WO2022199373A1

WO2022199373A1 - Quinazoline compound and use of pharmaceutical composition

Info

Publication number: WO2022199373A1
Application number: PCT/CN2022/079678
Authority: WO
Inventors: 许祖盛
Original assignee: 上海璎黎药业有限公司
Priority date: 2021-03-26
Filing date: 2022-03-08
Publication date: 2022-09-29
Also published as: TW202245786A; CN115120596A

Abstract

Disclosed are a quinazoline compound and the use of a pharmaceutical composition. The substance X of the present invention is the quinazoline compound, as represented by formula A; a pharmaceutically acceptable salt thereof; and a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention comprises the substance X and a pharmaceutical excipient. The substance X or the pharmaceutical composition provided in the present invention has a good treatment effect on B-cell hematologic neoplasms, and especially has a good treatment effect on follicular lymphoma, and has high efficiency and a good degree of safety.

Description

Application of a kind of quinazoline compound and pharmaceutical composition

technical field

The present invention relates to the application of a quinazoline compound and a pharmaceutical composition.

Background technique

The full name of PI3K is Phosphatidylinositol 3-kinase (phosphatidylinositol 3-kinase), which is involved in the regulation of various cellular functions such as cell proliferation, differentiation, apoptosis and glucose transport. PI3K can be divided into class I, class II and class III kinases, and the most widely studied is class I PI3K that can be activated by cell surface receptors. Class I PI3Ks in mammalian cells are further divided into class Ia and class Ib according to their structure and receptors, which transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors, respectively. Class Ia PI3Ks include PI3Kα, PI3Kβ, PI3Kδ isoforms, and class Ib PI3Ks include PI3Kγ isoforms (Trends. Biochem. Sci., 1997, 22, 267-272). Class Ia PI3K is a dimeric protein composed of a catalytic subunit p110 and a regulatory subunit p85, with dual activities of lipid kinase and protein kinase (Nat. Rev. Cancer 2002, 2, 489-501), and is considered to be related to cell proliferation It is associated with cancer development, immune diseases and diseases involving inflammation.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) in Europe and the United States, accounting for about 22-35% of all newly diagnosed NHL. The annual incidence has gradually increased from 2-3/100,000 in the 1950s to about 5/100,000. Different from western countries, FL accounts for about 8% of B cell NHL in my country, which is lower than that in western countries.

Although follicular lymphoma accounts for only 8% of B-cell lymphomas in my country, the number of patients is still large due to the large population base in China. FL has a high incidence in the middle-aged and elderly population, and with the acceleration of the aging process, the incidence of follicular lymphoma in China has been on the rise in recent years. At present, follicular lymphoma cannot be completely cured. After the treatment achieves remission, FL will recur repeatedly, and it is easy to turn into an aggressive type after repeated attacks. With the increase in the number of relapses, the remission period will become shorter and shorter, and the probability of refractory treatment will increase, resulting in a shortening of overall survival. At present, there is no unified standard treatment for relapsed and refractory FL. Moreover, the current drugs for the treatment of FL are limited, and there is an urgent need to develop drugs with better efficacy.

Among them, phosphoinositide 3-kinase-delta (PI3Kdelta) inhibitors are one of the therapeutic approaches, PI3Kdelta is an intracellular signal transduction component, mainly expressed in blood cell lineages, including cell-induced or mediated malignant hematology sick.

At present, three PI3Kδ inhibitor drugs have been successfully launched in the world, namely Idelalisib, Copanlisib and Duvelisb, all of which are used for the treatment of circulatory system cancers.

The results of a clinical trial of Idelalisib in relapsed follicular B-cell non-Hodgkin lymphoma (FL) have been reported in the literature (Clinical Trial Registration Number: NCT01282424), and the inclusion criteria were previous treatment with rituximab combined with alkylating agents Patients with FL who relapsed within the next 6 months and who have received at least 2 systemic treatments.

Results of the study showed that the median age of the subjects was 62 years (range 33-84 years), 54% were male and 90% were Caucasian. At inclusion, 92% of patients had a baseline ECOG performance status of 0 or 1; median disease duration was 4-7 years; and median number of prior treatments was 4 (range 2-12). The most common prior regimens were R-CHOP (49%) (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (50%) (bendamustine, tuximab), and R-CVP (28%) (rituximab, cyclophosphamide, vincristine, prednisone). At baseline, 33% of patients had extranodal metastases and 26% had bone marrow metastases.

Patients were treated with Idelalisib 150 mg twice daily until disease progression or unacceptable toxicity. Efficacy in neoplastic lymphoma was assessed according to the International Working Group Response Criteria. The primary endpoint was the overall response rate (ORR) assessed by an independent review committee.

Efficacy results are shown in the table below: median time to response was 1.9 months (range 1.6-8.3).

疗效终点Efficacy endpoint	N＝72N=72
ORR 95％CIORR 95%CI	39(54％)(42，66％)39 (54%) (42, 66%)
CRCR	6(8％)6 (8%)
PRPR	33(46％)33 (46%)
DOR中位数，月数(范围)DOR median, months (range)	中位数不能评价(0.0+，14.8+)The median cannot be evaluated (0.0+, 14.8+)

CI = confidence interval; CR = complete response; PR = partial response; *Kaplan-Meier estimate;

DOR=Duration of response, duration of remission=the duration of PR/CR.

References for the above data sources: Ajay K.Gopal, M.D., Brad S.Kahl, M.D., Sven de Vos, M.D., Ph.D.et al.PI3KδInhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma[J].N Engl J Med .2014 March 13;370(11):1008–1018.

The drugs currently on the market still have problems such as low efficiency and large side effects, and it is very necessary to develop new drugs including PI3Kδ inhibitors for the treatment of follicular lymphoma.

The quinazoline compound whose chemical structure is shown in formula A is a PI3Kδ small molecule inhibitor, which has been disclosed in the CN104557872A patent (compound 10),

Compared with other existing PI3Kδ inhibitors, the selectivity to PI3Kδ is improved and the activity to PI3Kγ is eliminated. Chinese patent CN110950844A discloses two polymorphs of the quinazoline compound represented by formula A.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is that the existing medicines for the treatment of FL in the prior art are relatively single, and the efficiency is not high and the side effects are large. Therefore, the present invention provides a quinazoline compound and a pharmaceutical composition. Application, the quinazoline compound has good therapeutic effect on B-cell hematoma, especially on follicular lymphoma, with high efficacy and good safety, and is expected to be applied to B-cell hematoma, especially follicular lymphoma. Treatment of lymphoma.

A kind of application of substance X or pharmaceutical composition in the preparation of medicine, it is characterized in that, described substance X is quinazoline compound as shown in formula A, its pharmaceutically acceptable salt, its solvate or its pharmacy The solvate of the above acceptable salt; the pharmaceutical composition comprises the substance X and pharmaceutical excipients; the drug is a drug for the treatment of B-cell hematoma;

In a certain scheme, the B-cell hematoma is a B-cell lymphoma, preferably, the B-cell lymphoma is a non-Hodgkin's lymphoma, more preferably, the non-Hodgkin's lymphoma is a filter Follicular lymphoma, most preferably, the follicular lymphoma is relapsed and/or refractory follicular lymphoma, eg, relapsed or refractory follicular lymphoma.

In a certain regimen, the drug is administered orally.

In one aspect, the Substance X is in a therapeutically effective amount.

In a certain scheme, the administration dose of the drug can be determined according to the body weight of the patient, and in terms of the content of the quinazoline compound shown in formula A, the administration dose of the drug is 0.33 mg/time. kg-3.33mg/kg, for example, 0.66mg/kg-2.3mg/kg, another example, 1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.33mg/kg, 1.4mg/kg, 1.5mg /kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg or 2.3 mg/kg.

In a certain scheme, based on the content of the quinazoline compound represented by formula A, the administration dose of the drug is 20 mg-200 mg/day, for example, 20 mg/day, 30 mg/day, 40 mg/day , 50mg/day, 60mg/day, 70mg/day, 80mg/day, 90mg/day, 100mg/day, 110mg/day, 120mg/day, 130mg/day, 140mg/day, 150mg/day, 160mg/day, 170mg /day, 180 mg/day, 190 mg/day or 200 mg/day, for another example, 80 mg/day.

In a certain regimen, the frequency of administration of the drug is 1-5 times/day, eg, 1 time/day, 2 times/day, 3 times/day, 4 times/day, or 5 times/day, and then For example, 1 time/day.

In a certain regimen, the drug is administered for a course of 14-84 days/course, eg, 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course, or 84 days/course Day/course, for another example, is 28 days/course.

In a certain scheme, the drug is administered for a total of 1-20 courses of treatment, preferably 10-20 courses of treatment, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 courses, another example, 12 courses.

In a certain scheme, the medicine is a tablet or a capsule, preferably a tablet.

In a certain scheme, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound represented by formula A is selected from 5mg-500mg, preferably 10mg-200mg, most preferably 20mg-100mg, for example 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg. Taking a tablet as an example, in the unit dosage form, the content of the quinazoline compound represented by formula A is 5 mg-500 mg/tablet.

In a certain regimen, the drug is administered to a patient with relapsed or refractory follicular lymphoma who has received one or more systemic therapy regimens, eg, relapsed after one or more systemic therapy regimens For patients with follicular lymphoma, preferably, the drug is administered to patients with relapsed or refractory follicular lymphoma who have received two or more systemic treatment regimens, for example, received two or more systemic treatment regimens. Patients with relapsed follicular lymphoma who have received one or more systemic therapy regimens.

In a certain scheme, the drug is administered to a patient who has progressed after receiving second-line or more systemic systemic therapy in the previous treatment regimen, and the second-line or more systemic therapy has received CD20 monoclonal antibody and at least one In patients with progression after treatment with alkylating agents, including but not limited to bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan, and nitroso one or more.

In a certain regimen, the drug administered in the previous treatment regimen is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamustine) , rituximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).

In one aspect, the medicament is administered to a human.

The present invention also provides a method of treating a disease comprising administering to a patient (eg, a human) a therapeutically effective amount of Substance X or a pharmaceutical composition;

The disease is B-cell hematoma; the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; The pharmaceutical composition includes the substance X and pharmaceutical excipients.

In a certain regimen, the mode of administration is oral.

In a certain scheme, the administered dose can be determined according to the body weight of the patient, and based on the content of the quinazoline compound shown in formula A, the administered dose is 0.33 mg/kg-3.33 mg once /kg, for example, 0.66mg/kg-2.3mg/kg, another example, 1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.33mg/kg, 1.4mg/kg, 1.5mg/kg, 1.6mg/kg mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg or 2.3 mg/kg.

In a certain scheme, based on the content of the quinazoline compound represented by formula A, the administered dose is 20-200 mg/day, for example, 20 mg/day, 30 mg/day, 40 mg/day, 50mg/day, 60mg/day, 70mg/day, 80mg/day, 90mg/day, 100mg/day, 110mg/day, 120mg/day, 130mg/day, 140mg/day, 150mg/day, 160mg/day, 170mg/day day, 180 mg/day, 190 mg/day or 200 mg/day, for another example, 80 mg/day.

In a certain regimen, the frequency of administration is 1-5 times/day, eg, 1 time/day, 2 times/day, 3 times/day, 4 times/day, or 5 times/day, for example, 1 time/day.

In a certain regimen, the course of administration is 14-84 days/course, eg, 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course or 84 days/course The course of treatment, for another example, is 28 days/course of treatment.

In a certain regimen, the patient receives a total of 1-20 courses of treatment, preferably 10-20 courses of treatment, eg, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20 courses of treatment, for another example, 12 courses of treatment.

In one aspect, the Substance X or pharmaceutical composition is a tablet.

In a certain scheme, the strength of Substance X or the pharmaceutical composition is 10-120 mg/tablet, for example, 20-100 mg/tablet, another example, 20 mg/tablet, 30 mg/tablet, 40 mg/tablet, 50 mg/tablet, 60mg/tablet, 70mg/tablet, 80mg/tablet, 90mg/tablet or 100mg/tablet, another example is 20mg/tablet, 80mg/tablet or 100mg/tablet.

In one regimen, the patient is a patient with relapsed or refractory follicular lymphoma who has received one or more regimens of systemic therapy, eg, relapsed follicular lymphoma who has received one or more regimens of systemic therapy A patient with lymphoma, preferably, the patient is a patient with relapsed or refractory follicular lymphoma who has received two or more systemic treatment regimens, for example, has received two or more systemic treatment regimens. Treatment options for patients with relapsed follicular lymphoma.

In a certain scheme, the patient is a patient who has progressed after receiving second-line or above systemic therapy, preferably, the patient is a patient who has progressed after receiving CD20 monoclonal antibody and at least one alkylating agent, The alkylating agent includes, but is not limited to, one or more of bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan, and nitroso.

In a certain scheme, the patient's previous treatment regimen is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamustine, tuximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).

In a certain scheme, the pharmaceutical excipients are selected from conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, and adsorption carriers in the pharmaceutical field , one or more of lubricants.

The invention provides the application of a substance X in the preparation of a B-cell hematoma inhibitor;

The substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

In a certain scheme, the inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or making a kit according to conventional methods in the art .

In a certain embodiment of the present invention, the substance X is the only active ingredient.

In a certain embodiment of the present invention, the substance X is in a therapeutically effective amount.

In a certain embodiment of the present invention, the quinazoline compound represented by formula A is the quinazoline compound represented by formula A in free base form, it should be understood that "free base form" is Refers to the case where the quinazoline compound represented by formula A is not in the form of a salt.

In certain embodiments of the present invention, the quinazoline compound represented by formula A is preferably the crystal form I of the quinazoline compound represented by formula A, wherein the quinazoline compound represented by formula A The crystal form I of the compound can be defined in any way described in Chinese Patent Publication No. CN110950844A.

In certain embodiments of the present invention, the pharmaceutical excipients include fillers selected from one or more of microcrystalline cellulose, mannitol and corn starch.

In a certain embodiment of the present invention, the filler is preferably selected from one or two of microcrystalline cellulose, mannitol and corn starch.

In one embodiment of the present invention, the filler is microcrystalline cellulose.

In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol.

In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and cornstarch.

In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol and cornstarch.

In a certain embodiment of the present invention, the filler is 10%-90% by weight of the total weight of the pharmaceutical composition, preferably 30%-70%, most preferably 45%-55%.

In a certain embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol, which is 10%-90% by weight of the total weight of the pharmaceutical composition, preferably 30%-70% %, most preferably 45%-55%.

In a certain embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose and the mannitol is selected from 10:1-1: 10.

In a certain embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose and the mannitol is preferably 6:1-2: 1, most preferably 4:1-3:1.

In a certain embodiment of the present invention, the pharmaceutical excipient further includes a disintegrant.

In a certain embodiment of the present invention, the disintegrant is crospovidone and/or croscarmellose sodium.

In one embodiment of the present invention, the disintegrant is crospovidone.

In a certain embodiment of the present invention, the disintegrant is croscarmellose sodium.

In one embodiment of the present invention, the disintegrant is not low-substituted hydroxypropyl cellulose.

In one embodiment of the present invention, the disintegrant is 1%-20% by weight of the total weight of the pharmaceutical composition, preferably 3%-15%, most preferably 4%-8%.

In a certain embodiment of the present invention, the disintegrant is croscarmellose sodium, which is 1%-20% by weight of the total weight of the pharmaceutical composition.

In a certain embodiment of the present invention, the disintegrant is croscarmellose sodium, which is 3%-15% by weight of the total weight of the pharmaceutical composition, most preferably 4%- 8%.

In a certain embodiment of the present invention, the pharmaceutical excipients further include lubricants.

In the present invention, the lubricant is selected from calcium stearate, glycerol monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate , one or more of sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micropowder silica gel and zinc stearate.

In one embodiment of the present invention, the lubricant is magnesium stearate.

In one embodiment of the present invention, the lubricant is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition, preferably 0.3%-2.0%, most preferably 0.8%-1.4%.

In a certain embodiment of the present invention, the lubricant is magnesium stearate, which is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition.

In a certain embodiment of the present invention, the lubricant is magnesium stearate, which is 0.3%-2.0% by weight of the total weight of the pharmaceutical composition, most preferably 0.8%-1.4%.

In a certain embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

1) 40%-50% of the quinazoline compound shown in formula A;

2) 45%-55% filler, the filler is selected from one, two or more of microcrystalline cellulose, mannitol and corn starch, preferably a mixture of microcrystalline cellulose and mannitol, most preferably A mixture of microcrystalline cellulose and mannitol, and its mass ratio is 4:1-3:1;

3) 4%-8% disintegrant, which is crospovidone and/or croscarmellose sodium, most preferably croscarmellose sodium;

4) 0.8%-1.4% lubricant, the lubricant is magnesium stearate.

In a certain embodiment of the present invention, the quinazoline compound represented by formula A is 40% by weight of the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the filler is 52.8% by weight of the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the disintegrant is 6% by weight of the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the lubricant is 1.2% by weight of the total weight of the pharmaceutical composition.

组分component	重量百分比(％)Weight percentage (%)
如式A所示的喹唑啉化合物Quinazoline compounds represented by formula A	40-5040-50
微晶纤维素microcrystalline cellulose	45-5545-55
交联聚维酮Crospovidone	4-84-8
硬脂酸镁Magnesium stearate	0.8-1.40.8-1.4

; Preferably, the pharmaceutical composition is composed of the above components.

组分component	重量百分比(％)Weight percentage (%)
如式A所示的喹唑啉化合物Quinazoline compounds represented by formula A	40-5040-50
微晶纤维素microcrystalline cellulose	45-5545-55
交联羧甲基纤维素钠Croscarmellose sodium	4-84-8
硬脂酸镁Magnesium stearate	0.8-1.40.8-1.4

组分component	重量百分比(％)Weight percentage (%)
如式A所示的喹唑啉化合物Quinazoline compounds represented by formula A	40-5040-50

微晶纤维素microcrystalline cellulose	30-4530-45
甘露醇Mannitol	5-155-15
交联聚维酮Crospovidone	4-84-8
硬脂酸镁Magnesium stearate	0.8-1.40.8-1.4

组分component	重量百分比(％)Weight percentage (%)
如式A所示的喹唑啉化合物Quinazoline compound represented by formula A	40-5040-50
微晶纤维素microcrystalline cellulose	30-4530-45
甘露醇Mannitol	5-155-15
交联羧甲基纤维素钠Croscarmellose sodium	4-84-8
硬脂酸镁Magnesium stearate	0.8-1.40.8-1.4

组分component	重量百分比(％)Weight percentage (%)
如式A所示的喹唑啉化合物Quinazoline compound represented by formula A	40-5040-50
微晶纤维素microcrystalline cellulose	30-4530-45
玉米淀粉corn starch	5-155-15
交联聚维酮Crospovidone	4-84-8
硬脂酸镁Magnesium stearate	0.8-1.40.8-1.4

组分component	重量百分比(％)Weight percentage (%)
如式A所示的喹唑啉化合物Quinazoline compound represented by formula A	40-5040-50
微晶纤维素microcrystalline cellulose	35-4535-45
玉米淀粉corn starch	5-155-15
交联羧甲基纤维素钠Croscarmellose sodium	4-84-8
硬脂酸镁Magnesium stearate	0.8-1.40.8-1.4

, preferably, the pharmaceutical composition is composed of the above components.

组分component	重量百分比(％)Weight percentage (%)
如式A所示的喹唑啉化合物Quinazoline compound represented by formula A	4040
微晶纤维素 microcrystalline cellulose	4040
甘露醇Mannitol	12.812.8

Croscarmellose sodium	6
Magnesium stearate	1.2

.

In a certain embodiment of the present invention, the pharmaceutical composition may be a solid preparation, preferably a solid oral preparation.

In a certain embodiment of the present invention, the pharmaceutical composition may be a tablet or a capsule, preferably a tablet.

In one embodiment of the present invention, the tablet is a coated tablet.

In a certain embodiment of the present invention, the coated tablet is a film-coated tablet.

In a certain embodiment of the present invention, when the coated tablet is a film-coated tablet, the coating agent used for the film-coated tablet is based on hydroxypropyl methylcellulose as the main film-forming agent Film coating premixes for polymers.

In a certain embodiment of the present invention, in the film-coated tablet, the coating agent of the film-coated tablet can be purchased from Colorcon, for example, under the trade name

film coating premix.

In a certain embodiment of the present invention, in the film-coated tablet, compared with the weight of the tablet core, the weight gain of the coating agent is selected from 2%-5%, preferably 2.5%-4.5%, most preferably 3.5%.

In a certain embodiment of the present invention, the pharmaceutical composition comprises two parts, a tablet core and a coating, and each contains the following components by weight:

Chip:

1) 40%-50% of the quinazoline compound shown in formula A;

2) 45%-55% filler, the filler is selected from one, two or more of microcrystalline cellulose, mannitol and corn starch, preferably a mixture of microcrystalline cellulose and mannitol, microcrystalline The mass ratio of cellulose and mannitol is preferably 4:1-3:1;

3) 4%-8% disintegrant, which is selected from at least one of crospovidone and croscarmellose sodium, most preferably croscarmellose sodium;

4) 0.8%-1.4% lubricant, the lubricant is magnesium stearate;

Coating:

5) The weight gain of the coating agent is selected from 2%-5%, preferably 2.5%-4.5%, most preferably 3.5%, compared to the tablet core weight.

Chip:

1) 40% of the quinazoline compound shown in formula A;

2) 45%-55% filler, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of microcrystalline cellulose and mannitol is 4:1-3:1;

3) 4%-8% disintegrant, which is croscarmellose sodium;

4) 0.8%-1.4% lubricant, the lubricant is magnesium stearate;

Coating:

5) The weight gain of the coating agent is 3.5% compared to the core weight.

In a certain embodiment of the present invention, described pharmaceutical composition, it comprises tablet core and coating two parts, and each contains the following components by weight:

Chip:

1) 40% of the quinazoline compound shown in formula A;

2) 40% microcrystalline cellulose and 12.8% mannitol;

3) 6% croscarmellose sodium;

4) 1.2% magnesium stearate;

Coating:

5) The weight gain of the film coating agent is 3.5% compared to the tablet core weight.

In a certain embodiment of the present invention, the pharmaceutical composition is prepared by the following preparation method, and the preparation method is powder direct compression.

Preferably, the preparation method of the pharmaceutical composition comprises the following steps:

1) Preprocessing

The quinazoline compound, filler and disintegrating agent shown in formula A are respectively passed through 30 mesh sieves, and lubricant is passed through 60 mesh sieves;

2) Master mix

According to the recipe quantity, the quinazoline compound as shown in formula A obtained according to step 1) is mixed with the filler in a mixer to obtain a premix 1;

Mix premix 1 and disintegrant in a mixer to obtain premix 2; use a granulator to sieve premix 2 to obtain premix 3;

Mixing the premix 3 and the lubricant in a mixer to obtain a total mixed material;

3) compressing the total mixture material obtained according to step 2) to obtain tablet cores;

4) Prepare 10% film coating premix coating liquid, and coat the tablet cores obtained according to step 3).

The "filler" used in the present invention, also called "diluent", refers to a class of adjuvants used to increase the volume and weight of the pharmaceutical composition product dosage form in the scientific context. Thus, fillers may be, for example, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, cellulose acetate, ethyl cellulose, fructose, lactose, lactitol, maltose, maltodextrin, maltitol, mannitol, Microcrystalline cellulose, polydextrose, polyethylene glycol, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, cornstarch, dextrin, sucrose, trehalose and xylitol.

The "disintegrant" used in the present invention refers to a class of excipients used in the scientific context to facilitate the breaking of the dosage form of the pharmaceutical composition product into smaller fragments in an aqueous environment. Thus, the disintegrant may be, for example: alginic acid, calcium alginate, calcium carboxymethyl cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, carboxymethyl cellulose Sodium starch base, low-substituted hydroxypropyl cellulose, hypromellose, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methyl cellulose, povidone, sodium alginate, carboxymethyl Sodium cellulose, sodium starch glycolate and starch.

The "lubricant" used in the present invention refers to a class of adjuvants used to improve the processing of pharmaceutical composition product dosage forms under the scientific background. Thus, the lubricant can be, for example, calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, benzene Sodium formate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micronized silica gel and zinc stearate.

The "coating agent" or "film coating premix" used in the present invention refers to a class of adjuvants used to improve the appearance of the dosage form of the pharmaceutical composition product under the scientific background. Thus, the coating agent may be, for example: sucrose, lactose, hydroxypropyl methylcellulose, hydroxypropylethylcellulose, cellulose acetate phthalate, polyvinyl alcohol, polyvinyl acetate phthalate , hypromellose phthalate and acrylic resin.

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine. When compounds of the present invention contain relatively basic functional groups, acid additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid), amino acids (eg, glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed. ., Wiley-VCH, 2002).

The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. Solvent molecules in solvates can exist in ordered or non-ordered arrangements. The solvent includes, but is not limited to, water, methanol, ethanol, and the like.

"Pharmaceutically acceptable salt" and "solvate" in the term "solvate of a pharmaceutically acceptable salt", as described above, refer to a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid A substance prepared by combining with a stoichiometric or non-stoichiometric amount of a solvent.

The term "therapeutically effective amount" refers to an amount of a compound administered to a patient sufficient to be effective in treating a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by those skilled in the art.

The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, which are all substances included in pharmaceutical preparations except active ingredients. 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).

The term "treatment" refers to therapeutic therapy. In relation to a specific disorder, treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

The term "progressive" means that the disease is not relieved or cured after treatment, or even worsens.

The term "patient" refers to any animal, preferably a mammal, and most preferably a human, who has been or is about to undergo treatment. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

On the basis of not violating common knowledge in the art, the above 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 positive improvement effect of the present invention is that: the quinazoline compound of the present invention has good therapeutic effect on B-cell hematoma, especially on follicular lymphoma, with high effective rate and good safety. It is expected to be applied to the treatment of B-cell hematoma, especially follicular lymphoma.

Description of drawings

Fig. 1 is the dissolution curve diagram of the pharmaceutical composition of the quinazoline compound represented by formula A provided in the second part of Examples 4 and 5 in 0.1 mol/L hydrochloric acid solution.

Figure 2 is a graph showing the dissolution profiles of the pharmaceutical compositions of the quinazoline compounds represented by formula A provided in the second part of Examples 4 and 5 in pH 6.8 phosphate buffer containing 0.2% SDS.

Detailed ways

first part:

Preparation Example 1: Synthetic route of the quinazoline compound represented by formula A.

The quinazoline compound represented by formula A is prepared according to the preparation method of compound 10 described in patent CN104557872A, and recrystallized according to the method of example 8 in patent CN110950844A.

Effect Example 1: In vitro inhibitory activity of the quinazoline compound represented by formula A and its analogs on PI3Kδ, and selectivity for other subtypes.

See paragraphs [0538]-[0549] of the CN104557872A specification.

Effect Example 2: Pharmacokinetic evaluation of the quinazoline compound represented by formula A and its analogs

experimental method:

Male SD rats were selected and divided into two groups, the dose of intravenous administration group (iv) was 2 mg/kg, and the dose of oral gavage administration group (po) was 10 mg/kg. After administration, blood was collected from the two groups at 0h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h, respectively, and the plasma was separated. , the concentration of the test compound in the plasma, and the pharmacokinetic parameters were calculated. The results are shown in Table 1.

C _max : peak drug concentration, AUC _last : area under the concentration-time curve from 0 point to the time point corresponding to the last measurable concentration, F%: bioavailability.

Table 1: Summary of PI3Kδ inhibitory activity, selectivity and pharmacokinetic data of quinazoline compounds and their analogs shown in formula A

--- means not tested.

From the results, although several compounds showed good PI3Kδ inhibitory activity in vitro and their structures were relatively similar, their pharmacokinetics were quite different. The quinazoline compounds shown in formula A were at the same dose The peak concentration, the area under the concentration-time curve corresponding to the time point from 0 point to the last measurable concentration, and the bioavailability were all higher.

Effect Example 3: Pharmacokinetic study of the quinazoline compound represented by formula A

Results of pharmacokinetic studies of quinazoline compounds represented by formula A in mice, rats and dogs

The pharmacokinetic studies of the quinazoline compound represented by formula A in mice, rats and dogs show that the oral absorption is good within the effective dose range, and the oral bioavailability is 90%, 65% and 60%, respectively. %above. After 7 consecutive days of administration, the exposure of the quinazoline compound represented by formula A in rats and dogs increased to a certain extent, which was about 1.28-2.20 times of the first administration, indicating that the risk of serious drug accumulation was small. The quinazoline compounds of formula A are moderately cleared in rats and relatively slowly in mice and dogs. The quinazoline compound represented by formula A has a wide tissue distribution, and the exposure amount of the quinazoline compound represented by formula A in other tissues is higher than that in plasma except brain tissue. There is a certain gender difference in the tissue distribution of the quinazoline compounds represented by formula A. The results of in vitro inhibition, induction and recombinase stability tests show that the quinazoline compound shown in formula A has no obvious inhibitory and induction effect on CYP enzymes, and CYP3A4 is the main metabolic enzyme of the quinazoline compound shown in formula A, Next is CYP2C8. The quinazoline compound represented by formula A is extensively metabolized in the body, but is mainly excreted in the original form through urine and feces, about 50%.

Table 2: Pharmacokinetic results of ICR mice, SD rats, and Beagle dogs after a single oral gavage administration

absorb

After oral administration of the quinazoline compound represented by formula A, the absorption in mice, rats and beagle dogs is good, and the oral bioavailability reaches 90%, 65% and 60% or more, respectively. In different dose groups of rats and dogs, the increase in plasma exposure and peak concentration of the quinazoline compound represented by Formula A was close to the dose increase, suggesting that the quinazoline compound represented by Formula A increases with There is a linear pharmacokinetic profile with increasing dose.

distributed

The results of the in vitro plasma protein binding rate test showed that the quinazoline compounds represented by formula A had moderate protein binding rates in mouse, rat, beagle and human plasma in the concentration range of 0.1-30 μM (51.1-30 μM). 85.6%); in monkey plasma, protein binding was moderate (89.3-89.6%) at low and intermediate concentrations (0.1-2 μM) and high (90.2%) at high concentrations (30 μM). The plasma protein binding rates of the quinazoline compounds represented by formula A in the five species are in descending order: cynomolgus monkey>human>CD1 mouse>SD rat>Beagle dog, among which cynomolgus monkey and Binding was similar in humans (85-90%), SD rats and beagle dogs (50-65%).

Steady-state apparent volume of distribution (V _ss , L /kg) were 4.22 (male mice), 4.55 (male rats), 5.18 (female rats), 4.70 (male dogs) and 4.08 (female dogs), which were 5.82 (male) of the total body fluid of each animal. mice), 6.80 (male rats), 7.75 (female rats), 7.79 (male dogs), and 6.76 (female dogs) times, suggesting that the quinazoline compound represented by formula A has a wider range in various animals. tissue distribution.

After gavage administration of 60 mg/kg to SD rats, the quinazoline compound shown in formula A is widely distributed in various tissues and organs, except for brain tissue, the quinazoline compound shown in formula A is in other tissues. The exposures of serotonin were significantly higher than their exposures in plasma, which were about 2-22 times the latter. There is a certain gender difference in the tissue distribution of the quinazoline compounds represented by formula A. The plasma and tissue drug concentrations were higher in male rats than in female rats at all time points. The exposure of the quinazoline compound represented by formula A in various tissues of male rats is about 1.49-3.70 times that of female rats. The half-life of the quinazoline compound represented by formula A is about 2.29-5.08 hr in various tissues of male rats, and the half-life in various tissues of female rats is about 2.25-4.45 hr (except brain tissue). For male rats, quinazoline compounds of formula A had the highest exposure in the stomach, followed by small intestine, liver, kidney, lung, spleen, large intestine, thymus, heart, testis, skeletal muscle, fat , plasma and brain. In female rats, the highest exposure to quinazoline compounds of formula A was in the small intestine, followed by stomach, liver, spleen, kidney, lung, large intestine, thymus, ovary, uterus, heart, skeletal muscle , fat, plasma and brain.

metabolism

The quinazoline compounds of formula A are stable in mouse, rat, canine and human liver microsomes (half-life > 120 min) and moderately metabolized in monkey liver microsomes (half-life = 30- 120 minutes). In addition, the quinazoline compounds of formula A were not significantly metabolized (half-life > 120 minutes) in in vitro hepatocyte assays in mice, rats, dogs, monkeys and humans.

From the perspective of the generation of metabolites mediated by various human recombinases, CYP3A4 is the main metabolic enzyme of the quinazoline compound represented by formula A, followed by CYP2C8. Although the quinazoline compound shown in formula A showed a 20%-30% reduction in the CYP2C8 incubation system, the same phenomenon also occurred in the two incubation systems of -NADPH and + inhibitor, so it cannot be explained that the mother Drug metabolism is dependent on the recombinase CYP2C8.

The quinazoline compounds represented by formula A have no significant inhibitory effect on CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 in human liver microsomes (IC ₅₀ >10 μM).

The quinazoline compound represented by formula A did not show an enhancement effect on enzyme activity or mRNA expression in terms of CYP1A2, CYP2B6 and CYP3A4 at three tested concentrations of 0.4, 4 and 40 μM.

The overall clearance of quinazoline compounds of formula A (CL, L/hr/ kg) were 1.25 (male mice), 1.45 (male rats), 2.18 (female rats), 0.224 (male dogs), and 0.191 (female dogs), which were 23.1% of the hepatic blood flow in each animal (male). mice), 43.8% (male rats), 66.0% (female rats), 12.1% (male dogs), and 10.3% (female dogs), suggesting that mice and dogs are more resistant to the quinazoline compound shown in formula A The metabolic clearance capacity is weak.

Judging from the types of metabolites generated in liver microsomes and their relative contents, combined with the metabolic stability of the quinazoline compounds shown in formula A in liver microsomes, rats and dogs were selected as rodent and non-rodent experimental animals The safety evaluation of the drug meets the requirements of the preclinical safety evaluation of the drug.

excretion

After 60mg/kg of quinazoline compound shown in formula A is given to SD rats by gavage, the excretion amounts of quinazoline compound shown in formula A in male rat urine, feces and bile in 0-72hr are respectively: 20.1 ± 6.48%, 24.5 ± 11.1% and 1.68 ± 0.890% of the dose; the excretion in female rat urine, feces and bile from 0-72 hr was 8.11 ± 2.62%, 7.58% of the dose, respectively ±3.95% and 10.9±1.29%. Therefore, the total excretion rates of the quinazoline compound represented by formula A in the urine, feces and bile of male and female SD rats after oral administration were 46.3% and 26.6%, respectively.

After oral administration of 10 mg/kg of the quinazoline compound shown in formula A to beagle dogs, the excretion amounts of the quinazoline compound shown in formula A in male dogs' urine and feces were 29.2 ± 29.2 ± of the administration amount, respectively. 13.5% and 19.5±16.2%, and their excretion in female dogs’ urine and feces were 41.4±12.4% and 9.21±7.08% of the administered dose, respectively, so the quinazole shown in formula A after oral administration The total excretion rates of morpholino compounds in male and female beagle dogs were 48.7% and 50.6%, respectively.

Effect Example 4: Inhibitory activity of the quinazoline compound represented by formula A on different cells

experimental method:

Add 100 μL of the cell suspension to be tested to the 96-well plate (except the peripheral wells). The plates were placed in a carbon dioxide incubator overnight. The prepared quinazoline compound represented by formula A (50 μM was the initial concentration, and 10 concentration gradients of the quinazoline compound represented by formula A were obtained by 3-fold dilution) were added to each well. Cell plates were incubated in a carbon dioxide incubator for 72 hours. Add 25 μL of CellTiter Glo reagent to the 96-well plate, shake it for 2 minutes in the dark, let it stand in the dark for 10 minutes at room temperature, put the culture plate into the microplate reader to read the chemiluminescence value, and use XLFit to draw the drug efficacy inhibition rate curve and analyze the results. _IC50 values were calculated.

The effect of quinazoline compounds of formula A on cell proliferation was tested in different tumor cells. The results show that the quinazoline compound represented by formula A has obvious inhibitory activity on some hematological tumor cells. For example, the _IC50 value in SU-DHL-6 cells was 0.2337 μM, and the _IC50 value in SU-DHL-5 cells was 1.7683 μM.

Effect Example 5: In vivo activity evaluation of quinazoline compound represented by formula A on SU-DHL-6 subcutaneous xenograft tumor model

experimental method:

CB17SCID mice, female, weighing 18-22 grams. SU-DHL-6 cells were cultured in vitro in suspension under RPMI1640 medium with 10% heat-inactivated fetal bovine serum, 100 U/ml penicillin and 100 μg/ml streptomycin at 37°C and 5% CO ₂ . Passaging twice a week. When cells are in exponential growth phase, cells are harvested for seeding. 0.2 ml of cell suspension (cells suspended in base RPMI1640 medium, RPMI1640:Matrigel (Matrigel) = 100 μl: 100 μl) containing 5×10^6 SU-DHL-6 cells was subcutaneously inoculated into the right side of each mouse. back. Group administration was started when the average tumor volume reached 95.79 mm ³ . Grouping method: animals were weighed before administration, and tumor volume was measured. According to tumor volume random grouping (random grouping design), grouping and dosing schedule are shown in Table 3 below. The experimental indicator is to examine whether tumor growth can be inhibited, delayed or cured. Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: V=0.5a×b ² , a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compounds was evaluated by TGI (%). TGI (%) reflects tumor growth inhibition rate. Calculation of TGI (%): TGI (%)=[1-(tumor volume at the end of treatment group administration-tumor volume at the beginning of treatment group administration)/(tumor volume at the end of solvent control group administration-solvent control group administration Tumor volume at the start of the drug)] × 100%. TGI ≥ 58% considered the drug to be effective; TGI ≥ 90% considered the drug extremely effective.

Table 3: Animal grouping and dosing schedule for in vivo pharmacodynamic experiments

The results show that by the 15th day of administration, the CAL-101 (that is, Idelalisib) 50mg/kg BID treatment group, the quinazoline compound shown in formula A 60mg/kg QD group, and the quinazoline compound shown in formula A The TGI of the compound 120 mg/kg QD group and the quinazoline compound 240 mg/kg QD group shown in formula A were 42.67%, 71.89%, 81.57% and 86.98%, respectively. Two-way ANOVA statistical analysis showed that the CAL-101 50mg/kg BID group, the quinazoline compound represented by formula A 60mg/kg QD group, the quinazoline compound represented by formula A 120mg/kg QD group and the formula A The tumor volume of the quinazoline compound 240 mg/kg QD group shown in A was significantly smaller than that of the solvent control group on Day 15 (all P values < 0.01). The quinazoline compounds of formula A were tolerated by tumor-bearing mice at all three therapeutic doses. Results for both tumor volume and weight show quinazoline compound as shown in formula A 60mg/kg QD treatment, quinazoline compound as shown in formula A 120mg/kg QD treatment and quinazoline compound as shown in formula A 240mg/kg QD treatment significantly inhibited the growth of SU-DHL-6 human lymphoma cell subcutaneous xenografts.

Effect Example 6: Clinical Phase I and Phase II Data of Quinazoline Compounds of Formula A

(1) Phase I clinical program design (climbing and expansion programs)

The patient inclusion criteria were patients with relapsed or refractory B-cell hematological tumors confirmed by histology or cytology. A total of 25 patients were included, including 10 patients with follicular lymphoma.

The study is divided into two phases: dose escalation and dose expansion; each phase includes single-dose and multiple-dose studies. Doses in the dose escalation phase included 20 mg/day, 40 mg/day, 80 mg/day, 140 mg/day, 200 mg/day. Except for the 20mg initial dose group, which was only enrolled in 1 group, 3-6 subjects were enrolled in each dose group, 3 subjects were enrolled in the 40 mg dose group, 3 subjects were enrolled in the 80 mg dose group, and 3 subjects were enrolled in the 140 mg dose group. 4 cases were enrolled in the 200 mg dose group; among them, 1 case of follicular lymphoma was enrolled at 40 mg and 200 mg respectively, and 2 cases were enrolled in the 80 mg group. After the end of the tolerance trial, a dose-expansion trial was conducted at a dose of 80 mg/day, and a total of 11 patients were enrolled, including 6 patients with follicular lymphoma. A total of 10 patients with follicular lymphoma were enrolled.

The mode of administration is: oral administration, once daily during the continuous administration period, until disease progression or intolerable toxicity.

The quinazoline compound tablet represented by formula A is a powder-mixing direct-compression coated tablet, which is prepared according to the process described in the second part of preparation example 1 and preparation example 2. The formulation was that of Example 5 in Part II, and 20 mg and 100 mg tablets were made.

(2) Phase I test results and effects

The quinazoline compound tablet represented by formula A shows good antitumor activity in patients with relapsed or refractory B cell hematological malignancies, especially in follicular lymphoma. The results are shown in the table below. Among the 25 subjects, the best overall curative effect was CR in 5 cases, PR in 11 cases, SD in 2 cases, PD in 7 cases, and the overall optimal curative effect ORR ratio was 64% (16/25) ( 95% CI: 45.2-82.8%), the DCR ratio was 72% (18/25) (95% CI: 54.4-89.6%). Among them, the ORR and DCR ratios of the best curative effect in follicular lymphoma were both 90.0% (9/10).

Overall response rate (ORR); Disease control rate (DCR); CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.

The efficacy evaluation criteria for B-cell lymphoma refer to "The efficacy evaluation criteria for lymphoma IRWG (excerpt), the revised criteria for the efficacy evaluation of malignant lymphomas".

Table 4: Optimal efficacy statistics table

(3) Phase I safety effect data

The patient inclusion criteria were patients with relapsed or refractory B-cell hematological tumors confirmed by histology or cytology. A total of 25 patients were included, including 10 patients with follicular lymphoma. The study is divided into two phases: dose escalation and dose expansion; each phase includes single-dose and multiple-dose studies. Doses in the dose escalation phase included 20 mg/day, 40 mg/day, 80 mg/day, 140 mg/day, 200 mg/day. Except for the 20mg initial dose group, which was only enrolled in 1 group, 3-6 subjects were enrolled in each dose group, 3 subjects were enrolled in the 40 mg dose group, 3 subjects were enrolled in the 80 mg dose group, and 3 subjects were enrolled in the 140 mg dose group. 4 cases were enrolled in the 200 mg dose group. Dose expansion studies were conducted in the 80 mg dose group. No dose-limiting toxicity (DLT) occurred during the 28-day observation period. In terms of the occurrence of adverse events, the single and multiple administrations of the quinazoline compound tablet shown in formula A were well tolerated.

According to phase I clinical results, it is proved that the quinazoline compound represented by formula A has good and controllable safety.

Based on preclinical results, single-arm, open-label, single- and multiple-dose administration of quinazoline compounds of formula A in patients with relapsed or refractory B-cell hematological malignancies who are refractory to or lack standard therapy Phase I clinical study on the tolerance and pharmacokinetics of the drug, dose escalation, and the results of the study suggest that the quinazoline compound represented by formula A has controllable safety and good tolerance.

In conclusion, the quinazoline compounds represented by formula A are safe and tolerable in the dose range of 20-200 mg, and can alleviate and control the progression of relapsed or refractory B-cell malignancies, especially in follicular lymphoma. showed a very good effect.

(4) Data comparison of listed drugs with the same target

The current FDA-approved PI3kδ inhibitor Idelalisib has an objective response rate (ORR) of 39% in the treatment of refractory and relapsed follicular lymphoma, while the PI3Kγ,δ inhibitor Duvelisib has an ORR of 42% in the treatment of refractory and relapsed follicular lymphoma The ORR of copanlisib in refractory relapsed follicular lymphoma was 59%. (Data obtained from marketed drug inserts).

The ORR of the quinazoline compound represented by formula A in the clinical phase I treatment of follicular lymphoma was 90.0% (9/10). A single-arm, open-label, multi-center phase II clinical trial of the quinazoline compound shown in formula A in the treatment of patients with relapsed and/or refractory follicular lymphoma, the inclusion criteria are after receiving second-line or more systemic therapy Progression (previously treated with CD20 monoclonal antibody and at least one alkylating agent, including but not limited to bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan, nitro), 93 subjects were enrolled. Subjects took quinazoline compound tablets of formula A, orally, once daily, 4 tablets of 20 mg each time, until disease progression or intolerable toxicity. 89 subjects underwent at least one imaging evaluation, and the results of independent data evaluation (IRWG Response Evaluation Criteria for Lymphoma) showed that the quinazoline compound shown in formula A was effective in 89 cases (evaluable cases) with relapsed/refractory filtration. In patients with vesicular lymphoma, the ORR is more than 80%. From the analysis of statistical results, the ORR has increased from about 50% of similar drugs to about 80%, which has obvious advantages over similar drugs.

the second part

The quinazoline compound represented by formula A used in the following examples was prepared according to the preparation method of compound 10 described in patent CN104557872A, and recrystallized according to the method of example 8 in patent CN110950844A.

The materials used in the following examples are shown in the table below:

The equipment used in the following examples is shown in the table below:

In Examples 1, 2, 3A and 3B, the dissolution methods were in accordance with the second method of the 2015 edition of "Chinese Pharmacopoeia", Part Four General Principles 0931, with 900 ml of pH 6.8 phosphate buffer solution containing 0.2% SDS at 37°C as the dissolution medium, The rotation speed was 75 rpm, sampling was performed at appropriate time intervals, the same volume of dissolution medium was replenished, filtered through a 0.45 μm filter membrane, and the content was determined by high-performance liquid phase to calculate the dissolution rate.

The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

Preparation Example 1. Chip preparation

The quinazoline compound shown in formula A and each auxiliary material of the recipe quantity are weighed according to the designed prescription composition, and the quinazoline compound shown in formula A, filler and disintegrating agent are respectively passed through a 30-mesh sieve, lubricating pass through a 60-mesh sieve; mix the quinazoline compound shown in formula A and the filler in a mixer to obtain a premix 1; add the disintegrant to the premix 1, and use a mixer to mix uniformly, to obtain premix 2; use a granulator to sieve premix 2 to obtain premix 3; mix premix 3 and lubricant in a mixer to obtain a total mixture; use equipment equipped with 5mm, D-type round die or rotary tableting machine with 11*5.5mm upper punched Half wire bond die to tablet the blended material to form quinazoline containing 20 mg or 100 mg of formula A, respectively Compound tablets.

Preparation example 2. Preparation of film-coated tablets

The film coating premix powder was added to the stirring purified water, and the stirring was continued for 45 minutes to prepare a coating liquid with a solid content of 10% (w/w) of the film coating premix. The tablet cores manufactured by the process described in Preparation Example 1 above were coated to a coating weight gain ranging from 2% to 5% to form film-coated tablets containing 20 mg or 100 mg of the quinazoline compound represented by Formula A, respectively.

Embodiment 1, tablet core prescription F1-F8

The type and amount of disintegrant directly affects the disintegration of the tablet and the release rate of the active pharmaceutical ingredient. The formulation compositions F1-F8 of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose as disintegrants were screened respectively, and the dosage of disintegrants in the formulations was screened. The pharmaceutical composition was manufactured by the process described in the above Preparation Example 1, and tablet cores containing 20 mg of the quinazoline compound represented by formula A were obtained respectively. Taking the smoothness of tableting and the dissolution rate during the tableting process as the investigation indicators, the formulation composition and results are shown in Table 5 below.

Table 5. Formulations F1-F8 and results

- Indicates that it is not used.

Experimental results: The tableting process of formulations F1-F8 was smooth and smooth, and there was no sticking phenomenon. The cores of formulations F1-F6 using only crospovidone or only croscarmellose sodium as disintegrant disintegrated Disintegration is rapid, the quinazoline compound shown in formula A dissolves rapidly, and the cumulative dissolution exceeds 90% in 30 minutes; the formulations F7 and F8 with low-substituted hydroxypropyl cellulose are added to the disintegrant, and the tablet core disintegrates Slow, the quinazoline compounds of formula A dissolve very slowly, with only 72% and 67% cumulative dissolution at 30 minutes.

Embodiment 2, film-coated tablet prescription F9-F10

The amount of lubricant used will affect the smoothness of tableting and the dissolution rate of the active pharmaceutical ingredient. On the basis of the optimal formulation F5 dissolved in Example 1, the formulation compositions F9 and F10 of different dosages of magnesium stearate as lubricant were screened respectively. The pharmaceutical composition was manufactured by the process described in the above Preparation Example 1, and tablet cores containing 20 mg of the quinazoline compound represented by formula A were obtained respectively. Formulation of Film Coating Premixes

A coating liquid with a solid content of 10% (w/w) was used to coat the tablet cores with a high-efficiency coating machine (BGB-5F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.) to give the formulations F9 and F10, respectively. A film-coated tablet containing 20 mg of a quinazoline compound of formula A with a coat weight gain of approximately 3.5%. Taking the smoothness of tableting out and the dissolution rate during the tableting process as the evaluation index, the formulation composition and results of the film-coated tablet (before coating) of Example 2 are shown in Table 6 below.

Table 6. Prescription F9-F10 and Results

Experimental results: The tableting process of formulations F9 and F10 was smooth, and there was no sticking phenomenon, and the film-coated tablets disintegrated rapidly. 92%, all meet the release standard of finished product dissolution (≥70%).

Example 3A and 3B, preparation of film-coated tablets (20 mg specification, 20,000 tablets)

The pharmaceutical composition was manufactured by the process described in the above-mentioned preparation example 1, and a tablet core containing 20 mg of the quinazoline compound represented by formula A was obtained. Formulation of Film Coating Premixes

The coating liquid with a solid content of 10% (w/w) was used to coat the tablet cores with a coating weight gain range of 2%-5% by using a high-efficiency coating machine (BGB-5F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.). coating to give about 20,000 film-coated tablets containing 20 mg of a quinazoline compound of formula A with a coating weight gain of 2.5% for Example 3A, and for Example 3B with a coating weight gain A 4.5% film-coated tablet containing 20 mg of the quinazoline compound represented by formula A is about 20,000. The batch formulations of the film-coated tablets (before coating) of Examples 3A and 3B are shown in Table 7 below.

Table 7. Formulation of film-coated tablets (before coating) manufactured in Examples 3A and 3B (20 mg strength, 20,000 tablets)

The dissolution results of the film-coated tablets of Examples 3A and 3B in phosphate buffer pH 6.8 containing 0.2% SDS are shown in Table 8 below. The results showed that the 20 mg film-coated tablets with coating weight gain of 2.5% and 4.5% disintegrated rapidly. 92%, all meet the release standard of finished product dissolution (≥70%).

Table 8. Dissolution results of film-coated tablets manufactured in Example 3A, 3B in 0.2% SDS in pH 6.8 phosphate buffer

Example 4: Preparation of pilot-scale film-coated tablets (20 mg specification, 300,000 tablets)

A powder direct compression process is used to manufacture pilot scale pharmaceutical compositions. The quinazoline compound shown in formula A, the filler and the disintegrating agent were respectively passed through a 30-mesh sieve, and the lubricant was passed through a 60-mesh sieve; Mix evenly in the hopper mixer (HBD200, Nantong Better Pharmaceutical Machinery Co., Ltd.) to obtain premix 1; add the disintegrant to premix 1, and use the hopper mixer to mix evenly to obtain premix 2 ; Sieve premix 2 using a granulator (Comil U10, QUADRO, Canada) equipped with a 032R screen and square impeller to obtain premix 3; mix premix 3 and lubricant in a hopper mixer, The blend was obtained; the blend was tabletted using a rotary tablet press (P2020, Fette, Germany) equipped with a 5mm D-type circular die to form tablets containing 20 mg of the quinazoline compound of formula A core. Formulation of Film Coating Premixes

A coating solution with a solid content of 10% (w/w) was used to coat the tablet cores with a high-efficiency coating machine (BGB-40F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.) until the coating weight increased by 3.5%, and a pilot test was obtained. A scale film-coated tablet containing 20 mg of the quinazoline compound of formula A. The film-coated tablet batch formulations of Example 4 are shown in Table 9 below.

Table 9. Pilot-scale film-coated tablet formulation (20 mg strength, 300,000 tablets)

^a : Calculated according to 50% coating efficiency in the manufacturing process, the actual batch recipe usage is 1.050Kg.

^b : Calculated according to 50% coating efficiency in the manufacturing process, the actual batch recipe usage is 9.450Kg, and purified water is removed during the coating process.

Example 5: Preparation of 100 mg film-coated tablets

The pharmaceutical composition was manufactured by the method described in Preparation Example 1 above, and a tablet core containing 100 mg of the quinazoline compound represented by formula A was obtained. Formulation of Film Coating Premixes

A coating solution with a solid content of 10% (w/w) is used to coat the tablet core with a high-efficiency coating machine until the coating weight is increased by 3.5% to obtain a film containing 100 mg of the quinazoline compound represented by formula A Coated tablet. The film-coated tablet batch formulations of Example 5 are shown in Table 10 below.

Table 10. Formulation of 100 mg film-coated tablet

^a : Calculated according to 50% coating efficiency in the manufacturing process, the actual batch recipe usage is 0.264Kg.

^b : Calculated according to 50% coating efficiency in the manufacturing process, the actual batch recipe usage is 2.376Kg, and purified water is removed during the coating process.

Test Example 1: Determination of key quality attributes of pharmaceutical compositions

The pharmaceutical composition manufactured in the above-mentioned embodiment 4 is carried out to measure the key quality attributes of the medicine, and the examination items include character, content uniformity, content, related substances, dissolution, and the examination results are shown in the following table 11.

Properties: Visually observe, record the appearance of the film-coated tablet, and the appearance of the tablet core after removing the coating.

Content uniformity: Take 10 pieces of the test sample, and measure the relative content xi of each single dose with the labeled amount of 100 according to the high-performance liquid chromatography method under the content determination conditions. According to the content uniformity inspection method (2015 edition of "Chinese Pharmacopoeia" four general chapters 0941), calculate A+2.2S.

Determination of related substances and content: According to high performance liquid chromatography (2015 edition of "Chinese Pharmacopoeia" four general rules 0512), use the principal component external standard method with response factor to calculate the quinazole shown in formula A in the pharmaceutical composition with the peak area The content of each known impurity, unknown impurity and total impurity of the quinazoline compound (reporting limit: 0.05%); the content of the quinazoline compound represented by formula A in the pharmaceutical composition was calculated by the peak area using the external standard method.

Dissolution: According to the dissolution test method (2015 edition of "Chinese Pharmacopoeia" four general rules 0931 second method), take 900ml of pH6.8 phosphate buffer containing 0.2% SDS as the dissolution medium, the speed is 75 rpm, take 6 Take 1 tablet of the test sample, and put 1 tablet in each dissolution cup. After 30 minutes, take 10 ml of the solution, filter it with a 0.45 μm filter membrane, measure the content by high-performance liquid phase, and calculate the dissolution rate of the quinazoline compound shown in formula A.

Table 11. Examination results of key quality attributes of pharmaceutical compositions manufactured in Example 4

Experimental results: The evaluation results of each key quality attribute of the film-coated tablet containing 20 mg of the quinazoline compound represented by Formula A manufactured in Example 4 all met the finished product release quality standards.

Test Example 2: Determination of Dissolution Profile of Pharmaceutical Compositions

Dissolution profile measurements were performed on the pharmaceutical compositions prepared in Examples 4 and 5 above, respectively.

According to the dissolution test method (2015 edition of "Chinese Pharmacopoeia" four general rules 0931 second method), the rotation speed is 75 rpm, with 0.1mol/L hydrochloric acid solution (9ml hydrochloric acid, add water to make 1000ml) or pH6 containing 0.2% SDS .8 900ml of phosphate buffer is the dissolution medium, take 6 pieces of the test sample from the film-coated tablets manufactured in each example, and put 1 piece in each dissolution cup, take samples at appropriate time intervals, and rehydrate with the same volume of dissolution medium , filtered through a 0.45 μm filter membrane, and the cumulative dissolution rate of the quinazoline compound shown in formula A was calculated by high-performance liquid phase determination. The measurement results are shown in Table 12 below and accompanying drawings 1-2.

Table 12. Determination results of dissolution profiles of pharmaceutical compositions manufactured in Examples 4 and 5

Experimental results: In 0.1mol/L hydrochloric acid solution, both 20mg and 100mg film-coated tablets can be rapidly and completely dissolved, and the cumulative dissolution reached 100% in 30 minutes. In pH 6.8 phosphate buffer containing 0.2% SDS, the dissolution rate of 100 mg film-coated tablets was slightly slower than that of 20 mg, and the cumulative dissolution rate was 88% in 30 minutes, which met the release standard for finished product dissolution (≥70%).

Effect Example 1: Influencing Factor Test

The pharmaceutical composition manufactured in Example 4 was exposed and placed under the influence factors of high temperature (60°C), high humidity (25±2°C, RH92.5%), and light (4500±500Lux) for 30 days. According to the above test example The test method in 1 assesses the stability of the pharmaceutical composition, and the assessment indicators include properties, related substances, dissolution rate and content. Specific results are shown in Tables 13-15 below.

Table 13. Summary of test results of high temperature influencing factors of the pharmaceutical composition manufactured in Example 4

Table 14. Summary of the test results of the high humidity influencing factors of the pharmaceutical composition manufactured in Example 4

^a : Moisture absorption and weight gain is the investigation item of the high humidity influencing factor test, with unlimited requirements.

Table 15. Summary of the test results of the factors affecting the illumination of the pharmaceutical composition manufactured in Example 4

The results in Tables 13-15 show that the pharmaceutical composition of the quinazoline compound represented by the formula A provided by the present invention is measured after being exposed and placed for 5 days, 10 days and 30 days under the conditions of high temperature, high humidity and light influence factors, respectively. , there was no significant change in the evaluation indicators of the pharmaceutical composition compared with those before the influence factor test treatment. When placed under high humidity conditions for 30 days, the pharmaceutical composition has no obvious hygroscopic weight gain.

It should be understood that the embodiments described in the present invention are only for illustrative purposes, and the embodiments will help to further understand the present invention, but are not intended to limit the content of the present invention. Numerous changes to both materials and methods, which are apparent to those skilled in the art, can be practiced without departing from the scope of the invention, which changes or modifications are included within the spirit and scope of this application and the scope of the appended claims.

Claims

A kind of application of substance X or pharmaceutical composition in the preparation of medicine, it is characterized in that, described substance X is quinazoline compound as shown in formula A, its pharmaceutically acceptable salt, its solvate or its pharmacy The solvate of the above acceptable salt; the pharmaceutical composition comprises the substance X and pharmaceutical excipients; the medicine is a medicine for the treatment of B-cell hematoma;
The use of the substance X or the pharmaceutical composition as claimed in claim 1 in the preparation of a medicine, wherein the substance X is a therapeutically effective amount;

And/or, the B-cell hematoma is a B-cell lymphoma;

and/or, the drug is administered orally;

And/or, in terms of the content of the quinazoline compound shown in formula A, the administration dose of the medicine is 0.33mg/kg-3.33mg/kg once;

And/or, in terms of the content of the quinazoline compound shown in formula A, the administration dose of the medicine is 20mg-200mg/day;

And/or, the administration frequency of described medicine is 1-5 times/day;

And/or, the administration course of treatment of described medicine is 14-84 days/course of treatment;

And/or, the medicine is administered for a total of 1-20 courses of treatment;

And/or, in the unit dosage form of the medicine, the content of the quinazoline compound shown in formula A is 5mg-500mg;

And/or, the administration object of described medicine is human;

And/or, the pharmaceutical excipients include fillers;

And/or, the pharmaceutical excipients include disintegrants;

And/or, the pharmaceutical excipients include lubricants;

And/or, the medicine is tablet or capsule.
The use of substance X or the pharmaceutical composition in the preparation of medicine according to claim 2, wherein when the B-cell hematoma is a B-cell lymphoma, the B-cell lymphoma is a non-Hodgkin's lymphoma tumor;

And/or, when the content of the quinazoline compound shown in formula A is measured, the administration dose of the medicine is 0.66mg/kg-2.3mg/kg once;

And/or, when the content of the quinazoline compound shown in the formula A is timed, the administration dose of the medicine is 20mg/day, 30mg/day, 40mg/day, 50mg/day, 60mg/day, 70mg/day, 80mg/day, 90mg/day, 100mg/day, 110mg/day, 120mg/day, 130mg/day, 140mg/day, 150mg/day, 160mg/day, 170mg/day, 180mg/day, 190mg/day day or 200mg/day;

And/or, when the administration frequency of the medicine is 1-5 times/day, the administration frequency of the medicine is 1 time/day, 2 times/day, 3 times/day, 4 times/day or 5 times /sky;

And/or, when the administration course of the medicine is 14-84 days/course, the administration course of the medicine is 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course. days/course or 84 days/course;

And/or, the medicine is administered for a total of 10-20 courses of treatment;

And/or, in the unit dosage form of the medicine, the content of the quinazoline compound shown in formula A is 10mg-120mg;

And/or, when the pharmaceutical adjuvant includes a filler, the filler is one or more of microcrystalline cellulose, mannitol and corn starch;

And/or, when the pharmaceutical adjuvant includes a filler, the filler is 10%-90% by weight of the total weight of the pharmaceutical composition;

And/or, when the pharmaceutical adjuvant includes a disintegrating agent, the disintegrating agent is crospovidone and/or croscarmellose sodium;

And/or, when the pharmaceutical adjuvant includes a disintegrant, the disintegrant is 1%-20% by weight of the total weight of the pharmaceutical composition;

And/or, when described pharmaceutical adjuvant comprises lubricant, described lubricant is selected from calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, One of loxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micronized silica gel and zinc stearate one or more;

And/or, when the pharmaceutical adjuvant includes a lubricant, the lubricant is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition;

And/or, when the medicine is a tablet or a capsule, the tablet is a coated tablet.
The use of the substance X or the pharmaceutical composition in the preparation of a medicine according to claim 3, wherein when the B-cell lymphoma is a non-Hodgkin's lymphoma, the non-Hodgkin's lymphoma is a filter vesicular lymphoma;

And/or, in terms of the content of the quinazoline compound shown in the formula A, the administration dosage of the medicine is 1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.33 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg or 2.3 mg/kg;

And/or, the administration course of treatment of described medicine is 28 days/course of treatment;

And/or, the pharmaceutical composition is administered for a total of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 courses of treatment;

And/or, in the unit dosage form of the medicine, the content of the quinazoline compound shown in formula A is 20-100 mg;

And/or, when the pharmaceutical adjuvant includes a filler, the filler is a mixture of microcrystalline cellulose, microcrystalline cellulose and mannitol, or a mixture of microcrystalline cellulose and corn starch;

And/or, when the pharmaceutical excipients include fillers, the fillers are 30%-70% by weight of the total weight of the pharmaceutical composition;

And/or, when the pharmaceutical adjuvant includes a disintegrating agent, the disintegrating agent is crospovidone or croscarmellose sodium;

And/or, when the pharmaceutical adjuvant includes a disintegrant, the disintegrant is 3%-15% by weight of the total weight of the pharmaceutical composition;

And/or, when described pharmaceutical adjuvant comprises lubricant, described lubricant is magnesium stearate;

And/or, when the pharmaceutical adjuvant includes a lubricant, the lubricant is 0.3%-2.0% by weight of the total weight of the pharmaceutical composition;

And/or, when the tablet is a coated tablet, the coated tablet is a film-coated tablet.
The use of substance X or the pharmaceutical composition in the preparation of a medicine according to claim 4, wherein when the non-Hodgkin's lymphoma is a follicular lymphoma, the follicular lymphoma is a recurrence and/or refractory follicular lymphoma, eg, relapsed or refractory follicular lymphoma;

And/or, the drug is administered to a patient with relapsed or refractory follicular lymphoma who has received one or more systemic therapy regimens, e.g., administered to a relapsed patient who has received one or more systemic therapy regimens in patients with follicular lymphoma;

And/or, the drug is administered to a patient who has progressed after receiving second-line or more systemic systemic therapy in the past, and the second-line or more systemic therapy has received CD20 monoclonal antibody and at least one alkylation drug treatment;

And/or, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound shown in formula A is 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg;

And/or, the pharmaceutical composition is administered for a total of 12 courses of treatment;

And/or, the pharmaceutical adjuvant includes a filler, and the filler is 45%-55% by weight of the total weight of the pharmaceutical composition;

And/or, when the filler is a mixture of microcrystalline cellulose and mannitol, the mass ratio of the microcrystalline cellulose and the mannitol is 10:1-1:10, for example, 6 : 1-2: 1, another example, 4: 1-3: 1;

And/or, when the pharmaceutical adjuvant includes a disintegrant, the disintegrant is 4%-8% by weight of the total weight of the pharmaceutical composition;

And/or, when the pharmaceutical adjuvant includes a lubricant, the lubricant is 0.8%-1.4% by weight of the total weight of the pharmaceutical composition;

And/or, when the coated tablet is a film-coated tablet, in the film-coated tablet, compared with the weight of the tablet core, the weight gain of the coating agent is selected from 2%-5%;

And/or, when the coated tablet is a film-coated tablet, the coating agent used for the film-coated tablet is a film coating based on hydroxypropyl methylcellulose as the main film-forming polymer premix.
The use of the substance X or the pharmaceutical composition in the preparation of a medicine according to claim 5, wherein when the medicine is administered to patients with relapsed or refractory follicular lymphoma who have received one or more systemic treatment regimens when the drug is administered to a patient with relapsed or refractory follicular lymphoma who has received two or more systemic treatment regimens, for example, is administered to a patient who has received two or more in patients with relapsed follicular lymphoma on systemic therapy;

And/or, the drug is administered to a patient who has progressed after receiving second-line or more systemic systemic therapy in the past, and the second-line or more systemic therapy has received CD20 monoclonal antibody and at least one alkylation The alkylating agent is one or more of bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan and nitroso; for example, the described The drug is administered to a patient who has received one or more of R-CHOP, BR, and R-CVP prior to treatment;

And/or, the pharmaceutical composition includes the following components by weight:

1) 40%-50% of the quinazoline compound shown in formula A;

2) 45%-55% filler, which is one, two or more of microcrystalline cellulose, mannitol and corn starch;

3) 4%-8% disintegrant, which is crospovidone and/or croscarmellose sodium;

4) 0.8%-1.4% lubricant, the lubricant is magnesium stearate;

And/or, when the coated tablet is a film-coated tablet, the coating agent used for the film-coated tablet is commercially available from Colorcon Company under the trade name
film coating premix;

And/or, when the coated tablet is a film-coated tablet, in the film-coated tablet, the weight gain of the coating agent is 3.5% compared to the weight of the tablet core.
The application of substance X or pharmaceutical composition in the preparation of medicine according to claim 6, characterized in that,

The pharmaceutical composition comprises the following components by weight:

component Weight percentage (%) Quinazoline compound represented by formula A 40-50 microcrystalline cellulose 30-45 Mannitol 5-15 Crospovidone 4-8 Magnesium stearate 0.8-1.4

or,

component Weight percentage (%) Quinazoline compound represented by formula A 40-50 microcrystalline cellulose 30-45 Mannitol 5-15 Croscarmellose sodium 4-8 Magnesium stearate 0.8-1.4

or,

component Weight percentage (%) Quinazoline compound represented by formula A 40-50 microcrystalline cellulose 30-45 corn starch 5-15 Crospovidone 4-8 Magnesium stearate 0.8-1.4

or,

component Weight percentage (%) Quinazoline compound represented by formula A 40-50 microcrystalline cellulose 35-45 corn starch 5-15 Croscarmellose sodium 4-8 Magnesium stearate 0.8-1.4

.
The application of substance X or pharmaceutical composition in the preparation of medicine as claimed in claim 7, wherein the pharmaceutical composition is composed of the following components:

component Weight percentage (%) Quinazoline compound represented by formula A 40 microcrystalline cellulose 40 Mannitol 12.8 Croscarmellose sodium 6 Magnesium stearate 1.2

Or, described pharmaceutical composition, it comprises tablet core and coating two parts, and each contains the following components by weight:

Chip:

1) 40% of the quinazoline compound shown in formula A;

2) 40% microcrystalline cellulose and 12.8% mannitol;

3) 6% croscarmellose sodium;

4) 1.2% magnesium stearate;

Coating:

5) The weight gain of the coating agent is 3.5% compared to the core weight.
An application of a substance X in the preparation of a B-cell lymphoma inhibitor, characterized in that,

The substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
The application of substance X in the preparation of B-cell lymphoma inhibitor according to claim 9, wherein the B-cell lymphoma is non-Hodgkin's lymphoma, preferably, the non-Hodgkin's lymphoma The tumor is follicular lymphoma, more preferably, the follicular lymphoma is relapsed and/or refractory follicular lymphoma.