CN112920168B - New application of talpimod and derivative or pharmaceutically acceptable salt thereof and mycobacterium tuberculosis inhibitor - Google Patents
New application of talpimod and derivative or pharmaceutically acceptable salt thereof and mycobacterium tuberculosis inhibitor Download PDFInfo
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- CN112920168B CN112920168B CN202110119671.XA CN202110119671A CN112920168B CN 112920168 B CN112920168 B CN 112920168B CN 202110119671 A CN202110119671 A CN 202110119671A CN 112920168 B CN112920168 B CN 112920168B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Abstract
The invention relates to novel application of talpidmod (Talmapimod, Scio 469, 6-chloro-5- [ [ (2R,5S) -4- [ (4-fluorophenyl) methyl ] -2, 5-dimethyl-1-piperazinyl ] formyl ] -N, N, 1-trimethyl-alpha-oxo-1H-indole-3-acetamide) and derivatives thereof, and a mycobacterium tuberculosis inhibitor, application of the talpidmod in preparation of drugs for preventing and/or tuberculosis and application of the talpidmod in preparation of the mycobacterium tuberculosis inhibitor. The tapeimod has a good inhibition effect on mycobacterium tuberculosis.
Description
Technical Field
The invention relates to novel application of talpidmod (Talmapimod, Scio 469, 6-chloro-5- [ [ (2R,5S) -4- [ (4-fluorophenyl) methyl ] -2, 5-dimethyl-1-piperazinyl ] formyl ] -N, N, 1-trimethyl-alpha-oxo-1H-indole-3-acetamide) and derivatives thereof and a mycobacterium tuberculosis inhibitor.
Background
Talpidmod (Talmapimod, Scio-469) is a selective, ATP-competitive inhibitor of small molecule p38 α with oral activity, IC50 ═ 9 nM. Can block the synthesis of tumor necrosis factor, interleukin-1 and cyclooxygenase-2 of patients with active rheumatoid arthritis, and is developed by Scios, Inc. for treating active rheumatoid arthritis; can also be applied before operation to treat acute pain; scio-469 treatment inhibited bone marrow microenvironment factors, inhibited multiple myeloma cell proliferation and adhesion, reduced multiple myeloma cell osteolytic activation, inhibited human myeloma cell growth in vivo both early and late stages of disease, and oral administration of 90-360 mg daily doses of tapenimod in clinical trials was well tolerated by patients with low risk myelodysplastic syndrome and demonstrated modest multi-lineage activity at all dose levels without dose-limiting toxicity.
The structural formula is as follows:
tuberculosis is a chronic infectious disease caused by infection with mycobacterium tuberculosis. Tubercle bacillus may invade various organs of the whole body of a human body, but mainly invades the lung, and is called pulmonary tuberculosis.
Mycobacterium tuberculosis (m. tuberculosis), commonly known as mycobacterium tuberculosis (tuberculosis), is the causative agent of tuberculosis. At present, the tuberculosis treatment mainly takes drug chemotherapy as a main treatment. Rifampin, isoniazid, ethambutol, streptomycin, pyrazinamide and the like are first-line antitubercular drugs. Failure of drugs or life threatening localized lesions, etc. can be treated by surgery. Also important in the treatment are symptomatic treatments, such as the treatment of fever, the prevention and treatment of hemoptysis, and the like.
Disclosure of Invention
One object of the present invention is to provide a new use of tapentamod and its derivatives or pharmaceutically acceptable salts.
Another object of the present invention is to provide a Mycobacterium tuberculosis inhibitor.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a new application of tapentamod and derivatives or pharmaceutically acceptable salts thereof, and an application of tapentamod and derivatives or pharmaceutically acceptable salts thereof in preparation of drugs for preventing and/or treating tuberculosis.
As a preferable embodiment of the present invention, the application of the tapentamod and its derivatives or pharmaceutically acceptable salts thereof in the preparation of mycobacterium tuberculosis inhibitors is provided.
As a preferred embodiment of the present invention, the prophylactic and/or tuberculosis drug can be introduced into the body by injection, oral administration, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other materials and introduced into body or wound.
As a preferred embodiment of the present invention, it is administered using a solid, semi-solid or liquid formulation.
As a preferred embodiment of the present invention, the drug for preventing and/or treating tuberculosis further comprises a pharmaceutically acceptable carrier; the carrier comprises one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, absorption carriers and lubricants in the pharmaceutical field.
As a preferred embodiment of the present invention, the tapentamod and its derivatives or pharmaceutically acceptable salts thereof include cis-trans structures and stereoisomers thereof.
As a preferable scheme of the invention, the mycobacterium tuberculosis comprises sensitive bacteria, single-drug-resistant, multi-drug-resistant and wide-drug-resistant mycobacterium tuberculosis.
As a preferable scheme of the invention, the medicine for preventing and/or treating tuberculosis can be prepared into injection, tablets, powder, granules, capsules, oral liquid, ointment, cream or other proper pharmaceutical dosage forms specified by pharmacopoeia.
In a preferred embodiment of the present invention, the medicament for preventing and/or treating tuberculosis contains 0.5-99Wt% of tapentamod and its derivatives or pharmaceutically acceptable salts thereof, based on the total weight of the medicament for preventing and/or treating tuberculosis.
The invention also provides a mycobacterium tuberculosis inhibitor, wherein the active ingredient of the mycobacterium tuberculosis inhibitor is tapeimod and derivatives or pharmaceutically acceptable salts thereof; the concentration of the tapentamod and the derivative or the pharmaceutically acceptable salt thereof is 0.049-200 mug/mL.
Compared with the prior art, the invention has the following beneficial effects:
the test result of the invention using the tapeimod against mycobacterium tuberculosis in vitro shows that the tapeimod has better inhibition effect on mycobacterium tuberculosis, and the minimum inhibitory concentration is 12.5-25 mug/mL.
Drawings
Fig. 1 is a microdilution assay for tapernimod according to the invention.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and drawings, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
The tapentamod and the derivative or the pharmaceutically acceptable salt thereof in the invention are compounds with the following structures.
It is understood that any cis-trans and stereoisomer that include those having this structural feature are included in the tapentamod and its derivatives or pharmaceutically acceptable salts thereof described herein.
The tapentamod and the derivative or the pharmaceutically acceptable salt thereof disclosed by the invention are used for preparing a medicament for preventing and/or treating tuberculosis.
The mycobacterium tuberculosis comprises sensitive bacteria, single-drug resistant, multi-drug resistant and wide-drug resistant mycobacterium tuberculosis.
The mycobacterium tuberculosis may be a member of the Mycobacterium Tuberculosis Complex (MTC).
Members of the Mycobacterium Tuberculosis Complex (MTC) include Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium africanum (Mycobacterium africanum), Mycobacterium bovis (Mycobacterium bovis), Mycobacterium bovis BCG (Mycobacterium bovis BCG), Mycobacterium cassiae (Mycobacterium canetti), Mycobacterium caprine (Mycobacterium caprae), Mycobacterium microti (Mycobacterium micropenium) and Mycobacterium marinum (Mycobacterium pinipedii). These mycobacteria are the causative agents of tuberculosis in humans and animals. Mycobacterium tuberculosis is the leading cause of tuberculosis in humans.
Tuberculosis in the present invention is caused by infection of Mycobacterium tuberculosis.
Mycobacterium tuberculosis may have drug resistance, including single, multiple and broad drug resistance.
In another aspect, the talpidmod and derivatives thereof or pharmaceutically acceptable salts thereof of the invention for use in the treatment of a disease caused by an infection with mycobacterium tuberculosis, wherein mycobacterium tuberculosis is selected from those described above.
Diseases caused by infection with mycobacterium tuberculosis include, but are not limited to, pulmonary tuberculosis, tuberculous pleuritis, tuberculous bronchitis, extrapulmonary tuberculosis, such as tuberculous meningitis, lymphoid tuberculosis, intestinal tuberculosis, tuberculous peritonitis, renal tuberculosis, tuberculosis of the reproductive system, tuberculosis of bones and joints, tuberculosis of the skin, and the like.
"pharmaceutically acceptable" in the context of the present invention refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts of the present invention include inorganic and organic salts, one preferred class of salts is that of the compounds of the present invention with acids, and representative pharmaceutically acceptable acid addition salts include, but are not limited to: 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), hexanoate (h.xanoate), octanoate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2, 5-dihydroxybenzoate, disuccinate, lauryl sulfate, edetate (edetate), etonate (lauryl sulfate), ethane-1, 2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactonate (mucate), gentisate (2, 5-dihydroxybenzoate), glucoheptonate (gluceptate), Gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylisophthalate, hippurate, hydrabamine (N, N' -bis (dehydroabietyl) -ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactoburonate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1, 5-disulfonate (napadisylate), naphthalene-2-sulfonate (naphthalenesulfonate), nicotinate, nitrate, oleate, palmitate, sulfanilate, p-aminosalicylate, pamoate (pamoate), pantothenate, pectate, persulfate, phenylacetate, phenylethylbarbiturate, nicotinate, nitrate, oleate, palmitate, pamoate (pamoate), pamoate, palmitate, persulfate, phenylacetate, phenylethylbarbiturate, salicylate, and the like, Phosphates, polygalacturonates, propionates, p-toluenesulfonates, pyroglutamates, pyruvates, salicylates, sebacates, stearates, hypoacetates, succinates, sulfamates, sulfates, tannins, tartrates, theachlorates (8-chlorotheophylline), thiocyanates, triiodonium, undecanoates, undecenates, and valerates.
Another preferred class of salts is that formed by a compound of the invention with a base, including, but not limited to, aluminum, 2-amino-2- (hydroxymethyl) -1, 3-propanediol (TRIS, tromethamine), arginine, benzphetamine (N-benzylphenethylamine), benzathine (N, N '-dibenzylethylenediamine), bis- (2-hydroxyethyl) amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p-chlorobenzyl-2-pyrrolidin-1' -ylmethylbenzimidazole), cyclohexylamine, benzhydrylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, p-methylpyridine, lithium, lysine, magnesium, meglumine (N-methylglucamine), Piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine and zinc.
In the present invention, the pharmaceutically acceptable salt is preferably a phosphate salt or an ammonium salt.
The tapentamod and its derivatives or pharmaceutically acceptable salts thereof according to the present invention can be prepared by methods well known to those skilled in the art, and the reaction parameters of each step are not particularly limited, and in addition, can be obtained in a commercially available manner.
The medicament for preventing and/or treating tuberculosis contains safe and effective dose of tapenimod and its derivatives or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or excipients. Such vectors include (but are not limited to): saline, buffer, dextrose, water, glycerol, ethanol, powders, and combinations thereof. The pharmaceutical preparation should be compatible with the mode of administration.
In the case of pharmaceutical compositions, the prophylactic and/or therapeutic drugs of the present invention can be prepared in the form of injections, for example, by conventional methods using physiological saline or aqueous solutions containing glucose and other adjuvants. Pharmaceutical compositions, such as tablets and capsules, can be prepared by conventional methods. Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under sterile conditions. The prophylactic and/or tuberculosis drug of the invention can also be prepared into powder for aerosol inhalation.
For the prophylactic and/or tuberculosis drug of the present invention, it can be introduced into the body such as muscle, subcutaneous, intradermal, vein, bone, mucosal tissue by injection, oral administration, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other materials and introduced into body or wound.
The medicament for preventing and/or treating tuberculosis, which is prepared from the talpidmod and the derivative or the pharmaceutically acceptable salt thereof, can be prepared into various forms such as injection, tablets, powder, granules, capsules, oral liquid, ointment, cream and the like. The medicines in various dosage forms can be prepared according to the method in the field of pharmacy.
Examples
The mycobacterium tuberculosis H37Rv, multi-drug resistant, single drug resistant and wide drug resistant bacteria are drug sensitive proficiency testing quality control strains in 2017 in national tuberculosis reference laboratory of China center for disease prevention and control.
A microdilution method is adopted.
The specific operation steps are as follows:
1) and (3) seed transformation culture:
h37Rv, 6(MDR-TB), 9(DR-TB) and 10(XDR-TB) were aseptically transferred to modified L-J medium and cultured at 37 ℃ for 28 days.
2) Preparing a drug-containing flat plate:
2.1) preparing a compound stock solution, dissolving the compound stock solution in dimethyl sulfoxide (DMSO) according to the weight and the titer of the tapentamod, and preparing a drug stock solution with the concentration of 10 mg/mL.
2.1) dilution by multiple ratio:
2.1.1) in 96-well plates 98. mu.L of 7H9 broth containing 10% DMSO was added to the first column and 50. mu.L to the remaining columns.
2.1.2) respectively adding 2 mu L of 10mg/mL of talpidmod into the first row of micropores of the 96-well plate, so that the highest working concentration of the medicine is 200 mu g/mL. And (3) after uniformly mixing the mixture by using an 8-channel pipette, sucking 50 mu L of the mixed solution into the second row of micropores, uniformly mixing the mixture with 50 mu L of liquid culture medium by blowing, sequentially operating to the last row, and sucking away 50 mu L of the mixed solution after uniformly mixing. The concentration of the compound was 200, 100, 50, 25 to 0.098. mu.g/mL in this order.
2.1.3) set DMSO as negative control, rifampicin as positive control, and set blank control, 3 replicates of each compound. Repeat 3 times.
3) Preparing a bacterial suspension:
3.1) scraping colonies from the solid medium in saline containing 0.2% Tween and glass beads. Vortex shaker for at least 30 seconds. After the bacterial suspension had settled naturally for 15 minutes, the turbidity was adjusted to 0.5McFarland standard using a turbidimeter.
3.2) transfer 15. mu.L of bacterial suspension to 7H9 liquid medium containing 15ml of 10% OADC, vortex and mix for 30 seconds. To obtain 1X 105CFU/mL (range is
) Inoculating the liquid. The preparation of the bacterial suspension and the removal of the bacterial suspension are completed within 30 minutes.
4) Inoculation: 50 mu L of bacterial suspension is added into each hole of the drug-containing micro-porous plate, and the final concentration of the compound is 100, 50, 25 to 0.049 mu g/mL in sequence.
5) Sealing the film:
all holes were covered with an adhesive sealing film, ensuring that all holes were completely covered. After the lid of the 96-well cell culture plate was closed, a bag made of a transparent plastic was placed and heat-sealed to ensure sufficient sealing.
6) And (3) incubation:
the growth was checked by incubation at 37 ℃ for 7-10 days. If the growth condition is not good after 10 days, putting the mixture into an incubator, and continuing to incubate the drug sensitive plate for 11 days again. During the incubation, a maximum of two panels were stacked.
7) Interpretation of Minimum Inhibitory Concentration (MIC) results: (see FIG. 1 and Table 1)
7.1) the results can be read with the naked eye or a microplate bottom scanner (without uncovering the sealing film). Growth is manifested as turbidity or colony deposition at the bottom of the well. The MIC value is the lowest concentration of compound at which growth is significantly inhibited.
7.2) reference strain H37Rv blank, negative and positive control wells were first read. If the strains grow in the blank control hole, the result is invalid, and the whole liquid culture medium is polluted; if no positive growth exists in the negative control wells, the result is invalid, which indicates that the DMSO concentration influences the bacterial activity; if positive growth occurs outside the quality control concentration range of the quality control strain in the positive control hole, the result is invalid, which indicates that the operation process has problems.
Table 1. results judgment and report:
as can be seen from FIG. 1 and Table 1, the inhibitor has good inhibitory effects on sensitive bacteria, drug-resistant bacteria, multi-drug-resistant bacteria and wide drug-resistant bacteria of Mycobacterium tuberculosis, and the minimum inhibitory concentration is 12.5-25 μ g/mL;
in fig. 1, a: DMSO negative control wells; b: rifampin drug control wells; c: a tapeimod detection well; d: blank control wells.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (4)
1. The application of the tapentamod and the pharmaceutically acceptable salts thereof is characterized in that the tapentamod and the pharmaceutically acceptable salts thereof are applied to preparation of drugs for preventing and/or treating tuberculosis.
2. The use of tapentamod and pharmaceutically acceptable salts thereof according to claim 1, wherein the use of tapentamod and pharmaceutically acceptable salts thereof for the preparation of mycobacterium tuberculosis inhibitors.
3. The use of tapenimod and pharmaceutically acceptable salts thereof according to claim 2, wherein the mycobacterium tuberculosis comprises sensitive bacteria, single-drug resistant, multi-drug resistant and broad-drug resistant mycobacterium tuberculosis.
4. The use of tapentamod and pharmaceutically acceptable salts thereof according to claim 1, wherein the medicament for preventing and/or treating tuberculosis comprises tapentamod and pharmaceutically acceptable salts thereof in an amount of 0.5-99Wt% based on the total weight of the medicament for preventing and/or treating tuberculosis.
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Non-Patent Citations (4)
| Title |
|---|
| Electroacupuncture Attenuates Spinal Nerve Ligation-Induced Microglial Activation Mediated by p38 Mitogen-Activated Protein Kinase;Liang Yi 等;《Chin J Integr Med》;20160930;第22卷(第9期);704-713 * |
| p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells;Teru Hideshima 等;《Oncogene》;20041118;第23卷(第54期);第8774页试剂部分，第8767-8768页的图1和图2 * |
| Teru Hideshima 等.p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells.《Oncogene》.2004,第23卷(第54期), * |
| 抗结核药物作用新靶点及其研究进展;陈浩等;《中国防痨杂志》;20200331;第42卷(第3期);286-292 * |
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