WO2006058457A1 - DÉRIVÉS DE 2-MÉTHYL-5-NITROIMIDAZOL-1-ÉTHANOL α-SUBSTITUÉS - Google Patents

DÉRIVÉS DE 2-MÉTHYL-5-NITROIMIDAZOL-1-ÉTHANOL α-SUBSTITUÉS Download PDF

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Publication number
WO2006058457A1
WO2006058457A1 PCT/CN2004/001380 CN2004001380W WO2006058457A1 WO 2006058457 A1 WO2006058457 A1 WO 2006058457A1 CN 2004001380 W CN2004001380 W CN 2004001380W WO 2006058457 A1 WO2006058457 A1 WO 2006058457A1
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WO
WIPO (PCT)
Prior art keywords
compound
methyl
present
preparation
ethanol
Prior art date
Application number
PCT/CN2004/001380
Other languages
English (en)
Chinese (zh)
Inventor
Junda Cen
Huijuan Zhong
Original Assignee
Lianyungang Hengbang Pharmaceutical Co. Ltd.
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
Application filed by Lianyungang Hengbang Pharmaceutical Co. Ltd. filed Critical Lianyungang Hengbang Pharmaceutical Co. Ltd.
Priority to PCT/CN2004/001380 priority Critical patent/WO2006058457A1/fr
Publication of WO2006058457A1 publication Critical patent/WO2006058457A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to an ⁇ -substituted 2-methyl-5-nitroimidazole-1-ethanol derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same and its use for the preparation of an anti-anaerobic drug. Background technique
  • chemotherapy for anaerobic infection usually begins with empirical therapy. Since most anaerobic infections are mixed infections with aerobic bacteria, the chemotherapy target must also consider coexisting aerobic conditions. bacteria.
  • the susceptibility of major anaerobic bacteria to chemotherapeutic drugs is listed in Table 1 below. Table 1 Sensitivity of anaerobic bacteria to chemotherapeutic drugs
  • metronidazole as a fungicide, has a wide spectrum of anti-anaerobic bacteria and is highly sensitive to Bacteroides fragilis, Bacteroides, Clostridium perfringens, Peptococcus, Streptococcus pneumoniae, Pyrex-producing bacteria, Porphyromonas is moderately sensitive and less sensitive to Gram-negative bacilli. Oral absorption is good, T max l-2h, widely distributed in the body, can enter saliva, milk, pus, can also penetrate into the cerebrospinal fluid. T 1/2 8h, mostly excreted in the urine, a small amount is excreted in the feces. It is mainly used for systemic and local infections caused by the above anaerobic bacteria.
  • the antibacterial spectrum and antibacterial effect of tinidazole are the same as those of metronidazole.
  • the semi-test period is longer than metronidazole (T 1/2 12-14h), and the treatment of abdominal cavity, pelvic cavity and postoperative anaerobic infection are satisfactory. Efficacy. A single dose of treatment can be used.
  • Another object of the present invention is to provide a process for the preparation of the novel compounds of the formula (I) according to the invention.
  • a further object of the present invention is to provide a composition comprising a therapeutically effective amount of the novel compound of the general formula (I) of the present invention, and
  • the present invention relates to the following aspects - in accordance with the contents of the present invention, the present invention particularly relates to a compound represented by the formula (I) and a hydrate or solvent compound of the compound of the formula (I) or a pharmaceutically acceptable Acceptable salt.
  • R is selected from the group consisting of CH 2 F, CHF 2 , CF
  • the invention also relates to a process for the preparation of a compound of formula (I) which comprises
  • the compound of the invention is obtained.
  • the invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of the above compound as an active ingredient together with a pharmaceutically acceptable carrier.
  • the compounds of the invention can be used in the preparation of medicaments against anaerobic bacteria.
  • the present invention relates to an ⁇ -substituted 2-methyl-5-nitroimidazole-1-ethanol derivative represented by the formula (I) and a hydrate or solvate of the compound of the formula (I) or pharmaceutically Acceptable salt.
  • the present invention also relates to a pharmaceutical composition containing these compounds which has excellent anti-anaerobic properties and is highly safe.
  • R wherein R is selected from CH 2 F, CHF 2 , CF
  • v 2-Methyl-5-nitroimidazole-1-ethanol compounds are known to have excellent anti-anaerobic activity.
  • the present inventors have found that certain specific ⁇ -substituted-2-methyl-5-nitroimidazole-1-ethanol compounds have better pharmacological effects and lower toxicity than existing drugs, thereby completing the present invention. .
  • the compound represented by the formula (I ) can be derived from the compound of the formula II with ⁇ _ / ;
  • compositions of the invention containing a compound of the invention can be prepared according to methods known in the art.
  • the active ingredient may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants, if desired, in a suitable form or dosage form for use as a human.
  • the pharmaceutical composition of the present invention can be administered in a unit dosage form, and the administration route can be intestinal or Parenteral, such as oral, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.
  • the administration route of the pharmaceutical composition of the present invention may be administered by injection. Injections include intravenous, intramuscular, subcutaneous, intradermal, and acupoint injections.
  • the dosage form can be a liquid dosage form or a solid dosage form.
  • the liquid dosage form may be a true solution, a colloid, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form.
  • Other dosage forms such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, and the like.
  • the pharmaceutical composition of the present invention can be formulated into a common preparation, a sustained release preparation, a controlled release preparation, a targeted preparation, and various microparticle delivery systems.
  • a carrier for example, a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • wetting agent and binder such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, sugar paddle, honey, glucose solution, gum arabic, gelatin pulp, carboxymethyl cellulose Sodium, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and tannic acid, calcium carbonate, polyoxyethylene Sorbitol fatty acid ester, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.
  • disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.
  • absorption promotion Agents such as quaternary ammonium salts, sodium decyl sulfate, etc.
  • lubricants such as talc, silica, corn starch
  • the carrier are, for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, Ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, and the like. . '
  • the drug delivery unit in order to prepare the drug delivery unit as a suppository, various carriers well known in the art can be widely used.
  • the carrier are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like.
  • the active ingredient is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule.
  • the active ingredient may also be formulated as a microcapsule, suspended in an aqueous medium to form a suspension, or may be enclosed in a hard capsule or used as an injection.
  • the composition of the present invention is formulated into an injectable preparation such as a solution, a suspension solution, an emulsion, or a lyophilized powder injection.
  • the preparation may be aqueous or non-aqueous, and may contain one type and/or more.
  • the diluent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like.
  • an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional cosolvent, a buffer, a pH adjuster or the like may be added. These excipients are commonly used in the field.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • compositions of the present invention can be used to treat systemic or localized infections caused by anaerobic bacteria in mammals, including humans.
  • the dose of the compound or pharmaceutical composition of the present invention depends on a number of factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, The number of drugs and the like, and thus the therapeutic dose of the present invention can vary widely.
  • the dosages of the pharmaceutical compositions of the present invention are well known to those skilled in the art.
  • the anaerobic infection of the present invention can be accomplished by appropriately adjusting the amount of the actual effective drug contained in the pharmaceutical preparation of the present invention or the final preparation in the composition to achieve a therapeutically effective amount thereof.
  • the above dosages may be administered in a single dosage form or divided into several, for example two, three or four dosage forms, which are limited by the dosing regimen of the clinical experience of the administering physician.
  • Dextran 40g 100 g of the compound 1 obtained in the examples was dissolved in water for injection, and 40 g of dextran was dissolved in water for injection.
  • the two solutions were uniformly mixed, diluted with water for injection to 2000 ml, and filtered through a 0.22 ⁇ m microporous membrane, under sterile conditions. They are packed in 10ml vials, placed in trays, sent to freeze-drying boxes, lyophilized, out of the box, rolled, and ready.
  • Example 11 The compound 1 obtained in Example 1 was uniformly mixed, and 8% starch slurry was added to prepare a software, which was granulated with a 14-mesh nylon sieve, dried at 70-80 ° C, added with magnesium stearate, and sieved through a 10-12 mesh wire. Whole grain, mixed hook, pressed with 12mm die.
  • Example 11 The compound 1 obtained in Example 1 was uniformly mixed, and 8% starch slurry was added to prepare a software, which was granulated with a 14-mesh nylon sieve, dried at 70-80 ° C, added with magnesium stearate, and sieved through a 10-12 mesh wire. Whole grain, mixed hook, pressed with 12mm die.
  • Example 11 Example 11
  • Powdered sugar 20 g Compound 2 was dissolved in water, and 80 g of starch and 20 g of powdered sugar were added, and flavor was added: :, mixed, granulated with 14-16 mesh, dried at 60 ° C or lower, and packaged.
  • Example 12
  • the anti-anaerobic test of the compound of the present invention by a method known to those skilled in the art shows that the compound provided by the present invention shown in Table 2 has good in vitro antibacterial activity against both anaerobic bacteria, and the effect is comparable to that of ornidazole. .
  • Table 2 In vitro antibacterial activity of two anaerobic bacteria
  • the anti-anaerobic test of the compound of the present invention by a method known to those skilled in the art shows that the compound provided by the present invention shown in Table 3 below has good in vivo antibacterial activity against oral or intravenous injection of both anaerobic bacteria in mice. Active, stronger than ornidazole, or equivalent to ornidazole.
  • mice Each group (10 mice, half male and half female) was orally or intraperitoneally injected with the compound of the present invention at a dose of 2000 mg/kg for two weeks.
  • Table 4 shows that the compounds of the present invention are less toxic and less than ornidazole.
  • Table 4. Mortality of mice in one oral or intraperitoneal injection.

Abstract

La présente invention concerne les dérivés de 2-méthyl-5-nitroimidazol-1-éthanol α-substitués ainsi que la méthode permettant de les synthétiser, la préparation pharmaceutique comprenant lesdits dérivés et leur emploi dans l’élaboration d’un médicament pour le traitement de bactéries anaérobies.
PCT/CN2004/001380 2004-11-30 2004-11-30 DÉRIVÉS DE 2-MÉTHYL-5-NITROIMIDAZOL-1-ÉTHANOL α-SUBSTITUÉS WO2006058457A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2004/001380 WO2006058457A1 (fr) 2004-11-30 2004-11-30 DÉRIVÉS DE 2-MÉTHYL-5-NITROIMIDAZOL-1-ÉTHANOL α-SUBSTITUÉS

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2004/001380 WO2006058457A1 (fr) 2004-11-30 2004-11-30 DÉRIVÉS DE 2-MÉTHYL-5-NITROIMIDAZOL-1-ÉTHANOL α-SUBSTITUÉS

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Publication Number Publication Date
WO2006058457A1 true WO2006058457A1 (fr) 2006-06-08

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007079653A1 (fr) * 2006-01-06 2007-07-19 Jiangsu Hansen Pharmaceutical Co., Ltd. Derives optiquement purs de 2-methyle-5-nitroimidazole-1-ethanol alpha substitue
CN102382061A (zh) * 2011-11-07 2012-03-21 陕西宏府怡悦制药有限公司 苯甲酰奥硝唑的合成
CN101279970B (zh) * 2007-04-05 2012-09-05 四川百利药业有限责任公司 2-甲基-5-硝基咪唑-1-(3-氯-2-羟基丙基)氯取代的衍生物、制备方法及其应用
CN104628651A (zh) * 2013-11-06 2015-05-20 江苏豪森药业股份有限公司 吗啉硝唑异构体及其制备方法
EP2793871A4 (fr) * 2011-12-23 2015-07-22 Auckland Uniservices Ltd Composés et procédés pour l'imagerie et/ou l'ablation sélectives
CN104829541A (zh) * 2015-05-05 2015-08-12 江苏豪森药业股份有限公司 高选择性及高纯度制备吗啉硝唑的方法
CN104844522A (zh) * 2015-05-05 2015-08-19 江苏豪森药业股份有限公司 吗啉硝唑晶体及其制备方法和医药用途
WO2016208699A1 (fr) * 2015-06-25 2016-12-29 セントラル硝子株式会社 Procédé pour la production industrielle d'oxyde de fluoroalkyl-éthylène optiquement actif

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ARYA V.P. ET AL: "Nitroimidazoles: Part XV. 1-Methyl-5-nitro-2-oxy(mercapto)imidazoles, 1-methyl-5-nitroimidazole-2-methanol(carboxaldehyde and glyoxalic ester) derivatives and 1-substituted alkyl-2-methyl-5 and -4-nitroimidazoles", INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY, vol. 21B, no. 12, 1982, pages 1078 - 1086 *
BONE W. ET AL: "Toxicity of ornidazole and its analogs to rat spermatozoa as reflected in motility parameters", INTERNATIONAL JOURNAL OF ANDROLOGY, vol. 20, no. 6, 1997, pages 347 - 355 *
SKUPIN R. ET AL: "Lipase-catalyzed resolution of both enantiomners of ornidazole and some analogs", TETRAHEDRON: ASYMMETRY, vol. 8, no. 14, 1997, pages 2453 - 2464 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007079653A1 (fr) * 2006-01-06 2007-07-19 Jiangsu Hansen Pharmaceutical Co., Ltd. Derives optiquement purs de 2-methyle-5-nitroimidazole-1-ethanol alpha substitue
CN101279970B (zh) * 2007-04-05 2012-09-05 四川百利药业有限责任公司 2-甲基-5-硝基咪唑-1-(3-氯-2-羟基丙基)氯取代的衍生物、制备方法及其应用
CN102382061A (zh) * 2011-11-07 2012-03-21 陕西宏府怡悦制药有限公司 苯甲酰奥硝唑的合成
EP2793871A4 (fr) * 2011-12-23 2015-07-22 Auckland Uniservices Ltd Composés et procédés pour l'imagerie et/ou l'ablation sélectives
CN104628651A (zh) * 2013-11-06 2015-05-20 江苏豪森药业股份有限公司 吗啉硝唑异构体及其制备方法
CN104628651B (zh) * 2013-11-06 2018-07-24 江苏豪森药业集团有限公司 吗啉硝唑异构体及其制备方法
CN104829541A (zh) * 2015-05-05 2015-08-12 江苏豪森药业股份有限公司 高选择性及高纯度制备吗啉硝唑的方法
CN104844522A (zh) * 2015-05-05 2015-08-19 江苏豪森药业股份有限公司 吗啉硝唑晶体及其制备方法和医药用途
CN104844522B (zh) * 2015-05-05 2017-07-25 江苏豪森药业集团有限公司 吗啉硝唑晶体及其制备方法和医药用途
WO2016208699A1 (fr) * 2015-06-25 2016-12-29 セントラル硝子株式会社 Procédé pour la production industrielle d'oxyde de fluoroalkyl-éthylène optiquement actif
US10336718B2 (en) 2015-06-25 2019-07-02 Central Glass Company, Limited Method for industrial production of optically active fluoroalkyl ethylene oxide

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