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CA2764376C - 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
CA2764376C
CA2764376C CA2764376A CA2764376A CA2764376C CA 2764376 C CA2764376 C CA 2764376C CA 2764376 A CA2764376 A CA 2764376A CA 2764376 A CA2764376 A CA 2764376A CA 2764376 C CA2764376 C CA 2764376C
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acid
substituted
unsubstituted
oxo
hpp
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CA2764376A
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French (fr)
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CA2764376A1 (en
Inventor
Chongxi Yu
Lina Xu
Yuhua Chen
Binbing Yan
Shiqian Tu
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Techfields Biochem Co Ltd
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Techfields Biochem Co Ltd
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Priority claimed from US12/482,373 external-priority patent/US20100040548A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/50—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in beta-position to the carboxamido radical
    • C07D499/52—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in beta-position to the carboxamido radical by oxygen or sulfur atoms
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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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    • A61P13/10—Drugs for disorders of the urinary system of the bladder
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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
    • 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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • 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
    • 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
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/46—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—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
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D499/74—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with carbocyclic rings directly attached to the carboxamido radical
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D499/76—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with hetero rings directly attached to the carboxamido radical
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D499/86—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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    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
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    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
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    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
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    • C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D503/12—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6
    • C07D503/14—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, attached in position 3
    • C07D503/16—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical
    • C07D503/18—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical by oxygen atoms
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    • C07D505/00—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
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    • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
    • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
    • C07D505/16—Nitrogen atoms
    • C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • 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
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • 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)]
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Abstract

High penetration complositions (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 claims priority to U.S. Patent Application No. 12/482,373, filed on June 10, 2009. The present application also claims priority to China Patent Application No. 200910141944.X, filed on June 10, 2009.
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.L.Demain and N.A. Solomon, Eds., Antibiotics Containing the Beta-lactam Structure, Vols, 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 GI 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 anti protozoals 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 0 (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-(2a1 pha,3beta,5alpha)]-3-Methy1-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-azabicyclo[3.2.0]heptane-2-carboxyl ic acid 4,4-dioxide sodium salt), sulbactam (2S,5R)-3,3-dimethy1-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium), and clavulanic acid ((2R,5R,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)methy1]-phosphonic acid mono-(4-nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methy1]-phosphonic acid mono-(3-pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-(N-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, rimocidin, 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, toxi noses, 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, men ingococcal 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, candid iasis, 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, transdermally, topically, subcutaneously and/or parenterally.
[0029a] The invention as claimed relates to:
- a compound having the following chemical structure:
Structure tn including stereoisomers and/or pharmaceutically acceptable salts thereof;
wherein F is selected from Structure FP-2, Structure FP-7, and Structure FI-4:

Date Recue/Date Received 2020-12-11 l' /1 Y3 CH, cN.......,,N1N H Is H3 ¨ S
/ N _____________________ 0 Nxo \
0 / \
Y2 y3 Structure FP-2 Structure FP-7 -i N---/ --.N
,cirJ/ __________________________________________ yi N

Structure FI-4 -T is Structure W-2 or Structure W-4 HA/Ri R11¨N R77¨Ria / ________________________________ R12 N ¨R12 HA
Structure W-2 Structure W-4 ;
HA is selected from nothing, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, disulfuric 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, glucuronic 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 nothing and substituted and unsubstituted alkyl;
Ri is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and 8a Date Recue/Date Received 2020-12-11 unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;
R5 is selected from H and substituted and unsubstituted alkyl;
R6 is selected from H, F, Cl, Br, I, C(=0)R5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-IH-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, and substituted and unsubstituted heteroaryl;
Rii-R13 are independently substituted and unsubstituted alkyl;
Yi-Y4 and Y31 are independently selected from H, OH, OC(=0)CH3, CH3, C2H5, C3H7, C4H9, R6, OCH3, 0C2H5, CH3S02, CH3S03, NO2, CN, CF3, OCF3, CH2C(=0)NH2, F, Br, I, Cl, 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 nothing, 0, S, -0-L3-, -S-L3-, and -N(L3)-;
L2 is selected from nothing, 0, S, -0-L3-, -S-L3-, and -N(L3)-;
L4 is C=0 or C=S; and each L3 is independently selected from nothing, H, substituted and unsubstituted alkyl and substituted and unsubstituted alkoxyl;
- a compound having the following chemical structure:
Structure 1,-1 8b Date Recue/Date Received 2020-12-11 including stereoisomers and/or pharmaceutically acceptable salts thereof;
wherein F is selected from Structure FP-11, Structure FP-84, Structure FP-85, and Structure Fl-86:
ocH3 o _________________________ N CH3 N CH3 CH

Structure FP-11 Structure FP-84 OH H H
S
CH3 s H3C ¨N N
N _______________________________________________ H

Structure FP-85 Structure FP-86 T is Structure W-2 or Structure W-4 /Rl R11¨N R11¨R13 / __________________________________ R12 N¨R12 Structure W-2 Structure W-4 ;
HA is selected from nothing, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, disulfuric 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, glucuronic 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 nothing and substituted and unsubstituted alkyl;
8c Date Recue/Date Received 2020-12-11 Ri is selected from 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 is selected from H and substituted and unsubstituted alkyl;
R6 is selected from H, F, Cl, Br, I, C(=0)R5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-IH-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, and substituted and unsubstituted heteroaryl;
Rii-R13 are independently substituted and unsubstituted alkyl;
Li is selected from nothing, 0, S, -0-L3-, -S-L3-, and -N(L3)-;
L2 is selected from nothing, 0, S, -0-L3-, -S-L3-, and -N(L3)-;
L4 is C=0 or C=S; and each L3 is independently selected from nothing, H, substituted and unsubstituted alkyl and substituted and unsubstituted alkoxyl; and - a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable carrier.
[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 8d Date Recue/Date Received 2020-12-11 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.
8e Date Recue/Date Received 2020-12-11 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-methy1-3-pheny1-2-isoxazoline-4-carboxamido)penicillinic acid 4-piperidineethyl ester hydrochloride (D), 643-(o-chloropheny1)-5-methy1-4-isoxazolecarboxamido]penicillinic acid 3-piperidine ethyl ester hydrochloride (E), 643-(2,6-dichloropheny1)-5-methyl-4-isoxazolecarboxamido]penicillinic acid 1-piperidineethyl ester hydrochloride (F), penicillin V (G), penicillin 0 (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(-)-a-aminophenylacetamidopenicillinic acid ethyl ester hydrochloride (A), D-a-[(imidazolidin-2-on-1-yOcarbonylamino]benzylpenicillin 2-pyrrolidinemethyl ester hydrochloride (B), 6R4243-(methylsulfony1)-2-oxo-1-imidazolidinecarboxamido]-2-phenylacetamido]penicillinic acid 1-pyrrolidineethyl ester hydrochloride (C), 6-D(-)-a-(4-ethy1-2,3-dioxo-1-pi perazinylcarbonylam ino)-a-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 -methy1-1H-tetrazol-5-y1)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (A), 3-[[(am inocarbonyl)oxy]methyl]-7[[2-furanyl(methoxyi mino)acetyl]ami no]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (B), 3-Eaminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetypamino]-5-thia-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (C), 7-[[[2-(acetylami nomethyl)phenyl]acetyl]amino]-3-E1-(ethoxylcarbonylmethyl)-tetrazol-5-yl]thio]methy1]-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)methyI]-7-[[(2-acetylamino-4-thiazoly1)(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-thiazolyI)(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-ethy1-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-acetoxyphenyl)acetyllam i no]-3-[[(1-methy1-1H-tetrazol-5-y1)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-thiazoly1)-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-acetyl am i no-4-th iazoly1)-2-((Z)-ethoxycarbonyl m ethoxy)i m i no]acetami do]-3-(vinyI)-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-(2a1pha,3beta,5a1pha)]-3-Methy1-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium salt (tazobactam, F), [2S-(2a1pha,3beta,5a1pha)]-3-Methy1-7-oxo-3-(1H-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-dimethy1-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium (sulbactam, G), (2S,5R)-3,3-dimethy1-7-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-hydroxyethyl idene)-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid (clavulanic acid, H), (2R,5R,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)methyI]-phosphonic acid mono-(4-nitrophenyl) ester sodium salt (I) , [(N-benzyloxycarbonylamino)methyI]-phosphonic acid (4-nitrophenyl)(N,N-diethylaminomethyl) ester.HCI salt (D), [(N-benzyloxycarbonylamino)methyI]-phosphonic acid mono-(3-pyridinyl) ester sodium salt (J), and [(N-benzyloxycarbonylamino)methyI]-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-(N-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1,4-dienecarboxylic acid, 6-oxo-3-(2-[4-(N-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1,4-dienecarboxylic acid (sulfasalazine, F), 6-oxo-3-(2-[4-(N-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]naphthyridine-3-carboxylic acid (nal id ixic acid, H), 1-ethyl-7-methyl-4-oxo-[1,8]naphthyridine-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 hiqh penetration prodruq (HPP) or hiqh penetration composition (H PC).
[0037] One aspect of the invention is directed to a high penetration prodrug (HPP) or a high penetration composition (H PC). 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 anti protozoals 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 0 (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, cefepi me, 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-(2a1pha,3beta,5a1pha)]-3-Methy1-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium salt), sulbactam ((2S,5R)-3,3-dimethy1-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium), and clavulanic acid ((2R,5R,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)methyI]-phosphonic acid mono-(4-nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methyI]-phosphonic acid mono-(3-pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-(N-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-ethy1-7-methy1-4-oxo-[1,8]naphthyridine-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, griseofulvin 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:
Rs 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(=0)R6, OC(=0)CH3, OC(=0)R6, OCH3, 002E15, OR6, CH3, C2H5, R6, CH3S03, R6503, NO2, CN, OF3, C2F5, 03F7, OCF3, 002F5, 003F7, F, Br, I, Cl, and substituted and unsubstituted alkyloxyl;

4 is selected from the group consisting of Structure NS-1, Structure NS-2, Structure NS-3, Structure NS-4 and Structure NS-5:
rz xi z z __ r.--- .ess,NCH3 .............X.
Xi 1 N N N
CH 3 Xi Xi Structure NS-1 Structure NS-2 Structure NS-3 Structure NS-4 Structure NS-5;
X1 is selected from the group consisting of H, OH, OCH3, 0C2H5, OR6, C(=0)NF12, CH20C(=0)NH2, CH20C(=0)CH3, CH20C(=0)R6, OC(=0)CH3, OC(=0)R6, CH2OCH3, CH3, C2H5, R6, CI, F, Br, I, HC=CHCH3, HC=CH2, CH2OCH3, CH2OR6, S(CH2)n-NHR7, Structure X1-1, Structure X1-2, Structure X1-3, Structure X1-4, Structure X1-5, Structure X1-6, Structure X1-7, Structure X1-8, Structure X1-9, Structure X1-10, Structure X1-11, Structure X1-12, Structure X1-13, Structure X1-14, Structure X1-15, Structure X1-16, Structure X1-17, Structure X1-18, Structure X1-19, Structure X1-20, Structure X1-21, Structure X1-22, Structure X1-23, Structure X1-24, Structure X1-25, Structure X1-26, Structure X1-27, Structure X1-28, Structure X1-29, Structure X1-30, Structure X1-31, Structure X1-32, Structure X1-33, Structure X1-34, Structure X1-35, Structure X1-36, Structure X1-37, Structure X1-38, Structure X1-39, Structure X1-40, Structure X1-41, Structure X1-42, Structure X1-43, Structure X1-44, Structure X1-45, Structure X1-46, Structure X1-47, Structure X1-48, Structure X1-49, Structure X1-50, Structure X1-51, Structure X1-52, Structure X1-53, Structure X1-54, Structure X1-55, Structure X1-56, Structure X1-57, Structure X1-58, Structure X1-59, Structure X1-60, Structure X1-61, Structure X1-62, Structure X1-63, Structure X1-64, Structure X1-65, Structure X1-66, Structure X1-67, Structure X1-68, Structure X1-69, Structure X1-70, Structure X1-71, Structure X1-72, Structure X1-73, Structure X17-4, Structure X1-75, Structure X1-76, Structure X1-77, Structure X1-78, Structure X1-79, Structure X1-80, Structure X1-81, and Structure X1-82:

H2 ¨C¨S
CS
N\ \ ')___.---__ \
¨CH2 X2 N
(:)- -=-=- N
R5 I\If Structure X1-1 Structure X1-2 Structure X1-3 _.S..N,..,., N.,...

N,.N,,, R"

Structure X1-4 Structure X1-5 N¨N N¨N
/ N
/ N
/ S

¨CH2 1 ¨CH2 1 , ¨CH2 X2 / x2 Structure X1-6 Structure X1-7 Structure X1-8 Y3 n Y1 , \ Y2 \\NI
S _________ ON X2 n (:) Yi , Structure X1-9 Structure X1-10 \ 1.=¨... ¨N
\ ____________________________________ H2C ¨ N N ) _______ R5 N
Structure X1-11 Structure X1-12 Y1 __________________________________ Y1 __ NVµ\sN Z:NNII
/ ) QECI) C
______________________ S n R5 S n R5 Structure X1-13 Structure X1-14 A
Y2, e Y2\
N
jj \
` , \
S ____ , (N \

Structure X1-15 Structure X1-16 y1 A Yi o Nr.\\ED H-7µ
.,.,, ____________________________________________ ,.....õ._ R5õ...... ./.
S, Structure X1-17 Structure X1-18 Y3 tY2 A
\ eeff\-y2 H2C¨N

_ \
R5 1 \ 1 N N¨R5 ' 0 Structure X1-19 Structure X1-20 ¨ CH2 \
( ¨µ.5Y2 Structure X1-21 Structure X1-22 A
/ _______ N"; NN
/ 77\=_(___ /
Y1 __________________________________ Y1 ___ S , S

Structure X1-23 Structure X1-24 Yi /
r_ \

/C¨NõNt NN.,.....
= _ N

k H2C¨N,µ 3 / )(...
7,, Y2 Structure X1-25 Structure X1-26 N
.,S,..,..,,-/IN ) C 0 H2 \\
H2 .........õ,=- -............ 7"N
S
S
0 , Structure X1-27 Structure X1-28 H2 I H)õ.., H2 I Els., C CH .....cc =""........."0"."---C"../...CH.....'.CH n NHR36 -VC
....'"*0'.../."..'e...- '.....-CH n NHC(=NR36)NHR46 NH NH

...,...õ, C ,...,.. ,,,,1/4.\==== C

I I
NH-AA NH-AA
Structure X1-29 Structure X1-30 H2 I H2..)...

H2 I H2 ..õ......õ.= C ,.,, ,,...../". H..s... H
.,,,.(C
C- C 3 NH C(=NR36)N
,./ C CH.. H H2 H R6 ,,,C..
I

HN¨AA H3C,.......H ........õ.....,..

I
NH-AA
Structure X1-31 Structure X1-32 OMe T2 N4N) I
( \ I
\=1¨ Y3 Y1 __ k Y3 Structure X1-33 Structure X1-34 ---S

N \ N
1 \
/\

Structure X1-35 Structure X1-36 C Ti ¨CH2 R5 N
I
\ /
e _____________________________________________________________ A
S N CH) X5 ___________ x4 n / \ ¨h./
S

Structure X1-37 Structure X1-38 Yi Y1 _____________________________________________________ (2 ____ A, c=c __ c __ X
H 5 ¨\
( \ X4 X5 __ H H

Structure X1-39 Structure X1-40 H20C \
-4='.- ..**"*.s., ./"'.\ ..., N N

/
\.,.., ....,./'''...õ,... õ...,..../\õ. ..õ....

Structure X1-41 Structure X1-42 Structure X1-43 t --( _______________________________________ R5 t N
N
¨C¨C ________________________________ C=C _________ Structure X1-44 Structure X1-45 R5 N----N\\ R5 __ C ______________ /\\N =C C=C __________________________ Elr¨--NH R7 Y1 Y2 Y1 Y2 µ / X5 _____________________________________________________ N

Structure X1-46 Structure X1-47 / \

\ C 5 =C

µ __________________________________________________________ Structure X1-48 Structure X1-49 Yi N C)NHR7 /x5 _____ <
/ J ,....,_ Structure X1-50 Structure X1-51 Yi Yi Y3 /-) _______________________________________ 1_ _________ 0 _______________________________________________________________ c ) Structure X1-52 Structure X1-53 Structure X1-54 \ \x5OR, \5 0, o ¨
o Structure X1-55 Structure X1-56 Structure X1-57 e/
\
/ N
\ N

N ^1\1 \ Y1C=C-X5 NH R7 X5 __ S
Structure X1-58 Structure X1-59 N-O-R8 Yi N----.......
(PCONH-.,..-----x5 Y2 Structure X1-60 Structure X1-61 _________________________ ( \

x4 ) Structure X1-62 Structure X1-63 Structure X1-64 1 o o N N __ \ ____________________ /
S N
______ N R8 ____________________ OR8 \

IR7IHN _______________ Structure X1-65 Structure X1-66 1 o s Y\i N
I
_______ N R8 1 -II R8 NH S
.. \j HN _______________________ < Y2 _______________________________________________ N R38 R371-IN ________ < 0 Structure X1-67 Structure X1-68 S /\,, S
N/
\ 1S Yi Structure X1-69 Structure X1-70 Ti / / N Yi ) \ ) ___ N

Structure X1-71 Structure X1-72 / >e/=1) _ S _____________________________________________________________ sI4 ) ______ \ ..,..
µ_ / Y1 / <
) 1 N-.

Structure X1-73 Structure X1-74 s /s i Structure X1-75 Structure X1-76 o ( \,, NN 1\l'-N
ORB ¨N

Structure X1-77 Structure X1-78 Structure X1-79 Structure X1-80 __________ NR8 NR8R7 ____________________________________________ NR8 Structure X1-81 Structure X1-82, Rs- taken together with Y is R6OCH2C(R5)=, or by itself is selected from the group consisting of R600CCH(NHR7)(CH2)nC(=0)NH-, R600CCH(N HR7)(CH2),SC(=0)N H-, CF3SCH2C(=0)NH-, CF3CH2C(=0)N H-, CH F2SCH2C(=0)N H-, CH2FSCH2C(=0)N H-, NH2C(=0)CHFS-CH2C(=0)N H-, R7N NCH (C(=0)0W)CH2SCH2C(=0)NH-, R7N HCH(L -L4-L2-W)CH2SCH2C(=0)N H-, CNCH2SCH2C(=0)NH-, CH3(CH2)nC(=0)NH-, R7N=CH NR7CH2CH2S-, R7N=C(NHR7)NHC(=0)-, R7N=C(N H R7)N HC(=0)CF12, CH3C(CI)=CHCH2SCH2C(=0)N H-, (CH3)2C(0R6)-, CNCH2C(=0)N H-, CNCH2CH2S-, R711 N=CH(N R7)CH2CH2S-, CH2=CHCH2SCH2C(=0)NH-, CH3CH (OH )-, CH3CH(0R8)-, CH3CH(Y1)-, (CH3)2CH-, CH3CH2-, CH3(CH2)nCH =CH (CH2)mC(=0)N H-, 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:
Yi H Yi CON H- X5,. ,,CONH--\1 CH

'.A? R5 , Structure Rs-1, Structure Rs-2, Yi N
z0Z¨ X3 /
Yi r_CONH CONH __ Y,4 _____________________________________ / 3 Y3 Y2 ' Structure Rs-3 Structure Rs-4 CO 2' NH-r CONN-r-\
[ CO
Y2 4c \\
' Y1 "32 Structure Rs-5 Structure Rs-6 Y3-K"),1 -Y4 ZNN ./'''''\()N/'..
Yl N N N CONN- .N- CONN-\ ______ / H H
, .N\

Structure Rs-7 Structure Rs-8 Yi r../
I
Y21 __ Y3 N -- N
/'-------CONH-R7 __ N , H
Structure Rs-9, Structure Rs-10 CONN-Y2 X5¨CH2 .7..
Y1 ç--c_Y3 /OW- r .1.1 yi c u,s i)¨v3 Structure Rs-11 Structure Rs-12 N=-%"----\ /CONN-I N- /
-_ C
N...õ----...: /

N
, CONN-R7-N ' H
Structure Rs-13 Structure Rs-14 OCHO

/\CONH--''',. '''''CONH-I

Y3 , Y2 Structure Rs-15 Structure Rs-16 H2N ________________________________________ N
______________________ CONN _____ R7HN __ ( / CONN-S S

0 , Structure Rs-17 Structure Rs-18 y1 H2 L\-*='= -7--CCONH-( CONH-YlL.1.7- Y2 Y2 C

, Structure Rs-19 Structure Rs-20 \/ H2 i _y3 _ N-C-CONH-WOOC CONH- , CI
Structure Rs-21 Structure Rs-22 s IR7FIN S y1 / \ /
N

Structure Rs-23 Structure Rs-24 Y3 %,Y4 O(NHR7 Y2 \ \
CONN-________________ CONN-Structure Rs-25 Structure Rs-26 _____________ 0 Ed-CONN-, yi 11 R7-N Y3 ><N-C

Structure Rs-27 Structure Rs-28 o 74 o _.,o ..4.
N s 1 1 R( N' 0 H H y3 I
LiN-C-N-C-CONH-../X'CONH

Structure Rs-29 Structure Rs-30 o o ) _______ <
H

\ __________ /
101111 , 1\r-COOW
Structure Rs-31 Structure Rs-32 ,,,/\., ..../".......
S¨N H3C N S CONH¨

H
Structure Rs-33 Structure Rs-34 ..........õ.CH3 HO Me \ ____ N/ \NNCONH¨ R7HN ___ ( i CONH¨

H
S
) ( Yi Structure Rs-35 Structure Rs-36 COOH

Yi riA, S H2 __________________ X5 C CONN¨

H
R7 N __ N
( \ CONH¨

/N Yi S
Y3 , Structure Rs-37 Structure Rs-38 Yi Yi Y3 ¨Y2 i r Y 2 \
I N N CONH- r.. F1'CONH-H

U
-., 0). <0 X4 Structure Rs-39 Structure Rs-40 oNH
1 ¨Y1 '-' .-' __ N Y3 \ Nr...CONH¨ Y1Y3 ( \ H

N
H I\1 Structure Rs-41 Structure Rs-42 o F

... Yi \ I

N 1 c00W

R7H N _______________________ c/IrCO NH-Y2 (CONN
S
Yi Structure Rs-43 Structure Rs-44 \..) I
-1 I \
./.. Y4 N

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:

R1 HA!
Ri 1 __________________________________________________________ N

0 ________________________________________ N
R
49' -.N...,.,,,,,..., R5 0 _______________________________ R _____ R ________ R13 -R
Structure Wa Structure W-1 Structure W-2 Structure W-3 I
.......Ri R11 ___________ R13 R11 _____________________________________ N HA Rii __ ....,....,..)/R12 N _____________ R12 ___________________________________ R13 _________________ R13 -R HA R
-R
Structure W-4 Structure W-5 Structure W-6 ./
R11 _______ N'iNit R11 __ N _____ R13 R11 ___________________________________________________ N j ___ R13 = E L \
,..õ.N R13 .."....- 12 -R14 N __ R12 __ R14 HA ..---"....... ..--''' Structure W-7 Structure W-8 Structure W-9 N _______________________________________ 13 HA
,....._ _______ R14 ........NEN, "Nis Ri ________________________ -(N R13 ..N4441, \N R13 -R HA 7 _____ R14 __ R ____ R12 R14 R Zr Structure W-10 Structure W-11 Structure W-12 HA
HA IIA
R11õ...... __ .11111111P R11 13 R1 _________ R13 D
, ,12 .4.41111%, 1\

-RV __________ R12 -R14 VR12 ___________________________________________________________ R14 Structure W-13 Structure W-14 Structure W-15 R14 R15 Ri 4 Ri -N HAHA
N4k R11 __ -N __ R13 R11 ___ -N

________ R13 __________________________ R12 __ R14 13 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(=0)-, and 0;
AA represents any amino acids;
each m and n is independently selected from the group of 0 and integer, e.g.
0, 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. hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, disulfuric 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, glucuronic 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(=0)0R6, 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 0, 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(=0)NF12, CH2CH2OR6, CH2CH2N(CH3)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(=0)-W, L1-L4-L2-W, and W;
R6, R36 and R46 are independently selected from the group consisting of H, F, Cl, Br, I, Nat, Kt, C(=0)R5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1H-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(=0)-W, -L1-L4-L2-W, and W;

R7 and R37 are independently selected from the group consisting of H, F, CI, Br, 1, CH3NHC(=0)CH2CH(NHR8)C(=0), R8N=C(NHR8)NHC(=0)-, C(=0)CH3, C(=0)R6, PO(0R8)0R8, 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, L1-L44-2-W, and C-(=0)-W;
R8 and R38 are independently selected from the group consisting of H, F, CI, Br, 1, CH3, C2H8, CF3, CH2CH2F, CH2CH2CI, CH2CH2Br, CH2CH21, CH2CHF2, CH2CF3,CH2F, 0H201, CH2Br, CH21, CH2NR8R7, CH(NHR7)CH2C(=0)NH2, C3H7, 04F18, 05F111, R6, C(=0)R8,C(=0)NH2, CH2C(=0)NH2, CH20C(=0)NH2, PO(0R8)0R8, C(CH3)2C(=0)0R6, CH(CH3)0(=0)0R6,CH2C(=0)0R6, C(=0)-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;
R11-R18 are independently selected from the group consisting of nothing, H, CH2C(=0)0R11, 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(=0), C(=S), CH2(CH2)n0R8, Cl, F, Br, I, NO2, ON, CF3, 02F5, 03F7, OCF3, 002F5, NH2, NHR6, CH3, 02H5, R6, C(=0)NH2, CH200(=0)NH2, CH2C(=0)0R5, CH2(CH2)nN(CF13)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, CI, Br, OH, OCH3, OR6, CH3, R6, C(=0), C(=S), C(=0)0W, OW, L1-L4-L2-W, 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(=0), C(=S), OC(=0), CH2, CH, S, 0 and NR5;
Yl, Y31, Y2, Y32, Y3, and Y4 are independently selected from the group consisting of H, OH, OW, OC(-0)W, L1-L4-L2-W, OC(-0)0H3, CH3, 02H5, 03H7, 04H9, R6, S03R6, CH2OR6, CH20C(=0)R6, CH2C(=0)0R5, OCH3, 002H5, OR6, CH3S02, R6S02, CH3S03, R6S03, NO2, ON, CF3, OCF3, CH2(CH2)nNR5R8, CH2(CH2)n0R8, CH(C(=0)NH2)NHR8, CH2C(=0)NH2, F, Br, I, CI, CH=CHC(=0)NHCH2C(=0)0W, CH=CHC(=0)NHCH2L1-L4-L2-W, NR8C(=0)R5, SO2NR5R8, C(=0)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;

L1 is selected from the group consisting of nothing, 0, S, -0-L3-, -S-L3-, -N(L3)-, -N(L3)-CH2-0, -N(L3)-CH2-N(L5)-, -0-CH2-0-, -0-CH(L3)-0, and -S-CH(L3)-0-;
L2 is selected from the group consisting of nothing, 0, S, -0-L3-, -S-L3-, -N(L3)-, -N(L3)-CH2-0, -N(L3)-CH2-N(L5)-, -0-CH2-0-, -0-CH(L3)-0, -S-CH(L3)-0-, -0-L3-, -S-L3-, -N(L3)-L5- and 1_3;
L4 is selected from the group consisting of C=0, C=S, , -C¨

and 0L3 =
for each Li, L2, and L4, L3 and L5 are independently selected from the group consisting of nothing, H, CH2C(=0)0L6, 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 0, 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 0, S, N, P(0)0L6, CH=CH, CC, CHL6,CL6L7, aryl, heteroaryl, or cyclic groups;
1_7 is independently selected from the group consisting of H, OH, CI, 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 0, S, N, P(0)0L6, CH=CH, CC, CHL6,CL6L7, aryl, heteroaryl, or cyclic groups; and any CH2 groups may be replaced with 0, 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 Fl-1, Structure Fl-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 Fl-11, Structure Fl-12, Structure Fl-13, Structure Fl-14, Structure FI-15, Structure Fl-16, Structure FI-17, Structure Fl-18, Structure Fl-19, Structure FI-20, Structure Fl-2i, Structure FI-22, Structure Fl-23, Structure Fl-24, Structure FI-25, Structure Fl-26, Structure FI-27, Structure Fl-28, Structure Fl-29, Structure FI-30, Structure Fl-3i, Structure FI-32, Structure Fl-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:

Y2 Yl Y2 Y, \ /
\ / 0 Y3¨ S
Y3¨ S CH3 / C N ___________________ Ya H CH3 Ya H2 H CH3 / \ N
N N

Structure FP-1 Structure FP-2 \ _...., y I A''7N 0 i 0 CH3 /CHVN
/ Cl- HI \ I \TS S.Z& Y4 H

Structure FP-3 Structure FP-4 N __________ CH3 N CH3 H
N 1 0 :/::-*". s H
ij''''CH.-.--....-.''N
zN ..........,.....õ 0 0 S
--_ CH3 / \

Structure FP-5 Structure FP-6 Yiµ
( Yi \N----N,...._ S
X,----CH=='\ N --H

Y31- 0 ^35 X
-Y4 0 \ 0 / \ IR, Structure FP-7 Structure FP-8 Yi )(5CHN ____________________ C
H
H H3 ).___...-3 N CH
N.---Z/'''' Structure FP-9 Structure FP-10 Y2 Yi \ i _ S_____..........
S

N __ / N __ / N N

Structure FP-11 Structure FP-12 .........., -- ...,,./ `,...,...
Y4 H CH3 Y3 ____ CH2 N N

Structure FP-13 Structure FP-14 Re-L32-1,-1_31 0 ______________ NI R6-L32-1-34-L31 0 H2 /N\ ) ( 1 ll N1 S

NH \ n _______________________________________________________ 1 HA NH, \ in / N,,,......,,,.....
/ N

Structure FP-15 Structure FP-16 \ ( \ c\ II H 0 N ________________________________ (c\ il H S

H \ /n FI2 / n /./ __ N,..,,,,,,i,....7,,...... HA NH2 0/7 z^f N.,N, ....õ,õ....c,, ..õ......

L1-1_4-L2-R5 Structure FP-17 Structure FP-18 <0 R6 ____________________________________________ 0 N __ , _______________ H r N _____ S
N........µõ,.......,.yi Nr2 Y4- 0/ , __ N
õ....,..,_,..55,....õ-....
Ya- 14110 -Y2 0/

Structure FP-19 Structure FP-20 HA.......i...õ R

H,N r S
, r,--, _______ 0,¨Nc-s----, \
r.- .,,..LN __ H rs H , z a Y4,j Y2 0 H2 I e I, Structure FP-21 Structure FP-22 HA o R, <0 =
H2N k HN
N ____________________________________________ N __ N'- r Structure FP-23 Structure FP-24 rS Y3 2N S.,,... H 0 y NT
Y, ¨0 Y H 2 L il ORs 0 H2 1, Structure FP-25 Structure FP-26 R.( N¨CicH2 \ 0 HN''''-k.
V yc N / _____________ NS

/.,,---'N \
Xs 4 N N
..õ 1 eN \
00N, . N OR, /
S..s.,....=7... y2 HN¨<
IR, Structure FP-27 Structure FP-28 s \ s H2N---- \
)rit. s.i N)YL"---H2N-lis.N-N
N\cõ, N, Structure FP-29 Structure FP-30 )LO 0 Yl HN--.----(¨X11,.
N N--..... r...
H X, yN
HN -...4.7...,,LN _______________________________________________ I
N, N I H \

0 ORe /¨N'cS N
0 H2 0 \ /¨N,............c.......s Structure FP-31 Structure FP-32 R7 S \ CIANI

S
HN".----4,, 1 I
N yN\ N

N I
0 \oR. /1¨N,,,.....".",,, ...,, cõ.S
\ /¨N.,........7/\,..,, c.....õs C) H2 ORs 0 H2 Structure FP-33 Structure FP-34 s y, R7Fic../y2 J\ \
HL Ns L...? H2 N N's EN11,_ i,õ nyN
N
I .---") r y2 N
I
N. S N, \,_._ ___________ N. ,...õ,...õ. ,c,,, NOR6 uNe 0 H2 0 H2 Structure FP-35 Structure FP-36 Y1 H2 Y2 R6.--'- )____ H2 y2 ..,,....0 Y1 ...., ,/./ N
HN''..--1J5).....1., 0 N
N
i---S X5 I *-.'"
I N------s )-----R, N r--,, x5yN
0 "0, "0õ

Structure FP-37 Structure FP-38 y3_ C ) _L y, j....N
I H

V2 00 ) __ N 7, I = - ,,,,,.====,c,'Ss\.../N
\

H
C

Structure FP-39 Structure FP-40 N
----51,I /S :L

I
N ___________________________________________________ r-s I
\ /1_, NO
0 ......._ /0 a, H / Cr H
, C

Ii2 ¨0 H2 CP---:------.0 Re Structure FP-41 Structure FP-42 s \
HN'''.4*=., 1 HA
r.S.' y2 H2N'...k, \ S
N I r Y2 R7 \ R, /¨NC¨ 11-Z....
ilr....( 0 H2 \ 4..., N \ OR; 0,¨ N ....\ j'' '....--""
'C¨N 1 N ft \ ........*N
N
Structure FP-43 Structure FP-44 Y, S \
)._... I N -----/s -..
)----- R, HC\
R7 HC\CH2 H2 /¨N "*....\.,"'''s y2 0 Structure FP-45 Structure FP-46 yl oi."2 N I ri-,H7s,, 0 ___________________________________ 0 il jp¨ N,N.4õ.........,.....õ, cAr 1\f, HC\
I N H2 Ci 1 \
7...."ye2 e /0.......< 0 _____________________________________________ N....,N
.
Structure FP-47 Structure FP-48 Oi..........S:t1 0 H .
Y2 ).....-N. r/S
i S Y1 ____________________ ,,,,, H 2C\
a /
3 Y.
0 __ X. ¨N.....,....õ.SrN
/ H2, . -- 0 ________ \
\ H2 IN
I C, H2 I I/ N-.......N
W
c HA )-----N N, H2 N 0¨R, Structure FP-49 Structure FP-50 0 H ' ,,j r S.,,, 1-bC\
s ,---N ,.......õ s.....õsrN
T H2g I
Re H . H2 \ \ /¨N.,..../..;.õõs..õ,SN......õ \
NI,... / IR7 HC' 0 H2 II /11 ,0\ 0¨R5 N
N 0¨Re H N
H
Structure FP-51 Structure FP-52 Y2 __ IN
ii3O
1' H 12 H........ ...1 rs,...... Hy 2C
X5 C / HN LI7S'\
H2 S Y.
_______________ \ / i, N..N..,.........,0 /CH2 N
,...,,Nc...,õS.Nr N
I \
Cr H 2 C) Structure FP-53 Structure FP-54 it 0 yi, H A

Hz N...H.õ..1....., i6 / ____ HN.....,, r_s c I-I, I S \
"P'N...,........................SN
I
. , . = 4C) s ' .1 /// 4. ) - Nõ............./..-..
.,...... ....f.0 H CH F2 Yl y-Ys 0 H , N-......N
Ye Structure FP-55 Structure FP-56 R'....
1._,...--0 Rs -10 Ocit, HN., .1..., T4 ____ N- r s' N......_ 1 S.

H --- ________ r 1H, _i_y2 _______ ye H2 I J ' I
N-..õ,...õ:.....õ,...7,....ce,*CH
yey 0 f, \, y H
N
ye Structure FP-57 Structure FP-58 ) __ kil,...,.., ..,'S \. .....õ1.... T4 S i5 N-----) __ r ...... _ 0¨C
,..\\........175H2 \
Y4 Y1 , N y.....7..õ...., / x, /1 N......,......y....7....õ. 0 ......../ 0 Y3 C'.-1 0.........e.... R5 Of/ H2 Ye Y1 .) Structure FP-59 Structure FP-60 127 / \
0 H2C H2C,......
N,...., > _______ INI S 0 __ ( H
HA \ __ r NH

/ S S
II2Th 112 ' N
......../. 0 H2 .........,' 0 H2 I
II Y1 ..y.,>Y 1 sy.

Structure FP-61 Structure FP-62 5() , R6 R7 0 \ n Y2 H
H2C-..... 0 N-..,_ I :,/
0-K .,, ________ ,S,.. N N
H

NH H2c I/ I y jp-N.....õ..,..?õ,,,,,...,..,..,, cr=S,..õ....,2-,N \
H) /-N ..C/S Y4 3 CV hk I

H2 N....2,N
IYi 0""---.----..'\.0-R5 Structure FP-63 Structure FP-64 .......,õ........1,... T2 Y2 y N I __ i! '3 1../S \ .....
r I i / ____________ N
H _______________________ 71 H-eY4 191/11. \ e',1_y i Y3 y3 4 f H2 NI----cN
N i.,.2 N , Structure FP-65 Structure FP-66 ({ HA 0 y H2N \)'L
o : 1 0 N-...., j .,..../ "........ N-----, H
Y4 , N...-***' VS Y2 r _________ K.---, , N,,,...,,,,,,....õ, y YI __ 1 0 T Cr 1 N
Structure FP-67 Structure FP-68 IL y, HN,.....õ..)L, H2C
/ HN __________________________________________ \
--,....1 ro...., i, cHF2 , __ H2 I , Y4 11'...4...),IY2 0" N ....'.' Y' CV
N , `1.,....\
N
y3 Structure FP-69 Structure FP-70 H

IH3C I H3 R6 ,.....õ............
N......,....
H
HA
id CH2 H H I 2 H H
1 ________________________________________________________ S' .......,. _______________________________________ N /
0'....
Structure FP-71 Structure FP-72 W H W R, H
1 H3C I H3C \\,....-N.,.......,,N ...,........, N= ,`"" I,/ 0 N µ''''' 4 - 0 I

H S'' H ________________ S
N / ,.../....- N /
0 0.......
Structure FP-73 Structure FP-74 R5H2N N...t........../ .............. \\.........N
õ....,.....,N.,,.......õ

1 91-13 H F.4. HA
CH2 I H Jd CH 2 X5 X5N .....__L
Ncr-j/4/4. _____________________________________ E 0 0 44,, ,, 7 Y f. Yi i =..
,......CH 2 N CH2 _____________________ S __________________________________ S
___________ N /

Structure FP-75 Structure FP-76 s V S
HA ....._.....(V
H 2N \ , HN"----4.\\-1,,,,rt. 0H3 =
N N __ i 1H N N ____ ' 1H
H I , OR, I H I ( N .....,..0 0."¨N ¨, ....... x5 N
H3C¨),.. IP I 0 H3C )..,. ....... I I
0 R, Structure FP-77 Structure FP-78 Yi Y1 HN
116/ R6,.....y.õ.= 't \l-z.....<

15 ) 3 II I CH3 X No, j,40,,,õ. ti ¨
. lo __________________________ S
N /
'Q 9 0...?õ, ________________________________________ 0...
Structure FP-79 Structure FP-80 0 R5 <5 r r \
HA \ N N I

1 TH3 d Ha Z )N Ji S
S
________________ N / hi 0' Structure FP-81 Structure FP-82 y rA 1 3 1_ Syk,.........0, .,1 Y4 \ C

Structure FP-83 Structure FP-84 Y\, , R6 0 \ ..,"

N...,...,/LI........H1 CH3 0 0...,...õ.. Y2 Y Vt.,.N" N%N
C N
yi_..õ.r....Th ,P1 k-A7 CH3 N

r'ii Y4 _________________________________________ -Y3 /..X

Structure FP-85 Structure FP-86 H- 0 ---, 0,.\\µ ,0 N¨Z-7 -------- X

N ______________________________________________________ 5i N PV I

Structure Fl-1 Structure F1-2 Structure FI-3 Lt 0,v0 cH3 Yi C¨N H2 ( 0õ,......0õ,,,,..N,....,0......õ.õ.......õ.0õ,,,..õ...........1 H2 ..,/.... Y1 U¨Y4 Structure FI-4 Structure FI-5 0 R5, ¨T-1 H2 Y1 20) L 0 V3 .....,' N,õ.s....,.." µ...õ........
1 I I 1 1 V4 __ \i i H

Y2 Ys N/

l'a Structure F1-6 Structure Fl-7 No yl o CI,E-2,,o7N 1 0 H 11 _ il ¨Y4 = 0 H
1 ________________________________________________ OO
Y2 Y, /

Structure F1-8 Structure Fl-9 Vi ri R5N0 0 , Ia'< I 0 13 ,ONNIVN /4-= \ , 071,........N..7N.J.......õ s ,...41'3 \ / H 11 1 \_IY H 11 1 1 0 '/.7'N i 0 Structure F1-10 Structure Fl-11
54 Yi VI
,N I_ I /=2\)L,N,/N, se ky 0 , r X5_5- / H 5 I

\ ./Fy4 Yf \CN
N-----/
Structure FI-12 Structure FI-13 g I ( () Y3 N:
Vi 1 H
0 y2 Y2 0 ...X. ,..,...õ,"..
% Nr4 c'N
N-----/
Structure FI-14 Structure F1-15 Vi Vi Y2 0 0 ./\\
Y2 0 0 ^../.

Structure FI-16 Structure FI-17 yi /-1¨\ R5N0 y3 \-Iri 1 I II H Il 1 0 0 Y2 ..../ ....õ,..\\

l'a Structure FI-18 Structure FI-19 Vi Vi /s=10 Ni R5N 01 I H Il _ II I H rl _ il I
Y2 0 0 Y3 Y4 ..." Y2 0 0 Y3 __________________________________________________________ Y4 Structure FI-20 Structure F1-21 il Y1 R5 , I II H II
N 0 1 ( __ / 1 Y2 Y2 N-4.,OC H 3 0 OCH3 Y' Ya Structure F1-22 Structure FI-23 VI
r1=\ r R5N7 Ya N.....-'0CH Y2 Ni....."-OCH3 0 )C' Ya Structure F1-24 Structure FI-25 C.}....01/"Ns, I__ _3=1.--- ()'\ /1\ Y3 X ¨'''4 / II H

Y2 NOCH 3 0 ,....A.....7.,N

\ __ ii y4 Y4 0 N I
Structure F1-26 Structure F1-27 VI
¨1)yrL. Vi /=1);
',...'43 Y4 Np .õõ,.."N. .....õ. X5................4 I I ri Y2 N 0 N ,,...., s.V2 OCH 3 "----ocH3 y3, Structure F1-28 Structure F1-29 , I H II I ] I H II Y2 0 0 N sõ....
.....xx:
Y20 0 y3õ....,4-4.,.....N...õ.....5..,' Structure F1-30 Structure FI-31 \ Y3 c cl).,=2,....õ0.7",,,N,../N _x5_......./......I
µ_ y4 \ / H 1 I
V2 0 y ......../..NõNõ,.....
Structure F1-32 Structure F1-33 R6 Y1 Yi ><, 0 -I- ) \ rl CID H vv I II ______ H
HN 6 () _______ N.5....x(õ.W No i ________________________________________________ \ / __ Nõ,.....xr, Structure FS-1 Structure FS-2 _________________________________________________________ H
I
__ Y3 _______ y___. ii cD i N Y3 s ___ c N i \ I \ I
/
,X6 0 I y4 R60....., X6 0 I

Structure FS-3 Structure FS-4 H2C1INI) NIR6116 r Hi 11j :1-1 / Frl ii = NH

/

Structure FS-5 Structure FS-6 R5 NH '''NH
OCH, OCH3 ''N'N/N1 OCH3 O'''N/N'v OCH3 H H

Structure FS-7 Structure FS-8 ....---R5 I N¨X6 0.........õ...N..z.k..N..../....." ",.......,..7.,",,z....6õ,õ...,,, N..N../...-...".:;.....v., 1 Y3 NI4.1 1 Y, N
Yi ./././........\Yi I
'====,.\.,...X., 0¨R6 Structure FS-9 Structure FS-10 Y1.,..1 I
< I Y2 All R5N r\l'.Y3 0 e. I I
N
I
H2C, s, r I
H2C,cH 3 CH3 T 4 7......i .......õ.......,Y1 iY3 RÃ
Structure ES-11 Structure FS-12 Structure FS-13 i Vi Yi ) N N

\.............k 0N
I
41.. H C
2 .....,c....../
..........,........0,N,........ R, I

Structure FS-14 Structure FS-15 Structure FS-16 yi / \ X5 / N ________________________________________________________________ <
\ ..1N
OVD,...
\------- /
Ya R3,..../ X5 /
F Y1 r H2 0 =...,...

¨NH
Structure FS-17 Structure FS-18 y, 0 0\\ /
Yl¨Ns, .---"' y: \
N

c...\

X3 Ya ,.0H2 0 ..,... ..1.=

R 5¨ X5 Structure FS-19 Structure FS-20 H H
0N........., 0.,....,z......õ.õ.õ,,,N ¨Nri:C1-, H
S,.......õ. N,.......

Y2,......,.._õ.õ.Y3 v r'l 1 Y1,.....õ......./"............,Y3 = 1¨
¨ Y2 LNZ.Z,- ... "......-0C H3 L

Yi N Y4 N

Structure FT-1 Structure FT-2 Structure FT-3 Vi --_ __x HA
Y2................õ,N .......,......,,,, H2 H H3 Y2 C C
1 FI3c.,./

I

Y 1 N Y3 H2C.N...., X7......_ Y3 H

Structure FT-4 Structure FT-5 Structure FT-6 X6 ¨R6 / '. R46 \, X6'... R6 ..õ..../sõ)1,,, N...õ../.\,....õ,/, ......r.,..).õ........õ,/,.NH
..) ..,,,,.... 0 ,....,,, )1 C H .3y.õ1 H 0 NH
,......s......õ,,LH N H
,.....,... 0 H

H
N 2N ...õ,..,.......,N

NH HN( I hN ,,/, ,L
X36 \ 0 Rao 0 0 .....
HN
X, R7\ ,õ..0 HN

''..............N
Structure FT-7 Structure FT-8 /X6 -R6 ...,/ X7'.....

\,.. X,.

HA /

..... j.............õ,.....N.w.õ0"....õ,,,,N.N.............,,,,,,.
......,,,,,,,,....,,,..NH2 N H
HH ......õ.1.............õ
.......õ..,,,.....,...õ-NNõ..........õ-^,,,.... ..........._õ"-NH2 N N
.....1 ..,.....,... 0 H
HN.
0 H H...........,õ,...L
H s.,...s.,.........L.,....."õ
'NI H
O'''.....' NH 0 H
He'''.
N H2N ss.............õ..N ,,' N

X36=== m 11H H N'n.--.
,s36 0 0 HN
./..0 X36 \

HN
-N N
H
-N./.....SµO
N
H
Structure FT-9 Structure FT-10 Y2 N-C )--CI H3C
I
1\N' 0 \ I >-0 R5\ OH O
H y`---CH3 NH

N-y-cH3 Yi H3c cH3 H3 N-N N 3 C= /M-CH
, - Y4 0 H \...... j Structure FT-11 Structure FT-12 Structure FT-13 yi 0 Yi 0 F
F

1 A..
Yi --ci .A N
i \,N N
........0 N

H:õ...0 Ya R35 A /
N / C \ IIA R5 Hy Structure FT-14 Structure FT-15 Structure FT-16 including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
n, R5, R7, X5, X35,Y1, Y2, Y31, Y32, Y3, and Y4 are defined the same as supra;
L31 is defined the same as L1 as supra, L32 is defined the same as L2 as supra, L34 is defined the same as L4 as supra, in certain embodiments, -L1-L4-L2- and L32- are independently selected from the group consisting of -0-, -X-, -0-X-, -N-X-, -S-X-, -X6-, -0-X6-, -N-X6-, -S-X6-, -0-X7-, -0-C(=0)-, -NH-C(=0)-, -C(=0)-, -C(=0)-0-, -C(=0)-N-, and C(=0)-X-;
X is selected from the group consisting of nothing, C(=0), OC(=0), CH2, CH, S, NH, NR6, and 0;
X6, X36 and X46 are independently selected from the group consisting of nothing, C(=0), C(=S), OC(=0), CH2, CH, S, 0 and NR6; and X7 is selected from the group consisting of nothing, C(=0), C(=S), OC(=0), CH2, CH, S, 0 and NR6.
[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 Fl-1, Structure Fl-2, Structure Fl-3, Structure Fl-4, Structure Fl-5, Structure Fl-6, Structure Fl-7, Structure Fl-8, Structure Fl-9, Structure Fl-b, Structure Fl-11, Structure Fl-12, Structure Fl-13, Structure Fl-14, Structure Fl-15, Structure Fl-16, Structure Fl-17, Structure Fl-18, Structure Fl-19, Structure Fl-20, Structure Fl-21, Structure Fl-22, Structure Fl-23, Structure Fl-24, Structure Fl-25, Structure Fl-26, Structure Fl-27, Structure Fl-28, Structure Fl-29, Structure Fl-30, Structure Fl-31, Structure Fl-32, Structure Fl-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 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, ...;
n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, ...;
R1 is selected from the group consisting of H, 01-020 alkyl, 01-020 alkyloxyl, Ci-020 alkenyl, 01-020 alkynyl, aryl, and heteroaryl;
R2 is selected from the group consisting of H, 01-020 alkyl, 01-020 alkyloxy, Ci-020 alkenyl, 01-C20 alkynyl, aryl, and heteroaryl residues;
R3 is selected from the group consisting of H, 01-020 alkyl, 01-020 alkyloxy, Ci-020 alkenyl, C1-C20 alkynyl, aryl and heteroaryl residues;
R5 and R35 are independently selected from the group consisting of H, -C(=0)NH2, CH2CH2OR6,CH2CH2N(CH3)2, CH2CH2N(CH2CH3)2, CH2CH2OR6, Cl, F, Br, I, 01-020 alkyl, 01-020 cycloalkyl, 01-020 alkyloxyl, 01-020 cycloalkyloxyl, 01-020 alkenyl, 01-020 cycloalkenyl, 01-020 cycloalkynyl, C1-C20 alkynyl, aryl, heteroaryl, C(=0)-W, and W;
R6, R36 and R46 are independently selected from the group consisting of H, F, Cl, Br, I, Na, K+, C(=0)R5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-1H-inden-5-yl, 4-hydroxy-1,5-naphthyridin-3-yl, C1-C12 lkyl, Ci-012 cycloalkyl, C1-C12 alkyloxyl, C1-012 cycloalkyloxyl, Ci-C12 alkenyl, 01-012 cycloalkenyl, 01-012 cycloalkynyl, alkynyl, aryl, heteroaryl, C(=0)-W, and W;
R7 and R37 are independently selected from the group consisting of H, F, Cl, Br, 1, CH3NHC(=0)CH2CH(NHR8)C(=0), R5N=C(NHR6)NHC(=0)-, C(=0)CH3, C(=0)R6, PO(0R5)0R6, 01-020 alkyl, 01-020 alkyloxyl, 01-020 alkenyl, 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, 02H5, CF3, CH2CH2F, 0H20H2CI, CH2CH2Br, 0H20H21, CH2CHF2, CH2CF3, CH2F,0H201, CH2Br, CH21, CH2NR6R7, CH(NHR7)CH2C(=0)NH2, 03H7, 04H9, 05E111, R6, C(=0)R6, C(=0)NF12, CH2C(=0)NF12, CH20C(=0)NF12, PO(0R8)0R6, C(CF13)20(=0)0R6, CH(CH3)C(=0)0R6, CH2C(=0)0R6, C(=0)-W;
X2 is selected from the group consisting of nothing, H, CH2(CH2)n0R8, Cl, F, Br, 1, NO2, CN, CF3, 02F5, 03F7, OCF3, 0C2F5, NH2, NHR6, CH3, 02H5, R6, C(=0)NH2, CH200(=0)NH2, CH2C(=0)0R5, CH2(CH2),N(CH3)2, CH2(CH2)nSO3R5, 01_8 alkyl, 01-8 alkylthio, 01_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(=0)0W, OW, and 1;
X4 is selected from the group consisting of nothing, N, CH, and CY1;
X8 and X38 are independently selected from the group consisting of nothing, C(=0), C(=S), OC(=0), CH2, CH, S, 0 and NR5;
each Y1, Y31, Y2, Y32, Y3, and Y4 are independently selected from the group consisting of H, OH, OW, OC(-0)W, OC(-0)0H3, CH3, C2H5, 03H7 , C4H9, S03R6, CH2OR6, CH200(=0)R6, CH2C(=0)0R8, OCH3, 0C2H5, CH3S02, R6S02, R6S030R6, CH3S03, R6S03, NO2, ON, CF3, OCF3, CH=CHC(=0)NHCH2C(=0)0W, CH2(CH2)nNR5R6, CH2(CH2)n0R6, CH(C(=0)NH2)NHR6, CH2C(=0)NH2, F, Br, I, and Cl;

Z, AA, HA, R, R, Y, R11-R16, X, L1, L2, L4, L31, L32, L34 and Ware defined the same as supra; and any CH2 groups may be replaced with 0, 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, sal icylate, 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),
[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, 0 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, -CH2-0H, -OCH3, 0Re, Re-OH, -Re1-O-Re2-, wherein Re, Rei and Re2 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(Br)-and ¨Re(I)-, 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, -Re1-S-Re2-, wherein Re, Rei and Re2 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, -Re-NH2, -Re1-N-Re2 and -Re-N(Re1)-Re2 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(0)-H), ketone group (-Re-C(0)-Rei), carboxylic acid group (Re-C(=0)0H), ester group (-Re-C(=0)0-Rei), carboxamide, (-Re-C(=0)0-N(Rei)Re2), enone group (-Re-C(0)-0(Rei)=C(Re2)Re3), acyl halide group (-Re-C(0)-Xh) and acid anhydride group (-Re-C(0)-0-0(0)-Rei), wherein Re, Rei, Re2 and Re3 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 fluor 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 (uheteroaryl"). Examples of aryl include, without limitation, phenyl, benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyridazinyl, 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:

Li L2 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 Fl-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 Fl-11, Structure Fl-12, Structure Fl-13, Structure FI-14, Structure Fl-15, Structure FI-16, Structure Fl-17, Structure Fl-18, Structure FI-19, Structure Fl-20, Structure FI-21, Structure Fl-22, Structure Fl-23, Structure FI-24, Structure Fl-25, Structure FI-26, Structure Fl-27, Structure Fl-28, Structure FI-29, Structure Fl-30, Structure FI-31, Structure Fl-32, Structure Fl-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, OX, N X, SX, X5-, -0-X5-, -N-X5-, -S-X5-, -0-C(=0)-, -NH-C(=0)-, -C(=0)-, -C(=0)-0-, -C(=0)-N-, and C(=0)-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 1-2, Structure 1-3, Structure 1-4, Structure 1-5, Structure 1-6, Structure 1-7, Structure 1-8, 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 1-22, Structure 1-23, Structure 1-24, Structure 1-25, Structure 1-26, Structure 1-27, Structure 1-28, Structure 1-29, Structure 1-30, Structure 1-31, Structure 1-32, Structure 1-33, 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 1-1, Structure T-2, Structure 1-3, Structure 1-4, Structure T-5, Structure 1-6, Structure 1-7, Structure T-8, Structure 1-9, Structure T-10, Structure T-11, Structure T-12, Structure T-13, Structure 1-14, Structure 1-15, and Structure T-16:

Attorney Docket No. 68961.8021.W000 =
...
=
1 ( s .¨

Y3 _________ 1 S CH3 t==
t,.) 4.
l'/-\CN\N _________________________ Y4 H2 H CH3 / cH
N

X\ X 0 \w 0 w n o Ni -.1 cy) A.
Structure P-1 Structure P-2 u, .., N) I--Hi 1 1 Y3 __ µ.,.

S

F-' u.)I

Y3 S /161'N
y.7-µ\ N

HA X

\
X\
-o w n o 0 n a _ a -a-, Structure P-3 Structure P-4 (..J
-.1 .4.
c.,, Attorney Docket No. 68961.8021.W000 S yiN 0 N

r.J
=
N N __ N
H
t.) X
4.
R6/,, 0 \

0'.---"(1:1------:.-F13 W 0 X
w _ y4 IYµ \') 0 n o Structure P-5 Structure P-6 N) .4 0, .,..
u4 ...1 Y2 " Y1 0 a) \ ------( 0 c J1 N

r CH

H S

_______________________________________________________________________________ ____________________________________ 1-H

N
o-__), X
Y31I! y4 0 \ w c) x35 X
\w 0 \ 0 o n n a _ a a Structure P-7 Structure (..J
..1 .4.
(,., Attorney Docket No. 68961.8021.W000 (1/ CH3 ON HA
S CH
3 ts4 =
.., S =
--, .., Xr-t,) C
H CH3 t=-) H
N .
X

cl^X35 X
\
\ 0 \

n Structure P-9 Structure P-10 0 Ni .4 0) UJ

a) r\ 1 S CH3 y3 S
OH
i i I - , r I
Y3 1....,.. H __ 1¨' 1.7. 7 CH3 N H CH3 uJI

0 \ R6-0 \w Pir\I X W

"d Structure P-11 Structure P-12 r.) n a _ a -a-, ,...
, .,..
,., Attorney Docket No. 68961.8021.W000 \ 71 0>
cH2 y3 - CH
CY2\/C1 0 (,,, S \ ., ts3 =
Y3 ______________________________________________________________ 3 _______________ 1 ."
....., ___________________________________ ----\7:' .

, ___ N ,..,.., t.) r..) 4.
07 .

CI\
W-X

W

n Structure P-13 Structure P-14 Ni .4 0, UJ
-,1 r-0, NJ
O\

l_H 0=1) ( ?i o i-C N-.........
_____________________________________ ,..'s. 12) 11 H
r r N
r -.,.._ s...,, 1-' u.)1 NH n o , __ N ., HA NH2 n C(/ , __ N, ^ R7 0 f fa./.../...õ,....
0 R., I

I "0 n n _ Structure P-15 Structure P-16 =
e-(..J
..1 .4.
(,., Attorney Docket No. 68961.8021.W000 Yi X.,...--W

>"------:----.N\

0 __________ c X5 ts.) S
N =
H2C NH ===..... r ....õ , ....
(C I
NH F12)__L
r,,S =
--, ..
., N t.) n.) n >,..,,-- Y2 ) N
.
/ __________________________________ N ,,/=., N,.
\\ / 0 o^ IR7 N ------N
0..
X-- w n Structure P-17 Structure P-18 N) .4 0, .,..
u4 ...1 ,, u.
a, N) HHA
I

Y4L, N-...._ jõ,N....^ .,y HNI,I.,,...õ....
N-õ,....
H
_______________________________________________________________________________ ______________ S
r 1 y2 1-, r r 1-' WI

-li Y2 0'7 N 1 -, ____ N

of.::**'i== n ?

X ---- W n =

-, =
I' (..J
Structure P-19 Structure P-20 ..1 .4.
(,., Attorney Docket No. 68961.8021.W000 HArci..,....._ Rs o iYi -, Yi =
--, jNS,,,...õ.., Nix Y2 n / ..
4.
I
r..) Y4 -K)I 0'7 H2 / N .,. S.,,.._, Nx n.) 4.
I '-- H2 o./.--......0 ,.. ......._.
1 e N

N

R5 y3 I
W
Structure P-21 Structure P-22 n Ni R6 (0 0) A.

HA
--.1 ,i N) o HN r-r H -____________________________________________________ N....., __ F-' u.)I

IS o/ __ N,...,.., ,.,,yi 0-i---"-' 0---1"-----X¨W -o In n _ Structure P-23 Structure P-24 =
'a-(..J
-.1 .4.
c.,, Attorney Docket No. 68961.8021.W000 (N,..õ......õ1,..... Y2 .1, j,..õ..õ

_______________________________________________________________________________ ________________________________ l,.) S
c, 0 -,, r , .6, ____________________________ N N/ N
w -K) Y2 0'7 C
I \CR
6 / __ N

=, `=, N i X ¨ W

X¨ VV
Structure P-25 Structure P-26 o o Ni o) A.
(,) Y 1 -.I
.--1 ____________________________ rs,, Ni HA \
/ N ¨CH2 0 ol o 1-' f12%, R.( CH, HN
I-' . N , __ N,,...,7777SN/ .,...,...._.,, o N\
X5 4 0'7 H2 N fi OR5 o/¨N
N
HN¨< 0¨R6 0.--.'---X¨ \ N *0 n n Structure P-27 Structure P-28 4 ..., ,..., 4, ,4 Attorney Docket No. 68961.8021.W000 Yi Yi S
HA (µ---5.1...._ S
vn .
H2N x s , .
=
NI N--....., N
N
4, n) =k /¨ N

ORs C

0.!....i'' ',..
...!=:''....%*..,, Structure P-29 Structure P-30 r) o iv o) A.
.1 oe S
. v ....)....N...,.. ol Ni HN
/ \
----XNN I N---'- _______________ r=-s--- )(5,N Yi "-...4------. L.N
N
0 ==
N
HN

rs..., N yN \y2 o 1-' I
1-`
I-' WI
N H

0 ,¨Nc<,,S

^IR6 N
0 0 \
, ___ N,=-=c s ot!.........õ
X- \A/ ci--:-.."'\
X -VV
*0 n Structure P-31 Structure P-32 n õ4 ,., -.4 4, ,4 Attorney Docket No. 68961.8021.W000 ______:..,õ.....õL
rN7 ....L....... 0 S \ 0 \
N
=
..., =

/ --, I
.", N N, N HN------4=
N
I
S

=.
4.
N
h) 4.
rL
N
I H ____ r y \

,R, N
S
\ ) __ N.., C S
CRe o/
_______________________________________________________________________________ _______ NI.,,,, v C

(D.
O'' \ X - W
0 ¨Rs n N) Structure P-33 Structure P-34 0, u, --.1 sz ..../0 H2 61 Yi Yi R7 (2 n) o r /
---'--- HA___IN \

NN
, N

i-F-' u.)1 H2N '' ''''' µ= I X5 Y2 H2 N N
SN X5 o N N
H ...,,... rs N
I
HN
N\ N\
/ ___ N
OR6 _________________________________ N ,,,...,,.5../,.... Zs C

O..' o----._;%" "0 0¨R5 0¨R5 n n _ Structure P-35 Structure P-36 =
e--(..J

.4.
(.4 Attorney Docket No. 68961.8021.W000 Fi2 y.2 R5 ../" . )rcH2 __r LY1 \ Ni._....._.</Y2 S
\ 0 HN -----.-c r, X5.,..,N

=
.4 N
I N s..........
H S

--, ..
4.
r..) 4.
, ____________________________________ N N\
0 0 Re C

C) 0¨R5 X¨W
Structure P-37 Structure P-38 c-) N) I

FP.
UJ

= 61 S S
N) H __________________________________ r .
.

i 1'1 r r F-' I , ___ N sx___ NI
u.)1 H
o N \
I

N.' ..
"'N.' 0------:--x..._ .,...
NiN 0)---.-- R 7 o w o/ N, H

/..------/
o.
I R6 ¨ 0 H2 /.......

n n Structure P-39 Structure P-40 4 _ --a--, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 Yi Yi S

IIA \

HN
r..) r. S N
S,_ =
.., =
N N-- __ H N
N

H
, ., "
n.) )----- R7 0 N ___________ N. C 2H 0 N / ____ NH 2 4.
rL
,,.c, ,0 C

/-CH
\At 7.----C 7 ¨x R7-0 o..!.ss..%. \,, n Structure P-41 Structure P-42 0 Ni .4 0, Yi .,..
u4 00 Yi .4 N) HA

HN.-....- S

'''.4=Srl- N

r ' N H H 2N...,, ______________ ,,,, -õ

N
H ------rs--, 1-' u.)I

)*.''.... R7 \
0 0 R6 / __ N/ \
ii------( 0 H2 \ N .,..,/,.. N
C-N
o---,..-!-.- X -W õ,...
N
o.---___.

n n Structure P-43 Structure P-44 4 a _ a -a-, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 Yi Yi S

r..) ..., N

=
, ., t=.) HC
HC n.) )....'.... R7 \ )..%'....
R7 \ 4.
rL
0 C H2 / __ N ,,,,7...._ y2 /X --....<

o..."-...%^=,,, W
o...:::'.'1%.,....s Structure P-45 Structure P-46 n NH2 o Ni Yi ,4 cy, r Y2 FP.
UJ

y1 o i ..õ.....õ:
r N... 61 lN) IIA.....4 \ y2 NJ

r s,. 0 <*4 r-N
I 0 __ N..,....i..",,N..,..,c,./.S,_ r F-' HC\
cH2 I 0 H2 II /\,N di , ____________ N.,./.7,,.,/"....õ... y32 0'/ o./ .....=.,...,... N

, N
R6--...<
X----W
o/.--4,........, 0 0¨R7 Structure P-47 Structure P-48 -o n n a _ a -a-, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 H , _______________________________________________________________________________ ______ r H2...-c N-......sl S', p r..) -........HN ________________________________________________________________ 71 .
.."
c.,:ti , .
, ,Yi j __ Nõ..,, .,,. Sx......, Ni .., _______________________________________________________________________________ _________________________________ 4.
C t=.) f j __ N ,s Sx...........N/

I \ N
I
N 4.
I 0'7 C
H2 I \N
0 0'7 o/..--',........, H2 N /
N
W
N-....... /
o./..--=
N 0¨R7 Structure P-49 Structure P-50 n N
0)......... H i ,4 N s........1 r7 S N'N, .1..
Ss, w ca y1 0, 1)11 H2 C\

n) o ______________________________ N
o, SN______. NI r-r , , / S

R7 ri 2C 0 H2 I 1 \ R7 H2 C'IS
I
\ N 1-0---;."-----. N e 0 0-7 H2 F-' u.)I
o N /
0 ¨1R6 N
0-----"-.---. N
0-------\\ )'-----K
0.-----X¨W
H N
Structure P-51 Structure P-52 n n a _ a -a-, ,...
, .,..
t=4 Attorney Docket No. 68961.8021.W000 Y2 Yi ,),(,, .)....õ.. ,r4 ts.) I H2N H 2C¨L
=
-, /
,7's \. N.,0 --...
H2 H '''' ____________________________________________________________________________ .., S
4.
\
1'1 r..) n.) 4.
0'/
, NõN.,, 0 _______________________________________________________________________ N
_, N.,,",,,,,====
,Sx............NI
C C H2 NC 0 H2 I \ N
o..--j--,.....
e N
X ¨W X¨ w n o Ni Structure P-53 Structure P-54 0, .,..
u, ..., r- 0 0, Ni r-H2C ¨11., r ..... õ..11,...ss. Y4 / HN
-...... j ,õ,/' S'= 1 i-H2 N \H 1 S S
F-' u.)1 C N ,....õ.
r.............. Y1 CH \ H F2 I
N .-c 7S \\,.....õ...N/
'r0 , ________________________ N.,CH
H2 I \

Y1 ¨,17Y3 0 H
N //
0------:--.-.
X¨W
0¨R6 n n _ Structure P-55 Structure P-56 '-a--(..J
-.1 .4.
c.,, Attorney Docket No. 68961.8021.W000 r..) HN,N.H......,L
. s , _______________________________________________________________________________ _________________________________ ..
c r-,.
,Y1 , /
..k ., N
I
Y2 / NC ---N\ n.) 4.
/ .,,,,/,. ,,,=_CH

N(4¨lj i,NI
)11¨y Y3 H
o..1:,---"--.....,,,. ¨
..., N
X VV
N
CD\
X¨W Y3 n Structure P-57 Structure P-58 N) .4 0, .,..
u4 00 o o a, u.
) __ H
..).".'\.

i t N-.."..... _________________________ rs...., , H2c [1,....._: rs,........., / , ,-o=c S ___________________ CH2 Y4 \\.)...,,.,././Yi , N.....,,,,,..
_______________________________________________________________________________ _______ NN,N.,,,,,, ,A
07 y3 C
R

y N
. 3 I y2 Y1 X¨W
"d n n Structure P-59 Structure P-60 4 a _ a -a-, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 ,,,'' N
RI
N-_;:----=N
R5 N---- \
\ 0 "

H2Csõ.. I N
0 ---__ L.,/ H2C
( ) __________________________________________________________________________ H ______________ N -, =
-.
r, r..)"
> _____________________ NI S 0 ____________________________ S,,,,, -...., HA

tt H2C ___________________________ r -N- , HC , ________________________________ s ) N
j ______________________________ N,,,, _.,,,,,,,N.c/
H2C\v......1 / .\c/s H2C,\
d/ H2 //

'Y
I I Yi 0---":"-------.. ii 0--------.. '' 0¨R6 X¨W
n Ni ,4 0) Structure P-61 Structure u, ,, o N) o/ R6 IN- ----*-.( Ni --=----zN 0 ' \
Y
u.)I

( > S N N
N -.....,...
r ..õ
H
Vi , _________________________________ r ,..õ
, ___________________ NH i u 0 1 12,, _____ , N ,.. C ,Ss.,........õ...--N \
H2C , ____ N /
)(4 Y3 0/

C
"0 0.--------0¨R5 4 , =
_ (di --I
.4.
Structure P-64 Structure P-64 c.,, Attorney Docket No. 68961.8021.W000 W
X/ x/VV

Y2 w "N''''s 1 I =
0. I 1 S
hl ....,..... 1 r,,,...,. 0 ________ õ, r _ , .., ,1 .
, ,yi 4.
____________________ y4 , __ NyS%.,,_.0õ--- N\ rj, , __________________________ N ,..,. cz Sc 1 N Y3 _________ N 7/ `=,,.
i N
----N
N

--=:---------- N
0¨ K

n Structure P-65 Structure P-66 0 Ni .4 0, A

,i HA 0 0, N) 1-, Y2 y r H2NN.,,_,,..õ,-,õ,õ_, 1 i H
o-N--,.....

0, FNi-------uJI

, N "
N
NI
).1 y2 / N.,..,,,,..

Y3 ¨L) 4 H2 Y4¨(. j 0 0-----1:--..--.. . N---____ ------='\,.0 I
n n a _ a a d Structure P-67 Structure P-68 ..1 t Attorney Docket No. 68961.8021.W000 HN N,...,..),........
/ HN -,.....1 ./õ/c) =
S
...
N-......... ,..../....'"=..õ.
=
H
_______________________________________________________________________________ ___________________ I
\
--, .., 4.
t.) C H F2 n.) \
C
4.
,/N ,..,."., y N
Yd M.N,TY2 0 N-....... i x---"w Structure P-69 Structure P-70 n H
N.) ,4 H
CH
2 cy, .1..
w ,.]

I
;
=
=
i N.1M

N., µõNµi WI.. %I,/ N

r-Om 4. : r ......Ø........CH 2 .....õ....õ,,CH 2 I
1¨
H S H
_______________________ S F-`
/
N
/
uil o N
X
\

W
"0 0 n n =
Structure P-71 Structure P-72 S' e---..1 (..J
-.1 .4.
c.,, Attorney Docket No. 68961.8021.W000 W H W

H
\ ------- kil N

X5 = X5N, ¨ 0 I
= 0 N
=
.¨+
=
0Wµ"11µ

,..
..

., N
H
4.
_____________________________ N
_______________________________________________ N
/

\
\

n Ni --.1 Structure P-73 Structure P-74 0, u., ...]

N

\ FN1 0 r-H HA

H
.------- 'i,',-' N \,.., r r = =
F¨' wi X5N ........sj =
= E 0 /4, 4, = Y1 Y 1 o _________________________________________ S
_________________________________________________ S
___________________________ N
/
_______________________________________________________________________________ N

"c1 \
X
\w n n =
_ 0 .
--a--, (..J
Structure P-75 Structure P-76 .4.
(.4 Attorney Docket No. 68961.8021.W000 S S-HA

¨
=
H
------(y ; 0 _ N N im=-=¨====1 H 1 N
1 N ' H tsJ

I
H =
--, N , .,7' R /
---, .., N
----,... 0 ., _______________________________________________________________________________ _______________ N ¨ ---, N rI5 '*s 0 '' N
II
)r N
.1.
H3C 0 0 R6 0 )"..,..........õ.õ...,.

r.....,..,.........õ. X¨VV 0 Structure P-77 Structure n Yi ...,....<1 H N

N
,4 ....õ...,../.........
cn A.
HA./ R6 cT, = R5 , 0H3 H
I
H 0 , NJ

G
r-X5 N \ ..........11,44, =
i I
, 1¨
'... ____________________________________________________________________ 0 ,i ___ __________________________ N
=
1 _______________________________________ S
o / _________________________________________________ N

\ R6 X
\
W
"d n n Structure P-79 Structure ¨
=
e---..1 (..J
-.1 .4.
c.,, Attorney Docket No. 68961.8021.W000 I

Yll I
\ N 0 HA \ N R6 N

, H

.-+
1 C H3 _ --, .., =
., X5 = _ 1,N0/j1111/0 =
z N
.1.
0 "4. ___ ______________________________ S I
S
________________ N
/ i N
............c......

\w 0\ R6 n Ni ,4 cy, .1..
w Structure P-81 Structure P-82 i.) o r-r H
wi rA '- 0 H

Y3 1 ,..., s 1....o NF1 N __ H
Y4 p: _2(_,. H _ 2 X
\ n \
o w o o w n =
_ a -a-, Structure P-83 Structure P-84 (..J
-.1 .4.
c.,, Attorney Docket No. 68961.8021.W000 Y
\i "-----C
-,R6 ....õN,, Yi--..,_ ...- N.;,....

H
Y2 y _______________________________________________________________________________ _________________________ NI t.) N, =
N-........./ -,,H...-.
_______________________________________________________________ 1 .."
C

=
=====...._ 1 H ----.
.r-_______________________________________________________________________________ ______ r s---S _________ .
,4 4.
x 1JT, 1 4 0 Y \\A/ ., y AA
...'.....................
=

n Structure P-85 Structure ,o H
cn A.
uo l,J

H .! 0 0 ---.........
T. X
iv 0 0 ---,......
S NN4)Crl o ......--------v 1-, SI-I 7 .----------I W
I
I--I
I-I

N
_______________________________________________________________________________ _____________________________________ ui N ______________________________________________________________ X5 N ___ X \
X
\w \w n Structure l-1 Structure 1-2 Structure 1-3 n a _ a a , t., , ,.
tõ

Attorney Docket No. 68961.8021.W000 131 \o , -i.
N
_...\VS CH3 N----__N
C¨N\<\

X
\ Y2 _______________________________________ Y1 Yi /

N

¨Y4 N
=
.4 =
--, .., 4.
N
N
4.

\AL."''--X----o n Structure 1-4 Structure 1-5 N) .4 0, .,..
u4 0 ¨1 R
,.]
w ),H 2 5 NO yi 0 0, NJ
o ( / 0 H
fl 1 Y

..kY3 r r 1-' u.)I
1 ......./......,,.,.......ej 4 o V\I- X
w õ...-X

n Structure 1-6 Structure 1-7 n a _ a -a-, ,...
, .,..
,., Attorney Docket No. 68961.8021.W000 0 ¨1 Yi R5, O H2 N
i1 0 W
N
X
\
rID7. H2 plY3 ts.) ( 0 N
H

H
=
¨, =
, t.) n.) W¨ X
Structure 1-8 Structure Y1 0 R5, Y3 i1 0 W N. 0 X

c\,oI7N. N 7N I ri=\ H2 / Y3 Ni ,4 \ _________________________________________________________________ 1 H
P ,, 0, .1..
w ,.]
0, r-NJ

r I
r V V - x WI

Structure 1-10 Structure -o n n a _ a -a-, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 0 R5 , Y3 No i1 N

C V= NVN I ¨I¨
X
CH2,0,7.N./'N I

5..f4 0 H ri--- X5 ---5= ¨ (I
=
..., =

0 /i\-, .., ., t,) N /
% ____________________________________________________________ Y2 N
Structure 1-12 Structure n '11 0 R5 N
¨
,4 X 0) ,+: C)c.r".1\1,7=N I x ¨
'Y'3 A.
UJ
,.1 !A CYi c N 0, h¨ X5 N

r-r 0 y N
sN", F-N /

i Structure 1-14 Structure -o n n a _ a -a-, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 Yi pl=), R5 N Y1 r_1),,,70,,,, w, P =, f ts.) =
'¨' --, .., ., t.) \N ¨X
Structure 1-16 Structure 1-17 Yli o ¨1}H1 1 R5 NO
Y3 r 1-w \x .
Ni \_1 (-NI
Y3 ,4 0) N
u, [I1HI I
c)) 1 n) z=

_,....õ.,,. Y2 Y2 Y2 0 0 r r WI
1N¨ X

Structure 1-18 Structure 1-19 n n a _ a -a-, ,...
, .,..
,õ

µ.0 ( / C

ild '.....-***"7¨ Y4 N
H
P
0, NJ

Attorney Docket D\ocket No. 68961.8021.W000 Yi (Y1 0 =
--H
li ..,,,,..t.......,....TY4 =
--, .., ., N

n.1 4.

VV--...., X ....---'*Nµ
\N--.....

Structure HIH-20 Structure 1-21 n Yi Y1 ¨1¨
Ni ,4 0, : ,ro-/
X d, w -.1 N
I-I

Y2 N.N. 'Y y2 11.--s,0 C H 3 0 i-I

o IN¨ X
Structure 1-22 Structure -o n n a _ a -a-, ,..
, ,.
,õ

Attorney Docket No. 68961.8021.W000 Yi Yi N

S_I _____________________________________________ / 1 1//NlIpi 4 ts.) =
P \
.4 =
--...
.., 4.
r..) N

n.) y ./-\

00,13 0 -----W ¨X
Structure 1-24 Structure 1-25 Yi Yi 1 o 0 R5 .,..... 30 W
Ni ¨ =>4....s.

-3¨

NM

Nv.N011 H
1_ IX] 5 I Y3 CI
I
oo N s,., 0 N

r-Y2 .\

r N /
Y4 j wi Structure 1-26 Structure 1-27 -o n n =
_ --a--, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 Vi Vi r1)..70 R5 N
W

N

/' X5-k'4 N
=

]
-, .., 4.
t.) n.) 1 II 1 4. ==,, N--.....

Structure 1-28 Structure Vi /=1) R5 sN Yi n N

vv 0 P
V4 ,4 cy, .1..
w /x5 0, NJ
sz I
ll 1 0 r-,,,,=,NN .,,, r i-1-' u.)I

Structure 1-30 Structure Vi o R5, Y3 Vi -- 1vH 2 ¨I¨

X

C 7. NVN
/
H
H rl X5 1 n 1 0 N ____ Y4 I

=

Y4 N ¨, =
-a-ca Structure 1-32 Structure 1-33 .4.
c.,, Attorney Docket No. 68961.8021.W000 R6 ., Y1 NI ,(........
_1_ _____________________________ N H IN
/--\ __________ H I I H
¨, I I \_1_, N\ .W
N

SN )( __ III
.*\ ,...\N

=
--, .., 4.
t=.) I
4.
Xs 0 Structure S-1 Structure S-2 yi o o n .., Y3 ___________ 11 N __ w (N 7,LN __ 1 I /=1=\

COss-....' 11 A = \
_______________________________________________________________________________ ___________________ H

Ni S 71 .112 -...... ...,...-1\11 ¨ _li N
.\ ./.' W

II

,4 cn A.
Lo ,.1 =

Fx I
cT) = Xs 0 =/-R6 Y2 6 y N

I-, r r 1-' Structure S-3 Structure S-4 wi CH3 ).............

N Xs 0 Yi 1 ¨I¨
II
HN
S 0 =
H
N
"d ).w...y_ Ni¨C )¨ N
/ /
II NH

N

W

n =

(..J
Structure S-5 Structure S-6 .4.
(,., Attorney Docket No. 68961.8021.W000 ..,-\

NH "
=
..., =
--...

OCH 3 .., 4.
N N
W
"

4.

N OCH3 0 './' kl..
N N

H H

Structure S-7 Structure S-8 n Ni \ 0 R
0) Y2 \( A.
UJ
=

,..^ R5 ......-W
X5 i..7.\õ.....õ,_. \

a) N

1 N __ X6 0 r-r 0.....7/N1..., N0.,...,,,, Nzkµ%.N,,,S\,,,,,,.., ve i-1 Y3 N ..1 Y3 Ni H
wi 0./..\''.
Y1 ..N.\==

X¨W¨ R6 "d n Structure S-9 Structure S-10 n eo =
_ --a--, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 < 1 'l I X W
=
..., =
---..
.., N Y R5 N '.

"

I
I

I 4 (..,... Y1 ../N.
N

I

n Structure S-11 Structure S-12 Structure S-13 o Ni cn .1..
w =
0, WI N
),....õ.
r-r r X \
u.)I
rN N 02N y \AI

rli Y3 "d n n Structure S-14 Structure S-15 Structure S-16 4 _ --a--, ,...
, .,..
,õ

0\.... j).........N y2 X Attorney Docket No. 68961.8021.W000 Yi / 212¨
\ ) / 5 /
N __ ,....-xePli"::

r..) E
, .., 4.
t,) n.) 4.
0 N ____________________________ N 0 qNikl F
________________________________________ NH C) H
/
----C.42 Yi 0 W ¨X
W
Structure S-17 Structure S-18 n Ni 0\\ / ---. N
cy, ut . N ____________ Yi¨N \
..]
=
0, t..) X5 ........ N /
(0 _______________________________________________________________________________ __________________ (------....-----.......õ-\ ..---- NN.k Y3 ../.....õ....1 CH2 iv 7....." N

,C) r r w,- X /CH 2 X
/
1-' wi 0.......õ =:. /0 /
Y2 Y4 \
R5¨X5 W
Structure S-19 Structure S-20 n n a _ a -a-, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 H H
0 N X5 ON¨N_=¨ CH
N\N.,V N=,. H
N/
S,,=,,,,.N.,.
H
p X5¨W
Y3 ---..*
=
--, ..
Y1 ( Y2 OC H3 4.
t,) n.) 4.

'N

sN..
o.\ ,/\INI
1 õ 2 1 ,, ^5 Structure 1-1 Structure T-2 Structure 1-3 n Yi 0 R5¨ X5¨ 0-..._.

Ni HA
,4 Y2N1,,, }A/ H 2 H 2 Y2 0 \ W 0) A.
UJ
.., ,.1 õ
/
_______________________________________________________________________________ _________________ S /5 0, NJ

4.
1 H3L, C

I k,r, 2 I

N
r ''''N H2C..õ....., Y1 Y3 X7N, i-1-' u.)1 Structure 1-4 Structure T-5 Structure 1-6 n n a _ a -a-, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 X6 -R6 , X5 ..," ',...
/ /
W c),, R46 % v 6 /µ

N
=
.,,,./.... N N õ,../N ..N,./../. \ ./., NH
H
I .., =
--.
NH
H H ,.." ,..,,,,N
,,,,,,,, ., t=.) N
N "
4.
.% 0 HN H H .

H H
0 NH , 0 H N
NHH 2N ,..N ,,N -,.....7., H H
NH H X36 2N ,,,.....,,, N,...,,,,../...,N,,,,.N., \

R36 0 0 .,=,,,,.,.

rµ36 0 HN n) \ ..,,,===\.., .././.
,4 0, X7 ¨N N
W A
. H
\ (.,) ,i 0, !Ji X5 ¨N N
H n) Structure 1-7 Structure T-8 r r H
wi -o n n a _ a -a-, ,...
, .,..
,õ

Attorney Docket No. 68961.8021.W000 ,x6¨R6 / R7 0.N., X
.../ R6 tsJ
=
,./N.,.N.,.,,,==, Nµõ,.,.N ..././N,,, N NH2 .4 H
=
--...
H H
.., =/.1.N1.=''\''N /'NH 2 ., N
0 1 NN,..;-NH 1 .,,,,.,.
HN

,.,.õ,.,.N N N.N,,,, H
IIH
H2Nõ.,..,.,N,"..,N
X36\

R36 0 0 ,....,,, ...,........, HN \ R36 0 0 ../../ ,..,.......õ
n HN
Ni X5 ¨N N

H
\ ,,,/=Sµ, ,.,, a) a, u) ..k X5 ¨N N -.]
=
H al ^, NJ
o Structure 1-9 T-9 Structure T-10 r r F-' LAI

W ¨X5 I
H0j....-......, ......õ..
Y2 N N H3C ¨( )--CI H3C
1 \ I oC H3>x lis õõOH 0 C H3 , *\., H \ R

wv /-N N N¨C¨CH3 "0 ,s5 H
I I Yi 3C
n n Y4 0õ7 HA . -L
=

e"

ca 4.
Structure 1-11 Structure 1-12 Structure 1-13 c.,, Attorney Docket No. 68961.8021.W000 X

___ N
IIA R5 1-1'N';4.c. Y2 Structure 1-14 Structure 1-15 Structure 1-16Ni 1.) a including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
m, n, R1, R2, R5, R35, R6, R36, R46, R7, R8, R38, T, W, X, X2, X4, X5, X35, X6, X36, X46, X7, Y1, Y2, Y31, Y32, Y3, Y4, Z, AA, HA, R, Rs, and R11-R16are defined the same as supra.
II. Pharmaceutical compositions comprisinc 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.
[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.
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, 140, 130, 15N, 125., -H, and 1311. 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, 6-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) p-D-galactosidase (6 -D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl- [3-D-galactosidase) or fluorogenic substrate 4-methylumbelliferyl- 13- 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.
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, appendicularia, 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 micro-encapsulated 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. 20th 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:

L OH
Structure F-C
is converted to a HPP having Structure L-1:

Li"L2 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.):

Li Wc Structure D
with compounds of Structure E (Scheme 1):

Structure E
wherein Wc is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy; and F, L1, L2, L4 and T are defined as supra.
T-L2-H + Fx // L4 )10. ./L4 z 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:
LA
Structure F-N
reacts with a compound having the following structure G:
WN

Structure G

to obtain a HPP of Structure L:
F\ /L4\ /T
Li L2 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; 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) HL{

\ /L4\ F
\ /
WN L2 Li L2 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(=0)0H, -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 acetonitrile. 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: C22H32CIN305S; MW: 486Ø
Calculated c1/0 C: 54.37; H: 6.64; N: 8.65; Cl: 7.29; 0: 16.46; S: 6.60; Found (:)/0 C: 54.32;
H: 6.68; N: 8.61; Cl: 7.32; 0: 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: C23H34CIN3065; MW: 516.05.
Calculated % C: 53.53; H: 6.64; N: 8.14; Cl: 6.87; 0: 18.60; S: 6.21; Found (:)/0 C: 53.49;
H: 6.68; N: 8.11; Cl: 6.90; 0: 18.64; S:6.18.
Preparation of acetamidophenylacetamidopenicillinic acid 2-diet hylaminopropyl 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:
C26H33CIN405S;
MW: 541.11. Calculated % C: 55.49; H: 6.89; N: 10.35; CI: 6.55; 0: 14.78; S:
5.92;
Found % C: 55.44; H: 6.92; N: 10.32; Cl: 6.58; 0: 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:
C26H33CIN405S; MW: 549.08. Calculated % C: 56.88; H: 6.06; N: 10.20; CI: 6.46;
0:
14.57; S: 5.83; Found % C: 56.85; H: 6.08; N: 10.19; CI: 6.47; 0: 14.59;
S:5.82.
Preparation of 3-1[1aminocarbonyl)oxy]methylk7-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]methy1]-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:
C22H31CIN407S2;
MW: 563.08. Calculated % C: 46.93; H: 5.55; N: 9.95; Cl: 6.30; 0: 19.89; S:
11.39;
Found (:)/0 C: 46.91; H: 5.57; N: 9.93; Cl: 6.32; 0: 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-pm 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 1 al , 1a2, 1a3, 1a4, 1 b, and 1 c. Apparent flux values of the tested compounds calculated from the slopes in the Figures 1 al , 1a2, 1a3 and 1a4 were summarized in Table la.
Apparent flux values of the tested compounds calculated from the slopes in the Figures lb and 1c are summarized in Tables lb and lc respectively.
[00152] Because the lowest detectable apparent flux values in this method was 1 pg /cm2/h, parent drugs that showed a apparent flux value equal to or less than 1 pg /cm2/h were considered as not detectable for penetrating across the skin tissue. For the parent compounds (e.g. penicillin V, penicillin 0) which had apparent flux values < 1 pg /cm2/h, their HPPs had detectable apparent flux values. For the parent compounds which had apparent flux values > 1 pg /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 la. In vitro Penetration Rate of HPPs and their Parent Compounds (1) HPP HPPs mg Parent mg Structure # /cm2/h compounds /cm2/h P-83 6-phenoxyacetacetamidopenicillanic 0.72 penicillin V <0.001 acid 2-diethylaminoethyl ester 0.06 hydrochloride P-84 Allylmercaptomethylpenicillinic acid 2- 0.65 penicillin 0 <0.001 dimethylaminoethyl ester hydrochloride 0.05 P-11 6-(2,6-dimethoxybenzamido)penicillinic 0.52 Methicillin <0.001 acid 2-dipropylaminoethyl ester 0.07 hydrochloride P-2 6-(5-methyl-3-phenyl-2-isoxazoline-4- 0.77 Oxacillin <0.001 carboxamido)penicillinic acid 4- 0.08 piperidineethyl ester hydrochloride P-2 6-[3-(o-chloropheny1)-5-methy1-4- 0.85 cloxacillin <0.001 isoxazolecarboxamido]penicillinic acid 3- 0.05 piperidineethyl ester hydrochloride P-2 6-[3-(2,6-dichloropheny1)-5-methy1-4- 0.58 Dicloxacillin <0.001 isoxazolecarboxamido]penicillinic acid 1- 0.05 piperidineethyl ester hydrochloride _ P-3 6-[D(-)-a- 0.82 Ampicillin <0.015 aminophenylacetamidopenicillinic acid 0.06 ethyl ester hydrochloride P-7 D-a-[(imidazolidin-2-on-1- 0.72 Azlocillin <0.001 yl)carbonylamino]benzylpenicillin 2- 0.05 pyrrolidinemethyl ester hydrochloride P-85 6R-[2-[3-(methylsulfony1)-2-oxo-1- 0.79 Mezlocillin <0.001 imidazolidinecarboxamido]-2- 0.07 phenylacetamido]penicillinic acid 1-pyrrolidineethyl ester hydrochloride P-1 6-D(-)-a-(4-ethyl-2,3-dioxo-1- 0.74 piperacillin <0.001 piperazinylcarbonylamino)-a- 0.08 phenylacetamidopenicillinic acid 2-HPP HPPs mg Parent mg Structure # /cm2/h compounds /cm2/h diethylaminoethyl ester hydrochloride P-19 7-(2-thienylacetamido)cephalosporanic 0.62 Cephalothin <0.001 acid 2-diethylaminoethyl ester 0.06 hydrochloride P-86 7-[(hydroxyphenylacetyl)amino]-3-[[(1- 0.75 Cefamandole <0.001 methyl-1H-tetrazol-5-yl)thio]methyl]-8- 0.05 oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride P-26 3-[[(aminocarbonyl)oxy]methyl]-7-[[2- 0.67 Cefuroxime <0.001 furanyl(methoxyimino)acetyl]amino]-8- 0.04 oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride P-14 3-[[(aminocarbonyl)oxy]methyl]-7- 0.61 cefoxitin <0.001 methoxy-8-oxo-7-[(2- 0.05 thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride P-62 7-[[[2- 0.52 Ceforanide <0.001 (acetylaminomethyl)phenyl]acetyl]amino] 0.04 -3-E1-(ethoxylcarbonylmethyl)-1H-tetrazol-5-yl]thio]methy1]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride P-20 7-[(acetylaminophenylacetyl)amino]-3- 0.71 Cefaclor <0.016 chloro-8-oxo-5-thia-1- 0.05 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride P-29 3-[(acetyloxy)methyI]-7-[[(2-acetylamino- 0.73 Cefotaxime <0.018 4-thiazolyI)(methoxyimino)acetyl]amino]- 0.06 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride P-28 7-[[(2-acetylamino-4- 0.62 Ceftizoxime <0.010 thiazolyI)(methoxyimino)acetyl]amino]-8- 0.05 oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl HPP HPPs mg Parent mg Structure # /cm2/h compounds /cm2/h ester hydrochloride P-39 7-[[[[(4-ethyl-2,3-dioxo-1- 0.57 Cefoperazone <0.015 piperazinyl)carbonyl]amino](4- 0.04 acetoxyphenyl)acetyl]amino]-3-[[(1-methy1-1H-tetrazol-5-y1)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride P-46 7-[2-(2-acetylamino-4-thiazoly1)-2-((Z)- 0.51 Cefpodoxime <0.001 methoxyimino)acetamido]-3- 0.03 proxetil (methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride P-45 7-[2-(2-acetylamino-4-thiazoly1)-2-((Z)- 0.58 Cefixime <0.010 ethoxycarbonylmethoxy)imino]acetamido 0.05 ]-3-(viny1)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride Table lb. In vitro Penetration Rate of HPPs of beta-lactamases inhibitors and their Parent Compounds (11) HPP HPPs mg Parent compounds mg Structure /cm2/h /cm2/h 1-4 [2S-(2a1pha,3beta,5a1pha)]-3- 0.32 [2S-(2a1pha,3beta,5a1pha)]-<0.001 Methyl-7-oxo-3-(1H-1,2,3- 0.03 3-Methy1-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1- triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2- azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide 1- carboxylic acid 4,4-dioxide piperidineethyl ester.HCI salt sodium salt (tazobactam) (tazobactam-PEE) 1-3 (2S,5R)-3,3-dimethy1-7-oxo- 0.35 (2S,5R)-3,3-dimethy1-7-oxo- <0.001 4-thia-1- 0.03 4-thia-l-azabicyclo[3.2.0]heptane-2- azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide carboxylic acid 4,4-dioxide N,N-diethylaminoethyl sodium (sulbactam), ester.HCI salt (sulbactam-DEE) 1-2 (2R,5R,Z)-3-(2- 0.29 (2R,5R,Z)-3-(2- <0.001 hydroxyethylidene)-7-oxo-4- 0.02 hydroxyethylidene)-7-oxo-4-oxa-1-aza- oxa-1-aza-bicyclo[3.2.0]heptane-2- bicyclo[3.2.0]heptane-2-carboxylic acid 4- carboxylic acid (clavulanic piperidineethyl ester.HCI salt acid) (clavulanic acid-PEE) 1-9 [(N- 0.37 [(N- <0.001 benzyloxycarbonylamino)met 0.03 benzyloxycarbonylamino)m hy1]-phosphonic acid (4- ethyl]-phosphonic acid nitrophenyl)(N,N- mono-(4-nitrophenyl) ester diethylaminomethyl) sodium salt ester.HCI salt 1-33 [(N- 0.25 [(N- <0.001 benzyloxycarbonylamino)met 0.04 benzyloxycarbonylamino)m hy1]-phosphonic acid (3- ethyl]-phosphonic acid pyridinyl)(1-piperidineethyl) mono-(3-pyridinyl) ester ester.HCI salt sodium salt Table 1c. In vitro Penetration Rate of HPPs of sulfonamides, sulfones, quinolones and their Parent Compounds (111) HPP HPPs mg Parent compounds mg Structure /cm2/h /cm2/h 5-1 4-(4- 0.18 4- <0.001 dimethylaminobutyryl)amidobe 0.03 aminobenzenesulfonami nzenesulfonamide.HCI de(sulfanilamide), salt(DMAB-sulfanilamide), S-9 6-oxo-3-(2-[4-(N-pyridin-2- 0.21 6-oxo-3-(2-[4-(N-pyridin- <0.001 ylsulfamoyl)phenyl]hydrazono)c 0.03 2-yclohexa-1,4-dienecarboxyl ic ylsulfamoyl)phenyl]hydra acid N,N-diethyaminopropyl zono)cyclohexa-1,4-ester.HCI salt (sulfasalazine- dienecarboxylic DEPE), acid(sulfasalazine) T-15 1-cyclopropyl- 6-fluoro- 4-oxo- 0.29 1-cyclopropyl- 6-fluoro-<0.001 7-piperazin- 1-yl- quinoline- 3- 0.02 4-oxo- 7-piperazin- 1-yl-carboxylic acid butyl ester.HCI quinoline- 3-carboxylic salt(ciprofloxacin-BE), acid, S-11 1-ethy1-7-methy1-4-oxo- 0.25 1-ethy1-7-methy1-4-oxo- <0.001 [1,8]naphthyridine-3-carboxylic 0.04 [1,8]naphthyridine-3-acid N,N-diethylaminoethyl carboxylic acid(nalidixic ester.HCI salt(nalidixic acid- acid), DEE), 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-chloropheny1)-5-methy1-4-isoxazolecarboxam ido]penici II inic 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 HPP 6-(2,6- 6-(5-methyl-3- 6-[3-(o-chlorophenyl)-5-dimethoxybenzamido)pe phenyl-2- methyl-4-n icill i nic acid 2- isoxazoline-4- isoxazolecarboxamidolpeni diethylaminoethyl ester carboxamido)penicil cillinic acid 2-hydrochloride linic acid 2-diethylaminoethyl ester diethylaminoethyl hydrochloride ester hydrochloride parent methicillin oxacillin cloxaciffin drug Amount of parent drug found in blood, liver, kidney, muscel and brain.
Blood 27 +/-6 28 +/-5 25 +/-8 (pg/g) Liver 15+/-5 18+/-7 14+1-6 (pg/g) Kidney 15+/-5 16+1-5 12+1-7 (pg/g) Muscel 20 +/-5 22 +/-5 20 +1-7 (pg/g) Brain 11 +/-6 8 +/-6 9 +/-5 (pg/g)
[00154] 90 lactating dairy cows were recruited. 500 mg of 6-phenoxyacetacetam idopenicil lanic acid 2-diethylaminoethyl ester hydrochloride (penicillin V-DEE), 6-(2,6-dimethoxybenzamido)penicillinic acid 2-diethylaminoethyl ester hydrochloride (methicillin-DEE), or 7-[[(2-acetylam ino-4-thiazoly1)(methoxyi mino)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 prod rugs 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 3.1n vivo penetration of HPP through blood-milk barrier HPP Parent drug Parent drug found in milk after topical application penicillin V-DEE penicillin V 23 +/-5 pg/g methicillin-DEE Methicillin 25 +/-8 pg/g ceftizoxime-DEE Ceftizoxime 28 +/-6 pg/g 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-PM E), methicillin, 7-[[(2-acetylamino-4-thiazolyI)(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. Coli.
Penicillin penicillin methicillin methicillin- ceftizoxime ceftizoxi V-PEE PME me-DEE
Drug 0.2 55 0.25 50 0.2 53 amount in cell (mmol/g wet cell) 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 HPP Parent Half life compounds (min) 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl penicillin V
8 +1-1 ester hydrochloride allylmercaptomethylpenicillinic acid 2-diethylaminoethyl ester penicillin 0 8 +/-1 hydrochloride 6-(2,6-dimethoxybenzamido)penicillinic acid 2- Methicillin 10 +/-1 diethylaminoethyl ester hydrochloride 6-(5-methyl-3-phenyl-2-isoxazoline-4-carboxamido)penicillinic Oxacillin 12 +/-1 acid 2-diethylaminoethyl ester hydrochloride 6-[3-(o-chlorophenyI)-5-methyl-4- cloxacillin 8 +/-1 isoxazolecarboxamido]penicillinic acid 2-diethylaminoethyl ester hydrochloride 6-[3-(2,6-dichlorophenyI)-5-methyl-4- Dicloxacillin 12+/-1 isoxazolecarboxamido]penicillinic acid 2-diethylaminoethyl ester hydrochloride 6-[D(-)-a-acetamidophenylacetamidopenicillinic acid 2- Ampicillin 10 +/-1 diethylaminoethyl ester hydrochloride D-a-[(imidazolidin-2-on-1-yl)carbonylamino]benzylpenicillin 2- Azlocillin 9 +/-1 diethylaminoethyl ester hydrochloride 6R-[2-[3-(methylsulfonyI)-2-oxo-1-imidazolidinecarboxamido]- Mezlocillin 13 +/-1 HPP Parent Half life compounds (min) 2-phenylacetamido]penicillinic acid 2-diethylaminoethyl ester hydrochloride 6-D(-)-a-(4-ethy1-2,3-dioxo-1-piperazinylcarbonylamino)-a- piperacillin 15 +/-1 phenylacetamidopenicillinic acid 2-diethylaminoethyl ester hydrochloride 7-(2-thienylacetamido)cephalosporanic acid 2- Cephalothin 9 +1-1 diethylaminoethyl ester hydrochloride 7-[(hydroxyphenylacetypamino]-3-[[(1-methyl-1H-tetrazol-5- Cefamandole 10 +/-1 yl)thio]methy1]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride 3-[[(aminocarbonyl)oxy]methyl]-74[2- Cefuroxime 8+/-1 furanyl(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2- cefoxitin 7+/-1 thienylacetyl)amino]-5-thia-1-azabicyclo[4.2 .0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride 7-[[[2-(acetylaminomethyl)phenyl]acetyl]amino]-3-[[[1- Ceforanide 9+/-1 (ethoxylcarbonylmethyl)-1H-tetrazol-5-yl]thio]methy11-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride 7-[(acetylaminophenylacetyl)amino]-3-chloro-8-oxo-5-thia-1- Cefaclor 8+/-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride 3-[(acetyloxy)methy1]-7-[[(2-acetylamino-4- Cefotaxime 10+/-1 thiazoly1)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride 7-[[(2-acetylamino-4-thiazoly1)(methoxyimino)acetyl]amino]-8- Ceftizoxime .. 11+/-1 oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride 7-[[[[(4-ethy1-2,3-dioxo-1-piperazinyl)carbonyl]amino](4- Cefoperazone 12+/-acetoxyphenyl)acetyl]am ino]-3-[[(1-methy1-1H-tetrazol-5-yl)thio]methy1]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride 7-[2-(2-acetylamino-4-thiazoly1)-2-((Z)- Cefpodoxime 8+/-1 methoxyimino)acetamido]-3-(methoxymethyl)-8-oxo-5-thia-1- proxetil azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride HPP Parent Half life compounds (min) 742-(2-acetylamino-4-thiazoly1)-24(Z)- Cefixime 9+1-1 ethoxycarbonylmethoxy)imino]acetamido]-3-(vinyI)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride 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 13-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-resi stant Staphylococcus aureus (M RSA) Penicillin Penicillin Methicillin Methicillin Ceftizoxi Ceftizoxim V V-PEE -PME me e-DEE
MIC 3524 1 2157 10 2786 0.5 (mg/L) Table 6b. MICs (mg/L) of various antibiotics plus beta-lactamase inhibitors or their pro-drugs.
Antibiotic E. coli K. E. cloacae B. fragilis pneumonlae Ceftriaxone 16 0.5 1 8 ceftriaxone / tazobactam 8/1 0.3/0.0375 0.3/0.0375 4/0.5 Ceftriaxone/tazobactam- 2/0.25 0.05/0.00625 0.1/0.0125 1/0.125 PEE
Ampicillin 6 0.3 5 68 Ampicillin/sulbactam 3/0.375 0.1/0.0125 3/0.375 30/3.75 Ampicillin/sulbactam- 0.5/0.0625 0.01/0.00125 0.05/0.00625 5/0.625 DEE
Table 6c. MICs (mg/L) of sulfonamide and quinolones and their pro-drugs.
Antibiotic E. coli S. aureus E. faecalis Sulfisoxazole 16 64 55 DMAB-acetylsulfisoxazole 0.5 1 1 Ciprofloxacin 10 128 2 ciprofloxacin-BE 0.2 5 0.05 nalidixic acid 6 158 64 nalidixic acid-DEE 0.2 5 1 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-thiazoly1)(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/I) of some prodrugs of beta-lactam antibiotics towards fungi in vitro.
Penicillin V- Methicillin- Ceftizoxime-Pathogens DEE DEE DEE
Aspergillus nidulans 3 8 4 Trichophyton mentagrophytes 12 22 9 Microsporum canis 2 8 2 Candida albicans 7 16 8 Aspergillus niger 3 9 4 Aspergillus tereus 2 12 4 Penicillium carylophilium 2 9 3 Fusarium oxisporum 3 8 5 Fusarium aquaductum 2 10 3 Aspergillus giganteus 3 9 5 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 71(2-acetylamino-4-thiazolyI)(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 Cure Rate (13/0) Prod rugs Number of Cows Day 3 Day 8 Day 15 Day 22 Penicillin V-DEE 30 50 90 93 97 Methicillin-DEE 30 43 90 97 100 Ceftizoxime-DEE 30 53 93 99 100 Table 8b. Bacteriological cure rates (day 22) of the topical treatment of cow mastitis with the novel prodrugs of antibiotics Pathogens HPP
Penicillin V-DEE Methicillin-DEE Ceftizoxime-DEE
Staphylococcus aureus No of cows 6 5 6 No. cured (`)/0) 4 (67%) 4 (80%) 5(83%) Streptococcus uberis No of cows 10 10 11 No. cured C70 8 (80%) 7 (70%) 9 (82%) E. coli No of cows 8 10 8 No. cured (%) 7 (87.5%) 8 (80%) 7 (87.5%) Coagulase-negative staphylococci No of cows 9 7 8 No. cured (%) 7 (78%) 6 (85.7%) 7 (87.5%) Enterobacteriaceae No of cows 7 8 6 No. cured (%) 6 (85.7%) 6 (75%) 5 (83.3%) 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 x107CFU, then the treatments began. Group A was untreated group (n=20), group B was the treated group with isoniazid/moxifoxacin/pyrazinamide (0.18/0.22/1.2mm01/kg, were given orally) for 45 days, group C was the treated group with isoniazid/moxifoxacin/pyrazinamide (0.18/0.22/1.2mmo1/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-cyclopropy1-7-[(1S, 6S)-2 , 8-diazabicyclo [4.3.0]non-8-yI]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid butyl ester(pro-moxifoxacin)/pyrazinoic acid N, N-diethylaminoethyl ester (pro- pyrazinoic acid, 0.18/0.22/1.2mmo1/kg, were given tansdermally) for 45 days, group E was the treated group with pro-isoniazid/pro-moxifoxacin/pro-pyrazinoic acid (0.18/0.22/1.2mm01/kg, were given tansdermally) for 90 days, group F is the treated group with pro-isoniazid/pro-moxifoxacin/pro-pyrazinoic acid (0.06/0.07/0.4mm01/kg, were given tansdermally) for 45 days, and group G
was the treated group with pro-isoniazid/pro-moxifoxacin/pro-pyrazinoic acid (0.06/0.07/0.4mm01/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 transdermally (Tables 9a and 9b).

Table 9a. Treatment regimens and results Mean lung CFU
Treatment regimen Before After 45days After 90 treatment of treatment days of treatment Untreated (A) 8.23 0.27 Died Died x107 isoniazid/moxifoxacin/pyrazinamide 3.23 0.35 0.18/0.22/1.2mmol/kg, orally x103 isoniazid/moxifoxacin/pyrazinamide 10.23 1.55 0.18/0.22/1.2mmol/kg, orally Pro-isoniazid/pro-moxifoxacin/pro- 1.23 0.35 pyrazinamide 0.18/0.22/1.2mmol/kg, transderm ally Pro-isoniazid/pro-moxifoxacin/pro- 0 pyrazinamide 0.18/0.22/1.2mmol/kg, transderm ally Pro-isoniazid/pro-moxifoxacin/pro- 4.23 0.55 pyrazinamide 0.06/0.07/0.4mm01/kg, transderm ally Pro-isoniazid/pro-moxifoxacin/pro- 0 pyrazinamide, 0.06/0.07/0.4mm01/kg, transdermally Table 9b. Outcomes of test-of-cure assessments Proportion (%) of mice cured Treatment regimen after treatment for After After 90 days of 45day5 of treatment treatment Untreated (A) 0/20 (0) 0/20 (0) isoniazid/moxifoxacin/pyrazinamide 2/20 (10) 0.18/0.22/1.2mmol/kg, orally isoniazid/moxifoxacin/pyrazinamide 5/20 (25) 0.18/0.22/1.2mmol/kg, orally Pro-isoniazid/pro-moxifoxacin/pro- 18/20 (90) pyrazinamide 0.18/0.22/1.2mmo1/kg, transderm ally Pro-isoniazid/pro-moxifoxacin/pro- 20/20 (100) pyrazinamide 0.18/0.22/1.2mm01/kg, transderm ally Pro-isoniazid/pro-moxifoxacin/pro- 10/20 (50) pyrazinamide 0.06/0.07/0.4mmo1/kg, transderm ally Pro-isoniazid/pro-moxifoxacin/pro- 20/20 (100) pyrazinamide, 0.06/0.07/0.4mm01/kg, transderm ally 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-cyclopropy1-7-[(1S,6S)-2,8-diazabicyclo [4.3.0]non-8-y1]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid butyl ester(pro-moxifoxacin)/40 mg of pyrazinoic acid N,N-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-dimethylaminobutyrylamidopheny1-4'-aminophenylsulfone (pro-dapsone)/ 50mg of 1-cyclopropy1-7-[(1S,6S)-2,8-diazabicyclo [4.3.0]non-8-y1]-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-a-[(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(-)-a-(4-ethy1-2,3-dioxo-1-piperazinylcarbonylamino)-a-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]methyI]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 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(-)-a-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-a-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-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 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]methy1]-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 (16)

CLAIMS:
1. A compound having the following chemical structure:
FN...., ...õ....õ.L.,_ ....õ,,T
L1 Llr SthNUM L-1 including stereoisomers and/or pharmaceutically acceptable salts thereof;
wherein F is selected from Structure FP-2, Structure FP-7, and Structure FI-4:
\ 0 N--1' /1 Y
0 cvN,.......N \ N
CH, H 3- CH 3 C H3 / N ____________________ 0 0 / \

Structure FP-2 Structure FP-7 N-----.
/\-------N
C¨N
H2 _______ Yi N

Structure FI-4 .

T is Structure W-2 or Structure W-4 HA/RI
R11¨N Rii¨Ri3 / _______________________________ R12 N¨R12 ¨R
Structure W-2 Structure W-4 ;

Date Recue/Date Received 2020-1 2-1 1 HA is selected from nothing, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, disulfuric 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, glucuronic 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 nothing and substituted and unsubstituted alkyl;
Ri is selected from 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 is selected from H and substituted and unsubstituted alkyl;
R6 is selected from H, F, CI, Br, I, C(=0)R6, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-IH-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, and substituted and unsubstituted heteroaryl;
Rii-R13 are independently substituted and unsubstituted alkyl;
Yi-Y4 and Y31 are independently selected from H, OH, OC(=0)CH3, CH3, C2H5, C3H7, C4H9, R6, OCH3, OC2H5, CH3S02, CH3S03, NO2, CN, CF3, OCF3, CH2C(=0)NH2, F, Br, I, CI, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and Date Recue/Date Received 2020-12-11 unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, and substituted and unsubstituted alkylcarbonyl;
Li is selected from nothing, 0, S, -0-L3-, -S-L3-, and -N(L3)-;
L2 is selected from nothing, 0, S, -0-L3-, -S-L3-, and -N(L3)-;
L4 iS C=0 or C=S; and each L3 is independently selected from nothing, H, substituted and unsubstituted alkyl and substituted and unsubstituted alkoxyl.
2. The compound according to claim 1, which is:
6-(5-methyl-3-phenyl-2-isoxazoline-4-carboxam ido)penicillinic acid 4-p iperid ineethyl ester. HA;
6-[3-(o-ch lorophenyl)-5-methyl-4-isoxazolecarboxam ido]penicillinic acid 3-p iperid ineethyl ester. HA;
6-[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarboxam ido]penicillinic acid 1-p iperid ineethyl ester. HA;
D-a-[(im idazolidin-2-on-1 -yl)carbonylam ino]benzylpenicillin 2-pyrrolidinemethyl ester.HA;
6R-[2-[3-(methylsulfonyl)-2-oxo-1-im idazolidinecarboxam ido]-2-phenylacetam ido]penicillinic acid 1-pyrrolidineethyl ester.HA; or [2S-(2a,3[3,5a)]-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.HA;
wherein HA is selected from nothing, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, disulfuric 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, Date Recue/Date Received 2020-12-11 maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, and pamoic acid.
3. A compound having the following chemical structure:

Stmturc L 1 including stereoisomers and/or pharmaceutically acceptable salts thereof;
wherein F is selected from Structure FP-11, Structure FP-84, Structure FP-85, and Structure Fl-86:

__________________________ N CH3 N

CH
Structure FP-11 Structure FP-84 (:) /CH3 O

N S

H
0 H.) 0 ______________________________________________________ N
Structure FP-85 Structure FP-86 T is Structure W-2 or Structure W-4 Date Recue/Date Received 2020-12-11 HA/R, R11¨N Rii ¨Ri3 / ______________________________ R12 N ¨R12 / HA
¨R ¨R
Structure W-2 Structure W-4 ;
HA is selected from nothing, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, disulfuric 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, glucuronic 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 nothing and substituted and unsubstituted alkyl;
Ri is selected from 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 is selected from H and substituted and unsubstituted alkyl;
R6 is selected from H, F, CI, Br, I, C(=0)Rs, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3-dihydro-IH-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, and substituted and unsubstituted heteroaryl;
Rii-R13 are independently substituted and unsubstituted alkyl;

Date Recue/Date Received 2020-12-11 Li is selected from nothing, 0, S, -0-L3-, -S-L3-, and -N(L3)-;
L2 is selected from nothing, 0, S, -0-L3-, -S-L3-, and -N(L3)-;
L4 is C=0 or C=S; and each L3 is independently selected from nothing, H, substituted and unsubstituted alkyl and substituted and unsubstituted alkoxyl.
4. The compound according to claim 3, which is:
allylm ercaptom ethylpen icill in ic acid 2-d iethylam inoethyl ester. HA{2-(diethylam ino)ethyl 3,3-d imethyl-7-oxo-6-[[(2-propenylthi io)acetyl]am ino]-4-th ia-1-azab icyclo[3.2 gheptanes-2-carboxylate. HA}, 6-(2,6-dimethoxybenzam ido)pen icillin ic acid 2-d ipropylam inoethyl ester.HA{2-(dipropylam ino)ethyl 6-[(2,6-dimethoxybenzoyl)am ino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2 gheptanes-carboxylate. HA}, 6R-[2-[3-(m ethylsu lfonyl)-2-oxo-1-im idazo lid inecarboxam ido]-2-phenylacetam ido]pen icillin ic acid 1-pyrrolidineethyl ester.HA{1-pyrrolidineethyl 3,3-d im ethyl-6-[[[[[(3-(m ethylsu lfonyl)-2-oxo-1-im idazo lidinyl]carbonyl]am ino]phenylacetyl]am ino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptanes-2-carboxylate.HAl, or 7-[(hydroxyphenylacetyl)amino]-[[(1-m ethyl-1H-tetrazol-5-yl)th io]m ethyl]-8-oxo-5-th ia-1-azab icyclo[4 .2 .0]oct-2-ene-2-carboxylic acid 2-d iethylam inoethyl ester. HA{2-(d iethylam ino)ethyl 7-[(hydroxyphenylacetyl)am ino]-3-[[(1-m ethyl-1H-tetrazol-5-yl)th io]m ethyl]-8-oxo-5-th ia-1-azabicyclo[4.2 goct-2-ene-2-carboxylate. HA 1;
wherein HA is selected from nothing, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, disulfuric 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, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, and pamoic acid.

Date Recue/Date Received 2020-12-11
5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition according to claim 5, the pharmaceutically acceptable carrier being polar.
7. The pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable carrier is selected from alcohol, acetone, ester, water, and aqueous solution.
8. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is for administration to a biological barrier which the compound penetrates.
9. The pharmaceutical composition according to any one of claims 5 to 8 for treating a condition in a biological subject.
10. The pharmaceutical composition according to claim 9, wherein the condition is selected from pain, injuries, and microorganism related conditions.
11. The pharmaceutical composition according to claim 10, wherein the microorganism related condition is selected from bacteria-related conditions, protozoa-related conditions, fungi-related conditions, and conditions caused by virus.
12. The pharmaceutical composition according to claim 11, wherein the bacteria-related condition is selected from 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 Date Recue/Date Received 2020-12-11 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.
13. The pharmaceutical composition according to claim 12, wherein the infection condition is selected from an infection condition in an organ selected from 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.
14. The pharmaceutical composition according to claim 11, wherein the protozoa-related condition is selected from malaria, sleeping sickness, and toxoplasmosis.
15. The pharmaceutical composition according to claim 11, wherein the fungi-related condition is selected from aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, h istoplasm os is, paracoccidiomycosis, sporotrichosis, and zygomycosis.
16. The pharmaceutical composition according to claim 11, wherein the condition caused by virus is selected from influenza, yellow fever, and AIDS.

Date Recue/Date Received 2020-12-11
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