CN111265668A - Composition comprising a histamine release-promoting substance and an inhibitory compound - Google Patents

Composition comprising a histamine release-promoting substance and an inhibitory compound Download PDF

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CN111265668A
CN111265668A CN202010282391.6A CN202010282391A CN111265668A CN 111265668 A CN111265668 A CN 111265668A CN 202010282391 A CN202010282391 A CN 202010282391A CN 111265668 A CN111265668 A CN 111265668A
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methyl
amino
benzo
phenyl
pyrido
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向飞
王群立
赵震震
范特
宋丰宇
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黄泳华
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

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Abstract

The invention provides a composition consisting of a histamine release promoter and an inhibitory compound, which is characterized in that the histamine release promoter is one of water-soluble inorganic salt, polyalcohol, polyvidone polymer, polysorbate polymer, poloxamer polymer, polyethylene glycol polymer, starch and derivatives thereof and cellulose derivatives, and the specific definition of each histamine release promoter is shown in the specification; the inhibitory compound is one selected from the group consisting of compounds defined according to the specification or a pharmaceutically acceptable salt thereof. The composition provided by the invention can obviously reduce the action of each histamine releaser for promoting histamine release.

Description

Composition comprising a histamine release-promoting substance and an inhibitory compound
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a composition consisting of a histamine release promoter and an inhibitory compound.
Background
The polyol compound represented by mannitol is a common diluent in solid preparations, and has good safety. However, the study by Peachell PT et al (Br J Radiol.1998Jan; 71(841):24-30.) demonstrated that mannitol in a hypertonic state promotes the release of histamine from Human Lung Mast Cells (HLMC) and basophils, and thus in some special cases, excessive accumulation of polyol compounds such as HMLC or mannitol in basophils to form a hypertonic state increases the risk of allergic reactions in the drug user due to histamine release.
The study by Peachell PT et al (Br J radio. 1998Jan; 71(841):24-30.) also indicated that the nature of hypertonicity is the underlying cause of mannitol to promote histamine release from HLMC and basophils at the concentrations tested, and that hypertonic saline has also been shown to promote histamine release in experiments such as Friedman M, Vidyasagar R, Joseph N.Larynggoscope.2006Jun; 116(6):878-82.
The povidone is a common auxiliary material in solid preparations, has good safety on the whole, but the accidental immunogenicity of the povidone is still a factor influencing the safety of the povidone, and allergic reaction cases caused by the povidone are frequently reported. For example, Yoshida K et al (Int Arch Allergy Immunol.2008; 146(2):169-73.) reported an example of an allergic reaction caused by povidone-iodine and also demonstrated that povidone stimulated histamine release in the presence of autologous serum. Earlier, Nichols PJ studies (Br J Ind Med.1976May; 33(2):127-9.) demonstrated that povidone promoted the release of histamine in ex vivo lung tissue. Studies by Morgan SJ et al (Toxicol pathol.2017 jan; 45(1):84-89) have demonstrated that subcutaneous injection of crospovidone also produces similar adverse effects.
Polysorbate polymers are commonly used auxiliary materials in solid and liquid preparations, but the histamine release promoting effect of the auxiliary materials has negative influence on the safety of the auxiliary materials. Masini E et al (AgentsActs. 1985Sep; 16(6):470-7.) in the early years confirmed this effect of polysorbate 80 by in vitro and in vivo experiments, while St.C.Yang Hui Du et al (drug evaluation St., 2019(03): 472-.
Sodium carboxymethyl starch is a commonly used auxiliary material in solid preparations and is also a commonly used blood plasma substitute. Celik I et al (Inflamm Res.2003Oct; 52(10):408-16.) demonstrated that hydroxyethyl starch has a histamine release-promoting effect. In view of the polymer nature of sodium carboxymethyl starch and other commonly used starch-based excipients, the inventor considers the histamine release promoting effect of the commonly used starch-based excipients, and obtains positive results.
Poloxamers are also a common class of polymeric adjuvants, and Carbonell a et al (Anaphylaxis Due to poloxamer 238.) report an allergic reaction to poloxamer 238, and the results of experiments using basophils from these cases confirmed the presence of a histamine release-promoting effect.
Polyethylene glycols of varying molecular weight are among the lubricants commonly used in tablets and capsules. Wenande EC et al (Jallergy Clin Immunol.2013 May; 131(5):1425-7.) also confirmed the presence of histamine release-promoting effects in cases of polyethylene glycol-induced allergic reactions.
Cellulose derivatives represented by sodium carboxymethylcellulose (CMCNa) are one of the commonly used auxiliary materials, and studies by Mori S et al prove that CMCNa has histamine release promoting activity.
A series of pyrazolo [3,4-d ] pyrimidines synthesized by Quintela JM et al (Eur J Med chem.2001Apr; 36(4):321-32.) inhibit the release of histamine from mast cells in animals.
US4668671 discloses a series of tricyclic compounds having antihistaminic activity; EP2217598 discloses a series of tetracyclic compounds with histamine receptor modulating activity.
Disclosure of Invention
The invention aims to provide a composition consisting of a histamine release accelerator and an inhibitory compound, which can remarkably reduce the action of the histamine release accelerator for accelerating histamine release.
In order to achieve the above object, the present invention provides a composition comprising a histamine releaser and an inhibitory compound, wherein the histamine releaser is one selected from the group consisting of water-soluble inorganic salts, polyols, povidone-based polymers, polysorbate-based polymers, poloxamer-based polymers, polyethylene glycol-based polymers, starch and its derivatives, and cellulose derivatives; the inhibitory compound is one selected from the following compounds or pharmaceutically acceptable salts thereof:
1- (4-chlorophenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (compound A1),
6- (4- ((5-amino-5-oxopentyl) amino) phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (compound A2),
1- (4-methoxyphenyl) -7-oxo-6- (4- (2-oxoazepan-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (compound A3),
1- (4-methoxyphenyl) -7-oxo-6- (4- (2-oxopyrrolidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (compound A4),
6- (4- (3-hydroxy-2-oxopiperidin-1-yl) phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (compound A5),
6- (4- (3-hydroxy-2-oxopiperidin-1-yl) phenyl) -1- (4-hydroxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (compound A6),
4- (3-carbamoyl-6- (4- (3-hydroxy-2-oxopiperidin-1-yl) phenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) phenyl hydrogen sulfonate (Compound A7),
4- (3-carbamoyl-7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) phenyl hydrogen sulfonate (Compound A8),
6- (4-aminophenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylic acid (compound A9),
methyl 5- ((4- (3-carbamoyl-1- (4-methoxyphenyl) -7-oxo-1, 4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) phenyl) amino) pentanoate (compound A10),
1- (4-methoxyphenyl) -6- (4- (2-methyl-6-oxopiperidin-1-yl) phenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-indazole-3-carboxamide (Compound A11),
1- (4-ethoxyphenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (compound A12),
ethyl 6- (4- (N- (4-chlorobutyl) carboxamido) phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylate (compound A13),
methyl 6- (4- (N- (4-chlorobutyl) carboxamido) phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylate (compound A14),
2-hydroxyethyl 1- (4-methoxyphenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylate (compound A15),
1- (4-hydroxyphenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylic acid (compound A16),
N-methyl-N- ((3S,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound A17),
N-methyl-N- ((3R,4S) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound A18),
(3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-ol (Compound A19),
N1-methyl-N1- ((3R,4R) -4-methyl-1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) piperidin-3-yl) malonamide (compound A20),
(3R,4R) -N, 4-dimethyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-amine (compound A21),
3- (4- (((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -3-oxopropanenitrile (Compound A22),
N2,N4-bis ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N2,N4-dimethyl-7H-pyrrolo [2,3-d]Pyrimidine-2, 4-diamine (compound A23),
3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid (Compound A24),
n- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound B1),
3- (4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3, 6-dihydropyridin-1 (2H) -yl) -3-oxopropanenitrile (Compound B2),
2-chloro-N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound B3),
3- ((3R,4R) -3- ((2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) (methyl) amino) -4-methylpiperidin-1-yl) -3-oxopropanenitrile (compound B4),
(3R,4R) -1- (2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -N, 4-dimethylpiperidin-3-amine (compound B5),
(3R,4R) -N, 4-dimethyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-amine (compound B6),
n- ((3S,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound B7),
n- ((3R,4S) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound B8),
(3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carbaldehyde (compound B9),
n- ((3S,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound B10),
n- ((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine oxide (compound B11),
3- ((3R,4R) -4-methyl-3- (methyl (7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile (Compound B12),
3- (4- (((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -3-oxopropanenitrile (compound B13),
n- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7- (p-toluenesulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound B14),
n- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound B15),
ethyl (E) -3-amino-2-cyano-5- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -5-oxopent-2-enoate (compound B16),
ethyl (E) -5-amino-2-cyano-3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -5-oxopent-2-enoate (compound B17),
3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) propionitrile (Compound B18),
N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H- [4,7 '-bispyrrolo [2,3-d ] pyrimidin ] -4' -amine (compound B19),
n- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -2,2' -dichloro-N-methyl-7H- [4,7' -bispyrrolo [2,3-d ] pyrimidin ] -4' -amine (compound B20),
(E) -3-hydroxy-2- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carbonyl) pent-2-enedinitrile (compound B21),
N-methyl-N- ((3R,4R) -4-methyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound B22),
tert-butyl (E) -3-amino-2-cyano-5- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -5-oxopent-2-enoic acid ester (compound B23),
tert-butyl 3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate (Compound B24),
n- ((3S,4S) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound C1),
(6R,12aR) -2-amino-6- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C2),
(1S,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide (Compound C3),
(6R,12aS) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2, 7-dimethyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C4),
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide (Compound C5),
(6S,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C6),
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-ethyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C7),
(6R,12aS) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C8),
(6R,12aR,12bR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -6A hydroxy-2-methyl-2, 3,6A,7,12a,12B hexahydropyrazine [1',2':1,5] pyrrolo [3,4-B ] quinoline-1, 4,12(6H) -trione (Compound C9),
(12bR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -12-hydroxy-2-methyl-2, 3,6,12B tetrahydropyrazino [1',2':1,5] pyrrolo [3,4-B ] quinoline-1, 4-dione (Compound C10),
n- ((6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -1, 4-dioxo-3, 4,6,7,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indol-2 (1H) -yl) acetamide (compound C11),
(6R,12aR) -2-methyl-6- (2-oxobenzo [ d ] [1,3] dioxolan-5-yl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C12),
(6S,12aS) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C13),
methyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (diethylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound C14),
methyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (dimethylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound C15),
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-hydroxypropyl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C16),
methyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2, 2-dichloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound C17),
(6R,12aR) -6- (3, 4-dimethoxyphenyl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C18),
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-cyclopentyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C19),
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid (Compound C20),
(5R,11aR) -5- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (3-ethylpentan-3-yl) -5,6,11,11 a-tetrahydro-1H-imidazo [1',5':1,6] pyrido [3,4-b ] indole-1, 3(2H) -dione (compound C21),
(5R,11aS) -5- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (3-ethylpentan-3-yl) -5,6,11,11 a-tetrahydro-1H-imidazo [1',5':1,6] pyrido [3,4-b ] indole-1, 3(2H) -dione (compound C22),
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-hydroxyethyl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound C23),
methyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound C24),
methyl (1R,3S) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D1),
methyl (1S,3S) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D2),
methyl (1S,3R) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (dipropylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D3),
(6R,12aR) -6- (benzo [ D ] [1,3] dioxolan-5-yl) -2-octyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound D4),
(6R,12aR) -6- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (((1E,2E) -3-phenylallylidene) amino) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound D5),
methyl (1S,3R) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D6),
methyl (1S,3S) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D7),
methyl (1S,3R) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D8),
methyl (1R,3S) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (dipropylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D9),
(6R,12aR) -6- (benzo [ D ] [1,3] dioxolan-5-yl) -2-butyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound D10),
(1R,3R) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide (Compound D11),
(6R,12aR) -6- (benzo [ D ] [1,3] dioxolan-5-yl) -2-methyl-2, 3,6, 7-tetrahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4,12(12aH) -trione (Compound D12),
methyl (1S,3R) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (3-chloropropionyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D13),
methyl (1R,3R) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (dipropylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D14),
methyl (1S,3S) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (dipropylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D15),
(6R,12aR) -6- (benzo [ D ] [1,3] dioxolan-5-yl) -2,3,6,7,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound D16),
(6R,12aR) -6- (benzo [ D ] [1,3] dioxolan-5-yl) -2, 7-dimethyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound D17),
(6R,12aR) -6- (benzo [ D ] [1,3] dioxolan-5-yl) -2-isopropyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound D18),
(6R,12aS) -6- (benzo [ D ] [1,3] dioxolan-5-yl) -2,3,6,7,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound D19),
methyl (1R,3S) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D20),
(1S,3R) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide (Compound D21),
ethyl (1R,3R) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (Compound D22),
(6R,12aR) -6- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (3-hydroxypropyl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound D23),
(1R,3R) -1- (benzo [ D ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid (Compound D24),
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (methylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid (Compound E1),
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide (Compound E2),
1- (benzo [ d ] [1,3] dioxolan-5-yl) -3- ((methylamino) methyl) -1, 2-dihydro-9H-pyrido [3,4-b ] indol-9-ol (compound E3),
n- ((1- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-3-yl) methyl) -N-methylhydroxl amine (compound E4),
(6S,12aS) -6- (3, 4-dihydroxyphenyl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound E5),
(6R,12aR) -6- (3, 4-dihydroxyphenyl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound E6),
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -N-ethyl-2-methyl-1, 4-dioxo-1, 3,4,6,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-7 (2H) -carboxamide (Compound E7),
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2, 9-bis (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid (Compound E8),
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -7- (2-chloroacetyl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione (Compound E9),
4- (4-aminophenyl) morpholin-2-one (compound E10),
(S) -3-chloro-N- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) thiophene-2-carboxamide (Compound E11),
(S) -4- (4- (5- (aminomethyl) -2-oxooxazolidin-3-yl) phenyl) morpholin-3-one (compound E12),
(S) -2- (((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) carbamoyl) benzoic acid (Compound E13),
(S) -5-chloro-N- ((3- (4- ((2-hydroxyethyl) amino) phenyl) -2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide (Compound E14),
(S) -2- ((4- (5- ((5-chlorothiophene-2-carboxamide) methyl) -2-oxooxazolidin-3-yl) phenyl) (2-hydroxyethyl) amino) -2-oxoacetic acid (Compound E15),
5-chloro-N- (((5S) -3- (4- (2-hydroxy-3-oxomorpholine) phenyl) -2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide (Compound E16),
5-chloro-N- (((5S) -3- (4- (2-hydroxy-5-oxomorpholine) phenyl) -2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide (Compound E17),
(R) -4- (4- (5- (hydroxymethyl) -2-oxooxazolidin-3-yl) phenyl) morpholin-3-one (Compound E18),
2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidine-5-carbaldehyde (compound E19),
4- (4- (5- (dihydroxymethyl) -2-oxooxazolidin-3-yl) phenyl) morpholin-3-one (compound E20),
2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidine-5-carboxylic acid (compound E21),
5-chloro-N- (4- (3-oxomorpholine) phenyl) -N- ((2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide (Compound E22),
5-chloro-N- (3- (5-chlorothiophene-2-carboxamide) -2-hydroxypropyl) -N- (4- (3-oxomorpholine) phenyl) thiophene-2-carboxamide (compound E23),
(R) -2- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) isoindoline-1, 3-dione (Compound E24),
4- (4- (((2- (5-chlorothien-2-yl) -4, 5-dihydrooxazol-5-yl) methyl) amino) phenyl) morpholin-3-one (compound F1),
(S)-N1-methyl-N2- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) phthalic acid diamide (compound F2),
(S) -2- (2- (5-chloro-N- (4- (5- ((5-chlorothien-2-carboxamido) methyl) -2-oxooxazolidin-3-yl) phenyl) thiophene-2-carboxamido) ethoxy) acetic acid (Compound F3),
4- (4- ((3-aminopropyl) amino) phenyl) morpholin-3-one (compound F4),
N1,N2bis ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) oxamide (compound F5),
2, 3-bis ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) -2, 3-dihydrophthalazine-1, 4-dione (compound F6),
(S) -1- (1, 3-dioxoisoindolin-2-yl) -3- ((ethoxycarbonyl) (4- (3-oxomorpholine) phenyl) amino) propan-2-yl 5-chlorothiophene-2-carboxylate (Compound F7),
1- (5-chlorothiophene-2-carboxamido) -3- ((4- (3-oxomorpholine) phenyl) amino) propan-2-ylhydrocarbonate (compound F8),
(3- (5-chlorothiophene-2-carboxamido) -2-hydroxypropyl) (4- (3-oxomorpholine) phenyl) carbamic acid (compound F9),
4- (4- (bis (3-chloro-2-hydroxypropyl) amino) phenyl) morpholin-3-one (compound F10),
(S) -4- (4- ((2, 3-bis (methylamino) propyl) amino) phenyl) morpholin-3-one (Compound F11),
(R) -N- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) methanesulfonamide (Compound F12),
1, 3-bis (4- (3-oxomorpholine) phenyl) urea (compound F13),
(S, Z) -4- (4- (5- (((4-chlorobenzylidene) amino) methyl) -2-oxooxazolidin-3-yl) phenyl) morpholin-3-one (Compound F14),
(S) -4- (4- ((2-hydroxy-3- (methylamino) propyl) amino) phenyl) morpholin-3-one (Compound F15),
(S) -5-chloro-N- (3- (5-chlorothiophene-2-carboxamido) -2-hydroxypropyl) -N- (4- (3-oxomorpholine) phenyl) thiophene-2-carboxamide (Compound F16),
(S) -1- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) urea (Compound F17),
(S) -1-methyl-3- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) urea (Compound F18),
(S) - (3- (5-chlorothiophene-2-carboxamido) -2-hydroxypropyl) (4- (3-oxomorpholine) phenyl) carbamic acid (Compound F19),
4- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) -6- (((4- (3-oxomorpholine) phenyl) amino) methyl) morpholin-2-one (compound F20),
2, 4-dichloro-6, 7-bis (2-methoxyethoxy) quinazoline (compound F21),
3- ((6, 7-bis (2-methoxyethoxy) quinazolin-4-yl) amino) benzoic acid (Compound F22),
6, 7-bis (2-methoxyethoxy) -N-phenylquinazolin-4-amine (compound F23),
n- (3-ethynylphenyl) -7, 8-bis (2-methoxyethoxy) quinazolin-4-amine (compound F24),
n- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) -N- (2-methoxyethyl) quinazolin-4-amine (compound G1),
6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (Compound G2),
2- ((4-chloro-7- (2-methoxyethoxy) quinazolin-6-yl) oxy) ethan-1-ol (Compound G3),
2- ((4-chloro-6- (2-methoxyethoxy) quinazolin-7-yl) oxy) ethan-1-ol (Compound G4),
2- ((4-chloro-6- (2-methoxyethoxy) quinazolin-7-yl) oxy) ethyl formate (Compound G5),
4-isopropoxy-6, 7-bis (2-methoxyethoxy) quinazoline (compound G6),
3- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4 (3H) -imine (compound G7),
2- ((4- ((3-ethynylphenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) oxy) ethylformate (compound G8),
2- ((4- ((3-ethynylphenyl) amino) -6- (2-methoxyethoxy) quinazolin-7-yl) oxy) ethylformate (compound G9),
2- (3- ((6, 7-bis (2-methoxyethoxy) quinazolin-4-yl) amino) phenyl) acetic acid (compound G10),
6, 7-bis (2-hydroxyethoxy) quinazolin-4 (3H) -one (compound G11),
6, 7-bis (2- (chloromethoxy) ethoxy) quinazolin-4 (3H) -one (compound G12),
4-chloro-6, 7-bis (2- (chloromethoxy) ethoxy) quinazoline (compound G13),
6, 7-bis (2-methoxyethoxy) -N- (m-tolyl) quinazolin-4-amine (compound G14),
4- ((3-ethynylphenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-ol (Compound G15),
4- ((3-ethynylphenyl) amino) -6- (2-methoxyethoxy) quinazolin-7-ol (Compound G16),
2,2' - ((4- ((3-ethynylphenyl) amino) quinazolin-6, 7-diyl) bis (oxy)) bis (ethan-1-ol) (compound G17),
8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound G18),
8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -6-vinylpyrido [2,3-d ] pyrimidin-7 (8H) -one (compound G19),
tert-butyl 4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (compound G20),
4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-sulfonic acid (compound G21),
8-cyclopentyl-6- (1-hydroxyethyl) -5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound G22),
2- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) -5- (piperazin-1-yl) pyridine 1-oxide (compound G23),
1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine 1-oxide (compound G24),
tert-butyl (E) -4- (6- ((6- (2-butoxyvinyl) -8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (compound H1),
tert-butyl (E) -4- (6- ((8-cyclopentyl-6- (2-ethoxyvinyl) -5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (compound H2),
2- (8-cyclopentyl-5-methyl-7-oxo-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -7, 8-dihydropyrido [2,3-d ] pyrimidin-6-yl) acetaldehyde (compound H3),
tert-butyl 4- (6- ((6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (compound H4),
tert-butyl 4- (6- ((2-chloro-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-6-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (compound H5),
2-acetyl-8-cyclopentyl-5-methyl-6- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H6),
6-bromo-5- (bromomethyl) -2-chloro-8-cyclopentylpyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H7),
2, 6-dibromo-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H8),
6-acetyl-8-cyclopentyl-2-hydroxy-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H9),
6-acetyl-2- ((5- ((2-aminoethyl) amino) pyridin-2-yl) amino) -8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H10),
6-acetyl-8-cyclopentyl-5-methyl-2- ((3- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H11),
6-acetyl-8-cyclopentyl-2- ((3, 6-di (piperazin-1-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H12),
6-bromo-8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H13),
8-cyclopentyl-5-methyl-2, 6-bis ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H14),
tert-butyl 4- (6- ((6-bromo-5- (bromomethyl) -8-cyclopentyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (compound H15),
6-bromo-8-cyclopentyl-2-hydroxy-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (compound H16),
ethyl (Z) -3- (2- (((4- (N' - ((hexane-2-yloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate (Compound H17),
ethyl (Z) -3- (2- (((4- (N' - ((hexane-3-yloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate (Compound H18),
ethyl (Z) -3- (2- (((4- (N' - ((hexane-2-yloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate (Compound H19),
ethyl 3- (1, 2-dimethyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (compound H20),
ethyl 3- (1-methyl-2-oxo-N- (pyridin-2-yl) -2, 3-dihydro-1H-benzo [ d ] imidazole-5-carboxamido) propionate (compound H21),
ethyl (Z) -2- (((4- (N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate (Compound H22),
ethyl 3- (2- (((4-cyanophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (compound H23),
ethyl 3- (2- (((4- (ethoxy (imino) methyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (compound H24),
methyl 3- (2- (((4- (N- ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (Compound I1),
hexyl (Z) - (amino (4- (((5- ((3-amino-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [ d ] imidazol-2-yl) methyl) amino) phenyl) methylene) carbamate (Compound I2),
ethyl 3- (2- (((4-carbamoylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (Compound I3),
ethyl 3- (2- (((4-carbamimidoylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (compound I4),
isopropyl (E) -3- (2- (((4- (N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate (Compound I5),
ethyl (E) -3- (2- (((4- (N' - ((2-ethylbutoxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate (Compound I6),
ethyl (E) -3- (2- (((4- (N' - (butoxycarbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (Compound I7),
ethyl (E) -3- (2- (((4- (N' - ((heptane-2-yloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate (Compound I8),
ethyl (E) -3- (1-methyl-2- (((4- (N' - ((octyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate (Compound I9),
3- (2- (((4- (N-carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionic acid (Compound I10),
ethyl 3- (2- (((4- (((hexyloxy) carbonyl) carbamoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (compound I11),
ethyl 2- (((4-carbamimidoylphenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate (compound I12),
ethyl 2- (((4- (ethoxy (imino) methyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate (Compound I13),
ethyl 4- (((5- ((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [ d ] imidazol-2-yl) methyl) amino) benzoate (compound I14),
ethyl 2- (((4- (ethoxycarbonyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate (Compound I15),
3- (2- (((4- (((hexyloxy) carbonyl) carbamoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionic acid (Compound I16),
methyl 3- (2- (((4- (((hexyloxy) carbonyl) carbamoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (Compound I17),
hexyl (E) - (amino (4- (((1-methyl-5- ((3-oxo-3- (pyridin-2-ylamino) propyl) (pyridin-2-yl) carbamoyl) -1H-benzo [ d ] imidazol-2-yl) methyl) amino) phenyl) methylene) carbamate (Compound I18),
ethyl 3- (2- (((chloromethyl) (4- (N- ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (compound I19),
1- (chloromethyl) -5- ((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -2- (((4- (N- ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazol-1-ium chloride (compound I20),
ethyl (E) -3- (2- (((4- (N- (chloromethyl) -N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate (compound I21),
n- (3-amino-3-oxopropyl) -2- (((4-carbamimidoylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamide (Compound I22),
3- (2- (((4-carbamoylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionic acid (Compound I23),
(E) -2- (((4- (N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylic acid (Compound I24),
ethyl 2- (((4- (((hexyloxy) carbonyl) carbamoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate (Compound J1),
(Z) -2- (N- (3-ethoxy-3-oxopropyl) -2- (((4- (N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxamido) pyridine 1-oxide (Compound J2),
3- (2- (((4-cyanophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionic acid (Compound J3),
methyl 3- (2- (((4-cyanophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate (Compound J4),
ethyl 2- (((4-cyanophenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate (compound J5),
(2S,3R,4R,5R) -2- ((R) -1, 2-dihydroxyethyl) -5- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetrahydrofuran-3, 4-diol (Compound J6),
(2S,3R,4R,5S) -2- ((R) -1, 2-dihydroxyethyl) -5- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetrahydrofuran-3, 4-diol (Compound J7),
(2R,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J8),
((2R,3S,4R,5R,6S) -6- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-yl) methyl acetate (Compound J9),
((2S,3S,4R,5R,6S) -6- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-yl) methyl acetate (Compound J10),
(2R,3S,4S,5S) -2- ((S) -1, 2-dihydroxyethyl) -5- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetrahydrofuran-3, 4-diol (Compound J11),
(2S,3R,4S,5S,6R) -2- (hydroxymethyl) -6- (2-methyl-3- ((5-phenylthiophen-2-yl) methyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J12),
(2S,3R,4S,5S,6S) -2- (hydroxymethyl) -6- (3- ((5-phenylthiophen-2-yl) methyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J13),
(2R,3S,4R,5R,6R) -2- (hydroxymethyl) -6- (4-methyl-3- ((5-phenylthiophen-2-yl) methyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J14),
(2S,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) (hydroperoxy) methyl) -4-methylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J15),
2- (4-fluorophenyl) -5- (2-methyl-5- ((2S,3R,4R,5S,6R) -3,4, 5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) benzyl) thiophene 1-oxide (Compound J16),
(2S,3R,4S,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol (Compound J17),
(2S,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4- (hydroxymethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J18),
(2S,3S,4R,5R,6S) -6- (3- ((5- (4-fluorophenyl) thiophen-2-yl) (hydroxy) methyl) -4-methylphenyl) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound J19),
(2S,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -2-methylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J20),
(3R,4R,5S,6R) -2- (4-chloro-3- (2-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J21),
(2S,3S,4S,5R,6S) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J22),
(2R,3S,4S,5R,6S) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J23),
(2S,3R,4R,5S,6R) -2- (3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound J24).
In one aspect, the histamine release-promoting substance in the composition of the present invention is preferably one selected from the group consisting of povidone, mannitol, sorbitol, glycerol, triethanolamine, xylitol, fructose, lactose monohydrate, glucose, sucralose, sucrose, calcium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, sodium carbonate, sodium bicarbonate, polysorbate, poloxamer, polyethylene glycol, starch, modified starch, hydrogenated starch hydrolysate, corn starch, pregelatinized starch, carboxymethyl starch sodium, low-substituted hypromellose, croscarmellose sodium, ethylene hydroxycellulose, hypromellose, hyprolose, hydroxyethyl methylcellulose, hydroxyethyl cellulose and sodium carboxymethyl cellulose.
More preferably, the histamine release-promoting substance in the composition according to the present invention is selected from povidone K30(PVP-K30), povidone K90(PVP-K90), crospovidone (cPVP), mannitol, sorbitol, glycerol, triethanolamine, xylitol, fructose, lactose monohydrate, glucose, sucralose, sucrose, calcium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, sodium carbonate, sodium bicarbonate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 1450, Polyethylene glycol 1500, polyethylene glycol 3000, polyethylene glycol 3350, polyethylene glycol 3500, polyethylene glycol 4000, polyethylene glycol 4500, polyethylene glycol 6000, polyethylene glycol 7000, polyethylene glycol 8000, polyethylene glycol 20000, starch, modified starch, hydrogenated starch hydrolysate, corn starch, pregelatinized starch, carboxymethyl starch sodium type A, carboxymethyl starch sodium type B, carboxymethyl starch sodium type C, low-substituted hypromellose, low-substituted hyprolose, croscarmellose sodium, ethylcellulose, hypromellose type 1828, hypromellose type 2208, hypromellose type 2906, hypromellose type 2910, hyprolose, hydroxyethyl methylcellulose, hydroxyethyl cellulose and sodium carboxymethyl cellulose.
In one aspect, the mass ratio of the histamine release accelerator to the inhibitory compound in the composition of the present invention is preferably 10:1 to 100000: 1; further preferably, the mass ratio is in the range of 10:1 to 63000: 1.
The histamine release promoting substances are auxiliary materials in Handbook of pharmaceutical Excipients (Six Edition) written by Raymond C Rowe et al, and meet the quality standard of the auxiliary materials.
In another aspect, the present invention provides an oral solid preparation comprising the composition as described above.
Preferably, the oral solid preparation of the present invention is one selected from the group consisting of tablets, capsules and granules.
Preferably, the active ingredient of the solid preparation of the present invention is selected from one of a factor Xa inhibitor, a phosphodiesterase 5 inhibitor and a JAK kinase inhibitor.
Further preferably, the active ingredient of the present invention is one selected from the group consisting of compounds i to ix shown below or a pharmaceutically acceptable salt thereof.
Figure BDA0002447183060000101
In vitro test results show that the composition provided by the invention can obviously reduce the effect of the histamine releasing promoter group on promoting histamine release.
Detailed Description
The technical solution of the present invention is described in detail and completely with reference to the following embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The mass ratio of the histamine release accelerator to the inhibitory compound is the mass ratio of the histamine release accelerator to the inhibitory compound.
The present invention is a composition comprising a "" linkage between a histamine release promoter and an inhibitory compound.
Example 1 preparation of the composition
The histamine release promoting substance and the inhibitory compound are fully mixed according to the corresponding mass ratio to obtain the histamine release promoting compound.
Test example 1 evaluation of the Effect of the composition for promoting histamine Release
RBL-2H3 cells in logarithmic growth phase were collected and adjusted to a concentration of 8X 104Perml, inoculated evenly into a 96-well plate at 200. mu.L cell suspension per well, 5% CO at 37 ℃2Culturing in a saturated humidity incubator for 24h, discarding the culture medium, 200 μ L of the test substance (histamine release and composition dispersed in PBS respectively), setting a reagent control group, adding 200 μ L of PBS to each well, and incubating at 37 deg.C for 30 min. After the incubation is finished, taking 100 mu L of cell supernatant out and placing the cell supernatant into a test fluorescent plate (the redundant supernatant is frozen and stored in a refrigerator at the temperature of minus 20 ℃ for standby), adding 50 mu L and 0.4mol/L NaOH into each hole of the test plate, immediately adding 10 mu L of 0.1% o-phthalaldehyde-methanol solution, uniformly mixing, placing the test plate at room temperature for 10min, adding 50 mu L and 0.5mol/L HCl to terminate the reaction, immediately detecting the A value (the incident wavelength is 360nm, the emission wavelength is 450nm) by an enzyme-labeling instrument, and counting all tested object groups as ASupernatant fluidThe solvent control group is counted as ABackground of the invention。
Cracking the rest cells in 96-well plate with 0.5% Triton100-PBS solution, incubating at 37 deg.C for 30min, placing 100 μ L of cell lysate in a test fluorescent plate (freezing the excess lysate in a refrigerator at-20 deg.C for use), adding 50 μ L and 0.4mol/L NaOH solution into each well of test plate, immediately adding 10 μ L of 0.1% o-phthalaldehyde-methanol solution, mixing, standing at room temperature for 10min, adding 50 μ L and 0.5mol/L HCl to terminate the reaction, mixing, immediately detecting A value (incident wavelength 360nm, emission wavelength 450nm) with a microplate reader, mixing with the A valueSupernatant fluidThe sum of the values is ASupernatant + lysisThe percent histamine release rate for each test substance was then calculated according to the following formula:
percent release (%) - (A)Supernatant fluid-ABackground of the invention)/(ASupernatant + lysis-ABackground of the invention)×100
In terms of concentration, the tested concentrations of the histamine release-promoting substances in the two compositions of the water-soluble inorganic salt-inhibiting compound and the polyalcohol-inhibiting compound are respectively saturated concentration, the tested concentrations of the histamine release-promoting substances in the rest compositions are respectively 200mg/mL, the mass ratio of each composition comprises 10, 100, 1000, 10000, 63000, 79000 and 100000, and in addition, a corresponding blank of the histamine release-promoting substances is arranged for each combination of the histamine release-inhibiting compounds.
Each test subject was assayed in 4 replicates.
For the test object which can not be completely dissolved, a uniform dispersion system can be formed by the aid of methods such as ultrasound and the like.
TABLE 1 minimum percentage release (%) (MIN) and corresponding Compound number (X) for the compositions of Histamine-stimulating substance (HRS) and Compounds A1-A24 at each mass ratio (R)
Figure BDA0002447183060000111
Figure BDA0002447183060000121
Figure BDA0002447183060000131
TABLE 2 minimum percentage release (%) (MIN) of the composition of histamine release-promoting substances (HRS) and compounds B1-B24 at each mass ratio (R) and the corresponding compound number (X)
Figure BDA0002447183060000132
Figure BDA0002447183060000141
Figure BDA0002447183060000151
TABLE 3 minimum percentage release (%) (MIN) of the composition of histamine release-promoting substances (HRS) and compounds C1-C24 at each mass ratio (R) and the corresponding compound number (X)
Figure BDA0002447183060000152
Figure BDA0002447183060000161
Figure BDA0002447183060000171
TABLE 4 minimum percentage release (%) (MIN) at each mass ratio (R) of the composition of histamine release-promoting substances (HRS) and compounds D1-D24 to the corresponding compound number (X)
Figure BDA0002447183060000172
Figure BDA0002447183060000181
Figure BDA0002447183060000191
TABLE 5 minimum percentage release (%) (MIN) of the composition of Histamine-stimulating substance (HRS) and Compounds E1-E24 at each mass ratio (R) and the corresponding Compound number (X)
Figure BDA0002447183060000192
Figure BDA0002447183060000201
Figure BDA0002447183060000211
TABLE 6 minimum percentage release (%) (MIN) of the composition of histamine release-promoting substances (HRS) and compounds F1-F24 at each mass ratio (R) and the corresponding compound number (X)
Figure BDA0002447183060000221
Figure BDA0002447183060000231
Figure BDA0002447183060000241
TABLE 7 minimum percentage release (%) (MIN) at each mass ratio (R) of the composition of histamine release-promoting substances (HRS) and compounds G1-G24 to the corresponding compound number (X)
Figure BDA0002447183060000242
Figure BDA0002447183060000251
Figure BDA0002447183060000261
TABLE 8 minimum percentage release (%) (MIN) at each mass ratio (R) of the composition of histamine release-promoting substances (HRS) and compounds H1-H24 to the corresponding compound number (X)
Figure BDA0002447183060000262
Figure BDA0002447183060000271
Figure BDA0002447183060000281
TABLE 9 minimum percentage release (%) (MIN) at each mass ratio (R) of the composition of histamine release-promoting substances (HRS) and compounds I1-I24 and the corresponding compound number (X)
Figure BDA0002447183060000282
Figure BDA0002447183060000291
Figure BDA0002447183060000301
TABLE 10 minimum percentage release (%) (MIN) at each mass ratio (R) of the composition of histamine release-promoting substances (HRS) and compounds J1-J24 to the corresponding compound number (X)
Figure BDA0002447183060000302
Figure BDA0002447183060000311
Figure BDA0002447183060000321
Example 2: preparation of solid preparation containing composition composed of histamine releaser and inhibitory compound
Prescription (1000 unit dose)
Figure BDA0002447183060000322
Method for producing
Taking the active ingredients, the composition and other auxiliary materials according to the prescription amount, and sieving the active ingredients, the composition and the other auxiliary materials with a 100-mesh sieve. Taking the active ingredients, the composition, the lactose, the microcrystalline cellulose, the crospovidone and the starch according to the prescription amount, and fully and uniformly mixing; 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;
taking the active ingredients, the composition and other auxiliary materials according to the prescription amount, and sieving the active ingredients, the composition and the other auxiliary materials with a 100-mesh sieve. Taking the active ingredients, the composition, the lactose, the microcrystalline cellulose, the crospovidone and the starch according to the prescription amount, and fully and uniformly mixing; 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;
taking the active ingredients, the composition and other auxiliary materials according to the prescription amount, and sieving the active ingredients, the composition and the other auxiliary materials with a 100-mesh sieve. Taking the active ingredients, the composition, the lactose, the microcrystalline cellulose, the crospovidone and the starch according to the prescription amount, and fully and uniformly mixing; 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 ℃. And (4) granulating by using a 16-mesh sieve, adding the superfine silica powder and the magnesium stearate according to the prescription amount, mixing uniformly, and tabletting to obtain the tablet.

Claims (9)

1. A composition comprising a histamine release-promoting substance and an inhibitory compound, wherein the histamine release-promoting substance is one selected from the group consisting of water-soluble inorganic salts, polyhydric alcohols, povidone-based polymers, polysorbate-based polymers, poloxamer-based polymers, polyethylene glycol-based polymers, starch and derivatives thereof, and cellulose derivatives; the inhibitory compound is one selected from the following compounds or pharmaceutically acceptable salts thereof:
1- (4-chlorophenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide
6- (4- ((5-amino-5-oxopentyl) amino) phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide
1- (4-methoxyphenyl) -7-oxo-6- (4- (2-oxoazepan-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide
1- (4-methoxyphenyl) -7-oxo-6- (4- (2-oxopyrrolidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide
6- (4- (3-hydroxy-2-oxopiperidin-1-yl) phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide
6- (4- (3-hydroxy-2-oxopiperidin-1-yl) phenyl) -1- (4-hydroxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide
4- (3-carbamoyl-6- (4- (3-hydroxy-2-oxopiperidin-1-yl) phenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) phenyl hydrogen sulfonate
4- (3-carbamoyl-7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) phenyl hydrogen sulfonate
6- (4-aminophenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylic acid
Methyl 5- ((4- (3-carbamoyl-1- (4-methoxyphenyl) -7-oxo-1, 4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) phenyl) amino) pentanoate
1- (4-methoxyphenyl) -6- (4- (2-methyl-6-oxopiperidin-1-yl) phenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-indazole-3-carboxamide
1- (4-ethoxyphenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide
Ethyl 6- (4- (N- (4-chlorobutyl) carboxamido) phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylate
Methyl 6- (4- (N- (4-chlorobutyl) carboxamido) phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylate
2-hydroxyethyl 1- (4-methoxyphenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylate
1- (4-hydroxyphenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylic acid
N-methyl-N- ((3S,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N-methyl-N- ((3R,4S) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
(3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-ol
N1-methyl-N1- ((3R,4R) -4-methyl-1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) piperidin-3-yl) malonamide
(3R,4R) -N, 4-dimethyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-amine
3- (4- (((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -3-oxopropanenitrile
N2,N4-bis ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N2,N4-dimethyl-7H-pyrrolo [2,3-d]Pyrimidine-2, 4-diamines
3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid
N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
3- (4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3, 6-dihydropyridin-1 (2H) -yl) -3-oxopropanenitrile
2-chloro-N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
3- ((3R,4R) -3- ((2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) (methyl) amino) -4-methylpiperidin-1-yl) -3-oxopropanenitrile
(3R,4R) -1- (2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -N, 4-dimethylpiperidin-3-amine
(3R,4R) -N, 4-dimethyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-amine
N- ((3S,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- ((3R,4S) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
(3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carbaldehyde
N- ((3S,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- ((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine oxide
3- ((3R,4R) -4-methyl-3- (methyl (7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile
3- (4- (((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -3-oxopropanenitrile
N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7- (p-toluenesulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine
Ethyl (E) -3-amino-2-cyano-5- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -5-oxopent-2-enoate
Ethyl (E) -5-amino-2-cyano-3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -5-oxopent-2-enoate
3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) propionitrile
N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H- [4,7 '-bispyrrolo [2,3-d ] pyrimidine ] -4' -amine
N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -2,2' -dichloro-N-methyl-7H- [4,7' -dipyrrolo [2,3-d ] pyrimidine ] -4' -amine
(E) -3-hydroxy-2- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carbonyl) pent-2-enedinitrile
N-methyl-N- ((3R,4R) -4-methyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Tert-butyl (E) -3-amino-2-cyano-5- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -5-oxopent-2-enoate
Tert-butyl 3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate
N- ((3S,4S) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
(6R,12aR) -2-amino-6- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(1S,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide
(6R,12aS) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2, 7-dimethyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide
(6S,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-ethyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aS) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aR,12bR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -6A hydroxy-2-methyl-2, 3,6A,7,12a,12B hexahydropyrazine [1',2':1,5] pyrrolo [3,4-B ] quinoline-1, 4,12(6H) -trione
(12bR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -12-hydroxy-2-methyl-2, 3,6,12B tetrahydropyrazino [1',2':1,5] pyrrolo [3,4-B ] quinoline-1, 4-dione
N- ((6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -1, 4-dioxo-3, 4,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indol-2 (1H) -yl) acetamide
(6R,12aR) -2-methyl-6- (2-oxobenzo [ d ] [1,3] dioxolan-5-yl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6S,12aS) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
Methyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (diethylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
Methyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (dimethylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-hydroxypropyl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
Methyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2, 2-dichloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
(6R,12aR) -6- (3, 4-dimethoxyphenyl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-cyclopentyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid
(5R,11aR) -5- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (3-ethylpentan-3-yl) -5,6,11,11 a-tetrahydro-1H-imidazo [1',5':1,6] pyrido [3,4-b ] indole-1, 3(2H) -dione
(5R,11aS) -5- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (3-ethylpentan-3-yl) -5,6,11,11 a-tetrahydro-1H-imidazo [1',5':1,6] pyrido [3,4-b ] indole-1, 3(2H) -dione
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-hydroxyethyl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
Methyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
Methyl (1R,3S) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
Methyl (1S,3S) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
Methyl (1S,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (dipropylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-octyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (((1E,2E) -3-phenylallylidene) amino) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
Methyl (1S,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
Methyl (1S,3S) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
Methyl (1S,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
Methyl (1R,3S) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (dipropylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-butyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-methyl-2, 3,6, 7-tetrahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4,12(12aH) -trione
Methyl (1S,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (3-chloropropionyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
Methyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (dipropylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
Methyl (1S,3S) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (dipropylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2, 7-dimethyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2-isopropyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aS) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
Methyl (1R,3S) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
(1S,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide
Ethyl (1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (3-hydroxypropyl) -2,3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2- (methylaminoacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxamide
1- (benzo [ d ] [1,3] dioxolan-5-yl) -3- ((methylamino) methyl) -1, 2-dihydro-9H-pyrido [3,4-b ] indol-9-ol
N- ((1- (benzo [ d ] [1,3] dioxolan-5-yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-3-yl) methyl) -N-methylhydroxl amine
(6S,12aS) -6- (3, 4-dihydroxyphenyl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aR) -6- (3, 4-dihydroxyphenyl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -N-ethyl-2-methyl-1, 4-dioxo-1, 3,4,6,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-7 (2H) -carboxamide
(1R,3R) -1- (benzo [ d ] [1,3] dioxolan-5-yl) -2, 9-bis (2-chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid
(6R,12aR) -6- (benzo [ d ] [1,3] dioxolan-5-yl) -7- (2-chloroacetyl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazine [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione
4- (4-aminophenyl) morpholin-2-one
(S) -3-chloro-N- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) thiophene-2-carboxamide
(S) -4- (4- (5- (aminomethyl) -2-oxooxazolidin-3-yl) phenyl) morpholin-3-one
(S) -2- (((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) carbamoyl) benzoic acid
(S) -5-chloro-N- ((3- (4- ((2-hydroxyethyl) amino) phenyl) -2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
(S) -2- ((4- (5- ((5-chlorothiophene-2-carboxamide) methyl) -2-oxooxazolidin-3-yl) phenyl) (2-hydroxyethyl) amino) -2-oxoacetic acid
5-chloro-N- (((5S) -3- (4- (2-hydroxy-3-oxomorpholine) phenyl) -2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
5-chloro-N- (((5S) -3- (4- (2-hydroxy-5-oxomorpholine) phenyl) -2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
(R) -4- (4- (5- (hydroxymethyl) -2-oxooxazolidin-3-yl) phenyl) morpholin-3-one
2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidine-5-carbaldehyde
4- (4- (5- (dihydroxymethyl) -2-oxooxazolidin-3-yl) phenyl) morpholin-3-one
2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidine-5-carboxylic acid
5-chloro-N- (4- (3-oxomorpholine) phenyl) -N- ((2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
5-chloro-N- (3- (5-chlorothiophene-2-carboxamide) -2-hydroxypropyl) -N- (4- (3-oxomorpholine) phenyl) thiophene-2-carboxamide
(R) -2- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) isoindoline-1, 3-dione
4- (4- (((2- (5-chlorothien-2-yl) -4, 5-dihydrooxazol-5-yl) methyl) amino) phenyl) morpholin-3-one
(S)-N1-methyl-N2- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) phthalic acid dimethylamide
(S) -2- (2- (5-chloro-N- (4- (5- ((5-chlorothiophene-2-carboxamido) methyl) -2-oxooxazolidin-3-yl) phenyl) thiophene-2-carboxamido) ethoxy) acetic acid
4- (4- ((3-aminopropyl) amino) phenyl) morpholin-3-one
N1,N2-bis ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) oxamide
2, 3-bis ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) -2, 3-dihydrophthalazine-1, 4-dione
(S) -1- (1, 3-dioxoisoindolin-2-yl) -3- ((ethoxycarbonyl) (4- (3-oxomorpholine) phenyl) amino) propan-2-yl 5-chlorothiophene-2-carboxylate
1- (5-chlorothiophene-2-carboxamido) -3- ((4- (3-oxomorpholine) phenyl) amino) propan-2-ylhydrocarbonate
(3- (5-chlorothiophene-2-carboxamido) -2-hydroxypropyl) (4- (3-oxomorpholine) phenyl) carbamic acid
4- (4- (bis (3-chloro-2-hydroxypropyl) amino) phenyl) morpholin-3-one
(S) -4- (4- ((2, 3-bis (methylamino) propyl) amino) phenyl) morpholin-3-one
(R) -N- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) methanesulfonamide
1, 3-bis (4- (3-oxomorpholine) phenyl) urea
(S, Z) -4- (4- (5- (((4-chlorobenzylidene) amino) methyl) -2-oxooxazolidin-3-yl) phenyl) morpholin-3-one
(S) -4- (4- ((2-hydroxy-3- (methylamino) propyl) amino) phenyl) morpholin-3-one
(S) -5-chloro-N- (3- (5-chlorothiophene-2-carboxamido) -2-hydroxypropyl) -N- (4- (3-oxomorpholine) phenyl) thiophene-2-carboxamide
(S) -1- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) urea
(S) -1-methyl-3- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) urea
(S) - (3- (5-chlorothiophene-2-carboxamido) -2-hydroxypropyl) (4- (3-oxomorpholine) phenyl) carbamic acid
4- ((2-oxo-3- (4- (3-oxomorpholine) phenyl) oxazolidin-5-yl) methyl) -6- (((4- (3-oxomorpholine) phenyl) amino) methyl) morpholin-2-one
2, 4-dichloro-6, 7-bis (2-methoxyethoxy) quinazoline
3- ((6, 7-bis (2-methoxyethoxy) quinazolin-4-yl) amino) benzoic acid
6, 7-bis (2-methoxyethoxy) -N-phenylquinazolin-4-amine
N- (3-ethynylphenyl) -7, 8-bis (2-methoxyethoxy) quinazolin-4-amine
N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) -N- (2-methoxyethyl) quinazolin-4-amine
6, 7-bis (2-methoxyethoxy) quinazolin-4-amine
2- ((4-chloro-7- (2-methoxyethoxy) quinazolin-6-yl) oxy) ethan-1-ol
2- ((4-chloro-6- (2-methoxyethoxy) quinazolin-7-yl) oxy) ethan-1-ol
2- ((4-chloro-6- (2-methoxyethoxy) quinazolin-7-yl) oxy) ethyl formate
4-isopropoxy-6, 7-bis (2-methoxyethoxy) quinazoline
3- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4 (3H) -imine
2- ((4- ((3-ethynylphenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) oxy) ethyl formate
2- ((4- ((3-ethynylphenyl) amino) -6- (2-methoxyethoxy) quinazolin-7-yl) oxy) ethyl formate
2- (3- ((6, 7-bis (2-methoxyethoxy) quinazolin-4-yl) amino) phenyl) acetic acid
6, 7-bis (2-hydroxyethoxy) quinazolin-4 (3H) -one
6, 7-bis (2- (chloromethoxy) ethoxy) quinazolin-4 (3H) -one
4-chloro-6, 7-bis (2- (chloromethoxy) ethoxy) quinazoline
6, 7-bis (2-methoxyethoxy) -N- (m-tolyl) quinazolin-4-amine
4- ((3-ethynylphenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-ol
4- ((3-ethynylphenyl) amino) -6- (2-methoxyethoxy) quinazolin-7-ol
2,2' - ((4- ((3-ethynylphenyl) amino) quinazoline-6, 7-diyl) bis (oxy)) bis (ethane-1-ol)
8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one
8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -6-vinylpyrido [2,3-d ] pyrimidin-7 (8H) -one
Tert-butyl 4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate
4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-sulfonic acid
8-cyclopentyl-6- (1-hydroxyethyl) -5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one
2- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) -5- (piperazin-1-yl) pyridine 1-oxide
1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine 1-oxide
Tert-butyl (E) -4- (6- ((6- (2-butoxyvinyl) -8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate
Tert-butyl (E) -4- (6- ((8-cyclopentyl-6- (2-ethoxyvinyl) -5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate
2- (8-cyclopentyl-5-methyl-7-oxo-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -7, 8-dihydropyrido [2,3-d ] pyrimidin-6-yl) acetaldehyde
Tert-butyl 4- (6- ((6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate
Tert-butyl 4- (6- ((2-chloro-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-6-yl) amino) pyridin-3-yl) piperazine-1-carboxylate
2-acetyl-8-cyclopentyl-5-methyl-6- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one
6-bromo-5- (bromomethyl) -2-chloro-8-cyclopentylpyrido [2,3-d ] pyrimidin-7 (8H) -one
2, 6-dibromo-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one
6-acetyl-8-cyclopentyl-2-hydroxy-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one
6-acetyl-2- ((5- ((2-aminoethyl) amino) pyridin-2-yl) amino) -8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one
6-acetyl-8-cyclopentyl-5-methyl-2- ((3- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one
6-acetyl-8-cyclopentyl-2- ((3, 6-di (piperazin-1-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one
6-bromo-8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one
8-cyclopentyl-5-methyl-2, 6-bis ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one
Tert-butyl 4- (6- ((6-bromo-5- (bromomethyl) -8-cyclopentyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate
6-bromo-8-cyclopentyl-2-hydroxy-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one
Ethyl (Z) -3- (2- (((4- (N' - ((hexane-2-yloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl (Z) -3- (2- (((4- (N' - ((hexane-3-yloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl (Z) -3- (2- (((4- (N' - ((hexane-2-yloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl 3- (1, 2-dimethyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl 3- (1-methyl-2-oxo-N- (pyridin-2-yl) -2, 3-dihydro-1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl (Z) -2- (((4- (N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate
Ethyl 3- (2- (((4-cyanophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl 3- (2- (((4- (ethoxy (imino) methyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Methyl 3- (2- (((4- (N- ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Hexyl (Z) - (amino (4- (((5- ((3-amino-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [ d ] imidazol-2-yl) methyl) amino) phenyl) methylene) carbamate
Ethyl 3- (2- (((4-carbamoylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl 3- (2- (((4-carbamimidoylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Isopropyl (E) -3- (2- (((4- (N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl (E) -3- (2- (((4- (N' - ((2-ethylbutoxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl (E) -3- (2- (((4- (N' - (butoxycarbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate
Ethyl (E) -3- (2- (((4- (N' - ((heptane-2-yloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl (E) -3- (1-methyl-2- (((4- (N' - ((octyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate
3- (2- (((4- (N-carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionic acid
Ethyl 3- (2- (((4- (((hexyloxy) carbonyl) carbamoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl 2- (((4-formamidinophenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate
Ethyl 2- (((4- (ethoxy (imino) methyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate
Ethyl 4- (((5- ((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [ d ] imidazol-2-yl) methyl) amino) benzoate
Ethyl 2- (((4- (ethoxycarbonyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate
3- (2- (((4- (((hexyloxy) carbonyl) carbamoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionic acid
Methyl 3- (2- (((4- (((hexyloxy) carbonyl) carbamoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Hexyl (E) - (amino (4- (((1-methyl-5- ((3-oxo-3- (pyridin-2-ylamino) propyl) (pyridin-2-yl) carbamoyl) -1H-benzo [ d ] imidazol-2-yl) methyl) amino) phenyl) methylene) carbamate
Ethyl 3- (2- (((chloromethyl) (4- (N- ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
1- (chloromethyl) -5- ((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -2- (((4- (N- ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazol-1-ium chloride
Ethyl (E) -3- (2- (((4- (N- (chloromethyl) -N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propanoate
N- (3-amino-3-oxopropyl) -2- (((4-carbamimidoylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamide
3- (2- (((4-carbamoylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionic acid
(E) -2- (((4- (N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylic acid
Ethyl 2- (((4- (((hexyloxy) carbonyl) carbamoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate
(Z) -2- (N- (3-ethoxy-3-oxopropyl) -2- (((4- (N' - ((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxamido) pyridine 1-oxide
3- (2- (((4-cyanophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionic acid
Methyl 3- (2- (((4-cyanophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamido) propionate
Ethyl 2- (((4-cyanophenyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-5-carboxylate
(2S,3R,4R,5R) -2- ((R) -1, 2-dihydroxyethyl) -5- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetrahydrofuran-3, 4-diol
(2S,3R,4R,5S) -2- ((R) -1, 2-dihydroxyethyl) -5- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetrahydrofuran-3, 4-diol
(2R,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol
((2R,3S,4R,5R,6S) -6- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-yl) methyl acetate
((2S,3S,4R,5R,6S) -6- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-yl) methyl acetate
(2R,3S,4S,5S) -2- ((S) -1, 2-dihydroxyethyl) -5- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetrahydrofuran-3, 4-diol
(2S,3R,4S,5S,6R) -2- (hydroxymethyl) -6- (2-methyl-3- ((5-phenylthiophen-2-yl) methyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triol
(2S,3R,4S,5S,6S) -2- (hydroxymethyl) -6- (3- ((5-phenylthiophen-2-yl) methyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triol
(2R,3S,4R,5R,6R) -2- (hydroxymethyl) -6- (4-methyl-3- ((5-phenylthiophen-2-yl) methyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triol
(2S,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) (hydroperoxy) methyl) -4-methylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol
2- (4-fluorophenyl) -5- (2-methyl-5- ((2S,3R,4R,5S,6R) -3,4, 5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) benzyl) thiophene 1-oxide
(2S,3R,4S,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol
(2S,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4- (hydroxymethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol
(2S,3S,4R,5R,6S) -6- (3- ((5- (4-fluorophenyl) thiophen-2-yl) (hydroxy) methyl) -4-methylphenyl) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid
(2S,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -2-methylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol
(3R,4R,5S,6R) -2- (4-chloro-3- (2-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol
(2S,3S,4S,5R,6S) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol
(2R,3S,4S,5R,6S) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol
(2S,3R,4R,5S,6R) -2- (3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol.
2. Composition according to claim 1, characterized in that, the histamine release-promoting substance in the composition is one selected from povidone, mannitol, sorbitol, glycerol, triethanolamine, xylitol, fructose, lactose monohydrate, glucose, sucralose, sucrose, calcium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, sodium carbonate, sodium bicarbonate, polysorbate, poloxamer, polyethylene glycol, starch, modified starch, hydrogenated starch hydrolysate, corn starch, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, ethylcellulose, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose and sodium carboxymethyl cellulose.
3. The composition of claim 2, wherein the histamine release-enhancing substance in said composition is selected from the group consisting of povidone K30, povidone K90, crospovidone, mannitol, sorbitol, glycerol, triethanolamine, xylitol, fructose, lactose monohydrate, glucose, sucralose, sucrose, calcium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, sodium carbonate, sodium bicarbonate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 1450, polyethylene glycol 1500, and mixtures thereof, Polyethylene glycol 3000, polyethylene glycol 3350, polyethylene glycol 3500, polyethylene glycol 4000, polyethylene glycol 4500, polyethylene glycol 6000, polyethylene glycol 7000, polyethylene glycol 8000, polyethylene glycol 20000, starch, modified starch, hydrogenated starch hydrolysate, corn starch, pregelatinized starch, carboxymethyl starch sodium type A, carboxymethyl starch sodium type B, carboxymethyl starch sodium type C, low-substituted hypromellose, low-substituted hyprolose, croscarmellose sodium, ethylcellulose, hypromellose type 1828, hypromellose type 2208, hypromellose type 2906, hypromellose type 2910, hypromellose, hydroxyethyl cellulose and sodium carboxymethyl cellulose.
4. The composition according to claim 1 or 2, wherein the mass ratio of histamine release-promoting substance to inhibitory compound in said composition is between 10:1 and 100000: 1.
5. Composition according to claim 4, characterized in that said mass ratio ranges between 10:1 and 63000: 1.
6. An oral solid preparation containing the composition according to claim 1 or 2.
7. The oral solid preparation according to claim 6, wherein the oral solid preparation is one selected from the group consisting of tablets, capsules and granules.
8. The oral solid preparation according to claim 6, wherein the active ingredient of the solid preparation is one selected from the group consisting of a factor Xa inhibitor, a phosphodiesterase 5 inhibitor and a JAK kinase inhibitor.
9. The oral solid preparation according to claim 8, wherein said active ingredient is one selected from the group consisting of compounds I to IX shown below:
Figure FDA0002447183050000091
CN202010282391.6A 2019-06-09 2020-04-12 Composition comprising a histamine release-promoting substance and an inhibitory compound Withdrawn CN111265668A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111333635A (en) * 2020-04-16 2020-06-26 东南大学 Rivaroxaban impurity reference substance and preparation method thereof
CN112094274A (en) * 2020-09-08 2020-12-18 杭州华东医药集团新药研究院有限公司 Improved tofacitinib synthesis method and impurity preparation method
CN115304589A (en) * 2021-05-06 2022-11-08 北京新康哌森医药科技有限公司 Preparation method of canagliflozin impurity

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111333635A (en) * 2020-04-16 2020-06-26 东南大学 Rivaroxaban impurity reference substance and preparation method thereof
CN112094274A (en) * 2020-09-08 2020-12-18 杭州华东医药集团新药研究院有限公司 Improved tofacitinib synthesis method and impurity preparation method
CN115304589A (en) * 2021-05-06 2022-11-08 北京新康哌森医药科技有限公司 Preparation method of canagliflozin impurity

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