CN105566213B - The prodrugs composition of antimicrobial and antimicrobial related compound with high-penetration - Google Patents

The prodrugs composition of antimicrobial and antimicrobial related compound with high-penetration Download PDF

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Publication number
CN105566213B
CN105566213B CN201610005542.7A CN201610005542A CN105566213B CN 105566213 B CN105566213 B CN 105566213B CN 201610005542 A CN201610005542 A CN 201610005542A CN 105566213 B CN105566213 B CN 105566213B
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structural formula
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antimicrobial
acid
formula
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CN105566213A (en
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于崇曦
徐丽娜
陈玉华
严彬冰
涂仕前
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Taifeier Biomedical Suzhou Co ltd
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Techfields Biochem Co Ltd
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Priority claimed from US12/482,373 external-priority patent/US20100040548A1/en
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Priority claimed from CN201080035539.0A external-priority patent/CN102803211B/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/50—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in beta-position to the carboxamido radical
    • C07D499/52—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in beta-position to the carboxamido radical by oxygen or sulfur atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D499/21—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
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    • C07D499/21—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/62—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by sulfur atoms
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    • C07D499/21—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
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    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
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    • C07D499/21—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/74—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with carbocyclic rings directly attached to the carboxamido radical
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    • C07D499/21—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
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    • C07D499/86—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
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    • C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
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    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
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    • C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D503/12—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6
    • C07D503/14—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, attached in position 3
    • C07D503/16—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical
    • C07D503/18—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical by oxygen atoms
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    • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
    • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
    • C07D505/16—Nitrogen atoms
    • C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
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    • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
    • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
    • C07D505/16—Nitrogen atoms
    • C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
    • C07F9/32—Esters thereof
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof

Abstract

It there is provided herein composition (the high penetration compositions with high-penetration of antimicrobial and antimicrobial related compound,) or the prodrug with high-penetration (high penetration prodrugs, HPP) HPC.HPC/HPP can be converted to female medicine or drug metabolite after penetrating biological barrier, to provide treatment.In addition, the region that the reachable female medicine of the HPC/HPP cannot reach, or sufficiently high concentration can be reached in targeting region, to provide a kind of completely new therapeutic modality.

Description

The prodrug of antimicrobial and antimicrobial related compound with high-penetration Composition
The application is based on June 10th, 2010 submitting application No. is 201080035539.0, entitled " have The divisional application of the application of the antimicrobial of high-penetration and the prodrugs composition of antimicrobial related compound ".
Prioity claim
The application is the continuation in part application case of U.S. Patent application 12/482,373 filed on June 10th, 2009 and wants Its priority is sought, which is incorporated herein in way of reference.The application simultaneously requires China filed on June 10th, 2009 The priority of patent application 200910141944.X, China application are incorporated herein in way of reference.
Technical field
The present invention relates to the pharmaceutical compositions that can penetrate one or more layers biological barrier and the pharmaceutical composition pre- Prevent, diagnose and/or treat on any antimicrobial and antimicrobial related compounds-treatable symptom of humans and animals Using.The purposes and these pharmaceutical compositions use that the invention further relates to these pharmaceutical compositions on screening new drug candidates In the purposes for certain symptom for diagnosing certain biological object.
Background technique
Antimicrobial is the substance that can kill or inhibit the microorganisms such as bacterium, fungi or protozoan to grow, It can destroy or inhibit viral growth.The main species of microorganism include, for example, the related indication antibiotic of bacterium can be treated, can The related indication antiviral drugs for the treatment of virus, can treat the related indication antifungal drug of fungi and can treat protozoan Related indication antiprotozoals.
Beta-lactam antibiotic is a kind of antibiotic in the molecular structure containing quaternary cyclic amides core.More than 100000 kinds Beta-lactam antibiotic is produced (L.A.Mitscher, et al., antibiosis by semi-synthetic or fully synthetic method Element and antimicrobial drug, in D.F.Smith, Ed., alloisomerism handbook: therapeutic agent, Boca Raton, FL, CRC Press, 1989；R.B.Morin and M.Gorman Eds., the chemistry and biology of beta-lactam antibiotic roll up 1-3, New York Academic Press, 1982；And A.LDemain and N.A.Solomon, Eds., the structure containing beta-lactam it is anti- Raw element, volume 1 and 2, materia medica test handbook, volume 67, New York, Springer, 1983).The example packet of beta-lactam antibiotic Include penicillin derivative, cephalosporin, monobactams, Carbapenems, beta-lactamase inhibitor, sulfamido and Quinolones.
With a large amount of uses of antimicrobial, pathogen is mutated with the time so that drug resistance becomes common and serious Problem.Therefore, exploitation novel anti-microbial agent becomes urgent and challenging.
Numerous antimicrobials can be sprayed by intravenous injection, intramuscular injection, subcutaneous injection, oral cavity, is oral and straight The mode of enteral administration treats the systemic disease as caused by bacterium.The shortcomings that oral antibiotic, is gastrointestinal tract combating microorganisms The low absorptivity of agent.Intravenous injection, subcutaneous injection or intramuscular injection not only pain and also can only be by the trained people of sub-fraction Injection is completed, the injury of syringe needle bring, infection or other damages are in addition also added.
It the use of another method of drug is cutaneous penetration, cutaneous penetration has many good qualities, for example avoids gastro-intestinal digestion Drug inactivation caused by " head is crossed " effect of road and liver.This method can make the local drug concentration in affected part reach optimal Level avoids the systemic exposure of drug.Fishman (Fishman；Robert, U.S. Patent number 7,052,715) it proposes to take orally Drug can generate other problems, and the concentration of drug is wanted in the blood needed when can effectively treat the pain or inflammation of distal locations It is more much higher than concentration actually required.If these concentration level ratios medicine can be accurately delivered to required when pain spot or injury Concentration it is much higher.But for most of antimicrobials, the mode of topical administration, which cannot be such that drug reaches, effectively to treat The concentration of disease.
Therefore, there is an urgent need in the art to can effectively be transferred to the new compositions of certain symptom (such as: disease) action site, from And is preventing, slowing down or treat symptom while reduces side effect.
Summary of the invention abstract
An aspect of of the present present invention provides the prodrug (High Penetration Prodrug, HPP) with high-penetration Or the composition (High Penetration Composition, HPC) with high-penetration, it is logical to contain a functional unit It crosses an attachment and is covalently attached to a transhipment unit." HPP " and " HPC " term can be used separately or cooperatively in the present invention, be removed Except in the case of particularly pointing out, it can replace mutually.
In some embodiments, the functional unit of HPP or HPC contains a part (moiety) of agent (agent), The agent is efficiently and effectively delivered to biological object wherein and/or the agent is made to pass through one or more layers biological barrier Realize that transhipment is expected to.
In some embodiments, functional unit can be hydrophilic, lipophilic or double property (it is i.e. not only hydrophilic but also Lipophilic).For example, the lipophilicity of functional unit can be it is intrinsic, or by converting lipophilic for the hydrophilic segment of functional unit Partially obtain.In some embodiments, the carboxyl of functional unit, amino, guanidine radicals or other hydrophilic radicals can use alkyl, virtue Base or heteroaryl base ester or amide group are protected to form the HPP or HPC of more lipophilic.
In some embodiments, the functional unit of HPP or HPC contains antimicrobial or antimicrobial related compounds Object.Antimicrobial is the substance that can kill or inhibit the microorganisms such as bacterium, fungi, protozoan to grow, and can also be destroyed Viral growth.
Antimicrobial related compound is to contain antimicrobial structure, antimicrobial metabolin knot in a structure Structure can be metabolised to antimicrobial or antimicrobial metabolin after HPP or HPC penetrate one or more layers biological barrier Therapeutic substance structure compound.Antimicrobial related compound further comprises antimicrobial or antimicrobial generation The analog or analogies (mimic) or certain therapeutic substance of object are thanked, wherein the therapeutic substance can be penetrated in HPP or HPC The analog or analogies of antimicrobial or antimicrobial metabolin are metabolized to after one or more layers biological barrier.
The example of antimicrobial includes, for example, can treat the related indication antibiotic of bacterium, can treat viral related disease The antiviral drugs of shape can treat the related indication antifungal drug of fungi and can treat the related indication antigen of protozoan Raw animal pharmaceuticals.
The example of antimicrobial includes, but are not limited to beta-lactam antibiotic, sulfamido and quinolones antibiosis Element.The example of beta-lactam antibiotic include, but are not limited to penicillin derivative, cephalosporin, penems antibiotics, Monobactams, Carbapenems, beta-lactamase inhibitor, with and combinations thereof.The example of penicillin derivative includes, But it is not limited to amino penicillin (such as: Amoxicillin, ampicillin and Epicillin), carboxyl penicillin (such as: carboxylic benzyl mould Element, Ticarcillin and temocillin), ureido-penicillins (such as: azlocillin, Piperacillin and mezlocillin), Mecillinam, sulphur Benzyl XiLin, tardocillin, benzyl penicillin (parasiticin), ospen (penicillin Vl phenoxymethylpenicillin), penicillin (allylmercaptomethylpenicillinic), procaine penicillin, oxacillin, methicillin, naphthlazole, Cloxacillin, dicloxacillin, flucloxacillin, Pivampicillin, hetacillin, Bacampicillin (becampicillin), beauty Smooth XiLin, Talampicillin, amoxicillin (Amoxicillin+clavulanic acid) and Piperacillin.Cephalosporins Example include but is not limited to: cefalexin, cefoxitin, cephazoline, Cefaclor, cefuroxime, Cefamandole, cephalo For smooth, Cefoxitin, ceforanide, ceftriaxone, cefotaxime, Cefpodoxime Proxetil, cefotaxime, Cefepime, cephalo piperazine Ketone, Ceftizoxime, Cefixime and Cefpirome.The example of penems antibiotics includes but is not limited to: faropenem.Single acyl The example of amine ring class antibiotic includes but is not limited to: aztreonam and Tigemonam.The example of carbapenem antibiotic include but It is not limited to: Biapenem, doripenem, ertapenem, Imipenem, Meropenem and Panipenem.Beta lactamase restrainer Example include but is not limited to: Tazobactam ([2S- (2 α, 3 β, 5 α)] -3- methyl -7- ketone -3- (1H-1,2,3- triazoles - 1- ylmethyl) -4- thia -1- azabicyclo [3.2.0] heptane -2- carboxylic acid -4,4 titanium dioxide sodium salt), Sulbactam ((2S, 5R) - 3,3- dimethyl -7- ketone -4- thia -1- azabicyclo [3.2.0] heptane -2- carboxylic acid -4,4 sodium dioxides) and clavulanic acid ((2R, 5R, Z) -3- (2- hydroxy ethylene) -7- ketone -4- oxa- -1- azabicyclo [3.2.0] heptane -2- carboxylic acid).Other are anti- The example of raw element includes but is not limited to: [(N- benzyloxycarbonyl amino) methyl]-phosphoric acid-(4- nitrobenzophenone) ester sodium salt, [(N- benzyl Oxygen carbonyl amino) methyl]-phosphoric acid-(3- pyridyl group) ester sodium salt, sulfanilamide (SN), (4- aminobenzene sulfonamide), sulfasalazine (6- - two olefinic carboxylic acid of ketone -3- (2- [4- (N- pyrimidine -2-base sulfamoyl) phenyl] hydrazono-) ring octyl- Isosorbide-5-Nitrae), 1- cyclopropyl -6- Fluoro- 4- ketone -7- piperazine -1-y1- quinoline-3-carboxylic acid and acidum nalidixicum (1- ethyl -7- methyl -4- ketone-[1,8] naphthyridines -3- carboxylic Acid).
The example of sulfa antibiotics includes but is not limited to: sulfaisodimidine, sulfanilamide (SN), sulphadiazine, sulfanilamide (SN) are different Oxazole, sulfamethoxazole, madribon, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, Bu Mei His Buddhist nun, chlorthalidone, clopamide, frusemide, Hydrochioro, indapamide, mefruside, metolazone, Xipamide, double chlorine are non- That amine, Dorzolamide, acetazolamide, ethoxzolamide, Sultiame, Zonisamide, mafenide, celecoxib, Rui Lawei, third Sulphur relaxes, Ang nitrogen Haptocil and sumatriptan.
The example of quinolone antibiotics includes but is not limited to: cinoxacin, flumequine, nalidixic acid, oxolinic acid, pyrroles Acid, pipemidic acid, Rosoxacin, Ciprofloxacin, Enoxacin, fleraxacin, Lomefloxacin, Nadifloxacin, Norfloxacin, oxygen fluorine Sha Xing, pefloxacin, Rufloxacin, Balofloxacin, gatifloxacin, Grepafloxacin, lavo-ofloxacin, Moxifloxacin, pa pearl are husky Star, Sparfloxacin, Temafloxacin, tosufloxacin, Clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, T-3811 draws Flucloxacillin (delafloxacin) and acidum nalidixicum according to pungent Norfloxacin (ecinofloxacin), moral.
The example of antiviral class drug includes but is not limited to: rifampin, zanamivir and oseltamivir.
The example of antimycotic drug includes but is not limited to: polyene antifungal class drug is (such as: natamycin, streptomysin, phenanthrene Restrain guest's rhzomorph, nystatin, amphotericin B and candicin), imidazoles antimycotic drug (such as: Miconazole, ketoconazole, gram mould Azoles, econazole, bifonazole, butoconazole, Fenticonazole, Isoconazole, Oxiconazole, Demlofix, sulconazole and tioconazole), Antifungal triazole class drug is (such as: Fluconazole, Itraconazole, Chinese mugwort Saperconazole, ravuconazole, posaconazole, voriconazole and spy Health azoles), thiazoles antimycotic drug (such as: Abafungin), Allylamines antimycotic drug (such as: Terbinafine, A Moluo Fragrant, Naftifine and Butenafine), echinocandin-class (such as: anidulafungin, Caspofungin and mikafen) and other antimycotics Drug such as benzoic acid, Ciclopirox, Tolnaftate, undecenoic acid, Flucytosine, griseofulvin and Haloprogin.
The example of antiprotozoals class drug includes but is not limited to: Eflornithine (elornithine), furazolidone, beauty Draw arsine alcohol, metronidazole, Ornidazole, paromomycin sulfate, Pan Ta meter Ding, pyrimethamine and Tinidazole.
In some embodiments, the transhipment unit of HPP or HPC contains protonated amino, can help to or mentions High HPP or HPC is transported through across one or more layers biological barrier.In some embodiments, protonated amino can be It is substantially protonated under the conditions of the pH for the biological barrier that HPP or HPC are penetrated.In some embodiments, which can It is protonated inversely or deprotonation.
In some embodiments, attachment can be covalently attached the functional unit of HPP and transhipment unit, the attachment contain A kind of chemical bond can be sheared after HPP penetrates one or more layers biological barrier.The key that can be sheared includes, for example, covalently Key, ehter bond, thioether bond, amido bond, ester bond, thioester bond, carbonic acid key, amino methyl key, phosphoric acid ester bond or oxime key.
In some embodiments, the HPP or HPC of antimicrobial or antimicrobial related compound contain one Or two can be at physiological ph with level-one, second level existing for protonated form or tertiary amine group.In some embodiments, HPP or HPC contains one can be at physiological ph with level-one, second level existing for protonated form or tertiary amine group.
Another aspect of the present invention is related to pharmaceutical composition, contains at least one antimicrobial or antimicrobial The HPP or HPC and pharmaceutically acceptable carrier of related compound.
Another aspect of the present invention is related to HPP or HPC using antimicrobial or antimicrobial related compound The method for penetrating biological barrier.
Another aspect of the present invention is related to HPP or HPC using antimicrobial or antimicrobial related compound Diagnose the generation, development or the method to improve of certain symptom in biological object.In some embodiments, the HPP (or HPC) or Its functional unit can be detected.In some embodiments, the HPP (or HPC) or its functional unit itself can be detected or By detectable label substance markers or conjugation.
Another aspect of the present invention is related to the characteristics of certain expectation screening function, attachment or transhipment unit Method.
Another aspect of the present invention is related to the method for preventing in biological object, alleviating or treating certain symptom, this method By to the composition in the biological object administration present invention.In some embodiments, this method is related in biological object The method for treating antimicrobial or antimicrobial related compounds-treatable symptom, by effective to the object drug treatment The antimicrobial of dosage or the HPP of antimicrobial related compound or its pharmaceutical composition.In some embodiments, Include, but are not limited to pain, injury and symptom relevant to microorganism with the medicable symptom of this method.With microbial The symptom of pass refers to as microorganism symptom as caused by bacterium, fungi, protozoan and virus.For example, the disease as caused by bacterium Shape (the relevant symptom of bacterium), the symptom as caused by protozoan (the relevant symptom of protozoan), the symptom as caused by fungi (the relevant symptom of fungi) and the symptom as caused by virus (the relevant symptom of virus).The relevant symptom of bacterium includes example Such as, infection (such as: the infection of a certain organ for example liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gall-bladder, Duodenum, rectum, stomach, Colon and rectum, intestines, vein, respiratory system, vascular, anal orifice and rectal intestine and pruritus ani, respiratory tract Infection, the infection of the upper respiratory tract, urinary tract infections, nosocomial infection, pseudomonas infection, coagulase-positive staphylococci infection are (such as: skin Skin infection, nosotoxicosis, acute infective endocarditis, septicaemia, necrotizing pneumonia), implantation prosthese postoperative infection, with septicaemia Infected with the chance of pneumonia), pestilence (such as: bubonic plague and pneumonic plague), anthrax (such as: malignant pustule, pulmonary anthrax stomach function regulating Intestinal anthrax), Lyme disease, brucellosis, pertussis, chordapsus, psittacosis, non-gonococcal urethritis, trachoma, newborn packet Contain body membranous conjunctivitis, lymphogranuloma venereum, pseudomembranous colitis, emphysematous gangrene, food poisoning, anaerobic cellulitis, Diphtheria, dysentery, neonatal meningitis, hemorrhagic colitis, hemolytic uremic syndrome, yatobyo, pneumonia, bronchitis, Gastric ulcer, legionaires' disease, Pang Tiya grams of heat, leptospirosis, listerellosis, leprosy, tuberculosis, Eaton agent pneumonia, leaching Disease, ophthalmia neomatorum, septic arthritis, successive eruption and prevalence meningococcosis, Waterhouse-Frederichsens syndrome are (acute sudden and violent Hair property meningococcus bacteremia), Rocky Mountain spotted fever, typhoid fever type salmonellosis (typhoid fever type Salmonellosis), with the salmonellosis of gastroenteritis and colitis, bacillary dysentery, bacillary dysentery, cystitis, brain Film inflammation, septicaemia, endometritis, tympanitis, nasosinusitis, syphilis, necrotizing fasciitis, streptococcal pharyngitis, scarlet fever, wind Damp and hot, impetigo, erysipelas, puerperal fever and cholera.Protozoan related symptoms include, for example: malaria, difussa and toxoplasm Disease.Fungi related symptoms include, for example: aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycosis, cryptococcosis, Histoplasmosis, paracoccidiomycosis, sporotrichosis and zygomycosis.Viral related symptoms include, for example: Influenza, yellow fever and AIDS.
In some embodiments, the pharmaceutical composition of HPP or HPC can deliver medicine to biological object through a variety of ways, packet It includes, but is not limited to, oral route, enteral routes, oral cavity route, nasal, topical route, anal route, vaginal approach, gas Mist agent approach, transmucosal route, epithelium approach, transdermal route, cutaneous routes, ocular route, pulmonary route, subcutaneous route and/ Or drug administration by injection approach.In some preferred embodiments, HPP or HPC can by oral, transdermal, external application, it is subcutaneous and/or Injection administration.
It is consistent with advantage of the invention, and be not intended to and limited by any specific mechanism, the HPP or HPC for the treatment of effective dose It can be locally administered in symptom site with relatively low-dose and obtain higher concentration.Advantage of the invention further includes, for example, avoiding system Administration reduces side effect (e.g., injection pain, gastrointestinal tract or kidney response or other side effects), and due to HPP, HPC or work The property possible new therapeutic modality of substance high local concentrations bring.Advantage of the invention further comprises, for example, HPP or HPC How bioavilability faster efficiently can be realized to being administered systemically for biological object, penetrate the biological barrier for being difficult to cross over (e.g., blood-brain barrier and rate of blood-milk barrier), and the new therapeutic modality as brought by through biological barrier.
Detailed description of the invention
Fig. 1 a1: by the 6- of the human skin tissue separated in the pond Franz (n=5) to benzene oxygen acetylamino penicillin Acid -2- lignocaine ethyl ester hydrochloride (A), allylmercaptomethylpenicillin acid -2- lignocaine ethyl ester hydrochloride (B), 6- (2,6- Dimethoxybenzarnide) penicillinic acid -2- lignocaine ethyl ester hydrochloride (C), 6- (5- methyl -3- phenyl -2- isoxazole Quinoline -4- formamido group) penicillinic acid -2- lignocaine ethyl ester hydrochloride (D), 6- [the different evil of 3- (Chloro-O-Phenyl) -5- methyl -4- Azoles formamido group] penicillinic acid -2- lignocaine ethyl ester hydrochloride (E), 6- [the different evil of 3- (2,6- dichlorophenyl) -5- methyl -4- Azoles formamido group] penicillinic acid -2- lignocaine ethyl ester hydrochloride (F), ospen (G), penicillin (H), methoxy benzene mould Plain (I), oxacillin (J), the accumulation total amount of cloxacillin (K) and dicloxacillin (L).In each example In, carrier solution is the phosphate buffer solution (0.2M) of pH 7.4.
Fig. 1 a2: by the 6- [D (-)-alpha-acetamido phenylacetyl of the human skin tissue separated in the pond Franz (n=5) Amino] penicillinic acid -2- lignocaine ethyl ester hydrochloride (A), D- α-[(imidazolidine -2- ketone -1- base) formamido group] benzyl mould Element -2- lignocaine ethyl ester hydrochloride (B), 6R- [2- [3- (mesyl) -2- ketone -1- imidazolidine formamido group] -2- benzene second Acylamino-] penicillinic acid -2- lignocaine ethyl ester hydrochloride (C), 6-D (-)-α-(4- ethyl -2,3- diketone -1- piperazine formyl Amino)-α-phenylacetylamino penicillinic acid -2- lignocaine ethyl ester hydrochloride (D), 7- (2- thiophenacetyl amino) cephalo alkane Acid -2- lignocaine ethyl ester hydrochloride (E), ampicillin (F), azlocillin (G), and mezlocillin (H), Piperacillin (I), With the accumulation total amount of cephalosporin (J).In each example, carrier solution is the phosphate buffer solution of pH 7.4 (0.2M)。
Fig. 1 a3: by 7- [(oxybenzene acetyl group) amino] -3- of the human skin tissue separated in the pond Franz (n=5) [[(1- methyl-1 H- tetrazole -5- base) sulphur] methyl] -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic Acid -2- lignocaine ethyl ester hydrochloride (A), 3- [[(amino carbonyl) oxygen] methyl] -7- [[2- furyl (methoxyimino) second Acylamino-] -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid -2- lignocaine ethyl ester hydrochloride (B), 3- [[(amino carbonyl) oxygen] methyl] -7- methoxyl group -8- ketone -7- [(2- thienyl acetyl) amino)] -5- thia -1- azepine pair Ring-[4.2.0]-oct-2-ene -2- carboxylic acid 2- lignocaine ethyl ester hydrochloride (C), 7- [[[2- (acetylamino methyl) phenyl] Acetyl group] amino] -3- [[[1- (ethoxy carbonyl methyl) -1H- tetrazole -5- base] sulphur] methyl] -8- ketone -5- thia -1- nitrogen Miscellaneous bicyclic [4.2.0] oct-2-ene -2- carboxylic acid -2- lignocaine ethyl ester hydrochloride (D), 7- [(acetylamino phenylacetyl) amino] - Chloro- 8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid -2- lignocaine ethyl ester hydrochloride (E) of 3-, cephalo Meng is more (F), cefuroxime (G), Cefoxitin (H), the accumulation total amount of ceforanide (I) and Cefaclor (J).In each example In son, carrier solution is the phosphate buffer solution (0.2M) of pH 7.4.
Fig. 1 a4: by 3- [(acetoxyl group) methyl] -7- of the human skin tissue separated in the pond Franz (n=5) [[(2- acetylaminohydroxyphenylarsonic acid 4- thiazolyl) (methoxyimino) acetyl group] amino] -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid -2- lignocaine ethyl ester hydrochloride (A), 7- [[(2- acetylaminohydroxyphenylarsonic acid 4- thiazolyl) (methoxy Imino group) acetyl group] amino] -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid -2- lignocaine second Ester hydrochloride (B), 7- [[[[(4- ethyl -2,3- diketone -1- piperazine) carbonyl] amino]-(4- acetoxyl group phenyl) acetyl group] Amino] -3- [[(1- methyl-1 H- tetrazolium -5- base) sulphur] methyl] -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene - 2- carboxylic acid -2- lignocaine ethyl ester hydrochloride (C), 7- [2- (2- acetylaminohydroxyphenylarsonic acid 4- thiazolyl) -2- ((Z)-methoxyimino) Acetylamino] -3- (methoxy) -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid -2- diethylamino Base carbethoxy hydrochloride (D), 7- [2- (2- acetylaminohydroxyphenylarsonic acid 4- thiazole) -2- ((Z)-ethoxycarbonylmethoxy) imino group] acetyl ammonia Base] -3- (vinyl) -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid -2- lignocaine ethyl ester hydrochloric acid The accumulation of salt (E), cefotaxime (F), Ceftizoxime (G), cefoperazone (H), Cefpodoxime Proxetil (I) and Cefixime (J) is total Amount.Carrier solution is the phosphate buffer solution (0.2M) of pH 7.4.
Fig. 1 b:[2S- (2a, 3b, 5a)] -3- methyl -7- ketone -3- (1H-1,2,3- triazole -1- ylmethyls) -4- sulphur Generation -1- azabicyclo [3,2,0] heptane -2- carboxylic acid -4,4- titanium dioxide sodium salt (Tazobactam Sodium, curve F), [2S- (2a, 3b, 5a)] -3- methyl -7- ketone -3- (1H-1,2,3- triazole -1- ylmethyls) thio -1- azabicyclo [3,2, the 0] heptane -2- of -4- Carboxylic acid -4,4- dioxide 1- piperidines carbethoxy hydrochloride (his azoles bar-PEE, curve A), (2S, 5R) -3,3- dimethyl -7- ketone - 4- thia -1- azabicyclo [3,2,0] heptane -2- carboxylic acid sodium -4,4- sodium dioxide (Sulbactam, curve G), (2S, 5R) -3, 3- dimethyl -7- ketone -4- thia -1- azabicyclo [3,2,0] heptane -2- carboxylic acid sodium -4,4- dioxide N, N- lignocaine Carbethoxy hydrochloride (Sulbactam-DEE, curve B), 2R- (2a, 3Z, 5a) -3- (2- hydroxyalkyl vinyl base) -7- ketone -4- oxa- -1- azepine Two rings [3.2.0]-heptane -2- carboxylic acid-(clavulanic acid-curve H), 2R- (2a, 3Z, 5a) -3- (2- hydroxyalkyl vinyl base) -7- ketone - 4- oxa- -1- azabicyclic [3.2.0]-heptane -2- carboxylic acid 4- piperidines carbethoxy hydrochloride (clavulanic acid-PEE, curve C), [(N- Benzene oxygen carbon acylamino) methyl] mono- (4- nitrobenzophenone) ester sodium salt (curve I) of-phosphonic acids, [(N- benzene oxygen carbon acylamino) methyl]- Phosphonic acids mono- (4- nitrobenzophenone) (N, N- Diethylaminomethyl) ester hydrochloride (curve D), [(N- benzene oxygen carbon acylamino) methyl]- Mono- (3- pyridyl group) ester sodium salt (curve J) of phosphonic acids and [(N- benzene oxygen carbon acylamino) methyl] mono- (3- pyridyl group)-(1- of-phosphonic acids Piperidinoethyl) ester hydrochloride (curve E) pass through the pond Frannz in fell accumulation total amount (n=5).Carrier solution is 0.2M The phosphate buffer solution of pH value 7.4.
Fig. 1 c: curve is respectively 4- aminobenzene sulfonamide (to amine benzsulfamide, E), 4- (4- dimethylamino bytyry) -4- Aminobenzene sulfonamide hydrochloride (DMAB- is to amine benzsulfamide, A), 6- ketone -3- (2- [4- (N- pyridine -2-y1 sulfamoyl) Phenyl] hydrazono-)-two olefinic carboxylic acid of hexamethylene-Isosorbide-5-Nitrae, 6- ketone -3- (the sub- connection of 2- [4- (N- pyridine -2-y1 sulfamoyl) phenyl] Amino)-two olefinic carboxylic acid (salicylazosulfapyridine, F) of hexamethylene-Isosorbide-5-Nitrae, 6- ketone -3- (2- [4- (N- pyridine -2-y1 sulfamoyl) benzene Base] hydrazono-)-two olefinic carboxylic acid N, N- lignocaine propyl ester hydrochloride (salicylazosulfapyridine-DEPE, B) of hexamethylene-Isosorbide-5-Nitrae, 1- The fluoro- Isosorbide-5-Nitrae of cyclopropyl -6--dihydro -4- ketone -7 (1- piperazinyl) -3- quinoline carboxylic acid (Ciprofloxacin, G), 1- cyclopropyl -6- are fluoro- Isosorbide-5-Nitrae-dihydro -4- ketone -7 (1- piperazinyl) -3- quinoline carboxylic acid butyl ester hydrochloride (Ciprofloxacin-BE, C), 1- ethyl-Isosorbide-5-Nitrae - Dihydro -7- methyl -4- ketone -1,8- naphthyridines -3- carboxylic acid (acidum nalidixicum, H), 1- ethyl-Isosorbide-5-Nitrae-dihydro -7- methyl -4- ketone -1,8- Naphthyridines -3- carboxylic acid N, N- lignocaine ethyl ester hydrochloride (acidum nalidixicum-DEE, D) passes through the accumulation total amount of fell in the pond Frannz (n=5).Carrier solution is pH value 7.40.2M phosphate buffer solution.
Detailed description
I. the prodrug (high penetration prodrug, HPP) of high-penetration or the composition (high of high-penetration Penetration composition, HPC) structure
An aspect of of the present present invention is related to the prodrug (high penetration prodrug, HPP) of high-penetration or height is worn The composition (high penetration composition, HPC) of permeability." prodrug of high-penetration " or " HPP " or " height is worn The composition of permeability " or " HPC " refer to certain composition in the present invention, contain through attachment (linker) covalent linkage Functional unit and transhipment unit.
The functional unit of HPP or HPC contains a part (moiety) of female medicine, 1) which has the property that Female medicine or HPP/HPC are transmitted into biological object and/or transport female medicine across certain biological barrier and is expected to；2)HPP/ HPC can be penetrated or across biological barrier；And 3) HPP/HPC can be sheared to make female medicine be partially converted into female medicine or mother The metabolin of medicine.
In some embodiments, functional unit can be hydrophilic, lipophilic or double property (it is i.e. not only hydrophilic but also Lipophilic).The lipophilic moieties of functional unit can be it is intrinsic, or by by one or more hydrophilic parts of functional unit It is converted into lipophilic moieties and obtains.For example, the lipophilic moieties of functional unit can be by by the one or more of functional unit Hydrophilic radical is converted into lipophilic group by organic synthesis.The example of hydrophilic radical includes, but are not limited to carboxyl, hydroxyl Base, mercaptan, amino, phosphate/phosphonate ester, guanidine radicals and carbonyl.By the lipophilic moieties for modifying the generation of these hydrophilic radicals Include, but are not limited to ether, thioether, ester, thioesters, carbonate, carbaminate, amide, phosphate and/or oxime.In certain implementations In mode, functional unit can pass through acetylation or acylated realization lipophilicity.In some embodiments, functional unit can pass through ester Change and realizes lipophilicity.
In some embodiments, female medicine of HPP or HPC can be selected from one group by antimicrobial or antimicrobial correlation The set of compound composition.Antimicrobial or a part of of antimicrobial related compound can be by further according to aforementioned Method is converted into lipophilic moieties.
Antimicrobial is the substance that can kill or inhibit the microorganisms such as bacterium, fungi or protozoan to grow, It can destroy or inhibit viral growth.The main type that antimicrobial includes has, for example, it is related indication anti-to treat bacterium Raw element can treat the related indication antiviral drugs of virus, can treat the related indication antifungal drug of fungi and can treat The related indication anti-parasite medicine of helminth.
Antimicrobial related compound is containing antimicrobial structure, antimicrobial metabolite structures or can quilt It is metabolized to the compound of the therapeutic substance structure of antimicrobial or antimicrobial metabolin.Antimicrobial related compound It further comprise analog or the simulation of the analog or analogies (mimic) or antimicrobial metabolin of antimicrobial Object or certain therapeutic substance, the therapeutic substance can be metabolized to resist micro- after HPP or HPC penetrate one or more layers biological barrier The analog or analogies of biological agent or antimicrobial metabolin.
The example of antimicrobial includes, for example, can treat the related indication antibiotic of bacterium, can treat viral related disease The antiviral drugs of shape can treat the related indication antifungal drug of fungi and can treat the related indication antigen of protozoan Raw animal pharmaceuticals.
The example of antibiotic includes, but are not limited to beta-lactam antibiotic, sulfamido and quinolone antibiotics.β- Lactam antibiotics in a variety of symptoms it is known in the art that and use.In the present invention, beta-lactam antibiotic refers to Compound containing beta-lactam core.
It is anti-that the example of beta-lactam antibiotic includes, but are not limited to penicillin derivative, cephalosporin, penems Raw element, monobactams, Carbapenems, beta-lactamase inhibitor, with and combinations thereof.The example of penicillin derivative Include, but are not limited to amino penicillin (such as: Amoxicillin, ampicillin and Epicillin), carboxyl penicillin (such as: carboxylic Parasiticin, Ticarcillin and temocillin), ureido-penicillins (such as: azlocillin, Piperacillin and mezlocillin), beauty XiLin, sulbenicillin, tardocillin, benzyl penicillin (parasiticin), ospen (penicillin Vl phenoxymethylpenicillin), penicillin (allylmercaptomethylpenicillinic), procaine penicillin, oxacillin, methicillin, naphthlazole, Cloxacillin, dicloxacillin, flucloxacillin, Pivampicillin, hetacillin, Bacampicillin (becampicillin), beauty Smooth XiLin, Talampicillin, amoxicillin (Amoxicillin+clavulanic acid) and Piperacillin.Cephalosporins Example include but is not limited to: cefalexin, cefoxitin, cephazoline, Cefaclor, cefuroxime, Cefamandole, cephalo For smooth, Cefoxitin, ceforanide, ceftriaxone, cefotaxime, Cefpodoxime Proxetil, cefotaxime, Cefepime, cephalo piperazine Ketone, Ceftizoxime, Cefixime and Cefpirome.The example of penems antibiotics includes but is not limited to: faropenem.Single acyl The example of amine ring class antibiotic includes but is not limited to: aztreonam and Tigemonam.The example of carbapenem antibiotic include but It is not limited to: Biapenem, doripenem, ertapenem, Imipenem, Meropenem and Panipenem.Beta lactamase restrainer Example include but is not limited to: Tazobactam ([2S- (2 α t, 3 β, 5 α)] -3- methyl -7- ketone -3- (1H-1,2,3- triazoles - 1- ylmethyl) -4- thia -1- azabicyclo [3.2.0] heptane -2- carboxylic acid -4,4 titanium dioxide sodium salt), Sulbactam (2S, 5R) - 3,3- dimethyl -7- ketone -4- thia -1- azabicyclo [3.2.0] heptane -2- carboxylic acid -4,4 sodium dioxides and clavulanic acid ((2R, 5R, Z) -3- (2- hydroxy ethylene) -7- ketone -4- oxa- -1- azabicyclo [3.2.0] heptane -2- carboxylic acid).Other are anti- The example of raw element includes but is not limited to: [(N- benzyloxycarbonyl amino) methyl]-phosphoric acid-(4- nitrobenzophenone) ester sodium salt, [(N- benzyl Oxygen carbonyl amino) methyl]-phosphoric acid-(3- pyridyl group) ester sodium salt, sulfanilamide (SN), (4- aminobenzene sulfonamide), sulfasalazine (6- - two olefinic carboxylic acid of ketone -3- (2- [4- (N- pyrimidine -2-base sulfamoyl) phenyl] hydrazono-) ring octyl- Isosorbide-5-Nitrae), 1- cyclopropyl -6- Fluoro- 4- ketone -7- piperazine -1-y1- quinoline-3-carboxylic acid and acidum nalidixicum (1- ethyl -7- methyl -4- ketone-[1,8] naphthyridines -3- carboxylic Acid).
The example of sulfa antibiotics includes but is not limited to: sulfaisodimidine, and sulfanilamide (SN), sulphadiazine, sulfanilamide (SN) are different Oxazole, sulfamethoxazole, madribon, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, Bu Mei His Buddhist nun, chlorthalidone, clopamide, frusemide, Hydrochioro, indapamide, mefruside, metolazone, Xipamide, double chlorine are non- That amine, Dorzolamide, acetazolamide, ethoxzolamide, Sultiame, Zonisamide, mafenide, celecoxib, Rui Lawei, third Sulphur relaxes, Ang nitrogen Haptocil and sumatriptan.
The example of quinolone antibiotics includes but is not limited to: cinoxacin, flumequine, nalidixic acid, oxolinic acid, pyrroles Acid, pipemidic acid, Rosoxacin, Ciprofloxacin, Enoxacin, fleraxacin, Lomefloxacin, Nadifloxacin, Norfloxacin, oxygen fluorine Sha Xing, pefloxacin, Rufloxacin, Balofloxacin, gatifloxacin, Grepafloxacin, lavo-ofloxacin, Moxifloxacin, pa pearl are husky Star, Sparfloxacin, Temafloxacin, tosufloxacin, Clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, T-3811 draws Flucloxacillin (delafloxacin) and acidum nalidixicum according to pungent Norfloxacin (ecinofloxacin), moral.
The example of antiviral class drug includes but is not limited to: rifampin, zanamivir and oseltamivir.
The example of antimycotic drug includes but is not limited to: polyene antifungal class drug is (such as: natamycin, streptomysin, phenanthrene Restrain guest's rhzomorph, nystatin, amphotericin B, candicin), imidazoles antimycotic drug (such as: Miconazole, ketoconazole, gram mould Azoles, econazole, bifonazole, butoconazole, Fenticonazole, Isoconazole, Oxiconazole, Demlofix, sulconazole and tioconazole), Antifungal triazole class drug (such as: Fluconazole, Itraconazole, Chinese mugwort Saperconazole, ravuconazole, posaconazole, voriconazole and Terconazole), thiazoles antimycotic drug (such as: Abafungin), Allylamines antimycotic drug (such as: Terbinafine, A Mo Luo Fen, Naftifine and Butenafine), echinocandin-class (such as: anidulafungin, Caspofungin and mikafen) and other antimycotic Class drug such as benzoic acid, Ciclopirox, Tolnaftate, undecenoic acid, Flucytosine, griseofulvin and Haloprogin.
The example of antiprotozoals class drug includes but is not limited to: Eflornithine (elornithine), furazolidone, beauty Draw arsine alcohol, metronidazole, Ornidazole, paromomycin sulfate, Pan Ta meter Ding, pyrimethamine and Tinidazole.
In some embodiments, the functional unit of the HPP of antimicrobial or antimicrobial related compound includes Structure with structural formula F-1:
Including its stereoisomer and its pharmaceutically acceptable salt.
Unless being otherwise noted in the description, Y is selected from the set being made of following group: H, OH, NHCHO, NHC (=O) R6, OC (=O) CH3, OC (=O) R6、OCH3、OC2H5、OR6、 CH3SO3、R6SO3、NO2、CN、CF3、OCF3、OC2F5、OC3F7、F、 Br, I, Cl and substitution and unsubstituted alkoxy；
Selected from by structural formula NS-1, structural formula NS-2, structural formula NS-3, structural formula NS-4 and structural formula The set of NS-5 composition:
X1Selected from the set being made of following group: H, OH, OCH3、OC2H5、OR6, C (=O) NH2、CH2OC (=O) NH2、 CH2OC (=O) CH3、CH2OC (=O) CH6, OC (=O) CH3, OC (=O) R6、CH2OCH3、CH3、C2H5、R6、Cl、F、Br、I、 HC=CHCH3, HC=CH2、CH2OCH3、CH2OR6、S(CH2)n-NHR7, structural formula X1- 1, structural formula X1- 2, structural formula X1- 3, it ties Structure Formula X1- 4, structural formula X1- 5, structural formula X1- 6, structural formula X1- 7, structural formula X1- 8, structural formula X1- 9, structural formula X1- 10, it ties Structure Formula X1- 11, structural formula X1- 12, structural formula X1- 13, structural formula X1- 14, structural formula X1- 15, structural formula X1- 16, structural formula X1- 17, structural formula X1- 18, structural formula X1- 19, structural formula X1- 20, structural formula X1- 21, structural formula X1- 22, structural formula X1-23、 Structural formula X1- 24, structural formula X1- 25, structural formula X1- 26, structural formula X1- 27, structural formula X1- 28, structural formula X1- 29, structural formula X1- 30, structural formula X1- 31, structural formula X1- 32, structural formula X1- 33, structural formula X1- 34, structural formula X1- 35, structural formula X1-36、 Structural formula X1- 37, structural formula X1- 38, structural formula X1- 39, structural formula X1- 40, structural formula X1- 41, structural formula X1- 42, structure Formula X1- 43, structural formula X1- 44, structural formula X1- 45, structural formula X1- 46, structural formula X1- 47, structural formula X1- 48, structural formula X1- 49, structural formula X1- 50, structural formula X1- 51, structural formula X1- 52, structural formula X1- 53, structural formula X1- 54, structural formula X1- 55, it ties Structure Formula X1- 56, structural formula X1- 57, structural formula X1- 58, structural formula X1- 59, structural formula X1- 60, structural formula X1- 61, structural formula X1- 62, structural formula X1- 63, structural formula X1- 64, structural formula X1- 65, structural formula X1- 66, structural formula X1- 67, structural formula X1-68、 Structural formula X1- 69, structural formula X1- 70, structural formula X1- 71, structural formula X1- 72, structural formula X1- 73, structural formula X1- 74, structural formula X1- 75, structural formula X1- 76, structural formula X1- 77, structural formula X1- 78, structural formula X1- 79, structural formula X1- 80, structural formula X1-81 With structural formula X1- 82:
RsR is cooperatively represented with Y6OCH2C(R5)=, itself is selected from the set being made of following group: R6OOCCH (NHR7)(CH2)nCONH-、R6OOCCH(NHR7)(CH2)nSCONH-、 CF3SCH2CONH-、CF3CH2CONH-、 CHF2SCH2CONH-、CH2FSCH2CONH-、 NH2COCHFS-CH2CONH-、R7NHCH(L1-L4-L2-W)CH2SCH2CONH-、 CNCH2SCH2CONH-、CH3(CH2)nCONH-、R7N=CHNR7CH2CH2S-、 R7N=C (NHR7)NHCO-、CH2、CH3C(Cl) =CHCH2SCH2CONH-、 (CH3)2C(OR6)-、CNCH2CONH-、CNCH2CH2S-、R7HN=CH (NR7)CH2CH2S-、 CH2 =CHCH2SCH2CONH-、CH3CH(OH)-、CH3CH(OR8)-、CH3CH(Y1)-、 (CH3)2CH-、CH3CH2-、CH3(CH2)nCH =CH (CH2) mCONH-, R7N=C (NHR7) NHC (=O) CH2, formula R s-1, formula R s-2, formula R s-3, structure Formula Rs-4, formula R s-5, formula R s-6, formula R s-7, formula R s-8, formula R s-9, formula R s-10, knot Structure formula Rs-11, formula R s-12, formula R s-13, formula R s-14, formula R s-15, formula R s-16, structural formula Rs-17, formula R s-18, formula R s-19, formula R s-20, formula R s-21, formula R s-22, formula R s- 23, formula R s-24, formula R s-25, formula R s-26, formula R s-27, formula R s-28, formula R s-29, knot Structure formula Rs-30, formula R s-31, formula R s-32, formula R s-33, formula R s-34, formula R s-35, structural formula Rs-36, formula R s-37, formula R s-38, formula R s-39, formula R s-40, formula R s-41, formula R s- 42, formula R s-43, formula R s-44, formula R s-45 and formula R s-46；
W is selected from the set being made of following group: H, substitution and unsubstituted alkyl, substitution and unsubstituted cyclic hydrocarbon radical, Replace and unsubstituted heterocyclic hydrocarbyl, substitution and unsubstituted oxyl, substitution and unsubstituted alkenyl, substitution and unsubstituted Alkynyl, substitution and unsubstituted aryl, substitution and unsubstituted heteroaryl, protonated amino, pharmaceutically acceptable substitution and meeting Substituted level-one amino, structural formula Wa, structural formula W-1, structural formula W-2, structural formula W-3, structural formula W-4, structural formula W-5, knot Structure formula W-6, structural formula W-7, structural formula W-8, structural formula W-9, structural formula W-10, structural formula W-11, structural formula W-12, structural formula W-13, structural formula W-14, structural formula W-15, structural formula W-16, structural formula W-17 and structural formula W-18:
Z is selected from the set being made of following group: CH2、S、SO、SO2、NH、NR6、CHCH3、 CHCH2CH3、CHR6、R6、-C (=O)-and O；
AA represents arbitrary amino acid；
Each m and n can be respectively and independently selected from the set being made of 0 and integer, such as 0, and 1,2,3,4,5,6,7,8,9, 10,11,12,13,14,15,16,17,18,19,20 ...；
HA is selected from the set being made of following group: nothing, pharmaceutically acceptable acid, such as: HCl, HBr, HI, nitric acid, sulphur Acid, sulfurous acid, phosphoric acid, phosphorous acid, phosphonic acids, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, acid wine Stone acid, ascorbic acid, succinic acid, maleic acid, gentianic acid (gentisinic acid), fumaric acid, gluconic acid, glucose Aldehydic acid (glucaronic acid), saccharic acid, formic acid, benzoic acid, glutamic acid, methane sulfonic acid, ethylsulfonic acid, benzene sulfonic acid, to first Benzene sulfonic acid and pamoic acid；
R is selected from the set being made of following group: nothing, CH2C (=O) OR6, replace and unsubstituted alkyl, substitution and not Substituted cyclic hydrocarbon radical, substitution and unsubstituted heterocyclic hydrocarbyl, substitution and unsubstituted oxyl, substitution and unsubstituted polyfluohydrocarbon Base, substitution and unsubstituted halohydrocarbyl, substitution and unsubstituted alkenyl, substitution and unsubstituted alkynyl, substitution and unsubstituted Aryl and replace and unsubstituted heteroaryl, wherein any CH in R2It can be by O, S, P, NR6Or any other pharmaceutically may be used The group of receiving substitutes；
R1-R3Can be separately selected from the set that is made of following group: H, substitution and unsubstituted alkyl, substitution and Unsubstituted cyclic hydrocarbon radical, substitution and unsubstituted heterocyclic hydrocarbyl, substitution and unsubstituted oxyl, substitution and unsubstituted alkene Base, substitution and unsubstituted alkynyl, substitution and unsubstituted aryl and substitution and unsubstituted heteroaryl；
R5And R35It can be separately selected from the set being made of following group: H, C (=O) NH2、 CH2CH2OR6、 CH2CH2N(CH3)2、CH2CH2N(CH2CH3)2, Cl, F, Br, I, substitution and unsubstituted alkyl, substitution and unsubstituted cyclic hydrocarbon Base, substitution and unsubstituted heterocyclic hydrocarbyl, substitution and unsubstituted oxyl, substitution and unsubstituted cyclic hydrocarbon oxygroup, replace and Unsubstituted aryl, substitution and unsubstituted heteroaryl, substitution and unsubstituted hydrocarbon carbonyl, substitution and unsubstituted hydrocarbon amino, - C (=O)-W, L1-L4-L2- W and W；
R6、R36And R46It can be separately selected from the set being made of following group: H, F, Cl, Br, I, Na+、K+、C (=O) R5, 2- ketone -1- imidazolidinyl, phenyl, 5- indanyl, 2,3- dihydro -1H- indenes -5- base, 4- hydroxyl -1,5- naphthyridines -3- It base, substitution and unsubstituted alkyl, substitution and unsubstituted cyclic hydrocarbon radical, substitution and unsubstituted heterocyclic hydrocarbyl, substitution and does not take Alkenyl, substitution and the unsubstituted alkynyl in generation, substitution and unsubstituted oxyl, substitution and unsubstituted cyclic hydrocarbon oxygroup replace With unsubstituted aryl, substitution and unsubstituted heteroaryl ,-C (=O)-W, L1-L4-L2- W and W；
R7And R37It can be separately selected from the set being made of following group: H, F, Cl, Br, I, CH3NHC (=O) CH2CH(NHR8) C (=O), R5N=C (NHR6) NHC (=O)-, C (=O) CH3, C (=O) R6、PO(OR5)OR6, replace and not Substituted alkyl, substitution and unsubstituted cyclic hydrocarbon radical, substitution and unsubstituted heterocyclic hydrocarbyl, substitution and unsubstituted oxyl, Replace and unsubstituted alkenyl, substitution and unsubstituted alkynyl, substitution and unsubstituted aryl, substitution and unsubstituted heteroaryl Base, substitution and unsubstituted hydrocarbon carbonyl, substitution and unsubstituted hydrocarbon amino, L1-L4-L2- W and C (=O)-W；
R8And R38It can be separately selected from the set being made of following group: H, F, Cl, Br, I, CH3、C2H5、CF3、 CH2CH2F、CH2CH2Cl、CH2CH2Br、CH2CH2I、CH2CHF2、 CH2CF3、CH2F、CH2Cl、CH2Br、CH2I、CH2NR6R7、CH (NHR7)CH2C (=O) NH2、 C3H7、C4H9、C5H11、R6, C (=O) R6, C (=O) NH2、CH2C (=O) NH2、 CH2OC (=O) NH2、PO(OR5)OR6、C(CH3)2C (=O) OR6、CH(CH3) C (=O) OR6、 CH2C (=O) OR6, C (=O)-W, L1-L4-L2- W, it W, substitution and unsubstituted polyfluoro alkyl, substitution and unsubstituted alkyl, substitution and unsubstituted cyclic hydrocarbon radical, substitution and does not take Heterocyclic hydrocarbyl, substitution and the unsubstituted oxyl in generation, substitution and unsubstituted hydrocarbon amino, substitution and unsubstituted polyfluohydrocarbon Base, substitution and unsubstituted halohydrocarbyl and substitution and unsubstituted hydrocarbon carbonyl；
R11-16It is respectively and independently selected from the set being made of following group: nothing, H, CH2C (=O) OR11, replace and it is unsubstituted Alkyl, substitution and unsubstituted cyclic hydrocarbon radical, substitution and unsubstituted heterocyclic hydrocarbyl, substitution and unsubstituted oxyl, substitution and Unsubstituted polyfluoro alkyl, substitution and unsubstituted halohydrocarbyl, substitution and unsubstituted alkenyl, substitution and unsubstituted alkynes Base, substitution and unsubstituted aryl and substitution and unsubstituted heteroaryl；
X2Selected from the set being made of following group: nothing, H, CH2(CH2)nOR8、Cl、F、Br、I、 NO2、CN、CF3、C2F5、 C3F7、OCF3、OC2F5、NH2、NHR6、CH3、C2H5、 R6, C (=O) NH2、CH2OC (=O) NH2、CH2C (=O) OR5、CH2 (CH2)nN(CH3)2、 CH2(CH2)nSO3R5, replace and unsubstituted alkyl, substitution and unsubstituted cyclic hydrocarbon radical, substitution and do not take The heterocyclic hydrocarbyl in generation, substitution and unsubstituted polyfluoro alkyl, substitution and unsubstituted alkyl, substitution and unsubstituted sulfenyl, Replace and unsubstituted hydrocarbon amino and substitution and unsubstituted oxyl；
X3Selected from the set being made of following group: nothing, H, N3、SO3W、F、Cl、Br、OH、 OCH3、OR6、CH3、R6、C (=O) OW, OW, L1-L4-L2- W and I；
X4Selected from the set being made of following group: nothing, N, CH and CY1；
X5And X35It is respectively and independently selected from the set being made of following group: nothing, C (=O), OC (=O), CH2、CH、S、O And NR5；
Y1、Y31、YY、Y32、Y3And Y4It is respectively and independently selected from the set being made of following group: H, OH, OW, OC (=O) W, L1-L4-L2- W, OC (=O) CH3、CH3、C2H5、C3H7、 C4H9、R6、SO3R6、CH2OR6、CH2OC (=O) R6、CH2C (=O) OR8、 OCH3、OC2H5、 OR6、CH3SO2、R6SO2、CH3SO3、R6SO3、NO2、CN、CF3、OCF3、 CH2(CH2)nNR5R6、CH2(CH2)nOR6, CH (C (=O) NH2)NHR6、CH2C (=O) NH2, F, Br, I, Cl, CH=CHC (=O) NHCH2C (=O) OW, CH= CHC (=O) NHCH2L1-L4-L2-W、NR8C (=O) R5、SO2NR5R8, C (=O) R5、 SR5, replace and unsubstituted polyfluohydrocarbon Base, substitution and unsubstituted oxyl, substitution and unsubstituted sulfenyl, substitution and unsubstituted hydrocarbon amino replace and do not take Polyfluoro alkyl, substitution and the unsubstituted halohydrocarbyl in generation and substitution and unsubstituted hydrocarbon carbonyl；
L1Selected from the set being made of following group: nothing, O, S ,-O-L3-、-S-L3-、-N(L3)-、 -N(L3)-CH2-O、- N(L3)-CH2-N(L5)-、-O-CH2-O-、-O-CH(L3)-O and-S-CH (L3)-O-；
L2Selected from the set being made of following group: nothing, O, S ,-O-L3-、-S-L3-、-N(L3)-、 -N(L3)-CH2-O、- N(L3)-CH2-N(L5)-、-O-CH2-O-、-O-CH(L3)-O、-S-CH(L3)-O-、 -O-L3-、-N-L3-、-S-L3-、-N (L3)-L5And L3；
L4Selected from the set being made of following group: C=O, C=S,With
For each L1、L2And L4, L3And L5The set being made of following groups can be respectively and independently selected from: nothing, H, CH2C (= O)OL6, replace and unsubstituted alkyl, substitution and unsubstituted cyclic hydrocarbon radical, substitution and unsubstituted heterocyclic hydrocarbyl, substitution and not Substituted aryl, substitution and unsubstituted heteroaryl, substitution and unsubstituted oxyl, substitution and unsubstituted sulfenyl take Generation and unsubstituted hydrocarbon amino, substitution and unsubstituted polyfluoro alkyl and substitution and unsubstituted halohydrocarbyl, wherein any carbon Atom or hydrogen atom can be respectively further by O, S, P, NL3Or any other pharmaceutically acceptable group replaces；
L6The set being made of following groups can be independently selected from: H, OH, Cl, F, Br, I, substitution and unsubstituted alkyl take Generation and unsubstituted cyclic hydrocarbon radical, substitution and unsubstituted heterocyclic hydrocarbyl, substitution and unsubstituted aryl, substitution and unsubstituted miscellaneous Aryl, substitution and unsubstituted oxyl, substitution and unsubstituted sulfenyl, substitution and unsubstituted hydrocarbon amino, replace and not Substituted polyfluoro alkyl and replace and unsubstituted halohydrocarbyl, wherein any carbon atom or hydrogen atom can respectively further by O, S、 N、P(O)OL6, CH=CH, C ≡ C, CHL6、CL6L7, aryl, heteroaryl or cyclic group replace；
L7The set being made of following groups can be independently selected from: H, OH, Cl, F, Br, I, substitution and unsubstituted alkyl take Generation and unsubstituted cyclic hydrocarbon radical, substitution and unsubstituted heterocyclic hydrocarbyl, substitution and unsubstituted aryl, substitution and unsubstituted miscellaneous Aryl, substitution and unsubstituted oxyl, substitution and unsubstituted sulfenyl, substitution and unsubstituted hydrocarbon amino, replace and not Substituted polyfluoro alkyl and replace and unsubstituted halohydrocarbyl, wherein any carbon atom or hydrogen atom can respectively further by O, S、 N、P(O)OL6, CH=CH, C ≡ C, CHL6、CL6L7, aryl, heteroaryl or cyclic group replace；And
Any CH2Group can be replaced by O, S or NH.
In some embodiments, the function list of the HPP or HPC of antimicrobial or antimicrobial related compound Member is selected from the structure for the set being formed by following structures: structural formula FP-1, structural formula FP-2, structural formula FP-3, structure comprising certain Formula FP-4, structural formula FP-5, structural formula FP-6, structural formula FP-7, structural formula FP-8, structural formula FP-9, structural formula FP-10, knot Structure formula FP-11, structural formula FP-12, structural formula FP-13, structural formula FP-14, structural formula FP-15, structural formula FP-16, structural formula FP-17, structural formula FP-18, structural formula FP-19, structural formula FP-20, structural formula FP-21, structural formula FP-22, structural formula FP- 23, structural formula FP-24, structural formula FP-25, structural formula FP-26, structural formula FP-27, structural formula FP-28, structural formula FP-29, Structural formula FP-30, structural formula FP-31, structural formula FP-32, structural formula FP-33, structural formula FP-34, structural formula FP-35, structure Formula FP-36, structural formula FP-37, structural formula FP-38, structural formula FP-39, structural formula FP-40, structural formula FP-41, structural formula FP-42, structural formula FP-43, structural formula FP-44, structural formula FP-45, structural formula FP-46, structural formula FP-47, structural formula FP- 48, structural formula FP-49, structural formula FP-50, structural formula FP-51, structural formula FP-52, structural formula FP-53, structural formula FP-54, knot Structure formula FP-55, structural formula FP-56, structural formula FP-57, structural formula FP-58, structural formula FP-59, structural formula FP-60, structural formula FP-61, structural formula FP-62, structural formula FP-63, structural formula FP-64, structural formula FP-65, structural formula FP-66, structural formula FP- 67, structural formula FP-68, structural formula FP-69, structural formula FP-70, structural formula FP-71, structural formula FP-72, structural formula FP-73, Structural formula FP-74, structural formula FP-75, structural formula FP-76, structural formula FP-77, structural formula FP-78, structural formula FP-79, structure Formula FP-80, structural formula FP-81, structural formula FP-82, structural formula FP-83, structural formula FP-84, structural formula FP-85, structural formula FP-86, structural formula FI-1, structural formula FI-2, structural formula FI-3, structural formula FI-4, structural formula FI-5, structural formula FI-6, structure Formula FI-7, structural formula FI-8, structural formula FI-9, structural formula FI-10, structural formula FI-11, structural formula FI-12, structural formula FI-13, Structural formula FI-14, structural formula FI-15, structural formula FI-16, structural formula FI-17, structural formula FI-18, structural formula FI-19, structure Formula FI-20, structural formula FI-21, structural formula FI-22, structural formula FI-23, structural formula FI-24, structural formula FI-25, structural formula FI- 26, structural formula FI-27, structural formula FI-28, structural formula FI-29, structural formula FI-30, structural formula FI-31, structural formula FI-32, Structural formula FI-33, structural formula FS-1, structural formula FS-2, structural formula FS-3, structural formula FS-4, structural formula FS-5, structural formula FS- 6, structural formula FS-7, structural formula FS-8, structural formula FS-9, structural formula FS-10, structural formula FS-11, structural formula FS-12, structural formula FS-13, structural formula FS-14, structural formula FS-15, structural formula FS-16, structural formula FS-17, structural formula FS-18, structural formula FS- 19, structural formula FS-20, structural formula FT-1, structural formula FT-2, structural formula FT-3, structural formula FT-4, structural formula FT-5, structural formula FT-6, structural formula FT-7, structural formula FT-8, structural formula FT-9, structural formula FT-10, structural formula FT-11, structural formula FT-12, knot Structure formula FT-13, structural formula FT-14, structural formula FT-15 and structural formula FT-16:
Including its stereoisomer and pharmaceutically acceptable salt class, in which:
n、R5、R7、X5、X35、Y1、Y2、Y31、Y32、Y3And Y4Definition as hereinbefore；
L31With aforementioned L1Define identical, L32With aforementioned L2Define identical, L34With aforementioned L4Define it is identical, in some embodiments In ,-L1-L4-L2And-L31-L34-L32Can be separately selected from the set that is made of following group :-O- ,-X- ,-O-X- ,- N-X-、-S-X-、-X5-、-O-X5-、-N-X5-、-S-X5-、 -O-X7,-O-C (=O)-,-NH-C (=O)-,-C (=O)-,-C (=O)-O- ,-C (=O)-N- and C (=O)-X-,
X is selected from the set being made of following group: nothing, C (=O), OC (=O), CH2、CH、S、 NH、NR5And O；
X6、X36And X46Separately selected from the set that is made of following group: nothing, C (=O), C (=S), OC (= O)、CH2, CH, S, O and NR5；And
X7It can be separately selected from the set being made of following group: nothing, C (=O), C (=S), OC (=O), CH2、 CH, S, O and NR5。
In some embodiments, the function list of the HPP or HPC of antimicrobial or antimicrobial related compound Member is comprising with the structure selected from the set being formed by following structures: structural formula F-1, structural formula FP-1, structural formula FP-2, structure Formula FP-3, structural formula FP-4, structural formula FP-5, structural formula FP-6, structural formula FP-7, structural formula FP-8, structural formula FP-9, structure Formula FP-10, structural formula FP-11, structural formula FP-12, structural formula FP-13, structural formula FP-14, structural formula FP-15, structural formula FP- 16, structural formula FP-17, structural formula FP-18, structural formula FP-19, structural formula FP-20, structural formula FP-21, structural formula FP-22, knot Structure formula FP-23, structural formula FP-24, structural formula FP-25, structural formula FP-26, structural formula FP-27, structural formula FP-28, structural formula FP-29, structural formula FP-30, structural formula FP-31, structural formula FP-32, structural formula FP-33, structural formula FP-34, structural formula FP- 35, structural formula FP-36, structural formula FP-37, structural formula FP-38, structural formula FP-39, structural formula FP-40, structural formula FP-41, knot Structure formula FP-42, structural formula FP-43, structural formula FP-44, structural formula FP-45, structural formula FP-46, structural formula FP-47, structural formula FP-48, structural formula FP-49, structural formula FP-50, structural formula FP-51, structural formula FP-52, structural formula FP-53, structural formula FP- 54, structural formula FP-55, structural formula FP-56, structural formula FP-57, structural formula FP-58, structural formula FP-59, structural formula FP-60, knot Structure formula FP-61, structural formula FP-62, structural formula FP-63, structural formula FP-64, structural formula FP-65, structural formula FP-66, structural formula FP-67, structural formula FP-68, structural formula FP-69, structural formula FP-70, structural formula FP-71, structural formula FP-72, structural formula FP- 73, structural formula FP-74, structural formula FP-75,
M=0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20 ...；
N=0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20 ...；
R1It can be selected from the set being made of following groups: H, C1-C20Alkyl, C1-C20Oxyl, C1-C20Alkenyl, C1-C20 Alkynyl, aryl and heteroaryl；
R2It can be selected from the set being made of following groups: H, C1-C20Alkyl, C1-C20Oxyl, C1-C20Alkenyl, C1-C20 Alkynyl, aryl and heteroaryl；
R3It can be selected from the set being made of following groups: H, C1-C20Alkyl, C1-C20Oxyl, C1-C20Alkenyl, C1-C20 Alkynyl, aryl and heteroaryl；
R5And R35The set being made of following groups: H ,-C (=O) NH can be respectively and independently selected from2、 CH2CH2OR6、 CH2CH2N(CH3)2、CH2CH2N(CH2CH3)2、CH2CH2OR6、Cl、F、 Br、I、C1-C20Alkyl, C1-C20Cyclic hydrocarbon radical, C1-C20Hydrocarbon Oxygroup, C1-C20Cyclic hydrocarbon radical oxygroup, C1-C20Alkenyl, C1-C20Cycloalkenyl, C1-C20Cycloalkynyl radical, C1-C20Alkynyl, aryl, heteroaryl, C (=O)-W and W；
R6、R36And R46The set being made of following groups: H, F, Cl, Br, I, Na can be respectively and independently selected from+、K+, C (= O)R5, 2- ketone -1- imidazolidinyl, phenyl, 5- indanyl, 2,3- dihydro -1H- indenes -5- base, 4- hydroxyl -1,5- naphthyridines -3- base, C1-C12Alkyl, C1-C12Cyclic hydrocarbon radical, C1-C12Oxyl, C1-C12Cyclic hydrocarbon radical oxygroup, C1-C12Alkenyl, C1-C12Cycloalkenyl, C1- C12Cycloalkynyl radical, C1-C12Alkynyl, aryl, heteroaryl, C (=O)-W and W,
R7And R37The set being made of following groups: H, F, Cl, Br, I, CH can be respectively and independently selected from3NHC (=O) CH2CH (NHR8) C (=O), R5N=C (NHR6) NHC (=O)-, C (=O) CH3, C (=O) R6、PO(OR5)OR6、C1-C20Alkyl, C1- C20Oxyl, C1-C20Alkenyl, C1-C20Alkynyl, aryl, heteroaryl, C (=O)-W and W；
R8And R38The set being made of following groups: H, F, Cl, Br, I, CH can independently be can be selected from3、C2H5、CF3、 CH2CH2F、CH2CH2Cl、CH2CH2Br、CH2CH2I、CH2CHF2、 CH2CF3、CH2F、CH2Cl、CH2Br、CH2I、CH2NR6R7、CH (NHR7)CH2C (=O) NH2、 C3H7、C4H9、C5H11、R6, C (=O) R6, C (=O) NH2、CH2C (=O) NH2、CH2OC (=O) NH2、 PO(OR5)OR6、C(CH3)2C (=O) OR6、CH(CH3) C (=O) OR6、CH2C (=O) OR6, C (=O)-W；
X2It can be selected from the set being made of following groups: nothing, H, CH2(CH2)nOR8、Cl、F、Br、 I、NO2、CN、CF3、 C2F5、C3F7、OCF3、OC2F5、NH2、NHR6、CH3、C2H5、 R6, C (=O) NH2、CH2OC (=O) NH2、CH2C (=O) OR5、CH2 (CH2)nN(CH3)2、 CH2(CH2)nSO3R5、C1-8Alkyl, C1-8Sulfenyl, C1-8Hydrocarbon amino and C1-8Oxyl,
X3It can be selected from the set being made of following groups: nothing, H, N3、SO3W、F、Cl、Br、OH、 OCH3、OR6、CH3、R6、C (=O) OW, OW and I；
X4It can be selected from the set being made of following groups: nothing, N, CH and CY1；
X5And X35The set being made of following groups can be respectively and independently selected from: nothing, C (=O), OC (=O), CH2、CH、S、 O and NR5；
Each Y1、Y31、Y2、Y32、Y3And Y4All it is independently selected from the set being made of following groups: H, OH, OW, OC (=O) W, OC (=O) CH3、CH3、C2H5、C3H7、C4H9、SO3R6、 CH2OR6、CH2OC (=O) R6、CH2C (=O) OR8、OCH3、OC2H5、 CH3SO2、R6SO2、 R6SO3OR6、CH3SO 3、R6SO3、NO2、CN、CF3、OCF3, CH=CHC (=O) NHCH2C (=O) OW, CH2(CH2)nNR5R6、CH2(CH2)nOR6, CH (C (=O) NH2)NHR6、CH2C (=O) NH2, F, Br, I and Cl；
Z、AA、HA、R、Rs、Y、R11-R16、X、L1、L2、L4、L31、L32、L34It is same as mentioned above with the definition of W,
Any CH2Group can be by O, S, NR6Or pharmaceutically acceptable any substituent group replaces.
In the present invention, " pharmaceutically acceptable salt " refer in object can security application the compound of the present invention Salt.Pharmaceutically acceptable salt includes the salt of acidic-group present in the compound of the present invention or basic group.Pharmaceutically may be used The acid addition salt of receiving includes, but are not limited to hydrochloride, hydrobromate, hydriodate, nitrate, sulfate, hydrogen sulfate Salt, phosphate, acid phosphate, isonicotinic acid salt, acetate, lactate, salicylate, citrate, tartrate, pantothenic acid Salt, acid tartrate, ascorbate, succinate, maleate, gentisate (gentisinate), fumaric acid Salt, gluconate, glucuronate salt (glucaronate), sugar lime, formates, benzoate, glutamate, first Base sulfonate, ethyl sulfonate, benzene sulfonate, tosilate and embonate (such as: 1,11--two-(2- of methylene Hydroxyl -3- naphthoate)).Certain compounds in the present invention can form pharmaceutically acceptable salt with a variety of amino acid.It is applicable in Basic salt include, but are not limited to aluminium salt, calcium salt, lithium salts, magnesium salts, sylvite, sodium salt, zinc salt and diethanolamine salt.About medicine The summary of acceptable salt can be found in BERGE ET AL., 66J.PHARM.SCI. 1-19 (1977) on, be described herein by reference Reference citation is incorporated to.
In the present invention, unless otherwise indicated, " alkyl " this term refers to branch or unbranched, saturation or unsaturated , the hydrocarbon group of unit price or multivalence, including saturated hydrocarbyl, alkenyl and alkynyl.The example of alkyl include, but are not limited to methyl, Ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, ten Dialkyl group, vinyl, acrylic, cyclobutenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decene Base, undecenyl, dodecenyl succinic, acetenyl, propinyl, butynyl, butynyl, pentynyl, hexin base, heptynyl, Octynyl, n-heptylacetylene base, decynyl, hendecyne base, dodecyne base, methylene, ethylene group (ethylene), trimethylene base (propylene), isopropyl support group (isopropylene), fourth support group (butylene), isobutyl support group (isobutylene), uncle Fourth support group (t-butylene), pentamethylene base (pentylene), hexamethylene base (hexylene), support group in heptan (heptylene), octamethylene Base (octylene), nonyl support group (nonylene), decamethylene base (decylene), 11 carbon support groups (undecylene) and 12 carbon Support group (dodecylene).In some embodiments, which contains 1 to 30 carbon atoms.In certain embodiments In, which contains 1 to 20 carbon atoms.In some embodiments, which contains 1 to 12 carbon atoms.
In the present invention, unless otherwise indicated, " cyclic hydrocarbon radical " this term refers to containing at least one ring and without containing virtue The alkyl of ring.The example of cyclic hydrocarbon radical include, but are not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, Cyclononyl, cyclodecyl, ring undecyl and cyclo-dodecyl.In some embodiments, which contains 1 to 30 Carbon atom.In some embodiments, which contains 1 to 20 carbon atoms.In some embodiments, the hydrocarbon-based 1 to 12 carbon atoms are contained in group.
In the present invention, unless otherwise indicated, " heterocyclic hydrocarbyl " this term refers to that at least one ring atom is non-carbon The cyclic hydrocarbon radical of atom.Non-carbon on ring includes, but are not limited to sulphur (S), oxygen (O) and nitrogen N).
In the present invention, unless otherwise indicated, " oxyl " this term refers to the hydrocarbon containing one or more oxygen atoms Base, cyclic hydrocarbon radical or heterocyclic hydrocarbyl.The example of oxyl includes, but are not limited to-CH2-OH、-OCH3、-O-Re、-Re-OH、-Re1- O-Re2, wherein Re, Re1And Re2It is identical or different alkyl, cyclic hydrocarbon radical or heterocyclic hydrocarbyl.
In the present invention, unless otherwise indicated, " halohydrocarbyl " this term refers to containing one or more halogen atoms Alkyl, cyclic hydrocarbon radical or heterocyclic hydrocarbyl." halogen " this term refers to fluorine, chlorine, bromine or iodine.The example of halohydrocarbyl includes, but It is not limited to ,-Rc-F、-Rc-Cl、-Rc-Br、-Rc-I、 -Rc(F)-、-Rc(Cl)-、-Rc(Br)-and-Rc(I)-, wherein RcIt is Alkyl, cyclic hydrocarbon radical or heterocyclic hydrocarbyl.
In the present invention, unless otherwise indicated, " sulfenyl (alkylthio) " this term refers to containing one or more Alkyl, cyclic hydrocarbon radical or the heterocyclic hydrocarbyl of sulphur atom.The example of sulfenyl includes, but are not limited to-CH2-SH、-SCH3、-S-Re、- Re-SH、-Re-S-Re1, wherein ReAnd Re1It is identical or different alkyl, cyclic hydrocarbon radical or heterocyclic hydrocarbyl.
In the present invention, unless otherwise indicated, " hydrocarbon amino (alkyamino) " this term refers to containing one or more Alkyl, cyclic hydrocarbon radical or the heterocyclic hydrocarbyl of nitrogen-atoms.The example of hydrocarbon amino includes, but are not limited to-CH2-NH、-NCH3、-N(Rc)- Rc1、-N-Rc、-Rc-NH2、-Rc-N-Rc1With-Re-N(Re1)-Re2, wherein Re, Re1And Re2It is identical or different alkyl, cyclic hydrocarbon Base or heterocyclic hydrocarbyl.
In the present invention, unless otherwise indicated, " hydrocarbon carbonyl (alkycarbonyl) " this term refer to containing one or Alkyl, cyclic hydrocarbon radical or the heterocyclic hydrocarbyl of multiple carbonyl groups.The example of hydrocarbon carbonyl includes, but are not limited to aldehyde radical (- Rc-C(O)- H), ketone group (- Rc-C(O)-Rc1), carboxylic acid group (Rc- C (=O) OH), ester group (- Rc- C (=O) O-Rc1), formamido group (- Rc-C (=O) O-N (Rc1)Rc2), ketenes base (- Rc-C(O)-C(Rc1)=C (Rc2)Rc3), acid halide (- Rc- C (O)-X) and acid anhydrides Base (- Rc-C(O)-O-C(O)-Rc1), wherein Rc, Rc1, Re2And Rc3It can be identical or different alkyl, cyclic hydrocarbon radical or heterocycle Alkyl.
In the present invention, unless otherwise indicated, " polyfluoro alkyl (perfluoroalkyl) " this term refers to containing one Alkyl, cyclic hydrocarbon radical or the heterocyclic hydrocarbyl of a or multiple fluorin radicals, including but not limited to, polyfluoro methyl, polyfluoro ethyl, polyfluoro third Base.
In the present invention, unless otherwise indicated, " aryl " this term refers to the chemistry knot containing one or more aromatic rings Structure.In some embodiments, one or more ring atoms are non-carbon, e.g., oxygen atom, nitrogen-atoms or sulphur atom (" heteroaryl ").The example of aryl includes, but are not limited to phenyl, benzyl, naphthalene, anthryl (anthracenyl), pyridyl group, quinoline Quinoline base, isoquinolyl, pyrazinyl, quinoxaline base (quinoxalinyl), acridinyl (acridinyl), pyrimidine radicals, quinazoline Base, pyridazinyl (pyridazinyl),Cinnoline base(cinnolinyl), imidazole radicals, benzimidazolyl, purine radicals, indyl, furan Mutter base, benzofuranyl, isobenzofuran-base, pyrrole radicals, indyl, isoindolyl, thienyl, benzothienyl, pyrazolyl, Indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzo isoxazolyl, thiazolyl (thiaxolyl), guanidine radicals and benzo thiophene Oxazolyl.
In some embodiments, the transhipment unit of HPP contains protonated amine groups, can promote HPP across or One or more layers biological barrier is transported through (e.g., than at least about 20 times fastly of female medicine, about 50 times, about 100 times, about 300 times, about 500 Again, about 1000 times).In some embodiments, protonated amine groups are substantially protonated in physiological pH.Certain In embodiment, the protonation of the amine groups is reversible.In some embodiments, which passes through one layer or more in HPP It may or may not be shear off from functional unit after layer biological barrier.In some embodiments, functional unit may contain There is a transhipment unit, especially for the antimicrobial containing at least one free amine groups and antimicrobial related compounds For object.
In some embodiments, protonated amino is selected from following group composition set: pharmaceutically acceptable to take It generation and unsubstituted level-one amine groups, pharmaceutically acceptable substitution and unsubstituted second level amine groups and can pharmaceutically connect The substitution received and unsubstituted tertiary amine group.
In some embodiments, protonated amino is selected from following structure composition set: structural formula W-1, structural formula W-2, structural formula W-3, structural formula W-4, structural formula W-5, structural formula W-6, structural formula W-7, structural formula W-8, structural formula W-9, knot Structure formula W-10, structural formula W-11, structural formula W-12, structural formula W-13, structural formula W-14, structural formula W-15, structural formula W-16, knot Structure formula W-17 and structural formula W-18 is defined as hereinbefore, including its stereoisomer and pharmaceutically acceptable salt class.
In some embodiments, the attachment of the functional unit and transhipment unit that connect HPP contains certain key, which can be HPP is sheared after being perforated through one or more layers biological barrier.The key that can be sheared includes, for example, covalent bond, ehter bond, thioether bond, acyl Amine key, ester bond, thioester bond, carbonic acid key, amino methyl key, phosphoric acid ester bond or oxime key.
In some embodiments, the HPP of beta-lactam antibiotic and beta-lactam antibiotic related compound has Just like the structure of flowering structure formula L-1:
Including its stereoisomer and pharmaceutically acceptable salt class.
F is the functional unit of the HPP of antimicrobial or antimicrobial related compound.The example of F includes structural formula F-1, structural formula FP-1, structural formula FP-2, structural formula FP-3, structural formula FP-4, structural formula FP-5, structural formula FP-6, structural formula FP-7, structural formula FP-8, structural formula FP-9, structural formula FP-10, structural formula FP-11, structural formula FP-12, structural formula FP-13, knot Structure formula FP-14, structural formula FP-15, structural formula FP-16, structural formula FP-17, structural formula FP-18, structural formula FP-19, structural formula FP-20, structural formula FP-21, structural formula FP-22, structural formula FP-23, structural formula FP-24, structural formula FP-25, structural formula FP- 26, structural formula FP-27, structural formula FP-28, structural formula FP-29, structural formula FP-30, structural formula FP-31, structural formula FP-32, knot Structure formula FP-33, structural formula FP-34, structural formula FP-35, structural formula FP-36, structural formula FP-37, structural formula FP-38, structural formula FP-39, structural formula FP-40, structural formula FP-41, structural formula FP-42, structural formula FP-43, structural formula FP-44, structural formula FP- 45, structural formula FP-46, structural formula FP-47, structural formula FP-48, structural formula FP-49, structural formula FP-50, structural formula FP-51, knot Structure formula FP-52, structural formula FP-53, structural formula FP-54, structural formula FP-55, structural formula FP-56, structural formula FP-57, structural formula FP-58, structural formula FP-59, structural formula FP-60, structural formula FP-61, structural formula FP-62, structural formula FP-63, structural formula FP- 64, structural formula FP-65, structural formula FP-66, structural formula FP-67, structural formula FP-68, structural formula FP-69, structural formula FP-70, knot Structure formula FP-71, structural formula FP-72, structural formula FP-73, structural formula FP-74, structural formula FP-75, structural formula FP-76, structural formula FP-77, structural formula FP-78, structural formula FP-79, structural formula FP-80, structural formula FP-81, structural formula FP-82, structural formula FP- 83, structural formula FP-84, structural formula FP-85, structural formula FP-86, structural formula FI-1, structural formula FI-2, structural formula FI-3, structure Formula FI-4, structural formula FI-5, structural formula FI-6, structural formula FI-7, structural formula FI-8, structural formula FI-9, structural formula FI-10, knot Structure formula FI-11, structural formula FI-12, structural formula FI-13, structural formula FI-14, structural formula FI-15, structural formula FI-16, structural formula FI-17, structural formula FI-18, structural formula FI-19, structural formula FI-20, structural formula FI-21, structural formula FI-22, structural formula FI- 23, structural formula FI-24, structural formula FI-25, structural formula FI-26, structural formula FI-27, structural formula FI-28, structural formula FI-29, Structural formula FI-30, structural formula FI-31, structural formula FI-32, structural formula FI-33, structural formula FS-1, structural formula FS-2, structural formula FS-3, structural formula FS-4, structural formula FS-5, structural formula FS-6, structural formula FS-7, structural formula FS-8, structural formula FS-9, structural formula FS-10, structural formula FS-11, structural formula FS-12, structural formula FS-13, structural formula FS-14, structural formula FS-15, structural formula FS- 16, structural formula FS-17, structural formula FS-18, structural formula FS-19, structural formula FS-20, structural formula FT-1, structural formula FT-2, structure Formula FT-3, structural formula FT-4, structural formula FT-5, structural formula FT-6, structural formula FT-7, structural formula FT-8, structural formula FT-9, structure Formula FT-10, structural formula FT-11, structural formula FT-12, structural formula FT-13, structural formula FT-14, structural formula FT-15 and structural formula FT-16, it is defined as described above；
T is the transhipment unit of the HPP of antimicrobial or antimicrobial related compound.For example, T can be selected from by with The set of flowering structure composition: protonated amino, it is pharmaceutically acceptable to replace with unsubstituted level-one amine groups, pharmaceutically It is acceptable substitution and unsubstituted second level amine groups and it is pharmaceutically acceptable substitution and unsubstituted tertiary amine group, Structural formula W-1, structural formula W-2, structural formula W-3, structural formula W-4, structural formula W-5, structural formula W-6, structural formula W-7, structural formula W-8, structural formula W-9, structural formula W-10, structural formula W-11, structural formula W-12, structural formula W-13, structural formula W-14, structural formula W-15, structural formula W-16, structural formula W-17 and structural formula W-18, it is defined as described above；And
L1、L31、L2、L32、L4And L34It is defined as described above.In some embodiments ,-L1-L4-L2And-L31- L34-L32Selected from the set being made of following group :-O- ,-X- ,-O-X- ,-N-X- ,-S-X- ,-X5,-O-X5,-N- X5,-S-X5,-O-X7,-O-C (=O)-,-NH-C (=O)-,-C (=O) ,-C (=O)-O- ,-C (=O)-N-, and-C (=O)-X-；Wherein X, X5And X7It is defined as described above.
In some embodiments, the HPP or HPC of antimicrobial or antimicrobial related compound include being selected from Structure below: structural formula P-1, structural formula P-2, structural formula P-3, structural formula P-4, structural formula P-5, structural formula P-6, structural formula P-7, structural formula P-8, structural formula P-9, structural formula P-10, structural formula P-11, structural formula P-12, structural formula P-13, structural formula P- 14, structural formula P-15, structural formula P-16, structural formula P-17, structural formula P-18, structural formula P-19, structural formula P-20, structural formula P-21, structural formula P-22, structural formula P-23, structural formula P-24, structural formula P-25, structural formula P-26, structural formula P-27, structure Formula P-28, structural formula P-29, structural formula P-30, structural formula P-31, structural formula P-32, structural formula P-33, structural formula P-34, structure Formula P-35, structural formula P-36, structural formula P-37, structural formula P-38, structural formula P-39, structural formula P-40, structural formula P-41, knot Structure formula P-42, structural formula P-43, structural formula P-44, structural formula P-45, structural formula P-46, structural formula P-47, structural formula P-48, knot Structure formula P-49, structural formula P-50, structural formula P-51, structural formula P-52, structural formula P-53, structural formula P-54, structural formula P-55, Structural formula P-56, structural formula P-57, structural formula P-58, structural formula P-59, structural formula P-60, structural formula P-61, structural formula P- 62, structural formula P-63, structural formula P-64, structural formula P-65, structural formula P-66, structural formula P-67, structural formula P-68, structural formula P- 69, structural formula P-70, structural formula P-71, structural formula P-72, structural formula P-73, structural formula P-74, structural formula P-75, structural formula P-76, structural formula P-77, structural formula P-78, structural formula P-79, structural formula P-80, structural formula P-81, structural formula P-82, structure Formula P-83, structural formula P-84, structural formula P-85, structural formula P-86, structural formula I-1, structural formula I-2, structural formula I-3, structural formula I-4, structural formula I-5, structural formula I-6, structural formula I-7, structural formula I-8, structural formula I-9, structural formula I-10, structural formula I-11, Structural formula I-12, structural formula I-13, structural formula I-14, structural formula I-15, structural formula I-16, structural formula I-17, structural formula I-18, Structural formula I-19, structural formula I-20, structural formula I-21, structural formula I-22, structural formula I-23, structural formula I-24, structural formula I-25, Structural formula I-26, structural formula I-27, structural formula I-28, structural formula I-29, structural formula I-30, structural formula I-31, structural formula I-32, Structural formula I-33, structural formula S-1, structural formula S-2, structural formula S-3, structural formula S-4, structural formula S-5, structural formula S-6, structural formula S-7, structural formula S-8, structural formula S-9, structural formula S-10, structural formula S-11, structural formula S-12, structural formula S-13, structural formula S- 14, structural formula S-15, structural formula S-16, structural formula S-17, structural formula S-18, structural formula S-19, structural formula S-20, structural formula T-1, structural formula T-2, structural formula T-3, structural formula T-4, structural formula T-5, structural formula T-6, structural formula T-7, structural formula T-8, knot Structure formula T-9, structural formula T-10, structural formula T-11, structural formula T-12, structural formula T-13, structural formula T-14, structural formula T-15 and Structural formula T-16:
Including its stereoisomer and pharmaceutically acceptable salt class, wherein m, n, R1, R2, R5, R35, R6, R36, R46, R7, R8, R38, T, W, X, X2, X4, X5, X35, X6, X36, X46, X7, Y1, Y2, Y31、Y32、Y3, Y4, Z, AA, HA, R, RsAnd R11-R16 Etc. substituent group it is as defined above.
II. containing the pharmaceutical composition of HPP
Another aspect of the present invention is related to certain pharmaceutical composition, the HPP containing at least one antimicrobial or anti- The HPP of microorganism agent related compound and certain pharmaceutically acceptable carrier.
" pharmaceutically acceptable carrier " word refers to certain pharmaceutically acceptable material, composition or matchmaker in the present invention It is situated between, such as certain liquid or solid filler, diluent, excipient, solvent or encapsulating material, participates in certain HPP from one Position, body fluid, tissue, organ (internal or external) or a part of of body deliver or transport another position, body fluid, group It knits, a part of organ (internal or external) or body.
" pharmaceutically acceptable " property of every kind of carrier is embodied in, can in preparation other ingredients such as certain HPP it is compatible, And be suitable for contacting the tissue or organ of certain biosystem, without excessive toxicity, irritation, allergic reaction, immunogenicity or its His problem or comprehensive and disease have reasonable benefit/risk ratio appropriate.
The examples of materials that can be used as pharmaceutically acceptable carrier includes: 1) carbohydrate, such as lactose, dextrose and saccharose；2) Starch, such as cornstarch and potato starch；3) cellulose family and its derivative, such as carboxymethyl cellulose, ethyl cellulose And cellulose acetate；4) powdered tragacanth；5) malt；6) gelatin；7) talcum powder；8) auxiliary material, such as cupu oil and suppository wax class； 9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil；10) glycols, such as propylene Ethylene glycol；11) polyol class, such as glycerol, sorbierite, mannitol and polyethylene glycol；12) esters, such as ethyl oleate And ethyl laurate；13) agar；14) buffer class, such as magnesium hydroxide and aluminium hydroxide；15) alginic acid；16) apyrogeneity Water；17) isotonic saline solution；18) Ringer's solution；19) alcohols, such as ethyl alcohol and propyl alcohol；20) phosphate buffer solution；And 21) its The nontoxic compatible substance such as acetone that he applies in pharmaceutical preparation.
Pharmaceutical composition may include close to pharmaceutically acceptable auxiliary substance needed for physiological condition, such as pH adjusting agent and PH buffer, toxicity modifiers and its homologue, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and its similar Object.
In one embodiment, pharmaceutically acceptable carrier is certain aqueous phase carriers, such as buffer salt.In certain embodiment party In formula, pharmaceutically acceptable carrier is certain polar solvent, such as acetone and alcohol.
In these formulations, the concentration of HPP can change in a wider range, can according to the specific administration mode of selection and The demand of biosystem, volume, viscosity, weight and its homologue for being based primarily upon fluid are selected.For example, the concentration (is pressed Poidometer) it can be arrived for 0.0001% to 100%, 0.001 % to 450%, 0.01% to 430%, 0.1% to 20%, 1% 10%.
Composition of the invention can be by being administered for preventing, treating, and/or health care.Such administration can be by outer With administration, mucosa delivery, such as oral, nasal cavity, vagina, rectum, injection, transdermal, subcutaneous, intramuscular, intravenously administrable, inhalation, Ophthalmic administration and other approach appropriate.Pharmaceutical composition can be administered according to medication with multiple unit dosage form. For example, the unit dosage form for being suitable for oral administration includes pulvis, tablet, pill, capsule and diamond shape agent (lozenge), Unit dosage form suitable for cutaneous penetration includes solution, suspension and gel.
Therefore, it can be each administration object daily about for transdermal, oral, intravenously administrable typical pharmaceutical compositions 10-10Gram arrive about 100 grams, about 10-10To about 10-3Gram, about 10-9Gram arrive about 10-6Gram, about 10-6Gram arrive about 100 grams, about 0.001 gram To about 100 grams, about 0.01 gram to about 10 grams, or about 0.01 gram to about 1 gram.The daily dosage of each administration object can be from about 0.01 milligram, arrive about 100 grams.The practical methods of the composition of drug administration by injection are prepared known in this field or for art technology Personnel be it will be apparent that and in the publication as Remington ' s Pharmaceutical Science, 21st ed., Mack Publishing Company, Easton, Pa. (2005) have more detailed description.
The application of III.HPP
I) the method for biological barrier is penetrated
Another aspect of the present invention is related to the method for penetrating one or more layers biological barrier using composition of the invention. This method includes certain biological object being administered certain HPP or certain antimicrobial or antimicrobial related compound or its drug The step of composition.In some embodiments, what certain HPP was shown can to the penetration speed of one or more layers biological barrier Higher than about 20 times or more, 50 times or more, 100 times or more, 200 times or more, 300 times or more, 500 times of its female medicine Or more, 1000 times or more.
" biological barrier " term refers in the present invention is divided into different spaces region or compartment for certain environment (compartments) certain biosphere, controllable (e.g., constrain, limit, the improving or do not act on) object of the separation (substance) or substance (material) from a compartment/region to another, compartment/region is penetrating, penetrates or transports. Different area of space or compartment in the present invention can have identical or different chemistry or biotic environment.It is mentioned in the present invention Biosphere includes, but are not limited to the inner surface of biomembrane, cellular layer, biological structure, object, organism, organ or body cavity, right As, organism, the outer surface of organ or body cavity, or arbitrary combine or its plural number.
The example of biomembrane includes lipid bilayer structure, eukaryotic cell membrane, prokaryotic cell film and intercellular membrane (e.g., nuclear membrane Or organelle film, as the film or coating of golgiosome, the film of rough surfaced endoplasmic reticulum (RER) and smooth surfaced endoplasmic reticulum or coating, ribosomal film or Coating, the film of vacuole or coating, the film of vesica or coating, the film of liposome or coating, the film of mitochondria or coating, lysosome The film or coating, peroxisome of film or coating, the film of nucleus or coating, the film of chloroplaset or coating, plastid (plastid) Film or coating or microbody film or coating).
Lipid bilayer structure in the present invention is a kind of double-layer structure of lipid molecule, includes, but are not limited to phosphatide and gallbladder Sterol.In certain particular implementation, the lipid of double-layer structure is two be made of terminal polar group and nonpolar fatty acid tail chain Property molecule.Double-layer structure is made of two layers of lipid structures, makes their hydrocarbon tails towards other side by dredging by certain arrangement Water effect is gathered to form oiliness core, and aqueous phase solution of their the electrification end group then towards film two sides.In another particular implementation In mode, which can contain one or more embeddings albumen therein and/or glycan molecule.
The example of cellular layer include eukaryocyte layer (e.g., epithelium, lamina propria (lamina propria) and smooth muscle or Muscular layer of mucosa (in gastrointestinal tract)), (e.g., superficial layer or S layers, refer to two be made of same protein or glycoprotein to prokaryotic cell layer Structure monolayer is tieed up, particularly, S layers refer to a part for being typically found in the cell envelope of bacterium and archaeal (archaea)), Biofilm (is encapsulated in structured microbiologic population in a kind of polymer substrate spontaneously formed, is adhered to biology or lazy Property surface) and plant cell layer (e.g., epidermis).Cell can be normal cell or diseased cells (e.g., disease cells, cancer Cell).
The example of biological structure includes being tightly coupled or closing to connect sealed structure, provides a kind of barrier blocking The entrance of toxin, bacterium and virus, e.g., rate of blood-milk barrier and blood-brain barrier (blood brain barrier, BBB).Especially, BBB is made of a kind of non-permeable endothelium, by closely connection combine the endothelial cell closed on constitute physical barriers and Transhipment barrier containing outlet transfer pump.Biological structure can also include the mixture (such as thrombus) of cell, albumen and carbohydrate.
Object, organism, organ or body cavity the example of inner surface include that buccal mucosa (buccal mucosa), esophagus are viscous Film, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, tunica mucosa bronchiorum, uterine mucosa and endometrium (mucous membrane in uterus, flower The cell wall internal layer of powder or the inner layer wall of spore), or combinations thereof or plural number.
Object, organism, organ or body cavity the example of outer surface include capillary (e.g., the blood capillary of heart tissue Pipe), the film (e.g., in nostril, lip, ear, genital area and anus) for the mucous membrane being connected with skin, the outer surface of organ is (e.g., Liver, lung, stomach, brain, kidney, the heart, ear, eye, nose, mouth, tongue, colon, pancreas, gall-bladder, duodenum, rectum, stomach, large intestine (colonrectum), intestines, vein, respiratory system, vascular and anal orifice and rectal intestine), skin, cuticula (e.g., epithelial cell or angling The superficial layer (superficial layer) of the dead cell layer of cell or the overlapping cell being covered on animal hair hair shaft is more Multilayered structure on the outside of kind invertebrate epidermis, Plant cuticle or polymer cutin (cutin) and/or glue film (cutan)), the cell wall outer layer of pollen grain or the outer wall of spore, with and combinations thereof or plural number.
In addition, biological barrier further comprises carbohydrate layer, protein layer or any other biological layer, or combinations thereof or it is multiple Number.For example, skin is a kind of biological barrier, there are many biospheres.Skin contains epithelial layer (outer surface), cortex and hypodermis Layer.Epithelial layer contain multilayered structure include basal cell layer, stratum spinosum epidermidis (spinous cell layer), granular cell layer, And cuticula.It is referred to as keratinocyte in the cell of epithelium.Cuticula (being also " horny layer ") is the outermost layer of epithelium, Wherein here cell is flat and shape is as scale (being in flakey).These cells contain a large amount of keratin, in a manner of multilayer Arrangement makes skin surface have toughness, grease proofness and waterproofness.
Ii the method for certain symptom in biosystem) is diagnosed
Another aspect of the present invention is related to being used to diagnose the side of certain symptom in biosystem using composition of the invention Method.The method includes the steps of:
1) composition containing antimicrobial or antimicrobial related compound HPP is delivered medicine into biological object；
2) detection HPP in the biological object, the presence of the functional groups of the HPP or its metabolin, position or contains Amount；And
3) symptom in the biological object is determined.
In some embodiments, HPP (or substance under shearing from HPP) is in the action site aggregation for symptom occur. In some embodiments, the presence of the functional groups of HPP, position or content are also detected.In some embodiments, phase Close the generation of symptom (e.g., infecting), development, process or slow down also are determined.
In some embodiments, HPP is labeled upper or the detectable substance of Mr. Yu is conjugated.Alternatively, HPP is in preparation It include into radioactive isotope for detection.A variety of detectable substances are available, are probably divided into following classification:
A) radioactive isotope, such as35S、14C、13C、15N、125I、3H, and131I.Diagnostic substances can be by well known in the art Radioactive isotope in technical mark, radioactivity can be measured by the method for scinticounting；In addition, diagnostic substances can pass through spin Label carries out electron paramagnetic resonance detection carbon and nitrogen label.
B) fluorescent material such as BODIPY, BODIPY analog, Rare Earth Chelate (Europium chelate), fluorescein and its derivative Object, FITC, 5, it is 6 Fluoresceincarboxylic acids, rhodamine and its derivative, red yellow acyl, Liz amine (Lissamine), phycoerythrin, green Color fluorescin, yellow fluorescence protein, red fluorescent protein and Dallas Pink (Texas Red).Fluorescence can pass through fluorometric quantification.
C) a variety of enzyme-substrate substances, as luciferase (e.g., firefly luciferase and bacterial luciferase), fluorescein, 2,3- dihydro phthalazine diketone classes (2,3-dihydrophthalazinediones), malic dehydrogenase, urease, peroxide Enzyme such as horseradish peroxidase (HRPO), alkaline phosphatase, beta galactosidase, glucoamylase, lysozyme, polysaccharide oxygen Change enzyme (saccharide oxidases) (e.g., glucose oxidase, galactose oxidase and G-6-P salt dehydrogenation Enzyme), Heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxisome (microperoxidase) and its homologue.Enzyme-substrate combination include, for example: (i) horseradish peroxidase (HRPO) with As the catalase of substrate, wherein catalase oxidation dye precursors (e.g., o-phenylenediamine (OPD) or 3,3 ', 5,5 '- Tetramethyl biphenyl amine hydrochlorate (TMB)；(ii) alkaline phosphatase (AP) and the p-nitrophenyl phosphoric acid as chromogenic substrate Ester；(iii) beta-D-galactosidase (β-D-Gal) and chromogenic substrate (e.g., p-nitrophenyl-β-D- galactoside) or fluorescence are raw At substrate 4-methyl umbelliferone-β-D- galactoside (4-nethylumbelliferyl- β-D-galactoside).
In some embodiments, detectable substance is not necessarily conjugated to diagnostic substances, but can recognize diagnostic substances In the presence of and diagnostic substances can be detected.
In some embodiments, HPP of the invention can be provided by way of whole set object (kit), that is, packaged The reagent of predetermined amount combines, the specification with operation diagnostic test.When HPP is marked with enzyme, which may include bottom Confactor needed for object and the enzyme (such as, it is possible to provide the substrate precursor of detectable chromophore or fluorophor).In addition, may be used also Including other additives such as stabilizer, buffer (e.g., Block buffer or lysis buffer) and its homologue.A variety of reactions The relative quantity of reagent can change in a wider scope, so that the reaction reagent solution of a variety of concentration is provided, it is substantially excellent Change the sensitivity of experiment.Particularly, reaction reagent can provide in the form of dry powder, general to be obtained by freeze-drying, wherein Excipient be may also comprise to provide the reaction reagent solution with suitable concentration after dissolution.
Iii the method that the characteristics of) it is expected for certain (desired character) screens substance
A kind of method for screening substance another aspect of the present invention relates to the characteristics of it is expected for certain.
In some embodiments, this method comprises:
1) by a test function unit by an attachment be covalently attached to a transhipment unit formed one test composition (or One functional unit is covalently attached to a test by an attachment and transports unit, or a functional unit is connected by a test Object is covalently attached to a transhipment unit)；
2) the test composition is delivered medicine into a biosystem；And
3) determine the test composition whether have the characteristics that desired property or.
In one embodiment, it is expected that the characteristics of may include, for example, 1) test function unit formed high-penetration combination The ability of object or convertible time female medicine；2) penetration capacity and/or speed of composition are tested；3) test composition efficiency and/ Or effect；4) turn-over capacity of test transhipment unit；And 5) test the property sheared of attachment.
Iv) the method for treating certain symptom of biological object
Another aspect of the present invention relates to the methods for certain symptom that composition of the invention is used to treat biosystem.It should Method includes that the pharmaceutical composition is delivered medicine to the biosystem.
" treatment " term in the present invention cure, alleviated, inhibited or prevented by fingering row.It " controls Treatment (verb) " term refers to healing, alleviation, inhibition or prevention in the present invention." treatment (noun) " term is in the present invention Refer to and cures, alleviates, inhibits or prevent.
" biosystem ", " biological object " or " object " these terms refer to a certain organ in the present invention, are that completion is specific Task and cooperative one group of organ, a certain organism or one group of organism." organism " this term refers in the present invention The set of molecule functions more or less as an entirety and has lived property, as animal, plant, fungi, Or microorganism.
" animal " this term refers to the most eukaryotes characterized by active movement in the present invention.The example packet of animal It includes, but is not limited to, vertebrate is (for example, the mankind, mammal, reptile, amphibian, fish, capsule cheek class, narrow heart guiding principle (leptocardia)), tunicate (e.g., Thaliacea, appendiculariae, deep water Ascidiacea, Ascidiacea (ascidioidea)), body It saves animal (e.g., Insecta, Myriapoda, malacapod, Arachnoidea, sea spider guiding principle, Merostomata, Crustachia and annelid), Cut toe brave (gehyrea) (anarthropoda) and worm (hehninthes) (e.g., wheel animalcule door).
" plant " this term refers to the organism for belonging to plant kingdom in the present invention.The example of plant includes, but are not limited to Seed plant, bryophyte, pteridophyte and quasi- fern plant.Phanerogamous example includes, but are not limited to cycad (cycads), ginkgo class, coniferals (conifers), sweetberry jointfir class (gnetophytes), angiosperm.The reality of bryophyte Example includes, but are not limited to Ye Tai (liverworts), hornwort and moss.The example of pteridophyte includes, but unlimited In Ophioglossales (ophioglossales) (e.g., contradiction grass (adders-tongues), Botrypus, botrychiam ternatum (grape-ferns)), Marattiaceae and the true fern of thin capsule (leptosporangiate ferns).The example packet of quasi- fern plant It includes, but is not limited to, Lycopidinae (e.g., lycopods, Selaginella tamariscina class (spikemosses) and quillwort (quillworts)), Psilotum nudum Section's (e.g., Lepidophyta and Psilotum nudum mesh) and Equisetaceae (such as equisetales).
" fungi " this term refers to the most eukaryotes for belonging to mycota a member in the present invention.The example of fungi includes, But it is not limited to, chytrid, blastocladiomycota, neocallimastigomycota, Zygomycota, polymerization bacterium door, ascus Bacterium door and Basidiomycota.
" microorganism " this term refers to micro- organism (e.g., length in the micron-scale) in the present invention.Microorganism Example includes, but are not limited to bacterium, fungi, archaeal, protozoan and micro- plant (e.g., green alga) and micro- animal (e.g., floats Trip biology, planarian and amoeba).
Certain examples of the medicable symptom of this method include in the medicable symptom of prodrug of HPP.
V) application method of antimicrobial and antimicrobial related compound and its pharmaceutical composition in the treatment
Another aspect of the present invention relates to the HPP for using antimicrobial or antimicrobial related compound or its medicines The method that compositions treat certain symptom in biosystem, this method resist micro- life by giving to the biosystem or object The HPP or its pharmaceutical composition of agent or antimicrobial related compound.
Antimicrobial and antimicrobial related compound can be used for regulating and controlling extensively in biosystem a variety of biological mistakes Journey.The relevant symptom of these bioprocess can be treated by corresponding antimicrobial or antimicrobial related compound, because This can also pass through antimicrobial or the HPP or HPC or its medicine composite for curing of antimicrobial related compound.
These symptoms include, but are not limited to pain, damage and microorganism related symptoms.Symptom relevant to microorganism is Refer to as microorganism symptom as caused by bacterium, fungi, protozoan and virus.For example, (bacterium is related for the symptom as caused by bacterium Symptom), the symptom as caused by protozoan (the relevant symptom of protozoan), (fungi is relevant for the symptom as caused by fungi Symptom) and the symptom as caused by virus (the relevant symptom of virus).
The relevant symptom of bacterium includes, for example, infection (such as: the infection of a certain organ for example liver, lung, stomach, brain, kidney, heart, Ear, eye, nose, mouth, tongue, colon, pancreas, gall-bladder, duodenum, rectum, stomach, Colon and rectum, intestines, vein, respiratory system, vascular, Anal orifice and rectal intestine and pruritus ani, respiratory tract infection, the infection of the upper respiratory tract, urinary tract infections, nosocomial infection, pseudomonad sense Dye, coagulase-positive staphylococci infection are (such as: skin infection, nosotoxicosis, acute infective endocarditis, septicaemia, gangrenosum acne Pneumonia), implantation prosthese postoperative infection is infected with the chance of septicaemia and pneumonia), pestilence is (such as: bubonic plague and pneumonia type mouse Epidemic disease), anthrax (such as: malignant pustule, pulmonary anthrax and gastrointestinal anthrax), Lyme disease, brucellosis, pertussis, chordapsus, breathing It is road infection, psittacosis, non-gonococcal urethritis, trachoma, newborn's inclusion conjunctivitis, lymphogranuloma venereum, pseudomembranosa Colitis, emphysematous gangrene, food poisoning, anaerobic cellulitis, diphtheria, dysentery, neonatal meningitis, hemorrhagic colon Inflammation, hemolytic uremic syndrome, yatobyo, pneumonia, bronchitis, gastric ulcer, legionaires' disease, Pang Tiya grams of heat, hook end spiral Body disease, listerellosis, leprosy, tuberculosis, Eaton agent pneumonia, stranguria syndrome, ophthalmia neomatorum, septic arthritis, in succession it is quick-fried Send out epidemic meningitis coccus disease, Waterhouse-Frederichsens syndrome (Friedreichsen-Waterhouse syndrome bacteremia), the mountain Luo Ji macula Heat, typhoid fever type salmonellosis (typhoid fevet type salmonellosis), with gastroenteritis and colitis Salmonellosis, bacillary dysentery/bacillary dysentery, cystitis, meningitis and septicaemia, endometritis, tympanitis, nasal sinus Inflammation, syphilis, necrotizing fasciitis, streptococcal pharyngitis, scarlet fever, rheumatic fever, impetigo, erysipelas, puerperal fever and cholera.
The relevant symptom of protozoan includes, for example: malaria, lethargic sleep and and toxoplasmosis.
The relevant symptom of fungi includes, for example: aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycosis, hidden Coccus disease, histoplasmosis, paracoccidiomycosis, sporotrichosis and zygomycosis.
Viral related symptoms include, for example: the relevant symptom of virus and include, for example: influenza, yellow fever and AIDS Disease.
In some embodiments, slow to available antimicrobial or antimicrobial related compound in biological object The method that solution or the symptom for the treatment of are treated includes the antimicrobial or anti-to the biological object drug treatment effective dose The HPP of microorganism agent related compound or its pharmaceutical composition.
HPP or its pharmaceutical composition can be administered to biosystem by any administration route known in the art, including, but It is not limited to, oral route, enteral routes, oral cavity route, nasal, topical route, anal route, vaginal approach, aerosol Approach, transmucosal route, transdermal route, epithelium approach, ocular route, pulmonary route, subcutaneous route, and/or drug administration by injection way Diameter.The pharmaceutical composition can be administered according to administration mode by multiple unit dosage form.
Drug administration by injection refers to administration route usually relevant to injection comprising but it is not limited to vein, intramuscular, artery, chest In interior, intracapsular (intracapsular), socket of the eye, heart is interior, under intradermal, intraperitoneal, transtracheal, sublingual, cuticula, it is intra-articular (intraarticular), under capsule, under arachnoid, intraspinal, and/or breastbone inner injection and/or instillation.
HPP or its pharmaceutical composition can be given pair by the dosage form or object form for being suitable for every kind of administration route As.The preparation that can be used for the method for the present invention includes one or more HPP, one or more pharmaceutically acceptable carriers, Yi Jiqi His therapeutic component.Preparation can easily be provided in the form of unit dose, can use any method system well-known in the field of pharmacy It is standby.Active constituent can form Single unit dosage forms in conjunction with carrier material, and the amount of the active constituent can be according to the object for receiving treatment And administration AD HOC and change.HPP can form pharmaceuticallyeffective amount in conjunction with carrier material, and the amount of the HPP is generally It can produce the amount of the HPP of therapeutic effect.In general, on the basis of 100%, the amount of the HPP can be about 1% to about 99% It is changed in the range of HPP, preferably from about 1% to about 20%.
The method for preparing these preparations or composition include by HPP and one or more pharmaceutically acceptable carriers and, Selectively, the step of one or more attachment components are associated.On the whole, the preparation of said preparation can be by uniform by HPP It ground and is closely associated with liquid-carrier, the solid carrier of subdivision, or both, and subsequent, if necessary, it will Formed product.
Dosage form suitable for oral administration can be capsule, cachet (cachets), pill, tablet, diamond shape agent (use Stir taste basis, usually sucrose, Arabic gum or tragcanth), pulvis, granule, or in water phase or nonaqueous phase liquid In solution or suspension or oil-in-water or Water-In-Oil liquid emulsion or elixir (elixir) or syrup or pastille (pastilles) (use inert base, such as gel and glycerol or sucrose and Arabic gum) and/or collutory and homologue, Every kind all contains the HPP of predetermined amount as active constituent.Compound can also pass through bolus (bolus), electuary (electuary) or paste is administered.
In the solid dosage forms for oral administration (such as capsule, tablet, pill, dragee, pulvis, granule and its Homologue), HPP is mixed with one or more pharmaceutically acceptable carriers, as sodium citrate or Dicalcium Phosphate, and/or from It is lower optional: (1) filler or additive, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid；(2) adhesive, Such as, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and/or Arabic gum；(3) moisturizer, such as Glycerol；(4) disintegrating agent, such as agar, calcium carbonate, potato or tapioca, alginic acid, certain silicates and sodium carbonate；(5) It dissolves moderator (solution retarding agents), such as paraffin；(6) absorption enhancers, such as quaternary ammonium compounds；(7) moisten Humectant, e.g., acetyl alcohol (acetyl alcohol) and glycerin monostearate；(8) absorbent, such as kaolin and bentonite (bentonite clay)；(9) lubricant, such as talcum powder, calcium stearate, magnesium stearate, solid polyethylene glycol, dodecyl Sodium sulphate and its mixture；(10) colorant.In the case where capsule, tablet and pill agent, pharmaceutical composition is also It may include buffer.The solid composite of similar type is alternatively arranged as the filler of soft filling and hard-filled gelatin capsule, uses If lactose or toffee (milk sugars) and the polyethylene glycol of high molecular weight and its homologue are as excipient.
Tablet can be prepared by the method for compacting or pressing mold, be optionally added one or more attached ingredients.Pressure Film-making agent can pass through adhesive (for example, gelatin or hydroxypropyl cellulose), lubricant, inert diluent, preservative, disintegrating agent (for example, Sodium Starch Glycolate (sodium starch glycolate) or sodium cellulose glycolate of crosslinking), surface-active Agent or dispersing agent preparation.The tablet of pressing mold can be by soaking by powdered beta-Lactam antibiotic or with inert liquid diluent Imitative peptide mixture in machine appropriate pressing mold be made.Tablet or other solid dosage forms, as dragee, capsule, pill and Granule, optionally scratch (scored) or be made coating and shell, as casing and other in field of pharmaceutical preparations known in Coating.They can also provide the sustained release or controlled release of HPP by preparation, for example, using the hypromellose of a variety of ratios To providing desired release profiles, using other polymers matrix, using liposome and/or microballoon is used.They can be gone out Bacterium, for example, membrane filtration is retained by bacterium, or by the way that bactericidal agent is added in aseptic solid composite, the sterile solid group Closing object can be dissolved at once in sterile water or in the solvent for the injection that other are sterile using preceding.These compositions also may be selected Property comfort agent (pacifying agents) containing flat, can only or tend to discharge in certain privileged site of gastrointestinal tract HPP is discharged optionally through the mode of delay.The example of available embedding composition includes polymeric material and wax class.HPP It can also be the form of microcapsules, can also have one or more above-mentioned excipient in the appropriate case.
Liquid dosage forms for oral administration includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup And elixir.In addition to HPP, liquid dosage form also contains inert diluent commonly used in the art, for example, water or other solvents, solubilising Agent and emulsifier, such as ethyl alcohol, isopropanol, ethyl carbonate (ethyl carbonate), ethyl acetate, benzyl alcohol, Benzyl Benzoate Ester, propylene glycol, 1,3- butanediol, oils (especially, cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil, And sesame oil), glycerol, tetrahydrofurfuryl alcohol (tetrahydrofuryl alcohol), polyethylene glycols and anhydrous sorbitol fat Acids and its mixture.Besides inert diluents, Orally administered composition also may include adjuvant such as wetting agent, emulsifier and help Suspension, sweetener stir taste agent, colorant, essence (perfuming agent) and preservative.
Suspension also contains suspending agent, for example, ethoxyquin i-octadecanol (ethoxylated in addition to containing HPP Isoste aryl alcohols), polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, oxygen aluminium hydroxide (aluminum metahydroxide), bentonite, agar and tragcanth and its mixture.
Rectum or vagina administration preparation can be the form of suppository, can be by by one or more HPP and a kind of or more Kind appropriate nonirritant excipient or carrier are mixed to prepare, and excipient or carrier include, for example, cupu oil, polyethylene glycol, Suppository wax or salicylate, excipient or carrier are solid in room temperature, but are liquid in body temperature, therefore in rectum or vaginal canal It is interior to melt and discharge active material.Preparation suitable for vagina administration further includes pessary, tampon (tampons), cream Frost, gel, paste, foaming agent or spray contain suitable carrier well known in the art.
The preparation of the transdermal or epidermis or percutaneous drug delivery that can be used for HPP composition includes pulvis, spray, ointment, paste Agent, creams agent, lotion (lotions), gelling agent, solution, patch (patches) and inhalant.Active constituent can be sterile Under conditions of mixed with pharmaceutically acceptable carrier, can be with any desired preservative, buffer or propellant (propellants) it mixes.Ointment, paste, creams agent and gelling agent can contain, and in addition to HPP composition, excipient is such as dynamic Object and plant fat, oils, wax class, paraffin, starch, tragcanth, cellulose derivative, polyethylene glycols, silicone, swelling Or mixtures thereof great soil group, silicic acid, talcum powder and zinc oxide,.Pulvis and spray can contain, in addition to HPP composition, excipient Such as lactose, talcum powder, silicic acid, aluminium hydroxide.The mixture of calcium silicates and polyamide or these substances.Spray can separately contain Propellant, such as chlorofluorocarbons and the unsubstituted hydrocarbon of volatility, such as butane and propane.For topical administration or transdermal give The best preparation of medicine is pure water, solution, aqueous phase solution, ethyl alcohol and aqueous solution and isopropanol and aqueous solution.
HPP or its pharmaceutical composition can separately pass through aerosol drug delivery.By preparing water phase aerosol, rouge containing HPP Liposome preparation or solids are realized.(e.g., fluorocarbon propellant) suspension of nonaqueous phase can also be used.Ultrasonic mist can also be used Change device.The preparation of water phase aerosol can by by the aqueous phase solution of drug or suspension and conventional pharmaceutically acceptable carrier and The common preparation of stabilizer obtains.Carrier and stabilizer can be changed according to the requirement of particular compound, but usually may include non-solution From surfactant (Tweens, general stream Buddhist nun gram (Pluronics) or polyethylene glycol), nontoxic protein such as serum globulins, dehydration Sorbierite esters, oleic-acid, lecithin lipid, amino acids such as glycine, buffer class, salt, carbohydrate or glycitols.Aerosol It can generally be prepared by isotonic solution.
Transdermal patch can also be used for transmitting HPP composition to target site.Such preparation can be by appropriate solvent Dissolution disperses drug to prepare.Absorption enhancers also can be used to increase the flow (flux) of drugs through skin.The control of the flow System can be dispersed in polymer substrate or gel by using rate-controlling membrane or by drug.
Ophthalmic preparation, eye ointments, pulvis, solution and its homologue are also included within the scope of the present invention.
Can be used for drug administration by injection preparation include HPP and one or more pharmaceutically acceptable sterile isotonic water phases or Non-aqueous solution agent, dispersing agent, suspension or emulsion, or can be recombinated using preceding current sterile injectable solution or dispersing agent Sterile powder, containing antioxidant, buffer, bacteriostatic agent, preparation can be made and inject object blood keep isotonic solute, Or suspending agent or thickener.
Workable water phase and the example of nonaqueous phase carrier include the preparation suitable for drug administration by injection, water, ethyl alcohol, more First alcohol (e.g., glycerol, propylene glycol, polyethylene glycol and its homologue) and its mixture appropriate, vegetable oil, as olive oil, With organic esters for injection class, such as ethyl oleate.Mobility appropriate can be kept, for example, by using coating material such as lecithin, By keeping required partial size in dispersing agent, and by using surfactant.
The preparation that can be used for drug administration by injection can also contain adjuvant, such as preservative, wetting agent, emulsifier and dispersing agent.It can lead to The effect that a variety of antibacteriums and antifungal substance is added to ensure against microorganism is crossed, antibacterium and antifungal substance are for example, Buddhist nun Moor gold, methaform, phenol sorbic acid and its homologue.Isotonic substance, such as carbohydrate, chlorine can be also preferably comprised in the composition Change sodium and its homologue.In addition, the substance that can be also absorbed by the way that delay is added extends injection such as aluminum monostearate and gelatin With the absorption of pharmaceutical preparation.
The accumulation preparation (depot forms) of injectable can be made by forming the microencapsule matrices of HPP or can be dropped in biology It is formed in object such as the polylactic acid-polyglycolide of depolymerizing.The control of drug releasing rate may depend on the ratio of HPP and polymer, And the property of certain particular polymers used.The example of other biological degradable polymer includes poly- (ortho esters) and poly- (acid Acid anhydride).Depot injection preparation preparation can also by HPP is encapsulated in the liposome or micro emulsion compatible with bodily tissue into Row.
In some embodiments, the HPP of the antimicrobial for the treatment of effective dose or antimicrobial related compound, Or its pharmaceutical composition can be passed to disease or tumor sites.Known in pharmacology field, the medicine effective dose of HPP it is accurate Amount can generate certain specific patient most effective as a result, the accurate amount depends on, for example, the work of specific HPP in terms for the treatment of curative effect Property, specific nature, pharmacokinetic properties, pharmacokinetic property and bioavilability, administration object physiological signs (including Race, age, or sex, weight, recipe, kinds of Diseases and stage, whole physical symptom, to specific dosage and treatment type Reactivity), disease caused by property, administration route and the frequency of acceptable carriers, target pathogenic microorganisms in preparation Chinese pharmacology Severity or tendency etc., only enumerate several herein.But above guideline can be used as and be fine-tuned to treatment Basis e.g. determines the optimal dose of administration, required conventional real no more than being made of monitoring administration object and regulating dosage It tests.It can refer to, Remington:The Science and Practice of Pharmacy (Gennaro ed.20.sup.th Edition, Williams&Wilkins PA, USA) (2000).
IV. advantage
Usually therefore, it is difficult to penetrate skin than more hydrophilic for antimicrobial such as antibiotic and antimicrobial related compound Envelope barrier.When antimicrobial and oral antimicrobial related compound, they can be inactivated by first-pass metabolism.In injection In the case of, the administration of antimicrobial will cause pain, need to make frequent calls on doctor for treatment chronic sympton in many cases And it spends very high.
It in some embodiments, should since HPP or HPC of the invention can penetrate one or more layers biological barrier HPP or HPC can be by local administration (e.g., external application or transdermal) to without being administered systemically (e.g., oral or injection administration) In the case of reach symptom occur site.It the local administration of HPP or HPC and penetrates so that the accessible therapeutant of HPP or HPC The local concentration of matter (agent) or drug be administered systemically female medicine or drug when local concentration in same level, but HPP or The dosage or dosage of HPC is far below the amount of be administered systemically female medicine or drug；In addition, higher office may be cannot achieve by being administered systemically Portion's concentration, or if even possible, be administered systemically and be also required to very high therapeutic substance dosage.HPP or HPC or its shearing The high local concentrations of female medicine afterwards make it more efficient to the treatment of certain symptom, or rapider than female medicine that is administered systemically, And new symptom that can not to treat in the past or unobservable can be treated.The local administration of HPP or HPC can reduce life Object object because of pain potential caused by being administered systemically, such as to the relevant side reaction of therapeutic substance system exposure, gastrointestinal reaction or Kidney response.In addition, local administration can make HPP or HPC by a variety of biological barriers and by, for example, global cycle, system is reached, There is no need to be administered systemically (as injected) and avoid pain relevant to drug administration by injection.
In some embodiments, e.g., the HPP in the present invention or HPC or pharmaceutical composition (can be taken orally by being administered systemically Or injection).The active therapeutic agent (such as drug or metabolin) of HPP or HPC or HPP or HPC can speed more faster than female medicine Into global cycle, and reach the action site of certain symptom.In addition, HPP or HPC can pass through biological barrier (such as blood-brain barrier, blood milk Barrier), and this biological barrier can not be penetrated if female medicine is only administered, therefore HPP or HPC can be that can not treat or not see in the past The symptom observed provides new treatment.
For example, the high-penetration composition (HPC) of antimicrobial or antimicrobial related compound of the invention shows The high-penetration speed to biological barrier is gone out, (for example, when being administered alone than antimicrobial or antimicrobial related compound It is higher by least about 10 times, about 50 times, about 100 times, about 200 times, about 300 times, about 1000 times).Using antimicrobial HPP Or do not observed in the object of HPC or almost do not observe side effect, and the object of antimicrobial is used under same dose In then observed side effect (as nausea).
With a large amount of uses of antimicrobial, pathogen is mutated with the time so that drug resistance becomes common and serious Problem.The high-penetration composition (HPC) of antimicrobial or antimicrobial related compound of the invention can be with higher speed Degree penetrates biological barrier, such as biofilm, and bacterium, fungi and other microorganism walls are to overcome drug resistance problems.
V. embodiment
Following embodiment is intended to be better described the invention of protection, and should not be construed as in any way to limit of the invention System.All concrete compositions as described below, material and method, all or part are included within the scope of the present invention. These concrete compositions, material and method should not limit the present invention, only illustrate specific embodiment within the scope of the present invention.This Field technical staff without creative work and without departing from the scope of the invention under the premise of, equivalent composition, material can be developed And method.It should be understood that the method that the present invention can be used to describe is made a variety of variations but is included within boundary of the invention.Hair Bright people thinks that such variation is included within the scope of the invention.
Embodiment 1, the method that prodrug is prepared by female medicine
In some embodiments, female medicine of the structure of formula F-C is had following structure:
The HPP of the structure with structural formula L-1 can be converted into:
Including its stereoisomer and pharmaceutically acceptable salt class, wherein F, L1、L2And L4It is defined as described above；
T is the transhipment unit of antimicrobial or antimicrobial related compound.For example, T can be selected from aforementioned W and R6Group At set.
In some embodiments of the present invention, the HPP with structural formula L-1 can be by that will have female medicine of structural formula D Or the derivative (for example, acyl chlorides or mixed acid anhydride of female drug compound) of female medicine:
With the compound in structural formula E (scheme 1):
T-L2-H
Structural formula E
It is prepared by organic synthesis.Wherein, WcSelected from by OH, halogen, alkyloxycarbonyl group and substituted aryloxycarbonyl The set of oxygroup composition；F,L1、L2、L4It is as defined above with T.
In some embodiments, the HPP with structural formula L-1 is prepared by following scheme 1, wherein L4It is C=O.
In some embodiments, female medicine of formula F is had following structure:
It is reacted with the compound with following structural G:
Obtain the HPP with structural formula L:
Including its stereoisomer and pharmaceutically acceptable salt class, in which:
F、L1、L2、L4And TNAs defined above；
T is the transhipment unit of antimicrobial or antimicrobial related compound.For example, T can be selected from foregoing W And R6The set of composition；And
M can be selected from can be selected from by the set of sodium, potassium or other metals composition by OH, halogen, alkyloxycarbonyl group and substitution Aryloxycarbonyl epoxide composition set (scheme 2).
Scheme 2. prepares HPP from female medicine (11)
In some embodiments, can be prepared by organic synthesis with the HPP of structural formula L-1, wherein can with transhipment Unit be connected with functional unit before by unwanted reaction site such as-C (=O) OH ,-NH2,-OH or-SH protect Come.In some embodiments, the protection HPP of acquisition further can partly or entirely deprotect to obtain protection respectively HPP or unprotected HPP.
The preparation of 6- benzene oxygen acetylamino penicillinic acid 2- lignocaine ethyl ester hydrochloride
39g ospeneff is taken to be dissolved in 100ml acetonitrile.39g 2- bromo-N, N- diethyl second in ethyl acetate The hydrogen bromide salt mixture of base amine is added into reaction mixture.Mixture is stirred at room temperature 16 hours.39g (0.15 mole) 2- bromo-N, N '-diethyl ethylamine hydrogen bromide salt and 30g sodium bicarbonate are added into reaction mixture.Mixture is in room Temperature stirring 12 hours again.It is filtered to remove solid.It is molten that the 3.5g hydrogen chloride gas being dissolved in 50ml ether is added into mixing under stiring In liquid.Solid product is collected by filtration.38g property product easy to moisture absorption, yield 78.2% are obtained after drying.Elemental analysis: C22H32ClN3O5S；Molecular weight: 486.0.Calculated value %C54.37, H:6.64, N:8.65, Cl:7.29, O:16.46, S: 6.60, measured value %C:54.32, H:6.68, N:8.61, Cl:7.32, O:16.51, S:6.56.
The preparation of 6- (2,6- dimethoxybenzarnide) penicillinic acid -2- lignocaine ethyl ester hydrochloride
38g6- (2,6- dimethoxybenzarnide) penicillinic acid is dissolved in 300ml chloroform.20.6g N is added, N '-dicyclohexylcarbodiimide.11.7g N, N- dimethylaminoethanol and 2 grams of 4-dimethylaminopyridine are added into reaction mixing In liquid.Reaction is stirred at room temperature 10 hours.Filter out solid.Chloroform layer is washed 2 times (2x100ml) with 5% sodium bicarbonate solution It is washed with water 3 times (3x100ml).It is filtered after organic layer anhydrous sodium sulfate drying.Lower 3.5g hydrogen chloride is stirred to be added into instead It answers in mixture, solid product is collected by filtration.40g property product easy to moisture absorption, yield 77.5% are obtained after drying.Elemental analysis: C23H34ClN3O6S；Molecular weight: 516.05. calculated value %C:53.53, H:6.64, N:8.14, Cl:6.87, O:18.60, S: 6.21, measured value %C:53.49, H:6.68, N:8.11, Cl:6.90, O:18.64, S:6.18.
The preparation of acetylamino phenyl acetylamino penicillinic acid 2- lignocaine propyl ester hydrochloride
43g acetylamino phenyl acetylamino penicillinic acid sodium is taken to be dissolved in 100ml acetonitrile.40g 2- bromo-N, N- Mixture of the diethylpropyl amine hydrogen bromide salt in ethyl acetate is added into instead
26H33ClN4O5S；Molecular weight: 541.11.Calculated value %55.49；H:6.89；N:10.35；Cl:6.55；O: 14.78；S:5.92；Measured value %C:55.44；H:6.92；N:10.32；Cl:6.58；O:14.82；S:5.92.
The preparation of 6- (5- methyl -3- phenyl -2- isoxazoline -4- formamido group) penicillinic acid 4- piperidines carbethoxy hydrochloride
50g 6- (5- methyl -3- phenyl -2- isoxazoline -4- formamido group) penicillinic acid sodium is taken to be dissolved in 100ml second In nitrile.Mixture of the 38g 4- piperidinoethyl bromine hydrogen bromide salt in ethyl acetate is added into reaction mixture.Mixture It is stirred at room temperature 16 hours.38g 4- piperidinoethyl bromine hydrogen bromide salt and 30g sodium bicarbonate are added into reaction mixture.It is mixed Object is closed to be stirred at room temperature 12 hours.It is filtered to remove solid.3.5 g hydrogen chloride gas being dissolved in 50ml ether are added under stiring In mixed solution.Solid product is collected by filtration.30g property product easy to moisture absorption is obtained after drying.Elemental analysis: C26H33ClN4O5S；Point Son amount: 549.08.Calculated value %C:56.88；H:6.06；N:10.20；Cl:6.46；O:14.57；S:5.83；Measured value %C: 56.85；H:6.08；N:10.19；Cl:6.47；O:14.59；S:5.82.
3- [[(amino carbonyl) oxygen] methyl] -7- methoxyl group -8- ketone -7- [(2- thienyl acetyl) amino)] -5- thia - 1- azabicyclo-[4.2.0]-oct-2-ene -2- carboxylic acid 2- lignocaine ethyl ester hydrochloride preparation
Take 41g 3- [[(amino carbonyl) oxygen] methyl] -7- methoxyl group -8- ketone -7- [(2- thienyl acetyl) amino)] - 5- thia -1- azabicyclo-[4.2.0]-oct-2-ene -2- carboxylic acid sodium is dissolved in 100ml acetonitrile.35g 2- bromo-N, N- Mixture of the diethyl ethylamine hydrogen bromide salt in ethyl acetate is added into reaction mixture.Mixture is stirred at room temperature 16 hours.30g 2- bromo-N, N '-diethyl ethylamine hydrogen bromide salt and 30g sodium bicarbonate are added into reaction mixture.It is mixed It closes object and continues stirring 12 hours in room temperature.It is filtered to remove solid.The 3.5g hydrogen chloride gas being dissolved in 50ml ether is added under stiring Enter into mixed solution.Solid product is collected by filtration.30g property product easy to moisture absorption is obtained after drying.Elemental analysis: C22H31ClN4O7S2；Molecular weight: 563.08.Calculated value %C:46.93；H:5.55；N:9.95；Cl:6.30；O:19.89；S: 11.39；Measured value %C:46.91；H:5.57；N:9.93；Cl:6.32；O:19.91；S:11.36.
The HPP of other antimicrobials or antimicrobial related compound can also be synthesized by similar method.
The HPP of embodiment 2, antimicrobial or antimicrobial related compound penetrates the speed of human skin in vitro It is faster than female medicine
By measuring in the improved pond Franz in vitro, the pond Franz has penetrance of these HPP in human skin Two ponds, upper storage reservoir are sample cell, and lower pond is acceptance pool, are isolated from the human skin tissue of thigh position above or below (360-400 μ n is thick) separates upper storage reservoir and acceptance pool.
Tested material [2ml, in 10% solution of the phosphate buffered saline solution (0.2 M) of pH 7.4] is placed in sample cell.It connects Contained the phosphate buffered saline solution (0.2M) of 10ml pH7.4 by pond.Receive solution with 600 turns of speed per minute stirring.It is tested The amount that object passes through skin is measured with specific high performance liquid chromatography.As a result such as Fig. 1 a1, Fig. 1 a2, Fig. 1 a3, Fig. 1 a4,1b With shown in Fig. 1 c, test the apparent penetrating value of compound according to fig. 1a 1, the slope of Fig. 1 a2, Fig. 1 a3 and Fig. 1 a4 be calculated, And it is summarised in table 1a.It is summarised in table 1b and table 1c respectively according to the apparent penetrating value that the slope of Fig. 1 b, Fig. 1 c are calculated.
Since the minimum detection limit of apparent penetrating value in the method is 1 μ g/cm2/ h, therefore apparent penetrating value is equal to Or less than 1 μ g/cm2Female medicine of/h is considered not detecting to penetrating for skin histology.For apparent penetrating value less than 1 μ g/cm2/ Female medicine (such as ospen, penicillin) of h, HPP have detectable apparent penetrating value.1 μ is greater than for apparent penetrating value g/cm2Female medicine of/h, HPP have higher detectable apparent penetrating value.Therefore antimicrobial or antimicrobial phase The HPP of related compounds shows the higher penetration speed (340-600 times) to skin histology compared with female medicine.
The penetration speed (I) of the HPP of table 1a. antimicrobial in vitro
The penetration speed (II) of the HPP of table 1b. beta-lactamase inhibitor in vitro
The penetration speed (III) of the HPP of table 1c. sulfamido and quinolones mother's medicine in vitro
Embodiment 3, HPP penetrate the penetration speed of skin and/or blood-brain barrier in vivo
Experiment compares prodrug and penetrates the hairless rate without the skin and blood-brain barrier of hurting mouse living.Donor is molten by 1ml Drug solns (6- (2,6- dimethoxybenzarnide) penicillinic acid -2- lignocaine ethyl ester hydrochloride before the 20% of isopropanol Solution, 6- (5- methyl -3- phenyl -2- isoxazoline -4- formamido group) penicillinic acid -2- lignocaine ethyl ester HCI solution Or 6- [3- (Chloro-O-Phenyl) -5- methyl -4- isoxazole formamido group] penicillinic acid -2- lignocaine ethyl ester HCI solution) Composition.It is applied to hairless mouse back 10cm2Position.After 2 hours, mouse is killed.Take 1g blood, 1g liver, 1g kidney, 1g muscle, 1g brain is separately added into 5ml methanol, is beaten with homogenizer, then is centrifuged and measured after five minutes with HPLC.Prodrug can be very well as the result is shown Penetrate blood-brain barrier.
The HPP of 2. beta-Lactam antibiotic of table in vivo penetrates biological barrier
Select the milk cow of 90 lactations.The phosphoric acid that 500mg is dissolved in 10ml pH value 7.4 is sprayed on the skin of breast 6- benzene oxygen acetylamino penicillinic acid 2- lignocaine ethyl ester hydrochloride (ospen-DEE), 6- in buffer solution (0.2M) (2,6- dimethoxybenzarnide) penicillinic acid 2- lignocaine ethyl ester hydrochloride (methicillinum-DEE) or 7- [[(2- Acetylaminohydroxyphenylarsonic acid 4- thiazolyl) (methoxyimino) acetyl group] amino] -8- ketone -5- thia -1- azabicyclo [4.2.0] octyl- 2- alkene -2- carboxylic acid 2- lignocaine ethyl ester hydrochloride (Ceftizoxime-DEE).1 hour after topical application, milk sample is taken to analyze. As the result is shown in table 3.Measure the content of female medicine in cow's milk.These prodrugs have very high penetrance to rate of blood-milk barrier as the result is shown. The high rate of blood-milk barrier penetrance of these prodrugs does not grudge them for treating brain, and chest, prostate and other inflammation are very useful.
Table 3.HPP in vivo penetrates rate of blood-milk barrier
The HPP of 4. antimicrobial of embodiment or antimicrobial related compound faster penetrates the thin of bacterium than its female medicine Cell wall
By 0.5 mM of a test-compound, (6- is to benzene oxygen acetylamino penicillinic acid 1- piperidines carbethoxy hydrochloride (ospen-PEE), ospen, 6- (2,6- dimethoxybenzarnide) penicillinic acid 2- nafoxidine methyl ester hydrochloride (first Oxygen benzopenicillin-PME), methicillinum, 7- [[(2- acetylaminohydroxyphenylarsonic acid 4- thiazolyl) (methoxyimino) acetyl group] ammonia Base] -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid 2- lignocaine ethyl ester hydrochloride (cephalo azoles Oxime-DEE) or Ceftizoxime) be added in 100ml E. coli suspension, rock suspension 3 minutes.It is centrifuged with 3000rpm The mixture outwells supernatant, and washes the centrifugation of large intestine bar three times with the phosphate buffer of pH 7.4.Finally by 10 milliliters of second Nitrile is added to Escherichia coli precipitating, and suspension heats 2 minutes at 60 DEG C.Acetonitrile solution is collected, then volatilization is dry.Medication amount by HPLC method determines.It the results are shown in Table shown in 4.
Table 4: into the medication amount of antibiotic and its HPP in Bacillus coli cells
Conversion of the embodiment 5.HPP to female medicine
The HPP of antimicrobial or antimicrobial related compound can be converted to mother to high-yield quick rule in human plasma Medicine antimicrobial or antimicrobial related compound.
10mg antimicrobial-prodrug is dissolved in the phosphate buffer solution that 0.1ml pH value is 7.4 (0.2M).By 1ml People's blood is added in solution after being preheated to 37 DEG C, and mixed liquor is placed in 37 DEG C of water-baths.At intervals of two minutes, 0.2ml sample is taken out, then 0.4ml methanol extraction plasma proteins is added.After centrifugation 5 minutes, efficient liquid phase chromatographic analysis is used.The results show that most of The HPP of antimicrobial or antimicrobial related compound is converted to female medicine antimicrobial or antimicrobial related compounds Object (table 5).
Half-life period of the table 5.HPP in blood plasma
The minimum inhibitory concentration (MIC) of the HPP of 6. antimicrobial of embodiment or antimicrobial related compound
Method (Jennifer M.Andrews, Journal of Antimicrobial according to the literature Chemotherapy 48, suppl.S1,5-16 (2001)) determine antimicrobial and their novel anti-microbial agent most Low Mlc (MIC).These results (table 6a-6c) illustrate according to minimum inhibitory concentration (MIC) these novel anti-microbial agents Prodrug can be efficiently against the drug resistance of methicillin resistant Staphylococcus aureus (MRSA).
The minimum inhibitory concentration of table 6a. antimicrobial and its prodrug to methicillin resistant Staphylococcus aureus (MRSA) (MIC)(mg/L).
The various antibiotic of table 6b. add beta lactamase restrainer or the minimum inhibitory concentration MICs (mg/L) of its HPP
The MICs (mg/L) of table 6c. sulfamido and quinolones and its prodrug
The antifungic action of 7. antimicrobial of embodiment or antimicrobial related compound HPP
(Roether W.et al., Mykosen 27 (1), 14-28 are measured according to the method for Roether W. report (1984)) 6- benzene oxygen acetylamino penicillinic acid 2- lignocaine ethyl ester hydrochloride (ospen-DEE), 6- (2,6- dimethoxies Yl-benzamide) penicillinic acid 2- lignocaine ethyl ester hydrochloride (methicillinum-DEE) or 7- [[(2- acetylaminohydroxyphenylarsonic acid 4- Thiazolyl) (methoxyimino) acetyl group] amino] -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid The antifungal activity of 2- lignocaine ethyl ester hydrochloride (Ceftizoxime-DEE).It the results are shown in Table shown in 7:
7. beta-lactam antibiotic prodrug of table antimycotic minimum inhibitory concentration (mg/L) in vitro
The HPP of the beta-lactam antibiotic of embodiment 8. or antimicrobial related compound treats clinical mastitis
Select the milk cow of 90 lactations.Bacteriological healing refers at the 17th day and the 22nd day from infected It obtains with cow and does not detect that bacterium clinical cure refers to that (clinical symptoms completely eliminate 1 day for the disappearances of clinical symptoms in sample After calculate clinical cure), the recovery of food-intake, 39.0 DEG C of rectal temperature <, good constitutional symptom, breast water in other words Swollen disappearance, cow's milk character is normal, the output of milk is normal.
500mg is twice daily sprayed on the skin of breast is dissolved in the 6- benzene in the phosphate buffer solution of 10ml pH value 7.4 Oxygen acetylamino penicillinic acid 2- lignocaine ethyl ester hydrochloride (ospen-DEE), 6- (2,6- dimethoxybenzarnide) Penicillinic acid 2- lignocaine ethyl ester hydrochloride (methicillinum-DEE) or 7- [[(2- acetylaminohydroxyphenylarsonic acid 4- thiazolyl) (first Oxyimino group) acetyl group] amino] -8- ketone -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid 2- lignocaine Carbethoxy hydrochloride (Ceftizoxime-DEE).As the result is shown in table 8a and table 8b.As a result illustrate that these prodrugs can achieve well Clinical cure rate and bacteriology cure rate.
Clinical cure rate of the novel antibiotic prodrug of table 8a. external application to cow mastitis
Table 8b: bacteriology cure rate (22 day) of the novel antibiotic prodrug of external application to cow mastitis
The treating pulmonery tuberculosis mycobacterium performance of the prodrug of 9. antimicrobial of embodiment
Six weeks female mices of age of mouse (BALB/c mouse) are allowed to infect 2.21 ± 0.15 x 10 by air borne mode3 The Mycobacterium tuberculosis H37Rv of CFU.After 20 days, the CFU average value of lung is 8.23 ± 0.27 x107CFU, then to small Mouse carries out drug therapy.A group is the control group (n=20) of blank, B group mouse isoniazid/Moxifloxacin/pyrazinamide (0.18/0.22/1.2mmol/kg takes orally) treatment 45 days, C group mouse isoniazid/Moxifloxacin/pyrazinamide (0.18/ 0.22/1.2mmol/kg, take orally) treatment 90 days, (prodrug-is different for the isoniazid-N`- with N- (N- methylphenylalanine) for D group mouse Cigarette hydrazine is reacted to obtain, cutaneous penetration by N- methylphenylalanine with isoniazid)/1- cyclopropyl -7- (- two ring of S, S-2,8- diazonium [4.3.0] nonane -8- base) fluoro- 8- methoxy-Isosorbide-5-Nitrae-dihydro -4- ketone -3- quinoline carboxylic acid butyl ester (the Moxifloxacin prodrugs)/pyrrole of -6- Piperazine acid N, N- lignocaine ethyl ester (pyrazine acid prodrug 0.18/0.22/1.2mmol/kg, cutaneous penetration) are treated 45 days, E group mouse It is treated 90 days with isoniazid prodrug/Moxifloxacin prodrugs/pyrazine acid prodrug (0.18/0.22/1.2mmol/kg, cutaneous penetration), F group mouse is controlled with isoniazid prodrug/Moxifloxacin prodrugs/pyrazine acid prodrug (0.06/0.07/0.4mmol/kg, cutaneous penetration) Treat 45 days, G group mouse with isoniazid prodrug/Moxifloxacin prodrugs/pyrazine acid prodrug (0.06/0.07/0.4mmol/kg, it is transdermal Administration) treatment 90 days.After treatment stops, mouse continues to feed (not medication) in 90 days, and cure rate (aobvious lung is measured after then putting to death Portion's feminine gender culture is to cure).As a result illustrate that prodrug is better than their female medicine, and can be with cutaneous penetration (table 9a and 9b).
CFU after table 9a. is treated in combination is counted
Cure rate after table 9b. combined therapy
Embodiment 10. treats adult pulmonary tuberculosis (children reduce dosage).
40mg N- (N- methylphenylalanine) isoniazid hydrochloride (isoniazid prodrug)/50mg 1- cyclopropyl -7- [- (1S, 6S) -2,8- diazabicyclo [4.3.0] nonane -8- base] the fluoro- 8- methoxy-Isosorbide-5-Nitrae-dihydro -4- ketone -3- quinoline carboxylic acid of -6- Butyl ester hydrochloride (moxifloxacin prodrug)/40mg pyrazine carboxylic acid N, N- lignocaine ethyl ester hydrochloride (pyrazine carboxylic acid prodrug) is dissolved in In 3ml water and it is applied to the chest of patient or the skin (close to infected organ) at the other any positions of body, daily the morning and evening each one Secondary (twice a day) continues 90 days or up to rehabilitation.
Embodiment 11. treats adult leprosy or Hansen ' s sick (HD) (children reduce dosage)
30mg 4- dimethylamino butyrylamino phenyl -4- aminobenzene sulfone hydrochloride (dapsone prodrug)/50mg 1- cyclopropyl The fluoro- 8- methoxy-Isosorbide-5-Nitrae-dihydro -4- ketone -3- of base -7- [- (1S, 6S) -2,8- diazabicyclo [4.3.0] nonane -8- base] -6- Quinoline carboxylic acid's butyl ester hydrochloride (moxifloxacin prodrug)/15mg mercaptophenylimidazole 4-N, N- dimethylamino butyric acid thioesters hydrochloride (mercapto Benzene imidazoles prodrug) chest of patient or the skin at the other any positions of body are dissolved in 3ml water and are applied to (close to infected device Official), once in the morning and once at night (twice a day), continue 6 months or up to rehabilitation.
Embodiment 12. treats ear infections
20mg 6- benzene oxygen acetylamino penicillinic acid 2- lignocaine ethyl ester hydrochloride is dissolved in 1ml water and is applied to patient On the skin of infected ear (close to infected organ), once in the morning and once at night (twice a day), continue two weeks or Until rehabilitation.
Embodiment 13. treats the treatment of adult's lower respiratory tract infection (children reduce dosage)
80mg D- α-[(imidazolidin-2-one -1- base) formamido group] parasiticin 2- nafoxidine methyl ester hydrochloride is dissolved in In 3ml water and it is applied on patient's neck or the skin in chest (close to infected organ), once in the morning and once at night (twice a day), Continue two weeks or up to rehabilitation.
Embodiment 14. treats the infection of the upper respiratory tract of adult (children reduce dosage)
80mg 6-D (-)-α-(4- ethyl -2,3- diketone -1- piperazine formamido group)-α-phenylacetylamino penicillinic acid - 2- lignocaine ethyl ester hydrochloride is dissolved in 2ml water and is applied on the skin of patient's neck (close to infected organ), early daily Evening is each primary (twice a day), continues two weeks or up to rehabilitation.
Embodiment 15. treats the infection of the upper respiratory tract of adult (children reduce dosage)
30mg 3- [[(amino carbonyl) oxygen] methyl] -7- methoxyl group -8- ketone -7- [(2- thienyl acetyl) amino)] -5- Thia -1- azabicyclo-[4.2.0]-oct-2-ene -2- carboxylic acid 2- lignocaine ethyl ester hydrochloride is dissolved in 2ml distilled water and by medicine It is sprayed onto the mouth or nose of patient, once in the morning and once at night (twice a day), continues two weeks or until restore.
Embodiment 16. treats adult meningitis (children reduce dosage)
80mg 6-D (-)-α-(4- ethyl -2,3- diketone -1- piperazine formamido group)-α-phenylacetylamino penicillinic acid - 2- lignocaine ethyl ester hydrochloride is dissolved in 3ml distilled water and is applied on the neck and head of patient, and once in the morning and once at night (daily two It is secondary), continue two weeks or up to rehabilitation.
Embodiment 17. treats diarrhea (children reduce dosage)
80mg 7- (2- thiophenacetyl amino) cephalosporanic acid -2- lignocaine ethyl ester hydrochloride is dissolved in 3 ml distilled water simultaneously It is applied on the skin near the navel of patient, once in the morning and once at night (twice a day), continues two weeks or until restore.
Embodiment 18. treats breast infection
50mg 7- [(oxybenzene acetyl group) amino] -3- [[(1- methyl-1 H- tetrazole -5- base) sulphur] methyl] -8- ketone - 5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid 2- lignocaine ethyl ester hydrochloride is dissolved in 2ml distilled water and applies On skin around the breast of patient Yu, once in the morning and once at night (twice a day), continue two weeks or up to rehabilitation.
Embodiment 19. treats sex genital system infection (children reduce dosage)
80mg 3- [[(amino carbonyl) oxygen] methyl] -7- [[2- furyl (methoxyimino) acetylamino] -8- ketone -5- Thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid 2- lignocaine ethyl ester hydrochloride is dissolved in 3ml water, is smeared In the affected part of patient, once in the morning and once at night (twice daily), for 2 weeks or until rehabilitation.

Claims (6)

1. compound, are as follows:
- two olefinic carboxylic acid N, N- bis- of 6- ketone -3- (2- [4- (N- pyridine -2- base-sulfamoyl) phenyl] hydrazono-) hexamethylene-Isosorbide-5-Nitrae Ethylamino propyl ester hydrochloride.
2. a kind of pharmaceutical composition contains compound as described in claim 1 and pharmaceutical acceptable carrier.
3. pharmaceutical composition as claimed in claim 2, wherein the pharmaceutical acceptable carrier is polar.
4. pharmaceutical composition as claimed in claim 2, wherein the pharmaceutical acceptable carrier is selected from the group of following components composition: Alcohol, ketone, ester and aqueous phase solution.
5. pharmaceutical composition as claimed in claim 2, wherein the pharmaceutical acceptable carrier is water.
6. compound as described in claim 1 or the pharmaceutical composition as described in any one of claim 2-5 are used in preparation In in biological object treat chordapsus, pseudomembranous colitis, hemorrhagic colitis, with the sramana of gastroenteritis and colitis Purposes in the drug of Salmonella disease or rheumatic fever.
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