TW200412849A - Antibacterial combined medicine - Google Patents

Abstract

This invention relates to a pharmaceutical composition having synergic antimicrobial effects. It comprises furbenicillin, its derivatives or their pharmaceutically accepted salts or hydrolysable in vivo esters, and β -lactamase inhibitor tazobactam, its derivatives or their pharmaceutically accepted salts or hydrolysable in vivo esters. Weight ratios of furbenicillin, its derivatives or their salts or esters to tazobactam, its derivative or their salts and esters is 20:1-1:10, preferably 8:1-1:1. The antibacterial spectrum of the pharmaceutical composition is broader, the antimicrobial efficacy is stronger.

Description

200412849 (1) Description of the invention [Technical field to which the invention belongs] The present invention relates to an antibacterial combination drug having a synergistic effect. 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 s which is easily hydrolyzed in vivo, and β- The lactamase inhibitor tazobactam, tazobactam derivative or pharmacologically acceptable salt or pharmaceutically acceptable hydrolysable ester of the body as active ingredients, has a broader antibacterial spectrum and antibacterial The effect is stronger. [Previous technology] Since the 1980s, due to the increased use and improper use of antibiotics 10, the clinical resistance of bacteria has increased. For example, 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 the first pathogen in the community of adults, especially the elderly (^ 1 \ 181 ^ 10%. (: 1 ^ 111 ^ 6 (^ 〇18, 1992; 14: 801, 809 · Nohynek H, et al. Am J Dis Chid, 1991; 145: 618-622. Marrie 15 TJ. Clin Infect Dis, 1994; 18: 501-505). Because Streptococcus pneumoniae has developed resistance to penicillin and other β-lactam antibiotics, penicillin-resistant Streptococcus pneumoniae has been widely spread throughout the world since the 1990s. The effect of treatment is reduced, which endangers the lives of patients. Pseudomonas aeruginosa, also known as Pseudomonas aeruginosa, is the most common pathogen in hospitals that acquires 20 sexy infections. It is extremely prone to acquire acquired drug resistance, and it is not easy to be killed by the respiratory defense mechanism. The clinical treatment is very 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 the most in-hospital infection in various hospitals. One of the broadest and most serious issues. So, The development of new and highly effective anti-infective drugs is very urgent and important. 5 200412849 玖, Description of the invention (2) · The enzyme uric acid (Furbenicillin) is a broad-spectrum semi-synthetic fluorene penicillin with strong antibacterial activity. Gram-positive bacteria such as hemolytic streptococcus, Streptococcus grass green, meningococcus, pneumococcus, enterococcus, influenza bacillus, domain-producing bacterium, Pneumococcus mutans, typhoid bacteria, typhoid, paratyphoid, and pseudomonas aeruginosa And negative bacteria have broad-spectrum antibacterial activity, high activity against Pseudomonas aeruginosa, and strong outer membrane penetrability. In furfuricillin and other carbamide penicillins, and other β-lactam antibiotics against E. coli κ_12 and green In protein affinity studies of Pseudomonas k799 / wt PBPs, it has been found that furfuricillin binds to two kinds of essential PBPs at both sites and has a strong binding effect. It has a high affinity for E. coli PBP2 and PBP3 and has high affinity for E. coli. pBpia and pBpib also have a strong affinity; aloxicillin in penicillin penicillin does not have as good affinity for the three lethal PBPs (PBPlb, PBP2, PBP3) of Escherichia coli. 'While meloxicillin and tacilcillin have less affinity for Escherichia coli PBpia, ρΒρ ^, 15 PBP2, and their affinity to Pseudomonas aeruginosa PBPla, PBP2, PBP3 is worse than foxacillin, and their affinity for pBp2, pBp3 Obviously surpasses the third-generation cephalosporins such as cephalosporins. From the perspective of safety and effectiveness, fluorenil penicillins are the most valuable antibiotics against Pseudomonas aeruginosa. The World Health Organization's Committee of Experts on Essential Medicines has classified carbamurones. Penicillin is listed as a basic substance and is mainly used for infection of Chlamydomonas aeruginosa (Li Jiatai, Chinese Internal Medicine 诘 1989; 6: 332). Furbenicillin (see, for example, Canadian Patent Can.966853, British Patent 1282742, US Patent 3479339) was issued by the United States in 1969 #

My: The company is synthesized, but has not been listed in foreign countries, and China has taken the lead in developing and listing. Furan M ¥ penicillin, like most β-lactam antibiotics, also has a weak point against β-lactam 6 200412849 发明, description of the invention (3) the enzyme is not stable, and the effect on some bacteria is still not strong enough. Tazobactam and its derivatives are irreversibly competitive beta-lactamase inhibitors developed by companies such as Taiho and others in Japan after 1985 (see, for example, U.S. Patent Nos. 4,562,073, 5763603), and are produced against Gram-positive and negative bacteria. Staining 5-body or plasmid-mediated inhibition of β-lactamase. Tatumbactam and its derivatives have only weak antibacterial activity, so they cannot be used alone as antibacterial drugs. They are mainly compatible with β-lactam antibiotics for various serious infections and resistant strains of infection. At present, a compound of tazobactam sodium and tacilcillin (1: 8) has been marketed. There have been no reports in the published literature on the synergistic effect of tazobactam in combination with furbenicillin. 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 furicillin, furopenicillin derivatives, or pharmaceutically acceptable salts or pharmaceutically acceptable salts thereof Acceptable hydrolysable esters in the body, and beta-lactamase inhibitors tababactam, tatabactam derivatives or their pharmaceutically acceptable salts or pharmaceutically acceptable in vivo The compatibility of easily hydrolyzable esters 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 breastfeeding. Animal bacterial infection. The 20 combination drugs have a more prominent advantage than single components in combating pathogenic bacteria such as Streptococcus pneumoniae and Pseudomonas aeruginosa, that is, a significant synergistic effect, which is conducive to significantly improving the antibacterial activity of furicillin or its derivatives. effect. [Summary of the Invention] The present invention relates to the technical field of medicines, and in particular, to a furanicillin (furbenicillin) containing 呋 25 urea penicillin, a furfuricin derivative 7 200412849 玖, invention description (4), or a pharmacologically acceptable Acceptable salts or pharmaceutically acceptable hydrolysable esters in vivo, and beta-lactamase inhibitor tazobactam, tazobactam derivatives or pharmaceutically acceptable salts thereof, or Antibacterial combination of pharmaceutically acceptable esters which are easily hydrolyzed in vivo. It is an object of the present invention to provide a combination medicine comprising the furfuricillin, furfuricillin derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, which is represented by the following formula (1): Hydrolyzed ester

Among them, R !, R2, and R3 may be the same or different, and represent a hydrogen atom, a nitro group 10, a bis (Ci-6 alkyl group) amino group, a Ci-6 alkyl group, an amino group, a meridian group, and a Ci-6 alkoxy group. , Cw alkyl, Cw alkoxy, sulfamoyl, chlorine, iodine, bromine, fluorine, or trifluoromethyl, z represents Cw alkyl, c4_7 cycloalkyl, mono-substituted Cw alkyl, dichloro Methyl, trimethyl, c2_6 alkenyl, and the following groups: 200412849 玖, Description of the invention (5)

〇2n-

FA〆

Br ^ V

15 In the formula, η is an integer from 0 to 3, R4, Rs, and r0 may be the same or different, and have the meanings of Ri, R2, and R3 described above, and tazobactam and tazobactam represented by the following formula (2) Derivatives or pharmaceutically acceptable salts or pharmaceutically acceptable esters which are easily hydrolyzed in the body:

r2 wherein R7 and Rs may be the same or different, and represent a hydrogen atom, tris (methanyl) pyridyl, sulfonium, or hydrazone, or a pharmacologically cut or esterified carboxyl group, 1g3 20 200412849 玖, description of the invention (6) wherein ) A compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester which is easily hydrolyzed in vivo and a compound of formula (2) or a pharmaceutically acceptable salt thereof or which is pharmaceutically acceptable easily hydrolyzed in vivo The weight ratio of the ester is 20: 1 to 1:10, preferably 8: 1 to 1: 1. 5 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. Metal salts such as bell salts and sodium salts are preferred. 10 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 which is easily hydrolyzed to a free acid in vivo. Examples of 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, erythromycin clock trihydrate, chloroamylpenicillin Test metal salt 15 and its hydrate, bromofuricillin alkali metal salt and its hydrate. According to a preferred embodiment of the present invention, the compound of formula (1) that can be used in the present invention may be selected from the group consisting of free acid of furicillin, sodium of furicillin, erythromycin sodium dihydrate, erythromycin potassium, erythromycin Penicillin unloads trihydrate. 20 According to a preferred embodiment of the present invention, in the compound of the above formula (2), one of 'R7 and Rs is a hydrogen atom, and the other is a fluorinated weidyl. Or, in the compound of the formula (2), R i and R 2 are both S radicals. The ammonium alkyl group is preferably an alkoxycarbonyl group, and the alkyl portion has 1 to 18 carbon atoms. According to a preferred embodiment of the present invention, in the compound of formula (2), 25, Ri and R2 are each a hydrogen atom, and the other is a carboxyl group forming a pharmaceutically acceptable salt 10 200412849 玖, invention description (7). According to another preferred embodiment of the present invention, one of 'R1 and R2 in the compound of the formula (2) is a tris (Cl_6alkyl) methanthyl group. Examples of tazobactam derivatives that can be used in the combination drugs of the present invention include 5 but are not limited to: tazobactam acid, tazobactam sodium, tazobactam potassium, tazobactam hemihydrate, and tazobactam Battana monohydrate. According to a preferred embodiment of the present invention, the compound of formula (2) useful in the present invention may be selected from tazobactam, tazobactam sodium, tazobactam, tazabactam hemihydrate, and He Jun Batana monohydrate. 10 It has been found through research that when using benzyl penicillin or its derivatives, a beta-lactamase inhibitor, such as tazobactam or its derivatives, which can effectively inhibit the action of beta-lactamase, is added. It is conducive to stably exert its antibacterial effect and improve the stability of β-lactamase, so that the combined drug has a larger antibacterial spectrum and a stronger antibacterial effect. 15 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 the like. The combination drug of the present invention can be administered in a single dose or multiple doses per day, for example, 2-3 doses per day. The dosage of the combination drug of the present invention varies depending on the age of the object to be administered, the condition, the symptoms to be treated, and the manner of administration. However, for patients weighing about 20 to 75 kg, the daily dose is usually 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 furfuricin 25 derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo 11 200412849 玖, description of the invention (8) hydrolyzed vinegar, And β-endosylamine inhibitor tababactam, tatabactam derivatives or pharmaceutically acceptable salts or pharmaceutically acceptable hydrolysable esters thereof in vivo. Or in addition to the above-mentioned active ingredients, the combination medicament of the present invention contains a conventional pharmaceutical excipient or carrier. The selection of the types and amounts of excipients or carriers based on the dosage form of the combination drug is a well-known technique in the art. For parenteral administration, 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 make 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 10 5% glucose solution or 0.9% physiological saline for injection. In addition, 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 combination of furicillin and tazobactam is preferably administered clinically by injection, mainly by intravenous drip. 15 The antibacterial combination drugs provided by the present invention can be used to treat bacterial infections, such as respiratory infections, hepatobiliary system 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 present invention is especially suitable for treating microbial infections sensitive to β-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 is also suitable for the treatment of infectious diseases in veterinary animals. Very good antibacterial effect. [Embodiment] 25 The present invention will be further described in detail with reference to the following embodiments. It should be noted that these 12 200412849 (9), the invention description (9) These embodiments are merely examples of the preferred embodiment of Ri Lin Fa Ri Yue, in any respect-does not constitute a limitation on the scope of the present invention. Example 1: A combined preparation was prepared from 1 g of M penicillin sodium and 5 g of salivatanna _ 5 10 15 20 g. Implementation Example 4: by. Fugly penicillin sodium gram is combined with a powder preparation to make red # CHENG-Na (U25 grams, made in Example 5 · from furfuryl main butyl. Makes a combined preparation, made into powder to make preparations: work, process: 2 grams And tazobactam sodium 0.25 g Example 6: The main sequence of furbenzyl was used. The combined preparation was made according to the powder injection fuyue, 4 g and tazobactam sodium 0.5 g. Example 7: Performed by the two masters: the procedure. The combined preparation was prepared according to the bundle of dry powder. 2 g of preparations were prepared with 0.5 g of salivatanam. Example 8: "penicillin: 4 =." Combination The preparation was prepared according to the formula of dry powder grams and tambatam L0 g. Example 9 :: Element 7 was performed in two steps. A combination preparation was prepared according to the amount of dried A Ύ 4 g of hydrate and tazobactam sodium i. Example 10: From furbenzyl :: training preparation process procedure. 1 g to make a combined preparation 'according to grams of powder and tazobactam sodium hydrate. Example 11: from bite joint process procedure. 0.125 g Combination of 1 gram and 1 gram of plain noodles and he < batam hemihydrate Example 12: It is performed by a process called: prime. T-hydrate 1 gram and tazobactam sodium 13 25 200412849 发明, invention said Ming (10) 0.125 g is made into a combined preparation, and it is carried out according to the powder injection preparation process procedure. Verification of the pathogenicity of the secret drug separation of the turn compound drug_Experimental in vitro test and a very well-known one The antibacterial effect is significantly enhanced, that is, there is a significant synergistic effect of fefivir. The results of the in vitro test are as follows: Panta / t shows the combination drug of the present invention (Ispenicillin sodium. Wang Ba i dena-hydrate!) Of: i Composition) in vitro antibacterial test results Table 1. Compositions of furbenicillin sodium and tazobactam sodium monohydrate (i: i ^ activity (MIC50mg / 1)) furoficin sodium tazobactam Sodium monohydrate composition bacterium (5) 0.031 _ 256 0.002 Table 2 shows the in vitro of the combination drug of the present invention (a 10: 1 composition of furfuricillin potassium hydrate and tazobactam sodium) of Example 2 Antibacterial Test Results 14 200412849

Table 3 shows the results of the in vitro antibacterial test of the combination drug of the present invention (a composition of potassium furfuricin potassium monohydrate and tazobactam sodium) in Example 3. Table 3. In vitro antibacterial activity (MIC50mg / 1) of a combination of furfuricillin potassium trihydrate and tazobactam sodium ____ Streptococcus pneumoniae (number of strains) _ penicillin trihydrate tazobactam Batam sodium composition 0.031 256 0.002 Table 4 shows the results of the in vitro antibacterial test of the combination drug of the present invention (a combination of furbenicillin sodium and tababatam sodium ·· 1) of Example 7 in Table 7. 15 Table 4. Composition of furicillin sodium and tazobactam sodium (4: in vitro anti-cellulite (number of strains) sigmaphorus sodium stigmatin sodium and saliva sweep sodium composition Streptococcus pneumoniae (5) 0.031 256 0.004 Table 5 shows In vitro antibacterial test results of the combination drug of the present invention (a composition of furbenicillin dehydrate and talbactam sodium 4 · 1) in Example 9 Table 5. Furbenicillin potassium trihydrate and tazobactam sodium Composition (* ·· 1 bacterium (number of strains) furfuricin · mycin potassium trihydrate he salivary nano-grade compound Streptococcus pneumoniae (5) 0.031 256 0.004 15 200412849 :-: Fire Humming: · .., ··-;; ........., Description of the invention (12) Table 6 shows the implementation Example 10 The combination drug of the present invention (furbenicillin sodium and tazobactam sodium monohydrate composition (4: ιυ in vitro antibacterial test results 0 Table 6 · Furicillin sodium and tazobactam sodium monohydrate composition (4:

Table 7 shows the in vitro antibacterial test results of the combination drug of the present invention (furacillin sodium and tazobactam hemihydrate composition (8: 0)) of Example 11 Table 7. Hemihydrate of furacillin sodium and tazobactam Composition (8: 10 ^ antibacterial activity (MIC50 mg / 1)

Table 8 shows the results of the in vitro antibacterial test of the combination drug of the present invention (furfuricillin potassium dihydrate and tazobactam sodium composition (8: 1)) in Example 12

15 Table 9 compares the combination drugs (furbenzyl aspirin sodium and tazobactam sodium composition (8: 1)) with the active ingredients alone and 16 200412849. Note (13) The results of the in vitro antibacterial test of ceftazidime. Table 9. Comparison of antibacterial activity in vitro of a combination of furicillin sodium and tazobactam sodium (MIC50mg ") bacteria (number of strains) a combination of furicillin penicillin (Example 6) tazobactam L ceftazidime. Staphylococcus aureus (8) 0.5 0.125 128 32 Meningococcus (4) 0.031 0.008 256 0.016 Streptococcus pneumoniae (12) 0.031 0.008 128 0.5 Hemolytic streptococcus (14) 0.062 0.016 256 0.5 E. coli (18) 4 0.125 256 0.5 Klebsiella (11) 128 4 256 1 Pseudomonas aeruginosa (7) 4 2 > 256 8 Influenza (12) 1 0.25 > 256 0.5 Proteus mirabilis (11) 8 0.25 > 256 0.06 Clostridium cloacae (8) 16 2 > 256 32 The in vitro antibacterial combination drug of the present invention has proved that its antibacterial activity and 5 antibacterial spectrum are stronger than those of the compound of formula (1) or (2) when used alone. In summary, the active ingredient of the combination drug according to the present invention, tazobactam or its derivative (2), has significant synergistic effects with furfuricillin or its derivative (1), which can significantly enhance furbenzyl. The antibacterial activity of penicillin or its derivatives and the expansion of its antibacterial spectrum are conducive to enhancing the clinical efficacy of the drug and rejuvenating the old medicine with new youth. The present invention has been described above with reference to preferred embodiments and examples. However, it should be understood that these embodiments and examples are only for those skilled in the art to better understand the purpose, embodiments and effects of the present invention, and are not 17 200412849 玖, invention description (14) is used to limit the scope of the present invention. After reading this specification, those skilled in the art can easily make various changes to the present invention without departing from the spirit and scope of the present invention. The invention is intended to include all such modifications and alterations.

18

Claims (1)

200412849 1. A combination drug, comprising furfuricillin, furfuricillin derivative or a pharmaceutically acceptable salt thereof represented by the following formula (1) and a pharmaceutically acceptable hydrolysable ester in vivo: NH-CZ 〇 (1) In Ri and II, Ri, R2, and R3 may be the same or different, and represent a hydrogen atom, nitrate- ~ (cw alkyl) amino group, Cu6 alkylamino group, amino group, hydroxyl group, and 6 group. , Cl_6 alkynyl, Ci6 alkoxy, ammonium, chloro, sincerium,> odor, fluorine or trifluoromethyl, ...,, == Cl-6 aryl, c4.7 cycloalkyl, monohalogen Substituted Ci6 alkyl, methyl, tris, methyl, C2_6 alkenyl, and the following groups: 19 200412849 Pick up and apply for patents κ 1 II ~~ 1 II—'F 〇2N and θ '-% less N , S, N Br- Cl- tr In the formula, "XI 疋 0-3 integer" R4, R5 and R6 may be the same or different and have the meanings of R1, R2 and R3 described above, and Tazobactam, a tazobactam derivative or a pharmaceutically acceptable parent salt and a pharmaceutically acceptable hydrolyzable ester in vivo represented by the following formula (2): R2 'C〇〇H, where' H and R8 may be the same or different, representing a hydrogen atom, tris (d group) methylsulfenyl group, Weyl group, or the formation of a %% ^ carboxylated carbohydrate '20 200412849' application for patent scope The weight ratio of the physically acceptable salt or ester to tazobactam, the tazobactam derivative, or the pharmaceutically acceptable salt or ester thereof of formula (2) is 20: 1 to 1: 10 ° 2 The combination drug according to item 1 of the scope of the patent application, wherein erythromycin, furopenicillin derivative of formula (1) or a pharmaceutically acceptable salt or ester thereof and tatabactam of formula (2) 1. The weight ratio of tatabactam derivative or a pharmaceutically acceptable salt or ester thereof is from 8 ·· 1 to 1: 1. 3. The combination drug according to item 1 of the scope of patent application, wherein the compound of formula (1) and / or the pharmaceutically acceptable salt of the compound of formula (2) is selected from metal test salt, soil test metal salt, organic Amine salts, test amino acid salts, ammonium salts, and hydrates thereof. 4. The combination drug according to item 1 of the scope of the patent application, wherein the compound of formula (1) can be selected from the group consisting of free furicillin, free furicillin sodium, furicillin sodium dihydrate, furicillin potassium, Furoxicillin potassium trihydrate. 5. The combination drug according to item 1 of the scope of patent application, wherein in the compound of formula (2), one of FU and R2 is a hydrogen atom and the other is an esterified carboxyl group. 6. The combination drug according to item 1 of the scope of patent application, wherein in the compound of formula (2), Ri and R2 are both esterified carboxyl groups. 7. The combination drug according to item 1 of the scope of patent application, wherein in the compound of formula (2), one of Ri and R2 is a hydrogen atom, and the other is a carboxyl group forming a pharmaceutically acceptable salt. 8. The combination drug according to item 1 of the scope of patent application, wherein in the compound of formula (2), one of Ri and R2 is a tri (Cw alkyl) silyl group. 9. The combination drug according to item 1 of the scope of the patent application, wherein the esterified weyl is an alkoxycarbonyl group and the alkyl portion has 1 to 18 carbon atoms. 21 200412849 :: Bi Bi Ling] 灵 | 輋 10. The combination drug described in item 1 of the scope of patent application, wherein the compound of formula (2) may be selected from tabatamic acid, tabatamic acid, and σ Zibatam unloading, he sigmabatam hemihydrate and tambatam monohydrate. 22 200412849 Lu, (a), the designated representative of this case is: Figure ___ (b), the representative symbols of this representative diagram are briefly explained: 柒, if there is a chemical formula in this case, please disclose the chemical that can best show the characteristics of the invention _1 义 缠 | __ 议 _ 靡 议 _ 园 议 _i_ 议 议 议