CN111329863A - Use of a composition containing a heterocyclic compound for the preparation of a medicament for the treatment of leukemia - Google Patents
Use of a composition containing a heterocyclic compound for the preparation of a medicament for the treatment of leukemia Download PDFInfo
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- CN111329863A CN111329863A CN202010149400.4A CN202010149400A CN111329863A CN 111329863 A CN111329863 A CN 111329863A CN 202010149400 A CN202010149400 A CN 202010149400A CN 111329863 A CN111329863 A CN 111329863A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention relates to an application of a composition containing heterocyclic compounds in preparing medicines for treating leukemia. In one aspect, there is provided the use of a composition comprising pyridylpyrimidine amines in the manufacture of a medicament for the treatment of leukaemia; in another aspect, the present invention provides the use of a composition comprising phenylcarbamoylthiazole compounds for the manufacture of a medicament for the treatment of leukemia; the invention also provides application of the quinoline compound in preparing medicaments for treating leukemia.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a composition containing a heterocyclic compound in preparation of a medicine for treating leukemia.
Background
The pyridylpyrimidine amine compound I with the structure shown in the specification is a clinically common therapeutic drug for Chronic Myelogenous Leukemia (CML), but the medicinal dose is high (100 mg-400 mg), which indicates that the anti-effect of the pyridylpyrimidine amine compound I needs to be further improved. For example, the results of the studies by Zhonghua et al show (theory and practice in diagnostics, 2010,9(05):469-472.), that imatinib acts on the IC of K562, K562/pc and K562/CYP3A5 cells50The values were (55.313. + -. 0.248), (57.043. + -. 0.486) and (72.910. + -. 0.776). mu.g/mL, respectively.
A study of Phenylcarbamoylthiazole compound II with the structure shown as follows, which is also an FDA approved CML therapeutic agent, Chua Shigella et al (China modern applied medicine, 2018,35(09):1275-1279.) shows that the IC50 of the compound II acting on K562 cells is about 244.00 mu g/mL, and the activity of the compound II is to be further improved.
Quinoline compound III with the structure shown in the specification is also a CML therapeutic drug approved by FDA, and the data quoted by Dachow of Zhejiang university in Ph.D.paper "research on the action and mechanism of hanfangchin A citrate as calmodulin antagonist against chronic myelocytic leukemia" refers to IC of bosutinib on K56250The concentration was 26.52. mu.g/L.
Disclosure of Invention
The invention aims to provide application of a composition containing pyridyl pyrimidinamine compounds and phenylcarbamoyl thiazole compounds in preparing a medicament for treating leukemia, wherein the anti-leukemia effect of the composition is obviously better than that of the compounds I, II and III.
In order to achieve the above objects, the present invention provides, in a first aspect, a use of a composition comprising a first pyridylpyrimidine amine compound and a second pyridylpyrimidine amine compound which are different from each other and selected from the group consisting of compounds 1 to 38 shown below, for the preparation of a medicament for the treatment of leukemia:
4,4' - (piperazine-1, 4-diylbis (methylene)) bis (N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide) (Compound 1),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -3- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 2),
4- (chloromethyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (compound 3),
6-methyl-N1- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine (compound 4),
n- (2-methyl-5-nitrophenyl) -4- (pyridin-3-yl) pyrimidin-2-amine (Compound 5),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide (Compound 6),
n- (2-methyl-5- (methylamino) phenyl) -N- (4- (pyridin-3-yl) pyrimidin-2-yl) carboxamide (Compound 7),
n- (4-methyl-3- (N- (4- (pyridin-3-yl) pyrimidin-2-yl) acetamido) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 8),
4-methyl-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (compound 9),
n- (3-methyl-4- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 10),
n- (4-methyl-3- ((4-methyl-6- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 11),
6-methyl-N1- (4-methyl-6- (pyridin-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine (compound 12),
2-methyl-N1- (4-methyl-6- (pyridin-3-yl) pyrimidin-2-yl) benzene-1, 4-diamine (compound 13),
n- (2-methyl-5- (4- ((4-methylpiperazin-1-yl) methyl) benzoylamino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -N- (4- (pyridin-3-yl) pyrimidin-2-yl) benzamide (compound 14),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- (piperazin-1-ylmethyl) benzamide (compound 15),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4- (4- ((4-methylpiperazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) benzamide (compound 16),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((3-methylpiperazin-1-yl) methyl) benzamide (compound 17),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) pivaloamide (compound 18),
N-methyl-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 19),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) benzoyl) benzamide (compound 20),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -N- (4- (piperazin-1-ylmethyl) benzoyl) benzamide (compound 21),
1-methyl-4- (4- ((4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzyl) piperazine 1-oxide (compound 22),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 23),
1-methyl-1, 4-bis (4- ((4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzyl) piperazin-1-ium (compound 24).
4-methyl-N- (3- (2-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 25),
n- (3- (1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 26),
n- (3- (2, 4-dimethyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 27),
4-methyl-N- (3- (5-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 28),
tert-butyl 4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoate (compound 29),
n- (3- (4- (hydroxymethyl) -1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 30),
4-methyl-1- (3- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoylamino) -5- (trifluoromethyl) phenyl) -1H-imidazole 3-oxide (Compound 31),
4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 32),
1- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) ethan-1-one (compound 33),
4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoic acid (compound 34),
methyl 4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoate (compound 35),
3- (2- ((2-methyl-5- ((3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) carbamoyl) phenyl) amino) pyrimidin-4-yl) pyridine 1-oxide (Compound 36),
1- (3- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoylamino) -5- (trifluoromethyl) phenyl) -1H-imidazole-4-carboxylic acid (compound 37),
4- (hydroxymethyl) -N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 38).
Preferably, the mass ratio of the first pyridylpyrimidine amine compound to the second pyridylpyrimidine amine compound according to the present invention is in the range of 0.01: 1-100: 1.
In another aspect, the present invention provides a use of a composition comprising a first phenylcarbamoyl thiazole compound and a second phenylcarbamoyl thiazole compound, which are different from each other, selected from the group consisting of compounds 39 to 71 shown below, for the preparation of a medicament for treating leukemia:
preferably, the mass ratio of the first phenylcarbamoyl thiazole compound to the second phenylcarbamoyl thiazole compound in the present invention is 0.01: 1-100: 1.
In another aspect, the present invention provides a use of a first quinoline compound and a second quinoline compound, which are different from each other, and are selected from compounds 72 to 82 shown below in the preparation of a medicament for treating leukemia:
preferably, the mass ratio of the first quinoline compound to the second quinoline compound is 0.01: 1-100: 1.
On the other hand, the medicament can be prepared into oral solid preparations; more preferably, the oral solid preparation is one selected from the group consisting of a capsule, a tablet and a granule.
In vitro test results show that the IC50 value of the composition disclosed by the invention on K562, K562/pc and K562/CYP3A5 cells is at ng/L level, and is obviously lower than that of the compounds I, II and III.
Detailed Description
The following description of the embodiments is only intended to aid in the understanding of the method of the invention and its core ideas. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The following description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.
Test example 1 inhibitory Effect of the composition on K562, K562/pc and K562/CYP3A5 cells
The invention adopts a method disclosed by Zhonghua et al (theory and practice in diagnostics, 2010,9(05):469-50The results are shown in tables 1 to 3.
TABLE 1 inhibition of K562 cells by compositions
TABLE 2 inhibitory Effect of the compositions on K562/pc cells
TABLE 3 inhibition of K562/CYP3A5 by the composition
EXAMPLE 1 oral solid preparation containing pyridylpyrimidine amine-based Compound and Process for producing the same
Prescription
Preparation method
The prescription dose of MIX (X-Y) and auxiliary materials are sieved by a 100-mesh sieve. Mixing MIX (X-Y), lactose, microcrystalline cellulose, polyvinylpolypyrrolidone and starch; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Granulating with 16 mesh sieve, adding prescription amount of silica gel micropowder and magnesium stearate, mixing, and encapsulating to obtain capsule with weight of 500 mg;
the prescription dose of MIX (X-Y) and auxiliary materials are sieved by a 100-mesh sieve. Mixing MIX (X-Y), lactose, microcrystalline cellulose, polyvinylpolypyrrolidone and starch; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Sieving with 16 mesh sieve, adding silica gel micropowder and magnesium stearate, mixing, and packaging to obtain granule with weight of 5g per bag.
The prescription dose of MIX (X-Y) and auxiliary materials are sieved by a 100-mesh sieve. Mixing MIX (X-Y), lactose, microcrystalline cellulose, polyvinylpolypyrrolidone and starch; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Sieving with 16 mesh sieve, adding prescription amount of silica gel micropowder and magnesium stearate, mixing, and tabletting to obtain tablet with weight of about 500 mg.
Claims (7)
1. Use of a composition comprising a first pyridylpyrimidine amine compound and a second pyridylpyrimidine amine compound which are different from each other and selected from the group consisting of compounds 1 to 38 shown below in the preparation of a medicament for the treatment of leukemia:
4,4' - (piperazine-1, 4-diylbis (methylene)) bis (N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide) (Compound 1),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -3- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 2),
4- (chloromethyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (compound 3),
6-methyl-N1- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine (compound 4),
n- (2-methyl-5-nitrophenyl) -4- (pyridin-3-yl) pyrimidin-2-amine (Compound 5),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide (Compound 6),
n- (2-methyl-5- (methylamino) phenyl) -N- (4- (pyridin-3-yl) pyrimidin-2-yl) carboxamide (Compound 7),
n- (4-methyl-3- (N- (4- (pyridin-3-yl) pyrimidin-2-yl) acetamido) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 8),
4-methyl-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (compound 9),
n- (3-methyl-4- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 10),
n- (4-methyl-3- ((4-methyl-6- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 11),
6-methyl-N1- (4-methyl-6- (pyridin-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine (compound 12),
2-methyl-N1- (4-methyl-6- (pyridin-3-yl) pyrimidin-2-yl) benzene-1, 4-diamine (compound 13),
n- (2-methyl-5- (4- ((4-methylpiperazin-1-yl) methyl) benzoylamino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -N- (4- (pyridin-3-yl) pyrimidin-2-yl) benzamide (compound 14),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- (piperazin-1-ylmethyl) benzamide (compound 15),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4- (4- ((4-methylpiperazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) benzamide (compound 16),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((3-methylpiperazin-1-yl) methyl) benzamide (compound 17),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) pivaloamide (compound 18),
N-methyl-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 19),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) benzoyl) benzamide (compound 20),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -N- (4- (piperazin-1-ylmethyl) benzoyl) benzamide (compound 21),
1-methyl-4- (4- ((4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzyl) piperazine 1-oxide (compound 22),
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (compound 23),
1-methyl-1, 4-bis (4- ((4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzyl) piperazin-1-ium (Compound 24),
4-methyl-N- (3- (2-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 25),
n- (3- (1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 26),
n- (3- (2, 4-dimethyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 27),
4-methyl-N- (3- (5-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 28),
tert-butyl 4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoate (compound 29),
n- (3- (4- (hydroxymethyl) -1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 30),
4-methyl-1- (3- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoylamino) -5- (trifluoromethyl) phenyl) -1H-imidazole 3-oxide (Compound 31),
4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 32),
1- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) ethan-1-one (compound 33),
4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoic acid (compound 34),
methyl 4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoate (compound 35),
3- (2- ((2-methyl-5- ((3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) carbamoyl) phenyl) amino) pyrimidin-4-yl) pyridine 1-oxide (Compound 36),
1- (3- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzoylamino) -5- (trifluoromethyl) phenyl) -1H-imidazole-4-carboxylic acid (compound 37),
4- (hydroxymethyl) -N- (3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) -3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) benzamide (compound 38).
2. Use according to claim 1, characterized in that the mass ratio of said first pyridylpyrimidinamine compound to said second pyridylpyrimidinamine compound is in the range from 0.01: 1-100: 1.
4. use according to claim 3, characterized in that the mass ratio of the first phenylcarbamoyl thiazole compound to the second phenylcarbamoyl thiazole compound is in the range of 0.01: 1-100: 1.
6. the use according to claim 5, wherein the mass ratio of the first quinoline compound to the second quinoline compound is in the range of 0.01: 1-100: 1.
7. The use according to any one of claims 1 to 6, wherein the medicament is formulated as an oral solid formulation; more preferably, the oral solid preparation is one selected from the group consisting of a capsule, a tablet and a granule.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN202010149400.4A CN111329863A (en) | 2020-03-04 | 2020-03-04 | Use of a composition containing a heterocyclic compound for the preparation of a medicament for the treatment of leukemia |
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CN112079821A (en) * | 2020-09-14 | 2020-12-15 | 中山万汉制药有限公司 | Conjugate formed by orlistat and phenylaminopyrimidine compound and preparation method and application thereof |
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Cited By (1)
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CN112079821A (en) * | 2020-09-14 | 2020-12-15 | 中山万汉制药有限公司 | Conjugate formed by orlistat and phenylaminopyrimidine compound and preparation method and application thereof |
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