WO2010142241A1 - High penetration compositions or prodrugs of antimicrobials and antimicrobial-related compounds - Google Patents

High penetration compositions or prodrugs of antimicrobials and antimicrobial-related compounds Download PDF

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Publication number
WO2010142241A1
WO2010142241A1 PCT/CN2010/073743 CN2010073743W WO2010142241A1 WO 2010142241 A1 WO2010142241 A1 WO 2010142241A1 CN 2010073743 W CN2010073743 W CN 2010073743W WO 2010142241 A1 WO2010142241 A1 WO 2010142241A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
group
acid
antimicrobial
Prior art date
Application number
PCT/CN2010/073743
Other languages
French (fr)
Inventor
Chongxi Yu
Lina Xu
Yuhua Chen
Binbing Yan
Shiqian Tu
Original Assignee
Techfields Biochem Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US12/482,373 external-priority patent/US20100040548A1/en
Priority to JP2012514336A priority Critical patent/JP5916129B2/en
Priority to RU2011152319/15A priority patent/RU2586287C2/en
Priority to CN201080035539.0A priority patent/CN102803211B/en
Priority to MX2011013314A priority patent/MX338552B/en
Priority to BRPI1012905A priority patent/BRPI1012905A8/en
Priority to MX2015003152A priority patent/MX366035B/en
Priority to KR1020177035075A priority patent/KR102102972B1/en
Priority to AU2010257905A priority patent/AU2010257905B2/en
Priority to EP10785754.2A priority patent/EP2440523A4/en
Priority to CA2764376A priority patent/CA2764376C/en
Application filed by Techfields Biochem Co., Ltd. filed Critical Techfields Biochem Co., Ltd.
Publication of WO2010142241A1 publication Critical patent/WO2010142241A1/en
Priority to US13/323,556 priority patent/US9969751B2/en
Priority to HK13106282.9A priority patent/HK1178537A1/en
Priority to AU2017200897A priority patent/AU2017200897B2/en
Priority to US15/947,983 priority patent/US11485744B2/en
Priority to US18/051,060 priority patent/US20230130980A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
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    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • 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
    • C07D499/46—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with acyclic hydrocarbon radicals or such radicals substituted by carbocyclic or heterocyclic rings, 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
    • 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
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D499/58—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
    • 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
    • C07D499/64—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
    • C07D499/76—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with hetero rings directly attached to the carboxamido radical
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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
    • C—CHEMISTRY; METALLURGY
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    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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
    • C07D501/22—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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    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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
    • C—CHEMISTRY; METALLURGY
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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
    • C07D501/26—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
    • C—CHEMISTRY; METALLURGY
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    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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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    • C07D503/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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 Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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 Table
    • 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof

Definitions

  • This invention relates to the field of pharmaceutical compositions capable of penetrating one or more biological barriers and methods of using the pharmaceutical compositions for preventing, diagnosing and/or treating conditions or diseases in humans and animals that are treatable by antimicrobials and antimicrobial- related compounds.
  • the invention also relates to methods of using the pharmaceutical compositions for screening new drug candidates and methods of using the pharmaceutical compositions for diagnosing a condition in a biological subject.
  • Antimicrobials are substances that kill or inhibit the growth of microorganisms such as bacteria, fungi, or protozoans, as well as destroying viruses.
  • the main classes of antimicrobials include, for example, antibiotics that treat bacterial- related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiprotozoals that treat protozoans-related conditions.
  • Beta-lactam antibiotics are a class of antibiotics that comprise a four- member ring beta-lactam nucleus in their molecular structures. Over a hundred thousand of beta-lactam antibiotics have been prepared by partial or total chemical synthesis (L. A. Mitscher, et al., Antibiotic and Antimicrobial Drugs, in D. F. Smith, Ed., Handbook of Stereoisomers: Therapeutic Drugs, Boca Raton, FL, CRC Press, 1989; R.B. Morin and M. Gorman Eds., Chemistry and Biology of Beta-lactam Antibiotics, Volumes 1-3, New York, Academic Press, 1982; and A.LDemain and N.A.
  • beta- lactam antibiotics include penicillin derivatives, cephalospotrins, monobactams, carbapenems, beta-lactamase inhibitors, sulfonamide and quinolones.
  • a wide variety of antimicrobial are administered through Intravenous infusion, intramuscular injection, subcutaneous, buccal, oral, and rectal routes.
  • Oral administration has disadvantage of poor absorption of the antibiotics from the Gl tract.
  • Intravenous, subcutaneous and intramuscular routes are not only painful, but also require administration by trained individuals and may incur other risks such as needle injury, infection, and other trauma.
  • Topical drug delivery has several advantages. This method avoids inactivation of a drug caused by first pass metabolism in the liver and gastro-intestinal tract. It also provides local delivery of appropriate concentrations of a drug to the intended site of action without systemic exposure. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) indicated that an additional problem associated with oral medications, is that the concentration levels which must be achieved in the bloodstream must be significant in order to effectively treat distal areas of pain, inflammation, or infection. These levels are often much higher than would be necessary if the drugs were accurately delivered to the particular site of pain or injury. For most of antimicrobials, topical administration cannot deliver an effective therapeutic level.
  • compositions that are capable of being delivered efficiently and effectively to the action site of a condition (e.g., a disease) to prevent, reduce or treat conditions as well as minimize adverse side effects.
  • a condition e.g., a disease
  • One aspect of the invention is directed to a high penetration prodrug
  • HPP high penetration composition
  • HPC high penetration composition
  • a functional unit of a HPP or HPC comprises a moiety of a parent drug, wherein the efficient and effective delivery of the parent drug to a biological subject and/or transportation of the parent drug across one or more biological barriers are/is desired.
  • a functional unit may be hydrophilic, lipophilic, or amphiphilic (i.e., both hydrophilic and lipophilic).
  • the lipophilic nature of a function unit may be inherent or achieved by converting the hydrophilic moieties of a functional unit to lipophilic moieties.
  • a carboxyl group, amino group, guanidine group or other hydrophilic group of a functional unit is protected with an alkyl, aryl, or heteroaryl ester or amide group to make the HPP or HPC more lipophilic.
  • a functional unit of a HPP or HPC comprises a moiety of an antimicrobial or an antimicrobial-related compound.
  • An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans, as well as destroying viruses.
  • An antimicrobial-related compound is a compound comprising an antimicrobial structure, an antimicrobial metabolite, or an agent that can be metabolized into an antimicrobial or antimicrobial metabolite after a HPP or HPC penetrates one or more biological barriers.
  • An antimicrobial-related compound further includes a compound that is an analog or mimic of an antimicrobial or an antimicrobial metabolite, or an agent that can be metabolized into an analogue or mimic of an antimicrobial or an antimicrobial metabolite, after a HPP or HPC penetrates one or more biological barriers.
  • Examples of antimicrobials include, for example, antibiotics that treat bacterial-related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiprotozoals that treat protozoans-related conditions.
  • antibiotics include, without limitation, beta-lactam antibiotics, sulfonamides and quinolones.
  • beta-lactam antibiotics include, but are not limited to, penicillin derivatives, cephalosporins, penems, monobactams, carbapenems, beta-lactamase inhibitors and combinations thereof.
  • penicillin derivatives include, but are not limited to, aminopenicillins (e.g. amoxicillin, ampicillin, and epicillin); carboxypenicillins (e.g. carbenicillin, ticarcillin, and temocillin); ureidopenicillins (e.g.
  • azlocillin, piperacillin and mezlocillin azlocillin, piperacillin and mezlocillin); mecillinam, sulbenicillin, benzathine penicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), penicillin O (allylmercaptomethylpenicillinic), procaine penicillin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, hetacillin, becampicillin, metampicillin, talampicillin, co-amoxiclav (amoxicillin plus clavulanic acid), and piperacillion.
  • sulbenicillin benzathine penicillin
  • penicillin G benzylpenicillin
  • penicillin V phenoxymethylpenicillin
  • penicillin O allylmercaptomethylpenicillinic
  • procaine penicillin oxacillin, methicillin,
  • cephalosporins include, but are not limited to, cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime and cefpirome.
  • penems include, without limitation, faropenem.
  • monobactams include, without limitation, aztreonam and tigemonam.
  • carbapenems include, but are not limited to, biapenem,-doripenem, ertapenem,-imipenem,-meropenem,-and panipenem.
  • beta-lactamase inhibitors include, but are not limited to, tazobactam ([2S- (2alpha,3beta,5alpha)]-3-Methyl-7-oxo-3-(1 H-1 ,2,3-triazoM -ylmethyl)-4-thia-1 - azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium salt), sulbactam (2S,5f?)- 3,3-dimethyl-7-oxo-4-thia-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium), and clavulanic acid ((2f?,5f?,Z)-3-(2-hydroxyethylidene)-7-ox
  • antibiotics include, without limitation, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4-nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(3- pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-( ⁇ /-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1 ,4-dienecarboxylic acid), 1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3-carboxylic acid, nalidixic acid (1-ethyl-7-methyl-4-oxo-[1 ,8]naphthyridine-3-carboxylic acid),
  • sulfonamides include, without limitation, sulfaisodimidine, sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfadimethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, xipamide, dichlorphenamide, dorzolamide, acetazolamide, ethoxzolamide, sultiame, zonisamide, mafenide, celecoxib, darunavir, probenecid, sulfasalazine, and sumatriptan.
  • Examples of quinolones include, without limitation, cinoxacin, flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin, ecinofloxacin, delafloxacin and nalidixic acid.
  • antivirals examples include, without limitation, rifampicin, zanamivir and oseltamivir.
  • antifungals include, without limitation, polyene antifungals
  • imidazole antifungals e.g. miconazole, ketoconazloe, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole
  • triazoles antifungals e.g.
  • thiazole antifungals e.g. abafungin
  • allyamines e.g. terbinafine, amorolfine, naftifine and butenafine
  • echinocandins e.g. anidulafungin, caspofungin and micafungin
  • antiprotozoals include, without limitation, elornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and tinidazole.
  • a transportational unit of a HPP or HPC comprises a protonatable amine group that is capable of facilitating or enhancing the transportation or crossing of the HPP or HPC through one or more biological barriers.
  • the protonatable amine group is substantially protonated at the pH of the biological barriers through which a HPP or HPC penetrates.
  • the amine group can be reversibly protonated or deprotonated.
  • a linker covalently links the functional unit to the transportational unit of a HPP and comprises a bond that is capable of being cleaved after the HPP penetrates across one or more biological barriers.
  • the cleavable bond comprises, for example, a covalent bond, an ether, a thioether, an amide, an ester, a thioester, a carbonate, a carbamate, a phosphate or an oxime bond.
  • a HPP or HPC of an antimicrobial or antimicrobial-related compound comprises one or two primary, secondary or tertiary amine groups that exist in the protonated form at physiological pH.
  • the HPP or HPC comprises one primary, secondary or tertiary amine group that exists in the protonated form at physiological pH.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one HPP or HPC of an antimicrobial or antimicrobial-related compound and a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to a method for penetrating a biological barrier using a HPP or HPC of an antimicrobial or antimicrobial-related compound.
  • Another aspect of the invention relates to a method for diagnosing the onset, development, or remission of a condition in a biological subject by using a HPP or HPC of an antimicrobial or antimicrobial-related compound.
  • the HPP (or HPC) or the functional unit thereof is detectable.
  • the HPP or the functional unit of the HPP is inherently detectable, labeled with, or conjugated to, a detectable marker.
  • Another aspect of the invention relates to a method for screening functional units, linkers, or transportational units for desired characteristics.
  • Another aspect of the invention relates to a method for preventing, ameliorating, or treating a condition in a biological subject by administering to the subject a composition in accordance with the invention.
  • the method relates to treating a condition in a subject treatable by antimicrobials or antimicrobial-related compounds by administering to the subject a therapeutically effective amount of a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof.
  • conditions treatable by the method include, without limitation, pain, injuries and microorganism related conditions.
  • Microoranism related conditions are conditions that are caused by microorganisms such as bacteria, fungi, protozoans and viruses.
  • Bacteria-related conditions conditions caused by bacteria (bacteria-related conditions), conditions caused by protozoa (protozoa-related conditions), conditions caused by fungi (fungi-related conditions) and conditions caused by virus (virus-related conditions).
  • Bacteria-related conditions include, for example, infections (e.g.
  • anorectum and pruritus ani respiratory infections, upper respiratory tract infections, urinary tract infections, nosocomial infections, pseudomonas infection, Coagulase-positive staphylococcal infections (e.g. skin infection, toxinoses, acute infective endocarditis, septicemia, necrotizing pneumonia), infections of implanted prostheses, opportunistic infections with septicemia and pneumonia), plague (e.g.
  • anthrax e.g. cutaneous anthrax, pulmonary anthrax and gastrointestinal antrax
  • lyme diseases brucellosis, whooping cough, acute enteritis, psittacosis, nongonococcal urethritis, trachoma, inclusion conjunctivitis of the newborn, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, diarrhea, meningitis in infants, hemorrhagic colitis, hemolytic-uremic syndrome, tularemia, pneumonia, bronchitis, peptic ulcer, legionnaire's disease, Pontiac fever, leptospirosis, listeriosis, leprosy, turberculosis, mycoplasma pneumonia, gonorrhea, ophthalmia neonatorum, septic arthritis, meningococcal disease,
  • anthrax e.g
  • Protozoa related conditions include, for example, malaria, sleeping sickness, and toxoplasmosis.
  • Fungi related conditions include, for example, aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, histoplasmosis, paracoccidiomycosis, sporotrichosis, and zygomycosis.
  • Virus related conditions include, for example, influenza, yellow fever and AIDS.
  • a pharmaceutical composition of a HPP or HPC is administrated to a biological subject via various routes including, but not limited to, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteral routes.
  • a pharmaceutical composition of a HPP or HPC is administered orally, transdermal ⁇ , topically, subcutaneously and/or parenterally.
  • a therapeutically effective amount of a HPP or HPC can be administered locally to a site of condition at a high concentration which results in a lower overall dosage than systemic administration.
  • the advantages of the invention also include, for example, avoidance of systematic administration, reduction of adverse effects (e.g., pain of injection, gastrointestinal/renal effects, and other side effects), and possible novel treatments due to high local concentration of a HPP, HPC or active agent.
  • the advantages further include, for example, systematic administration of a HPP or HPC to a biological subject to achieve faster and more efficient bioavailability, penetration of biological barriers (e.g., the blood brain barrier and the blood milk barrier) which have been difficult to cross, and new indications as a result of passing through biological barriers.
  • biological barriers e.g., the blood brain barrier and the blood milk barrier
  • Figure 1a1 Cumulative amounts of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl ester hydrochloride (A), allylmercaptomethylpenicillinic acid 2- dimethylaminoethyl ester hydrochloride (B), 6-(2,6-dimethoxybenzamido)penicillinic acid 2-dipropylaminoethyl ester hydrochloride (C), 6-(5-methyl-3-phenyl-2-isoxazoline-4- carboxamido)penicillinic acid 4-piperidineethyl ester hydrochloride (D), 6-[3-(o- chlorophenyl)-5-methyl-4-isoxazolecarboxamido]penicillinic acid 3-piperidine ethyl ester hydrochloride (E), 6-[3-(2,6-dichlorophenyl)-5-methyl-4- isoxazolecarboxamido]penicillinic acid 1-piper
  • Figure 1a2 Cumulative amounts of 6-[D(-)- ⁇ - aminophenylacetamidopenicillinic acid ethyl ester hydrochloride (A), D- ⁇ -[(imidazolidin- 2-on-1-yl)carbonylamino]benzylpenicillin 2-pyrrolidinemethyl ester hydrochloride (B), 6R-[2-[3-(methylsulfonyl)-2-oxo-1-imidazolidinecarboxamido]-2- phenylacetamido]penicillinic acid 1-pyrrolidineethyl ester hydrochloride (C), 6-D(-)- ⁇ -(4- ethyl-2,3-dioxo-1 -piperazinylcarbonylamino)- ⁇ -phenylacetamidopenicillinic acid 2- diethylaminoethyl ester hydrochloride (D), 7-(2-thienylacetamido)cephalosporanic acid 2-diethy
  • Figure 1a3 Cumulative amounts of 7-[(hydroxyphenylacetyl)amino]-3-
  • Figure 1a4 Cumulative amounts of 3-[(acetyloxy)methyl]-7-[[(2- acetylamino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (A), 7-[[(2-acetylamino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (B), 7-[[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-acetoxyphenyl)ace
  • Figure 1 b Cumulative amounts of [2S-(2alpha,3beta,5alpha)]-3-Methyl-
  • HPP high penetration prodrug
  • HPC high penetration composition
  • HPP high penetration prodrug
  • HPP high penetration composition
  • HPC high penetration composition
  • a functional unit of a HPP or HPC which comprises a moiety of a parent drug has the properties of: 1 ) the delivery of the parent drug or the HPP/HPC into a biological subject and/or the transportation of the parent drug across a biological barrier are/is desired, 2) the HPP/HPC is capable of penetrating or crossing a biological barrier, and 3) the HPP/HPC is capable of being cleaved so as to turn the moiety of a parent drug into the parent drug or a metabolite of the parent drug.
  • a functional unit may be hydrophilic, lipophilic, or amphiphilic (hydrophilic and lipophilic).
  • the lipophilic moiety of the functional unit may be inherent or achieved by converting one or more hydrophilic moieties of the functional unit to lipophilic moieties.
  • a lipophilic moiety of a functional unit is produced by converting one or more hydrophilic groups of the functional unit to lipophilic groups via organic synthesis. Examples of hydrophilic groups include, without limitation, carboxylic, hydroxyl, thiol, amine, phosphate/phosphonate, guanidine and carbonyl groups.
  • Lipophilic moieties produced via the modification of these hydrophilic groups include, without limitation, ethers, thioethers, esters, thioesters, carbonates, carbamates, amides, phosphates and oximes.
  • a functional unit is lipophilicized by acetylation or acylation(alkanoylation).
  • a functional unit is lipophilicized by esterification.
  • a parent drug of a HPP or HPC is selected from the group consisting of an antimicrobial and antimicrobial-related compound.
  • the moiety of an antimicrobial or antimicrobial-related compound can be further converted to a lipophilic moiety as described supra.
  • Antimicrobials are substances that kill or inhibit the growth of microorganisms such as bacteria, fungi, or protozoans, as well as destroying or inhibit the growth of viruses.
  • the main classes of antimicrobials include, for example, antibiotics that treat bacterial-related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiparastics that treat parasite-related conditions.
  • An antimicrobial-related compound is a compound comprising an antimicrobial structure, an antimicrobial metabolite, or an agent that can be metabolized into an antimicrobial or antimicrobial metabolite after a HPP or HPC penetrates one or more biological barriers.
  • An antimicrobial-related compound further includes a compound that is an analog or mimic of an antimicrobial or an antimicrobial metabolite, or an agent that can be metabolized into an analog or mimic of an antimicrobial or an antimicrobial metabolite, after a HPP or HPC penetrates one or more biological barriers.
  • antimicrobials include, for example, antibiotics that treat bacterial-related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiprotozoals that treat protozoans-related conditions.
  • antibiotics include, without limitation, beta-lactam antibiotics, sulfonamides and quinolones.
  • Beta-lactam antibiotics are well known in the art and are used in connection with various conditions.
  • a beta-lactam antibiotics refers to a compound that comprises a beta-lactam nucleus.
  • beta-lactam antibiotics include, but are not limited to, penicillin derivatives, cephalosporins, penems, monobactams, carbapenems, beta- lactamase inhibitors and combinations thereof.
  • penicillin derivatives include, but are not limited to, aminopenicillins (e.g. amoxicillin, ampicillin, and epicillin), carboxypenicillins (e.g. carbenicillin, ticarcillin, and temocillin), ureidopenicillins (e.g.
  • azlocillin, piperacillin and mezlocillin mecillinam
  • sulbenicillin benzathine penicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), penicillin O (allylmercaptomethylpenicillinic), procaine penicillin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, hetacillin, becampicillin, metampicillin, talampicillin, co-amoxiclav (amoxicillin plus clavulanic acid), and piperacillion.
  • cephalosporins include, but are not limited to, cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime and cefpirome.
  • penems include, without limitation, faropenem.
  • monobactams include, without limitation, aztreonam and tigemonam.
  • carbapenems include, but are not limited to, biapenerrvdoripenem, ertapenem,-imipenem,-meropenem,-and panipenem.
  • beta-lactamase inhibitors include, but are not limited to, tazobactam ([2S- (2alpha,3beta,5alpha)]-3-Methyl-7-oxo-3-(1 H-1 ,2,3-triazoM -ylmethyl)-4-thia-1 - azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium salt), sulbactam ((2S,5R)-3,3-dimethyl-7-oxo-4-thia-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4- dioxide sodium), and clavulanic acid ((2f?,5f?,Z)-3-(2-hydroxyethylidene)-7-oxox
  • antibiotics include, without limitation, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4- nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(3-pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-( ⁇ /-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1 ,4- dienecarboxylic acid), 1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3- carboxylic acid, and nalidixic acid (1-ethyl-7-methyl-4-oxo-[1 ,8]naphthyridine-3- carboxylic acid),
  • sulfonamides include, without limitation, sulfaisodimidine, sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfadimethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, xipamide, dichlorphenamide, dorzolamide, acetazolamide, ethoxzolamide, sultiame, zonisamide, mafenide, celecoxib, darunavir, probenecid, sulfasalazine, and sumatriptan.
  • Examples of quinolones include, without limitation, cinoxacin, flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin, ecinofloxacin, delafloxacin and nalidixic acid.
  • antivirals include, without limitation, rifampicin, zanamivir and oseltamivir.
  • antifungals include, without limitation, polyene antifungals
  • imidazole antifungals e.g. miconazole, ketoconazloe, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole
  • triazoles antifungals e.g.
  • thiazole antifungals e.g. abafungin
  • allyamines e.g. terbinafine, amorolfine, naftifine and butenafine
  • echinocandins e.g. anidulafungin, caspofungin and micafungin
  • antiprotozoals include, without limitation, elornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and tinidazole.
  • a functional unit of a HPP of an antimicrobial or antimicrobial-related compound comprises a moiety having a structure of Structure F-1 :
  • Structure F-1 including stereoisomers and pharmaceutically acceptable salts thereof.
  • W is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, the protonatable amine group, pharmaceutically acceptable substituted and unsubstituted primary amine groups, Structure Wa, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18:
  • Z is selected from the group consisting of CH 2 , S, SO, SO 2 , NH, NR 6 , CHCH 3 , CHCH 2 CH 3 , CHR 6 , R 6 , -C(O)-, and O;
  • AA represents any amino acids; each m and n is independently selected from the group of O and integer, e.g. O, 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 group consisting of nothing, and pharmaceutically acceptable acid, e.g. hydrochloride hydrobromide, hydroiodide, nitric acid , sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid and pamoic acid;
  • pharmaceutically acceptable acid e.g. hydrochloride hydrobromide, hydroiodide, nitric acid , sul
  • R1-R3 are independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues;
  • X 4 is selected from the group consisting of nothing, N, CH, and CYi;
  • Yi, Y31, Y2, Y32, Y3, and Y 4 are independently selected from the group consisting of H, OH, OW, OC(O)W, L 1 -L 4 -L 2 -W, OC(O)CH 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , R 6 , SO 3 R 6 , CH 2 OR 6 , CH 2 OC(O)R 6 , CH 2 C(O)OR 8 , OCH 3 , OC 2 H 5 , OR 6 , CH 3 SO 2 , R 6 SO 2 , CH 3 SO 3 , R 6 SO 3 , NO 2 , CN, CF 3 , OCF 3 , CH 2 (CH 2 ) n NR 5 R 6 , CH 2 (CH 2 ) n OR 6, CH(C(O)NH 2 )NHR 6 , CH 2 C(O)NH 2, F, Br, I, Cl, CHOHC(O)NHCH 2 C(O)
  • L 2 is selected from the group consisting of nothing, O, S, -0-L 3 -, -S-L 3 -, -N(L 3 )-, -
  • a functional unit of a HPP or HPC of an antimicrobial or antimicrobial-related compound comprises a moiety having a structure selected from the group consisting of Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38
  • L-31 is defined the same as Li as supra
  • L 32 is defined the same as L 2 as supra
  • L 34 is defined the same as L 4 as supra
  • a functional unit of a HPP of a antimicrobial and antimicrobial-related compound comprises a moiety having a structure of Structure F-1 , Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38, Structure Structure FP
  • Ri is selected from the group consisting of H, C1-C20 alkyl, C1-C20 alkyloxyl, d- C 2 O alkenyl, CrC 20 alkynyl, aryl, and heteroaryl;
  • R 2 is selected from the group consisting of H, C r C 20 alkyl, C r C 20 alkyloxy, C r C 20 alkenyl, CrC 20 alkynyl, aryl, and heteroaryl residues;
  • R 3 is selected from the group consisting of H, CrC 20 alkyl, CrC 20 alkyloxy, d- C 20 alkenyl, CrC 20 alkynyl, aryl and heteroaryl residues;
  • X 2 is selected from the group consisting of nothing, H, CH 2 (CH 2 ) n OR 8 , Cl, F, Br, I, NO 2 , CN, CF 3 , C 2 F 5 , C 3 F 7 , OCF 3 , OC 2 F 5 , NH 2 , NHR 6 , CH 3 , C 2 H 5 , R 6 , C(O)NH 2 , CH 2 OC(O)NH 2 , CH 2 C(O)OR 5 , CH 2 (CH 2 ) n N(CH 3 ) 2 , CH 2 (CH 2 ) n SO 3 R 5 , C 1-8 alkyl, C 1-8 alkylthio, C 1-8 alkylamino, and C 1-8 alkyloxyl;
  • X 3 is selected from the group consisting of nothing, H, N 3 , SO 3 W, F, Cl, Br, OH, OCH 3 , OR 6 , CH 3 , R 6 , C(O)OW, OW, and I;
  • X 4 is selected from the group consisting of nothing, N, CH, and CY 1 ;
  • any CH 2 groups may be replaced with O, S, NR 6 or any other pharmaceutically acceptable groups .
  • pharmaceutically acceptable salt means those salts of compounds of the invention that are safe for application in a subject.
  • Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1 ,11- methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
  • alkyl means a branched or unbranched, saturated or unsaturated, monovalent or multivalent hydrocarbon group, including saturated alkyl groups, alkenyl groups and alkynyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl,
  • cycloalkyl means an alkyl which contains at least one ring and no aromatic rings.
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • the hydrocarbon chain contains 1 to 30 carbons.
  • the hydrocarbon group contains 1 to 20 carbons.
  • the hydrocarbon group contains 1 to 12 carbons.
  • heterocycloalkyl means a cycloalkyl wherein at least one ring atom is a non-carbon atom.
  • non-carbon ring atom include, but are not limited to, S, O and N.
  • alkoxyl means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more oxygen atoms.
  • alkoxyl include, but are not limited to, -CH 2 -OH, -OCH 3 , -O-R e , -R e -OH, - R e i-O-Re2-, wherein R e , R e i and R ⁇ 2 can be the same or different alkyl, cycloalkyl or heterocycloalkyl.
  • alkyl halide means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more halogen atoms, wherein the halogen atoms can be the same or different.
  • halogen means fluorine, chlorine, bromine or iodine.
  • alkyl halide examples include, but are not limited to, -R e -F, -R e -CI, -R e -Br, -R e -I, -Re(F)-, -Re(CI)-, -Re(Br)- and -R e (l)-, wherein R e is an alkyl, cycloalkyl or heterocycloalkyl.
  • alkylthio means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more sulfur atoms.
  • alkylthio include, but are not limited to, -CH 2 -SH, -SCH 3 , -S-R e , -Re-SH, - R e i-S-Re2-, wherein R e , R e i and R ⁇ 2 are the same or different alkyl, cycloalkyl or heterocycloalkyl.
  • alkylamino means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more nitrogen atoms.
  • alkylamino include, but are not limited to, -CH 2 -NH, -NCH 3 , - N(Rei)-Re2, -N-Re, -Re-NH 2 , -R 61 -N-Re 2 and -R e -N(Rei )-R ⁇ 2 wherein R e , R e i and R e2 are the same or different alkyl, cycloalkyl or heterocycloalkyl.
  • alkylcarbonyl means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more carbonyl groups.
  • perfluoroalkyl means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more fluoro group, including, without limitation, perfluoromethyl, perfluoroethyl, perfluoropropyl.
  • aryl means a chemical structure comprising one or more aromatic rings.
  • the ring atoms are all carbon.
  • one or more ring atoms are non- carbon, e.g. oxygen, nitrogen, or sulfur ("heteroaryl").
  • aryl examples include, without limitation, phenyl, benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyhdazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl, furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl, thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxolyl, quanidino and benzothiazolyl.
  • a transportational unit of a HPP comprises a protonatable amine group that is capable of facilitating the transportation or crossing of the HPP through one or more biological barriers (e.g., > about 20 times, > about 50 times, > about 100 times, > about 300 times, > about 500 times, > about 1 ,000 times faster than the parent drug).
  • the protonatable amine group is substantially protonated at a physiological pH.
  • the amine group can be reversibly protonated.
  • a transportational unit may or may not be cleaved from the functional unit after the penetration of HPP through one or more biological barriers.
  • a functional unit may also contain one or more transportational units, especially for antimicrobials and antimicrobial-related compounds that have at least a free amino group.
  • the protonatable amine group is selected from the group consisting of pharmaceutically acceptable substituted and unsubstituted primary amine groups, pharmaceutically acceptable substituted and unsubstituted secondary amine groups, and pharmaceutically acceptable substituted and unsubstituted tertiary amine groups.
  • the protonatable amine group is selected from the group consisting of pharmaceutically acceptable substituted and unsubstituted primary amine groups, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18 as defined supra, including stereoisomers and pharmaceutically acceptable salts thereof.
  • a linker covalently linking a functional unit and a transportational unit of a HPP comprises a bond that is capable of being cleaved after the HPP penetrates across one or more BBs.
  • the cleavable bond comprises, for example, a covalent bond, an ether, thioether, amide, ester, thioester, carbonate, carbamate, phosphate or oxime bond.
  • a HPP of a antimicrobials and antimicrobial- related compound has the following Structure L-1 :
  • F is a functional unit of a HPP of an antimicrobial or antimicrobial-related compound.
  • Examples of F include Structure F-1 , Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38, Structure FP-39, Structure FP-40, Structure
  • T is a transportational unit of a HPP of an antimicrobial or antimicrobial-related compound.
  • T is selected from the group consisting of the protonatable amine group, pharmaceutically acceptable substituted and unsubstituted primary amine groups, pharmaceutically acceptable substituted and unsubstituted secondary amine groups, and pharmaceutically acceptable substituted and unsubstituted tertiary amine groups, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18 as defined supra; and
  • a HPP or HPC of antimicrobial or antimicrobial- related compound comprises a structure selected from the group consisting of Structure P-1 , Structure P-2, Structure P-3, Structure P-4, Structure P-5, Structure P-6, Structure P-7, Structure P-8, Structure P-9, Structure P-10, Structure P-11 , Structure P-12, Structure P-13, Structure P-14, Structure P-15, Structure P-16, Structure P-17, Structure P-18, Structure P-19, Structure P-20, Structure P-21 , Structure P-22, Structure P-23, Structure P-24, Structure P-25, Structure P-26, Structure P-27, Structure P-28, Structure P-29, Structure P-30, Structure P-31 , Structure P-32, Structure P-33, Structure P-34, Structure P-35, Structure P-36, Structure P-37, Structure P-38, Structure P-39, Structure P-40, Structure P-41 , Structure P-42, Structure P-43, Structure P-44, Structure P-45, Structure P-46, Structure P-47, Structure P-
  • X 46 , X 7 , Yi , Y2, Y31 , Y32, Y3, Y4, Z, AA, HA, R, R 8 , and Rn-R 16 are defined the same as supra.
  • compositions comprising HPPs
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one HPP of an antimicrobial or antimicrobial-related compound and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a HPP from one location, body fluid, tissue, organ (interior or exterior), or portion of the body, to another location, body fluid, tissue, organ, or portion of the body.
  • Each carrier is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients, e.g., a HPP, of the formulation and suitable for use in contact with the tissue or organ of a biological system without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Some examples of materials which can serve as pharmaceutically- acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • the pharmaceutically acceptable carrier is an aqueous carrier, e.g. buffered saline and the like.
  • the pharmaceutically acceptable carrier is a polar solvent, e.g. acetone and alcohol.
  • the concentration of HPP in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the biological system's needs.
  • the concentration can be 0.0001 % to 100%, 0.001 % to 50%, 0.01 % to 30%, 0.1 % to 20%, 1 % to 10% wt.
  • compositions of the invention can be administered for prophylactic, therapeutic, and/or hygienic use.
  • Such administration can be topical, mucosal, e.g., oral, nasal, vaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, via inhalation, ophthalmic and other convenient routes.
  • the pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration.
  • unit dosage forms suitable for oral administration include powder, tablets, pills, capsules and lozenges and for transdermal administration include solution, suspension and gel.
  • a typical pharmaceutical composition for transdermal, oral, and intravenous administrations would be about 10 ⁇ 10 g to about 100 g, about 10 ⁇ 10 g to about 10 ⁇ 3 g, about 10 ⁇ 9 g to about 10 ⁇ 6 g, about 10 ⁇ 6 g to about 100 g, about 0.001 g to about 100 g, about 0.01 g to about 10 g, or about 0.1 g to about 1 g per subject per day. Dosages from about 0.01 mg, up to about 100 g, per subject per day may be used. Actual methods for preparing parenterally administrable compositions will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington: The Science and Practice of Pharmacy 21st ed., Mack Publishing Company, Easton, Pa. (2005).
  • Another aspect of the invention relates to a method of using a composition of the invention in penetrating one or more biological barriers in a biological subject.
  • the method comprises a step of administering to a biological subject a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof.
  • a HPP exhibits more than about 20 times or higher, 50 times or higher, > about 100 times or higher, > about 200 time higher, >about 300 times or higher, >about 500 times or higher, >about 1 ,000 times or higher penetration rate through one or more biological barriers than its parent drug.
  • biological barrier refers to a biological layer that separates an environment into different spatial areas or compartments, which separation is capable of modulating (e.g. restricting, limiting, enhancing or taking no action in) the passing through, penetrating or translocation of substance or matter from one compartment/area to another.
  • the different spatial areas or compartments as referred to herein may have the same or different chemical or biological environment(s).
  • the biological layer as referred herein includes, but is not limited to, a biological membrane, a cell layer, a biological structure, an inner surface of subjects, organisms, organs or body cavities, an external surface of subjects, organisms, organs or body cavities, or any combination or plurality thereof.
  • a biological membrane examples include a lipid bilayer structure, eukaryotic cell membrane, prokaryotic cell membrane, and intracellular membrane (e.g., nucleus or organelle membrane, such as membrane or envelope of Golgi apparatus, rough and smooth endoplasmic reticulum (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosome, nucleus, chloroplasts, plastids, peroxisomes or microbodies).
  • the lipid bilayer referred to herein is a double layer of lipid-class molecules, including, but not limited to, phospholipids and cholesterol.
  • lipids for bilayer are amphiphilic molecules consisting of polar head groups and non- polar fatty acid tails.
  • the bilayer is composed of two layers of lipids arranged so that their hydrocarbon tails face one another to form an oily core held together by the hydrophobic effect, while their charged heads face the aqueous solutions on either side of the membrane.
  • the lipid bilayer may contain one or more embedded protein and/or sugar molecule(s).
  • Examples of a cell layer include a lining of eukaryotic cells (e.g., epithelium, lamina intestinal and smooth muscle or muscularis mucosa (in gastrointestinal tract)), a lining of prokaryotic cells (e.g., surface layer or S-layer which refers to a two dimensional structure monomolecular layer composed of identical proteins or glycoproteins, specifically, an S-layer refers to a part of a cell envelope commonly found in bacteria and archaea), a biofilm (a structured community of microorganisms encapsulated within a self-developed polymeric matrix and adherent to a living or inert surface), and a plant cell layer (e.g., empidermis).
  • the cells may be normal cells or pathological cells (e.g. disease cells, cancer cells).
  • Examples of biological structures include structures sealed by tight or occluding junctions that provide a barrier to the entry of toxins, bacteria and viruses, e.g. the blood milk barrier and the blood brain barrier (BBB).
  • BBB blood brain barrier
  • the biological structure may also include a mixture of cells, proteins and sugars (e.g. blood clots).
  • Examples of the inner surface of subjects, organisms, organs or body cavities include buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa and endometrium (the mucosa of the uterus, inner layer of the wall of a pollen grain or the inner wall layer of a spore), or a combination or plurality thereof.
  • Examples of the external surface of subjects, organisms, organs or body cavities include capillaries (e.g. capillaries in the heart tissue), mucous membranes that are continuous with skin (e.g. such as at the nostrils, the lips, the ears, the genital area, and the anus), outer surface of an organ (e.g. liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, anorectum and pruritus ani), skin, cuticle (e.g.
  • a biological barrier further includes a sugar layer, a protein layer or any other biological layer, or a combination or plurality thereof.
  • skin is a biological barrier that has a plurality of biological layers.
  • a skin comprises an epidermis layer (outer surface), a demis layer and a subcutaneous layer.
  • the epidermis layer contains several layers including a basal cell layer, a spinous cell layer, a granular cell layer, and a stratum corneum.
  • the cells in the epidermis are called keratinocytes.
  • the stratum corneum (“horny layer”) is the outmost layer of the epidermis, wherein cells here are flat and scale-like (“squamous”) in shape. These cells contain a lot of keratin and are arranged in overlapping layers that impart a tough and oilproof and waterproof character to the skin's surface.
  • Another aspect of the invention relates to a method of using a composition of the invention in diagnosing a condition in a biological system.
  • the method comprises the following steps:
  • the HPP (or the agent cleaved from the HPP) aggregates in the site of action where a condition occurs.
  • the presence, location or amount of the functional unit of the HPP is also detected.
  • the onset, development, progress, or remission of a condition (e.g., infection) associated is also determined.
  • the HPP is labeled with or conjugated to a detectable agent.
  • the HPP is prepared to include radioisotopes for detection.
  • detectable agents are available which can be generally grouped into the following categories:
  • Radioisotopes such as 35 S, 14 C, 13 C, 15 N, 125 I, 3 H, and 131 I.
  • the diagnostic agent can be labeled with the radioisotope using the techniques known in the art and radioactivity can be measured using scintillation counting; in addition, the diagnostic agent can be spin labeled for electron paramagnetic resonance for carbon and nitrogen labeling.
  • Fluorescent agents such as BODIPY, BODIPY analogs, rare earth chelates (europium chelates), fluorescein and its derivatives, FITC, 5,6 carboxyfluorescein, rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin, green fluorescent protein, yellow fluorescent protein, red fluorescent protein and Texas Red. Fluorescence can be quantified using a fluorometer.
  • luciferases e.g., firefly luciferase and bacterial luciferase
  • luciferin 2,3-dihydrophthalazinediones
  • malate dehydrogenase urease
  • peroxidase such as horseradish peroxidase (HRPO)
  • HRPO horseradish peroxidase
  • alkaline phosphatase ⁇ - galactosidase
  • glucoamylase lysozyme
  • saccharide oxidases e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase
  • heterocyclic oxidases such as uricase and xanthine oxidase
  • lactoperoxidase lactoperoxidase
  • microperoxidase and the like.
  • enzyme-substrate combinations include, for example: (i) Horseradish peroxidase (HRPO) with hydrogen peroxidase as a substrate, wherein the hydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylene diamine (OPD) or 3, 3', 5,5'- tetramethyl benzidine hydrochloride (TMB)); (ii) alkaline phosphatase (AP) with para- Nitrophenyl phosphate as chromogenic substrate; and (iii) ⁇ -D-galactosidase ( ⁇ -D-GaI) with a chromogenic substrate (e.g., p-nitrophenyl- ⁇ -D-galactosidase) or fluorogenic substrate 4-methylumbelliferyl- ⁇ - D-galactosidase.
  • HRPO Horseradish peroxidase
  • OPD orthophenylene diamine
  • TMB 3, 3', 5,5'- t
  • the detectable agent is not necessarily conjugated to the diagnostic agent but is capable of recognizing the presence of the diagnostic agent and the diagnostic agent can be detected.
  • the HPP of the invention can be provided in a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing the diagnostic assay.
  • the kit will include substrates and cofactors required by the enzyme (e.g., a substrate precursor which provides the detectable chromophore or fluorophore).
  • substrates and cofactors required by the enzyme e.g., a substrate precursor which provides the detectable chromophore or fluorophore
  • other additives may be included such as stabilizers, buffers (e.g., a block buffer or lysis buffer) and the like.
  • the relative amounts of the various reagents may be varied widely to provide for concentrations in solution of the reagents which substantially optimize the sensitivity of the assay.
  • the reagents may be provided as dry powders, usually lyophilized, including excipients which on dissolution will provide a reagent solution having the appropriate concentration.
  • Another aspect of the invention relates to a method of screening a HPP for a desired character.
  • the method comprises: covalently linking a test functional unit to a transportational unit through a linker to form a test composition (or covalently linking a functional unit to a test transportational unit through a linker, or covalently linking a functional unit to a transportational unit through a test linker)
  • test composition has the desired nature or character.
  • a desired character may include, for example, 1 ) the ability of a test functional unit to form a high penetration composition or convert back to a parent drug, 2) the penetration ability and/or rate of a test composition, 3) the efficiency and/or efficacy of a test composition, 4) the transportational ability of a test transportational unit, and 5) the cleavability of a test linker.
  • Another aspect of the invention relates to a method of using a composition of the invention in treating a condition in a biological system.
  • the method comprises administrating the pharmaceutical composition to the biological system.
  • treating means curing, alleviating, inhibiting, or preventing.
  • treat means cure, alleviate, inhibit, or prevent.
  • treatment means cure, alleviation, inhibition or prevention.
  • biological system means an organ, a group of organs that work together to perform a certain task, an organism, or a group of organisms.
  • organ as used herein means an assembly of molecules that function as a more or less stable whole and has the properties of life, such as animal, plant, fungus, or micro-organism.
  • animal means a eukaryotic organism characterized by voluntary movement.
  • animals include, without limitation, vertebrata (e.g. human, mammals, birds, reptiles, amphibians, fishes, marsipobranchiata and leptocardia), tunicata (e.g. thaliacea, appendiculaha, sorberacea and ascidioidea), articulata (e.g. insecta, myriapoda, malacapoda, arachnida, pycnogonida, merostomata, Crustacea and annelida), gehyrea (anarthropoda), and helminthes (e.g. rotifera).
  • vertebrata e.g. human, mammals, birds, reptiles, amphibians, fishes, marsipobranchiata and leptocardia
  • tunicata e.g. thaliacea, appendiculaha, sorberacea and ascidio
  • plant as used herein means organisms belonging to the kindom Plantae.
  • plant include, without limitation, seed plants, bryophytes, ferns and fern allies.
  • seed plants include, without limitation, cycads, ginkgo, conifers, gnetophytes, angiosperms.
  • bryophytes include, without limitation, liverworts, hornworts and mosses.
  • ferns include, without limitation, ophioglossales (e.g. adders-tongues, moonworts, and grape-ferns), marattiaceae and leptosporangiate ferns.
  • fern allies include, without limitation, lycopsida (e.g. clubmosses, spikemosses and quillworts), psilotaceae (e.g. lycopodiophyta and whisk ferns) and equisetaceae (e.g. horsetails).
  • lycopsida e.g. clubmosses, spikemosses and quillworts
  • psilotaceae e.g. lycopodiophyta and whisk ferns
  • equisetaceae e.g. horsetails.
  • fungus as used herein means a eukaryotic organism that is a member of the kingdom Fungi. Examples of fungus include, without limitation, chytrids, blastocladiomycota, neocallimastigomycota, zygomycota, glomeromycota, ascomycota and basidiomycota.
  • microorganism as used herein means an organism that is microscopic (e.g. with length scale of micrometer). Examples of microorganism include, without limitation, bacteria, fungi, archaea, protists and microscopic plants (e.g. green algae) and microscopic animals (e.g. plankton, planarian and amoeba).
  • Some examples of the conditions the method can treat include conditions that can be treated by the parent drug of the HPP.
  • Another aspect of the invention relates to a method of using HPPs of antimicrobials or antimicrobial-related compounds, or pharmaceutical compositions thereof in treating a condition in a biological system or subject by administrating a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof to the biological system or subject.
  • Antimicrobials and antimicrobial-related compounds can be used to regulate a wide range of biological processes in a biological system. Conditions that are related to such biological processes are treatable by the corresponding antimicrobials or antimicrobial-related compounds, and therefore treatable by HPPs/HPCs of the antimicrobials or antimicrobial-related compounds, and a pharmaceutical composition thereof.
  • Such conditions include, but are not limited to, pain, injuries and microorganism related conditions.
  • Microoranism related conditions are conditions that are caused by microorganisms such as bacteria, fungi, protozoans and viruses. For example, conditions caused by bacteria (bacteria-related conditions), conditions caused by protozoa (protozoa-related conditions), conditions caused by fungi (fungi-related conditions) and conditions caused by virus (virus-related conditions).
  • Bacteria-related conditions include, for example, infections (e.g. infection condition in an organ such as liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, anorectum and pruritus ani, respiratory infections, upper respiratory tract infections, urinary tract infections, nosocomial infections, pseudomonas infection, Coagulase-positive staphylococcal infections (e.g.
  • cutaneous anthrax, pulmonary anthrax and gastrointestinal antrax lyme diseases, brucellosis, whooping cough, acute enteritis, respiratory infection, psittacosis, nongonococcal urethritis, trachoma, inclusion conjunctivitis of the newborn, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, diarrhea, meningitis in infants, hemorrhagic colitis, hemolytic-uremic syndrome, tularemia, pneumonia, bronchitis, peptic ulcer, legionnaire's disease, Pontiac fever, leptospirosis, listeriosis, leprosy, turberculosis, mycoplasma pneumonia, gonorrhea, ophthalmia neonatorum, septic arthritis, meningococcal disease, waterhouse-friderichsen syndrome, Rocky mountain spotted
  • Protozoa related conditions include, for example, malaria, sleeping sickness, and toxoplasmosis.
  • Fungi related conditions include, for example, aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, histoplasmosis, paracoccidiomycosis, sporotrichosis, and zygomycosis.
  • Virus related conditions include, for example, influenza, yellow fever and
  • a method of treating a condition in a subject amelioratable or treatable with antimicrobials or antimicrobial-related compounds comprises administering a therapeutic effective amount of a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof to the subject.
  • a HPP or a pharmaceutical composition thereof can be administered to a biological system by any administration route known in the art, including without limitation, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteral administration.
  • the pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration.
  • a parenteral administration refers to an administration route that typically relates to injection which includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intra cardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and/or intrasternal injection and/or infusion.
  • a HPP or a pharmaceutical composition thereof can be given to a subject in the form of formulations or preparations suitable for each administration route.
  • the formulations useful in the methods of the invention include one or more HPPs, one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic ingredients.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration.
  • the amount of a HPP which can be combined with a carrier material to produce a pharmaceutically effective dose will generally be that amount of a HPP which produces a therapeutic effect.
  • Methods of preparing these formulations or compositions include the step of bringing into association a HPP with one or more pharmaceutically acceptable carriers and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a HPP with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non- aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a HPP as an active ingredient.
  • a compound may also be administered as a bolus, electuary, or paste.
  • the HPP is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1 ) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarding agents, such as paraffin, (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1 ) fillers or extenders, such as star
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered antimicrobials or peptidomimetic moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of a HPP therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain pacifying agents and may be of a composition that they release the HPP(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the HPP can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • Suspensions in addition to the HPP, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more HPPs with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Formulations for the topical or transdermal or epidermal or dermal administration of a HPP composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to the HPP composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the HPP composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • a HPP or a pharmaceutical composition thereof can be alternatively administered by aerosol. This can be accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the HPPs.
  • a nonaqueous (e. g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers can also be used.
  • An aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • Transdermal patches can also be used to deliver HPP compositions to a target site.
  • Such formulations can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the peptidomimetic across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the peptidomimetic in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • Formulations suitable for parenteral administration comprise a HPP in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacterostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (e. g., such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols e. g., such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Formulations suitable for parenteral administration may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Injectable depot forms are made by forming microencapsule matrices of a HPP or in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the HPP to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the HPP in liposomes or microemulsions which are compatible with body tissue.
  • a HPP of an antimicrobial or antimicrobial- related compound, or a pharmaceutical composition thereof is delivered to a disease or tumor action site in a therapeutically effective dose.
  • the precise amount of the pharmaceutically effective dose of a HPP that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon, for example, the activity, the particular nature, pharmacokinetics, pharmacodynamics, and bioavailability of a particular HPP, physiological condition of the subject (including race, age, sex, weight, diet, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), the nature of pharmaceutically acceptable carriers in a formulation, the route and frequency of administration being used, and the severity or propensity of a disease caused by pathogenic target microbial organisms, to name a few.
  • Amtimicrobials e.g. antibiotics
  • antimicrobial-related compounds are often hydrophilic and are difficult to penetrate skin membrane barrier. When antimicrobials or antimicrobial-related compounds are taken orally, they may be inactivated by first pass metabolism. In the case of injection, administration of antimicrobials and amtimicrobial-related compounds is painful and may require frequent and costly office visits.
  • a HPP or HPC of the invention is capable of crossing one or more biological barriers
  • the HPP or HPC can be administered locally (e.g., topically or transdermally) to reach a location where a condition occurs without the necessity of a systematic administration (e.g., oral or parenteral administration).
  • a local administration and penetration of a HPP or HPC allows the HPP or HPC to reach the same level of local concentration of an agent or drug with much less amount or dosage of HPP or HPC in comparison to a systematic administration of a parent agent or drug; alternatively, a higher level of local concentration which may not be afforded in the systematic administration, or if possible, requires significantly higher dosage of an agent in the systematic administration.
  • the high local concentration of the HPP/HPC or its parent agent if being cleaved enables the treatment of a condition more effectively or much faster than a systematically delivered parent agent and the treatment of new conditions that may not be previously possible or observed.
  • the local administration of the HPP or HPC may allow a biological subject to reduce potential suffering from a systemic administration, e.g., adverse reactions associated with the systematic exposure to the agent, gastrointestinal/renal effects. Additionally, the local administration may allow the HPP or HPC to cross a plurality of biological barriers and reach systematically through, for example, general circulation and thus avoid the needs for systematic administration (e.g., injection) and obviate the pain associated with the parenteral injection.
  • a HPP/HPC or a pharmaceutical composition according to the invention can be administered systematically (e.g., orally or parenterally).
  • the HPP/HPC or the active agent (e.g., drug or metabolite) of the HPP/HPC may enter the general circulation with a faster rate than the parent agent and gain faster access to the action site a condition.
  • the HPP/HPC can cross a biological barrier (e.g., blood brain barrier and blood milk barrier) which has not been penetrated if a parent agent is administered alone and thus offer novel treatment of conditions that may not be previously possible or observed.
  • HPPs/HPCs of antimicrobials or antimicrobial-related compounds in the invention demonstrated high penetration rate through a biological barrier (e.g., > about 10 times, > about 50 times, >about 100 times, >about 200 times, >about 300 times, > about 1000 times higher than if the antimicrobials or antimicrobial- related compounds are administered alone).
  • a biological barrier e.g., > about 10 times, > about 50 times, >about 100 times, >about 200 times, >about 300 times, > about 1000 times higher than if the antimicrobials or antimicrobial- related compounds are administered alone.
  • No or few adverse side effects were observed from the subjects that took antimicrobial HPP/HPC, while side effects (such as nausea) were observed from the subjects that took the parent antimicrobials at the similar dosage.
  • HPP/HPC or a pharmaceutical composition according to the invention can penetrate one or more biological barriers, such as biofilm, cell wall of bacteria, fungi and other microorganisms, at much higher rate and can overcome the drug resistance.
  • Example 1 Preparation of a HPP from a parent drug.
  • T is a transportational unit of a HPP of an antimicrobial or antimicrobial-related compound.
  • T is selected from the group consisting of W and R6 as defined supra.
  • a HPP having Structure L-1 is prepared according to organic synthesis by reacting the parent compounds or derivatives of the parent compounds having Structure D (e.g. acid halides, mixed anhydrides of the parent compounds, etc.):
  • W c is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy;
  • F, l_i, L 2 , L 4 and T are defined as supra.
  • T is a transportational unit of a HPP of an antimicrobial or antimicrobial-related compound.
  • T is selected from the group consisting of W and Re as defined supra;
  • M is selected from the group consisting of Na, K, or other metal.
  • W N is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy.
  • the obtained protected HPP may be further partially or completely deprotected to render a partially protected HPP or an unprotected HPP respectively.
  • HPPs of an antimicrobial or antimicrobial-related compound can be synthesized by similar procedures.
  • HPPs of antimicrobials and antimicrobial-related compounds have higher in vitro penetration rates across human skin comparing to their parent drugs.
  • a test compound (2 ml_, 10% in 0.2 M phosphate buffer, pH 7.4) was added to the sample chamber of a Franz cell.
  • the receiving chamber contained 10 ml of 0.2 M phosphate buffer which was stirred at 600 rpm.
  • the amount of the tested compound penetrating the skin was determined by high-performance liquid chromatography (HPLC) method.
  • HPLC high-performance liquid chromatography
  • the results were shown in Figures 1a1 , 1a2, 1a3, 1a4, 1 b, and 1c.
  • Apparent flux values of the tested compounds calculated from the slopes in the Figures 1a1 , 1a2, 1a3 and 1 a4 were summarized in Table 1a.
  • Apparent flux values of the tested compounds calculated from the slopes in the Figures 1 b and 1c are summarized in Tables 1 b and 1c respectively.
  • parent drugs that showed a apparent flux value equal to or less than 1 ⁇ g /cm 2 /h were considered as not detectable for penetrating across the skin tissue.
  • parent compounds e.g. penicillin V, penicillin O
  • their HPPs had detectable apparent flux values.
  • their HPPs had higher detectable apparent flux values. Therefore the HPPs of antimicrobials or antimicrobial-related compounds showed a higher penetration rate (340-600 times higher) across the skin tissue comparing to their parent compounds.
  • Example 3 In vivo penetration rate of HPPs through skin and/or blood-brain barrier
  • mice After 2 hours, the mice were killed. 5 ml of methanol was added to 1 g of homogenized blood, liver, kidney, muscle, or brain. The samples were centrifuged for 5 min and analyzed by HPLC (Table 2). No drug was detected for the mice treated with only the parent drug (methicillin, oxacillin, and cloxacillin). The results showed that these prodrugs have high pentration rate of blood- brain barrier while the respective parent drugs were not able to penetrate the skin.
  • HPPs of antimicrobials or antimicrobial-related compounds penetrate cell wall of bacteria faster than that of their parent drugs.
  • 1-piperidineethyl ester hydrochloride penicillin V-PEE
  • penicillin V penicillin V
  • 6-(2,6- dimethoxybenzamido)penicillinic acid 2-pyrrolidinemethyl ester hydrochloride
  • methicillin-PME methicillin
  • 7-[[(2-acetylamino-4- thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 2-diethylaminoethyl ester hydrochloride (ceftizoxime-DEE), or ceftizoxime) was added into 100 ml of E. coli suspension and stirred for 3 minutes.
  • Table 4 The amount of antibiotics and their HPPs entered cells of E. CoIi.
  • HPPs of antimicrobials or antimicrobial-related compounds converted to the parent antimicrobials or antimicrobial-related compounds quickly in good yield in human plasma.
  • a HPP of antimicrobial or antimicrobial-related compound (10 mg) was dissolved in 0.1 ml of 0.2M pH 7.4 phosphate buffer. 1 ml of human plasma, preheated to 37 ° C, was added into the mixture. The mixture was kept in a water bath at 37 ° C, and at every 2 min intervals 0.2 ml of samples were withdrawn and added to 0.4 ml of methanol to precipitate the plasma protein. The samples were centrifuged for 5 min and analyzed by HPLC. The results showed that most of the HPPs of antimicrobials or antimicrobial-related compounds were converted back to the parent antimicrobials or antimicrobial-related compounds (Table 5).
  • MICs Minimum inhibitory concentrations of the antimicrobials and their pro-drugs were assessed according to Jennifer M. Andrews, Journal of Antimicrobial Chemotherapy 48, suppl. S1 , 5-16 (2001 ). The results (Tables 6a-6c) showed that the HPPs of antimicrobials were able to overcome ⁇ -lactam resistance in methicillin- resistant Staphylococcus aureus (MRSA) according to Minimum inhibitory concentrations (MICs).
  • MRSA methicillin- resistant Staphylococcus aureus
  • Example 8 Treatment of clinical mastitis using HPPs of beta-lactam antibiotics or related compounds.
  • Example 9 Anti-M. tuberculosis activity of the pro-drugs of antimicrobial drugs.
  • group B was the treated group with isoniazid/moxifoxacin/pyrazinamide (0.18/0.22/1.2mmol/kg, were given orally) for 45 days
  • group C was the treated group with isoniazid/moxifoxacin/pyrazinamide (0.18/0.22/1.2mmol/kg, were given orally) for 90 days
  • group D was the treated group with N-(N-methyl-phenylalanyl)isoniazid (pro- isoniazid, made from N-methylphenylalanine and isoniazid, were given tansdermally)/ 1- cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo [4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo- quinoline-3-carboxylic acid butyl ester(pro-moxifoxacin)/pyrazinoic acid N, N- diethylamin
  • mice were held for an additional 90 days without treatment and then sacrificed to determine the proportion with negative lung cultures indicating cure.
  • the results showed that the pro-drugs were superior to their parent drugs and they can be used transdermal ⁇ (Tables 9a and 9b).
  • Example 10 Treatment of tuberculosis in adults (reduced dosage for child).
  • Example 12 Treatment of ear infection.
  • Example 13 Treatment of lower respiratory tract infection in adults (reduced dosage for child).
  • Example 14 Treatment of upper respiratory tract infection in adults (reduced dosage for child).
  • Example 16 Treatment of meningitis in adults (reduced dosage for child).
  • Example 17 Treatment of diarrheal diseases (reduced dosage for child).
  • Example 18 Treatment of breast infection.

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Abstract

High penetration comp1ositions (HPCs) or prodrugs (HPPs) of antimicrobials and antimicrobial-related compounds are provided. The HPCs/HPPs are capable of being converted to parent drugs or drug metabolites after crossing the biological barrier and thus can render treatments. Additionally, the HPCs/HPPs are capable of reaching areas that their parent drugs may not be able to access and rendering a sufficient concentration at the target areas and therefore render novel treatments.

Description

HIGH PENETRATION COMPOSITIONS OR PRODRUGS OF ANTIMICROBIALS AND
ANTIMICROBIAL-RELATED COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation in part application of and claims priority to U.S. Patent Application No. 12/482,373, filed on June 10, 2009, which is incorporated herein by reference. The present application also claims priority to China Patent Application No. 200910141944.X, filed on June 10, 2009, which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to the field of pharmaceutical compositions capable of penetrating one or more biological barriers and methods of using the pharmaceutical compositions for preventing, diagnosing and/or treating conditions or diseases in humans and animals that are treatable by antimicrobials and antimicrobial- related compounds. The invention also relates to methods of using the pharmaceutical compositions for screening new drug candidates and methods of using the pharmaceutical compositions for diagnosing a condition in a biological subject.
BACKGROUND OF THE INVENTION
[0003] Antimicrobials are substances that kill or inhibit the growth of microorganisms such as bacteria, fungi, or protozoans, as well as destroying viruses. The main classes of antimicrobials include, for example, antibiotics that treat bacterial- related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiprotozoals that treat protozoans-related conditions.
[0004] Beta-lactam antibiotics are a class of antibiotics that comprise a four- member ring beta-lactam nucleus in their molecular structures. Over a hundred thousand of beta-lactam antibiotics have been prepared by partial or total chemical synthesis (L. A. Mitscher, et al., Antibiotic and Antimicrobial Drugs, in D. F. Smith, Ed., Handbook of Stereoisomers: Therapeutic Drugs, Boca Raton, FL, CRC Press, 1989; R.B. Morin and M. Gorman Eds., Chemistry and Biology of Beta-lactam Antibiotics, Volumes 1-3, New York, Academic Press, 1982; and A.LDemain and N.A. Solomon, Eds., Antibiotics Containing the Beta-lactam Structure, VoIs, 1 and 2, Handbook of experimental Pharmacology, vol. 67, New York, Springer, 1983). Examples of beta- lactam antibiotics include penicillin derivatives, cephalospotrins, monobactams, carbapenems, beta-lactamase inhibitors, sulfonamide and quinolones.
[0005] Along with the extensive use of antimicrobials, drug resistance becomes a common and serious problem as the pathogens mutate over time. Therefore, it is an urgent and challenging task to develop new antimicrobials.
[0006] A wide variety of antimicrobial are administered through Intravenous infusion, intramuscular injection, subcutaneous, buccal, oral, and rectal routes. Oral administration has disadvantage of poor absorption of the antibiotics from the Gl tract. Intravenous, subcutaneous and intramuscular routes are not only painful, but also require administration by trained individuals and may incur other risks such as needle injury, infection, and other trauma.
[0007] One alternative method of drug administration is topical delivery.
Topical drug delivery has several advantages. This method avoids inactivation of a drug caused by first pass metabolism in the liver and gastro-intestinal tract. It also provides local delivery of appropriate concentrations of a drug to the intended site of action without systemic exposure. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) indicated that an additional problem associated with oral medications, is that the concentration levels which must be achieved in the bloodstream must be significant in order to effectively treat distal areas of pain, inflammation, or infection. These levels are often much higher than would be necessary if the drugs were accurately delivered to the particular site of pain or injury. For most of antimicrobials, topical administration cannot deliver an effective therapeutic level.
[0008] Therefore, a need exists in the art for novel compositions that are capable of being delivered efficiently and effectively to the action site of a condition (e.g., a disease) to prevent, reduce or treat conditions as well as minimize adverse side effects.
SUMMARY OF THE INVENTION
[0009] One aspect of the invention is directed to a high penetration prodrug
(HPP) or high penetration composition (HPC) comprising a functional unit covalently linked to a transportational unit through a linker. The terms "HPP" and "HPC" are used alone or together herein and are interchangeable unless specifically noted.
[0010] In certain embodiments, a functional unit of a HPP or HPC comprises a moiety of a parent drug, wherein the efficient and effective delivery of the parent drug to a biological subject and/or transportation of the parent drug across one or more biological barriers are/is desired.
[0011] In certain embodiments, a functional unit may be hydrophilic, lipophilic, or amphiphilic (i.e., both hydrophilic and lipophilic). For example, the lipophilic nature of a function unit may be inherent or achieved by converting the hydrophilic moieties of a functional unit to lipophilic moieties. In certain embodiments, a carboxyl group, amino group, guanidine group or other hydrophilic group of a functional unit is protected with an alkyl, aryl, or heteroaryl ester or amide group to make the HPP or HPC more lipophilic.
[0012] In certain embodiments, a functional unit of a HPP or HPC comprises a moiety of an antimicrobial or an antimicrobial-related compound. An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans, as well as destroying viruses.
[0013] An antimicrobial-related compound is a compound comprising an antimicrobial structure, an antimicrobial metabolite, or an agent that can be metabolized into an antimicrobial or antimicrobial metabolite after a HPP or HPC penetrates one or more biological barriers. An antimicrobial-related compound further includes a compound that is an analog or mimic of an antimicrobial or an antimicrobial metabolite, or an agent that can be metabolized into an analogue or mimic of an antimicrobial or an antimicrobial metabolite, after a HPP or HPC penetrates one or more biological barriers. [0014] Examples of antimicrobials include, for example, antibiotics that treat bacterial-related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiprotozoals that treat protozoans-related conditions.
[0015] Examples of antibiotics include, without limitation, beta-lactam antibiotics, sulfonamides and quinolones. Examples of beta-lactam antibiotics include, but are not limited to, penicillin derivatives, cephalosporins, penems, monobactams, carbapenems, beta-lactamase inhibitors and combinations thereof. Examples of penicillin derivatives include, but are not limited to, aminopenicillins (e.g. amoxicillin, ampicillin, and epicillin); carboxypenicillins (e.g. carbenicillin, ticarcillin, and temocillin); ureidopenicillins (e.g. azlocillin, piperacillin and mezlocillin); mecillinam, sulbenicillin, benzathine penicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), penicillin O (allylmercaptomethylpenicillinic), procaine penicillin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, hetacillin, becampicillin, metampicillin, talampicillin, co-amoxiclav (amoxicillin plus clavulanic acid), and piperacillion. Examples of cephalosporins include, but are not limited to, cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime and cefpirome. Examples of penems include, without limitation, faropenem. Examples of monobactams include, without limitation, aztreonam and tigemonam. Examples of carbapenems include, but are not limited to, biapenem,-doripenem, ertapenem,-imipenem,-meropenem,-and panipenem. Examples of beta-lactamase inhibitors include, but are not limited to, tazobactam ([2S- (2alpha,3beta,5alpha)]-3-Methyl-7-oxo-3-(1 H-1 ,2,3-triazoM -ylmethyl)-4-thia-1 - azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium salt), sulbactam (2S,5f?)- 3,3-dimethyl-7-oxo-4-thia-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium), and clavulanic acid ((2f?,5f?,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-aza- bicyclo[3.2.0]heptane-2-carboxylic acid). Other examples of antibiotics include, without limitation, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4-nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(3- pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-(Λ/-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1 ,4-dienecarboxylic acid), 1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3-carboxylic acid, nalidixic acid (1-ethyl-7-methyl-4-oxo-[1 ,8]naphthyridine-3-carboxylic acid),
[0016] Examples of sulfonamides include, without limitation, sulfaisodimidine, sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfadimethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, xipamide, dichlorphenamide, dorzolamide, acetazolamide, ethoxzolamide, sultiame, zonisamide, mafenide, celecoxib, darunavir, probenecid, sulfasalazine, and sumatriptan.
[0017] Examples of quinolones include, without limitation, cinoxacin, flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin, ecinofloxacin, delafloxacin and nalidixic acid.
[0018] Examples of antivirals include, without limitation, rifampicin, zanamivir and oseltamivir.
[0019] Examples of antifungals include, without limitation, polyene antifungals
(e.g. natamycin, hmocidin, filipin, nystatin, amphotericin B, candicin), imidazole antifungals (e.g. miconazole, ketoconazloe, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole), triazoles antifungals (e.g. fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, and terconazole), thiazole antifungals (e.g. abafungin), allyamines (e.g. terbinafine, amorolfine, naftifine and butenafine), echinocandins (e.g. anidulafungin, caspofungin and micafungin) and other antifungals such as benzoic acid, ciclopirox, tolnaftate, undecylenic acid, flucytosine, griseofulvin, haloprogin. [0020] Examples of antiprotozoals include, without limitation, elornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and tinidazole.
[0021] In certain embodiments, a transportational unit of a HPP or HPC comprises a protonatable amine group that is capable of facilitating or enhancing the transportation or crossing of the HPP or HPC through one or more biological barriers. In certain embodiments, the protonatable amine group is substantially protonated at the pH of the biological barriers through which a HPP or HPC penetrates. In certain embodiments, the amine group can be reversibly protonated or deprotonated.
[0022] In certain embodiments, a linker covalently links the functional unit to the transportational unit of a HPP and comprises a bond that is capable of being cleaved after the HPP penetrates across one or more biological barriers. The cleavable bond comprises, for example, a covalent bond, an ether, a thioether, an amide, an ester, a thioester, a carbonate, a carbamate, a phosphate or an oxime bond.
[0023] In certain embodiments, a HPP or HPC of an antimicrobial or antimicrobial-related compound comprises one or two primary, secondary or tertiary amine groups that exist in the protonated form at physiological pH. In certain embodiments, the HPP or HPC comprises one primary, secondary or tertiary amine group that exists in the protonated form at physiological pH.
[0024] Another aspect of the invention relates to a pharmaceutical composition comprising at least one HPP or HPC of an antimicrobial or antimicrobial-related compound and a pharmaceutically acceptable carrier.
[0025] Another aspect of the invention relates to a method for penetrating a biological barrier using a HPP or HPC of an antimicrobial or antimicrobial-related compound.
[0026] Another aspect of the invention relates to a method for diagnosing the onset, development, or remission of a condition in a biological subject by using a HPP or HPC of an antimicrobial or antimicrobial-related compound. In certain embodiments, the HPP (or HPC) or the functional unit thereof is detectable. In certain embodiments, the HPP or the functional unit of the HPP is inherently detectable, labeled with, or conjugated to, a detectable marker.
[0027] Another aspect of the invention relates to a method for screening functional units, linkers, or transportational units for desired characteristics.
[0028] Another aspect of the invention relates to a method for preventing, ameliorating, or treating a condition in a biological subject by administering to the subject a composition in accordance with the invention. In certain embodiments, the method relates to treating a condition in a subject treatable by antimicrobials or antimicrobial-related compounds by administering to the subject a therapeutically effective amount of a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof. In certain embodiments, conditions treatable by the method include, without limitation, pain, injuries and microorganism related conditions. Microoranism related conditions are conditions that are caused by microorganisms such as bacteria, fungi, protozoans and viruses. For example, conditions caused by bacteria (bacteria-related conditions), conditions caused by protozoa (protozoa-related conditions), conditions caused by fungi (fungi-related conditions) and conditions caused by virus (virus-related conditions). Bacteria-related conditions include, for example, infections (e.g. infection condition in an organ such as liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, anorectum and pruritus ani, respiratory infections, upper respiratory tract infections, urinary tract infections, nosocomial infections, pseudomonas infection, Coagulase-positive staphylococcal infections (e.g. skin infection, toxinoses, acute infective endocarditis, septicemia, necrotizing pneumonia), infections of implanted prostheses, opportunistic infections with septicemia and pneumonia), plague (e.g. bubonic plague and pneumonic plague), anthrax (e.g. cutaneous anthrax, pulmonary anthrax and gastrointestinal antrax), lyme diseases, brucellosis, whooping cough, acute enteritis, psittacosis, nongonococcal urethritis, trachoma, inclusion conjunctivitis of the newborn, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, diarrhea, meningitis in infants, hemorrhagic colitis, hemolytic-uremic syndrome, tularemia, pneumonia, bronchitis, peptic ulcer, legionnaire's disease, Pontiac fever, leptospirosis, listeriosis, leprosy, turberculosis, mycoplasma pneumonia, gonorrhea, ophthalmia neonatorum, septic arthritis, meningococcal disease, waterhouse-friderichsen syndrome, Rocky mountain spotted fever, typhoid fever type salmonellosis, salmonellosis with gastroenteritis and enterocolitis, bacillary dysentery, shigellosis, cystitis, meningitis, septicemia, endometritis, otitis media, sinusitis, syphilis, necrotizing fasciitis, streptococcal pharyngitis, scarlet fever, rheumatic fever, impetigo, erysipelas, puerperal fever, and cholera. Protozoa related conditions include, for example, malaria, sleeping sickness, and toxoplasmosis. Fungi related conditions include, for example, aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, histoplasmosis, paracoccidiomycosis, sporotrichosis, and zygomycosis. Virus related conditions include, for example, influenza, yellow fever and AIDS.
[0029] In certain embodiments, a pharmaceutical composition of a HPP or HPC is administrated to a biological subject via various routes including, but not limited to, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteral routes. In certain preferred embodiments, a pharmaceutical composition of a HPP or HPC is administered orally, transdermal^, topically, subcutaneously and/or parenterally.
[0030] In accordance with the advantages of the invention, without intending to be limited by any particular mechanism, a therapeutically effective amount of a HPP or HPC can be administered locally to a site of condition at a high concentration which results in a lower overall dosage than systemic administration. The advantages of the invention also include, for example, avoidance of systematic administration, reduction of adverse effects (e.g., pain of injection, gastrointestinal/renal effects, and other side effects), and possible novel treatments due to high local concentration of a HPP, HPC or active agent. The advantages further include, for example, systematic administration of a HPP or HPC to a biological subject to achieve faster and more efficient bioavailability, penetration of biological barriers (e.g., the blood brain barrier and the blood milk barrier) which have been difficult to cross, and new indications as a result of passing through biological barriers. BRIEF DESCRIPTION OF THE FIGURES
[0031] Figure 1a1 : Cumulative amounts of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl ester hydrochloride (A), allylmercaptomethylpenicillinic acid 2- dimethylaminoethyl ester hydrochloride (B), 6-(2,6-dimethoxybenzamido)penicillinic acid 2-dipropylaminoethyl ester hydrochloride (C), 6-(5-methyl-3-phenyl-2-isoxazoline-4- carboxamido)penicillinic acid 4-piperidineethyl ester hydrochloride (D), 6-[3-(o- chlorophenyl)-5-methyl-4-isoxazolecarboxamido]penicillinic acid 3-piperidine ethyl ester hydrochloride (E), 6-[3-(2,6-dichlorophenyl)-5-methyl-4- isoxazolecarboxamido]penicillinic acid 1-piperidineethyl ester hydrochloride (F), penicillin V (G), penicillin O (H), methicillin (I), oxacillin (J), cloxacillin (K), and dicloxacillin (L), crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).
[0032] Figure 1a2: Cumulative amounts of 6-[D(-)-α- aminophenylacetamidopenicillinic acid ethyl ester hydrochloride (A), D-α-[(imidazolidin- 2-on-1-yl)carbonylamino]benzylpenicillin 2-pyrrolidinemethyl ester hydrochloride (B), 6R-[2-[3-(methylsulfonyl)-2-oxo-1-imidazolidinecarboxamido]-2- phenylacetamido]penicillinic acid 1-pyrrolidineethyl ester hydrochloride (C), 6-D(-)-α-(4- ethyl-2,3-dioxo-1 -piperazinylcarbonylamino)-α-phenylacetamidopenicillinic acid 2- diethylaminoethyl ester hydrochloride (D), 7-(2-thienylacetamido)cephalosporanic acid 2-diethylaminoethyl ester hydrochloride (E), ampicillin (F), azlocillin (G), mezlocillin (H), piperacillion (I), and cephalothin (J), crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).
[0033] Figure 1a3: Cumulative amounts of 7-[(hydroxyphenylacetyl)amino]-3-
[[(1 -methyl-1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 2-diethylaminoethyl ester hydrochloride (A), 3- [[(aminocarbonyl)oxy]methyl]-7-[[2-furanyl(methoxyimino)acetyl]amino]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (B), 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (C), 7-[[[2-(acetylaminomethyl)phenyl]acetyl]amino]-3-[[[1-(ethoxylcarbonylmethyl)-1 H- tetrazol-5-yl]thio]methyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2- diethylaminoethyl ester hydrochloride (D), 7-[(acetylaminophenylacetyl)amino]-3-chloro- 8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (E), cefamandole (F), cefuroxime (G), cefoxitin (H), ceforanide (I), and cefaclor (J), crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).
[0034] Figure 1a4: Cumulative amounts of 3-[(acetyloxy)methyl]-7-[[(2- acetylamino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (A), 7-[[(2-acetylamino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (B), 7-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-acetoxyphenyl)acetyl]amino]-3- [[(1 -methyl-1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 2-diethylaminoethyl ester hydrochloride (C), 7-[2-(2-acetylamino-4- thiazolyl)-2-((Z)-methoxyimino)acetamido]-3-(methoxymethyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (D), 7-[2-(2-acetylamino-4-thiazolyl)-2-((Z)-ethoxycarbonylmethoxy)imino]acetamido]-3- (vinyl)-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (E), cefotaxime (F), ceftizoxime (G), cefoperazone (H), cefpodoxime proxetil (I), and cefixime (J), crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).
[0035] Figure 1 b: Cumulative amounts of [2S-(2alpha,3beta,5alpha)]-3-Methyl-
7-oxo-3-(1 H-1 ,2,3-thazol-1 -ylmethyl)-4-thia-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium salt (tazobactam, F), [2S-(2alpha,3beta,5alpha)]-3-Methyl-7- oxo-3-(1 H-1 ,2,3-triazol-1 -ylmethyl)-4-thia-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide 1-piperidineethyl ester.HCI salt (tazobactam-PEE, A), (2S,5R)-3,3-dimethyl- 7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium (sulbactam, G), (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1 -azabicyclo[3.2.0]heptane-2- carboxylic acid 4,4-dioxide N,N-diethylaminoethyl ester.HCI salt (sulbactam-DEE, B), (2R,5R,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2- carboxylic acid (clavulanic acid, H), (2f?,5f?,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1- aza-bicyclo[3.2.0]heptane-2-carboxylic acid 4-piperidineethyl ester.HCI salt (clavulanic acid-PEE, C), [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4- nitrophenyl) ester sodium salt (I) , [(N-benzyloxycarbonylamino)methyl]-phosphonic acid (4-nitrophenyl)(N,N-diethylaminomethyl) ester.HCI salt (D), [(N- benzyloxycarbonylamino)methyl]-phosphonic acid mono-(3-pyridinyl) ester sodium salt (J), and [(N-benzyloxycarbonylamino)methyl]-phosphonic acid (3-pyridinyl)(1 -piperidinyl) ester.HCI salt (E), crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).
[0036] Figure 1c: Cumulative amounts of 4-aminobenzenesulfonamide
(sulfanilamide, E), 4-(4-dimethylaminobutyryl)amidobenzenesulfonamide.HCI salt (DMAB-sulfanilamide, A), 6-oxo-3-(2-[4-(Λ/-pyridin-2- ylsulfamoyl)phenyl]hydrazono)cyclohexa-1 ,4-dienecarboxylic acid, 6-oxo-3-(2-[4-(Λ/- pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1 ,4-dienecarboxylic acid
(sulfasalazine, F), 6-oxo-3-(2-[4-(Λ/-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa- 1 ,4-dienecarboxylic acid N,N-diethyaminopropyl ester.HCI salt (sulfasalazine-DEPE, B), 1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3-carboxylic acid (ciprofloxacin, G), 1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3- carboxylic acid butyl ester.HCI salt (ciprofloxacin-BE, C), 1-ethyl-7-methyl-4-oxo- [1 ,8]naphthyhdine-3-carboxylic acid (nalidixic acid, H), 1-ethyl-7-methyl-4-oxo- [1 ,8]naphthyhdine-3-carboxylic acid N,N-diethylaminoethyl ester.HCI salt (nalidixic acid- DEE, D), crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).
DETAILED DESCRIPTION OF THE INVENTION
I. Structures of high penetration prodrug (HPP) or high penetration composition (HPC).
[0037] One aspect of the invention is directed to a high penetration prodrug
(HPP) or a high penetration composition (HPC). The term "high penetration prodrug" or "HPP" or "high penetration composition" or "HPC" as used herein refers to a composition comprising a functional unit covalently linked to a transportational unit through a linker.
[0038] A functional unit of a HPP or HPC which comprises a moiety of a parent drug has the properties of: 1 ) the delivery of the parent drug or the HPP/HPC into a biological subject and/or the transportation of the parent drug across a biological barrier are/is desired, 2) the HPP/HPC is capable of penetrating or crossing a biological barrier, and 3) the HPP/HPC is capable of being cleaved so as to turn the moiety of a parent drug into the parent drug or a metabolite of the parent drug.
[0039] In certain embodiments, a functional unit may be hydrophilic, lipophilic, or amphiphilic (hydrophilic and lipophilic). The lipophilic moiety of the functional unit may be inherent or achieved by converting one or more hydrophilic moieties of the functional unit to lipophilic moieties. For example, a lipophilic moiety of a functional unit is produced by converting one or more hydrophilic groups of the functional unit to lipophilic groups via organic synthesis. Examples of hydrophilic groups include, without limitation, carboxylic, hydroxyl, thiol, amine, phosphate/phosphonate, guanidine and carbonyl groups. Lipophilic moieties produced via the modification of these hydrophilic groups include, without limitation, ethers, thioethers, esters, thioesters, carbonates, carbamates, amides, phosphates and oximes. In certain embodiments, a functional unit is lipophilicized by acetylation or acylation(alkanoylation). In certain embodiments, a functional unit is lipophilicized by esterification.
[0040] In certain embodiments, a parent drug of a HPP or HPC is selected from the group consisting of an antimicrobial and antimicrobial-related compound. The moiety of an antimicrobial or antimicrobial-related compound can be further converted to a lipophilic moiety as described supra.
[0041] Antimicrobials are substances that kill or inhibit the growth of microorganisms such as bacteria, fungi, or protozoans, as well as destroying or inhibit the growth of viruses. The main classes of antimicrobials include, for example, antibiotics that treat bacterial-related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiparastics that treat parasite-related conditions. [0042] An antimicrobial-related compound is a compound comprising an antimicrobial structure, an antimicrobial metabolite, or an agent that can be metabolized into an antimicrobial or antimicrobial metabolite after a HPP or HPC penetrates one or more biological barriers. An antimicrobial-related compound further includes a compound that is an analog or mimic of an antimicrobial or an antimicrobial metabolite, or an agent that can be metabolized into an analog or mimic of an antimicrobial or an antimicrobial metabolite, after a HPP or HPC penetrates one or more biological barriers.
[0043] Examples of antimicrobials include, for example, antibiotics that treat bacterial-related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiprotozoals that treat protozoans-related conditions.
[0044] Examples of antibiotics include, without limitation, beta-lactam antibiotics, sulfonamides and quinolones. Beta-lactam antibiotics are well known in the art and are used in connection with various conditions. As used herein, a beta-lactam antibiotics refers to a compound that comprises a beta-lactam nucleus.
[0045] Examples of beta-lactam antibiotics include, but are not limited to, penicillin derivatives, cephalosporins, penems, monobactams, carbapenems, beta- lactamase inhibitors and combinations thereof. Examples of penicillin derivatives include, but are not limited to, aminopenicillins (e.g. amoxicillin, ampicillin, and epicillin), carboxypenicillins (e.g. carbenicillin, ticarcillin, and temocillin), ureidopenicillins (e.g. azlocillin, piperacillin and mezlocillin), mecillinam, sulbenicillin, benzathine penicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), penicillin O (allylmercaptomethylpenicillinic), procaine penicillin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, hetacillin, becampicillin, metampicillin, talampicillin, co-amoxiclav (amoxicillin plus clavulanic acid), and piperacillion. Examples of cephalosporins include, but are not limited to, cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime and cefpirome. Examples of penems include, without limitation, faropenem. Examples of monobactams include, without limitation, aztreonam and tigemonam. Examples of carbapenems include, but are not limited to, biapenerrvdoripenem, ertapenem,-imipenem,-meropenem,-and panipenem. Examples of beta-lactamase inhibitors include, but are not limited to, tazobactam ([2S- (2alpha,3beta,5alpha)]-3-Methyl-7-oxo-3-(1 H-1 ,2,3-triazoM -ylmethyl)-4-thia-1 - azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium salt), sulbactam ((2S,5R)-3,3-dimethyl-7-oxo-4-thia-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4- dioxide sodium), and clavulanic acid ((2f?,5f?,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1- aza-bicyclo[3.2.0]heptane-2-carboxylic acid). Other examples of antibiotics include, without limitation, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4- nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(3-pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-(Λ/-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1 ,4- dienecarboxylic acid), 1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3- carboxylic acid, and nalidixic acid (1-ethyl-7-methyl-4-oxo-[1 ,8]naphthyridine-3- carboxylic acid),
[0046] Examples of sulfonamides include, without limitation, sulfaisodimidine, sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfadimethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, xipamide, dichlorphenamide, dorzolamide, acetazolamide, ethoxzolamide, sultiame, zonisamide, mafenide, celecoxib, darunavir, probenecid, sulfasalazine, and sumatriptan.
[0047] Examples of quinolones include, without limitation, cinoxacin, flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin, ecinofloxacin, delafloxacin and nalidixic acid.
[0048] Examples of antivirals include, without limitation, rifampicin, zanamivir and oseltamivir. [0049] Examples of antifungals include, without limitation, polyene antifungals
(e.g. natamycin, rimocidin, filipin, nystatin, amphotericin B and candicin), imidazole antifungals (e.g. miconazole, ketoconazloe, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole), triazoles antifungals (e.g. fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, and terconazole), thiazole antifungals (e.g. abafungin), allyamines (e.g. terbinafine, amorolfine, naftifine and butenafine), echinocandins (e.g. anidulafungin, caspofungin and micafungin) and other antifungals such as benzoic acid, ciclopirox, tolnaftate, undecylenic acid, flucytosine, ghseofulvin and haloprogin.
[0050] Examples of antiprotozoals include, without limitation, elornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and tinidazole.
[0051] In certain embodiments, a functional unit of a HPP of an antimicrobial or antimicrobial-related compound comprises a moiety having a structure of Structure F-1 :
Figure imgf000016_0001
Structure F-1 including stereoisomers and pharmaceutically acceptable salts thereof.
[0052] Unless otherwise specified in the specification, Y is selected from the group consisting of H, OH, NHCHO, NHC(=O)R6, OC(=O)CH3, OC(O)R6, OCH3, OC2H5, OR6, CH3, C2H5, R6, CH3SO3, R6SO3, NO2, CN, CF3, C2F5, C3F7, OCF3, OC2F5, OC3F7, F, Br, I, Cl, and substituted and unsubstituted alkyloxyl;
Figure imgf000017_0001
is selected from the group consisting of Structure NS-1 , Structure NS-2, Structure NS-3, Structure NS-4 and Structure NS-5:
Figure imgf000017_0002
Structure NS-1 Structure NS-2 Structure NS-3 Structure NS-4 Structure NS-5;
Xi is selected from the group consisting of H, OH, OCH3, OC2H5, OR6, C(O)NH2, CH2OC(=O)NH2, CH2OC(=O)CH3, CH2OC(=O)R6, OC(O)CH3, OC(=O)R6, CH2OCH3, CH3, C2H5, R6, Cl, F, Br, I, HC=CHCH3, HC=CH2, CH2OCH3, CH2OR6, S(CH2)n-NHR7, Structure Xi-1 , Structure Xi-2, Structure Xi-3, Structure Xi-4, Structure Xi-5, Structure X1-6, Structure Xr7, Structure Xr8, Structure Xr9, Structure Xi-10, Structure Xi-11 , Structure Xr12, Structure Xr13, Structure Xr14, Structure Xr15, Structure Xr16, Structure Xi-17, Structure Xr18, Structure Xi-19, Structure Xr20, Structure Xi-21 , Structure Xi-22, Structure Xi-23, Structure Xi-24, Structure Xi-25, Structure Xr26, Structure Xi-27, Structure Xr28, Structure Xi-29, Structure Xr30, Structure Xi-31 , Structure Xi-32, Structure Xr33, Structure Xi-34, Structure Xr35, Structure Xr36, Structure Xi-37, Structure Xr38, Structure Xr39, Structure Xr40, Structure Xi-41 , Structure Xi-42, Structure Xi-43, Structure Xr44, Structure Xi-45, Structure Xr46, Structure Xi-47, Structure Xi-48, Structure Xr49, Structure Xi-50, Structure Xi-51 , Structure Xi-52, Structure Xi-53, Structure Xi-54, Structure Xi-55, Structure Xi-56, Structure Xi-57, Structure Xr58, Structure Xr59, Structure X1-6O, Structure X1-6I , Structure Xr62, Structure Xr63, Structure Xr64, Structure Xr65, Structure Xr66, Structure Xr67, Structure Xr68, Structure Xr69, Structure Xr70, Structure Xi-71 , Structure Xi-72, Structure Xi-73, Structure Xi7-4, Structure Xi-75, Structure Xr76, Structure Xi-77, Structure Xr78, Structure Xi-79, Structure Xr80, Structure X1-8I , and Structure Xr82:
Figure imgf000018_0001
Structure Xi-1 Structure Xi-2 Structure Xi -3
Figure imgf000018_0002
tructure Xi-5
Figure imgf000018_0004
Figure imgf000018_0003
Structure Xr6 Structure Xr7 Structure Xr8
Figure imgf000018_0005
Figure imgf000018_0006
Structure Xi -10
Figure imgf000019_0001
Structure Xi -11 Structure Xi -12
Figure imgf000019_0002
Structure Xi -13 Structure Xi -14
Figure imgf000019_0003
Structure Xi-15
Figure imgf000019_0005
Figure imgf000019_0004
Structure Xi -17 Structure Xi-18
Figure imgf000020_0001
Structure Xi -19 Structure Xr20
Figure imgf000020_0002
Structure Xr21
Figure imgf000020_0004
Figure imgf000020_0003
Structure X1 -23 Structure Xi -24
Figure imgf000021_0001
Structure Xr25
Figure imgf000021_0002
Figure imgf000021_0003
Structure Xr27 Structure Xr28
Figure imgf000021_0004
Structure Xr29 Structure Xi-30
Figure imgf000021_0005
Structure Xr31 Structure Xi-32
Figure imgf000022_0001
Structure Xr33 Structure Xi -34
Figure imgf000022_0002
Structure Xr35 Structure Xr36
Figure imgf000022_0003
Structure Xr37 Structure Xr38
Figure imgf000022_0004
Structure Xr39 Structure Xr40
Figure imgf000023_0001
Structure X1 -41 Structure Xi -42 Structure Xi -43
Figure imgf000023_0002
Structure X1 -44 Structure X1 -45
Figure imgf000023_0003
Structure X1 -48 Structure X1 -49
Figure imgf000024_0001
Structure Xi -50 Structure Xi-51
Figure imgf000024_0002
Structure Xi -52 Structure Xr53 Structure Xi-54
Figure imgf000024_0003
Structure Xi-55 Structure Xr56 Structure Xi-57
Figure imgf000024_0004
Structure Xi -58 Structure Xr59
Figure imgf000025_0001
Structure X1-6O Structure Xr61
Figure imgf000025_0002
Structure Xr62 Structure Xr63 Structure Xr64
Figure imgf000025_0003
Figure imgf000025_0005
Figure imgf000025_0004
Structure Xr67 Structure Xr68
Figure imgf000026_0001
Structure Xr69 Structure Xr70
Figure imgf000026_0002
Structure Xi-71 Structure Xr72
Figure imgf000026_0003
Structure Xi -73 Structure Xr74
Figure imgf000026_0004
Structure Xi-75 Structure Xr76
Figure imgf000026_0005
Structure Xi -77 Structure Xr78
Figure imgf000027_0001
Structure Xr79 Structure X1-8O
Figure imgf000027_0002
Structure Xr81 Structure Xr82,
Rs- taken together with Y is R6OCH2C(R5)=, or by itself is selected from the group consisting of R6OOCCH(NHR7)(CH2)nC(=O)NH-, R6OOCCH(NHR7)(CH2)nSC(=O)NH-, CF3SCH2C(=O)NH-, CF3CH2C(=O)NH-, CHF2SCH2C(=O)NH-, CH2FSCH2C(=O)NH-, NH2C(=O)CHFS-CH2C(=O)NH-, R7NHCH(C(=O)OW)CH2SCH2C(=O)NH-, R7NHCH(Li-L4-L2-W)CH2SCH2C(=O)NH-, CNCH2SCH2C(=O)NH-, CH3(CH2)nC(=O)NH-, R7N=CHNR7CH2CH2S-, R7N=C(NHR7)NHC(O)-, R7N=C(NHR7)NHC(O)CH2,
CH3C(CI)=CHCH2SCH2C(=O)NH-, (CH3)2C(OR6)-, CNCH2C(=O)NH-, CNCH2CH2S-, R7HN=CH(NR7)CH2CH2S-, CH2=CHCH2SCH2C(=O)NH-, CH3CH(OH)-, CH3CH(OR8)-, CH3CH(Y1)-, (CHa)2CH-, CH3CH2-, CH3(CH2)nCH=CH(CH2)mC(=O)NH-, Structure Rs-1 , Structure Rs-2, Structure Rs-3, Structure Rs-4, Structure Rs-5, Structure Rs-6, Structure Rs-7, Structure Rs-8, Structure Rs-9, Structure Rs-10, Structure Rs-11 , Structure Rs-12, Structure Rs-13, Structure Rs-14, Structure Rs-15, Structure Rs-16, Structure Rs-17, Structure Rs-18, Structure Rs-19, Structure Rs-20, Structure Rs-21 , Structure Rs-22, Structure Rs-23, Structure Rs-24, Structure Rs-25, Structure Rs-26, Structure Rs-27, Structure Rs-28, Structure Rs-29, Structure Rs-30, Structure Rs-31 , Structure Rs-32, Structure Rs-33, Structure Rs-34, Structure Rs-35, Structure Rs-36, Structure Rs-37, Structure Rs-38, Structure Rs-39, Structure Rs-40, Structure Rs-41 , Structure Rs-42, Structure Rs-43, Structure Rs-44, Structure Rs-45, and Structure Rs- 46:
Figure imgf000028_0001
H-
Figure imgf000028_0002
Structure Rs-5 Structure Rs-6
Figure imgf000029_0001
Structure Rs-7 Structure Rs-8
Figure imgf000029_0002
Structure Rs-9, Structure Rs-10
Figure imgf000029_0003
Structure Rs-11 Structure Rs-12
Figure imgf000030_0001
Structure Rs-13 Structure Rs-14
Figure imgf000030_0002
Structure Rs-15 Structure Rs-16
Figure imgf000030_0003
Structure Rs-17 Structure Rs-18
Figure imgf000030_0004
Structure Rs-19 Structure Rs-20
Figure imgf000031_0001
Structure Rs-21 Structure Rs-22
Figure imgf000031_0002
Structure Rs-23 Structure Rs-24
Figure imgf000031_0003
Structure Rs-25 Structure Rs-26
Figure imgf000032_0001
structure Rs-27
Figure imgf000032_0002
Figure imgf000032_0003
Structure Rs-29 Structure Rs-30
Figure imgf000032_0004
Structure Rs-31 Structure Rs-32
Figure imgf000033_0001
Structure Rs-33 Structure Rs-34
Figure imgf000033_0002
Structure Rs-35 Structure Rs-36
Figure imgf000033_0003
Structure Rs-37 Structure Rs-38
Figure imgf000034_0001
Structure Rs-39 Structure Rs-40
Figure imgf000034_0002
Structure Rs-41 Structure Rs-42
Figure imgf000034_0003
Structure Rs-43 Structure Rs-44
Figure imgf000035_0001
Structure Rs-45 Structure Rs-46;
W is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, the protonatable amine group, pharmaceutically acceptable substituted and unsubstituted primary amine groups, Structure Wa, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18:
Figure imgf000035_0002
Structure Wa Structure W-1 Structure W-2 Structure W-3
Figure imgf000036_0001
Structure W-4 Structure W-5 Structure W-6
Figure imgf000036_0002
Structure W-7 Structure W-8 Structure W-9
Figure imgf000036_0003
Structure W-10 Structure W-11 Structure W-12
Figure imgf000036_0004
Structure W-13 Structure W-14 Structure W-15
Figure imgf000037_0001
Structure W-16 Structure W- 17 Structure W-18;
Z is selected from the group consisting of CH2, S, SO, SO2, NH, NR6, CHCH3, CHCH2CH3, CHR6, R6, -C(O)-, and O;
AA represents any amino acids; each m and n is independently selected from the group of O and integer, e.g. O, 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 group consisting of nothing, and pharmaceutically acceptable acid, e.g. hydrochloride hydrobromide, hydroiodide, nitric acid , sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid and pamoic acid;
R is selected from the group consisting of nothing, H, CH2C(=O)OR6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH2 in R may be further replaced with O, S, P, NR6, or any other pharmaceutically acceptable groups;
R1-R3 are independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues;
R5 and R35 are independently selected from the group consisting of H, C(=O)NH2, CH2CH2OR6, CH2CH2N(CHa)2, CH2CH2N(CH2CH3)2, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C(=O)-W, LrL4-L2-W, and W;
R6, R36 and R46 are independently selected from the group consisting of H, F, Cl, Br, I, Na+, K+, C(=O)R5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1 H-inden- 5-yl, 4-hydroxy-1 ,5-naphthyridin-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C(=O)-W, -L1-L4-L2-W, and W; R7 and R37 are independently selected from the group consisting of 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, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, Li-L4-L2-W, and C-(=0)-W;
R8 and R38 are independently selected from the group consisting of H, F, Cl, Br, I, CH3, C2H5, CF3, CH2CH2F, CH2CH2CI, CH2CH2Br, CH2CH2I, CH2CHF2, CH2CF3 CH2F CH2CI, CH2Br, CH2I, CH2NR6R7, CH(NHR7)CH2C(=O)NH2, C3H7, C4H9, C5Hn, 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(=0)-W, LrL4-L2-W, W, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide and substituted and unsubstituted alkylcarbonyl;
Rii-Ri6 are independently selected from the group consisting of nothing, H, CH2C(=O)ORii, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; X2 is selected from the group consisting of nothing, H, C(=O), C(=S), CH2(CH2)n0R8, CI, 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, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, and substituted and unsubstituted alkyloxyl;
X3 is selected from the group consisting of nothing, H, N3, SO3W, F, Cl, Br, OH, OCH3, OR6, CH3, R6, C(=O), C(=S), C(O)OW, OW, L1-L4-L2-W, and I;
X4 is selected from the group consisting of nothing, N, CH, and CYi;
X5 and X35 are independently selected from the group consisting of nothing, C(O), C(=S), OC(O), CH2, CH, S, O and NR5;
Yi, Y31, Y2, Y32, Y3, and Y4 are independently selected from the group consisting of 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, CHOHC(O)NHCH2C(O)0W, CHOHC(O)NHCH2L1-L4- L2-W, NR8C(O)R5, SO2NR5R8, C(O)R5, SR5, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide and substituted and unsubstituted alkylcarbonyl; Li is selected from the group consisting of nothing, O, S, -0-L3-, -S-L3-, -N(L3)-, ■
N(L3)-CH2-O, -N(La)-CH2-N(L5)-, -0-CH2-O-, -O-CH(L3)-O, and -S-CH(L3J-O-;
L2 is selected from the group consisting of nothing, O, S, -0-L3-, -S-L3-, -N(L3)-, -
N(L3)-CH2-O, -N(La)-CH2-N(L5)-, -0-CH2-O-, -O-CH(L3)-O, -S-CH(L3J-O-, -0-L3-, -N-L3-, -S-L3-, -N(L3)-L5- and L3;
L4 is selected from the group consisting of C=O, C=S,
Figure imgf000041_0001
Figure imgf000041_0002
for each Li, L2, and L4, L3 and L5 are independently selected from the group consisting of nothing, H, CH2C(=O)OL6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NL3, or any other pharmaceutically acceptable groups;
L6 is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl, or cyclic groups;
L7 is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl, or cyclic groups; and any CH2 groups may be replaced with O, S, or NH.
[0053] In certain embodiments, a functional unit of a HPP or HPC of an antimicrobial or antimicrobial-related compound comprises a moiety having a structure selected from the group consisting of Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38, Structure FP-39, Structure FP-40, Structure FP-41 , Structure FP-42, Structure FP-43, Structure FP-44, Structure FP-45, Structure FP-46, Structure FP-47, Structure FP-48, Structure FP-49, Structure FP-50, Structure FP-51 , Structure FP-52, Structure FP-53, Structure FP-54, Structure FP-55, Structure FP-56, Structure FP-57, Structure FP-58, Structure FP-59, Structure FP-60, Structure FP-61 , Structure FP-62, Structure FP-63, Structure FP-64, Structure FP-65, Structure FP-66, Structure FP-67, Structure FP-68, Structure FP-69, Structure FP-70, Structure FP-71 , Structure FP-72, Structure FP-73, Structure FP-74, Structure FP-75, Structure FP-76, Structure FP-77, Structure FP-78, Structure FP-79, Structure FP-80, Structure FP-81 , Structure FP-82, Structure FP-83, Structure FP-84, Structure FP-85, Structure FP-86, Structure FI-1 , Structure FI-2, Structure FI-3, Structure FI-4, Structure FI-5, Structure FI-6, Structure FI-7, Structure Fl- 8, Structure FI-9, Structure FI-10, Structure FI-11 , Structure FI-12, Structure FI-13, Structure FI-14, Structure FI-15, Structure FI-16, Structure FI-17, Structure FI-18, Structure FI-19, Structure FI-20, Structure FI-21 , Structure FI-22, Structure FI-23, Structure FI-24, Structure FI-25, Structure FI-26, Structure FI-27, Structure FI-28, Structure FI-29, Structure FI-30, Structure FI-31 , Structure FI-32, Structure FI-33, Structure FS-1 , Structure FS-2, Structure FS-3, Structure FS-4, Structure FS-5, Structure FS-6, Structure FS-7, Structure FS-8, Structure FS-9, Structure FS-10, Structure FS-11 , Structure FS-12, Structure FS-13, Structure FS-14, Structure FS-15, Structure FS-16, Structure FS-17, Structure FS-18, Structure FS-19, Structure FS-20, Structure FT-1 , Structure FT-2, Structure FT-3, Structure FT-4, Structure FT-5, Structure FT-6, Structure FT-7, Structure FT-8, Structure FT-9, Structure FT-10, Structure FT-11 , Structure FT-12, Structure FT-13, Structure FT-14, Structure FT-15, and Structure FT-16:
Figure imgf000044_0001
Structure FP-2
Figure imgf000044_0002
Structure FP-3 Structure FP-4
Figure imgf000044_0003
Structure FP-5 Structure FP-6
Figure imgf000045_0001
Structure FP-7 Structure FP-8
Figure imgf000045_0002
Structure FP-9 Structure FP-10
Figure imgf000045_0003
Structure FP-11 Structure FP-12
Figure imgf000045_0004
Structure FP-13 Structure FP-14
Figure imgf000046_0001
Structure FP-15 Structure FP-16
Figure imgf000046_0002
Structure FP-17 Structure FP-18
Figure imgf000046_0003
Structure FP-19 Structure FP-20
Figure imgf000046_0004
Structure FP-21 Structure FP-22
Figure imgf000047_0001
Structure FP-23 Structure FP-24
Figure imgf000047_0002
Structure FP-25 Structure FP-26
Figure imgf000047_0003
Structure FP-27 Structure FP-28
Figure imgf000047_0004
Structure FP-29 Structure FP-30
Figure imgf000048_0001
Structure FP-31 Structure FP-32
Figure imgf000048_0002
Structure FP-33 Structure FP-34
Figure imgf000048_0003
Structure FP-35 Structure FP-36
Figure imgf000048_0004
Structure FP-37 Structure FP-38
Figure imgf000049_0001
Structure FP-39 Structure FP-40
Figure imgf000049_0002
Structure FP-41 Structure FP-42
Figure imgf000049_0003
Structure FP-43 Structure FP-44
Figure imgf000049_0004
Structure FP-45 Structure FP-46
Figure imgf000050_0001
Structure FP-47 Structure FP-48
Figure imgf000050_0002
Structure FP-49 Structure FP-50
Figure imgf000050_0003
Structure FP-51 Structure FP-52
Figure imgf000050_0004
Structure FP-53 Structure FP-54
Figure imgf000051_0001
Structure FP-55 Structure FP-56
Figure imgf000051_0002
Structure FP-57 Structure FP-58
Figure imgf000051_0003
Structure FP-59 Structure FP-60
Figure imgf000051_0004
Structure FP-61 Structure FP-62
Figure imgf000052_0001
Structure FP-63 Structure FP-64
Figure imgf000052_0002
Structure FP-65 Structure FP-66
Figure imgf000052_0003
Structure FP-67 Structure FP-68
Figure imgf000052_0004
Figure imgf000052_0005
Structure FP-70
Figure imgf000053_0001
Structure FP-71 Structure FP-72
Figure imgf000053_0002
Structure FP-73 Structure FP-74
Figure imgf000053_0003
Structure FP-75 Structure FP-76
Figure imgf000053_0004
Structure FP-77 Structure FP-78
Figure imgf000054_0001
Structure FP-79 Structure FP-80
Figure imgf000054_0002
Structure FP-81 Structure FP-82
Figure imgf000054_0003
Structure FP-83 Structure FP-84
Figure imgf000054_0004
Structure FP-85 Structure FP-86
Figure imgf000055_0001
Structure F 1-1 Structure FI-2 Structure FI-3
Figure imgf000055_0002
Structure FI-4 Structure FI-5
Figure imgf000055_0003
Structure FI-6 Structure FI-7
Figure imgf000055_0004
Structure FI-8 Structure FI-9
Figure imgf000055_0005
Structure FI-10 Structure FI-11
Figure imgf000056_0001
Structure FI-12 Structure F I- 13
Figure imgf000056_0002
Structure FI-14 Structure FI-15
Figure imgf000056_0003
Structure FI-16 Structure FI-17
Figure imgf000056_0004
Structure FI-18 Structure FI-19
Figure imgf000056_0005
Structure FI-20 Structure FI-21
Figure imgf000057_0001
Structure FI-22 Structure FI-23
Figure imgf000057_0002
Structure FI-24 Structure FI-25
Figure imgf000057_0003
Structure FI-26 Structure F I -27
Figure imgf000057_0004
Structure FI-28 Structure F I -29
Figure imgf000057_0005
Structure FI-30 Structure FI-31
Figure imgf000058_0001
Structure FI-32 Structure FI-33
Figure imgf000058_0002
Structure FS-1 Structure FS-2
Figure imgf000058_0003
Structure FS-3 Structure FS-4
Figure imgf000058_0004
Structure FS-5 Structure FS-6
Figure imgf000058_0005
Structure FS-7 Structure FS-8
Figure imgf000059_0001
Structure FS-9 Structure FS-10
Figure imgf000059_0002
Structure FS-11 Structure FS-12 Structure FS-13
Figure imgf000059_0003
Structure FS-14 Structure FS-15 Structure FS-16
Figure imgf000059_0004
Structure FS-17 Structure FS-18
Figure imgf000060_0001
Structure FS-19 Structure FS-20
Figure imgf000060_0002
Structure FT-1 Structure FT-2 Structure FT-3
Figure imgf000060_0003
Structure FT-4 Structure FT-5 Structure FT-6
Figure imgf000060_0004
Structure FT-7 Structure FT-8
Figure imgf000061_0001
Structure FT-9 Structure FT-10
Figure imgf000061_0002
Structure FT-11 Structure FT-12 Structure FT-13
Figure imgf000061_0003
Structure FT-14 Structure FT-15 Structure FT-16 including stereoisomers and pharmaceutically acceptable salts thereof, wherein: n, R5, R7, X5, X35Υ1, Y2, Y31, Y32, Y3, and Y4 are defined the same as supra;
L-31 is defined the same as Li as supra, L32 is defined the same as L2 as supra, L34 is defined the same as L4 as supra, in certain embodiments, -LrL4-L2- and -L3I-L34- L32- are independently selected from the group consisting of -O-, -X-, -O-X-, -N-X-, -S- X-, -X5-, -0-X5-, -N-X5-, -S-X5-, -0-X7-, -O-C(=O)-, -NH-C(=O)-, -C(=O)-, -C(=O)-O-, - C(O)-N-, and C(O)-X-;
X is selected from the group consisting of nothing, C(=O), OC(=O), CH2, CH, S, NH, NR6, and O;
Xe, X36 and X46 are independently selected from the group consisting of nothing, C(=O), C(=S), OC(=O), CH2, CH, S, O and NR5; and
X7 is selected from the group consisting of nothing, C(=O), C(=S), OC(=O), CH2, CH, S, O and NR5.
[0054] In certain embodiments, a functional unit of a HPP of a antimicrobial and antimicrobial-related compound comprises a moiety having a structure of Structure F-1 , Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38, Structure FP-39, Structure FP-40, Structure FP-41 , Structure FP-42, Structure FP-43, Structure FP-44, Structure FP-45, Structure FP-46, Structure FP-47, Structure FP-48, Structure FP-49, Structure FP-50, Structure FP-51 , Structure FP-52, Structure FP-53, Structure FP-54, Structure FP-55, Structure FP-56, Structure FP-57, Structure FP-58, Structure FP-59, Structure FP-60, Structure FP-61 , Structure FP-62, Structure FP-63, Structure FP-64, Structure FP-65, Structure FP-66, Structure FP-67, Structure FP-68, Structure FP-69, Structure FP-70, Structure FP-71 , Structure FP-72, Structure FP-73, Structure FP-74, Structure FP-75, Structure FP-76, Structure FP-77, Structure FP-78, Structure FP-79, Structure FP-80, Structure FP-81 , Structure FP-82, Structure FP-83, Structure FP-84, Structure FP-85, Structure FP-86, Structure FI-1 , Structure FI-2, Structure FI-3, Structure FI-4, Structure FI-5, Structure FI-6, Structure FI-7, Structure FI-8, Structure FI-9, Structure FI-10, Structure FI-11 , Structure FI-12, Structure FI-13, Structure FI-14, Structure FI-15, Structure FI-16, Structure FI-17, Structure FI-18, Structure FI-19, Structure FI-20, Structure FI-21 , Structure FI-22, Structure FI-23, Structure FI-24, Structure FI-25, Structure FI-26, Structure FI-27, Structure FI-28, Structure FI-29, Structure FI-30, Structure FI-31 , Structure FI-32, Structure FI-33, Structure FS-1 , Structure FS-2, Structure FS-3, Structure FS-4, Structure FS-5, Structure FS-6, Structure FS-7, Structure FS-8, Structure FS-9, Structure FS-10, Structure FS-11 , Structure FS-12, Structure FS-13, Structure FS-14, Structure FS-15, Structure FS-16, Structure FS-17, Structure FS-18, Structure FS-19, Structure FS-20, Structure FT-1 , Structure FT-2, Structure FT-3, Structure FT-4, Structure FT-5, Structure FT-6, Structure FT-7, Structure FT-8, Structure FT-9, Structure FT-10, Structure FT-11 , Structure FT-12, Structure FT-13, Structure FT-14, Structure FT-15, and Structure FT-16 as defined supra, including stereoisomers and pharmaceutically acceptable salts thereof, wherein: m = O, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, ...; n = 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, ...;
Ri is selected from the group consisting of H, C1-C20 alkyl, C1-C20 alkyloxyl, d- C2O alkenyl, CrC20 alkynyl, aryl, and heteroaryl;
R2 is selected from the group consisting of H, CrC20 alkyl, CrC20 alkyloxy, Cr C20 alkenyl, CrC20 alkynyl, aryl, and heteroaryl residues;
R3 is selected from the group consisting of H, CrC20 alkyl, CrC20 alkyloxy, d- C20 alkenyl, CrC20 alkynyl, aryl and heteroaryl residues;
R5 and R35 are independently selected from the group consisting of H, - C(O)NH2, CH2CH2OR6, CH2CH2N(CHa)2, CH2CH2N(CH2CHa)2, CH2CH2OR6, Cl, F, Br, I, CrC20 alkyl, CrC20 cycloalkyl, CrC20 alkyloxyl, CrC20 cycloalkyloxyl, CrC20 alkenyl, CrC20 cycloalkenyl, CrC20 cycloalkynyl, CrC20 alkynyl, aryl, heteroaryl, C(=O)-W, and W;
R6, R36 and R46 are independently selected from the group consisting of H, F, Cl, Br, I, Na+, K+, C(=O)R5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1 H-inden- 5-yl, 4-hydroxy-1 ,5-naphthyridin-3-yl, C1-C12 Ikyl, C1-C12 cycloalkyl, C1-C12 alkyloxyl, C1- C12 cycloalkyloxyl, C1-C12 alkenyl, C1-C12 cycloalkenyl, C1-C12 cycloalkynyl, C1-C12 alkynyl, aryl, heteroaryl, C(=0)-W, and W;
R7 and R37 are independently selected from the group consisting of 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, C1-C20 alkyl, C1-C20 alkyloxyl, C1-C20 alkenyl, C1-C20 alkynyl, aryl, heteroaryl, C(=0)-W, and W;
R8 and R38 are independently selected from the group consisting of H, F, Cl, Br, I, CH3, C2H5, CF3, CH2CH2F, CH2CH2CI, CH2CH2Br, CH2CH2I, CH2CHF2, CH2CF3, CH2F1 CH2CI, 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;
X2 is selected from the group consisting of 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, C1-8 alkyl, C1-8 alkylthio, C1-8 alkylamino, and C1-8 alkyloxyl;
X3 is selected from the group consisting of nothing, H, N3, SO3W, F, Cl, Br, OH, OCH3, OR6, CH3, R6, C(O)OW, OW, and I;
X4 is selected from the group consisting of nothing, N, CH, and CY1;
X5 and X35 are independently selected from the group consisting of nothing, C(O), C(=S), OC(O), CH2, CH, S, O and NR5; each Y1, Y31, Y2, Y32, Y3, and Y4 are independently selected from the group consisting of 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, CH3SO3, R6SO3, NO2, CN, CF3, OCF3, CHOHC(O)NHCH2C(O)0W, 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, L34 and W are defined the same as supra; and any CH2 groups may be replaced with O, S, NR6 or any other pharmaceutically acceptable groups . [0055] As used herein, the term "pharmaceutically acceptable salt" means those salts of compounds of the invention that are safe for application in a subject. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1 ,11- methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review on pharmaceutically acceptable salts see BERGE ET AL., 66 J. PHARM. SCI. 1 - 19 (1 977), incorporated herein by reference.
[0056] As used herein, unless specified otherwise, the term "alkyl" means a branched or unbranched, saturated or unsaturated, monovalent or multivalent hydrocarbon group, including saturated alkyl groups, alkenyl groups and alkynyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene and dodecylene. In certain embodiments, the hydrocarbon group contains 1 to 30 carbons. In certain embodiments, the hydrocarbon group contains 1 to 20 carbons. In certain embodiments, the hydrocarbon group contains 1 to 12 carbons.
[0057] As used herein, unless specified otherwise, the term "cycloalkyl" means an alkyl which contains at least one ring and no aromatic rings. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In certain embodiments, the hydrocarbon chain contains 1 to 30 carbons. In certain embodiments, the hydrocarbon group contains 1 to 20 carbons. In certain embodiments, the hydrocarbon group contains 1 to 12 carbons.
[0058] As used herein, unless specified otherwise, the term "heterocycloalkyl" means a cycloalkyl wherein at least one ring atom is a non-carbon atom. Examples of the non-carbon ring atom include, but are not limited to, S, O and N.
[0059] As used herein, unless specified otherwise, the term "alkoxyl" means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more oxygen atoms. Examples of alkoxyl include, but are not limited to, -CH2-OH, -OCH3, -O-Re, -Re-OH, - Rei-O-Re2-, wherein Re, Rei and RΘ2 can be the same or different alkyl, cycloalkyl or heterocycloalkyl.
[0060] As used herein, unless specified otherwise, the term "alkyl halide" means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more halogen atoms, wherein the halogen atoms can be the same or different. The term "halogen" means fluorine, chlorine, bromine or iodine. Examples of alkyl halide include, but are not limited to, -Re-F, -Re-CI, -Re-Br, -Re-I, -Re(F)-, -Re(CI)-, -Re(Br)- and -Re(l)-, wherein Re is an alkyl, cycloalkyl or heterocycloalkyl.
[0061 ] As used herein, unless specified otherwise, the term "alkylthio" means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more sulfur atoms. Examples of alkylthio include, but are not limited to, -CH2-SH, -SCH3, -S-Re, -Re-SH, - Rei-S-Re2-, wherein Re, Rei and RΘ2 are the same or different alkyl, cycloalkyl or heterocycloalkyl.
[0062] As used herein, unless specified otherwise, the term "alkylamino" means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more nitrogen atoms. Examples of alkylamino include, but are not limited to, -CH2-NH, -NCH3, - N(Rei)-Re2, -N-Re, -Re-NH2, -R61-N-Re2 and -Re-N(Rei )-Rθ2 wherein Re, Rei and Re2 are the same or different alkyl, cycloalkyl or heterocycloalkyl.
[0063] As used herein, unless specified otherwise, the term "alkylcarbonyl" means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more carbonyl groups. Examples of alkylcarbonyl group include, but are not limited to, aldehyde group (-Re-C(O)-H), ketone group (-Re-C(O)-Rei), carboxylic acid group (Re-C(=O)OH), ester group (-Re-C(=O)O-Rei), carboxamide, (-Re-C(=O)O-N(Rei)Re2), enone group (-Re- C(O)-C(ReI )=C(Re2)Re3), acyl halide group (-Re-C(O)-Xh) and acid anhydride group (-Re- C(O)-O-C(O)-ReI ), wherein Re, Rei, Re2 and Rθ3 are the same or different alkyl, cycloalkyl, or heterocycloalkyl; and Xh is a halogen.
[0064] As used herein, unless specified otherwise, the term "perfluoroalkyl" means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more fluoro group, including, without limitation, perfluoromethyl, perfluoroethyl, perfluoropropyl.
[0065] As used herein, unless specified otherwise, the term "aryl" means a chemical structure comprising one or more aromatic rings. In certain embodiments, the ring atoms are all carbon. In certain embodiments, one or more ring atoms are non- carbon, e.g. oxygen, nitrogen, or sulfur ("heteroaryl"). Examples of aryl include, without limitation, phenyl, benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyhdazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl, furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl, thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxolyl, quanidino and benzothiazolyl.
[0066] In certain embodiments, a transportational unit of a HPP comprises a protonatable amine group that is capable of facilitating the transportation or crossing of the HPP through one or more biological barriers (e.g., > about 20 times, > about 50 times, > about 100 times, > about 300 times, > about 500 times, > about 1 ,000 times faster than the parent drug). In certain embodiments, the protonatable amine group is substantially protonated at a physiological pH. In certain embodiments, the amine group can be reversibly protonated. In certain embodiments, a transportational unit may or may not be cleaved from the functional unit after the penetration of HPP through one or more biological barriers. In certain embodiments, a functional unit may also contain one or more transportational units, especially for antimicrobials and antimicrobial-related compounds that have at least a free amino group. [0067] In certain embodiments, the protonatable amine group is selected from the group consisting of pharmaceutically acceptable substituted and unsubstituted primary amine groups, pharmaceutically acceptable substituted and unsubstituted secondary amine groups, and pharmaceutically acceptable substituted and unsubstituted tertiary amine groups.
[0068] In certain embodiments, the protonatable amine group is selected from the group consisting of pharmaceutically acceptable substituted and unsubstituted primary amine groups, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18 as defined supra, including stereoisomers and pharmaceutically acceptable salts thereof.
[0069] In certain embodiments, a linker covalently linking a functional unit and a transportational unit of a HPP comprises a bond that is capable of being cleaved after the HPP penetrates across one or more BBs. The cleavable bond comprises, for example, a covalent bond, an ether, thioether, amide, ester, thioester, carbonate, carbamate, phosphate or oxime bond.
[0070] In certain embodiments, a HPP of a antimicrobials and antimicrobial- related compound has the following Structure L-1 :
Figure imgf000068_0001
Structure L-1
including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
F is a functional unit of a HPP of an antimicrobial or antimicrobial-related compound. Examples of F include Structure F-1 , Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38, Structure FP-39, Structure FP-40, Structure FP-41 , Structure FP-42, Structure FP-43, Structure FP-44, Structure FP-45, Structure FP-46, Structure FP-47, Structure FP-48, Structure FP-49, Structure FP-50, Structure FP-51 , Structure FP-52, Structure FP-53, Structure FP-54, Structure FP-55, Structure FP-56, Structure FP-57, Structure FP-58, Structure FP-59, Structure FP-60, Structure FP-61 , Structure FP-62, Structure FP-63, Structure FP-64, Structure FP-65, Structure FP-66, Structure FP-67, Structure FP-68, Structure FP-69, Structure FP-70, Structure FP-71 , Structure FP-72, Structure FP-73, Structure FP-74, Structure FP-75, Structure FP-76, Structure FP-77, Structure FP-78, Structure FP-79, Structure FP-80, Structure FP-81 , Structure FP-82, Structure FP-83, Structure FP-84, Structure FP-85, Structure FP-86, Structure FI-1 , Structure FI-2, Structure FI-3, Structure FI-4, Structure FI-5, Structure FI-6, Structure Fl- 7, Structure FI-8, Structure FI-9, Structure FI-10, Structure FI-11 , Structure FI-12, Structure FI-13, Structure FI-14, Structure FI-15, Structure FI-16, Structure FI-17, Structure FI-18, Structure FI-19, Structure FI-20, Structure FI-21 , Structure FI-22, Structure FI-23, Structure FI-24, Structure FI-25, Structure FI-26, Structure FI-27, Structure FI-28, Structure FI-29, Structure FI-30, Structure FI-31 , Structure FI-32, Structure FI-33, Structure FS-1 , Structure FS-2, Structure FS-3, Structure FS-4, Structure FS-5, Structure FS-6, Structure FS-7, Structure FS-8, Structure FS-9, Structure FS-10, Structure FS-11 , Structure FS-12, Structure FS-13, Structure FS-14, Structure FS-15, Structure FS-16, Structure FS-17, Structure FS-18, Structure FS-19, Structure FS-20, Structure FT-1 , Structure FT-2, Structure FT-3, Structure FT-4, Structure FT-5, Structure FT-6, Structure FT-7, Structure FT-8, Structure FT-9, Structure FT-10, Structure FT-11 , Structure FT-12, Structure FT-13, Structure FT-14, Structure FT-15, and Structure FT-16 as defined supra;
T is a transportational unit of a HPP of an antimicrobial or antimicrobial-related compound. For example, T is selected from the group consisting of the protonatable amine group, pharmaceutically acceptable substituted and unsubstituted primary amine groups, pharmaceutically acceptable substituted and unsubstituted secondary amine groups, and pharmaceutically acceptable substituted and unsubstituted tertiary amine groups, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18 as defined supra; and
L1, L31, L2, L32, L4, and L34 are defined the same as supra, in certain embodiments, -L1-L4-L2- and -L31-L34-L32- are independently selected from the group consisting of -0-, -X-, -0-X-, -N-X-, -S-X-, -X5-, -0-X5-, -N-X5-, -S-X5-, -0-X7-, -O-C(=O)-, -NH-C(=O)-, -C(=O)-, -C(=O)-O-, -C(=O)-N-, and C(=O)-X- wherein X, X5 and X7 are defined the same as supra.
[0071] In certain embodiments, a HPP or HPC of antimicrobial or antimicrobial- related compound comprises a structure selected from the group consisting of Structure P-1 , Structure P-2, Structure P-3, Structure P-4, Structure P-5, Structure P-6, Structure P-7, Structure P-8, Structure P-9, Structure P-10, Structure P-11 , Structure P-12, Structure P-13, Structure P-14, Structure P-15, Structure P-16, Structure P-17, Structure P-18, Structure P-19, Structure P-20, Structure P-21 , Structure P-22, Structure P-23, Structure P-24, Structure P-25, Structure P-26, Structure P-27, Structure P-28, Structure P-29, Structure P-30, Structure P-31 , Structure P-32, Structure P-33, Structure P-34, Structure P-35, Structure P-36, Structure P-37, Structure P-38, Structure P-39, Structure P-40, Structure P-41 , Structure P-42, Structure P-43, Structure P-44, Structure P-45, Structure P-46, Structure P-47, Structure P-48, Structure P-49, Structure P-50, Structure P-51 , Structure P-52, Structure P-53, Structure P-54, Structure P-55, Structure P-56, Structure P-57, Structure P-58, Structure P-59, Structure P-60, Structure P-61 , Structure P-62, Structure P-63, Structure P-64, Structure P-65, Structure P-66, Structure P-67, Structure P-68, Structure P-69, Structure P-70, Structure P-71 , Structure P-72, Structure P-73, Structure P-74, Structure P-75, Structure P-76, Structure P-77, Structure P-78, Structure P-79, Structure P-80, Structure P-81 , Structure P-82, Structure P-83, Structure P-84, Structure P-85, Structure P-86, Structure 1-1 , Structure I-2, Structure I-3, Structure I-4, Structure I-5, Structure I-6, Structure I-7, Structure I-8, Structure 1-9, Structure 1-10, Structure 1-11 , Structure 1-12, Structure 1-13, Structure 1-14, Structure 1-15, Structure 1-16, Structure 1-17, Structure 1-18, Structure 1-19, Structure I- 20, Structure 1-21 , Structure I-22, Structure I-23, Structure I-24, Structure I-25, Structure I-26, Structure I-27, Structure I-28, Structure I-29, Structure I-30, Structure 1-31 , Structure I-32, Structure I-33, Structure S-1 , Structure S-2, Structure S-3, Structure S-4, Structure S-5, Structure S-6, Structure S-7, Structure S-8, Structure S-9, Structure S-10, Structure S-11 , Structure S-12, Structure S-13, Structure S-14, Structure S-15, Structure S-16, Structure S-17, Structure S-18, Structure S-19, Structure S-20, Structure T-1 , Structure T-2, Structure T-3, Structure T-4, Structure T-5, Structure T-6, Structure T-7, Structure T-8, Structure T-9, Structure T-10, Structure T-11 , Structure T- 12, Structure T-13, Structure T-14, Structure T-15, and Structure T-16:
Attorney Docket No. 68961.8021.WOOO
Figure imgf000072_0001
Structure P- 1 Structure P-2
Figure imgf000072_0002
Structure P-3 Structure P-4
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Figure imgf000073_0001
Structure P-5 Structure P-6
Figure imgf000073_0002
Structure P-7 Structure P-8
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Figure imgf000074_0001
Structure P-9 Structure P-10
Figure imgf000074_0002
Structure P- 11 Structure P-12
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Figure imgf000075_0001
Structure P-13 Structure P-14
Figure imgf000075_0002
Structure P-15 Structure P-16
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Figure imgf000076_0001
Structure P-17 Structure P-18
Figure imgf000076_0002
Structure P-19 Structure P-20
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Figure imgf000077_0001
Structure P-21 Structure P-22
Figure imgf000077_0002
Structure P-23 Structure P-24
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Figure imgf000078_0001
Structure P-25 Structure P-26
Figure imgf000078_0002
Structure P-27 Structure P-28
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Figure imgf000079_0001
Structure P-29 Structure P-30
Figure imgf000079_0002
Structure P-31 Structure P-32
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Figure imgf000080_0001
Structure P-33 Structure P-34
Figure imgf000080_0002
Structure P-35 Structure P-36
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Figure imgf000081_0001
Structure P-37 Structure P-38
Figure imgf000081_0002
Structure P-39 Structure P-40
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Figure imgf000082_0001
Structure P-41 Structure P-42
Figure imgf000082_0002
Structure P-43 Structure P-44
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Figure imgf000083_0001
Structure P-45 Structure P-46
Figure imgf000083_0002
Structure P-47 Structure P-48
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Figure imgf000084_0001
Structure P-49 Structure P-50
Figure imgf000084_0002
Structure P-51 Structure P-52
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Figure imgf000085_0001
Structure P-53 Structure P-54
Figure imgf000085_0002
Structure P-55 Structure P-56
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Figure imgf000086_0001
Structure P-57 Structure P-58
Figure imgf000086_0002
Structure P-59 Structure P-60
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Figure imgf000087_0001
Structure P-61 Structure P-62
00
Figure imgf000087_0002
Structure P-64 Structure P-64
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Figure imgf000088_0001
Structure P-65 Structure P-66
Figure imgf000088_0002
Structure P-67 Structure P-68
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Figure imgf000089_0001
Structure P-69 Structure P-70
Figure imgf000089_0002
Structure P-71 Structure P-72
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Figure imgf000090_0001
Structure P-73 Structure P-74
00
Figure imgf000090_0002
Structure P-75 Structure P-76
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Figure imgf000091_0001
Structure P-77 Structure P-78
Figure imgf000091_0002
Structure P-79 Structure P-80
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Figure imgf000092_0001
VO
Structure P-81 Structure P-82
Figure imgf000092_0002
Structure P-83 Structure P-84
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Figure imgf000093_0001
Structure P-85 Structure P-86
Figure imgf000093_0002
Structure 1-1 Structure I-2 Structure I-3
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Figure imgf000094_0001
Structure I -4 Structure I-5
Figure imgf000094_0002
Structure I -6 Structure I-7
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Figure imgf000095_0001
Structure I -8 Structure I-90
Figure imgf000095_0002
Structure 1-10 Structure 1-11
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Figure imgf000096_0001
Structure 1-12 Structure 1-13
Figure imgf000096_0002
Structure 1-14 Structure 1-15
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Figure imgf000097_0001
Structure 1-16 Structure 1-17
Figure imgf000097_0002
Structure 1-18 Structure 1-19
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Figure imgf000098_0001
Structure I-20 Structure 1-21
Figure imgf000098_0002
Structure I -22 Structure 1-23
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Figure imgf000099_0001
Structure I -24 Structure I-25
Figure imgf000099_0002
Structure I-26 Structure I-27
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Figure imgf000100_0001
Structure I-28 Structure I-29
Figure imgf000100_0002
Structure I-30 Structure 1-31
Figure imgf000100_0003
Structure I -32 Structure I-33
Attorney Docket No. 68961 .8021.WOOO
Figure imgf000101_0001
Structure S- 1 Structure S-2
Figure imgf000101_0002
Structure S-3 Structure S-4
Figure imgf000101_0003
Structure S-5 Structure S-6
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Figure imgf000102_0001
Structure S-7 Structure S-8
Figure imgf000102_0002
Structure S-9 Structure S-10
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Figure imgf000103_0001
Structure S-11 Structure S-12 Structure S-13
Figure imgf000103_0002
Structure S-14 Structure S-15 Structure S-16
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Figure imgf000104_0001
Structure S-17 Structure S- 18
Figure imgf000104_0002
Structure S-19 Structure S-20
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Figure imgf000105_0001
Structure T- 1 Structure T-2
Figure imgf000105_0003
Figure imgf000105_0002
Structure T-4 Structure T-5 Structure T-6
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Figure imgf000106_0001
Structure T-7 Structure T-8
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Figure imgf000107_0001
Structure T-9 Structure T- 10
Figure imgf000107_0002
Structure T- 11 Structure T-12 Structure T-13
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Figure imgf000108_0001
Structure T-14 Structure T-15 Structure T-16
O
including stereoisomers and pharmaceutically acceptable salts thereof, wherein: m, n, Ri , R2, R5, R35, RΘ, R36, R46, R7, Re, R38, T, W, X, X2, X4, X5, X35, XΘ, X36,
X46, X7, Yi , Y2, Y31 , Y32, Y3, Y4, Z, AA, HA, R, R8, and Rn-R16are defined the same as supra.
II. Pharmaceutical compositions comprising HPPs
[0072] Another aspect of the invention relates to a pharmaceutical composition comprising at least one HPP of an antimicrobial or antimicrobial-related compound and a pharmaceutically acceptable carrier.
[0073] The term "pharmaceutically acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a HPP from one location, body fluid, tissue, organ (interior or exterior), or portion of the body, to another location, body fluid, tissue, organ, or portion of the body.
[0074] Each carrier is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients, e.g., a HPP, of the formulation and suitable for use in contact with the tissue or organ of a biological system without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
[0075] Some examples of materials which can serve as pharmaceutically- acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) alcohol, such as ethyl alcohol and propane alcohol; (20) phosphate buffer solutions; and (21 ) other non-toxic compatible substances employed in pharmaceutical formulations such as acetone.
[0076] The pharmaceutical compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
[0077] In one embodiment, the pharmaceutically acceptable carrier is an aqueous carrier, e.g. buffered saline and the like. In certain embodiments, the pharmaceutically acceptable carrier is a polar solvent, e.g. acetone and alcohol.
[0078] The concentration of HPP in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the biological system's needs. For example, the concentration can be 0.0001 % to 100%, 0.001 % to 50%, 0.01 % to 30%, 0.1 % to 20%, 1 % to 10% wt.
[0079] The compositions of the invention can be administered for prophylactic, therapeutic, and/or hygienic use. Such administration can be topical, mucosal, e.g., oral, nasal, vaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, via inhalation, ophthalmic and other convenient routes. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration. For example, unit dosage forms suitable for oral administration include powder, tablets, pills, capsules and lozenges and for transdermal administration include solution, suspension and gel.
[0080] Thus, a typical pharmaceutical composition for transdermal, oral, and intravenous administrations would be about 10~10 g to about 100 g, about 10~10 g to about 10~3 g, about 10~9 g to about 10~6 g, about 10~6 g to about 100 g, about 0.001 g to about 100 g, about 0.01 g to about 10 g, or about 0.1 g to about 1 g per subject per day. Dosages from about 0.01 mg, up to about 100 g, per subject per day may be used. Actual methods for preparing parenterally administrable compositions will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington: The Science and Practice of Pharmacy 21st ed., Mack Publishing Company, Easton, Pa. (2005).
III. Applications of HPPs
i) Methods for penetrating a biological barrier.
[0081] Another aspect of the invention relates to a method of using a composition of the invention in penetrating one or more biological barriers in a biological subject. The method comprises a step of administering to a biological subject a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof. In certain embodiments, a HPP exhibits more than about 20 times or higher, 50 times or higher, > about 100 times or higher, > about 200 time higher, >about 300 times or higher, >about 500 times or higher, >about 1 ,000 times or higher penetration rate through one or more biological barriers than its parent drug.
[0082] The term "biological barrier" as used herein refers to a biological layer that separates an environment into different spatial areas or compartments, which separation is capable of modulating (e.g. restricting, limiting, enhancing or taking no action in) the passing through, penetrating or translocation of substance or matter from one compartment/area to another. The different spatial areas or compartments as referred to herein may have the same or different chemical or biological environment(s). The biological layer as referred herein includes, but is not limited to, a biological membrane, a cell layer, a biological structure, an inner surface of subjects, organisms, organs or body cavities, an external surface of subjects, organisms, organs or body cavities, or any combination or plurality thereof.
[0083] Examples of a biological membrane include a lipid bilayer structure, eukaryotic cell membrane, prokaryotic cell membrane, and intracellular membrane (e.g., nucleus or organelle membrane, such as membrane or envelope of Golgi apparatus, rough and smooth endoplasmic reticulum (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosome, nucleus, chloroplasts, plastids, peroxisomes or microbodies). [0084] The lipid bilayer referred to herein is a double layer of lipid-class molecules, including, but not limited to, phospholipids and cholesterol. In a particular embodiment, lipids for bilayer are amphiphilic molecules consisting of polar head groups and non- polar fatty acid tails. The bilayer is composed of two layers of lipids arranged so that their hydrocarbon tails face one another to form an oily core held together by the hydrophobic effect, while their charged heads face the aqueous solutions on either side of the membrane. In another particular embodiment, the lipid bilayer may contain one or more embedded protein and/or sugar molecule(s).
[0085] Examples of a cell layer include a lining of eukaryotic cells (e.g., epithelium, lamina propria and smooth muscle or muscularis mucosa (in gastrointestinal tract)), a lining of prokaryotic cells (e.g., surface layer or S-layer which refers to a two dimensional structure monomolecular layer composed of identical proteins or glycoproteins, specifically, an S-layer refers to a part of a cell envelope commonly found in bacteria and archaea), a biofilm (a structured community of microorganisms encapsulated within a self-developed polymeric matrix and adherent to a living or inert surface), and a plant cell layer (e.g., empidermis). The cells may be normal cells or pathological cells (e.g. disease cells, cancer cells).
[0086] Examples of biological structures include structures sealed by tight or occluding junctions that provide a barrier to the entry of toxins, bacteria and viruses, e.g. the blood milk barrier and the blood brain barrier (BBB). In particular, BBB is composed of an impermeable class of endothelium, which presents both a physical barrier through tight junctions adjoining neighboring endothelial cells and a transport barrier comprised of efflux transporters. The biological structure may also include a mixture of cells, proteins and sugars (e.g. blood clots).
[0087] Examples of the inner surface of subjects, organisms, organs or body cavities include buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa and endometrium (the mucosa of the uterus, inner layer of the wall of a pollen grain or the inner wall layer of a spore), or a combination or plurality thereof.
Ill [0088] Examples of the external surface of subjects, organisms, organs or body cavities include capillaries (e.g. capillaries in the heart tissue), mucous membranes that are continuous with skin (e.g. such as at the nostrils, the lips, the ears, the genital area, and the anus), outer surface of an organ (e.g. liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, anorectum and pruritus ani), skin, cuticle (e.g. dead layers of epidermal cells or keratinocytes or superficial layer of overlapping cells covering the hair shaft of an animal, a multi-layered structure outside the epidermis of many invertebrates, plant cuticles or polymers cutin and/or cutan), external layer of the wall of a pollen grain or the external wall layer of a spore), and a combination or plurality thereof.
[0089] In addition, a biological barrier further includes a sugar layer, a protein layer or any other biological layer, or a combination or plurality thereof. For example, skin is a biological barrier that has a plurality of biological layers. A skin comprises an epidermis layer (outer surface), a demis layer and a subcutaneous layer. The epidermis layer contains several layers including a basal cell layer, a spinous cell layer, a granular cell layer, and a stratum corneum. The cells in the epidermis are called keratinocytes. The stratum corneum ("horny layer") is the outmost layer of the epidermis, wherein cells here are flat and scale-like ("squamous") in shape. These cells contain a lot of keratin and are arranged in overlapping layers that impart a tough and oilproof and waterproof character to the skin's surface.
H) Methods for diagnosing a condition in a biological system.
[0090] Another aspect of the invention relates to a method of using a composition of the invention in diagnosing a condition in a biological system. The method comprises the following steps:
1 ) administrating a composition comprising a HPP of an antimicrobial or antimicrobial-related compound to the biological subject;
2) detecting the presence, location or amount of the HPP, the functional unit of the HPP or a metabolite thereof in the biological subject; and
3) determining a condition in the biological system. [0091] In certain embodiments, the HPP (or the agent cleaved from the HPP) aggregates in the site of action where a condition occurs. In certain embodiments, the presence, location or amount of the functional unit of the HPP is also detected. In certain embodiments, the onset, development, progress, or remission of a condition (e.g., infection) associated is also determined.
[0092] In certain embodiments, the HPP is labeled with or conjugated to a detectable agent. Alternatively, the HPP is prepared to include radioisotopes for detection. Numerous detectable agents are available which can be generally grouped into the following categories:
(a) Radioisotopes, such as 35S, 14C, 13C, 15N, 125I, 3H, and 131I. The diagnostic agent can be labeled with the radioisotope using the techniques known in the art and radioactivity can be measured using scintillation counting; in addition, the diagnostic agent can be spin labeled for electron paramagnetic resonance for carbon and nitrogen labeling.
(b) Fluorescent agents such as BODIPY, BODIPY analogs, rare earth chelates (europium chelates), fluorescein and its derivatives, FITC, 5,6 carboxyfluorescein, rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin, green fluorescent protein, yellow fluorescent protein, red fluorescent protein and Texas Red. Fluorescence can be quantified using a fluorometer.
(c) Various enzyme-substrate agents, such luciferases (e.g., firefly luciferase and bacterial luciferase), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase, β- galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like. Examples of enzyme-substrate combinations include, for example: (i) Horseradish peroxidase (HRPO) with hydrogen peroxidase as a substrate, wherein the hydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylene diamine (OPD) or 3, 3', 5,5'- tetramethyl benzidine hydrochloride (TMB)); (ii) alkaline phosphatase (AP) with para- Nitrophenyl phosphate as chromogenic substrate; and (iii) β-D-galactosidase (β -D-GaI) with a chromogenic substrate (e.g., p-nitrophenyl- β-D-galactosidase) or fluorogenic substrate 4-methylumbelliferyl- β- D-galactosidase.
[0093] In certain embodiments, the detectable agent is not necessarily conjugated to the diagnostic agent but is capable of recognizing the presence of the diagnostic agent and the diagnostic agent can be detected.
[0094] In certain embodiments, the HPP of the invention can be provided in a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing the diagnostic assay. Where the HPP is labeled with an enzyme, the kit will include substrates and cofactors required by the enzyme (e.g., a substrate precursor which provides the detectable chromophore or fluorophore). In addition, other additives may be included such as stabilizers, buffers (e.g., a block buffer or lysis buffer) and the like. The relative amounts of the various reagents may be varied widely to provide for concentrations in solution of the reagents which substantially optimize the sensitivity of the assay. Particularly, the reagents may be provided as dry powders, usually lyophilized, including excipients which on dissolution will provide a reagent solution having the appropriate concentration.
Hi) Methods for screening a substance for a desired character
[0095] Another aspect of the invention relates to a method of screening a HPP for a desired character.
[0096] In certain embodiments, the method comprises: covalently linking a test functional unit to a transportational unit through a linker to form a test composition (or covalently linking a functional unit to a test transportational unit through a linker, or covalently linking a functional unit to a transportational unit through a test linker)
2) administrating the test composition to a biological system; and
3) determining whether the test composition has the desired nature or character.
[0097] In one embodiment, a desired character may include, for example, 1 ) the ability of a test functional unit to form a high penetration composition or convert back to a parent drug, 2) the penetration ability and/or rate of a test composition, 3) the efficiency and/or efficacy of a test composition, 4) the transportational ability of a test transportational unit, and 5) the cleavability of a test linker.
iv) Methods for treating a condition in a biological subject
[0098] Another aspect of the invention relates to a method of using a composition of the invention in treating a condition in a biological system. The method comprises administrating the pharmaceutical composition to the biological system.
[0099] The term "treating" as used herein means curing, alleviating, inhibiting, or preventing. The term "treat" as used herein means cure, alleviate, inhibit, or prevent. The term "treatment" as used herein means cure, alleviation, inhibition or prevention.
[00100] The term "biological system," "biological subject" or "subject" as used herein means an organ, a group of organs that work together to perform a certain task, an organism, or a group of organisms. The term "organism" as used herein means an assembly of molecules that function as a more or less stable whole and has the properties of life, such as animal, plant, fungus, or micro-organism.
[00101] The term "animal" as used herein means a eukaryotic organism characterized by voluntary movement. Examples of animals include, without limitation, vertebrata (e.g. human, mammals, birds, reptiles, amphibians, fishes, marsipobranchiata and leptocardia), tunicata (e.g. thaliacea, appendiculaha, sorberacea and ascidioidea), articulata (e.g. insecta, myriapoda, malacapoda, arachnida, pycnogonida, merostomata, Crustacea and annelida), gehyrea (anarthropoda), and helminthes (e.g. rotifera).
[00102] The term "plant" as used herein means organisms belonging to the kindom Plantae. Examples of plant include, without limitation, seed plants, bryophytes, ferns and fern allies. Examples of seed plants include, without limitation, cycads, ginkgo, conifers, gnetophytes, angiosperms. Examples of bryophytes include, without limitation, liverworts, hornworts and mosses. Examples of ferns include, without limitation, ophioglossales (e.g. adders-tongues, moonworts, and grape-ferns), marattiaceae and leptosporangiate ferns. Examples of fern allies include, without limitation, lycopsida (e.g. clubmosses, spikemosses and quillworts), psilotaceae (e.g. lycopodiophyta and whisk ferns) and equisetaceae (e.g. horsetails).
[00103] The term "fungus" as used herein means a eukaryotic organism that is a member of the kingdom Fungi. Examples of fungus include, without limitation, chytrids, blastocladiomycota, neocallimastigomycota, zygomycota, glomeromycota, ascomycota and basidiomycota.
[00104] The term "microorganism" as used herein means an organism that is microscopic (e.g. with length scale of micrometer). Examples of microorganism include, without limitation, bacteria, fungi, archaea, protists and microscopic plants (e.g. green algae) and microscopic animals (e.g. plankton, planarian and amoeba).
[00105] Some examples of the conditions the method can treat include conditions that can be treated by the parent drug of the HPP.
v). Methods of using HPPs of antimicrobials and antimicrobial-related compounds and pharmaceutical compositions thereof in treatments.
[00106] Another aspect of the invention relates to a method of using HPPs of antimicrobials or antimicrobial-related compounds, or pharmaceutical compositions thereof in treating a condition in a biological system or subject by administrating a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof to the biological system or subject.
[00107] Antimicrobials and antimicrobial-related compounds can be used to regulate a wide range of biological processes in a biological system. Conditions that are related to such biological processes are treatable by the corresponding antimicrobials or antimicrobial-related compounds, and therefore treatable by HPPs/HPCs of the antimicrobials or antimicrobial-related compounds, and a pharmaceutical composition thereof.
[00108] Such conditions include, but are not limited to, pain, injuries and microorganism related conditions. Microoranism related conditions are conditions that are caused by microorganisms such as bacteria, fungi, protozoans and viruses. For example, conditions caused by bacteria (bacteria-related conditions), conditions caused by protozoa (protozoa-related conditions), conditions caused by fungi (fungi-related conditions) and conditions caused by virus (virus-related conditions).
[00109] Bacteria-related conditions include, for example, infections (e.g. infection condition in an organ such as liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, anorectum and pruritus ani, respiratory infections, upper respiratory tract infections, urinary tract infections, nosocomial infections, pseudomonas infection, Coagulase-positive staphylococcal infections (e.g. skin infection, toxinoses, acute infective endocarditis, septicemia, necrotizing pneumonia), infections of implanted prostheses, opportunistic infections with septicemia and pneumonia), plague (e.g. bubonic plague and pneumonic plague), anthrax (e.g. cutaneous anthrax, pulmonary anthrax and gastrointestinal antrax), lyme diseases, brucellosis, whooping cough, acute enteritis, respiratory infection, psittacosis, nongonococcal urethritis, trachoma, inclusion conjunctivitis of the newborn, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, diarrhea, meningitis in infants, hemorrhagic colitis, hemolytic-uremic syndrome, tularemia, pneumonia, bronchitis, peptic ulcer, legionnaire's disease, Pontiac fever, leptospirosis, listeriosis, leprosy, turberculosis, mycoplasma pneumonia, gonorrhea, ophthalmia neonatorum, septic arthritis, meningococcal disease, waterhouse-friderichsen syndrome, Rocky mountain spotted fever, typhoid fever type salmonellosis, salmonellosis with gastroenteritis and enterocolitis, bacillary dysentery/shigellosis, cystitis, meningitis and septicemia, endometritis, otitis media, sinusitis, syphilis, necrotizing fasciitis, streptococcal pharyngitis, scarlet fever, rheumatic fever, impetigo, erysipelas, puerperal fever, and cholera.
[00110] Protozoa related conditions include, for example, malaria, sleeping sickness, and toxoplasmosis.
[00111] Fungi related conditions include, for example, aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, histoplasmosis, paracoccidiomycosis, sporotrichosis, and zygomycosis. [00112] Virus related conditions include, for example, influenza, yellow fever and
AIDS.
[00113] In certain embodiments, a method of treating a condition in a subject amelioratable or treatable with antimicrobials or antimicrobial-related compounds comprises administering a therapeutic effective amount of a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof to the subject.
[00114] A HPP or a pharmaceutical composition thereof can be administered to a biological system by any administration route known in the art, including without limitation, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteral administration. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration.
[00115] A parenteral administration refers to an administration route that typically relates to injection which includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intra cardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and/or intrasternal injection and/or infusion.
[00116] A HPP or a pharmaceutical composition thereof can be given to a subject in the form of formulations or preparations suitable for each administration route. The formulations useful in the methods of the invention include one or more HPPs, one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic ingredients. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. The amount of a HPP which can be combined with a carrier material to produce a pharmaceutically effective dose will generally be that amount of a HPP which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of the HPP, preferably from about 1 percent to about 20 percent. [00117] Methods of preparing these formulations or compositions include the step of bringing into association a HPP with one or more pharmaceutically acceptable carriers and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a HPP with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
[00118] Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non- aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a HPP as an active ingredient. A compound may also be administered as a bolus, electuary, or paste.
[00119] In solid dosage forms for oral administration (e. g., capsules, tablets, pills, dragees, powders, granules and the like), the HPP is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1 ) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarding agents, such as paraffin, (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [00120] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered antimicrobials or peptidomimetic moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of a HPP therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain pacifying agents and may be of a composition that they release the HPP(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The HPP can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
[00121] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the HPP, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
[00122] Suspensions, in addition to the HPP, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[00123] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more HPPs with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent. Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
[00124] Formulations for the topical or transdermal or epidermal or dermal administration of a HPP composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to the HPP composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the HPP composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. The best formulations for the topical or transdermal administration are pure water, solution, aqueous solution, ethanol and water solution, and isopropanol and water solution. [00125] A HPP or a pharmaceutical composition thereof can be alternatively administered by aerosol. This can be accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the HPPs. A nonaqueous (e. g., fluorocarbon propellant) suspension could be used. Sonic nebulizers can also be used. An aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
[00126] Transdermal patches can also be used to deliver HPP compositions to a target site. Such formulations can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the peptidomimetic across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the peptidomimetic in a polymer matrix or gel.
[00127] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
[00128] Formulations suitable for parenteral administration comprise a HPP in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacterostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
[00129] Examples of suitable aqueous and nonaqueous carriers which may be employed in the formulations suitable for parenteral administration include water, ethanol, polyols (e. g., such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[00130] Formulations suitable for parenteral administration may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[00131] Injectable depot forms are made by forming microencapsule matrices of a HPP or in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the HPP to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the HPP in liposomes or microemulsions which are compatible with body tissue.
[00132] In certain embodiments, a HPP of an antimicrobial or antimicrobial- related compound, or a pharmaceutical composition thereof is delivered to a disease or tumor action site in a therapeutically effective dose. As is known in the art of pharmacology, the precise amount of the pharmaceutically effective dose of a HPP that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon, for example, the activity, the particular nature, pharmacokinetics, pharmacodynamics, and bioavailability of a particular HPP, physiological condition of the subject (including race, age, sex, weight, diet, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), the nature of pharmaceutically acceptable carriers in a formulation, the route and frequency of administration being used, and the severity or propensity of a disease caused by pathogenic target microbial organisms, to name a few. However, the above guidelines can be used as the basis for fine-tuning the treatment, e. g., determining the optimum dose of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage. Remington: The Science and Practice of Pharmacy (Gennaro ed. 20.sup.th edition, Williams & Wilkins PA, USA) (2000).
IV. ADVANTAGES
[00133] Amtimicrobials (e.g. antibiotics) and antimicrobial-related compounds are often hydrophilic and are difficult to penetrate skin membrane barrier. When antimicrobials or antimicrobial-related compounds are taken orally, they may be inactivated by first pass metabolism. In the case of injection, administration of antimicrobials and amtimicrobial-related compounds is painful and may require frequent and costly office visits.
[00134] In certain embodiments, since a HPP or HPC of the invention is capable of crossing one or more biological barriers, the HPP or HPC can be administered locally (e.g., topically or transdermally) to reach a location where a condition occurs without the necessity of a systematic administration (e.g., oral or parenteral administration). A local administration and penetration of a HPP or HPC allows the HPP or HPC to reach the same level of local concentration of an agent or drug with much less amount or dosage of HPP or HPC in comparison to a systematic administration of a parent agent or drug; alternatively, a higher level of local concentration which may not be afforded in the systematic administration, or if possible, requires significantly higher dosage of an agent in the systematic administration. The high local concentration of the HPP/HPC or its parent agent if being cleaved enables the treatment of a condition more effectively or much faster than a systematically delivered parent agent and the treatment of new conditions that may not be previously possible or observed. The local administration of the HPP or HPC may allow a biological subject to reduce potential suffering from a systemic administration, e.g., adverse reactions associated with the systematic exposure to the agent, gastrointestinal/renal effects. Additionally, the local administration may allow the HPP or HPC to cross a plurality of biological barriers and reach systematically through, for example, general circulation and thus avoid the needs for systematic administration (e.g., injection) and obviate the pain associated with the parenteral injection.
[00135] In certain embodiments, a HPP/HPC or a pharmaceutical composition according to the invention can be administered systematically (e.g., orally or parenterally). The HPP/HPC or the active agent (e.g., drug or metabolite) of the HPP/HPC may enter the general circulation with a faster rate than the parent agent and gain faster access to the action site a condition. Additionally, the HPP/HPC can cross a biological barrier (e.g., blood brain barrier and blood milk barrier) which has not been penetrated if a parent agent is administered alone and thus offer novel treatment of conditions that may not be previously possible or observed.
[00136] For example, HPPs/HPCs of antimicrobials or antimicrobial-related compounds in the invention demonstrated high penetration rate through a biological barrier (e.g., > about 10 times, > about 50 times, >about 100 times, >about 200 times, >about 300 times, > about 1000 times higher than if the antimicrobials or antimicrobial- related compounds are administered alone). No or few adverse side effects were observed from the subjects that took antimicrobial HPP/HPC, while side effects (such as nausea) were observed from the subjects that took the parent antimicrobials at the similar dosage.
[00137] Along with the extensive use of antimicrobials, drug resistance has become a common and serious problem as the pathogens have mutated over time. The HPP/HPC or a pharmaceutical composition according to the invention can penetrate one or more biological barriers, such as biofilm, cell wall of bacteria, fungi and other microorganisms, at much higher rate and can overcome the drug resistance.
V. EXAMPLES
[00138] The following examples are provided to better illustrate the claimed invention and are not to be interpreted in any way as limiting the scope of the invention. All specific compositions, materials, and methods described below, in whole or in part, fall within the scope of the invention. These specific compositions, materials, and methods are not intended to limit the invention, but merely to illustrate specific embodiments falling within the scope of the invention. One skilled in the art may develop equivalent compositions, materials, and methods without the exercise of inventive capacity and without departing from the scope of the invention. It will be understood that many variations can be made in the procedures herein described while still remaining within the bounds of the invention. It is the intention of the inventors that such variations are included within the scope of the invention.
Example 1. Preparation of a HPP from a parent drug.
[00139] In certain embodiments, a parent compound having the following
Structure F-C:
Figure imgf000127_0001
Structure F-C
is converted to a HPP having Structure L-1 :
Figure imgf000127_0002
Structure L-1
including stereoisomers and pharmaceutically acceptable salts thereof, wherein: F, L1 , L2, and L4 are defined as supra;
T is a transportational unit of a HPP of an antimicrobial or antimicrobial-related compound. For example, T is selected from the group consisting of W and R6 as defined supra.
[00140] In certain embodiments of the invention, a HPP having Structure L-1 is prepared according to organic synthesis by reacting the parent compounds or derivatives of the parent compounds having Structure D (e.g. acid halides, mixed anhydrides of the parent compounds, etc.):
Figure imgf000128_0001
Structure D
with compounds of Structure E (Scheme 1 ):
T-L2-H
Structure E
wherein Wc is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy; and
F, l_i, L2, L4 and T are defined as supra.
Figure imgf000128_0002
Scheme 1. Preparation of a HPP from a parent compound (I).
[00141] In certain embodiments, a HPP having Structure L-1 is prepared following Scheme 1 as described supra, wherein L4 is C=O.
[00142] In certain embodiments, a parent compound having the following
Structure F:
Figure imgf000128_0003
Structure F-N
reacts with a compound having the following structure G:
WN\L/T
L2
Structure G to obtain a HPP of Structure L:
Figure imgf000129_0001
Structure L-1
including stereoisomers and pharmaceutically acceptable salts thereof, wherein: F, L1 , L2, and L4 are defined as supra;
T is a transportational unit of a HPP of an antimicrobial or antimicrobial-related compound. For example, T is selected from the group consisting of W and Re as defined supra; and
M is selected from the group consisting of Na, K, or other metal. WN is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy. (Scheme 2)
Figure imgf000129_0002
Scheme 2. Preparation of a HPP from a parent compound (II).
[00143] In certain embodiments, a HPP having a structure of Structure L-1 is prepared by organic synthesis wherein the unwanted reactive sites such as -C(=O)OH, - NH2, -OH, or -SH are protected before linking a transportational unit with a functional unit according to one of the synthetic route as described supra. In certain embodiments, the obtained protected HPP may be further partially or completely deprotected to render a partially protected HPP or an unprotected HPP respectively. Preparation of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl ester hydrochloride
[00144] 39 g of Penicillin V potassium was dissolved in 100 ml of acetonithle. 39 g of 2-Bromo-N,N-diethylethylamine. HBr in ethyl acetate was added into the reaction mixture. The mixture was stirred for 16 h at RT. 39 g (0.15 mol) of 2-Bromo-N,N- diethylethylamine.HBr and 30 g of sodium bicarbonate was added into the reaction mixture. The mixture was stirred for another 12 h at RT. The solid was removed by filtration. 3.5 g of HCI in 50 ml of ether was added into the reaction mixture with stirring. The solid product was collected by filtration. After drying, it yielded 38 g of the desired hygroscopic product (78.2%). Elementary analysis: C22H32CI N3O5S; MW: 486.0. Calculated % C: 54.37; H: 6.64; N: 8.65; Cl: 7.29; O: 16.46; S: 6.60; Found % C: 54.32; H: 6.68; N: 8.61 ; Cl: 7.32; O: 16.51 ; S: 6.56.
Preparation of 6-(2,6-dimethoxybenzamido)penicillinic acid 2-diethylaminoethyl ester hydrochloride
[00145] 38 g of 6-(2,6-dimethoxybenzamido)penicillinic acid was dissolved in
300 ml of chloroform. 20.6 g of N, N'-Dicyclohexylcarbodiimide was added into the reaction mixture. 11.7 g of N,N-dimethylaminoethanol and 2g of 4- dimethylaminopyridine were added into the reaction mixture. The mixture was stirred for 10 hours at RT. The solid was removed by filtration. The chloroform solution was washed with 5% NaHCO3 (2 x 100 ml) and water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 3.5 g of HCI in 50 ml of ether was added into the reaction mixture with stirring. The solid product was collected by filtration. After drying, it yielded 40 g of the desired hygroscopic product (77.5%). Elementary analysis: C23H34CIN3O6S; MW: 516.05. Calculated % C: 53.53; H: 6.64; N: 8.14; Cl: 6.87; O: 18.60; S: 6.21 ; Found % C: 53.49; H: 6.68; N: 8.11 ; Cl: 6.90; O: 18.64; S:6.18.
Preparation of acetamidophenylacetamidopenicillinic acid 2-diethylaminopropyl ester hydrochloride [00146] 43 g of acetamidophenylacetamidopenicillinic acid sodium salt was dissolved in 100 ml of acetonitrile. 40 g of 2-Bromo-N,N-diethylpropylamine. HBr in ethyl acetate was added into the reaction mixture. The mixture was stirred for 16 h at RT. 40 g of 2-Bromo-N,N-diethylpropylamine.HBr and 30 g of sodium bicarbonate was added into the reaction mixture. The mixture was stirred for another 12 h at RT. The solid was removed by filtration. 3.5 g of HCI in 50 ml of ether was added into the reaction mixture with stirring. The solid product was collected by filtration. After drying, it yielded 35 g of the desired hygroscopic product. Elementary analysis: C26H33CIN4O5S; MW: 541.11. Calculated % C: 55.49; H: 6.89; N: 10.35; Cl: 6.55; O: 14.78; S: 5.92; Found % C: 55.44; H: 6.92; N: 10.32; Cl: 6.58; O: 14.82; S:5.92.
Preparation of 6-(5-methyl-3-phenyl-2-isoxazoline-4-carboxamido)penicillinic acid 4-piperidineethyl ester hydrochloride
[00147] 50 g of 6-(5-methyl-3-phenyl-2-isoxazoline-4-carboxamido)penicillinic acid sodium salt was dissolved in 100 ml of acetonitrile. 38 g of 4-piperidineethyl bromide. HBr in ethyl acetate was added into the reaction mixture. The mixture was stirred for 16 h at RT. 38 g of 4-piperidineethyl bromide. HBr and 30 g of sodium bicarbonate was added into the reaction mixture. The mixture was stirred for another 12 h at RT. The solid was removed by filtration. 3.5 g of HCI in 50 ml of ether was added into the reaction mixture with stirring. The solid product was collected by filtration. After drying, it yielded 30 g of the desired hygroscopic product. Elementary analysis: C26H33CIN4O5S; MW: 549.08. Calculated % C: 56.88; H: 6.06; N: 10.20; Cl: 6.46; O: 14.57; S: 5.83; Found % C: 56.85; H: 6.08; N: 10.19; Cl: 6.47; O: 14.59; S:5.82.
Preparation of 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2- thienylacetyl)amino]-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2- diethylaminoethyl ester hydrochloride
[00148] 41 g of 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2- thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt was dissolved in 100 ml of acetonitrile. 35 g of 2-Bromo-N,N-diethylethylamine. HBr in ethyl acetate was added into the reaction mixture. The mixture was stirred for 16 h at RT. 30 g of 2-Bromo-N,N-diethylethylamine.HBr and 30 g of sodium bicarbonate was added into the reaction mixture. The mixture was stirred for another 12 h at RT. The solid was removed by filtration. 3.5 g of HCI in 50 ml of ether was added into the reaction mixture with stirring. The solid product was collected by filtration. After drying, it yielded 30 g of the desired hygroscopic product. Elementary analysis: C22H31 CIN4O7S2; MW: 563.08. Calculated % C: 46.93; H: 5.55; N: 9.95; Cl: 6.30; O: 19.89; S: 11.39; Found % C: 46.91 ; H: 5.57; N: 9.93; Cl: 6.32; O: 19.91 ; S: 11.36.
[00149] Other HPPs of an antimicrobial or antimicrobial-related compound can be synthesized by similar procedures.
Example 2. HPPs of antimicrobials and antimicrobial-related compounds have higher in vitro penetration rates across human skin comparing to their parent drugs.
[00150] Penetration rates of HPPs and their parent drugs through human skin were measured in vitro by modified Franz cells. A Franz cell had two chambers, the top sample chamber and the bottom receiving chamber. The human skin tissue (360-400 μm thick) that separated the top and the receiving chambers was isolated from the anterior or posterior thigh areas.
[00151] A test compound (2 ml_, 10% in 0.2 M phosphate buffer, pH 7.4) was added to the sample chamber of a Franz cell. The receiving chamber contained 10 ml of 0.2 M phosphate buffer which was stirred at 600 rpm. The amount of the tested compound penetrating the skin was determined by high-performance liquid chromatography (HPLC) method. The results were shown in Figures 1a1 , 1a2, 1a3, 1a4, 1 b, and 1c. Apparent flux values of the tested compounds calculated from the slopes in the Figures 1a1 , 1a2, 1a3 and 1 a4 were summarized in Table 1a. Apparent flux values of the tested compounds calculated from the slopes in the Figures 1 b and 1c are summarized in Tables 1 b and 1c respectively.
[00152] Because the lowest detectable apparent flux values in this method was
1 μg /cm2/h, parent drugs that showed a apparent flux value equal to or less than 1 μg /cm2/h were considered as not detectable for penetrating across the skin tissue. For the parent compounds (e.g. penicillin V, penicillin O) which had apparent flux values < 1 μg /cm /h, their HPPs had detectable apparent flux values. For the parent compounds which had apparent flux values > 1 μg /cm2/h, their HPPs had higher detectable apparent flux values. Therefore the HPPs of antimicrobials or antimicrobial-related compounds showed a higher penetration rate (340-600 times higher) across the skin tissue comparing to their parent compounds.
Table 1 a. In vitro Penetration Rate of HPPs and their Parent Compounds (I)
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Table 1 b. In vitro Penetration Rate of HPPs of beta-lactamases inhibitors and their
Parent Compounds (II)
Figure imgf000136_0001
Table 1 c. In vitro Penetration Rate of HPPs of sulfonamides, sulfones, quinolones and their Parent Compounds
Figure imgf000137_0001
Example 3. In vivo penetration rate of HPPs through skin and/or blood-brain barrier
[00153] In vivo rates of penetration of HPPs of beta-lactam antibiotics through skin and blood-brain barrier of intact hairless mice were studied. The donor consisted of a 20% solution of 6-(2,6-dimethoxybenzamido)penicillinic acid 2-diethylaminoethyl ester hydrochloride, 6-(5-methyl-3-phenyl-2-isoxazoline-4-carboxamido)penicillinic acid 2-diethylaminoethyl ester hydrochloride, 6-[3-(o-chlorophenyl)-5-methyl-4- isoxazolecarboxamido]penicillinic acid 2-diethylaminoethyl ester hydrochloride, methicillin, oxacillin, and cloxacillin in 1 ml_ of isopropanol were applied to a 10 cm2 on the backs of hairless mice respectively. After 2 hours, the mice were killed. 5 ml of methanol was added to 1 g of homogenized blood, liver, kidney, muscle, or brain. The samples were centrifuged for 5 min and analyzed by HPLC (Table 2). No drug was detected for the mice treated with only the parent drug (methicillin, oxacillin, and cloxacillin). The results showed that these prodrugs have high pentration rate of blood- brain barrier while the respective parent drugs were not able to penetrate the skin.
Table 2. In vivo penetration results of HPPs of beta-lactam antibiotics
Figure imgf000138_0001
[00154] 90 lactating dairy cows were recruited. 500 mg of 6- phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl ester hydrochloride (penicillin V-DEE), 6-(2,6-dimethoxybenzamido)penicillinic acid 2-diethylaminoethyl ester hydrochloride (methicillin-DEE), or 7-[[(2-acetylamino-4- thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 2-diethylaminoethyl ester hydrochloride (ceftizoxime-DEE) in 10 ml of pH 7.4 phosphate buffer (0.2 M) was sprayed on the skin of udder twice per day. After 1 hours of topical application, milk samples were taken and analysized (Table 3). The amount of the parent drugs was detected. The results have shown that these prodrugs have very high penetration rate of blood-milk barrier. Their very high penetration rates of blood-milk or blood-brain barrier make them very valuable for treatment of brain, breast, prostate gland and other infections. Table 3. In vivo penetration of HPP through blood-milk barrier
Figure imgf000139_0001
Example 4. HPPs of antimicrobials or antimicrobial-related compounds penetrate cell wall of bacteria faster than that of their parent drugs.
[00155] 0.5 mmol of a test compound (6-phenoxyacetacetamidopenicillanic acid
1-piperidineethyl ester hydrochloride (penicillin V-PEE), penicillin V, 6-(2,6- dimethoxybenzamido)penicillinic acid 2-pyrrolidinemethyl ester hydrochloride (methicillin-PME), methicillin, 7-[[(2-acetylamino-4- thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 2-diethylaminoethyl ester hydrochloride (ceftizoxime-DEE), or ceftizoxime) was added into 100 ml of E. coli suspension and stirred for 3 minutes. The mixture was centrifuged at 3000 rpm. The supernatant was discarded and the pellet was washed three times with pH 7.4 phosphate buffer. Acetonitril (100 ml) was added into the pellet and the mixture was heated to 60 °C for 2 minutes. The acetonitrile solution was collected and evaporated to dryness. The amount of test compound was determined using HPLC. The results were shown in Table 4.
Table 4 : The amount of antibiotics and their HPPs entered cells of E. CoIi.
Figure imgf000139_0002
Example 5 Conversion of HPPs to their parent drugs.
[00156] HPPs of antimicrobials or antimicrobial-related compounds converted to the parent antimicrobials or antimicrobial-related compounds quickly in good yield in human plasma.
[00157] A HPP of antimicrobial or antimicrobial-related compound (10 mg) was dissolved in 0.1 ml of 0.2M pH 7.4 phosphate buffer. 1 ml of human plasma, preheated to 37 °C, was added into the mixture. The mixture was kept in a water bath at 37 °C, and at every 2 min intervals 0.2 ml of samples were withdrawn and added to 0.4 ml of methanol to precipitate the plasma protein. The samples were centrifuged for 5 min and analyzed by HPLC. The results showed that most of the HPPs of antimicrobials or antimicrobial-related compounds were converted back to the parent antimicrobials or antimicrobial-related compounds (Table 5).
Table 5. Half life of HPPs in plasma
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Example 6. Minimum inhibitory concentrations (MICs) of HPPs of antimicrobials or antimicrobial-related compounds
[00158] Minimum inhibitory concentrations (MICs) of the antimicrobials and their pro-drugs were assessed according to Jennifer M. Andrews, Journal of Antimicrobial Chemotherapy 48, suppl. S1 , 5-16 (2001 ). The results (Tables 6a-6c) showed that the HPPs of antimicrobials were able to overcome β-lactam resistance in methicillin- resistant Staphylococcus aureus (MRSA) according to Minimum inhibitory concentrations (MICs).
Table 6a. MICs (mg/L) of various antimicrobials and their pro-drugs to methicillin- resistant Staphylococcus aureus (MRSA)
Figure imgf000142_0002
Table 6b. MICs (mg/L) of various antibiotics plus beta-lactamase inhibitors or their pro-drugs.
Figure imgf000143_0001
Table 6c. MICs (mg/L) of sulfonamide and quinolones and their pro-drugs.
Figure imgf000143_0002
Example 7. Antifungal activities of HPPs of antimicrobials or antimicrobial-related compounds
[00159] Antifungal activities of 6-phenoxyacetacetamidopenicillanic acid 2- diethylaminoethyl ester hydrochloride (penicillin V-DEE), 6-(2,6- dimethoxybenzamido)penicillinic acid 2-diethylaminoethyl ester hydrochloride (methicillin-DEE), and 7-[[(2-acetylamino-4-thiazolyl)(methoxyimino)acetyl]amino]-8- oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (ceftizoxime-DEE) were assessed according to Roether W. et al., Mykosen 27 (1 ), 14-28 (1984). The results were listed in Table 7 below.
Table 7. Minimum inhibitory concentration (mg/l) of some prodrugs of beta-lactam antibiotics towards fungi in vitro.
Figure imgf000144_0001
Example 8. Treatment of clinical mastitis using HPPs of beta-lactam antibiotics or related compounds.
[00160] 90 lactating dairy cows were recruited. Bacteriological cure was considered to have been achieved if the samples taken from the affected quarter on day 17 and day 22 were free of the bacterial species isolated in the pretreatment sample. Clinical cure was defined as the disappearance of clinical signs of disease which were observed on day 1 before treatment, in other words by the return to normal feed intake, rectal temperature<39.0°C, good general condition, absence of udder edema, normal milk appearance, and normal milk yield.
[00161] 500 mg of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl ester hydrochloride (penicillin V-DEE), 6-(2,6-dimethoxybenzamido)penicillinic acid 2- diethylaminoethyl ester hydrochloride (methicillin-DEE), or 7-[[(2-acetylamino-4- thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 2-diethylaminoethyl ester hydrochloride (ceftizoxime-DEE) in 10 ml of pH 7.4 phosphate buffer (0.2 M) was sprayed on the skin of udder twice per day. The results are shown in Tables 8a and 8b. The prodrugs have demonstrated very high Clinical cure rates and Bacteriological cure rates.
Table 8a. Clinical cure rates of the topical treatment of cow mastitis with the novel prodrugs of antibiotics
Figure imgf000145_0001
Table 8b. Bacteriological cure rates (day 22) of the topical treatment of cow mastitis with the novel prodrugs of antibiotics
Figure imgf000146_0001
Example 9. Anti-M. tuberculosis activity of the pro-drugs of antimicrobial drugs.
[00162] Six-week-old female mice (BALB/c mice) were infected with 2.21 ±0.15 x 103 CFU of M. tuberculosis H37Rv by an airborne route. 20 days later, the mean CFU in lungs was 8.23±0.27 x107 CFU, then the treatments began. Group A was untreated group (n=20), group B was the treated group with isoniazid/moxifoxacin/pyrazinamide (0.18/0.22/1.2mmol/kg, were given orally) for 45 days, group C was the treated group with isoniazid/moxifoxacin/pyrazinamide (0.18/0.22/1.2mmol/kg, were given orally) for 90 days, group D was the treated group with N-(N-methyl-phenylalanyl)isoniazid (pro- isoniazid, made from N-methylphenylalanine and isoniazid, were given tansdermally)/ 1- cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo [4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo- quinoline-3-carboxylic acid butyl ester(pro-moxifoxacin)/pyrazinoic acid N, N- diethylaminoethyl ester (pro- pyrazinoic acid, 0.18/0.22/1.2mmol/kg, were given tansdermally) for 45 days, group E was the treated group with pro-isoniazid/pro- moxifoxacin/pro-pyrazinoic acid (0.18/0.22/1.2mmol/kg, were given tansdermally) for 90 days, group F is the treated group with pro-isoniazid/pro-moxifoxacin/pro-pyrazinoic acid (0.06/0.07/0.4mmol/kg, were given tansdermally) for 45 days, and group G was the treated group with pro-isoniazid/pro-moxifoxacin/pro-pyrazinoic acid (0.06/0.07/0.4mmol/kg, were given tansdermally) for 90 days. After the treatment stopped, the mice were held for an additional 90 days without treatment and then sacrificed to determine the proportion with negative lung cultures indicating cure. The results showed that the pro-drugs were superior to their parent drugs and they can be used transdermal^ (Tables 9a and 9b).
Table 9a. Treatment regimens and results
Figure imgf000148_0001
Table 9b. Outcomes of test-of-cure assessments
Figure imgf000149_0001
Example 10. Treatment of tuberculosis in adults (reduced dosage for child).
[00163] 40 mg of N-(N-methyl-phenylalanyl)isoniazid (pro-isoniazid)/ 50mg of 1- cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo [4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo- quinoline-3-carboxylic acid butyl ester(pro-moxifoxacin)/40 mg of pyrazinoic acid N1N- diethylaminoethyl ester (pro- pyrazinoic acid) in 3 ml of water is applied to the skin of chest or any other skin of the patient's body (near the infected organs) every morning and evening (twice per day) for 90 days or until the disease-free. Example 11. Treatment of Leprosy or Hansen's disease (HD) in adults (reduced dosage for child).
[00164] 30 mg of 4-dimethylaminobutyrylamidophenyl-4'-aminophenylsulfone
(pro-dapsone)/ 50mg of 1-cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo [4.3.0]non-8-yl]-6- fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid butyl ester(pro-moxifoxacin)/ 15 mg of 2(4-dimethylaminobutyrylthiobenzimidazole in 3 ml of water is applied to the skin near the infected organs of the patient's body every morning and evening (twice per day) for 6 months or until the disease-free.
Example 12. Treatment of ear infection.
[00165] 20 mg of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl ester hydrochloride in 1 ml of water is applied to the skin near the infected ears of the patient every morning and evening (twice per day) for 2 weeks or until the disease-free.
Example 13. Treatment of lower respiratory tract infection in adults (reduced dosage for child).
[00166] 80 mg of D-α-[(imidazolidin-2-on-1-yl)carbonylamino]benzylpenicillin 2- pyrrolidinemethyl ester hydrochloride in 3 ml of water is applied to the skin near the neck and/or chest of the patient every morning and evening (twice per day) for 2 weeks or until the disease-free.
Example 14. Treatment of upper respiratory tract infection in adults (reduced dosage for child).
[00167] 80 mg of 6-D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α- phenylacetamidopenicillinic acid 2-diethylaminoethyl ester hydrochloride in 2 ml of water is applied to the skin near the neck of the patient every morning and evening (twice per day) for 2 weeks or until the disease-free. Example 15. Treatment of upper respiratory tract infection in adults (reduced dosage for child).
[00168] 30 mg of 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2- thienylacetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2- diethylaminoethyl ester hydrochloride in 2 ml of water is spayed into the mouth or nose of the patient every morning and evening (twice per day) for 2 weeks or until the disease-free
Example 16. Treatment of meningitis in adults (reduced dosage for child).
[00169] 80 mg of 6-D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α- phenylacetamidopenicillinic acid 2-diethylaminoethyl ester hydrochloride in 3 ml of water is applied to the skin near the neck and head of the patient every morning and evening (twice per day) for 2 weeks or until the disease-free.
Example 17. Treatment of diarrheal diseases (reduced dosage for child).
[00170] 80 mg of 7-(2-thienylacetamido)cephalosporanic acid 2- diethylaminoethyl ester hydrochloride in 3 ml of water is applied to the skin near the navel of the patient every morning and evening (twice per day) for 2 weeks or until the disease-free.
Example 18. Treatment of breast infection.
[00171] 50 mg of 7-[(hydroxyphenylacetyl)amino]-3-[[(1-methyl-1 H-tetrazol-5- yl)thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2- diethylaminoethyl ester hydrochloride in 2 ml of water is applied to the skin near the breast of the patient every morning and evening (twice per day) for 2 weeks or until the disease-free. Example 19. Treatment of male or female reproductive system infection (reduced dosage for child).
[00172] 80 mg of 3-[[(aminocarbonyl)oxy]methyl]-7-[[2- furanyl(methoxyimino)acetyl]amino]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 2-diethylaminoethyl ester hydrochloride in 3 ml of water is applied to the skin near the pubic area of the patient every morning and evening (twice per day) for 2 weeks or until the disease-free.

Claims

WHAT IS CLAIMED IS:
1. A high penetration composition of an antimicrobial or an antimicrobial-related compound comprising a) a functional unit; b) a linker c) a transportational unit; the functional unit being covalently linked to the transportational unit via the linker; the functional unit comprising a moiety of the antimicrobial or the antimicrobial-related compound; the transportational unit comprising a protonatable amine group; and the linker comprising a chemical bond that is capable of being cleaved after the high penetration composition penetrates across a biological barrier.
2. The high penetration composition according to claim 1 , the chemical bond being selected from the group consisting of a covalent chemical bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond.
3. The high penetration composition according to claim 1 , the moiety of the antimicrobial or the antimicrobial -related compound being converted to the antimicrobial or the antimicrobial -related compound upon cleavage of the cleavable bond.
4. The high penetration composition according to claim 1 , the functional unit comprising a lipophilic derivative of a moiety of the beta-lactam antibiotics or the beta- lactam antibiotics-related compound.
5. The high penetration composition according to claim 4, the lipophilic derivative being selected from the group consisting of carbonate, ester, amide, carbamate, N- mannich base, ether, thioether, thioester, phosphate, oxime and imine.
6. The high penetration composition according to claim 1 , the beta-lactam antibiotics or the beta-lactam antibiotics-related compound being selected from the group consisting of beta-lactam antibiotics, beta-lactam antibiotics metabolites, and agents that can be metabolized into a beta-lactam antibiotics or a beta-lactam antibiotics metabolite, and analogs thereof.
7. The high penetration composition according to claim 1 , the protonatable amine group being selected from the group consisting of a substituted and unsubstituted primary amine group, a substituted and unsubstituted secondary amine group, and a substituted and unsubstituted tertiary amine group.
8. The high penetration composition according to claim 7, the protonatable amine group being selected from the group consisting of Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18, including stereoisomers and pharmaceutically acceptable salts thereof;
HA being selected from the group consisting of nothing, hydrochloride, hydrobromide, hydroiodide, nitric acid , sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid and pamoic acid;
R being selected from the group consisting of nothing, H, CH2COOR6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH2 in R may be further replaced with O, S, P, NR6, or any other pharmaceutically acceptable groups; RrR2 being independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues;
R5 being selected from the group consisting of H, CONH2, CH2CH2OR6, CH2CH2N(CHa)2, CH2CH2N(CH2CH3)2, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, COW, Li-L4- L2-W, and W;
R6 being selected from the group consisting of H, F, Cl, Br, I, Na+, K+, COR5, 2- oxo-1 -imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1 H-inden-5-yl, 4-hydroxy-1 ,5- naphthyridin-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C(=O)-W, -LrL4-L2-W, and W;
R11-R16 being independently selected from the group consisting of nothing, H, CH2COORH , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;
L1 being selected from the group consisting of nothing, O, S, -0-L3-, -S-L3-, - N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L5)-, -0-CH2-O-, -O-CH(L3)-O, and -S-CH(L3)-O-;
L2 being selected from the group consisting of nothing, O, S, -0-L3-, -S-L3-, - N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L5)-, -0-CH2-O-, -O-CH(L3)-O, -S-CH(L3)-O-, -0-L3-, -N-L3-, -S-L3-, -N(La)-L5- and L3; L4 being selected from the group consisting of C=O, C=S,
Figure imgf000156_0001
Figure imgf000156_0002
for each l_i, L2, and L4, L3 and L5 are independently selected from the group consisting of nothing, H, CH2C(=O)OL6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NL3, or any other pharmaceutically acceptable groups;
L6 being independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl, or cyclic groups; and
L7 being independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl, or cyclic groups; and
W being selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17, Structure W-18 and Structure Wa.
9. A high penetration composition having the following chemical structure:
L1 L2
Structure L-1 including stereoisomers and pharmaceutically acceptable salts thereof;
F comprising a moiety of a beta-lactam antibiotics or a beta-lactam antibiotics- related compound, having a structure selected from the group consisting of Structure F- 1 , Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38, Structure FP-39, Structure FP-40, Structure FP-41 , Structure FP-42, Structure FP-43, Structure FP-44, Structure FP-45, Structure FP-46, Structure FP-47, Structure FP-48, Structure FP-49, Structure FP-50, Structure FP-51 , Structure FP-52, Structure FP-53, Structure FP-54, Structure FP-55, Structure FP-56, Structure FP-57, Structure FP-58, Structure FP-59, Structure FP-60, Structure FP-61 , Structure FP-62, Structure FP-63, Structure FP-64, Structure FP-65, Structure FP-66, Structure FP-67, Structure FP-68, Structure FP-69, Structure FP-70, Structure FP-71 , Structure FP-72, Structure FP-73, Structure FP-74, Structure FP-75, Structure FP-76, Structure FP-77, Structure FP-78, Structure FP-79, Structure FP-80, Structure FP-81 , Structure FP-82, Structure FP-83, Structure FP-84, Structure FP-85, Structure FP-86, Structure FI-1 , Structure FI-2, Structure FI-3, Structure FI-4, Structure FI-5, Structure FI-6, Structure FI-7, Structure FI-8, Structure FI-9, Structure FI-10, Structure FI-11 , Structure FI-12, Structure FI-13, Structure FI-14, Structure FI-15, Structure FI-16, Structure FI-17, Structure FI-18, Structure FI-19, Structure FI-20, Structure FI-21 , Structure FI-22, Structure FI-23, Structure FI-24, Structure FI-25, Structure FI-26, Structure FI-27, Structure FI-28, Structure FI-29, Structure FI-30, Structure FI-31 , Structure FI-32, Structure FI-33, Structure FS-1 , Structure FS-2, Structure FS-3, Structure FS-4, Structure FS-5, Structure FS-6, Structure FS-7, Structure FS-8, Structure FS-9, Structure FS-10, Structure FS-11 , Structure FS-12, Structure FS-13, Structure FS-14, Structure FS-15, Structure FS-16, Structure FS-17, Structure FS-18, Structure FS-19, Structure FS-20, Structure FT-1 , Structure FT-2, Structure FT-3, Structure FT-4, Structure FT-5, Structure FT-6, Structure FT-7, Structure FT-8, Structure FT-9, Structure FT-10, Structure FT-11 , Structure FT-12, Structure FT-13, Structure FT-14, Structure FT-15, and Structure FT-16, including stereoisomers and pharmaceutically acceptable salts thereof;
Y being selected from the group consisting of 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 substituted and unsubstituted alkyloxyl;
Figure imgf000158_0001
being selected from the group consisting of Structure NS-1 , Structure NS-2, Structure NS-3, Structure NS-4 and Structure NS-5:
Figure imgf000159_0001
Structure NS-1 Structure NS-2 Structure NS-3 Structure NS-4 Structure NS-5;
Xi being selected from the group consisting of H, OH, OCH3, OC2H5, OR6, C(O)NH2, CH2OC(O)NH2, CH2OC(O)CH3, CH2OC(=O)R6, OC(O)CH3, OC(O)R6, CH2OCH3, CH3, C2H5, R6, Cl, F, Br, I, HCOHCH3, HCOH2, CH2OCH3, CH2OR6, S(CH2)n-NHR7, Structure X1-I , Structure Xr2, Structure Xr3, Structure Xr4, Structure Xi-5, Structure Xr6, Structure Xr7, Structure Xr8, Structure Xr9, Structure Xi-10, Structure X1-11 , Structure Xi-12, Structure Xi-13, Structure Xi-14, Structure Xi-15, Structure X1-16, Structure Xi-17, Structure X1-18, Structure Xi-19, Structure X1 -20, Structure Xi-21 , Structure Xi-22, Structure Xi-23, Structure Xi-24, Structure Xi-25, Structure X1 -26, Structure Xi-27, Structure X1 -28, Structure Xi-29, Structure X1 -30, Structure Xi-31 , Structure Xi-32, Structure Xr33, Structure Xi-34, Structure Xr35, Structure X1 -36, Structure Xi-37, Structure X1 -38, Structure X1 -39, Structure X1 -40, Structure Xr41 , Structure Xr42, Structure Xr43, Structure Xr44, Structure Xr45, Structure X1 -46, Structure Xi-47, Structure X1 -48, Structure X1 -49, Structure X1 -50, Structure Xi-51 , Structure Xi-52, Structure Xr53, Structure Xi-54, Structure Xr55, Structure X1 -56, Structure Xi-57, Structure X1 -58, Structure X1 -59, Structure X1 -60, Structure X1-6I , Structure Xr62, Structure Xr63, Structure Xr64, Structure Xr65, Structure Xr66, Structure Xr67, Structure Xr68, Structure Xr69, Structure Xr70, Structure Xr71 , Structure Xr72, Structure Xr73, Structure Xi7-4, Structure Xr75, Structure Xr76, Structure Xi-77, Structure Xr78, Structure Xi-79, Structure Xr80, Structure X1-8I , and Structure Xr82,
Rs- taken together with Y is R6OCH2C(R5)=, or by itself being selected from the group consisting of R600CCH(NHR7)(CH2)nC(O)NH-, R600CCH(NHR7)(CH2)nSC(O)NH-, CF3SCH2C(O)NH-, CF3CH2C(O)NH-, CHF2SCH2C(O)NH-, CH2FSCH2C(O)NH-, NH2C(O)CHFS-CH2C(O)NH-, R7NHCH(C(O)OW)CH2SCH2C(O)NH-, R7NHCH(L1-L4-L2-W)CH2SCH2C(O)NH-, CNCH2SCH2C(O)NH-, CH3(CH2)nC(O)NH-, R7NOHNR7CH2CH2S-, R7N=C(NHR7)NHC(=O)-, R7N=C(NHR7)NHC(=O)CH2,
CH3C(CI)=CHCH2SCH2C(=O)NH-, (CH3)2C(OR6)-, CNCH2C(=O)NH-, CNCH2CH2S-, R7HN=CH(NR7)CH2CH2S-, CH2=CHCH2SCH2C(=O)NH-, CH3CH(OH)-, CH3CH(OR8)-, CH3CH(Yi)-, (CHa)2CH-, CH3CH2-, CH3(CH2)nCH=CH(CH2)mC(=O)NH- wherein, n or m= 0, 1 , 2, 3, 4, 5, 6, ..., Structure Rs-1 , Structure Rs-2, Structure Rs-3, Structure Rs-4, Structure Rs-5, Structure Rs-6, Structure Rs-7, Structure Rs-8, Structure Rs-9, Structure Rs-10, Structure Rs-11 , Structure Rs-12, Structure Rs-13, Structure Rs-14, Structure Rs-15, Structure Rs-16, Structure Rs-17, Structure Rs-18, Structure Rs-19, Structure Rs-20, Structure Rs-21 , Structure Rs-22, Structure Rs-23, Structure Rs-24, Structure Rs-25, Structure Rs-26, Structure Rs-27, Structure Rs-28, Structure Rs-29, Structure Rs-30, Structure Rs-31 , Structure Rs-32, Structure Rs-33, Structure Rs-34, Structure Rs-35, Structure Rs-36, Structure Rs-37, Structure Rs-38, Structure Rs-39, Structure Rs-40, Structure Rs-41 , Structure Rs-42, Structure Rs-43, Structure Rs-44, Structure Rs-45, and Structure Rs-46;
W being selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure Wa, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18;
Z being selected from the group consisting of CH2, S, SO, SO2, NH, NR6, CHCH3, CHCH2CH3, CR6, R6, -C(=O)-, and O;
AA representing any amino acids; each m and n being independently selected from the group of O and integer;
HA being selected from the group consisting of nothing, hydrochloride, hydrobromide, hydroiodide, nitric acid , sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid and pamoic acid;
R being selected from the group consisting of nothing, H, CH2C(=O)OR6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH2 in R may be further replaced with O, S, P, NR6, or any other pharmaceutically acceptable groups;
R1-R3 being independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues;
R5 and R35 being independently selected from the group consisting of H, C(O)NH2, CH2CH2OR6, CH2CH2N(CHa)2, CH2CH2N(CH2CHa)2, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C(=O)-W, LrL4-L2-W, and W;
R6. R36 and R46 being independently selected from the group consisting of H, F, Cl, Br, I, Na+, K+, C(=O)R5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1 H- inden-5-yl, 4-hydroxy-1 ,5-naphthyridin-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C(=O)-W, -L1-L4-L2-W, and W; R7 and R37 being independently selected from the group consisting of 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, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, Li-L4-L2-W, and C-(O)-W;
Rs and R3s being independently selected from the group consisting of H, F, Cl, Br, I, CH3, C2H5, CF3, CH2CH2F, CH2CH2CI, CH2CH2Br, CH2CH2I, CH2CHF2, CH2CF3, CH2F, CH2CI, CH2Br, CH2I, CH2NR6R7, CH(NHR7)CH2C(O)NH2, C3H7, C4H9, C5H11, R6, C(=O)R6, C(=O)NH2, CH2C(O)NH21 CH2OC(O)NH21 PO(OR5)OR6, C(CH3)2C(=O)OR6, CH(CH3)C(O)OR6, CH2C(=O)OR6, C(O)-W, L1-L4-L2-W, W, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide and substituted and unsubstituted alkylcarbonyl;
R11-R16 being independently selected from the group consisting of nothing, H, CH2C(O)OR11, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;
X being selected from the group consisting of nothing, C(O), OC(O), CH2, CH, S, NH, NR6, and O;
X2 being selected from the group consisting of 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, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, and substituted and unsubstituted alkyloxyl;
X3 being selected from the group consisting of nothing, H, N3, SO3W, F, Cl, Br, OH, OCH3, OR6, CH3, R6, C(O)OW, OW, LrL4-L2-W, and I;
X4 being selected from the group consisting of nothing, N, CH, and CYi;
X5 and X35 being independently selected from the group consisting of nothing, C(O), OC(O), CH2, CH, S, O and NR5;
X6, X36 and X46 being independently selected from the group consisting of nothing, C(O), OC(O), CH2, CH, S, O and NR5;
X7 being selected from the group consisting of nothing, C(O), OC(=O), CH2, CH, S, O and NR5.
Yi, Y31, Y2, Y32, Y3, and Y4 being independently selected from the group consisting of 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)NHCH2Li-L4-L2-W, NR8C(O)R5, SO2NR5R8, C(O)R5, SR5, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide and substituted and unsubstituted alkylcarbonyl;
Li and L31 being independently selected from the group consisting of nothing, O, S, -0-L3-, -S-L3-, -N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L5)-, -0-CH2-O-, -O-CH(L3)-O, and -S-CH(L3)-O-;
L2 and L32 being independently is selected from the group consisting of nothing, O, S, -0-L3-, -S-L3-, -N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L5)-, -0-CH2-O-, -O-CH(L3)-O, -S-CH(L3)-O-, -0-L3-, -N-L3-, -S-L3-, -N(L3J-L5- and L3; L4 and L34 being independently is selected from the group consisting of C=O, o
OL3 Il
-OL, N' -o- ■u-
C=S, c L5 , ^ and OL3 ■
for each Li, L3i, L2, L32, L4, and L34, L3 and L5 being independently selected from the group consisting of nothing, H, CH2C(=O)OL6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NL3, or any other pharmaceutically acceptable groups;
L6 being independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl, or cyclic groups;
L7 being independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl, or cyclic groups; and any CH2 groups may being replaced with O, S, or NH.
10. The high penetration composition according to claim 9, having a structure selected from the group consisting of Structure P-1 , Structure P -2, Structure P-3, Structure P-4, Structure P-5, Structure P-6, Structure P-7, Structure P-8, Structure P-9, Structure P-10, Structure P-11 , Structure P-12, Structure P-13, Structure P-14, Structure P-15, Structure P-16, Structure P-17, Structure P-18, Structure P-19, Structure P-20, Structure P-21 , Structure P-22, Structure P-23, Structure P-24, Structure P-25, Structure P-26, Structure P-27, Structure P-28, Structure P-29, Structure P-30, Structure P-31 , Structure P-32, Structure P-33, Structure P-34, Structure P-35, Structure P-36, Structure P-37, Structure P-38, Structure P-39, Structure P-40, Structure P-41 , Structure P-42, Structure P-43, Structure P-44, Structure P-45, Structure P-46, Structure P-47, Structure P-48, Structure P-49, Structure P-50, Structure P-51 , Structure P-52, Structure P-53, Structure P-54, Structure P-55, Structure P-56, Structure P-57, Structure P-58, Structure P-59, Structure P-60, Structure P-61 , Structure P-62, Structure P-63, Structure P-64, Structure P-65, Structure P-66, Structure P-67, Structure P-68, Structure P-69, Structure P-70, Structure P-71 , Structure P-72, Structure P-73, Structure P-74, Structure P-75, Structure P-76, Structure P-77, Structure P-78, Structure P-79, Structure P-80, Structure P-81 , Structure P-82, Structure P-83, Structure P-84, Structure P-85, Structure P-86, Structure 1-1 , Structure I-2, Structure I-3, Structure I-4, Structure I-5, Structure I-6, Structure I-7, Structure I-8, Structure I-9, Structure 1-10, Structure 1-11 , Structure 1-12, Structure 1-13, Structure 1-14, Structure 1-15, Structure I- 16, Structure 1-17, Structure 1-18, Structure 1-19, Structure I-20, Structure 1-21 , Structure I-22, Structure I-23, Structure I-24, Structure I-25, Structure I-26, Structure I-27, Structure I-28, Structure I-29, Structure I-30, Structure 1-31 , Structure I-32, Structure I- 33, Structure S-1 , Structure S-2, Structure S-3, Structure S-4, Structure S-5, Structure S-Q, Structure S-7, Structure S-8, Structure S-9, Structure S-10, Structure S-11 , Structure S-12, Structure S-13, Structure S-14, Structure S-15, Structure S-16, Structure S-17, Structure S-18, Structure S-19, Structure S-20, Structure T-1 , Structure T-2, Structure T-3, Structure T-4, Structure T-5, Structure T-6, Structure T-7, Structure T-8, Structure T-9, Structure T-10, Structure T-11 , Structure T-12, Structure T-13, Structure T-14, Structure T-15, and Structure T-16, including stereoisomers and pharmaceutically acceptable salts thereof; m, n, Ri, R2, R5, R35, RΘ, R36, R46, R7, Re, R38, T, W, X, X2, X4, X5, X35, XΘ, X36, X46, X7, Yi, Y2, Y31 , Y32, Y3, Y4, Z, AA, HA, R, Rs, and Rn-Ri6 being defined the same as supra in claims 8 and 9.
11. A pharmaceutical composition comprising a high penetration composition according to claim 9 and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition according to claim 11 , the pharmaceutically acceptable carrier being polar.
13. The pharmaceutical composition according to claim 11 , the pharmaceutically acceptable carrier being selected from the group of alcohol, acetone, ester, water, and aqueous solution.
14. A method for penetrating a biological barrier, comprising administrating to the biological barrier a pharmaceutical composition according to claim 11.
15. A method for screening a HPP of a antimicrobial or a antimicrobial-related compound for a desired character, comprising the following steps:
1 ) covalently linking a functional unit comprising a antimicrobial or a antimicrobial-related compound to a transportational unit through a linker to form a test composition;
2) administrating the test composition to a biological subject or a biological barrier; and
3) determining whether the test composition has a desired character.
16. The method according to claim 15, the desired character being selected from the group consisting of:
1 ) the ability of the test composition to penetrate the biological barriers;
2) the ability of the test composition to convert to a parent drug or to an active agent; 3) the penetration rate of the test composition;
4) the efficiency of the test composition; and
5) the efficacy of the test composition.
17. A method for diagnosing a condition in a biological subject, comprising the following steps:
1 ) administrating a composition according to any one of claim 9 to the biological subject;
2) detecting the presence, location or amount of the composition in the biological subject; and
3) detecting a condition in the biological subject.
18. The method according to claim 17, the composition being labeled.
19. A method for diagnosing a condition in a biological subject, comprising the following steps:
1) administrating a composition according to any one of claim 11 to the biological subject;
2) detecting the presence, location or amount of the composition in the biological subject; and
3) detecting a condition in the biological subject.
20. The method according to claim 19, the composition being labeled.
21. A method for treating a condition in a biological subject, comprising administrating to the biological subject the high penetration composition according to claim 9 or the pharmaceutical composition according to claim 11.
22. The method according to claim 21 , the condition being selected from the group consisting of pain, injuries and microorganism related conditions.
23. The method according to claim 22, the microorganism related condition being selected from the group consisting of bacteria-related conditions, protozoa-related conditions, fungi-related conditions and conditions caused by virus.
24. The method according to claim 23, the bacteria-related condition being selected from the group consisting of infections, plague, bubonic plague and pneumonic plague, anthrax, cutaneous anthrax, pulmonary anthrax and gastrointestinal antrax, lyme diseases, brucellosis, whooping cough, acute enteritis, respiratory infection, psittacosis, nongonococcal urethritis, trachoma, inclusion conjunctivitis of the newborn, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, diarrhea, meningitis in infants, hemorrhagic colitis, hemolytic-uremic syndrome, tularemia, pneumonia, bronchitis, peptic ulcer, legionnaire's disease, Pontiac fever, leptospirosis, listeriosis, leprosy, turberculosis, mycoplasma pneumonia, gonorrhea, ophthalmia neonatorum, septic arthritis, meningococcal disease, waterhouse-fhderichsen syndrome, Rocky mountain spotted fever, typhoid fever type salmonellosis, salmonellosis with gastroenteritis and enterocolitis, bacillary dysentery/shigellosis, cystitis, meningitis and septicemia, endometritis, otitis media, sinusitis, syphilis, necrotizing fasciitis, streptococcal pharyngitis, scarlet fever, rheumatic fever, impetigo, erysipelas, puerperal fever, and cholera
25. The method according to claim 24, the infection condition being selected from the group consisting of infection condition in an organ selected from the group consisting of liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, anorectum and pruritus ani, respiratory infections, upper respiratory tract, urinary tract, nosocomial infections, pseudomonas infection, coagulase-positive staphylococcal infections, skin infection, toxinoses, acute infective endocarditis, septicemia, necrotizing pneumonia, infections of implanted prostheses, and opportunistic infections with septicemia and pneumonia.
26. The method according to claim 23, the protozoa -related condition being selected from the group consisting of malaria, sleeping sickness, and toxoplasmosis.
27. The method according to claim 23, the fungi-related condition being selected from the group consisting of aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, histoplasmosis, paracoccidiomycosis, sporotrichosis, and zygomycosis.
28. The method according to claim 23, the virus -related condition being selected from the group consisting of influenza, yellow fever and AIDS.
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WO2013170655A1 (en) * 2012-05-16 2013-11-21 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions
US11857545B2 (en) 2012-05-16 2024-01-02 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions
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CN111012914A (en) * 2012-05-16 2020-04-17 苏州泰飞尔医药有限公司 High penetration prodrug compositions and pharmaceutical compositions for treating pulmonary diseases
AU2013262320B2 (en) * 2012-05-16 2018-02-22 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions
CN107929743A (en) * 2012-05-16 2018-04-20 苏州泰飞尔医药有限公司 Treat the high penetrating power prodrugs composition and medical composition of pulmonary disease
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US9044485B2 (en) 2013-03-15 2015-06-02 Calixa Therapeutics, Inc. Ceftolozane antibiotic compositions
US10420841B2 (en) 2013-03-15 2019-09-24 Merck, Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US11278622B2 (en) 2013-03-15 2022-03-22 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US9320740B2 (en) 2013-03-15 2016-04-26 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US8968753B2 (en) 2013-03-15 2015-03-03 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US10933053B2 (en) 2013-09-09 2021-03-02 Merck Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US8906898B1 (en) 2013-09-27 2014-12-09 Calixa Therapeutics, Inc. Solid forms of ceftolozane
CN108396007B (en) * 2018-03-15 2021-07-23 东北农业大学 Method for in-vitro construction of three-dimensional model of blood and milk barrier of dairy cow
WO2023134733A1 (en) * 2022-01-17 2023-07-20 Techfields Pharma Co., Ltd. Treatment of signs, symptoms and/or complications of viral, bacterial, protozoal, and/or fungal infections by high penetration prodrugs

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EP2440523A1 (en) 2012-04-18
BRPI1012905A2 (en) 2017-09-12
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