CN112168816A - Composition containing orlistat and dihydropyrimidine compound and application thereof - Google Patents

Composition containing orlistat and dihydropyrimidine compound and application thereof Download PDF

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CN112168816A
CN112168816A CN202011228981.7A CN202011228981A CN112168816A CN 112168816 A CN112168816 A CN 112168816A CN 202011228981 A CN202011228981 A CN 202011228981A CN 112168816 A CN112168816 A CN 112168816A
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dihydropyrimidine
thiazol
fluorophenyl
carboxylate
bromo
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CN112168816B (en
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李鉴有
李翠玉
黄海石
吴彦勍
杜志博
彭韪
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Zhongshan Wanhan Pharmaceutical Co ltd
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Abstract

The invention provides a composition containing orlistat and dihydropyrimidine compounds, wherein the specific definition of the dihydropyrimidine compounds is shown in the specification: in vitro test results show that orlistat and the dihydropyrimidine compound of the invention can generate synergistic inhibition effect on HBV DNA replication in Hep G2.2.15 cells in the range of the molar ratio (combination drug index CI < 1).

Description

Composition containing orlistat and dihydropyrimidine compound and application thereof
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a composition containing orlistat and dihydropyrimidine compounds and application thereof.
Background
Hepatitis B is a potentially lethal liver infectious disease caused by Hepatitis B Virus (HBV), and can increase the risk of cirrhosis and liver cancer death of patients. The World Health Organization (WHO) states that about 2570 million people worldwide carry HBV infection, while 88.7 million people die of HBV in 2015, most of which die of HBV-induced complications including cirrhosis and hepatocellular carcinoma, and thus HBV is a public health challenge common to countries worldwide. Esser K et al found that Lipase inhibitor orlistat (orlistat) can prevent infection of host cells by acting on the early stages of HBV viral life cycle, and found that 20 μ M orlistat has an inhibitory rate on HBV viral replication of about 30% (see: CN108524472A)
Yu J et al, Design, synthesis, and evaluation of novel heterocyclic derivatives as non-nucleoside inhibitors by expanding the solvent-amplified region, a Chem Biol Drug Des.0 202Jun; 95(6): 567) -583, disclose dihydropyrimidine compounds having anti-hepatitis B virus activity which inhibit HBV DNA replication at the tested concentration of 20 μ M at a rate of between about 0.4% and about 97%.
Ting-Chao Chou et al, in the scientific basis, experimental design, and formulated synergy of synergy and anti-inflammatory in drug combination participants (Pharmacol Rev.2006 Sep; 58(3):621-81) noted that synergy against multiple targets in combination with a single target can bring about numerous therapeutic benefits, while whether the combination produces synergy or antagonism is highly unpredictable. However, there is no technical suggestion in the prior art that orlistat and dihydropyrimidine compounds are used together to produce synergistic inhibitory effect on the DNA replication of HBV.
Disclosure of Invention
The invention aims to provide a composition containing orlistat and dihydropyrimidine compounds and application thereof in preparing a medicament for treating hepatitis B virus infection, wherein the composition can generate a synergistic inhibition effect on the DNA replication of hepatitis B virus.
In order to achieve the above object, according to one aspect of the present invention, there is provided a composition comprising orlistat and a dihydropyrimidine compound, wherein the dihydropyrimidine compound is selected from the group consisting of:
ethyl 4- (2-bromo-4-fluorophenyl) -6- (methylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (ethylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (propylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (cyclopropylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -6- ((thiophene-2-sulfonylamino) methyl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((pyridine-3-sulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (phenylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((2-methylphenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((3-methylphenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-methylphenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((2-nitrophenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((3-nitrophenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-nitrophenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-fluorophenylsulphonamido) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-methoxyphenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-cyanophenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -6- ((2,4, 6-trimethylphenylsulfonylamino) methyl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((naphthalene-2-sulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (morpholinylmethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 6- ((4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) methyl) -4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 6- ((4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) methyl) -4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4- (pyridin-2-yl) -1H-1,2, 3-triazol-1-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -6- ((4- (thiophen-2-yl) -1H-1,2, 3-triazol-1-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-phenyl-1H-1, 2, 3-triazol-1-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 6- ((4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) methyl) -4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 6- ((1H-1,2, 3-triazol-1-yl) methyl) -4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4- (1-hydroxypentyl) -1H-1,2, 3-triazol-1-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4- ((4-methylbenzamido) methyl) -1H-1,2, 3-triazol-1-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, with
One of ethyl 4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -6- ((4- ((2,4, 6-trimethylphenylsulfonylamino) methyl) -1H-1,2, 3-triazol-1-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylate.
In one aspect, the molar ratio of orlistat to dihydropyrimidine compound in the composition of the invention is preferably (0.01-100): 1.
In another aspect, the composition of the present invention preferably further comprises pharmaceutically acceptable excipients; further preferably, the pharmaceutically acceptable auxiliary material is at least one selected from tartaric acid, starch slurry, talcum powder and liquid paraffin
On the other hand, the composition can be prepared into oral solid preparations; further preferably, the oral solid preparation is one selected from the group consisting of tablets, capsules and granules.
In another aspect, the present invention provides the use of a composition as described above in the manufacture of a medicament for the treatment of hepatitis b virus infection.
In vitro test results show that orlistat and the dihydropyrimidine compounds of the invention can generate synergistic inhibition effect on Hep G2.2.15 intracellular HBV DNA replication in the molar ratio range (combination drug index CI <1)
Detailed Description
Test example 1 HBV inhibition test
The following test substances were examined for their effect on the HBV DNA copy number in Hep G2.2.15 cells at different concentrations (day 2) by the method disclosed in the article by PanxiaBen et al, phosphoesterase inhibitor okadaic acid on replication of hepatitis B virus in HepG2.2.15 cells (Ex: Chinese medicinal biotechnology 2007(06): 405-410).
A test substance (i): orlistat
A test object (c): the dihydropyrimidine compound shown in the table 1 is marked as a compound x, and x is selected from 1-29;
TABLE 1 chemical name and numbering of test Compounds
Figure BDA0002764527400000041
Figure BDA0002764527400000051
Tested object (c): the mixture of the compound x and orlistat in a specific molar ratio (R) is marked as MIX (x-OsT) (x is selected from 1 to 29)
The Inhibitory Rate (IR) of HBV DNA replication of various concentrations of the test substance was calculated according to the following formula
IR ═ 1-test substance-treated group DNA copy number/control group DNA copy number
Log (c) of test concentration (nM) for each IR pair of test substances]Performing linear regression (for the test object, the concentration is calculated according to the compound x), and calculating the IC of each test object according to the linear regression equation50The Combination Index (CI) was then calculated according to the following formula.
CI＝a/A+a/(R×B)
Wherein a represents IC of a test object50(based on compound x), A, B represents IC of the test substances (i) and (ii)50。
When CI <1, synergistic effect is indicated, and the smaller CI, the stronger synergistic effect is indicated, and the results are shown in Table 2.
TABLE 2 inhibition of HBV DNA replication by each test substance
Figure BDA0002764527400000061
Figure BDA0002764527400000071
Figure BDA0002764527400000081
Figure BDA0002764527400000091
Example 2 oral solid preparation containing MIX (x-OsT) and method for preparing the same
Prescription
Figure BDA0002764527400000092
Figure BDA0002764527400000101
Tablet preparation method
Mixing MIX (x-OsT) and starch 1/3, adding 15% starch slurry (containing tartaric acid) to prepare soft material for 10-15 min, or preparing wet granules by 14 meshes, drying at 70 ℃, preparing dry granules by 12 meshes, mixing the granules with residual starch (dried at 100-105 ℃) and talcum powder absorbed with liquid paraffin, sieving by 12 meshes, and tabletting the granules into tablets with the weight of 200mg after the content is determined to be qualified.
Capsule preparation method
Mixing MIX (x-OsT) and starch 1/3, adding 15% starch slurry (containing tartaric acid) to prepare soft material for 10-15 min, or preparing wet granules by 14 meshes, drying at 70 ℃, preparing dry granules by 12 meshes, mixing the granules with residual starch (dried at 100-105 ℃) and talcum powder absorbed with liquid paraffin, sieving by 12 meshes, and filling the granules into capsules with the weight of 200mg after the content of the granules is determined to be qualified.
Preparation method of granules
Mixing MIX (x-OsT) and starch 1/3, adding 15% starch slurry (containing tartaric acid) to prepare soft material for 10-15 min, or preparing wet granules by 14 meshes, drying at 70 ℃, preparing dry granules by 12 meshes, mixing the granules with residual starch (dried at 100-105 ℃) and talcum powder absorbed with liquid paraffin, sieving by 12 meshes, and subpackaging the qualified granules into granules with the weight of about 5g per bag after content measurement.

Claims (7)

1. The composition containing orlistat and dihydropyrimidine compounds is characterized in that the dihydropyrimidine compounds are selected from the following groups:
ethyl 4- (2-bromo-4-fluorophenyl) -6- (methylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (ethylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (propylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (cyclopropylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -6- ((thiophene-2-sulfonylamino) methyl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((pyridine-3-sulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (phenylsulfonylaminomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((2-methylphenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((3-methylphenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-methylphenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((2-nitrophenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((3-nitrophenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-nitrophenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-fluorophenylsulphonamido) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-methoxyphenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-cyanophenylsulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -6- ((2,4, 6-trimethylphenylsulfonylamino) methyl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((naphthalene-2-sulfonylamino) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- (morpholinylmethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 6- ((4- (2-aminophenyl) -1H-1,2, 3-triazol-1-yl) methyl) -4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 6- ((4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) methyl) -4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4- (pyridin-2-yl) -1H-1,2, 3-triazol-1-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -6- ((4- (thiophen-2-yl) -1H-1,2, 3-triazol-1-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4-phenyl-1H-1, 2, 3-triazol-1-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 6- ((4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) methyl) -4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 6- ((1H-1,2, 3-triazol-1-yl) methyl) -4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4- (1-hydroxypentyl) -1H-1,2, 3-triazol-1-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,
ethyl 4- (2-bromo-4-fluorophenyl) -6- ((4- ((4-methylbenzamido) methyl) -1H-1,2, 3-triazol-1-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, with
One of ethyl 4- (2-bromo-4-fluorophenyl) -2- (thiazol-2-yl) -6- ((4- ((2,4, 6-trimethylphenylsulfonylamino) methyl) -1H-1,2, 3-triazol-1-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylate.
2. The composition according to claim 1, wherein the molar ratio of orlistat to dihydropyrimidine compound in the composition is (0.01-100): 1.
3. The composition according to claim 1 or 2, characterized in that said composition further comprises pharmaceutically acceptable excipients.
4. The composition of claim 3, wherein said pharmaceutically acceptable excipient is at least one selected from the group consisting of tartaric acid, starch slurry, talc, and liquid paraffin.
5. The composition of claim 1 or 2, wherein said composition is formulated as an oral solid dosage form.
6. The composition according to claim 5, wherein the oral solid preparation is one selected from the group consisting of tablets, capsules and granules.
7. Use of a composition according to claim 1 or 2 in the manufacture of a medicament for the treatment of hepatitis b virus infection.
CN202011228981.7A 2020-11-06 2020-11-06 Composition containing orlistat and dihydropyrimidine compound and application thereof Active CN112168816B (en)

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CN108524472A (en) * 2018-04-18 2018-09-14 中山万汉制药有限公司 Purposes of the nanoparticle containing orlistat in preparing anti-hepatic-B virus medicine
CN108947996A (en) * 2018-07-12 2018-12-07 山东大学 Dihydro-pyrimidin-sulfonic acid amide derivatives and the preparation method and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150139949A1 (en) * 2011-04-06 2015-05-21 Emre Koyuncu Anti-viral combination therapy
WO2015180631A1 (en) * 2014-05-30 2015-12-03 南京明德新药研发股份有限公司 Dihydropyrimido loop derivative as hbv inhibitor
CN108524472A (en) * 2018-04-18 2018-09-14 中山万汉制药有限公司 Purposes of the nanoparticle containing orlistat in preparing anti-hepatic-B virus medicine
CN108947996A (en) * 2018-07-12 2018-12-07 山东大学 Dihydro-pyrimidin-sulfonic acid amide derivatives and the preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KNUD ESSER等: "Lipase inhibitor orlistat prevents hepatitis B virus infection by targeting an early step in the virus life cycle", 《ANTIVIRAL RESEARCH》 *

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