WO2023046182A1 - Application of pyrido[1,2-a]pyrimidone compound - Google Patents

Abstract

Provided is an application of a pyrido[1,2-a]pyrimidone compound, and specifically involved is an application of a substance X in preparation of a drug. The substance X is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; and the drug is used for treating pancreatic neuroendocrine tumors. The compound can inhibit the growth of pancreatic neuroendocrine tumors and improve the blood glucose level.

Description

Application of a kind of pyrido[1,2-a]pyrimidinone compound

This application claims the priority of Chinese patent application 2021111383820 with a filing date of September 27, 2021. This application cites the full text of the above-mentioned Chinese patent application.

technical field

The invention relates to the application of a pyrido[1,2-a]pyrimidinone compound.

Background technique

Insulinomas are very rare neuroendocrine tumors characterized clinically by hyperinsulinemia leading to hypoglycemic syndrome. Although insulinomas are less malignant, long-term hypoglycemia caused by insulinomas can cause irreversible damage to vital organs of the human body, seriously affecting the quality of life of patients and even threatening their lives. For example, the symptoms of hypoglycemia caused by insulinoma include: slow thinking, abnormal speech behavior, limb paralysis, and finally coma and death. Controlling hypoglycemic syndrome and inhibiting tumor growth are the goals of treating insulinoma.

Limited-stage neuroendocrine tumors can be surgically resected. However, about half of neuroendocrine tumors are diagnosed as locally advanced or have distant metastases. Radical surgical resection is difficult, and drug therapy is required to delay tumor progression and prolong patient survival.

For insulinomas, most patients have small lesions. It has been reported that 24% of insulinoma patients had lesions smaller than 1 cm, 42% had lesions between 1-2 cm, 30% had lesions between 2-3 cm, and only 4% had lesions larger than 3 cm (Ref. : Surgical approach to insulinomas. Assessing the need for preoperative localization). Too small lesions will undoubtedly increase the difficulty of local resection and increase the requirements for surgical equipment. Postoperative complications should not be ignored, including diabetes (reference: Incidence and management of postoperative hyperglycemia in patients undergoing insulinoma resection; Overtly manifested diabetes mellitus after resection of insulinoma. Intern.), pancreatic fistula (reference: Diagnosis and management of insulinoma; Risk factors, predictors and prevention of pancreatic fistula formation after pancreatoduodenectomy.), etc.

In addition, some lesions are located deep in the head of the pancreas close to the pancreatic duct or in the deep end of the tail of the pancreas, and the risk of pancreatic duct injury and fistula formation after surgery is high (reference: Beta-islet cell tumors of the pancreas: results of a study on 1,067 cases). For inoperable patients, such as those who refuse surgery, those who are elderly, those who are in poor general condition, those who have had multiple abdominal surgeries, or those who are at increased risk of postoperative complications for other reasons (reference: Diagnosis and management of insulinoma), treatment options lacking.

The FDA approved Everolimus in May 2011 for the treatment of progressive neuroendocrine tumors of pancreatic origin. Everolimus has been reported to alleviate the hypoglycemia effect caused by insulinoma in many clinical trials, but there are still reports that Everolimus cannot improve the symptoms of hypoglycemia in patients with insulinoma (reference Management of Intractable Hypoglycemia With Yttirum- 90 Radioembolization in a Patient With Malignant Insulinoma).

In summary, it is an urgent problem to develop drugs with good glucose control effect and strong tumor suppressor effect to treat pancreatic neuroendocrine tumors and control blood sugar syndrome.

Contents of the invention

The technical problem to be solved by the present invention is that the existing drug structure for treating pancreatic neuroendocrine tumors is relatively single, and cannot well improve the hypoglycemia symptoms of patients. Therefore, the present invention provides an application of pyrido[1,2-a]pyrimidinone compounds. The compound was able to inhibit the growth of pancreatic neuroendocrine tumors and increase blood sugar levels.

The present invention provides a kind of application of substance X in the preparation of medicine, and said substance X is the compound as shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt A solvate; the drug is a drug for treating pancreatic neuroendocrine tumors;

Wherein, E is a C _1-6 alkyl group optionally substituted by R ₃ , a C _3-10 cycloalkyl group optionally substituted by R ₃ or a C _3-10 heterocycloalkyl group optionally substituted by R ₃ ; the C "Hetero" in _3-10 heterocyclic hydrocarbon group means heteroatom or heteroatom group, independently -C(=O)N(R _a )-, -N(R _a )-, -C(=NR _a )- , -S(=O) ₂ N(R _a )-, -S(=O)N(R _a )-, -O-, -S-, -C(=O)O-, -C(=O )-, -C(=S)-, -S(=O)-, -S(=O) ₂ - or -N(R _a )C(=O)N(R _a )-;

L is -C(R ₃ )(R ₃ )-, -C(=O)N(R _a )-, -N(R _a )-, -C(=NR _a )-, -S(=O) ₂ N(R _a )-, -S(=O)N(R _a )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C(= S)-, -S(=O)-, -S(=O) ₂ - or -N(R _a )C(=O)N(R _a )-;

Q is a single bond or -C(R ₃ )(R ₃ )-;

A is N or C (R ₃ );

0 or 1 of X, Y and Z is N, and the rest are C (R ₃ );

m ₁ is 0, 1, 2 or 3;

R ₁ , R ₂ and R ₃ are independently H, F, Cl, Br, I, CN, -OR _a , -N(R _b )(R _c ), C _1-3 alkane optionally substituted by R _d base,

D ₁ is independently a single bond, -C(R _e )(R _e )-, -C(=O)N(R _a )-, -N(R _a )-, -C(=NR _a )-, -S(=O) ₂ N(R _a )-, -S(=O)N(R _a )-, -O-, -S-, -C(=O)O-, -C(=O) -, -C(=S)-, -S(=O)-, -S(=O) ₂ - or -N(R _a )C(=O)N(R _a )-;

n is independently 1, 2, 3, 4, 5 or 6;

D ₂ is independently -C(R _a )(R _a )-;

R _a , R _b and R _c are independently H, C _1-6 alkyl optionally substituted by R _d or C _3-6 cycloalkyl optionally substituted by R _d ;

R _e is H, C _1-6 alkyl optionally substituted by R _d , C _1-6 alkoxy optionally substituted by R _d , C _3-6 cycloalkyl optionally substituted by R _d , or any A C _3-6 cycloalkoxy group substituted by R _d ;

The number of _Rd is independently 1, 2 or 3; _Rd is independently F, Cl, Br, I, CN, -OH, -CHO, -COOH, _CH3- , _CF3- , _CH3O- or _{CH3CH2O- ;}

Optionally, between any two R ₁ , between R _a and R _a in the same D ₂ , between two D ₂ , or between R _a and a D ₂ are jointly connected to the same carbon atom or oxygen One or two 3, 4, 5 or 6-membered carbocyclic rings or oxygen heterocyclic rings are formed on the atoms, and the number of oxygen atoms is 1 or 2.

In the described application, the definition of certain groups in the described compound shown in formula I can be as follows, and the definition of all the other groups is as described in any other scheme:

E is C _1-6 alkyl substituted by R ₃ or C _3-6 cycloalkyl substituted by R ₃ , and the number of R ₃ is 1, 2 or 3 independently.

In the described application, the definition of certain groups in the described compound shown in formula I can be as follows, and the definition of all the other groups is as described in any other scheme:

E is C _1-6 alkyl or C _3-6 cycloalkyl.

In the described application, the definition of certain groups in the described compound shown in formula I can be as follows, and the definition of all the other groups is as described in any other scheme:

E is

in,

0, 1, 2 or 3 of G _{1 to 5} are N, and the rest are C (R ₃ );

G ₆ is -C(R ₃ )(R ₃ )-, -C(=O)N(R ₃ )-, -N(R ₃ )-, -C(=NR ₃ )-, -S(=O ) ₂ N(R ₃ )-, -S(=O)N(R ₃ )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C( =S)-, -S(=O)-, -S(=O) ₂ - or -N(R ₃ )C(=O)N(R ₃ )-;

0, 1 or 2 of G _7-9 are N, and the rest are C (R ₃ );

0, 1, 2, 3 or 4 of G _10-16 are N, and the rest are C (R ₃ );

G ₁₇ is N or C (R ₃ );

0, 1, 2 or 3 of G _18-22 are independently -C(=O)N(R ₃ )-, -N(R ₃ )-, -C(=NR ₃ )-, -S( =O) ₂ N(R ₃ )-, -S(=O)N(R ₃ )-, -O-, -S-, -C(=O)O-, -C(=O)-, - C(=S)-, -S(=O)-, -S(=O) ₂ - or -N(R ₃ )C(=O)N(R ₃ )-, the rest are -C(R ₃ ) (R ₃ )-.

In said application, said substance X can be a compound represented by formula (Ia), its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate;

In the application, the XRPD spectrum analysis data of the compound represented by formula (Ia) can be shown in Table 1 (crystal form I), table 2 (crystal form II), table 3 (crystal form III), Shown in Table 4 (Form IV), Table 5 (Form V) or Table 6 (Form VI):

Table 1

Table 2

table 3

Table 4

No. 2θ d(A) I% No. 2θ d(A) I% 1 5.246 16.8322 47.8 15 16.681 5.3102 29.6 2 6.074 14.5392 7.9 16 18.371 4.8255 8.5 3 6.723 13.1361 47.2 17 19.894 4.4593 16.0 4 7.708 11.4600 100.0 18 20.818 4.2634 5.5 5 10.308 8.5742 9.1 19 22.712 3.9119 9.0 6 11.098 7.9658 37.7 20 23.934 3.7149 10.1 7 12.182 7.2595 5.5 twenty one 24.389 3.6467 8.5 8 12.656 6.9887 18.4 twenty two 24.804 3.5866 15.0

9 12.836 6.8911 24.5 twenty three 26.026 3.4208 5.5 10 13.501 6.5530 34.3 twenty four 26.817 3.3217 12.3 11 14.355 6.1651 30.7 25 28.965 3.0800 6.6 12 15.356 5.7655 5.8 26 29.513 3.0242 6.4 13 15.729 5.6293 6.1 27 29.992 2.9769 5.3 14 16.145 5.4854 7.5 28 32.587 2.7456 4.9

table 5

No. 2θ d(A) I% No. 2θ d(A) I% 1 5.282 16.7167 36.0 16 19.969 4.4427 21.6 2 6.070 14.5476 60.5 17 21.075 4.2120 13.8 3 6.745 13.0937 30.9 18 22.161 4.0080 11.5 4 10.329 8.5569 14.5 19 22.576 3.9351 16.3 5 11.240 7.8654 47.0 20 23.642 3.7602 6.1 6 12.200 7.2489 12.2 twenty one 24.273 3.6638 13.9 7 12.656 6.9885 25.3 twenty two 24.446 3.6382 17.7 8 13.524 6.5419 27.8 twenty three 24.762 3.5925 15.2 9 13.883 6.3735 8.2 twenty four 25.124 3.5416 93.8 10 14.428 6.1339 18.5 25 25.712 3.4620 11.8 11 14.842 5.9639 6.7 26 28.060 3.1774 21.2 12 15.380 5.7565 8.1 27 29.637 3.0117 25.4 13 16.069 5.5112 100.0 28 30.708 2.9091 11.3 14 16.779 5.2794 8.7 29 35.117 2.5533 6.6 15 18.772 4.7233 16.3 30 38.690 2.3253 4.7

Table 6

No. 2θ d(A) I% No. 2θ d(A) I% 1 8.735 10.1143 7.3 20 25.663 3.4684 8.9

2 10.470 8.4419 13.7 twenty one 26.412 3.3717 22.9 3 12.424 7.1185 100.0 twenty two 27.159 3.2807 4.7 4 13.786 6.4183 50.6 twenty three 27.617 3.2273 11.7 5 15.166 5.8372 1.7 twenty four 27.970 3.1873 15.0 6 16.883 5.2471 10.9 25 30.714 2.9086 8.8 7 18.006 4.9222 1.3 26 31.291 2.8562 2.4 8 18.711 4.7385 4.1 27 31.781 2.8133 1.8 9 19.386 4.5749 5.7 28 32.389 2.7618 10.4 10 19.604 4.5247 2.5 29 33.730 2.6551 2.3 11 20.572 4.3138 11.7 30 34.838 2.5731 2.1 12 20.986 4.2296 2.9 31 35.198 2.5476 1.6 13 21.402 4.1484 11.4 32 35.603 2.5195 2.9 14 22.425 3.9614 13.2 33 35.902 2.4992 5.2 15 23.297 3.8150 2.7 34 37.087 2.4221 3.2 16 24.123 3.6863 79.2 35 37.641 2.3877 1.2 17 24.596 3.6164 11.8 36 38.231 2.3522 2.2 18 25.013 3.5570 3.5 37 38.760 2.3213 1.6 19 25.306 3.5165 5.2 38 39.747 2.2659 2.7 .

In the application, the XRPD pattern of the compound represented by formula (Ia) can be as shown in Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 or Figure 6 .

In said application, said pancreatic neuroendocrine tumor may be insulinoma, amine precursor uptake and decarboxylation cell tumor, vasoactive intestinal peptide tumor, glucagon tumor, pancreatic polypeptide tumor or gastrinoma.

In said application, said drug is a drug used for treating pancreatic neuroendocrine tumors and increasing blood sugar concentration.

In another aspect, the present invention provides a method of treating pancreatic neuroendocrine tumors comprising administering to a patient in need thereof a therapeutically effective amount of substance X as described herein.

In the method, the pancreatic neuroendocrine tumor may be an insulinoma, an amine precursor uptake and decarboxylation cell tumor, a vasoactive intestinal peptide tumor, a glucagon tumor, a pancreatic polypeptide tumor, or a gastrinoma.

In said uses and methods:

The administration regimen of substance X (including administration route, administration dose, administration interval, etc.) can be adjusted by those skilled in the art as needed to provide the optimal therapeutic effect.

The substance X can be administered by any suitable route known in the art, including oral, injection (eg intravenous, intramuscular, subcutaneous) and the like.

In some embodiments, the substance X is administered orally.

The substance X can be administered according to the weight of the patient, a non-limiting example range can be 0.01-1 mg/kg (referring to a single dose), such as 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg kg, 0.2mg/kg, 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg kg, 0.8mg/kg, 0.9mg/kg or 1mg/kg.

In some embodiments, the dose of Compound I is 0.05-0.2 mg/kg, such as 0.05 mg/kg, 0.1 mg/kg or 0.2 mg/kg.

The above doses of the substance X may be administered according to the frequency of QD (once a day), QOD (one day apart) or QW (once a week).

In some embodiments, the substance X is administered on a QD frequency.

In some embodiments, the substance X is administered orally according to the dosage and frequency mentioned above.

In some embodiments, the substance X is administered orally at 0.2 mg/kg, QD.

In some embodiments, the substance X is administered orally at 0.2 mg/kg, QD, and the substance X is a compound represented by formula (Ia).

The substance X may also be administered to the patient in fixed doses, ie a fixed or predetermined amount of dose is given to the patient. A non-limiting example of a fixed dose (referred to as a single dose) may range from 0.01 to 50 mg, such as 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg or 50mg.

The above-mentioned fixed doses of the substance X may be administered at a frequency of QD (once a day), QOD (once a day) or QW (once a week).

In some embodiments, the substance X is administered on a QD frequency.

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 use by patients) acid or base. When the compound contains relatively acidic functional groups, base addition salts 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. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like. When the compound contains relatively basic functional groups, acid addition salts 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. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, and the like. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.

The term "solvate" refers to a substance formed when a compound is combined with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

The term "solvate of a pharmaceutically acceptable salt" refers to a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, solvent (including but not limited to: water, methanol, ethanol etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent is stoichiometric or non-stoichiometric. Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The crystal forms I, II, III, IV, V and VI used in the present invention are prepared according to the method described in CN201680072859.0.

The positive progress effect of the present invention lies in that the compound can inhibit the growth of pancreatic neuroendocrine tumors and improve the blood sugar level.

Description of drawings

Figure 1 is the Cu-Kα radiation XRPD spectrum of Form I.

Fig. 2 is the Cu-Kα radiation XRPD spectrum of the II crystal form.

Fig. 3 is the Cu-Kα radiation XRPD spectrum of the III crystal form.

Fig. 4 is the Cu-Kα radiation XRPD spectrum of the IV crystal form.

Fig. 5 is the Cu-Kα radiation XRPD spectrum of V crystal form.

Fig. 6 is the Cu-Kα radiation XRPD spectrum of VI crystal form.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

由上海嘉坦医药科技有限公司提供，按照CN 105461712 A实施例176制备得到。 Compound (Ia) in the following examples refers to

Provided by Shanghai Jiatan Pharmaceutical Technology Co., Ltd., prepared according to Example 176 of CN 105461712 A.

The XRPD pattern analysis data of compound (Ia) are shown in Table 1, Table 2, Table 3, Table 4, Table 5 or Table 6; the XRPD pattern of compound (Ia) is shown in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5 or Figure 6.

Example 1:

Purpose of the study: To evaluate the pharmacodynamics of the test compound (Ⅰa) in the hypoglycemia model of rat-derived insulinoma INS-1 subcutaneous xenograft BALB/c female nude mice

Experimental materials: DMSO (purchased from Sigma), Matrigel (purchased from Corning), fetal bovine serum (purchased from GIBCO), PRMI1640 (purchased from GIBCO), trypsin (purchased from GIBCO), INS-1 cells (purchased from Shanghai Fuxiang Biotechnology Co., Ltd.);

Experimental model: rat-derived insulinoma INS-1 cell line subcutaneously allografted female BALB/c nude mouse model;

experimental method:

Cell culture: In vitro monolayer culture of rat insulinoma INS-1 cells, the culture conditions are RPMI1640 medium plus 10% fetal bovine serum, 100 U/mL penicillin and 100 μg/mL streptomycin, 37 ° C, 5% CO _2. Cultivate under the condition of 95% relative humidity, passage with trypsin twice a week, when the cells are in the logarithmic growth phase, digest the cells for inoculation.

Experimental animals: BALB/c nude mice, female, 7-8 weeks (the age of mice at the time of tumor cell inoculation), weighing 19-23 g, provided by Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

Tumor inoculation: Experimental mice were subcutaneously inoculated with 10 ⁷ /mouse INS-1 cells, the cells were resuspended in 1:1 PBS and Matrigel, and the tumor growth was observed regularly. The day of tumor cell inoculation was defined as day 0. The initial blood glucose of 5 animals was randomly measured before inoculation. Afterwards, the blood glucose of 5 animals was randomly measured every week to monitor the blood glucose changes during the growth of insulinoma. After the blood glucose of some animals was observed to drop to <4mM, the blood glucose at the tip of the tail of all animals was taken to measure the blood glucose. Grouped according to the blood sugar level, and started administration, the average blood sugar level of each group before administration was 5.36mM (the 23rd day).

Experimental grouping: The test was divided into vehicle control group, test compound (Ia) (0.2mg/kg) group, test compound (Ia) (0.1mg/kg) group, test compound (Ia) (0.05mg/kg) group and Everolimus (1mg/kg) group, 5 rats in each group, the test compound (Ia) and Everolimus were administered orally by gavage, once a day, see Table 7 for details. Three days after administration, the blood glucose curve was analyzed.

Table 7

Remark:

Vehicle one: 1% DMSO + 99% (1% methylcellulose aqueous solution), the percentages are volume percentages.

Experimental results:

1) On the 26th day after tumor inoculation (the 3rd day after administration), the average blood glucose of mice in the vehicle control group was 3.90mmol/L, the second group of compound (Ia), 0.2mg/kg treatment group, the third group of compound ( Ⅰa), the 0.1mg/kg treatment group and the fourth compound (Ⅰa), 0.05mg/kg treatment group mean blood glucose were 9.28mmol/L, 7.68mmol/L and 6.32mmol/L respectively. Compared with the control group, the high, middle and low dose groups of compound (Ia) all showed obvious blood sugar-increasing effect. And compared with the control group, there are statistically significant differences in the compound (Ia) high, middle and low dose groups (p<0.001, p=0.0011 and p=0.0366). The fifth group Everolimus, 1mg/kg treatment group average blood sugar was 5.02mmol/L, compared with the control group, there was no statistically significant difference (p=0.5165). See Table 8 and Table 9 for the blood glucose status of the mice in each treatment group and control group (the blood glucose status of the mice in each treatment group and control group, the unit of each number in the table is mmol/L).

Table 8 Blood glucose situation of mice in each treatment group and control group

Table 9 Blood glucose situation of mice in each treatment group and control group

2) On the 26th day after tumor inoculation (the 3rd day after administration), the average tumor volume of mice in the vehicle control group was 2465.09mm ³ , the second group of compound (Ia), 0.2mg/kg treatment group, the third group of compound ( Ⅰa), 0.1mg/kg treatment group, the fourth compound (Ⅰa), 0.05mg/kg treatment group and the fifth Everolimus, 1mg/kg treatment group mean tumor volumes were 1902.62mm ³ , 2113.97mm ³ , 2233.47mm ³ and 2162.24mm ³ . Compared with the control group, only the second group of compound (Ia), the 0.2mg/kg treatment group had a significant inhibitory effect on the tumor, with a TGI of 82%, and there was a statistically significant difference (p<0.05). Compared with the vehicle control group, Everolimus group had P=0.86, showing no tumor-inhibiting effect.

The tumor volumes of mice in each treatment group and control group are shown in Table 10-11 (tumor volume growth curves of mice in each treatment group and control group).

Table 10 Tumor volume growth curves of mice in each treatment group and control group

Table 11 Tumor volume growth curves of mice in each treatment group and control group

Experimental conclusion: 3 days after administration, compared with the control group (blood sugar is 3.90mmol/L), compound (Ia) high (0.2mg/kg), medium (0.1mg/kg), low (0.05mg/kg) dose Both groups showed obvious blood sugar-raising effects, with average blood sugar levels of 9.28mmol/L, 7.68mmol/L and 6.32mmol/L, respectively. The Everolimus, 1mg/kg treatment group average blood sugar was 5.02mmol/L.

Three days after administration, the relative tumor growth rate (TGI) of compound (Ia) high (0.2 mg/kg) and medium (0.1 mg/kg) dose groups were 82% and 64%, respectively. And Everolimus, the TGI of 1mg/kg treatment group was 33%.

In the hypoglycemia model of insulinoma INS-1 xenograft mice, compound (Ia) can significantly increase the blood glucose and inhibit tumor growth in mice. In addition, compared with Everolimus, compound (Ia) has a stronger effect on improving blood sugar level and inhibiting tumor growth in mice.

Claims (12)

An application of a substance X in the preparation of a medicine, the substance X is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; The drug is a drug for treating pancreatic neuroendocrine tumors;

Wherein, E is a C _1-6 alkyl group optionally substituted by R ₃ , a C _3-10 cycloalkyl group optionally substituted by R ₃ or a C _3-10 heterocycloalkyl group optionally substituted by R ₃ ; the C "Hetero" in _3-10 heterocyclic hydrocarbon group means heteroatom or heteroatom group, independently -C(=O)N(R _a )-, -N(R _a )-, -C(=NR _a )- , -S(=O) ₂ N(R _a )-, -S(=O)N(R _a )-, -O-, -S-, -C(=O)O-, -C(=O )-, -C(=S)-, -S(=O)-, -S(=O) ₂ - or -N(R _a )C(=O)N(R _a )-; L is -C(R ₃ )(R ₃ )-, -C(=O)N(R _a )-, -N(R _a )-, -C(=NR _a )-, -S(=O) ₂ N(R _a )-, -S(=O)N(R _a )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C(= S)-, -S(=O)-, -S(=O) ₂ - or -N(R _a )C(=O)N(R _a )-; Q is a single bond or -C(R ₃ )(R ₃ )-; A is N or C (R ₃ ); 0 or 1 of X, Y and Z is N, and the rest are C (R ₃ ); m ₁ is 0, 1, 2 or 3; R ₁ , R ₂ and R ₃ are independently H, F, Cl, Br, I, CN, -OR _a , -N(R _b )(R _c ), C _1-3 alkane optionally substituted by R _d base,

D ₁ is independently a single bond, -C(R _e )(R _e )-, -C(=O)N(R _a )-, -N(R _a )-, -C(=NR _a )-, -S(=O) ₂ N(R _a )-, -S(=O)N(R _a )-, -O-, -S-, -C(=O)O-, -C(=O) -, -C(=S)-, -S(=O)-, -S(=O) ₂ - or -N(R _a )C(=O)N(R _a )-; n is independently 1, 2, 3, 4, 5 or 6; D ₂ is independently -C(R _a )(R _a )-; R _a , R _b and R _c are independently H, C _1-6 alkyl optionally substituted by R _d or C _3-6 cycloalkyl optionally substituted by R _d ; R _e is H, C _1-6 alkyl optionally substituted by R _d , C _1-6 alkoxy optionally substituted by R _d , C _3-6 cycloalkyl optionally substituted by R _d , or any A C _3-6 cycloalkoxy group substituted by R _d ; The number of _Rd is independently 1, 2 or 3; _Rd is independently F, Cl, Br, I, CN, -OH, -CHO, -COOH, _CH3- , _CF3- , _CH3O- or _{CH3CH2O- ;} Optionally, between any two R ₁ , between R _a and R _a in the same D ₂ , between two D ₂ , or between R _a and a D ₂ are jointly connected to the same carbon atom or oxygen One or two 3, 4, 5 or 6-membered carbocyclic rings or oxygen heterocyclic rings are formed on the atoms, and the number of oxygen atoms is 1 or 2. _{The application according to claim 1, characterized in that, E is C 1-6 alkyl} substituted by R or C _3-6 cycloalkyl substituted by R , and the number of R _{3 is} independently 1, 2 or 3. The application according to claim 1, characterized in that, E is C _1-6 alkyl or C _3-6 cycloalkyl. The application according to claim 1, wherein E is

in, 0, 1, 2 or 3 of G _{1 to 5} are N, and the rest are C (R ₃ ); G ₆ is -C(R ₃ )(R ₃ )-, -C(=O)N(R ₃ )-, -N(R ₃ )-, -C(=NR ₃ )-, -S(=O ) ₂ N(R ₃ )-, -S(=O)N(R ₃ )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C( =S)-, -S(=O)-, -S(=O) ₂ - or -N(R ₃ )C(=O)N(R ₃ )-; 0, 1 or 2 of G _7-9 are N, and the rest are C (R ₃ ); 0, 1, 2, 3 or 4 of G _10-16 are N, and the rest are C (R ₃ ); G ₁₇ is N or C (R ₃ ); 0, 1, 2 or 3 of G _18-22 are independently -C(=O)N(R ₃ )-, -N(R ₃ )-, -C(=NR ₃ )-, -S( =O) ₂ N(R ₃ )-, -S(=O)N(R ₃ )-, -O-, -S-, -C(=O)O-, -C(=O)-, - C(=S)-, -S(=O)-, -S(=O) ₂ - or -N(R ₃ )C(=O)N(R ₃ )-, the rest are -C(R ₃ ) (R ₃ )-. The application according to claim 1, characterized in that, said substance X is the compound shown in formula (Ia), its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvates;

The application according to claim 5, wherein the XRPD spectrum analysis data of the compound shown in the formula (Ia) is as shown in Table 1, Table 2, Table 3, Table 4, Table 5 or Table 6 : Table 1

Table 2

table 3

Table 4 No. 2θ d(A) I% No. 2θ d(A) I% 1 5.246 16.8322 47.8 15 16.681 5.3102 29.6 2 6.074 14.5392 7.9 16 18.371 4.8255 8.5 3 6.723 13.1361 47.2 17 19.894 4.4593 16.0 4 7.708 11.4600 100.0 18 20.818 4.2634 5.5 5 10.308 8.5742 9.1 19 22.712 3.9119 9.0 6 11.098 7.9658 37.7 20 23.934 3.7149 10.1 7 12.182 7.2595 5.5 twenty one 24.389 3.6467 8.5 8 12.656 6.9887 18.4 twenty two 24.804 3.5866 15.0 9 12.836 6.8911 24.5 twenty three 26.026 3.4208 5.5 10 13.501 6.5530 34.3 twenty four 26.817 3.3217 12.3 11 14.355 6.1651 30.7 25 28.965 3.0800 6.6 12 15.356 5.7655 5.8 26 29.513 3.0242 6.4 13 15.729 5.6293 6.1 27 29.992 2.9769 5.3 14 16.145 5.4854 7.5 28 32.587 2.7456 4.9 table 5 No. 2θ d(A) I% No. 2θ d(A) I% 1 5.282 16.7167 36.0 16 19.969 4.4427 21.6 2 6.070 14.5476 60.5 17 21.075 4.2120 13.8 3 6.745 13.0937 30.9 18 22.161 4.0080 11.5 4 10.329 8.5569 14.5 19 22.576 3.9351 16.3 5 11.240 7.8654 47.0 20 23.642 3.7602 6.1 6 12.200 7.2489 12.2 twenty one 24.273 3.6638 13.9 7 12.656 6.9885 25.3 twenty two 24.446 3.6382 17.7 8 13.524 6.5419 27.8 twenty three 24.762 3.5925 15.2 9 13.883 6.3735 8.2 twenty four 25.124 3.5416 93.8 10 14.428 6.1339 18.5 25 25.712 3.4620 11.8 11 14.842 5.9639 6.7 26 28.060 3.1774 21.2 12 15.380 5.7565 8.1 27 29.637 3.0117 25.4 13 16.069 5.5112 100.0 28 30.708 2.9091 11.3 14 16.779 5.2794 8.7 29 35.117 2.5533 6.6 15 18.772 4.7233 16.3 30 38.690 2.3253 4.7 Table 6 No. 2θ d(A) I% No. 2θ d(A) I% 1 8.735 10.1143 7.3 20 25.663 3.4684 8.9 2 10.470 8.4419 13.7 twenty one 26.412 3.3717 22.9 3 12.424 7.1185 100.0 twenty two 27.159 3.2807 4.7 4 13.786 6.4183 50.6 twenty three 27.617 3.2273 11.7 5 15.166 5.8372 1.7 twenty four 27.970 3.1873 15.0 6 16.883 5.2471 10.9 25 30.714 2.9086 8.8 7 18.006 4.9222 1.3 26 31.291 2.8562 2.4 8 18.711 4.7385 4.1 27 31.781 2.8133 1.8 9 19.386 4.5749 5.7 28 32.389 2.7618 10.4 10 19.604 4.5247 2.5 29 33.730 2.6551 2.3 11 20.572 4.3138 11.7 30 34.838 2.5731 2.1 12 20.986 4.2296 2.9 31 35.198 2.5476 1.6 13 21.402 4.1484 11.4 32 35.603 2.5195 2.9 14 22.425 3.9614 13.2 33 35.902 2.4992 5.2 15 23.297 3.8150 2.7 34 37.087 2.4221 3.2 16 24.123 3.6863 79.2 35 37.641 2.3877 1.2 17 24.596 3.6164 11.8 36 38.231 2.3522 2.2 18 25.013 3.5570 3.5 37 38.760 2.3213 1.6 19 25.306 3.5165 5.2 38 39.747 2.2659 2.7 . The application according to claim 5, characterized in that, the XRPD spectrum of the compound represented by formula (Ia) is as shown in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5 or Figure 6. The use according to at least one of claims 1 to 7, wherein the neuroendocrine tumor of the pancreas is insulinoma, amine precursor uptake and decarboxylation cell tumor, vasoactive intestinal peptide tumor, glucagon tumor , Pancreatic polypeptide tumor or gastrinoma. The application according to at least one of claims 1 to 7, wherein the neuroendocrine tumor of the pancreas is an insulinoma; And/or, the substance X is administered according to the patient's body weight in a single dose of 0.01-1 mg/kg, such as 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg , 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg , 0.9mg/kg or 1mg/kg; And/or, the substance X is administered to the patient in a fixed dose, a single dose of 0.01-50 mg, for example 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg , 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg , 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg or 50mg. The use according to at least one of claims 1-7, characterized in that the drug is a drug used for treating pancreatic neuroendocrine tumors and increasing blood sugar concentration. A method of treating pancreatic neuroendocrine tumors, comprising administering a therapeutically effective amount of substance X according to at least one of claims 1-7 to a patient in need thereof. The method according to claim 11, wherein the pancreatic neuroendocrine tumor is insulinoma, amine precursor uptake and decarboxylation cell tumor, vasoactive intestinal peptide tumor, glucagon tumor, pancreatic polypeptide tumor or gastric Secretinoma; And/or, the substance X is administered according to the patient's body weight in a single dose of 0.01-1 mg/kg, such as 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg , 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg , 0.9mg/kg or 1mg/kg; And/or, the substance X is administered to the patient in a fixed dose, a single dose of 0.01-50 mg, for example 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg , 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg , 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg or 50mg.

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