WO2021047525A1 - Salt of benzothiopyrone compound, and preparation method therefor and application thereof - Google Patents
Salt of benzothiopyrone compound, and preparation method therefor and application thereof Download PDFInfo
- Publication number
- WO2021047525A1 WO2021047525A1 PCT/CN2020/114126 CN2020114126W WO2021047525A1 WO 2021047525 A1 WO2021047525 A1 WO 2021047525A1 CN 2020114126 W CN2020114126 W CN 2020114126W WO 2021047525 A1 WO2021047525 A1 WO 2021047525A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyclohexylmethyl
- piperazin
- nitro
- benzothiopyran
- trifluoromethyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- -1 benzothiopyrone compound Chemical class 0.000 title claims abstract description 9
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Definitions
- the invention belongs to the field of medical technology.
- it relates to salts of benzothiopyrone compounds: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 represented by formula (I) -Nitro-benzothiopyran-4-one salt, its preparation method, pharmaceutical composition using the salt as an active ingredient, and their preparation for the treatment and/or prevention of infectivity caused by Mycobacterium tuberculosis Application of disease drugs.
- Tuberculosis (Tuberculosis, TB) is a chronic fatal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that endangers human health and causes human death. According to WHO estimates, there were approximately 1.7 billion people latently infected with tuberculosis worldwide in 2017, and the latent infection rate was 23%. There are about 10 million new cases of tuberculosis in the world, and about 1.4 million deaths. The incidence of tuberculosis is 133 per 100,000. Among them, children younger than 15 years old and HIV-infected people account for 10% and 9% of the new cases, respectively.
- the unique cell wall of Mycobacterium tuberculosis has a multi-layered structure.
- the biosynthetic pathways of these unique components are a rich source of potential drug targets.
- the first-line drugs isoniazid and ethambutol act on mycolic acid and arabinan layers, respectively. Synthesis, interferes with the formation of the cell wall of Mycobacterium tuberculosis.
- the main component of the arabinogalactan layer and arabinomannan layer of the outer membrane of Mycobacterium tuberculosis cell wall is a kind of arabinose with DPA as an important precursor. Studies have shown that DPA is mainly composed of DPR in DprE1 and DprE2.
- Epimerization is obtained under the joint action, so inhibiting the activity of DprE1 can hinder the synthesis of cell wall and ultimately achieve the purpose of killing Mycobacterium tuberculosis two-step epimerization of decaprenylphosphoryl ribose. Journal of bacteriology 2005,187(23),8020-8025).
- the benzothiopyrone core structure has been determined as the dominant skeleton and applied for Patent (Patent No.: 201810092333.X and PCT/CN2018/080787), through systematic and in-depth research, obtained the benzothiopyrone compound 6b(2) with significant anti-tuberculosis and drug-resistant tuberculosis activity and low toxicity -(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one)(Identification of novel benzothiopyranone compounds against against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones[J].Eur.J.Med.Chem.,2018,160,157-170).
- Patent 201810092333.X and PCT/CN2018/080787 disclose 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyridine Examples of pyran-4-one and its hydrochloride salt, but no specific examples and experimental results of other pharmaceutically acceptable salts are disclosed.
- the technical problem to be solved by the present invention is to provide a 2-(4-(cyclohexylmethyl)piperazin-1-yl) which has significantly improved pharmacokinetic properties and physical and chemical properties and has strong activity against Mycobacterium tuberculosis in vivo and in vitro.
- Salt of 6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one The present invention found that the salt of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one has Strong anti-Mycobacterium tuberculosis effect in vivo and in vitro.
- the present invention provides the following technical solutions:
- the first aspect of the technical scheme of the present invention provides 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzo represented by formula (I)
- salt of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one does not include salt Acid salt.
- the salt of any one of the first aspect of the present invention is characterized in that it is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-
- the maleate, fumarate, citrate and L-malate of benzothiopyran-4-one is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- The maleate, fumarate, citrate and L-malate of benzothiopyran-4-one.
- the salt of any one of the first aspect of the present invention is characterized in that it is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- Benzothiopyran-4-one ⁇ 1 maleate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- Benzothiopyran-4-one 1/2 maleate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro -Benzothiopyran-4-one ⁇ 3/2 maleate; 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 -Nitro-benzothiopyran-4-one ⁇ 1 fumarate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 -N
- the second aspect of the technical solution of the present invention provides a method for preparing the salt according to the first aspect of the present invention, which comprises the following steps:
- the third aspect of the technical solution of the present invention provides a pharmaceutical composition, which comprises a therapeutically and/or preventively effective amount of a pharmaceutically acceptable salt of the compound according to the first aspect of the present invention, and optionally one or A variety of pharmaceutically acceptable carriers, excipients, diluents, excipients and vehicles.
- the fourth aspect of the technical solution of the present invention provides a pharmaceutically acceptable salt of the compound of the first aspect of the present invention, or the pharmaceutical composition of the third aspect of the present invention is used in the preparation of treatment and/or prevention caused by Mycobacterium tuberculosis Application of medicines for infectious diseases.
- room temperature refers to a temperature from 10°C to 40°C. In some embodiments, “room temperature” refers to a temperature from 20°C to 30°C; in other embodiments, room temperature refers to 25°C.
- the term "effective amount” refers to the amount of a drug that can achieve the desired treatment of the disease or condition of the present invention in a subject.
- the term "pharmaceutically acceptable”, for example, when describing “pharmaceutically acceptable salt”, means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic material that is of pharmaceutically useful value. substance.
- composition can also refer to a “composition”, which can be used to achieve the treatment of the disease or condition of the present invention in a subject, especially a mammal.
- the "treatment” of the disease includes:
- a “therapeutically effective amount” refers to an amount of a compound that is sufficient to achieve treatment of the disease when administered to a mammal for the treatment of the disease.
- the therapeutically effective amount will vary depending on the compound, the disease to be treated and its severity, and the mammal's age, weight, sex and other factors.
- a therapeutically effective amount can also refer to any amount of the compound sufficient to achieve the desired beneficial effect, including the prevention, suppression or alleviation of diseases as described in (1)-(3) above.
- the amount of compound may be between 0.1-250 mg/kg, or preferably, 0.5-100 mg/kg, or more preferably, 1-50 mg/kg, or even more preferably, 2-20 mg/kg.
- the amount of the compound is administered to the mammal twice a day. More preferably, the amount of the compound is administered to the mammal once a day.
- the term "disease and/or disorder” refers to a physical state of the subject, which physical state is related to the disease and/or disorder described in the present invention.
- the diseases and/or conditions described in the present invention refer to infectious diseases of Mycobacterium tuberculosis.
- the term "subject” may refer to a patient or other animal, particularly a mammal, that receives a salt of the compound of formula (I) of the present invention or a pharmaceutical composition thereof to treat the disease or condition of the present invention, for example People, dogs, monkeys, cows, horses, etc.
- Another aspect of the present invention also relates to a pharmaceutical composition using the compound of the present invention as an active ingredient.
- the pharmaceutical composition can be prepared according to methods known in the art.
- the compound of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants to prepare any dosage form suitable for human or animal use.
- the compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous injection, nasal cavity, oral mucosa, eye, Lung and respiratory tract, skin, vagina, rectum, etc.
- the dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
- Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops
- the solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
- the compound of the present invention can be made into ordinary preparations, and can also be made into sustained-release preparations, controlled-release preparations, targeted preparations and various particulate drug delivery systems.
- diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
- wetting agent can be water, ethanol, Isopropanol, etc.
- the binder can be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia syrup, gelatin syrup, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl Methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
- the disintegrant can be dry starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
- the wetting agent can be water, ethanol, Isopropanol, etc.
- the binder can be starch syrup, de
- the tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
- the active ingredient of the compound of the present invention can be mixed with a diluent and a co-solvent, and the mixture can be directly placed in a hard or soft capsule.
- the active ingredient of the compound of the present invention can also be prepared into granules or pellets with diluents, binders, and disintegrants, and then placed in hard or soft capsules.
- the various diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare the compound tablets of the present invention can also be used to prepare the compound capsules of the present invention.
- solubilizers, cosolvents, pH regulators, and osmotic pressure regulators commonly used in this field can be added.
- the solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.
- the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.
- the osmotic pressure regulator can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc.
- mannitol, glucose, etc. can also be added as proppants.
- coloring agents can also be added to the pharmaceutical preparations.
- the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
- the compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.
- the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.
- the inventor of the present invention synthesized the salt of the compound represented by formula (I), and performed the minimum inhibitory concentration (MIC ) with M. tuberculosis H 37 Rv strain by the MABA (Microplate alamar blue assay) method.
- the test showed strong anti-Mycobacterium tuberculosis activity.
- 5 salts with MIC ⁇ 0.016 ⁇ g/mL were obtained, which was significantly stronger than isoniazid, the first-line anti-tuberculosis drug.
- the maleate, fumarate, citrate and L-malate of the compound of formula (I) of the present invention are superior to the hydrochloride of the compound of formula (I) in cell permeability, indicating that the present invention Salt has better absorption properties.
- mice showed that the bioavailability of the maleate and L-malate of the compound of formula (I) was significantly improved compared to that of the compound (I).
- the results of rat pharmacokinetic experiments showed that compared with the compound of formula (I) and its hydrochloride, the maleate of the compound of formula (I) has significantly increased in vivo exposure (AUC) and bioavailability, which indicates that the present invention
- the salt has better pharmacokinetic properties than the free base and hydrochloride.
- In vivo pharmacodynamic experiments in mice showed that the maleate of the compound of formula (I) has stronger anti-tuberculosis activity in vivo than the compound of formula (I) at the same dose.
- the test results of influencing factors show that the maleate of the compound of formula (I) is very stable when placed under light, high temperature and high humidity conditions for ten days, especially under light conditions, the stability is significantly better than that of compound (I), which indicates
- the salt of the invention has a significant improvement in light stability.
- the present invention provides a class of salts of benzothiopyrone compounds with strong anti-tuberculosis activity, significantly improved pharmacokinetic properties and physical and chemical properties, which can be used for infectious diseases caused by bacteria, especially tuberculosis branches.
- the treatment or preventive treatment of tuberculosis caused by bacilli can also be used to overcome the problems related to drug resistance.
- the structure of the compound was determined by proton nuclear magnetic resonance spectroscopy ( 1 H NMR).
- the chemical shift ( ⁇ ) of the proton nuclear magnetic resonance spectrum is given in units of parts per million (ppm).
- the coupling constant (J) is in Hertz (Hz).
- the NMR spectrum was measured with a Mercury-400 nuclear magnetic resonance instrument, deuterated methanol (CD 3 OD) and deuterated dimethyl sulfoxide (DMSO-d 6 ) were used as solvents, and tetramethylsilane (TMS) was used as an internal standard.
- the electronic balance adopts the Japanese Yanaco LY-300 electronic balance.
- Anhydrous solvents are processed by standard methods.
- Other reagents are commercially available analytical grade.
- CFU is the colony forming unit
- MIC is the minimum inhibitory concentration
- iv is intravenous administration
- AUC is the area under the drug concentration-time curve
- T max is the peak time
- MABA Microplate Alamar Blue Assay
- Alamar Blue added to the culture medium can be used as a redox indicator, and the color changes from blue to red, reflecting the consumption of oxygen molecules by the studied microorganisms.
- the color change of Alamar Blue can be measured with a photometer, and its emission wavelength is 590nm.
- Caco-2 cells are human cloned colon adenocarcinoma cells, similar in structure and function to differentiated epithelial cells, with microvilli and other structures, and are widely used in vitro to simulate the penetration and absorption of drugs in the intestinal tract.
- the apparent permeability coefficient (Papp) of the compound is calculated by the following formula:
- dQ/dt is the permeation rate of drug molecules across the membrane
- C 0 is the initial concentration of the drug
- A is the area of the monolayer.
- mice Male weighing 23-25 grams were used in each group for the pharmacokinetic study of compounds 1, 2, 3 and 5.
- Compounds 1, 2, 3 and 5 were prepared as 5 mg/mL suspensions with 0.5% carboxymethyl cellulose, respectively, and were administered orally at a dose of 50 mg/kg.
- Compounds 1, 2, 3 and 5 were prepared as 1 mg/mL solutions with 20% HP- ⁇ -CD and 1N hydrochloric acid, respectively, and were given a dose of 5 mg/kg intravenously.
- Plasma samples were collected at 5, 15, 30 minutes, and 1, 2, 4, 7, and 24 hours after oral and intravenous administration. The collected plasma samples are stored at -80°C until used for analysis. Plasma samples were extracted with acetonitrile containing terfenadine internal standard, and the ratio of extractant to plasma was 20:1.
- the analyte was quantified by LC/TSQ Quantum Access mass spectrometer (AB Sciex5500). Chromatographic conditions: Column: Kinetex C18 100A (30mm ⁇ 3.0mm, 2.6 ⁇ m); column temperature: room temperature, mobile phase: acetonitrile/water (80:20, v/v) (containing 0.1% formic acid); flow rate: 0.8mL /min.
- the compound detection on the mass spectrometer is carried out in electrospray positive ionization mode.
- the WinNonlin software (6.3Pharsight Corporation, Mountain View, USA) was used to calculate the pharmacokinetic parameters.
- the bioavailability (F) of the compounds 1, 2, 3 and 5 of the present invention is 18.9-28.0%.
- the bioavailability of the free base 6b (compound (I)) of compounds 1, 2, 3 and 5 reported in the comparative document (Eur. J. Med. Chem., 2018, 160, 157-170) is 13.1%.
- the bioavailability of compounds 1, 2, 3 and 5 is improved, among which compounds 1 and 5 are increased by about 1 times, indicating that the compound of the present invention has better pharmacokinetic properties.
- Compound 1 Compound (I) and its hydrochloride were prepared into a 5 mg/mL suspension with 0.5% carboxymethyl cellulose, respectively, and were administered orally at a dose of 50 mg/kg.
- HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
- Plasma samples were collected 5, 15, 30 minutes after oral and intravenous administration, and 1, 2, 4, 7, 12, and 24 hours. The collected plasma samples are stored at -80°C until used for analysis. The WinNonlin software (6.3Pharsight Corporation, Mountain View, USA) was used to calculate the pharmacokinetic parameters.
- Balb/c mice were infected with Mycobacterium tuberculosis H37Rv by aerosol, and were given drug treatment (25, 50, 100 mg/kg) 10 days after infection, once a day, 5 times a week, three weeks after the administration, Anatomy, with the lung CFU as the main evaluation index, a blank control group was set up to give 0.5% CMC, and the first-line clinical drug isoniazid was used as the positive control drug to investigate the anti-tuberculosis activity of compound (I) and compound 1 in vivo.
- the CMC group is a blank control group, given 0.5% CMC.
- test results show that compound (I) has strong anti-tuberculosis activity at doses of 25, 50 and 100 mg/kg, and the number of viable lung tissues in mice decreased by 2.28, 3.58 and 3.73 log 10 CFU respectively compared with the blank control group.
- the CMC group is a blank control group, given 0.5% CMC.
- test results show that compound 1 has strong anti-tuberculosis activity at doses of 25, 50 and 100 mg/kg, and shows a significant dose-effect relationship.
- the number of viable lung tissues in mice decreased by 3.01, respectively, compared with the blank control group. 3.99 and 4.68 log 10 CFU.
- compound 1 of the present invention can reduce Log 10 CFU values more than compound (I) at doses of 25, 50 and 100 mg/kg, especially at doses of 100 mg/kg. Compared with the blank control group, compound 1 can reduce 4.68 Log 10 CFU, which is significantly better than compound (I) (reducing 3.73 Log 10 CFU), indicating that compound 1 has stronger anti-tuberculosis activity in vivo.
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Abstract
The present invention relates to the technical field of medicine, and provides a salt of a benzothiopyrone compound, and a preparation method therefor and an application thereof, in particular, a salt of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one as represented by formula (I), a preparation method therefor, a pharmaceutical composition thereof, and an application thereof in preparation of a drug for treating and/or preventing an infectious disease caused by Mycobacterium tuberculosis. The present invention aims to prepare a salt of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one having significantly improved pharmacokinetic properties and physicochemical properties and having strong anti-Mycobacterium tuberculosis activity in vivo and in vitro; as a potential novel drug, the salt can be used for treatment or preventive treatment of an infectious disease caused by bacteria, particularly tuberculosis (TB) caused by Mycobacterium tuberculosis, and can also be used for overcoming a problem related to drug resistance of Mycobacterium tuberculosis.
Description
本发明属于医药技术领域。特别涉及苯并硫代吡喃酮类化合物的盐:式(I)所示的2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的盐,其制备方法,以该盐为活性成分的药物组合物,以及它们在制备治疗和/或预防由结核分枝杆菌引起的感染性疾病药物中的应用。The invention belongs to the field of medical technology. In particular, it relates to salts of benzothiopyrone compounds: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 represented by formula (I) -Nitro-benzothiopyran-4-one salt, its preparation method, pharmaceutical composition using the salt as an active ingredient, and their preparation for the treatment and/or prevention of infectivity caused by Mycobacterium tuberculosis Application of disease drugs.
结核病(Tuberculosis,TB)是由结核分枝杆菌引起的一种慢性致死性疾病,是危害人类健康和导致人类死亡的重大传染性疾病。据WHO估算,2017年全球的结核病潜伏感染人群约为17亿,潜伏感染率为23%。全球新发结核病患者约1000万,死亡患者约140万,结核病发病率为133/10万,其中小于15岁的儿童患者和艾滋病病毒感染者分别占新发患者的10%和9%。在2017年的结核病患者中,耐药结核病例55.8万,82%为多重耐药结核病(MDR-TB),同时广泛耐药(XDR-TB)结核病上升速率亦较快,耐药结核的治愈率全球仅为55%。Tuberculosis (Tuberculosis, TB) is a chronic fatal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that endangers human health and causes human death. According to WHO estimates, there were approximately 1.7 billion people latently infected with tuberculosis worldwide in 2017, and the latent infection rate was 23%. There are about 10 million new cases of tuberculosis in the world, and about 1.4 million deaths. The incidence of tuberculosis is 133 per 100,000. Among them, children younger than 15 years old and HIV-infected people account for 10% and 9% of the new cases, respectively. Among TB patients in 2017, there were 558,000 drug-resistant tuberculosis cases, 82% of which were multi-drug-resistant tuberculosis (MDR-TB). At the same time, extensively drug-resistant (XDR-TB) tuberculosis is increasing rapidly, and the cure rate of drug-resistant tuberculosis Only 55% globally.
结核分枝杆菌特有的细胞壁具有多层次的结构,这些独特成分的生物合成途径是潜在药物靶标的丰富来源,例如一线药物异烟肼和乙胺丁醇分别作用于霉菌酸和阿拉伯聚糖层的合成,干扰结核分枝杆菌细胞壁的形成。结核分枝杆菌细胞壁外膜的阿拉伯半乳聚糖层及阿拉伯甘露聚糖层的主要组成部分是一种以DPA为重要前体的阿拉伯糖,研究表明,DPA主要是由DPR在DprE1和DprE2的共同作用下差向异构化得到,因此抑制DprE1的活性可阻碍细胞壁的合成最终达到杀灭结核分枝杆菌的目的(Decaprenylphosphoryl arabinofuranose,the donor of the D-arabinofuranosyl residues of mycobacterial arabinan,is formed via a two-step epimerization of decaprenylphosphoryl ribose.Journal of bacteriology 2005,187(23),8020-8025)。The unique cell wall of Mycobacterium tuberculosis has a multi-layered structure. The biosynthetic pathways of these unique components are a rich source of potential drug targets. For example, the first-line drugs isoniazid and ethambutol act on mycolic acid and arabinan layers, respectively. Synthesis, interferes with the formation of the cell wall of Mycobacterium tuberculosis. The main component of the arabinogalactan layer and arabinomannan layer of the outer membrane of Mycobacterium tuberculosis cell wall is a kind of arabinose with DPA as an important precursor. Studies have shown that DPA is mainly composed of DPR in DprE1 and DprE2. Epimerization is obtained under the joint action, so inhibiting the activity of DprE1 can hinder the synthesis of cell wall and ultimately achieve the purpose of killing Mycobacterium tuberculosis two-step epimerization of decaprenylphosphoryl ribose. Journal of bacteriology 2005,187(23),8020-8025).
目前,DprE1抑制剂还没有药物上市,其中共价结合型化合物PBTZ169已进入II期临床的研究。近年来,本申请发明人针对具有良好研发前景的靶标DprE1,进行了深入的研究,通过活性、毒性和早期成药性评价,确定了苯并硫代吡喃酮母核结构为优势骨架,并申请了专利(专利号:201810092333.X和PCT/CN2018/080787),通过系统深入的研究,获得了具有显著抗结核及耐药结核 活性和低毒性的苯并硫代吡喃酮类化合物6b(2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮)(Identification of novel benzothiopyranone compounds against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones[J].Eur.J.Med.Chem.,2018,160,157-170)。At present, there are no drugs on the market for DprE1 inhibitors, and the covalently bound compound PBTZ169 has entered phase II clinical research. In recent years, the inventors of the present application have conducted in-depth research on DprE1, a target with good research and development prospects. Through the evaluation of activity, toxicity and early druggability, the benzothiopyrone core structure has been determined as the dominant skeleton and applied for Patent (Patent No.: 201810092333.X and PCT/CN2018/080787), through systematic and in-depth research, obtained the benzothiopyrone compound 6b(2) with significant anti-tuberculosis and drug-resistant tuberculosis activity and low toxicity -(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one)(Identification of novel benzothiopyranone compounds against against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones[J].Eur.J.Med.Chem.,2018,160,157-170).
专利201810092333.X和PCT/CN2018/080787公开了2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮及其盐酸盐的实施例,但未公开其它药学上可接受盐的具体实施例和实验结果。Patent 201810092333.X and PCT/CN2018/080787 disclose 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyridine Examples of pyran-4-one and its hydrochloride salt, but no specific examples and experimental results of other pharmaceutically acceptable salts are disclosed.
发明内容Summary of the invention
本发明要解决的技术问题是提供一种药代性质和理化性质显著改善并具有很强体内外抗结核分枝杆菌活性的2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的盐。本发明发现,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的盐具有很强的体内外抗结核分枝杆菌作用,可用于由细菌引起的感染性疾病,特别是由结核分枝杆菌引起的肺结核疾病的治疗或预防性治疗,同时在药代性质和理化性质等成药性方面相比游离碱和盐酸盐具有了明显的改善。本发明基于以上发现而得以完成。The technical problem to be solved by the present invention is to provide a 2-(4-(cyclohexylmethyl)piperazin-1-yl) which has significantly improved pharmacokinetic properties and physical and chemical properties and has strong activity against Mycobacterium tuberculosis in vivo and in vitro. Salt of 6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one. The present invention found that the salt of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one has Strong anti-Mycobacterium tuberculosis effect in vivo and in vitro. It can be used in the treatment or preventive treatment of infectious diseases caused by bacteria, especially tuberculosis diseases caused by Mycobacterium tuberculosis. At the same time, it has pharmacokinetic properties and physicochemical properties. Compared with free base and hydrochloride, it has a significant improvement in performance. The present invention has been completed based on the above findings.
为解决本发明的技术问题,本发明提供如下技术方案:In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:
本发明技术方案的第一方面提供式(I)所示2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的药学上可接受的盐,The first aspect of the technical scheme of the present invention provides 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzo represented by formula (I) A pharmaceutically acceptable salt of thiopyran-4-one,
其中,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的盐不包括盐酸盐。Wherein, the salt of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one does not include salt Acid salt.
本发明第一方面任一项的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的马来酸盐、富马酸盐、枸橼酸盐以及L-苹果酸盐。The salt of any one of the first aspect of the present invention is characterized in that it is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- The maleate, fumarate, citrate and L-malate of benzothiopyran-4-one.
本发明第一方面任一项的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1马来酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2马来酸盐,2-(4-(环己基甲基) 哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2马来酸盐;2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1富马酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2富马酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2富马酸盐;2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2枸橼酸盐或2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1L-苹果酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2L-苹果酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2L-苹果酸盐。The salt of any one of the first aspect of the present invention is characterized in that it is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- Benzothiopyran-4-one·1 maleate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- Benzothiopyran-4-one 1/2 maleate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro -Benzothiopyran-4-one·3/2 maleate; 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 -Nitro-benzothiopyran-4-one·1 fumarate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 -Nitro-benzothiopyran-4-one·1/2 fumarate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl) -8-nitro-benzothiopyran-4-one·3/2 fumarate; 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl Yl)-8-nitro-benzothiopyran-4-one·1 citrate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl) Yl)-8-nitro-benzothiopyran-4-one 1/2 citrate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(three Fluoromethyl)-8-nitro-benzothiopyran-4-one 3/2 citrate or 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6- (Trifluoromethyl)-8-nitro-benzothiopyran-4-one·1L-malate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6- (Trifluoromethyl)-8-nitro-benzothiopyran-4-one 1/2L-malate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)- 6-(Trifluoromethyl)-8-nitro-benzothiopyran-4-one·3/2L-malate.
本发明技术方案的第二方面提供了制备本发明第一方面所述的盐的方法,其包括以下步骤:The second aspect of the technical solution of the present invention provides a method for preparing the salt according to the first aspect of the present invention, which comprises the following steps:
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮与酸(例如药学上的常见酸,优选马来酸、富马酸、枸橼酸以及L-苹果酸)反应,在合适的溶剂(例如甲醇、乙醇、丙酮、乙腈,优选甲醇)中,于20-140℃下反应2-8小时,优选20-100℃条件下反应2-5小时,经过成盐反应得到式(I)所示的化合物的盐。2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one and acid (e.g. pharmaceutically Common acids, preferably maleic acid, fumaric acid, citric acid and L-malic acid) are reacted in a suitable solvent (such as methanol, ethanol, acetone, acetonitrile, preferably methanol) at 20-140°C 2 -8 hours, preferably at 20-100°C for 2-5 hours, the salt of the compound represented by formula (I) is obtained through the salt-forming reaction.
本发明技术方案的第三方面提供了一种药物组合物,其包括治疗和/或预防有效量的本发明第一方面所述的化合物的药学上可接受的盐,以及任选的一种或多种药学上可接受的载体、赋形剂、稀释剂、辅料和媒介物。The third aspect of the technical solution of the present invention provides a pharmaceutical composition, which comprises a therapeutically and/or preventively effective amount of a pharmaceutically acceptable salt of the compound according to the first aspect of the present invention, and optionally one or A variety of pharmaceutically acceptable carriers, excipients, diluents, excipients and vehicles.
本发明技术方案的第四方面提供了本发明第一方面所述化合物的药学可接受的盐,或者本发明第三方面所述药物组合物在制备治疗和/或预防由结核分枝杆菌引起的感染性疾病的药物中的应用。The fourth aspect of the technical solution of the present invention provides a pharmaceutically acceptable salt of the compound of the first aspect of the present invention, or the pharmaceutical composition of the third aspect of the present invention is used in the preparation of treatment and/or prevention caused by Mycobacterium tuberculosis Application of medicines for infectious diseases.
前面所述内容只概述了本发明的某些方面,但并不限于这方面。这些方面及其他的方面内容将在下面做更加具体完整的描述。The foregoing content only outlines certain aspects of the present invention, but is not limited to this aspect. These and other aspects will be described in more detail and complete below.
发明详述Detailed description of the invention
下面对本发明的各个方面和特点作进一步的描述。The various aspects and features of the present invention will be further described below.
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这 些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。下面是本发明所用多种术语的定义,这些定义适用于本申请整个说明书中所用的术语,除非在具体情况中另作说明。All the documents cited in the present invention, their entire contents are incorporated herein by reference, and if the meaning expressed by these documents is inconsistent with the present invention, the description of the present invention shall prevail. In addition, various terms and phrases used in the present invention have general meanings known to those skilled in the art. Even so, the present invention still hopes to provide more detailed descriptions and explanations of these terms and phrases here. The terms and phrases mentioned are such as If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail. The following are definitions of various terms used in the present invention. These definitions apply to the terms used throughout the specification of this application, unless otherwise specified in specific circumstances.
本发明中“室温”指的是温度由10℃到40℃。在一些实施例中,“室温”指的是温度由20℃到30℃;在另一些实施例中,室温指的是25℃。In the present invention, "room temperature" refers to a temperature from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 20°C to 30°C; in other embodiments, room temperature refers to 25°C.
如本文所述的,术语“有效量”是指可在受试者中实现所期望的治疗本发明所述疾病或病症的药物用量。As described herein, the term "effective amount" refers to the amount of a drug that can achieve the desired treatment of the disease or condition of the present invention in a subject.
如本文所述的,术语“药学可接受的”例如在描述“药学可接受的盐”时,表示该盐不但是受试者生理学上可接受,而且还可指在药学上有使用价值的合成物质。As described herein, the term "pharmaceutically acceptable", for example, when describing "pharmaceutically acceptable salt", means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic material that is of pharmaceutically useful value. substance.
如本文所述的,术语“药物组合物”,其还可以是指“组合物”,其可用于在受试者特别是哺乳动物中实现治疗本发明所述疾病或病症。As described herein, the term "pharmaceutical composition" can also refer to a "composition", which can be used to achieve the treatment of the disease or condition of the present invention in a subject, especially a mammal.
疾病的“治疗”包括:The "treatment" of the disease includes:
(1)预防该疾病,即,使暴露至或易感染该疾病但未经历或显示该疾病症状的哺乳动物不发生该疾病的临床症状,(1) Preventing the disease, that is, preventing the occurrence of clinical symptoms of the disease in mammals that have been exposed to or susceptible to the disease but have not experienced or displayed symptoms of the disease,
(2)抑制该疾病,即,阻止或减少该疾病或其临床症状的进展,(2) Inhibit the disease, that is, prevent or reduce the progression of the disease or its clinical symptoms,
(3)减轻该疾病,即,引起该疾病或其临床症状的复原。(3) Alleviate the disease, that is, cause the recovery of the disease or its clinical symptoms.
“治疗有效量”指为了治疗疾病向哺乳动物施用时足以实现对该疾病的治疗的化合物的量。治疗有效量将根据化合物、待治疗的疾病及其严重性以及哺乳动物的年龄、体重、性别等因素而变化。治疗有效量还可指足以实现所需的有益效果的化合物的任何量,该有益效果包括如以上(1)-(3)所述的预防疾病、抑制疾病或减轻疾病。例如化合物的量可以介于0.1-250mg/kg,或优选地,0.5-100mg/kg,或更优选地,1-50mg/kg,或甚至更优选地,2-20mg/kg。优选地,所述量的化合物每天两次向哺乳动物施用。更优选地,所述量的化合物每天一次向哺乳动物施用。A "therapeutically effective amount" refers to an amount of a compound that is sufficient to achieve treatment of the disease when administered to a mammal for the treatment of the disease. The therapeutically effective amount will vary depending on the compound, the disease to be treated and its severity, and the mammal's age, weight, sex and other factors. A therapeutically effective amount can also refer to any amount of the compound sufficient to achieve the desired beneficial effect, including the prevention, suppression or alleviation of diseases as described in (1)-(3) above. For example, the amount of compound may be between 0.1-250 mg/kg, or preferably, 0.5-100 mg/kg, or more preferably, 1-50 mg/kg, or even more preferably, 2-20 mg/kg. Preferably, the amount of the compound is administered to the mammal twice a day. More preferably, the amount of the compound is administered to the mammal once a day.
如本文所述的,术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。例如,本发明所述疾病和/或病症指结 核分枝杆菌感染性疾病。As described herein, the term "disease and/or disorder" refers to a physical state of the subject, which physical state is related to the disease and/or disorder described in the present invention. For example, the diseases and/or conditions described in the present invention refer to infectious diseases of Mycobacterium tuberculosis.
如本文所述的,术语“受试者”可以指患者或者其它接受本发明式(I)化合物的盐或其药物组合物以治疗本发明所述疾病或病症的动物,特别是哺乳动物,例如人、狗、猴、牛、马等。As described herein, the term "subject" may refer to a patient or other animal, particularly a mammal, that receives a salt of the compound of formula (I) of the present invention or a pharmaceutical composition thereof to treat the disease or condition of the present invention, for example People, dogs, monkeys, cows, horses, etc.
本发明再一方面还涉及以本发明中的化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。Another aspect of the present invention also relates to a pharmaceutical composition using the compound of the present invention as an active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. The compound of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants to prepare any dosage form suitable for human or animal use.
本发明中的化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。The compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous injection, nasal cavity, oral mucosa, eye, Lung and respiratory tract, skin, vagina, rectum, etc.
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。The dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops The solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
本发明化合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。The compound of the present invention can be made into ordinary preparations, and can also be made into sustained-release preparations, controlled-release preparations, targeted preparations and various particulate drug delivery systems.
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;润湿剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。In order to prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, Isopropanol, etc.; the binder can be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia syrup, gelatin syrup, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl Methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked Polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium lauryl sulfonate, etc.; lubricant and auxiliary The solvent may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。The tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助溶剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。In order to make the administration unit into a capsule, the active ingredient of the compound of the present invention can be mixed with a diluent and a co-solvent, and the mixture can be directly placed in a hard or soft capsule. The active ingredient of the compound of the present invention can also be prepared into granules or pellets with diluents, binders, and disintegrants, and then placed in hard or soft capsules. The various diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare the compound tablets of the present invention can also be used to prepare the compound capsules of the present invention.
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。In order to prepare the compound of the present invention into an injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used as a solvent and an appropriate amount of solubilizers, cosolvents, pH regulators, and osmotic pressure regulators commonly used in this field can be added. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc. For the preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppants.
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。In addition, if necessary, coloring agents, preservatives, fragrances, flavors or other additives can also be added to the pharmaceutical preparations.
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.
有益技术效果Beneficial technical effect
本发明的发明人经过广泛的研究,合成式(I)所示化合物的盐,并通过MABA(Microplate alamar blue assay)法以M.tuberculosis H
37Rv菌株进行最低抑菌浓度MIC(Minimum inhibitory concentration)测定,显示出较强的抗结核分枝杆菌活性,其中获得MIC<0.016μg/mL的盐5个,显著强于抗结核一线药物异烟肼。本发明的式(I)化合物的马来酸盐、富马酸盐、枸橼酸盐以及L-苹果酸盐在细胞渗透性上优于式(I)化合物的盐酸盐,预示本发明的盐具有更优的吸收性质。在小鼠药代动力学试验结果显示,式(I)化合物的马来酸盐和L-苹果酸盐的生物利用度相比化合物(I)显著提高。大鼠药代动力学实验结果显示,式(I)化合物的马来酸 盐相比式(I)化合物及其盐酸盐,体内暴露量(AUC)和生物利用度均显著提高,预示本发明的盐具有相比游离碱和盐酸盐更优的药代动力学性质。小鼠体内药效学实验显示,式(I)化合物的马来酸盐相比式(I)化合物,在相同剂量下,具有更强的体内抗结核活性。影响因素试验考察结果显示,在光照、高温及高湿条件下放置十天,式(I)化合物的马来酸盐非常稳定,尤其是光照条件下,稳定性显著优于化合物(I),预示本发明的盐在光照稳定性方面有明显改善。本发明提供了一类抗结核活性强、药代动力学性质和理化性质显著改善的苯并硫代吡喃酮类化合物的盐,可用于由细菌引起的感染性疾病,特别是由结核分枝杆菌引起的结核病的治疗或预防性治疗,同时也可用于克服与耐药性有关的问题。
After extensive research, the inventor of the present invention synthesized the salt of the compound represented by formula (I), and performed the minimum inhibitory concentration (MIC ) with M. tuberculosis H 37 Rv strain by the MABA (Microplate alamar blue assay) method. The test showed strong anti-Mycobacterium tuberculosis activity. Among them, 5 salts with MIC<0.016μg/mL were obtained, which was significantly stronger than isoniazid, the first-line anti-tuberculosis drug. The maleate, fumarate, citrate and L-malate of the compound of formula (I) of the present invention are superior to the hydrochloride of the compound of formula (I) in cell permeability, indicating that the present invention Salt has better absorption properties. The results of the pharmacokinetic test in mice showed that the bioavailability of the maleate and L-malate of the compound of formula (I) was significantly improved compared to that of the compound (I). The results of rat pharmacokinetic experiments showed that compared with the compound of formula (I) and its hydrochloride, the maleate of the compound of formula (I) has significantly increased in vivo exposure (AUC) and bioavailability, which indicates that the present invention The salt has better pharmacokinetic properties than the free base and hydrochloride. In vivo pharmacodynamic experiments in mice showed that the maleate of the compound of formula (I) has stronger anti-tuberculosis activity in vivo than the compound of formula (I) at the same dose. The test results of influencing factors show that the maleate of the compound of formula (I) is very stable when placed under light, high temperature and high humidity conditions for ten days, especially under light conditions, the stability is significantly better than that of compound (I), which indicates The salt of the invention has a significant improvement in light stability. The present invention provides a class of salts of benzothiopyrone compounds with strong anti-tuberculosis activity, significantly improved pharmacokinetic properties and physical and chemical properties, which can be used for infectious diseases caused by bacteria, especially tuberculosis branches. The treatment or preventive treatment of tuberculosis caused by bacilli can also be used to overcome the problems related to drug resistance.
通过下面的实施例可以对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进是显而易见的。The present invention can be described in detail through the following embodiments, but it is not meant to impose any disadvantageous restriction on the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements to the specific embodiments of the present invention are to be made without departing from the spirit and scope of the present invention. Obvious.
对于以下全部实施例,可使用本领域技术人员已知的标准操作和纯化方法。除非另有说明,所有温度以℃(摄氏度)表示。化合物的结构是通过核磁共振谱(NMR)来确定的。For all the following examples, standard operations and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in °C (Celsius). The structure of the compound was determined by nuclear magnetic resonance spectroscopy (NMR).
制备实施例部分Preparation example part
化合物的结构是通过核磁共振氢谱(
1H NMR)来确定的。核磁共振氢谱化学位移(δ)以百万分之一(ppm)的单位给出。耦合常数(J)以赫兹(Hz)为单位。核磁共振谱用Mercury-400型核磁共振仪测定,氘代甲醇(CD
3OD)和氘代二甲基亚砜(DMSO-d
6)作溶剂,四甲基硅烷(TMS)为内标。
The structure of the compound was determined by proton nuclear magnetic resonance spectroscopy ( 1 H NMR). The chemical shift (δ) of the proton nuclear magnetic resonance spectrum is given in units of parts per million (ppm). The coupling constant (J) is in Hertz (Hz). The NMR spectrum was measured with a Mercury-400 nuclear magnetic resonance instrument, deuterated methanol (CD 3 OD) and deuterated dimethyl sulfoxide (DMSO-d 6 ) were used as solvents, and tetramethylsilane (TMS) was used as an internal standard.
电子天平采用日本Yanaco LY-300型电子天平。The electronic balance adopts the Japanese Yanaco LY-300 electronic balance.
无水溶剂均通过标准方法处理。其它试剂均为市售分析纯。Anhydrous solvents are processed by standard methods. Other reagents are commercially available analytical grade.
本发明采用下述缩略词:The present invention uses the following acronyms:
CFU为菌落形成单位CFU is the colony forming unit
MIC为最小抑菌浓度MIC is the minimum inhibitory concentration
Papp为表观渗透系数Papp is the apparent permeability coefficient
po为口服给药po for oral administration
iv为静脉给药iv is intravenous administration
AUC为药物浓度-时间曲线下面积AUC is the area under the drug concentration-time curve
F为生物利用度F is bioavailability
t
1/2β为消除半衰期
t 1/2β is the elimination half-life
C
max为达峰浓度
C max is the peak concentration
T
max为达峰时间
T max is the peak time
对比例Comparison
对比例1Comparative example 1
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮(化合物(I))2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one (compound (I))
化合物(I)参照专利201810092333.X和PCT/CN2018/080787实施例11(化合物11)合成。Compound (I) was synthesized with reference to patent 201810092333.X and PCT/CN2018/080787 Example 11 (Compound 11).
对比例2Comparative example 2
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1盐酸盐(化合物(I)·1盐酸盐)2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one·1 hydrochloride (compound (I) 1 hydrochloride)
化合物(I)·1盐酸盐参照专利201810092333.X和PCT/CN2018/080787实施例15(化合物22)合成。Compound (I)·1 hydrochloride was synthesized with reference to patent 201810092333.X and PCT/CN2018/080787 Example 15 (Compound 22).
实施例Example
实施例1Example 1
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1马来酸盐 (化合物1)2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one·1 maleate ( Compound 1)
合成路线:synthetic route:
将化合物(I)(1.14g,2.5mmol)加入100mL三口瓶中,加入21mL无水甲醇,室温搅拌均匀,常温缓慢加入马来酸(0.348g,3.0mmol),加完2-3min后,溶液开始析出黄色固体,保持常温搅拌3小时后,抽滤,滤饼用5mL甲醇冲洗,干燥得到黄色粉末状固体1.23g,收率:86%。Add compound (I) (1.14g, 2.5mmol) into a 100mL three-necked flask, add 21mL of anhydrous methanol, stir evenly at room temperature, and slowly add maleic acid (0.348g, 3.0mmol) at room temperature. After adding 2-3min, the solution A yellow solid began to precipitate, and after stirring at room temperature for 3 hours, it was filtered with suction, the filter cake was washed with 5 mL of methanol, and dried to obtain 1.23 g of a yellow powdery solid, with a yield of 86%.
1H NMR(400MHz,CD
3OD)δ:9.02(d,J=2.2Hz,1H),8.90(d,J=2.2Hz,1H),6.40(s,1H),6.27(s,2H),3.98(brs,4H),3.32(brs,4H),2.94-2.92(m,2H),1.86-1.79(m,5H),1.76-1.72(m,1H),1.39-1.21(m,3H),1.12-1.03(m,2H).
1 H NMR (400MHz, CD 3 OD) δ: 9.02 (d, J = 2.2 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 6.40 (s, 1H), 6.27 (s, 2H), 3.98 (brs, 4H), 3.32 (brs, 4H), 2.94-2.92 (m, 2H), 1.86-1.79 (m, 5H), 1.76-1.72 (m, 1H), 1.39-1.21 (m, 3H), 1.12-1.03(m,2H).
实施例2Example 2
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2富马酸盐(化合物2)2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one·3/2 fumaric acid Salt (Compound 2)
合成路线:synthetic route:
将化合物(I)(0.228g,0.5mmol)加入25mL单口瓶中,加入6mL无水甲醇,室温搅拌均匀,加入富马酸(0.232g,2.0mmol),加完后,保持80℃回流搅拌3小时后,自然冷却至室温,冰浴10min后抽滤,滤饼用1mL甲醇冲洗,干燥得到黄色粉末状固体0.25g,收率:79%。Add compound (I) (0.228g, 0.5mmol) into a 25mL single-necked flask, add 6mL of anhydrous methanol, stir evenly at room temperature, add fumaric acid (0.232g, 2.0mmol), after the addition, keep at 80°C under reflux and stir 3 After hours, it was cooled to room temperature naturally, and the filter cake was washed with 1 mL of methanol and dried to obtain 0.25 g of yellow powdery solid. Yield: 79%.
1H NMR(400MHz,DMSO-d
6)δ:13.08(brs,2H),8.85-8.83(m,2H),6.62(s,3H),6.30(s,1H),3.66-3.64(m,4H),2.48(brs,4H),2.16-2.14(m,2H),1.76-1.65(m,5H),1.54-1.48(m,1H),1.27-1.12(m,3H),0.90-0.82(m,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ: 13.08 (brs, 2H), 8.85-8.83 (m, 2H), 6.62 (s, 3H), 6.30 (s, 1H), 3.66-3.64 (m, 4H) ), 2.48 (brs, 4H), 2.16-2.14 (m, 2H), 1.76-1.65 (m, 5H), 1.54-1.48 (m, 1H), 1.27-1.12 (m, 3H), 0.90-0.82 (m ,2H).
实施例3Example 3
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1枸橼酸盐(化合物3)2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one·1 citrate ( Compound 3)
合成路线:synthetic route:
将化合物(I)(0.2g,0.44mmol)加入25mL单口瓶中,加入5mL无水甲醇,室温搅拌均匀,加入枸橼酸(0.127g,0.66mmol),保持80℃回流搅拌3小时后,自然冷却至室温,室温搅拌5min后抽滤,滤饼用1mL甲醇冲洗,干燥得到黄色粉末状固体0.27g,收率:83%。Add compound (I) (0.2g, 0.44mmol) into a 25mL single-necked flask, add 5mL of anhydrous methanol, stir evenly at room temperature, add citric acid (0.127g, 0.66mmol), keep at 80°C under reflux and stir for 3 hours. After cooling to room temperature, stirring at room temperature for 5 minutes, and then suction filtration, the filter cake was washed with 1 mL of methanol, and dried to obtain 0.27 g of a yellow powdery solid, with a yield of 83%.
1H NMR(400MHz,DMSO-d
6)δ:8.85-8.84(m,2H),6.61(s,1H),3.69-3.66(m,4H),2.74(d,J=15.4Hz,2H),2.64(d,J=15.4Hz,2H),2.57(brs,4H),2.24-2.22(m,2H),1.77-1.62(m,5H),1.56-1.50(m,1H),1.27-1.13(m,3H),0.91-0.82(m,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ: 8.85-8.84 (m, 2H), 6.61 (s, 1H), 3.69-3.66 (m, 4H), 2.74 (d, J = 15.4Hz, 2H), 2.64(d,J=15.4Hz,2H), 2.57(brs,4H), 2.24-2.22(m, 2H), 1.77-1.62(m, 5H), 1.56-1.50(m, 1H), 1.27-1.13( m,3H),0.91-0.82(m,2H).
实施例4Example 4
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2枸橼酸盐(化合物4)2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one·3/2 citric acid Salt (Compound 4)
合成路线:synthetic route:
将化合物(I)(0.2g,0.44mmol)加入25mL单口瓶中,加入5mL无水甲醇,室温搅拌均匀,加入枸橼酸(0.42g,2.2mmol),保持80℃回流搅拌4小时后,自 然冷却至室温过夜,抽滤,滤饼用1mL甲醇冲洗,干燥得到黄色固体0.25g,收率:76%。Add compound (I) (0.2g, 0.44mmol) into a 25mL single-necked flask, add 5mL of anhydrous methanol, stir evenly at room temperature, add citric acid (0.42g, 2.2mmol), keep at 80°C under reflux and stir for 4 hours. Cooled to room temperature overnight, filtered with suction, the filter cake was washed with 1 mL of methanol, and dried to obtain 0.25 g of yellow solid, yield: 76%.
1H NMR(400MHz,DMSO-d
6)δ:8.83(brs,2H),6.29(s,1H),3.67(brs,4H),2.74(d,J=15.4Hz,3H),2.64(d,J=15.4Hz,3H),2.58(brs,4H),2.24-2.22(m,2H),1.76-1.62(m,5H),1.55-1.50(m,1H),1.24-1.12(m,3H),0.91-0.82(m,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ: 8.83 (brs, 2H), 6.29 (s, 1H), 3.67 (brs, 4H), 2.74 (d, J = 15.4 Hz, 3H), 2.64 (d, J = 15.4Hz, 3H), 2.58 (brs, 4H), 2.24-2.22 (m, 2H), 1.76-1.62 (m, 5H), 1.55-1.50 (m, 1H), 1.24-1.12 (m, 3H) ,0.91-0.82(m,2H).
实施例5Example 5
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1L-苹果酸盐(化合物5)2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one·1L-malate ( Compound 5)
合成路线:synthetic route:
将化合物(I)(0.228g,0.5mmol)加入25mL单口瓶中,加入6mL无水甲醇,室温搅拌均匀,加入L-苹果酸(0.268g,2.0mmol),加完后,保持80℃回流搅拌5小时后,自然冷却至室温,滤除不溶物,滤液冰浴下缓慢加入6mL冰水,保持冰浴搅拌30min后抽滤,干燥得到土黄色固体0.1g,收率:34%。Add compound (I) (0.228g, 0.5mmol) into a 25mL single-neck flask, add 6mL of anhydrous methanol, stir evenly at room temperature, add L-malic acid (0.268g, 2.0mmol), after the addition, keep at 80°C under reflux and stir After 5 hours, cool to room temperature naturally, filter out the insoluble matter, slowly add 6 mL ice water to the filtrate under ice bath, keep the ice bath stirring for 30 min, suction filtration, and dry to obtain 0.1 g of ochre solid, yield: 34%.
1H NMR(400MHz,CD
3OD)δ:9.00(s,1H),8.87(s,1H),6.33(s,1H),4.46-4.43(m,1H),3.81(brs,4H),2.82-2.77(m,5H),2.65-2.59(m,1H),2.40-2.38(m,2H),1.86-1.64(m,6H),1.37-1.21(m,3H),1.01-0.92(m,2H).
1 H NMR (400MHz, CD 3 OD) δ: 9.00 (s, 1H), 8.87 (s, 1H), 6.33 (s, 1H), 4.46-4.43 (m, 1H), 3.81 (brs, 4H), 2.82 -2.77(m,5H),2.65-2.59(m,1H),2.40-2.38(m,2H),1.86-1.64(m,6H),1.37-1.21(m,3H),1.01-0.92(m, 2H).
实验例Experimental example
生物活性测试Biological activity test
实验例1、体外抗结核活性测试Experimental example 1. In vitro anti-tuberculosis activity test
测定方法:Microplate Alamar Blue Assay(MABA)法测定体外抗结核活性。Determination method: Microplate Alamar Blue Assay (MABA) method to determine the anti-tuberculosis activity in vitro.
实验原理:Alamar Blue加入培养基可作为氧化还原指示剂,颜色由蓝色向红色转变,反映所研究的微生物对氧分子的消耗。Alamar Blue的颜色改变可用光度计测定,其发射波长为590nm。Experimental principle: Alamar Blue added to the culture medium can be used as a redox indicator, and the color changes from blue to red, reflecting the consumption of oxygen molecules by the studied microorganisms. The color change of Alamar Blue can be measured with a photometer, and its emission wavelength is 590nm.
实验方法:参照文献(专利201810092333.X和Antimicrob Agents Chemother,2011,55,5185-5193.)进行。Experimental method: refer to the literature (Patent 201810092333.X and Antimicrob Agents Chemother, 2011, 55, 5185-5193.).
表1、本发明部分化合物体外抗结核分枝杆菌H
37R
v活性
Table 1. In vitro activities of some compounds of the present invention against Mycobacterium tuberculosis H 37 R v
由表1数据可知,本发明中的化合物具有很强的体外抗结核分枝杆菌活性。It can be seen from the data in Table 1 that the compound of the present invention has strong in vitro anti-Mycobacterium tuberculosis activity.
实验例2、Caco-2细胞渗透性测试Experimental example 2: Caco-2 cell permeability test
实验方法:参照文献(Advanced drug delivery reviews,2001,46,27-43.)进行。Experimental method: refer to the literature (Advanced drug delivery reviews, 2001, 46, 27-43.).
Caco-2细胞是一种人克隆结肠腺癌细胞,结构和功能类似于分化的上皮细胞,具有微绒毛等结构,广泛地被用于体外模拟药物在肠道的渗透和吸收。化合物的表观渗透系数(Papp)通过下式计算:Caco-2 cells are human cloned colon adenocarcinoma cells, similar in structure and function to differentiated epithelial cells, with microvilli and other structures, and are widely used in vitro to simulate the penetration and absorption of drugs in the intestinal tract. The apparent permeability coefficient (Papp) of the compound is calculated by the following formula:
Papp=(dQ/dt)/(C
0×A)
Papp=(dQ/dt)/(C 0 ×A)
其中dQ/dt是药物分子过膜渗透速率,C
0为药物初始浓度,A为单分子层的面积。
Where dQ/dt is the permeation rate of drug molecules across the membrane, C 0 is the initial concentration of the drug, and A is the area of the monolayer.
表2、本发明部分化合物的Caco-2细胞渗透性数据Table 2. Caco-2 cell permeability data of some compounds of the present invention
由表2数据可知,本发明的化合物相比化合物(I)·1盐酸盐具有更好的渗透性,预示本发明的化合物具有更好的吸收性质。It can be seen from the data in Table 2 that the compound of the present invention has better permeability than compound (I)·1 hydrochloride, which indicates that the compound of the present invention has better absorption properties.
实验例3、小鼠体内药代动力学试验Experimental example 3: In vivo pharmacokinetic test in mice
实验方法:experimental method:
每组采用三只重量为23-25克的Balb/c小鼠(雄性)进行化合物1、2、3和5的药代动力学研究。化合物1、2、3和5分别以0.5%羧甲基纤维素配置成5mg/mL悬液,口服给予50mg/kg的剂量。化合物1、2、3和5分别以20%HP-β-CD和1N盐酸配置成1mg/mL溶液,静脉给予5mg/kg的剂量。Three Balb/c mice (male) weighing 23-25 grams were used in each group for the pharmacokinetic study of compounds 1, 2, 3 and 5. Compounds 1, 2, 3 and 5 were prepared as 5 mg/mL suspensions with 0.5% carboxymethyl cellulose, respectively, and were administered orally at a dose of 50 mg/kg. Compounds 1, 2, 3 and 5 were prepared as 1 mg/mL solutions with 20% HP-β-CD and 1N hydrochloric acid, respectively, and were given a dose of 5 mg/kg intravenously.
在口服和静脉给药后5,15,30分钟,以及1,2,4,7,24小时收集血浆样本。收集的血浆样本储存在-80℃直到用于分析。血浆样本用含有特非那丁内标的乙腈进行提取,提取剂与血浆比率为20:1。通过LC/TSQ Quantum Access质谱仪(AB Sciex5500)进行分析物定量。色谱条件:色谱柱:Kinetex C18 100A(30mm×3.0mm,2.6μm);柱温:室温,流动相:乙腈/水(80:20,v/v)(含0.1%甲酸);流速:0.8mL/min。质谱仪上的化合物检测以电喷雾正离子化模式进行。应用WinNonlin软件(6.3Pharsight Corporation,Mountain View,USA)计算药代动力学参数。Plasma samples were collected at 5, 15, 30 minutes, and 1, 2, 4, 7, and 24 hours after oral and intravenous administration. The collected plasma samples are stored at -80°C until used for analysis. Plasma samples were extracted with acetonitrile containing terfenadine internal standard, and the ratio of extractant to plasma was 20:1. The analyte was quantified by LC/TSQ Quantum Access mass spectrometer (AB Sciex5500). Chromatographic conditions: Column: Kinetex C18 100A (30mm×3.0mm, 2.6μm); column temperature: room temperature, mobile phase: acetonitrile/water (80:20, v/v) (containing 0.1% formic acid); flow rate: 0.8mL /min. The compound detection on the mass spectrometer is carried out in electrospray positive ionization mode. The WinNonlin software (6.3Pharsight Corporation, Mountain View, USA) was used to calculate the pharmacokinetic parameters.
表3、小鼠血浆药代动力学参数Table 3. Mouse plasma pharmacokinetic parameters
由表3可知本发明的化合物1、2、3和5生物利用度(F)为18.9~28.0%。对比文件(Eur.J.Med.Chem.,2018,160,157-170)中报道的化合物1、2、3和5的游离碱6b(化合物(I))生物利用度为13.1%。相比游离碱,化合物1、2、3和5的生物利用度提高,其中化合物1和5提高了1倍左右,预示本发明的化合物具有更优的药代动力学性质。It can be seen from Table 3 that the bioavailability (F) of the compounds 1, 2, 3 and 5 of the present invention is 18.9-28.0%. The bioavailability of the free base 6b (compound (I)) of compounds 1, 2, 3 and 5 reported in the comparative document (Eur. J. Med. Chem., 2018, 160, 157-170) is 13.1%. Compared with the free base, the bioavailability of compounds 1, 2, 3 and 5 is improved, among which compounds 1 and 5 are increased by about 1 times, indicating that the compound of the present invention has better pharmacokinetic properties.
实验例4、大鼠体内药代动力学试验Experimental Example 4. In vivo pharmacokinetic test in rats
实验方法:experimental method:
每组采用三只重量为223-245克的SD大鼠(雄性)进行化合物1,化合物(I)及其盐酸盐的药代动力学研究。化合物1,化合物(I)及其盐酸盐分别以0.5%羧甲基纤维素配置成5mg/mL悬液,口服给予50mg/kg的剂量。化合物1,化合物 (I)及其盐酸盐分别以20%HP-β-CD(羟丙基-β-环糊精)和1N盐酸配置成1mg/mL溶液,静脉给予5mg/kg的剂量。Three SD rats (male) weighing 223-245 grams were used in each group to study the pharmacokinetics of compound 1, compound (I) and its hydrochloride. Compound 1, Compound (I) and its hydrochloride were prepared into a 5 mg/mL suspension with 0.5% carboxymethyl cellulose, respectively, and were administered orally at a dose of 50 mg/kg. Compound 1, Compound (I) and its hydrochloride were prepared into a 1 mg/mL solution with 20% HP-β-CD (hydroxypropyl-β-cyclodextrin) and 1N hydrochloric acid, respectively, and administered at a dose of 5 mg/kg intravenously.
在口服和静脉给药后5,15,30分钟,以及1,2,4,7,12,24小时收集血浆样本。收集的血浆样本储存在-80℃直到用于分析。应用WinNonlin软件(6.3Pharsight Corporation,Mountain View,USA)计算药代动力学参数。Plasma samples were collected 5, 15, 30 minutes after oral and intravenous administration, and 1, 2, 4, 7, 12, and 24 hours. The collected plasma samples are stored at -80°C until used for analysis. The WinNonlin software (6.3Pharsight Corporation, Mountain View, USA) was used to calculate the pharmacokinetic parameters.
表4、大鼠血浆药代动力学参数Table 4. Rat plasma pharmacokinetic parameters
由表4可知本发明的化合物1,在相同剂量下,较化合物(I)及其盐酸盐,口服C
max,AUC及生物利用度(F)均明显提高,预示化合物1具有更优的药代动力学性质。
It can be seen from Table 4 that the compound 1 of the present invention, at the same dose, compared with compound (I) and its hydrochloride, oral C max , AUC and bioavailability (F) are significantly improved, indicating that compound 1 has a better drug Generation dynamics properties.
实验例5、小鼠体内抗结核活性试验Experimental Example 5. Anti-tuberculosis activity test in mice
实验方法:experimental method:
Balb/c小鼠以气溶胶方式感染结核分枝杆菌H37Rv,于感染10天后给予药物治疗(25,50,100mg/kg),每天给药一次,每周给药5次,给药三周后,解剖,以肺部的CFU值为主要评价指标,设立空白对照组给予0.5%CMC,以临床一线用药异烟肼作为阳性对照药,考察化合物(I)和化合物1的体内抗结核活性。Balb/c mice were infected with Mycobacterium tuberculosis H37Rv by aerosol, and were given drug treatment (25, 50, 100 mg/kg) 10 days after infection, once a day, 5 times a week, three weeks after the administration, Anatomy, with the lung CFU as the main evaluation index, a blank control group was set up to give 0.5% CMC, and the first-line clinical drug isoniazid was used as the positive control drug to investigate the anti-tuberculosis activity of compound (I) and compound 1 in vivo.
实验步骤根据文献(Antimicrobial agents and chemotherapy 2011,55(11),5185-5193)进行。The experimental steps were carried out according to the literature (Antimicrobial agents and chemotherapy 2011, 55(11), 5185-5193).
表5、化合物(I)的体内抗结核活性Table 5. Anti-tuberculosis activity of compound (I) in vivo
*CMC组为空白对照组,给予0.5%CMC。*The CMC group is a blank control group, given 0.5% CMC.
试验结果显示,化合物(I)在25,50和100mg/kg剂量下均具有很强的抗结核活性,小鼠肺组织活菌数较空白对照组分别下降了2.28、3.58和3.73log
10CFU。
The test results show that compound (I) has strong anti-tuberculosis activity at doses of 25, 50 and 100 mg/kg, and the number of viable lung tissues in mice decreased by 2.28, 3.58 and 3.73 log 10 CFU respectively compared with the blank control group.
表6、化合物1的体内抗结核活性Table 6. Anti-tuberculosis activity of compound 1 in vivo
*CMC组为空白对照组,给予0.5%CMC。*The CMC group is a blank control group, given 0.5% CMC.
试验结果显示,化合物1在25,50和100mg/kg剂量下均具有很强的抗结核活性,且呈现出明显的量效关系,小鼠肺组织活菌数较空白对照组分别下降了3.01、3.99和4.68log
10CFU。
The test results show that compound 1 has strong anti-tuberculosis activity at doses of 25, 50 and 100 mg/kg, and shows a significant dose-effect relationship. The number of viable lung tissues in mice decreased by 3.01, respectively, compared with the blank control group. 3.99 and 4.68 log 10 CFU.
由表5和表6可知,本发明的化合物1在25,50和100mg/kg剂量下,较化合物(I),均可以下降更多的Log
10CFU数值,尤其是在100mg/kg剂量下,化合物1较空白对照组可以降低4.68Log
10CFU,显著优于化合物(I)(降低3.73Log
10CFU),预示化合物1具有更强的体内抗结核活性。
It can be seen from Table 5 and Table 6 that compound 1 of the present invention can reduce Log 10 CFU values more than compound (I) at doses of 25, 50 and 100 mg/kg, especially at doses of 100 mg/kg. Compared with the blank control group, compound 1 can reduce 4.68 Log 10 CFU, which is significantly better than compound (I) (reducing 3.73 Log 10 CFU), indicating that compound 1 has stronger anti-tuberculosis activity in vivo.
实验例6、稳定性考察Experimental example 6, stability investigation
采用HPLC考察化合物1和化合物(I)及其盐酸盐在光照、高温、高湿条件下放置10天的稳定性,结果如表7所示。The stability of compound 1 and compound (I) and its hydrochloride salt under light, high temperature and high humidity conditions were investigated by HPLC. The results are shown in Table 7.
表7、稳定性考察结果Table 7. Results of stability investigation
采用Waters e2695-PDA HPLC系统检测化合物纯度。色谱条件:色谱柱:Kromasil C18(250mm×4.6mm,5μm);柱温:30℃,流动相:乙腈/水(84:16, v/v)等梯度;流速:1.0mL/min。由表7可知本发明的化合物1在光照、高温及高湿条件下非常稳定。专利(201810092333.X)中报道的化合物11(式(I)所示化合物)为本专利化合物1的游离碱,在光照条件下,外观发生变化并且纯度降低,因此,本发明的化合物1具有更优的理化性质。Waters e2695-PDA HPLC system was used to detect the purity of the compound. Chromatographic conditions: Chromatographic column: Kromasil C18 (250mm×4.6mm, 5μm); column temperature: 30°C, mobile phase: acetonitrile/water (84:16, v/v) isogradient; flow rate: 1.0 mL/min. It can be seen from Table 7 that the compound 1 of the present invention is very stable under light, high temperature and high humidity conditions. The compound 11 (compound represented by formula (I)) reported in the patent (201810092333.X) is the free base of compound 1 of the patent. Under light conditions, the appearance changes and the purity decreases. Therefore, compound 1 of the present invention has more Excellent physical and chemical properties.
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can comment on the above-mentioned embodiments within the scope of the present invention. The embodiment undergoes changes, modifications, substitutions, and modifications.
Claims (6)
- 式(I)所示的2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的药学上可接受的盐:2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one represented by formula (I) The pharmaceutically acceptable salt of:其中,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的药学上可接受的盐不包括盐酸盐。Among them, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one is pharmaceutically acceptable The salt does not include the hydrochloride.
- 根据权利要求1所述的药学上可接受的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的马来酸盐、2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的富马酸盐、2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的枸橼酸盐、2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的L-苹果酸盐。The pharmaceutically acceptable salt according to claim 1, which is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8- Nitro-benzothiopyran-4-one maleate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro Benzyl-benzothiopyran-4-one fumarate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro -Citrate of benzothiopyran-4-one, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- The L-malate of benzothiopyran-4-one.
- 根据权利要求2的药学上可接受的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1马来酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2马来酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2马来酸盐;2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1富马酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2富马酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2富马酸盐;2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1L-苹果酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2L-苹果酸盐,或2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2L-苹果酸盐。The pharmaceutically acceptable salt according to claim 2, which is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro -Benzothiopyran-4-one·1 maleate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro -Benzothiopyran-4-one·1/2 maleate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8- Nitro-benzothiopyran-4-one·3/2 maleate; 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)- 8-nitro-benzothiopyran-4-one·1 fumarate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)- 8-Nitro-benzothiopyran-4-one·1/2 fumarate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl) )-8-nitro-benzothiopyran-4-one·3/2 fumarate; 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoro Methyl)-8-nitro-benzothiopyran-4-one·1 citrate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoro Methyl)-8-nitro-benzothiopyran-4-one·1/2 citrate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-( Trifluoromethyl)-8-nitro-benzothiopyran-4-one·3/2 citrate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6 -(Trifluoromethyl)-8-nitro-benzothiopyran-4-one·1L-malate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6 -(Trifluoromethyl)-8-nitro-benzothiopyran-4-one·1/2L-malate, or 2-(4-(cyclohexylmethyl)piperazin-1-yl )-6-(Trifluoromethyl)-8-nitro-benzothiopyran-4-one·3/2L-malate.
- 制备权利要求1至3任一项所述的药学上可接受的盐的方法,其包括以下步骤:2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮与药学上的常见酸反应,在醇类或丙酮、乙腈中,于常温或回流条件下反应2-8小时,经过成盐反应得到式(I)所示的化合物的盐。The method for preparing the pharmaceutically acceptable salt according to any one of claims 1 to 3, which comprises the following steps: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoro (Methyl)-8-nitro-benzothiopyran-4-one reacts with common pharmacological acids, in alcohols, acetone, acetonitrile, under normal temperature or reflux conditions for 2-8 hours. The salt reaction yields the salt of the compound represented by formula (I).
- 一种药物组合物,其特征在于,所述的药物组合物包括治疗和/或预防有效量的权利要求1至3任一项所述的药学上可接受的盐,以及任选的一种或多种药学上可接受的载体、赋形剂、稀释剂、辅料和媒介物。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises a therapeutically and/or preventively effective amount of the pharmaceutically acceptable salt according to any one of claims 1 to 3, and optionally one or A variety of pharmaceutically acceptable carriers, excipients, diluents, excipients and vehicles.
- 权利要求1-3任一项所述的药学上可接受的盐或者权利要求5所述药物组合物在制备治疗和/或预防由结核分枝杆菌引起的感染性疾病的药物中的应用。Use of the pharmaceutically acceptable salt according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 5 in the preparation of a medicine for the treatment and/or prevention of infectious diseases caused by Mycobacterium tuberculosis.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS49101379A (en) * | 1973-02-05 | 1974-09-25 | ||
CN104211708A (en) * | 2013-05-29 | 2014-12-17 | 中国医学科学院药物研究所 | Benzoxazinone derivatives and application thereof as antibacterial agent |
CN108929329A (en) * | 2017-05-24 | 2018-12-04 | 中国医学科学院药物研究所 | 2- azacyclo- -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds |
CN108947952A (en) * | 2017-05-24 | 2018-12-07 | 中国医学科学院药物研究所 | 2- substituted-amino -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds and its preparation method and application |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS49101379A (en) * | 1973-02-05 | 1974-09-25 | ||
CN104211708A (en) * | 2013-05-29 | 2014-12-17 | 中国医学科学院药物研究所 | Benzoxazinone derivatives and application thereof as antibacterial agent |
CN108929329A (en) * | 2017-05-24 | 2018-12-04 | 中国医学科学院药物研究所 | 2- azacyclo- -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds |
CN108947952A (en) * | 2017-05-24 | 2018-12-07 | 中国医学科学院药物研究所 | 2- substituted-amino -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds and its preparation method and application |
Non-Patent Citations (1)
Title |
---|
LI PENG; WANG BIN; ZHANG XINWEI; BATT SARAH M.; BESRA GURDYAL S.; ZHANG TINGTING; MA CHEN; ZHANG DONGFENG; LIN ZIYUN; LI GANG; HUA: "Identification of novel benzothiopyranone compounds againstMycobacterium tuberculosisthrough scaffold morphing from benzothiazinones", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 160, 17 September 2018 (2018-09-17), AMSTERDAM, NL, pages 157 - 170, XP085521522, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2018.09.042 * |
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