WO2003063863A1 - Composition pharmaceutique antibacterienne - Google Patents

Composition pharmaceutique antibacterienne Download PDF

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Publication number
WO2003063863A1
WO2003063863A1 PCT/CN2003/000102 CN0300102W WO03063863A1 WO 2003063863 A1 WO2003063863 A1 WO 2003063863A1 CN 0300102 W CN0300102 W CN 0300102W WO 03063863 A1 WO03063863 A1 WO 03063863A1
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WO
WIPO (PCT)
Prior art keywords
tazobactam
formula
pharmaceutically acceptable
furicillin
combination drug
Prior art date
Application number
PCT/CN2003/000102
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English (en)
Chinese (zh)
Inventor
Li Liu
Original Assignee
Li Liu
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN 02115482 external-priority patent/CN1247197C/zh
Priority claimed from CN 02115654 external-priority patent/CN1448135A/zh
Application filed by Li Liu filed Critical Li Liu
Publication of WO2003063863A1 publication Critical patent/WO2003063863A1/fr

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • 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

Definitions

  • the present invention relates to a synergistic antibacterial combination drug. More specifically, the present invention relates to a combination drug comprising furicillin, a furicillin derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolyzable ester in vivo, and ⁇ -lactam
  • the enzyme inhibitor tazobactam, tazobactam derivative, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester that is easily hydrolyzed in the body as an active ingredient has a broader antibacterial spectrum and stronger antibacterial effect.
  • Streptococcus pneumoniae is an important pathogen that causes bacterial meningitis, otitis media, sepsis, and pneumonia. It is the main pathogen of out-of-hospital infections in children. It is also the first pathogen in the community of adults, especially the elderly (Musher DM. Clin Infect Dis, 1992; 14: 801-809. Nohynek H, et al. Am J Dis Chid, 1991; 145: 618-622. Marrie TJ. Clin Infect Dis, 1994; 18: 501-505).
  • Streptococcus pneumoniae has developed resistance to penicillin and other ⁇ -lactam antibiotics, penicillin-resistant Streptococcus pneumoniae has been widely spread throughout the world since the 1990s, and the therapeutic effect of drugs has declined, endangering patients' lives.
  • Pseudomonas aeruginosa also known as Pseudomonas aeruginosa
  • Pseudomonas aeruginosa is a common pathogen of the most serious hospital-acquired infections. It is highly prone to acquire acquired drug resistance, and it is not easy to be killed by the respiratory defense mechanism, which makes clinical treatment difficult.
  • the mortality rate of Pseudomonas aeruginosa pneumonia is as high as 30%, and the mortality rate of Pseudomonas aeruginosa septicaemia is as high as 80-90%.
  • Pseudomonas aeruginosa is currently one of the most widespread and serious problems in nosocomial infections in hospitals. Therefore, the development of new highly effective anti-infective drugs is very urgent and important.
  • Flurbenicillin is a broad-spectrum semi-synthetic ureide penicillin with strong antibacterial properties. Activity against Gram-positive bacteria such as hemolytic streptococcus, Streptococcus grass greens, meningococcus, pneumococcus, enterococcus, influenzae bacillus, alcaligenes, proteus mirabilis, typhoid, paratyphoid, and pseudomonas And negative bacteria have broad antibacterial activity, high activity against Pseudomonas aeruginosa, and strong outer membrane penetration. It has been found in the studies of the protein affinity of flavicillin and other ureide penicillins, and other ⁇ -lactam antibiotics to E.
  • PBP Pseudomonas aeruginosa K799 / WT PBPS that furacillin and two bacteria must be PBP is multi-site binding and has a strong binding effect. It has a high affinity for E. coli PB2 and PB3, and also has a strong affinity for E. coli PBPla and PBPlb. Among the ureide penicillins, aloxicillin is lethal to E. coli.
  • ureide penicillins are the most valuable antibiotics against Pseudomonas aeruginosa.
  • the WHO Expert Committee on Essential Medicines has listed ureide penicillins as essential medicines, mainly used for Pseudomonas aeruginosa infection (Li Jiatai, Chinese Journal of Internal Medicine 1989; 6: 332),
  • Furbenicillin (see, for example, Canadian Patent Can.966853, British Patent 1282742, US Patent 3479339) was synthesized by the United States Bristol-Myer Company in 1969, but has not been listed abroad, and it was the first to be marketed in China. As with most ⁇ -lactam antibiotics, furamycin also has the weakness of being unstable to ⁇ -lactamase, and its effect on some bacteria is still not strong enough.
  • Tazobactam and its derivatives are irreversible and competitive ⁇ -lactamase inhibitors developed by companies such as Taiho and other Japanese companies after 1985 (see, for example, U.S. Patent Nos. 4,562,073 and 5763603). Chromosomal or plasmid-mediated inhibition of ⁇ -lactamase. Tazobactam and its derivatives have only weak antibacterial activity, so they cannot be used alone as antibacterial drugs, mainly with ⁇ -lactam antibiotics. It is compatible with all kinds of severe infections and resistant strains. At present, a compound of tazobactam sodium and piperacillin (Tazocin) (1: 8) has been marketed. There is no report in the published literature on the synergistic effect of tazobactam combined with furfuricin.
  • the inventors of the present invention have conducted research on the combined use of furicillin and its derivatives with tazobactam and its derivatives, and found that furacillin, furacillin derivatives or pharmaceutically acceptable salts or pharmaceutically acceptable salts thereof Compatible esters that are readily hydrolyzed in the body, and beta-lactamase inhibitor tazobactam, tazobactam derivatives or pharmaceutically acceptable salts or pharmaceutically acceptable hydrolysable esters that are compatible in the body It can produce a synergistic effect, thereby providing a broader antibacterial spectrum and a stronger antibacterial effect.
  • An antibacterial combination drug comprising a furicillin derivative and a tazobactam derivative can be used to treat bacterial infections in mammals. .
  • the combined drug has a more prominent advantage than a single component, especially in the fight against pathogenic bacteria such as Streptococcus pneumoniae and Pseudomonas aeruginosa, that is, a significant synergistic effect, which is conducive to significantly improving the antibacterial effect of furicillin or its derivative .
  • the present invention relates to the field of pharmaceutical technology, and in particular, to a ureide penicillin-containing furbenicillin, furbenicillin derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrolysable substance in vivo.
  • Ri, R 2, R 3 may be the same or different, represent a hydrogen atom, a nitro group, di (D_ 6 alkyl) amino, ⁇ _ ⁇ 6 alkanoylamino group, an amino group, a hydroxyl group, ⁇ _ 6 alkanoyloxymethyl Radical, d. 6 alkyl, d_ 6 alkoxy, sulfamoyl, chlorine, iodine, bromine, fluorine or trifluoromethyl,
  • Z represents d_ 6 alkyl, C 4 _ 7 cycloalkyl, mono-substituted prime d_ 6 alkyl, dichloromethyl, trichloromethyl, C 2 _ 6 alkenyl group, and the following groups:
  • n is an integer from 0 to 3
  • R 4 , 11 5 and 11 6 may be the same or different, and have the meanings of Ri, 11 2 and 11 3 described above, and
  • Tazobactam, a tazobactam derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolysable ester in vivo represented by the following formula (2):
  • R 7 and R 8 may be the same or different, and represent a hydrogen atom, a tri (d- 6 alkyl) silyl group, a carboxyl group, or a carboxyl group forming a pharmaceutically acceptable salt, or an esterified carboxyl group, wherein the formula (1) A compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolyzable ester in vivo and a compound of formula (2) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolyzable ester in vivo The weight ratio is 20: 1 to 1:10, preferably 8: 1 to 1: 1.
  • a pharmaceutically acceptable salt of a compound of formula (1) and / or a compound of formula (2) suitable for use in the present invention may be selected from alkali metal salts of the compound, such as potassium salts, sodium salts; alkaline earth metal salts, such as calcium salts , Magnesium salts; organic amine salts, such as salts of triethylamine, 2-hydroxyethylamine, procaine, etc .; basic amino acid salts, ammonium salts, and hydrates thereof.
  • Alkali metal salts such as potassium salts and sodium salts are preferred.
  • a pharmaceutically acceptable ester of a compound of formula (1) and / or a compound of formula (2) suitable for use in the present invention is an ester that is easily hydrolyzed to a free acid in vivo.
  • the furicillin derivatives that can be used in the combination medicine of the present invention include, but are not limited to: furicillin sodium, furicillin sodium dihydrate, furicillin potassium, furicillin potassium trihydrate, clofuricillin Alkali metal salts and their hydrates, bromofurin penicillin alkali metal salts and their hydrates.
  • the compound of the formula (1) which can be used in the present invention may be selected from the group consisting of free benzyl penicillin, furenicin sodium, furenicin sodium dihydrate, furenicin potassium, furenzin Penicillin potassium trihydrate.
  • one of R 7 and R 8 is a hydrogen atom, and the other is an esterified carboxyl group.
  • R 2 are both esterified carboxyl groups.
  • the esterified carboxyl group is preferably an alkoxycarbonyl group, and the alkyl portion has 1 to 18 carbon atoms.
  • one of 1 ⁇ and 11 2 is a tri (d- 6 alkyl) silyl group.
  • tazobactam derivatives useful in the combination drugs of the present invention include, but are not limited to: tazobactam, tazobactam sodium, tazobactam potassium, tazobactam hemihydrate, and tazobactam Tantalum monohydrate.
  • the compound of formula (2) useful in the present invention may be selected from tazobactam acid, tazobactam sodium, tazobactam potassium, tazobactam hemihydrate and Tazobactam sodium monohydrate.
  • the combination drug of the present invention can be administered by various routes, such as enteral administration Such as oral administration, or parenteral administration such as intravenous injection, transdermal injection and so on.
  • the combination medicament of the present invention may be administered in a single dose or multiple doses per day, for example, 2-3 doses per day.
  • the administration amount of the combination medicine of the present invention varies according to the age of the subject to be administered, the disease condition, the symptoms to be treated, and the mode of administration. However, for patients weighing about 75 kg, the daily dose is typically about 2-9 grams.
  • the combination medicine of the present invention can be made into various dosage forms, such as powder injection, lyophilized powder injection, injection solution and the like. They can be prepared by techniques known in the art, such as common mixing, dissolving, and lyophilizing methods.
  • the combination medicine of the present invention may contain only the above-mentioned furbenicillin, a furfuricillin derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolyzable ester in vivo, and a ⁇ -lactamase inhibitor tazobactam , Tazobactam derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester which is easily hydrolyzed in vivo.
  • the combination medicament of the present invention also contains conventional pharmaceutical excipients or carriers. The selection of the type and amount of the excipient or carrier according to the dosage form of the combination drug is a well-known technique in the art.
  • the active ingredient of the combination drug of the present invention can be dissolved or dispersed in, for example, water for injection, an oily solvent such as a fatty oil, etc., to prepare a solution or a suspension.
  • a solution or a suspension For intramuscular or intravenous application, it can be diluted with diluent (0.9% physiological saline for injection, sterile water for injection or 0.5% lidocaine hydrochloride), and then further diluted with 5% glucose solution or 0.9% physiological saline for injection.
  • the two active ingredients can also be filled in two different bottles to form a combined package, which exerts its synergistic effect in clinical treatment.
  • the antibacterial combination drug of furicillin and tazobactam is preferably administered clinically by injection, mainly by intravenous drip.
  • the antibacterial combination medicine provided by the present invention can be used to treat bacterial infections, such as respiratory infections, hepatobiliary infections, abdominal cavity infections, urinary tract infections, soft tissue and wound infections, pelvic infections, sepsis, meningitis, gynecological infections, bacterial infections, and Multiple microbial infections.
  • the combination medicine of the invention is especially suitable for treating microbial infections sensitive to ⁇ -lactam antibiotics, and is also effective for some penicillin-resistant microorganisms.
  • the combination medicine of the present invention can be used for the treatment of infectious diseases in humans, and also for the treatment of infectious diseases in animals. Very good antibacterial effect.
  • Example 1 A combined preparation was prepared from 1 g of furbenicillin sodium and 1 g of tazobactam sodium monohydrate, and the powder injection preparation process was carried out.
  • Example 2 A combined preparation was prepared from 1 g of furbenicillin potassium trihydrate and 0.1 g of tazobactam sodium, which was performed according to the powder injection preparation process.
  • Example 3 A combined preparation is prepared from 1 g of furbenicillin potassium trihydrate and 1 g of tazobactam sodium, and is performed according to the powder injection preparation process.
  • Example 4 A combination preparation was prepared from 1 g of furbenicillin sodium and 0.125 g of tazobactam sodium, and the powder injection preparation process was carried out.
  • Example 5 A combined preparation was prepared from 2 g of furbenicillin sodium and 0.25 g of tazobactam sodium, and was performed according to the powder injection preparation process.
  • Example 6 A hydrazone combined preparation was prepared from 4 g of furicillin sodium and 0.5 g of tazobactam sodium, and the powder injection preparation process was performed.
  • Example 7 A combined preparation was prepared from 2 g of furicillin sodium and 0.5 g of tazobactam sodium, and the preparation process was performed according to a lyophilized powder injection preparation process.
  • Example 8 A combined preparation was prepared from 4 g of furbenicillin sodium and 1.0 g of tazobactam sodium, and the preparation process was performed according to a lyophilized powder injection preparation process.
  • Example 9 A combined preparation was prepared from 4 g of furbenicillin potassium trihydrate and 1 g of tazobactam sodium, and the preparation process was performed according to a lyophilized powder injection preparation process.
  • Example 10 A combined preparation was prepared from 4 g of furbenicillin sodium and 1 g of tazobactam sodium monohydrate, and was performed according to a powder injection preparation process.
  • Example 11 A combined preparation was prepared from 1 g of furbenicillin sodium and 0.125 g of tazobactam hemihydrate, which was performed according to the powder injection preparation process.
  • Example 12 A combined preparation was prepared from 1 g of furbenicillin-bell trihydrate and 0.125 g of tazobactam sodium, which was performed according to the powder injection preparation process.
  • the in vitro test of the antibacterial combination drug of the present invention using clinically isolated pathogenic bacteria has shown that its antibacterial effect is significantly enhanced than that of any single component, that is, it has a very obvious synergistic effect.
  • the results of the in vitro tests are as follows:
  • Table 1 shows the results of the in vitro antibacterial test of the combination drug of the present invention (1: 1 composition of furfuricillin sodium and tazobactam sodium monohydrate) of Example 1.
  • Bacteria (number of strains) Furoxicillin potassium trihydrate tazobactam sodium composition Streptococcus pneumoniae (5) 0.031 256 0.008
  • Table 3 shows the combination drug of the present invention (Furacillin potassium trihydrate and tazobazole) of Example 3 Results of in vitro antibacterial test of batam sodium (1: 1 composition).
  • Bacteria (number of strains) Furoxicillin potassium trihydrate Tasalactam sodium composition Streptococcus pneumoniae (5) 0.031 256 0.004
  • Table 6 shows the combination drug of the present invention (Furacillin sodium and tazobactam sodium) of Example 10 Monohydrate composition (4: 1)) Results of in vitro antibacterial test.
  • Bacteria (number of strains) benzyl penicillin combination drug tasaltan ceftazidime
  • the in vitro antibacterial combination drug of the present invention has proved that its antibacterial activity and antibacterial activity are stronger than those of the compound of formula (1) or (2) when used alone.
  • tazobactam or its derivative (2) the active ingredient of the combination drug according to the present invention and furazin or its derivative (1).
  • the effect can obviously enhance the antibacterial activity of furicillin or its derivative, expand its antibacterial spectrum, and is conducive to enhancing the clinical efficacy of the drug and rejuvenating the old medicine with new youth.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique à action antimicrobienne, qui comprend de la furbénicilline, ses dérivés ou leurs sels pharmaceutiquement acceptables ou hydrolysables dans des esters in vivo; et un tazobactame inhibiteur des bêta-lactames, ses dérivés ou leurs sels pharmaceutiquement acceptables ou hydrolysables dans des esters in vivo. Des rapports de masse de la furbénicilline, ses dérivés ou leurs sels ou esters au tazobactame, ses dérivés ou leurs sels et esters sont de 20:1-1:10, de préférence 8:1-1:1. Le champ d'activité de la composition pharmaceutique est plus étendu et l'efficacité antimicrobienne plus importante.
PCT/CN2003/000102 2002-01-29 2003-01-29 Composition pharmaceutique antibacterienne WO2003063863A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN 02115482 CN1247197C (zh) 2002-01-29 2002-01-29 抗菌组合药物
CN02115482.1 2002-01-29
CN02115654.9 2002-04-01
CN 02115654 CN1448135A (zh) 2002-04-01 2002-04-01 高效抗菌组合药物

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Publication Number Publication Date
WO2003063863A1 true WO2003063863A1 (fr) 2003-08-07

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PCT/CN2003/000102 WO2003063863A1 (fr) 2002-01-29 2003-01-29 Composition pharmaceutique antibacterienne

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TW (1) TW200412849A (fr)
WO (1) WO2003063863A1 (fr)

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
LI JIATAI ET AL.: "Identification of beta-lactamases of gram-negative bacteria and antibacterial activity of furbenicillin to this strain of bacteria", ZHONG HUA YI XUE ZAZHI (JOURNAL OF CHINA MEDICINE), vol. 64, no. 8, 1984, pages 486 - 489 *
LI JIATAI ET AL.: "Studys of antibacterial effects of furbenicillin against zymogenic drug-resistant negative bacteria", YIXUE YANJIU TONGXUN (BULLETIN OF MEDICAL RESEARCH), vol. 14, no. 3, 1985, pages 87 - 88 *
PALMER S.M. ET AL.: "An evaluation of the bactericidal activity of ampicillin/sulbactam, piperacillin/tazobatam, imipenem or nafcillin alone and in combination with vancomycin against methicillin-resistant staphylococcus aureus(MRSA) in time-kill curves with infected .....", J. ANTIMICROB. CHEMOTHER., vol. 39, no. 4, April 1997 (1997-04-01), pages 515 - 518 *
XIE NAN ET AL.: "Studys of in vitro synergic effects of national enzyme inhibitor sulbactam and penicillins antibiotics", ZHONG HUA KANG SHENG SU ZA ZHI (JOURNAL OF CHINA ANTIBIOTICS), vol. 13, no. 4, 1988, pages 252 - 256 *

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