A nitrogen-containing compound, a method for preparing the same, and a use thereof

Abstract

The application discloses a nitrogen-containing compound and a preparation method and application thereof. The application specifically discloses a compound as shown in formula I or a pharmaceutically acceptable salt thereof, which has one or more advantages of accurate targeting of tumor cells, long tumor retention and inhibition time, and safe use in diagnosis, staging and / or treatment of malignant tumors.

Description

Technical Field

[0001] This invention relates to a nitrogen-containing compound, its preparation method, and its uses. Background Technology

[0002] In recent years, radiopharmaceuticals targeting fibroblast activating protein (FAP) have attracted significant attention in the integrated diagnosis and treatment of malignant tumors. FAP is a protein expressed in the tumor stroma, playing a crucial role in tumor progression and metastasis, and is an important target for tumor diagnosis and treatment. By labeling FAP, radiopharmaceuticals can precisely target tumor cells and surrounding stromal cells in vivo, enabling non-invasive, visual diagnosis and internal radiation therapy for malignant tumors. FAP-2286 exhibits high affinity for both recombinant FAP protein and FAP expressed on the surface of fibroblasts, and demonstrates longer tumor retention and inhibition times than other FAP-targeting inhibitors, making it safe for use in the diagnosis, staging, and restaging of malignant tumors.

[0003] Given the importance of diagnosis and treatment of malignant tumors, there is an urgent need to develop a radioactive compound that has good targeting, long tumor retention and inhibition time, and can be safely used for the diagnosis, staging and / or treatment of malignant tumors. Summary of the Invention

[0004] The technical problem this invention aims to solve is to overcome the deficiency of existing technologies in the use of single compounds for the diagnosis and treatment of malignant tumors. To this end, this invention provides a nitrogen-containing compound, its preparation method, and its uses. The compound of this invention has one or more of the following advantages: precise targeting of tumor cells, long-term tumor retention and inhibition, and safe use for the diagnosis, staging, and / or treatment of malignant tumors.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0006] This invention provides a compound I or a pharmaceutically acceptable salt thereof.

[0007]

[0008] A consists of a chelating group and a radioactive nuclide;

[0009] X is (*Position directly related to L) 2 (connected);

[0010] n1 is an integer selected from 1 to 20;

[0011] n2 is selected from integers from 1 to 10;

[0012] L 1 and L 2 Independently -C1-C6 alkylene-;

[0013] R is In one embodiment of the present invention, compound I is

[0014] Preferably, compound I is selected from the following structures:

[0015] More preferably, compound I is selected from the following structures:

[0016] In one aspect of the present invention, in A, the chelating group is a conventional chelating group in the art; preferably, the chelating group is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), or 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTA-GA). Based on the structures of 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODA-GA), diethylenetriaminepentaacetic acid (DTPA), N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC), or mercaptoacetyltriglycine (MAG3), a structure is formed by removing a hydroxyl group from a carboxyl group, such as the structure formed by removing a hydroxyl group from a carboxyl group in DOTA.

[0017] In one embodiment of the present invention, n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, for example, n1 is an integer from 1 to 10, or n1 is 2.

[0018] In one embodiment of the present invention, n2 is 1, 2, 3, 4, 5, 6, 7, 8 or 9, for example, n2 is an integer from 1 to 5, or n2 is 1.

[0019] In one aspect of the present invention, L 1 and L 2 In this context, "-C1-C6 alkylene-" is independently -C1-C3 alkylene-, for example...

[0020] In one aspect of the present invention, L 1 In the text, "-C1-C6 alkylene-" refers to...

[0021] In one aspect of the present invention, L 2In the text, "-C1-C6 alkylene-" refers to...

[0022] In one embodiment of the present invention, in A, the chelating group is chelated with a radionuclide.

[0023] In one embodiment of the present invention, the radionuclide is a diagnostic radionuclide or a therapeutic radionuclide.

[0024] In one embodiment of the present invention, the diagnostic radionuclide is 18 F, 68 Ga、 99m Tc or 64 Cu.

[0025] In one embodiment of the present invention, the therapeutic radionuclide is 177 Lu、 188 Re、 225 Ac、 212 Pb, 211 At or 67 Cu.

[0026] In one embodiment of the present invention, the radioactive nuclide is 18 F, 68 Ga、 177 Lu、 99m Tc, 188 Re、 64 Cu、 67 Cu、 225 Ac、 212 Pb or 211 At.

[0027] In one aspect of the present invention, the valence state of the radionuclide is monovalent, divalent, trivalent, or tetravalent, for example, trivalent.

[0028] In one embodiment of the present invention, A is... Composed of radioactive nuclides, wherein the radioactive nuclides are 177 Lu or 68 Ga; preferably, A is composed of It is composed of a chelate with a radioactive nuclide, wherein the radioactive nuclide is 177 Lu or 68 Ga, for example

[0029] In one embodiment of the present invention, the structure of compound I is as follows:

[0030]

[0031] The present invention also provides compound II or a pharmaceutically acceptable salt thereof.

[0032]

[0033] B consists of chelating groups and non-radioactive nuclides;

[0034] The chelating groups, X, L 1 L 2 The definitions of R and R are as described in any of the previous schemes.

[0035] In one embodiment of the present invention, the non-radioactive nuclide is F, Ga, Lu, Tc, Re, Cu, Cu, Ac, Pb, or At.

[0036] In one embodiment of the present invention, compound II is

[0037]

[0038] The present invention also provides a compound III or a pharmaceutically acceptable salt thereof.

[0039]

[0040] Wherein, C is a chelating group;

[0041] The chelating groups, X, L 1 L 2 The definitions of R and R are as described in any of the previous schemes.

[0042] In one embodiment of the present invention, compound III is

[0043]

[0044] The present invention also provides a pharmaceutical composition comprising substance D and a pharmaceutical excipient, wherein substance D is a pharmaceutically acceptable salt of said compound I, compound II, compound III or thereof (“therefore” represents said compound I, compound II or compound III).

[0045] The present invention also provides a kit comprising substance D and instructions, wherein substance D is a pharmaceutically acceptable salt of said compound I, compound II, compound III or thereof (“therefore” represents said compound I, compound II or compound III).

[0046] The present invention also provides the use of substance D in the preparation of a medicament for treating diseases associated with FAP, wherein substance D is a pharmaceutically acceptable salt of compound I, compound II, compound III or thereof (“therefore” represents compound I, compound II or compound III);

[0047] The FAP-related diseases are preferably cancers with high FAP expression, more preferably pancreatic cancer, breast cancer, ovarian cancer, or rectal cancer.

[0048] The present invention also provides the use of said compound I, compound III or a pharmaceutically acceptable salt thereof (“therefore” represents said compound I or compound III) in the preparation of a medicament for treating and / or preventing cancer.

[0049] The cancer is preferably a cancer with high FAP expression, more preferably pancreatic cancer, breast cancer, ovarian cancer or rectal cancer.

[0050] The present invention also provides the use of said compound I, compound III or a pharmaceutically acceptable salt thereof (“therefore” represents said compound I or compound III) in the preparation of a developer.

[0051] The imaging agent is preferably an imaging agent used for diagnosing cancer; the cancer is preferably a cancer with high FAP expression, such as pancreatic cancer, breast cancer, ovarian cancer, or rectal cancer.

[0052] The present invention also provides a compound IV or a pharmaceutically acceptable salt thereof.

[0053]

[0054] Among them, L 1 The definition is as described in the previous scheme.

[0055] In one embodiment of the present invention, compound IV is

[0056]

[0057] Terminology Explanation:

[0058] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.

[0059] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1 to C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0060] In this invention, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group.1-6 Alkylene refers to an alkylene having 1 to 6 carbon atoms, such as methylene, ethylene (e.g., -CH2CH2-, -CH(CH3)-), propylene (e.g., -CH2CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-), butylene (e.g., -CH2CH2CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)CH2-), n-pentylene, or n-hexylene.

[0061] In this invention, the term "alkeneoxy" refers to -O-alkylene-, wherein the definition of alkylene is as described above.

[0062] In this invention, the term "alkylenethionyl" refers to -S-alkylene-, wherein the definition of alkylene is as described above.

[0063] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6 to C5). 10 Aryl groups are cyclic groups consisting only of carbon atoms, and can be monocyclic or fused-ring. Aryl groups include, but are not limited to, phenyl or naphthyl groups.

[0064] The terms "pharmaceuticalally acceptable excipients" and "pharmaceutical excipients" refer to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. They are all substances included in pharmaceutical preparations, excluding the active ingredient. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009).

[0065] The term “treatment” refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; or (3) slowing the development of one or more biological manifestations of a disease.

[0066] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0067] The reagents and raw materials used in this invention are all commercially available.

[0068] The positive and progressive effects of this invention are as follows: the compounds of this invention have one or more of the following advantages: precise targeting of tumor cells, long duration of tumor retention and inhibition, and safe use for the diagnosis, staging, and treatment of malignant tumors. Attached Figure Description

[0069] Figure 1 for 177 SPECT / CT images of Lu-DOTA-Tri-FAP2286 in mice after 0.5 h;

[0070] Figure 2 for 177 SPECT / CT images of Lu-DOTA-Tri-FAP2286 in mice after 1 hour;

[0071] Figure 3 for 177 SPECT / CT images of Lu-DOTA-Tri-FAP2286 in mice after 2 hours;

[0072] Figure 4 for 177 SPECT / CT images of Lu-DOTA-Tri-FAP2286 in mice after 4 hours;

[0073] Figure 5 for 177 SPECT / CT images of Lu-DOTA-Tri-FAP2286 in mice after 6 hours;

[0074] Figure 6 for 177 SPECT / CT images of Lu-DOTA-Tri-FAP2286 in mice after 24 hours;

[0075] Figure 7 for 177 SPECT / CT images of Lu-DOTA-Tri-FAP2286 in mice after 48 hours;

[0076] Figure 8 for 177 SPECT / CT images of Lu-DOTA-Tri-FAP2286 in mice after 72 hours. Detailed Implementation

[0077] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0078] Example 1 Radionuclide 177 Lu marks DOTA-N3

[0079] DOTA-N3 solution preparation: DOTA-N3 (Formula 1) was prepared by dissolving it in a 0.5M acetate-sodium acetate buffer solution with a pH of 5.2±0.1, wherein the concentration of DOTA-N3 was 0.2 mg / mL.

[0080] 8μL 177A mixture of LuCl3 solution (radioactivity approximately 3.8 mCi, solvent 0.04 mol / L hydrochloric acid) and 35 μL LOTA-N3 solution was heated at 95 °C for 15 min to obtain a solution containing... 177 The reaction solution of Lu-DOTA-N3 (43 μL) showed a labeling rate of 87.58% as detected by Radio-HPLC (see Table 1 below); among which, chromatographic peak 4 was... 177 The chromatographic peak corresponding to Lu-DOTA-N3.

[0081]

[0082] Radio-HPLC detection conditions:

[0083] Column: ZORBAX Eclipse Plus C18 (4.6mm × 250mm, 5μm)

[0084] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN. Gradient: 0-5-10-14-15-17 min, 1-1-10-10-1-1%. Flow rate: 1 mL / min.

[0085] Wavelength: 220nm

[0086] Column temperature: 30℃.

[0087] Table 1

[0088]

[0089] Example 2 Click Chemical Reaction

[0090] Synthetic route of FAP2286-alkynyl group:

[0091]

[0092] Compd 1 (1 eq) was dissolved in DMF solvent, TEA was added, and the pH was adjusted to 8.5. Then, 1,3,5-tris(bromomethyl)benzene (1.5 eq) and cysteamine (10 eq) were added to the mixture. The mixture was allowed to react at room temperature for 2 h. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under vacuum, dried, and purified by reverse phase to obtain Compd2.

[0093] Compd2 (1 eq) was dissolved in DMF, and then DIPEA (5 eq) and compd3 (2 eq) were added sequentially. The mixture was reacted at room temperature for 2 hours. The reaction was monitored by LC-MS. After the reactants were completely reacted, the mixture was concentrated under vacuum, dried, and purified by reversed-phase chromatography to obtain the target product FAP2286-alkynyl.

[0094] Preparation of FAP2286-alkynyl solution: FAP2286-alkynyl is prepared by dissolving FAP2286-alkynyl in DMF, wherein the concentration of FAP2286-alkynyl is 0.7 mg / mL.

[0095] Preparation of copper sulfate solution: Copper sulfate was prepared by dissolving it in a 0.5M acetate-sodium acetate buffer solution with a pH of 5.2±0.1, wherein the concentration of copper sulfate was 3.2 mg / mL.

[0096] Preparation of sodium ascorbate solution: Sodium ascorbate was prepared by dissolving sodium ascorbate in 0.5M acetate-sodium acetate buffer solution with pH 5.2±0.1, wherein the concentration of sodium ascorbate was 15 mg / mL.

[0097] 45 μL of FAP2286-alkynyl solution was mixed with the aforementioned... 177 The reaction mixture of 42 μL of Lu-DOTA-N3, 13 μL of copper sulfate solution, and 15 μL of sodium ascorbate solution was mixed and heated at 40 °C for 60 min to obtain a solution containing Lu-DOTA-N3. 177 115 μL of the reaction solution of Lu-DOTA-Tri-FAP2286 was analyzed by Radio-HPLC under the same analytical conditions. 177 The peak position of Lu-DOTA-Tri-FAP2286 and the cold reference compound 175 Lu-DOTA-Tri-FAP2286 (cold reference compound uses non-radioactive raw materials, employing...) 177 It was prepared using a similar method to Lu-DOTA-Tri-FAP2286; the molecular weight of the product was determined by LC-MS. 175 The value of Lu-DOTA-Tri-FAP2286 is consistent with the theoretical value; confirmed by Radio-HPLC detection. 175 The peak positions of Lu-DOTA-Tri-FAP2286 were consistent. The labeling rate, as determined by Radio-HPLC, was 41.05%, as shown in Table 2 below; among which, peak 8 was... 177 The chromatographic peak corresponding to Lu-DOTA-Tri-FAP2286.

[0098] The aforementioned 177 115 μL of the reaction solution of Lu-DOTA-Tri-FAP2286 was diluted to 2 mL with sterile water for injection to prepare the purification solution. The 2 mL purification solution was purified by C18 column to obtain a product with a radiochemical purity of 96.31%, as shown in Table 3 below; among them, chromatographic peak 6 is the chromatographic peak corresponding to 177Lu-DOTA-Tri-FAP2286.

[0099]

[0100] Radio-HPLC detection conditions:

[0101] Column: ZORBAX Eclipse Plus C18 (4.6mm × 250mm, 5μm)

[0102] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN

[0103] Gradient: 0-20-22-27-30-35min, 20-40-40-100-20-20% B

[0104] Flow rate: 1 mL / min

[0105] Wavelength: 220nm

[0106] Column temperature: 30℃

[0107] C18 column purification conditions (C18 column model: Waters, Sep-Pak Light-C18 solid phase extraction column):

[0108] C18 column activation: First rinse the C18 column with 5 mL of ethanol, then rinse with 5 mL of sterile water for injection.

[0109] C18 column purification: Pass 2 mL of the above-mentioned solution to be purified through a C18 column (i.e., elute onto a C18 column); rinse the C18 column with 1.5 mL of sterile water for injection to remove radioactive impurities; rinse the C18 column with 0.5 mL of anhydrous ethanol, and collect the eluent with the higher concentration to obtain the target product: 177 0.4 mL of an ethanol solution of Lu-DOTA-Tri-FAP2286.

[0110] Table 2

[0111]

[0112]

[0113] Table 3

[0114]

[0115] Example 3 In vitro stability

[0116] 60 μL of the target product obtained in Example 2 was diluted with 1 mL of 0.5 M acetate-sodium acetate buffer solution at pH 5.2 and placed in a stability test chamber at 25 °C. The initial radiochemical purity of the target product was 96.31%, and after 24 h, the radiochemical purity of the target product remained essentially unchanged at 95.65%.

[0117] Example 4: Effect Example

[0118] Preparation of radioactive injection solution: The target product obtained in Example 2 (i.e., 177 The ethanol solution of Lu-DOTA-Tri-FAP2286 was prepared by diluting it with 0.5M acetate-sodium acetate buffer at pH 5.2.

[0119] (1) Biodistribution studies:

[0120] Using BxPC-3 pancreatic cancer model mice, radioactive injection solution was injected into the mice via the tail vein (approximately 100 μCi / mouse, 4 mice / group, for a total of four groups). The animals were sacrificed at 0.5 h, 1 h, 4 h, and 24 h after injection. The tissues and organs of interest were dissected and weighed. The radioactivity count was measured using a gamma counter, and the ID% / g of the tissues and organs was calculated (calculation formula: ID% / g = tissue count / total count in the injected mouse / tissue weight * 100%).

[0121] (2) Animal SPECT / CT Imaging Study:

[0122] Using BxPC-3 pancreatic cancer model mice, radioactive injection solution was injected into the mice via the tail vein (approximately 600 μCi / mouse, 5 mice in total). In vivo scans were performed on the small animals at 0.5h, 1h, 2h, 4h, 6h, 24h, 48h, 72h, 96h and 120h after injection.

[0123] 177 Lu-DOTA-Tri-FAP2286 can precisely target tumor cells, and based on its radioactivity, it can achieve non-invasive, visual diagnosis and treatment of tumors.

[0124] (3) Treatment effect

[0125] Taken 177 Lu-DOTA-Tri-FAP2286 and 177 Lu-FAP-2286 was injected into two groups (5 mice per group) of tumor-bearing mice via tail vein injection. The tumor size and volume of the mice were measured every other day along with those of the control group (5 mice, without any drug injection). The therapeutic effects of the two drugs on mice were evaluated by comparing the tumor size.

[0126] 177 Lu-DOTA-Tri-FAP2286 has a long retention time in tumor tissue and a good inhibitory effect.

[0127] Example 5: Effects

[0128] Preparation of radioactive injection solution: The target product obtained in Example 2 (i.e., 177The ethanol solution of Lu-DOTA-Tri-FAP2286 was prepared by diluting it with 0.5M acetate-sodium acetate buffer at pH 5.2.

[0129] (1) Biodistribution studies:

[0130] Using U87MG glioblastoma mice, radioactive injection solution was injected into the mice via the tail vein (approximately 100 μCi / mouse, 4 mice / group, for a total of four groups). The animals were sacrificed at 0.5h, 1h, 4h and 24h after injection, and the tissues and organs of interest were dissected and weighed. The radioactivity count was measured using a gamma counter and the ID% / g of the tissues and organs was calculated (calculation formula: ID% / g = tissue count / total count in injected mice / tissue weight * 100%).

[0131] Table 4 177 Comparison of Lu-DOTA-Tri-FAP2286 uptake in various tissues of U87MG tumor-bearing mice at different time points after administration (unit: ID% / g)

[0132] 0.5h 1h 4h 24h Blood 3.42±0.43 1.43±0.20 0.21±0.10 0.0036±0.00079 brain 0.11±0.03 0.07±0.03 0.02±0.01 0.0018±0.00035 Heart 1.04±0.11 0.45±0.08 0.11±0.03 0.03±0.00 liver 1.78±0.10 0.91±0.25 0.33±0.07 0.15±0.04 spleen 0.64±0.08 0.35±0.10 0.12±0.06 0.05±0.01 lung 2.47±0.40 1.20±0.18 0.20±0.08 0.04±0.00 kidney 11.47±0.22 7.38±1.04 4.15±1.30 1.44±0.73 Stomach 1.77±0.64 0.80±0.28 0.66±0.27 0.03±0.01 Small intestine 1.93±0.76 0.91±0.57 0.31±0.14 0.03±0.01 the large intestine 1.31±0.28 0.64±0.11 0.30±0.10 0.04±0.00 bone 3.44±0.66 2.96±0.67 0.82±0.30 0.18±0.05 muscle 1.49±0.11 0.78±0.12 0.20±0.04 0.04±0.01 tumor 12.59±3.74 8.56±2.84 2.84±0.87 0.48±0.18 Tumor / blood 3.69±1.09 5.86±1.08 14.32±3.23 133.28±33.59 Tumor / Muscle 8.45±2.41 10.77±2.00 13.75±1.41 13.50±7.07 Tumor / Kidney 1.10±0.33 1.15±0.27 0.69±0.02 0.35±0.10

[0133] (2) Animal SPECT / CT Imaging Study:

[0134] Using U87MG glioblastoma model mice, radioactive injection solution was injected into the mice via the tail vein (approximately 600 μCi / mouse, 5 mice in total). In vivo scans were performed on the mice at 0.5h, 1h, 2h, 4h, 6h, 24h, 48h, and 72h post-injection. Results are shown below. Figures 1-8 .

[0135] 177 Lu-DOTA-Tri-FAP2286 can precisely target tumor cells, and based on its radioactivity, it enables non-invasive, visual diagnosis and treatment of tumors. Furthermore... 177 Lu-DOTA-Tri-FAP2286 is rapidly eliminated from the body, especially through excretion in the bladder.

[0136] (3) Treatment effect

[0137] 177 The structure of Lu-FAP-2286 is as follows:

[0138]

[0139] Taken 177 Lu-DOTA-Tri-FAP2286 and 177Lu-FAP-2286 was injected via tail vein (injection volume: 100 μL / mouse, injection activity: 1.5 mCi / mouse) into two groups (4 mice / group) of male U87MG tumor-bearing mice. The tumor size and volume of the mice were measured every other day along with the control group (4 mice, no drug injection, only 0.9% NaCl aqueous solution injection). The therapeutic effects of the two drugs on mice were evaluated by comparing the tumor size.

[0140] 177 Lu-DOTA-Tri-FAP2286 has a long retention time in tumor tissue and a good inhibitory effect.

[0141] The changes in tumor volume over time in the experimental and control groups of mice are shown in Table 5 below:

[0142] Days <![CDATA[ 177 Lu-DOTA-Tri-FAP2286]]> <![CDATA[ 177 Lu-FAP-2286]]> control group 0 73.87 70.14 91.28 2 106.59 119.75 166.05 5 150.11 153.76 231.75 7 212.67 163.91 349.40 9 267.28 190.46 446.31 12 530.27 423.65 1083.70 15 786.99 590.38 1270.97 16 963.59 739.30 — 19 1093.07 767.88 —

[0143] The volume values ​​in the table above are the average tumor volumes of mice in each group, in mm. 3 ;

[0144] "—" indicates that the first test mouse died at that time.

[0145] The changes in body weight of mice in the experimental and control groups over time are shown in Table 6 below:

[0146] Days <![CDATA[ 177 Lu-DOTA-Tri-FAP2286]]> <![CDATA[ 177 Lu-FAP-2286]]> control group 0 21.84 22.54 21.98 2 22.15 22.96 22.74 5 23.00 23.63 24.10 7 23.30 23.75 24.86 9 23.40 23.97 25.22 12 24.37 24.51 25.31 15 24.57 24.37 24.87 16 24.20 24.40 — 19 23.52 23.57 —

[0147] The weight values ​​in the table above are the average weights of mice in each group, in grams.

[0148] "—" indicates that the first test mouse died at that time.

[0149] The survival status of mice in the experimental and control groups over time is shown in Table 7 below:

[0150]

[0151]

[0152] Based on the experimental results, the compound of this application 177 Lu-DOTA-Tri-FAP2286 was superior to [the previous treatment] in terms of therapeutic efficacy and mouse survival rate. 177 Lu-FAP-2286.

[0153] Regarding mouse survival rate: 177 One mouse in the Lu-DOTA-Tri-FAP2286 group died on day 21, two mice died on day 27, and one mouse survived to the end of the experiment. 177Two mice in the Lu-FAP2286 group died on day 21 and two mice died on day 27. At the end of the experiment, no mice survived. All mice died.

Claims

1. A compound I or a pharmaceutically acceptable salt thereof, ； in, A is composed of chelating groups and radioactive nuclides; The chelating group is a structure formed by removing a hydroxyl group from a carboxyl group based on the DOTA, NOTA, DOTA-GA or NODA-GA structure. The radioactive nuclide is 177 Lu; X is ; n1 is 1, 2, 3 or 4; L 1 and L 2 Independently -C1-C6 alkylene-; R is .

2. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) L 1 and L 2 In this context, "-C1-C6 alkylene-" is independently -C1-C3 alkylene-; (2) In A, the chelating group is chelated with a radionuclide; (3) Compound I is or .

3. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, n1 is 2.

4. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) In A, the chelating group is ; (2) L 1 In the text, "-C1-C6 alkylene-" refers to... ; (3) L 2 In the text, "-C1-C6 alkylene-" refers to... or ; (4) Compound I is selected from the following structures: , , or .

5. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or two of the following conditions: (1) A is from Composed of radioactive nuclides, wherein the radioactive nuclides are 177 Lu; (2) Compound I is selected from the following structures: , , or .

6. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, A by It is composed of a chelate with a radioactive nuclide, wherein the radioactive nuclide is 177 Lu.

7. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, A is .

8. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of compound I is as follows: .

9. A compound III or a pharmaceutically acceptable salt thereof, ； in, C is a chelating group; The chelating groups, X, L 1 L 2 The definition of R is as described in any one of claims 1-8.

10. The compound III of claim 9 or a pharmaceutically acceptable salt thereof, characterized in that, The compound III is .

11. A pharmaceutical composition comprising substance D and a pharmaceutical excipient, wherein substance D is compound I or a pharmaceutically acceptable salt thereof as described in any one of claims 1-8.

12. A kit comprising substance D and instructions, wherein substance D is compound I as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof.

13. The use of a substance D in the preparation of a medicament for treating diseases associated with FAP, wherein the substance D is compound I as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof; The diseases associated with FAP are cancers with high FAP expression; The cancers that express FAP highly are pancreatic cancer, breast cancer, ovarian cancer, rectal cancer, or glioblastoma.

14. The use of compound I as described in any one of claims 1-8, a pharmaceutically acceptable salt thereof, compound III as described in claim 9 or 10, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and / or preventing cancer; The cancer in question is one that highly expresses FAP. The cancers that express FAP highly are pancreatic cancer, breast cancer, ovarian cancer, rectal cancer, or glioblastoma.

15. The use of compound I or a pharmaceutically acceptable salt thereof as described in any one of claims 1-8 in the preparation of a developer.

16. The application as described in claim 15, characterized in that, The imaging agent is used for diagnosing cancer.

17. The application as described in claim 16, characterized in that, The cancer in question is one that highly expresses FAP. The cancers that express FAP highly are pancreatic cancer, breast cancer, ovarian cancer, rectal cancer, or glioblastoma.

18. A compound IV or a pharmaceutically acceptable salt thereof, ； in, L 1 The definition is as described in any one of claims 1-5.

19. Compound IV as claimed in claim 18, or a pharmaceutically acceptable salt thereof, characterized in that, The compound IV is .

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