1.66-1.58(m,1H),1.53-1.46(m,1H),1.40-1.33(m,2H),1.29-1.23(m,2H). 13 C NMR(151MHz,DMSO-d6)δ174.66,174.28,174.18,173.97,173.82,171.32,171.23,171.10,166.03,165.41,157.40,151.38,142.74,136.23,134.92,133.03,132.68,131.85,130.40,127.97,127.54,127.51,127.49,127.38,126.78,126.04,125.44,121.15,55.04,53.38,52.37,52.22,51.75,41.91,38.62,37.85,31.83,30.61,30.25,29.99,28.86,27.62,27.25,26.83,22.71. 19F NMR(376MHz,DMSO-d6)δ39.24.HRMS calcd for C 50 H 56 F7O 19 S[M+H] + :1110.3408,found 1110.3370.[α] 25 D =-6.00 (c = 0.1, CH3OH).

[0077] Example 2

[0078] Preparation of compound b

[0079]

[0080] Dissolve 0.5 mmol of compound II in 6 ml of anhydrous dichloromethane, add 3-((fluorosulfonyl)oxy)benzoic acid (0.43 mmol), HATU (202.4 mg, 0.53 mmol), HOAt (72.4 mg, 0.53 mmol) and DIPEA (185 μL, 1.06 mmol) in an ice-water bath. Naturally warm to room temperature and stir overnight. Add 30 mL of dichloromethane to dilute, wash with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, dry and concentrate the organic layer, and separate on a preparative plate to obtain compound IVb.

[0081] IVb obtained above was dissolved in 8 ml of trifluoroacetic acid and stirred at room temperature overnight. The next day, the trifluoroacetic acid was removed by concentrating under reduced pressure, and 8 ml of trifluoroacetic acid was added and stirred for 4 h. The trifluoroacetic acid was removed by concentrating under reduced pressure, and 10 ml of dichloromethane was added to dissolve the solution, and the solution was concentrated under reduced pressure again. This was repeated 4 times to obtain compound b.

[0082] The structural characterization data of compound b are as follows:

[0083] 1H NMR(600MHz,DMSO-d6)δ12.32(s,3H),8.76(d,J=7.4Hz,1H),8.53(d,J=8.4Hz,1H),8.41(t,J=5.9Hz,1H),8.18(d,J=7.8Hz,1H),8.09(t,J=5.6Hz,1H),8.05(s,1H),8.01(d,J=7.9Hz,1H),7.82(d,J=7.9Hz,1H),7.81-7.76(m,4H),7.73(d,J=8.2Hz,2H),7.68(t,J=8.0Hz,1H),7.52-7.48(m,1H),7.47-7.39(m,2H),7.27(d,J=8.2Hz,2H),6.32(d,J=8.2Hz,1H),6.29(d,J=8.1Hz,1H),4.79-4.72(m,1H),4.48-4.43(m,1H),4.30(d,J=5.7Hz,2H),4.29-4.24(m,1H),4.13-4.08(m,1H),4.06-4.00(m,1H),3.24(dd,J=13.6,4.5Hz,2H),3.18-3.14(m,1H),3.13-3.06(m,2H),3.04-2.98(m,1H),2.41-2.33(m,2H),2.31-2.18(m,4H),2.10-2.01(m,1H),1.99-1.87(m,3H),1.84-1.76(m,1H),1.76-1.66(m,1H),1.65-1.58(m,1H),1.52-1.44(m,1H),1.40-1.32(m,2H),1.28-1.2(m,2H). 13 C NMR(151MHz,DMSO-d6)δ174.66,174.28,174.17,173.97,173.83,171.29,171.25,171.11,166.03,164.76,157.41,149.57,142.77,136.66,136.23,133.03,132.66,131.86,131.04,128.44,127.98,127.54,127.51,127.49,127.39,126.77,126.05,125.45,124.11,120.21,55.04,53.38,52.37,52.28,51.76,41.90,38.63,37.85,31.83,30.63,30.27,29.99,28.86,27.62,27.25,26.85,22.71.19 F NMR(376MHz,DMSO-d6)δ39.21.HRMS calcd forC 50 H 56 F7O 19 S[M+H] + :1110.3408,found 1110.3371,[MH]:1108.3263,found 1108.3288.[α] 25 D =-8.00 (c=0.1, CH3OH).

[0084] Example 3

[0085] Preparation of compound c

[0086]

[0087] Dissolve 0.5 mmol of compound II in 6 ml of anhydrous dichloromethane, add 6-((fluorosulfonyl)oxy)-2-naphthoic acid (0.43 mmol), HATU (202.4 mg, 0.53 mmol), HOAt (72.4 mg, 0.53 mmol) and DIPEA (185 μL, 1.06 mmol) in an ice-water bath. Naturally warm to room temperature and stir overnight. Add 30 mL of dichloromethane to dilute, wash with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, dry and concentrate the organic layer, and separate on a preparative plate to obtain compound IVc.

[0088] IVc obtained above was dissolved in 8 ml of trifluoroacetic acid and stirred at room temperature overnight. The next day, the trifluoroacetic acid was removed by vacuum concentration, and 8 ml of trifluoroacetic acid was added and stirred for 4 hours. The trifluoroacetic acid was removed by vacuum concentration, and 10 ml of dichloromethane was added to dissolve it, and the vacuum concentration was repeated 4 times to obtain compound c.

[0089] The structural characterization data of compound c are as follows:

[0090] 1H NMR(600MHz,DMSO-d6)δ12.31(s,4H),8.77(d,J=7.4Hz,1H),8.61(s,1H),8.54(d,J=8.4Hz,1H),8.44(t,J=5.9Hz,1H),8.30(d,J=2.1Hz,1H),8.27(d,J=9.1Hz,1H),8.17(d,J=7.8Hz,1H),8.14(d,J=8.7Hz,1H),8.10(t,J=5.6Hz,1H),8.08-8.05(m,1H),7.83-7.76(m,5H),7.74(d,J=8.1Hz,2H),7.50(d,J=8.4Hz,1H),7.45-7.38(m,2H),7.28(d,J=8.2Hz,2H),6.32(d,J=8.3Hz,1H),6.29(d,J=8.2Hz,1H),4.78-4.72(m,1H),4.54-4.49(m,1H),4.31(d,J=6.1Hz,2H),4.30-4.28(m,1H),4.14-4.08(m,1H),4.06-4.01(m,1H),3.24(dd,J=13.6,4.4Hz,2H),3.18-3.14(m,1H),3.14-3.06(m,2H),3.05-2.97(m,1H),2.44-2.36(m,2H),2.31-2.21(m,4H),2.13-2.06(m,1H),2.02-1.89(m,3H),1.86-1.78(m,1H),1.77-1.67(m,1H),1.66-1.58(m,1H),1.53-1.44(m,1H),1.40-1.33(m,2H),1.30-1.23(m,2H). 13C NMR(151MHz,DMSO-d6)δ174.65,174.27,174.21,173.97,173.81,171.45,171.24,171.10,166.41,166.01, 157.39,148.33,142.76,136.23,134.38,133.02,132.95,132.66,132.41,131.84,131.52,128.31,128.00 ,127.97,127.54,127.50,127.48,127.37,126.77,126.27,126.02,125.42,120.12,119.06,55.04,53.37,52.36,52.24,51.75,41.91,38.62,37.84,31.82,30.67,30.26,29.98,28.86,27.62,27.30,26.93,22.70. 19 FNMR(376MHz,DMSO-d6)δ39.15.HRMS calcd for C 54 H 58 F7O 19 S[M+H] + :1160.3565,found1160.3555.[α] 25 D =-1.00 (c=0.1, CH3OH).

[0091] Example 4

[0092] Preparation of compound d

[0093]

[0094] Dissolve 0.5 mmol of compound II in 6 ml of anhydrous dichloromethane, add 6-((fluorosulfonyl)oxy)-1-naphthoic acid (0.43 mmol), HATU (202.4 mg, 0.53 mmol), HOAt (72.4 mg, 0.53 mmol) and DIPEA (185 μL, 1.06 mmol) under ice-water bath conditions. Naturally warm to room temperature and stir overnight. Add 30 mL of dichloromethane to dilute, wash with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, dry and concentrate the organic layer, and separate on a preparative plate to obtain compound IVd.

[0095] IVd obtained above was dissolved in 8 ml of trifluoroacetic acid and stirred at room temperature overnight. The next day, the trifluoroacetic acid was removed by concentration under reduced pressure, and 8 ml of trifluoroacetic acid was added and stirred for 4 h. The trifluoroacetic acid was removed by concentration under reduced pressure, and 10 ml of dichloromethane was added to dissolve the solution, and the solution was concentrated under reduced pressure again. This was repeated 4 times to obtain compound d.

[0096] The structural characterization data of compound d are as follows:

[0097] 1 H NMR(600MHz,DMSO-d6)δ12.31(s,4H),8.82(d,J=7.5Hz,1H),8.55-8.51(m,2H),8.45(d,J=9.4 Hz,1H),8.31(d,J=2.5Hz,1H),8.20(d,J=7.9Hz,1H),8.18(d,J=8.4Hz,1H),8.09(t,J=5.6Hz, 1H),7.83-7.77(m,5H),7.75(d,J=8.1Hz,2H),7.73-7.69(m,2H),7.50(d,J=9.1Hz,1H),7.46- 7.39(m,2H),7.29(d,J=8.2Hz,2H),6.32(d,J=8.2Hz,1H),6.29(d,J=8.2Hz,1H),4.78-4.72(m, 1H),4.56-4.52(m,1H),4.40-4.30(m,3H),4.13-4.08(m,1H),4.06-4.01(m,1H),3.24(dd,J=1 3.5,4.4Hz,1H),3.18-3.13(m,1H),3.14-3.06(m,2H),3.04-2.98(m,1H),2.44-2.37(m,2H),2 .34-2.21(m,4H),2.10-2.03(m,1H),2.02-1.96(m,1H),1.95-1.88(m,2H),1.87-1.80(m,1H), 1.76-1.68(m,1H),1.66-1.58(m,1H),1.52-1.46(m,1H),1.41-1.32(m,2H),1.28-1.22(m,2H). 13C NMR(151MHz,DMSO-d6)δ174.65,174.27,174.13,174.01,173.81,171.39,171.27,171.08,168.34,166.01, 157.39,147.36,142.76,136.22,134.56,133.44,133.02,132.68,131.84,130.33,129.28,129.23,127.97 ,127.55,127.50,127.48,127.37,127.13,127.04,126.75,126.02,125.42,119.92,119.42,55.04,53.16,52.36,52.19,51.75,41.92,38.62,37.84,31.82,30.62,30.19,29.98,28.86,27.62,27.54,26.80,22.70. 19 F NMR(376MHz,DMSO-d6)δ39.03.HRMS calcd for C 54 H 58 F7O 19 S[M+H] + :1160.3565,found 1160.3555.[α] 25 D =-14.00 (c=0.1, CH3OH).

[0098] Example 5

[0099] Preparation of compound e

[0100]

[0101] Dissolve 0.5 mmol of compound II in 6 ml of anhydrous dichloromethane, add 5-((fluorosulfonyl)oxy)nicotinic acid (0.43 mmol), HATU (202.4 mg, 0.53 mmol), HOAt (72.4 mg, 0.53 mmol) and DIPEA (185 μL, 1.06 mmol) in an ice-water bath. Naturally warm to room temperature and stir overnight. Add 30 mL of dichloromethane to dilute, wash with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, dry and concentrate the organic layer, and separate on a preparative plate to obtain compound IVe.

[0102] IVe obtained above was dissolved in 8 ml of trifluoroacetic acid and stirred at room temperature overnight. The next day, the trifluoroacetic acid was removed by concentration under reduced pressure, and 8 ml of trifluoroacetic acid was added and stirred for 4 hours. The trifluoroacetic acid was removed by concentration under reduced pressure, and 10 ml of dichloromethane was added to dissolve it, and the mixture was concentrated under reduced pressure again. This was repeated 4 times to obtain compound e.

[0103] The structural characterization data of compound e are as follows:

[0104] 1 H NMR (600MHz, DMSO-d6) δ12.31(s,2H),9.16(d,J=1.4Hz,1H),9.06(d,J=2.6Hz,1H),8.98(d,J=7 .5Hz,1H),8.55-8.49(m,2H),8.43(t,J=5.9Hz,1H),8.23(d,J=7.7Hz,1H),8.09(t,J=5.6Hz,1H ),7.82(d,J=7.9Hz,1H),7.80-7.77(m,3H),7.73(d,J=8.2Hz,2H),7.50(d,J=8.6Hz,1H),7.47- 7.40(m,2H),7.27(d,J=8.2Hz,2H),6.33(d,J=8.2Hz,1H),6.29(d,J=8.1Hz,1H),4.77-4.72(m, 1H),4.52-4.47(m,1H),4.30(d,J=5.8Hz,2H),4.29-4.25(m,1H),4.13-4.08(m,1H),4.06-4.00 (m,1H),3.24(dd,J=13.5,4.4Hz,1H),3.16-3.12(m,1H),3.11-3.06(m,1H),3.03-2.97(m,1H), 2.42-2.34(m,2H),2.32-2.19(m,4H),2.12-2.04(m,1H),1.99-1.88(m,3H),1.85-1.76(m,1H), 1.74-1.67(m,1H),1.65-1.58(m,1H),1.53-1.44(m,1H),1.41-1.33(m,2H),1.28-1.24(m,2H). 13C NMR(151MHz,DMSO-d6)δ174.66,174.28,174.14,173.98,173.84,171.26,171.12,171.06,166.0 4,163.39,157.42,149.27,146.65,145.13,142.79,136.23,133.04,132.67,131.86,131.50,12 8.51,127.99,127.54,127.52,127.50,127.39,126.75,126.05,125.45,55.05,53.30,52.38,52.35,51.76,41.90,38.63,37.86,31.83,30.58,30.29,30.00,28.86,27.62,27.22,26.93,22.71. 19 F NMR(376MHz,DMSO-d6)δ40.28.HRMS calcd forC 49 H 55 F8O 19 S[M+H] + :1111.3361,found 1111.3351.[α] 25 D =-10.00 (c=0.1, CH3OH).

[0105] Example 6

[0106] Preparation of compound f

[0107]

[0108] Dissolve 0.5 mmol of compound II in 6 ml of anhydrous dichloromethane, add 4-((fluorosulfonyl)oxy)-3-methoxybenzoic acid (0.43 mmol), HATU (202.4 mg, 0.53 mmol), HOAt (72.4 mg, 0.53 mmol) and DIPEA (185 μL, 1.06 mmol) under ice-water bath conditions. Naturally warm to room temperature and stir overnight. Add 30 mL of dichloromethane to dilute, wash with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, dry and concentrate the organic layer, and separate on a preparative plate to obtain compound IVf.

[0109] IVf obtained above was dissolved in 8 ml of trifluoroacetic acid and stirred at room temperature overnight. The next day, the trifluoroacetic acid was removed by vacuum concentration, and 8 ml of trifluoroacetic acid was added and stirred for 4 h. The trifluoroacetic acid was removed by vacuum concentration, and 10 ml of dichloromethane was added to dissolve it, and the vacuum concentration was repeated 4 times to obtain compound f.

[0110] The structural characterization data of compound f are as follows:

[0111] 1 H NMR (600MHz, DMSO-d6) δ12.33(s,3H),8.71(d,J=7.4Hz,1H),8.53(d,J=8.2Hz,1H),8.43(t,J =5.3Hz,1H),8.15(d,J=7.6Hz,1H),8.09(t,J=4.7Hz,1H),7.81(d,J=7.7Hz,1H),7.80-7.76( m,3H),7.75-7.72(m,3H),7.68(d,J=8.3Hz,1H),7.58(d,J=8.3Hz,1H),7.50(d,J=8.4Hz,1H) ,7.46-7.38(m,2H),7.27(d,J=7.8Hz,2H),6.32(d,J=8.0Hz,1H),6.29(d,J=7.9Hz,1H),4.78- 4.72(m,1H),4.50-4.44(m,1H),4.30(d,J=5.2Hz,2H),4.29-4.25(m,1H),4.13-4.07(m,1H), 4.06-4.00(m,1H),3.94(s,3H),3.26-3.20(m,1H),3.15-3.06(m,2H),3.04-2.97(m,1H),2.3 9-2.33(m,2H),2.30-2.19(m,4H),2.10-2.02(m,1H),2.00-1.88(m,3H),1.85-1.76(m,1H),1 .74-1.67(m,1H),1.64-1.58(m,1H),1.53-1.44(m,1H),1.40-1.32(m,2H),1.30-1.23(m,2H). 13C NMR(151MHz,DMSO-d6)δ174.56,174.18,174.09,173.88,173.73,171.21,171.17,171.01,165.93,1 65.24,157.32,150.25,142.67,139.87,136.13,135.88,132.93,132.56,131.75,127.88,127.44,12 7.41,127.39,127.28,126.65,125.94,125.34,122.30,120.56,113.39,56.66,54.95,53.21,52.27,52.18,51.66,41.80,38.52,37.75,31.72,30.53,30.15,29.89,28.76,27.52,27.16,26.77,22.61. 19 F NMR(376MHz,DMSO-d6)δ41.20.HRMS calcd for C 51 H 58 F7O 20 S[M+H] + :1140.3514,found 1140.3488.[α] 25 D =-8.00 (c=0.1, CH3OH).

[0112] Example 7

[0113] Preparation of compound g

[0114]

[0115] Dissolve 0.5 mmol of compound II in 6 ml of anhydrous dichloromethane, add 3-cyano-4-((fluorosulfonyl)oxy)benzoic acid (0.43 mmol), HATU (202.4 mg, 0.53 mmol), HOAt (72.4 mg, 0.53 mmol) and DIPEA (185 μL, 1.06 mmol) under ice-water bath conditions. Naturally warm to room temperature and stir overnight. Add 30 mL of dichloromethane to dilute, wash with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, dry and concentrate the organic layer, and separate on a preparative plate to obtain compound IVg.

[0116] IVg obtained above was dissolved in 8 ml of trifluoroacetic acid and stirred at room temperature overnight. The next day, the trifluoroacetic acid was removed by concentration under reduced pressure, and 8 ml of trifluoroacetic acid was added and stirred for 4 hours. The trifluoroacetic acid was removed by concentration under reduced pressure, and 10 ml of dichloromethane was added to dissolve it, and the mixture was concentrated under reduced pressure again. This was repeated 4 times to obtain compound g.

[0117] The structural characterization data of compound g are as follows:

[0118] 1 H NMR (600MHz, DMSO-d6) δ12.30(s,4H),8.87(d,J=7.4Hz,1H),8.60(d,J=2.2Hz,1H),8.53(d,J=8. 4Hz, 1H), 8.40 (t, J = 5.9Hz, 1H), 8.32 (dd, J = 8.8, 2.2Hz, 1H), 8.18 (d, J = 7.8Hz, 1H), 8.10 (t, J = 5. 6Hz,1H),8.04(d,J=8.7Hz,1H),7.82(d,J=7.9Hz,1H),7.80-7.77(m,3H),7.74(d,J=8.2Hz,2H), 7.50(d,J=9.4Hz,1H),7.46-7.40(m,2H),7.27(d,J=8.2Hz,2H),6.32(d,J=8.2Hz,1H),6.29(d,J= 8.1Hz,1H),4.78-4.73(m,1H),4.49-4.43(m,1H),4.30(d,J=5.9Hz,2H),4.29-4.25(m,1H),4.13 -4.08(m,1H),4.06-4.01(m,1H),3.24(dd,J=13.5,4.4Hz,1H),3.16-3.07(m,2H),3.04-2.97(m,1 H),2.41-2.33(m,2H),2.30-2.19(m,4H),2.10-2.02(m,1H),1.98-1.89(m,3H),1.84-1.75(m,1H ),1.75-1.67(m,1H),1.66-1.58(m,1H),1.53-1.45(m,1H),1.41-1.34(m,2H),1.30-1.23(m,2H). 13C NMR(151MHz,DMSO-d6)δ174.65,174.27,174.13,173.95,173.81,171.20,171.09,171.04,166.01,1 63.71,157.39,150.61,142.74,136.22,135.53,135.44,134.22,133.02,132.66,131.84,127.97,12 7.53,127.50,127.47,127.37,126.77,126.02,125.42,122.92,113.35,106.04,55.03,53.44,52.36,52.27,51.74,41.90,38.61,37.85,31.82,30.55,30.27,29.98,28.86,27.61,27.22,26.91,22.70. 19 F NMR(376MHz,DMSO-d6)δ41.70.HRMS calcdfor C 51 H 55 F8O 19 S[M+H] + :1135.3361,found 1135.3357.[α] 25 D =-7.00 (c = 0.1, CH3OH).

[0119] Example 8

[0120] Preparation of compound h

[0121]

[0122] Dissolve 0.5 mmol of compound II in 6 ml of anhydrous dichloromethane, and add (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((fluorosulfonyl)oxy)phenyl)propanoic acid (0.43 mmol), HATU (202.4 mg, 0.53 mmol), HOAt (72.4 mg, 0.53 mmol) and DIPEA (185 μL, 1.06 mmol) under ice-water bath conditions. Naturally warm to room temperature and stir overnight. Add 30 mL of dichloromethane to dilute, wash with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, dry and concentrate the organic layer, and separate on a preparative plate to obtain compound IVh.

[0123] IVh obtained above was dissolved in 8 ml of trifluoroacetic acid and stirred at room temperature overnight. The next day, the trifluoroacetic acid was removed by concentration under reduced pressure, and 8 ml of trifluoroacetic acid was added and stirred for 4 h. The trifluoroacetic acid was removed by concentration under reduced pressure, and 10 ml of dichloromethane was added to dissolve it, and the mixture was concentrated under reduced pressure again. This was repeated 4 times to obtain compound h.

[0124] The structural characterization data of compound h are as follows:

[0125] 1 H NMR(600MHz,DMSO-d6)δ12.34(s,3H),8.71(d,J=7.8Hz,1H),8.55-8.49(m,2H),8 .29(d,J=7.7Hz,1H),8.16(s,3H),8.11(t,J=5.6Hz,1H),7.82(d,J=7.9Hz,1H),7 .80-7.77(m,3H),7.74(d,J=8.1Hz,2H),7.54(d,J=8.6Hz,2H),7.50(d,J=8.7Hz, 1H),7.47-7.39(m,4H),7.27(d,J=8.2Hz,2H),6.33(d,J=8.2Hz,1H),6.30(d,J=8. 2Hz,1H),4.78-4.72(m,1H),4.42-4.38(m,1H),4.33-4.26(m,3H),4.15-4.07(m, 2H),4.06-4.02(m,1H),3.24(dd,J=13.5,4.3Hz,1H),3.16-3.06(m,3H),3.04-2. 96(m,2H),2.33-2.19(m,6H),1.98-1.88(m,3H),1.84-1.76(m,2H),1.74-1.67(m ,1H),1.66-1.58(m,1H),1.52-1.44(m,1H),1.40-1.32(m,2H),1.30-1.24(m,2H). 13C NMR (151MHz, DMSO-d6) δ174.67,174.28,174.05,173.92,173.84,171.13,170.62,167.78,166. 02,157.42,149.05,142.78,136.32,136.23,133.04,132.69,132.09,131.87,127.99,127.56,1 27.53,127.49,127.39,126.78,126.06,125.46,121.19,55.04,53.10,52.38,52.25,52.04,51.77,41.91,38.64,37.87,36.25,31.84,30.28,30.16,30.00,28.86,27.86,27.63,27.49,22.72. 19 F NMR(376MHz,DMSO-d6)δ38.31.HRMS calcd for C 52 H 61 F8O 19 S[M+H] + :1153.3830,found 1153.3807,[MH]:1151.3685,found 1151.3742.[α] 25 D =-6.00 (c = 0.1, CH3OH).

[0126] Example 9

[0127] radioactivity 18 F Mark:

[0128] radioactivity of compound ah 18 F labeling, the specific labeling process is as follows: Compounds ah are dissolved in anhydrous DMSO, and then dried activated F-18 ions are added, reacted at 80°C for 10 minutes, and then diluted with water, solid phase extracted with C18 column, washed with water to remove DMSO and free F-18 ions, and then eluted with ethanol. Among them, the labeled compound with radiochemical purity> 99% can be obtained 18 Fa, 18 Fb, 18 Fc, 18 Fd, 18 Ff and 18 Fh; Compounds e and g cannot be 18 F labeling. The radioactive HPLC spectra of the above 6 labeled compounds are shown in Figure 1-6 .

[0129] Example 10

[0130] In vivo PET / CT imaging of prostate cancer in mice:

[0131] SCID mice, male, weighing 18-20 g, were provided by Shanghai Slake Experimental Animal Co., Ltd. and raised in the SPF animal laboratory of the Experimental Animal Department of Fudan University. After two days of adaptive breeding in the animal room, LNCaP human prostate cancer cells were injected subcutaneously into the nude mice’s armpits with an injection volume of 0.2 ml (1×10 7 cells / ml dispersed in 50% matrix gel). Continue to culture for 4-6 weeks after injection until the solid tumor mass grows to 500-600mm 3 Used for imaging experiments.

[0132] Inject approximately 150 μCi of 18 Fa, 18 Fb, 18 Fc, 18 Fd, 18 Ff and 18 Fh were injected into mice, and PET / CT imaging was performed 1h and 2h after injection. Figure 7-12 .

[0133] Embodiment 11

[0134] PSMA protein affinity experiment:

[0135] Human recombinant PSMA (rhPSMA) was diluted to 0.4 μg / mL with assay buffer (50 mM HEPES, 0.1 M NaCl, pH 7.5). The substrate Ac-Asp-Glu (final concentration 40 μM) was mixed with compound ah at concentrations ranging from 0.001 nM to 10000 nM in a final volume of 125 μL of assay buffer. After mixing, 125 μL of rhPSMA solution (0.4 μg / mL) was added and incubated at 37°C for 1 h. The reaction was stopped by heating at 95°C for 5 minutes. 250 μL of 15 mM o-phthalaldehyde solution was added to all vials and incubated at room temperature for 10 minutes. Finally, 200 μL of the reaction solution was loaded onto a black 96-well plate and read using a microplate reader at excitation and emission wavelengths of 330 and 450 nm, respectively. The results are shown in the following table. The final results obtained using Graphpad processing are shown in Figure 13-20 .

[0136] Table 1

[0137] Compound <![CDATA[IC 50 (nM)]]> 95%CI(nM) a 5.151 3.591-7.375 b 2.145 1.465-3.148 c 2.580 1.903-3.496 d 3.391 2.639-4.342 e 1.854 1.328-2.588 f 2.967 2.079-4.240 g 3.346 2.279-4.891 h 4.159 3.245-5.318

[0138] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable ordinary technicians in the field to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made based on the essence of the content of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound targeting prostate-specific membrane antigen, characterized in that: Having the structure shown in formula (I): In formula (I): X is C 0-10 An alkylene group, wherein the alkylene group may contain heteroatoms; R1 is selected from hydrogen, cyano, nitro, C1-C 10 Alkyl, C1-C 10 alkoxy, halogen, carboxyl, ester, hydroxyl or fluorosulfonate; R2 is selected from hydrogen, cyano, nitro, C1-C 10 Alkyl, C1-C 10 alkoxy, halogen, carboxyl, ester, hydroxyl or fluorosulfonate; Ar is an aromatic ring.

2. The compound according to claim 1, characterized in that In formula (I): X is C 0-6 The alkylene group, wherein the heteroatom is O and / or N; R1 is selected from hydrogen, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, carboxyl, ester, hydroxyl or fluorosulfonate; R2 is selected from hydrogen, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, carboxyl, ester, hydroxyl or fluorosulfonate; Ar is selected from phenylene, naphthylene, pyridylene, furylene, thiazolylene or pyrazolylene.

3. The compound according to claim 1, characterized in that In formula (I): X is C 0-2 An alkylene group, wherein the heteroatom is N; R1 is selected from H, OMe or CN; R2 is selected from H, OMe or CN; Ar is selected from phenylene, naphthylene or pyridylene.

4. The compound according to claim 1, characterized in that Formula (I) is selected from the compounds shown in the following formula ah:

5. The compound according to claim 1, characterized in that The fluorine atom of the fluorosulfonate in the structural formula (I) is selected from 19 F or 18 F.

6. The method for preparing the compound according to claim 1, characterized in that: Prepared by the following steps: The first step is to dissolve the compound represented by formula (II) or formula (III) in an organic solvent, add a condensing agent, an auxiliary condensing agent, and an organic base, stir at a certain temperature for a certain time, and separate and purify to obtain a compound represented by formula (IV); In the second step, the compound represented by formula (IV) is mixed with an acid and stirred at a certain temperature for a certain period of time, and the compound represented by formula (I) is obtained by separation and purification.

7. The preparation method according to claim 6, characterized in that: The organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, and N,N-dimethylformamide; The condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and 1-propylphosphoric acid cyclic anhydride; The auxiliary condensing agent is selected from N-hydroxy-7-azabenzotriazole and 1-hydroxybenzotriazole; The organic base is selected from triethylamine and N,N-diisopropylethylamine; The first step reaction temperature is -20 to 50 degrees, and the reaction time is 1 to 24 hours; The acid is selected from trifluoroacetic acid, hydrogen chloride-organic solution, hydrogen bromide-organic solution; The reaction temperature of the second step is 0 to 60 degrees, and the reaction time is 2 to 20 hours.

8. A pharmaceutical composition, characterized in that The invention comprises the fluorosulfonate compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt of the fluorosulfonate compound, and a pharmaceutically acceptable carrier, diluent, excipient or auxiliary material.

9. Use of the compound according to any one of claims 1 to 5 or the pharmaceutical composition according to any one of claims 8 in the preparation of a diagnostic or therapeutic drug, medicament or kit for a disease with high expression of prostate surface membrane antigen.

10. The use according to claim 9, characterized in that The disease with high expression of prostate surface membrane antigen is specifically prostate cancer and / or its metastatic lesions.

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