WO2018219189A1 - Application de cefmétazole dans la préparation d'un médicament pour la prévention/le traitement de l'hypertension pulmonaire - Google Patents

Application de cefmétazole dans la préparation d'un médicament pour la prévention/le traitement de l'hypertension pulmonaire Download PDF

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WO2018219189A1
WO2018219189A1 PCT/CN2018/087994 CN2018087994W WO2018219189A1 WO 2018219189 A1 WO2018219189 A1 WO 2018219189A1 CN 2018087994 W CN2018087994 W CN 2018087994W WO 2018219189 A1 WO2018219189 A1 WO 2018219189A1
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cefmetazole
group
pulmonary
preparation
preventing
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PCT/CN2018/087994
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English (en)
Chinese (zh)
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刘复银
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上海颢峰医药科技有限公司
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Priority claimed from CN201810455906.0A external-priority patent/CN108938643A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to a medicament, in particular to a new use of the antibiotic cefmetazole, in particular to a new application of cefmetazole in the preparation of a medicament for preventing/treating pulmonary hypertension.
  • Pulmonary Arterial Hypertension is characterized by progressive elevation of pulmonary vascular resistance and pulmonary artery pressure, which leads to excessive right ventricular overload and right ventricular hypertrophy, which can eventually lead to death of right heart failure.
  • the hemodynamic diagnosis criteria for PAH were: at the sea level and at rest, the right heart catheter was used to detect the mean pulmonary artery pressure (mPAP) ⁇ 25 mmHg. The incidence of PAH is high. According to American epidemiological data, the prevalence of various types of pulmonary hypertension has exceeded 30-50 people/1 million people.
  • PAH is a kind of disease with high mortality and poor prognosis, which has attracted extensive attention in the field of global medical research.
  • pulmonary hypertension involves multiple pathways such as cell abnormalities, molecular mediators and genetic factors.
  • a variety of cellular abnormalities such as endothelial cells, smooth muscle cells, fibroblasts and platelets are involved in the formation of abnormalities, and the imbalance of various vasoactive substances promotes their occurrence.
  • Genetic factors also play an important role in its pathogenesis.
  • the pathological changes of PAH are pulmonary occlusion and the number of effective circulating vascular beds. Pulmonary vascular endothelial cell injury leads to enhanced vasoconstriction and pulmonary artery smooth muscle cell hyperplasia, hypertrophy, peripheral small vessel muscle formation, and extracellular matrix. Lead to pulmonary vascular remodeling.
  • PAH clinical classification was updated at the Fifth World Pulmonary Hypertension Forum held in Nice, France in 2013, and PAH was divided into five categories: (1) arterial pulmonary hypertension, including idiopathic pulmonary hypertension, hereditary pulmonary hypertension, and drugs. And toxin-associated pulmonary hypertension, disease-related pulmonary hypertension (connective tissue disease, HIV infection, portal hypertension, congenital heart disease, and schistosomiasis) and neonatal persistent pulmonary hypertension; (2) left heart disease-associated lung High pressure, including systolic dysfunction, diastolic dysfunction, valvular disease and congenital, acquired left ventricular inflow/outflow obstruction; (3) pulmonary disease and/or hypoxic-associated pulmonary hypertension, including chronic obstructive pulmonary disease, Interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation syndrome, long-term residence in the high altitude environment and pulmonary dysplasia; (4) chronic thromboembolic pulmonary hypertension; (5) pulmonary hyper
  • PAH is a progressive disease
  • the current treatment is mainly for vasoconstriction, vascular remodeling, thrombosis and cardiac insufficiency, aiming to reduce pulmonary vascular resistance and pressure, improve heart function, increase cardiac output, and improve life. Quality, improve symptoms and prognosis.
  • PAH treatment was the era of traditional treatment. The main drugs were digoxin, diuretics, and oxygen to treat heart failure. In 1992, the first drug that selectively targeted pulmonary vasculature, epoprostenol, entered the clinic and changed the history of PAH treatment.
  • Targeted therapeutic drugs for PAH are mainly divided into three categories: 1) cyclic prostaglandin receptor (IP receptor) agonists, including epoprostenol, treprostinil, bepexcycline, iloprost, race Lexipa; 2) endothelin receptor antagonists, including bosentan, sitaxsentan, ambrisentan; 3) phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, He is Dalafil and Vardenafil.
  • IP receptor cyclic prostaglandin receptor
  • PDE-5 phosphodiesterase-5
  • Cephalosporins are ⁇ -lactam antibiotics. Compared with penicillins, cephalosporin antibiotics have the advantages of broad antibacterial spectrum, strong bactericidal power, high tissue fluid concentration, stable ⁇ -lactamase and less allergic reactions. Therefore, it is widely used in clinical practice.
  • the main route of administration of cephalosporin antibiotics is oral or injection.
  • cephalosporin antibiotics in clinical It is mainly used for upper and lower respiratory tract infections, skin and soft tissue infections, urinary tract infections, sepsis, endocarditis caused by methicillin-sensitive staphylococcus, hemolytic streptococcus and Streptococcus pneumoniae. It can also be used for influenza bloodsucking. Urinary tract infections caused by bacilli, Proteus mirabilis, Escherichia coli sensitive strains, and pneumonia.
  • the second-generation cephalosporin antibiotics are mainly applied to gram-positive cocci, such as methicillin-sensitive Staphylococcus, Streptococcus, Streptococcus pneumoniae, and sensitive strains such as Haemophilus influenzae, Escherichia coli, and Proteus mirabilis. Respiratory infections, urinary tract infections, skin and soft tissue infections, sepsis, bone and joint infections, and abdominal and pelvic infections caused by strains.
  • the third-generation cephalosporin antibiotics are mainly applied to serious infections caused by Gram-negative bacilli such as susceptible Enterobacteriaceae.
  • Cefmetazole belongs to the second-generation cephalosporin antibiotics and is a semi-synthetic cephalosporin derivative. Clinically, it is mainly suitable for the treatment of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus, Morganella, Buffalo, Bacteroides, and Streptococcus mutans which are sensitive to cefmetazole sodium.
  • Infections caused by Provoviruses including acute bronchitis, pneumonia, secondary respiratory disease secondary infection, lung abscess, empyema, cholangitis, cholecystitis, peritonitis, pyelonephritis, bladder Inflammation, vestibular gland inflammation, intrauterine infection, uterine annexitis, para-uterine tissue inflammation, cellulitis around the jaw, jawitis, sepsis, etc.
  • Cefmetazole is used clinically by intravenous or intravenous drip.
  • cefmetazole has been widely used in bacterial infection of the lungs, but no report on the use of cefmetazole for PAH has been found so far.
  • the inventors confirmed by pharmacological experiments that cefmetazole has a significant therapeutic effect on pulmonary hypertension, and it is advisable to further research and develop its new clinical use.
  • the technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies and to study the new use of cefmetazole in the preparation of a medicament for treating/preventing PAH.
  • the invention provides the application of cefmetazole in the preparation of a medicament for preventing/treating pulmonary hypertension.
  • the application of the prevention/treatment of pulmonary hypertension in the present invention is to reduce pulmonary artery pressure, reduce right ventricular hypertrophy, relieve pulmonary vascular remodeling, reduce pulmonary vascular thickness, and inhibit pulmonary vascular smooth muscle cell proliferation.
  • the cefmetazole of the present invention includes a pharmaceutically acceptable salt form such as cefmetazole sodium salt.
  • Pulmonary hypertension according to the present invention includes various clinically occurring types, such as arterial pulmonary hypertension (including idiopathic, hereditary, drug and ortotoxin-related, disease-related, and neonatal persistent pulmonary hypertension).
  • Left heart disease-associated pulmonary hypertension including systolic dysfunction, diastolic dysfunction, valvular disease and congenital, acquired left ventricular inflow/outflow obstruction), pulmonary disease, and/or hypoxic-associated pulmonary hypertension (including chronic Obstructive pulmonary disease, interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation syndrome, long-term resident high altitude environment and abnormal lung development, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension (including hematology) caused by unexplained or multiple mechanisms Any one or more of diseases, systemic diseases, metabolic diseases, and others.
  • hypoxic-associated pulmonary hypertension including chronic Obstructive pulmonary disease, interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation syndrome, long-term resident high altitude environment and abnormal lung development, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension (including hematology) caused by unexplained or multiple mechanisms Any one or
  • the present inventors have confirmed the prevention and treatment of PAH induced by monocrotaline in rats by cefmetazole (intravenous injection).
  • Pharmacological experiments confirmed that the results of the experiment on the RVSP of PAH rats after intravenous administration of cefmetazole showed that it was compared with the control group.
  • the model group was significantly different (P ⁇ 0.001), indicating successful modeling; compared with the model group, cefmetazole low dose group (P ⁇ 0.001), middle dose group (P ⁇ 0.001), high dose group ( Both P ⁇ 0.001 and Selexipag (P ⁇ 0.001) significantly reduced RVSP.
  • the high dose of cefmetazole had a better effect on reducing RVSP in PAH rats.
  • cefmetazole inhalation administration group can significantly reduce MRVP in PAH rats (P ⁇ 0.05).
  • the 0.01 mg/kg cefometazole aerosol inhalation administration group was superior to the 10 mg/kg cefmetazole intravenous administration group and was equivalent to the positive control drug Selexipag (Fig. 2).
  • the cefmetazole tail vein injection group and the inhalation administration group can effectively reduce the pulmonary vascular thickness and have a certain protective effect on the pulmonary blood vessels; the effect of reducing the pulmonary vascular thickness in the 1 mg/kg inhalation group is comparable to that of the positive drug Selexipag ( 0.32 ⁇ 0.05 vs 0.31 ⁇ 0.06).
  • cefmetazole can be used for the preparation of a medicament for preventing/treating pulmonary hypertension.
  • the medicament according to the present invention is a pharmaceutical composition prepared by using cefmetazole or a salt thereof, crystal water or hydrate as a pharmaceutically active ingredient and a conventional pharmaceutical auxiliary.
  • the cefmetazole pharmaceutical composition of the present invention is an injectable preparation or an inhaled preparation for pulmonary administration, such as an atomized solution, a dry powder inhaler or an aerosol.
  • the therapeutic effect of the pulmonary inhalation on PAH is obviously superior to the intravenous administration route, and the dosage is obviously reduced, the effect is fast, and the safety is good. .
  • the technical solution of the present invention further includes cefmetazole and other drugs for preventing and treating pulmonary hypertension such as iloprost, celecoxib, bosentan, sitaxantan, sildenafil, tadalafil, and leoxi. It is used in the composition of pharmaceutical compositions for the treatment of pulmonary hypertension and its associated cardiovascular related diseases.
  • the invention provides the application of cefmetazole in the preparation of a medicament for preventing/treating pulmonary hypertension, and the pharmacological experiment proves that the curative effect is good, which is significantly better than the control group.
  • Cefmetazole can reduce pulmonary artery pressure at lower doses by pulmonary administration, and the effect is significantly better than intravenous administration.
  • the invention provides a new medicine for preventing/treating pulmonary hypertension and has a good clinical application prospect.
  • the ordinate is the right ventricular systolic pressure RVSP (mmHg); the abscissa is the control group, the monocrotoline (MCT)-induced pulmonary hypertension rat model group, the Selexipag positive drug group (twice a day), Tyvaso administration group, 10 mg/kg cefmetazole intravenous administration group, 0.001 mg/kg cefmetazole inhalation group, 0.01 mg/kg cefmetazole inhalation group, 0.1 mg/kg Cefmetazole inhalation group, 1 mg/kg ceftimaze inhalation group, 10 mg/kg ceftimezazole inhalation group and 100 mg/kg ceftimalid inhalation group.
  • the ordinate is the right ventricular mean pressure MRVP (mmHg); the abscissa is the control group, the MCT model group, the positive drug Selexipag (twice a day), the Tyvaso administration group, and the 10 mg/kg cefmetazole intravenously.
  • the drug group 0.001 mg/kg ceftimezazole inhalation group, 0.01 mg/kg ceftimezazole inhalation group, 0.1 mg/kg ceftimezazole inhalation group, 1 mg/kg ceftimezazole inhalation group, 10 mg/kg ceftimezazole inhalation group and 100 mg/kg cefometazole inhalation group.
  • the ordinate is the right ventricular hypertrophy index RVHI (%); the abscissa is the control group, the MCT model group, the positive drug Selexipag (twice a day), the Tyvaso administration group, 10 mg/kg cefmetazole intravenously
  • the drug group 0.001 mg/kg ceftimezazole inhalation group, 0.01 mg/kg ceftimezazole inhalation group, 0.1 mg/kg ceftimezazole inhalation group, 1 mg/kg ceftimezazole inhalation group, 10 mg/kg ceftimezazole inhalation group and 100 mg/kg cefometazole inhalation group.
  • Figure 1 Normal HE staining of pulmonary arterioles in control rats, normal blood vessel thickness; 2: Normal HE staining of pulmonary arterioles in MCT model group, blood vessel thickness was significantly thickened or even blocked; 3:1 mg/ In the kg Selexipag (twice a day) administration group, the pulmonary arterioles were examined by conventional HE staining, and the blood vessel thickness was significantly lower than that of the model group; 4:1 mg/kg ceftimalid inhalation (once a day) administration group The conventional HE staining of the pulmonary arterioles was significantly lower than that of the model group; the effect of improving pulmonary vascular remodeling was significant.
  • the sodium salt of cefmetazole was purchased from Hubei Jusheng Technology Co., Ltd.; Specification: Pharmaceutical grade; Content: 98%
  • Wild lily base was purchased from Shanghai Huito Biotechnology Co., Ltd.
  • Example 1 Cefmetazole (intravenous injection) on the prevention and treatment of PAH induced by monocrotaline in rats
  • mice Rats were randomly divided into normal control group, monocrotaline (MCT) model group, 1 mg/kg Selexipag oral administration group, 10 mg/kg cefmetazole intravenous administration group, 100 mg/kg cefmetazole intravenous group. In the drug-administered group, 350 mg/kg cefmetazole intravenous administration group, 6 in each group. Except for the normal control group, all rats were injected subcutaneously with monocrotaline once at a concentration of 60 mg/kg to establish an animal model of pulmonary hypertension. During the modeling process, all rats were orally administered saline or drugs by gavage or intravenously for 21 days.
  • the preparation method of the right heart catheter is as follows: take a steel wire with a length of 12cm and a diameter of 0.5mm, and take a polyethylene plastic hose with the same length as the steel wire. The inner diameter is 0.58mm and the outer diameter is 0.96mm. Into the hose, bend one end into a small bend, put it in water at 60-70 °C for 5-10min, remove it and then cool it, and take out the steel wire in the polyethylene plastic hose to complete the preparation of the right heart catheter.
  • RVHI right ventricular hypertrophy index
  • Example 2 Inhibitory effect of cefmetazole on rat PAH induced by monocrotaline
  • Inhalation drug delivery system Inhalation drug delivery system of Shanghai Ruiman Information Technology Co., Ltd.
  • Rats were randomly divided into normal control group, monocrotaline (MCT) model group, 1 mg/kg Selexipag oral administration group, 1.62 ⁇ g/kg treprostinil (Tyvaso) inhalation group, 10 mg/ Kg cefmetazole intravenous administration group, 0.001 mg/kg ceftimezazole inhalation group, 0.01 mg/kg ceftimezazole inhalation group, 0.1 mg/kg ceftimezazole inhalation group, 1 mg/kg cefotaxime The azole inhalation administration group, the 10 mg/kg ceftimaze inhalation administration group, and the 100 mg/kg ceftimezazole inhalation administration group, 6 in each group.
  • the cefmetazole sodium and Tyvaso are administered by nebulization.
  • the compound is first dissolved in physiological saline, and then the solution is made into an aerosol by a nebulizer to inhale the nose and mouth of the rat.
  • all rats were injected subcutaneously with monocrotaline once at a concentration of 60 mg/kg to establish an animal model of pulmonary hypertension.
  • all rats were given saline or drugs by gavage, vein and inhalation daily by weight and group for 21 days.
  • the weight of the MCT model group was significantly reduced, the hair was dull and dull, and there was obvious right heart hypertrophy.
  • the above conditions of the rats in the drug-administered group and the positive drug group were significantly improved.
  • the RVSP, MRVP and RVHI changes of the rats in each group of the experiment are shown in Table 2.
  • cefmetazole inhalation administration group can significantly reduce MRVP in PAH rats (P ⁇ 0.05).
  • the 0.01 mg/kg cefometazole aerosol inhalation administration group was superior to the 10 mg/kg cefmetazole intravenous administration group and was equivalent to the positive control drug Selexipag (Fig. 2).
  • Example 3 Effect of cefmetazole on pulmonary vascular thickness in PAH rats induced by monocrotaline
  • Thickness thickness between inner and outer elastic plates, MT
  • outer diameter diameter between outer elastic films, ED
  • lumen area A
  • wall area MA
  • total area of blood vessels TAA
  • the MCT model group had a significantly increased vascular thickness compared with the control group (the median thickness was 0.27 ⁇ 0.05 and 0.48 ⁇ 0.13, respectively), and the positive drugs Selexipag and Tyvaso significantly reduced the vascular thickness change (the median thickness percentage was 0.31 ⁇ 0.06 and 0.31 ⁇ 0.10).
  • the cefmetazole tail vein injection group and the inhalation administration group can effectively reduce pulmonary vascular thickness, improve pulmonary vascular remodeling, and have certain protective effects on pulmonary blood vessels; 1 mg/kg inhalation administration group can reduce pulmonary vascular thickness and improve The effect of pulmonary vascular remodeling was comparable to that of the positive drug Selexipag (0.32 ⁇ 0.05 vs 0.31 ⁇ 0.06).
  • a pathological section of the pulmonary blood vessels is shown in Figure 4.
  • Example 4 Prophylactic/therapeutic effect of cefmetazole on oral administration of monocrotaline-induced PAH in rats
  • Rats were randomly divided into normal control group, monocrotaline (MCT) model group, 1 mg/kg Selexipag intragastric administration group (twice a day), 350 mg/kg cefmetazole administered by intragastric administration group. , 6 in each group.
  • MCT monocrotaline
  • All rats were injected subcutaneously with monocrotaline once at a concentration of 60 mg/kg to establish an animal model of pulmonary hypertension.
  • all rats were given saline or drugs by grouping by weight and daily for 21 days.

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Abstract

La présente invention concerne une application de cefmétazole dans la préparation d'un médicament pour la prévention/le traitement de l'hypertension pulmonaire. Grâce à des expériences pharmacologiques sur l'effet préventif et thérapeutique du cefmétazole sur HTAP chez des rats induits par la monocrotaline, les inventeurs confirment que l'effet curatif du cefmétazole est bon et significativement meilleur que celui des médicaments existants sur un groupe témoin. Le cefmétazole peut réduire la pression artérielle pulmonaire à des doses inférieures par administration pulmonaire, avec un effet curatif significativement meilleur que celui de l'administration intraveineuse. La présente invention concerne un nouveau médicament pour la prévention/le traitement de l'hypertension pulmonaire et a une bonne perspective d'application clinique.
PCT/CN2018/087994 2017-05-27 2018-05-23 Application de cefmétazole dans la préparation d'un médicament pour la prévention/le traitement de l'hypertension pulmonaire WO2018219189A1 (fr)

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CN201710389715 2017-05-27
CN201710389715.4 2017-05-27
CN201810455906.0 2018-05-14
CN201810455906.0A CN108938643A (zh) 2017-05-27 2018-05-14 头孢美唑在制备预防/治疗肺动脉高压药物中的应用

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Cited By (1)

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CN111393455A (zh) * 2020-04-28 2020-07-10 福建省福抗药业股份有限公司 头孢美唑杂质的制备方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111393455A (zh) * 2020-04-28 2020-07-10 福建省福抗药业股份有限公司 头孢美唑杂质的制备方法

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