EP2440523A1 - High penetration compositions or prodrugs of antimicrobials and antimicrobial-related compounds - Google Patents
High penetration compositions or prodrugs of antimicrobials and antimicrobial-related compoundsInfo
- Publication number
- EP2440523A1 EP2440523A1 EP10785754A EP10785754A EP2440523A1 EP 2440523 A1 EP2440523 A1 EP 2440523A1 EP 10785754 A EP10785754 A EP 10785754A EP 10785754 A EP10785754 A EP 10785754A EP 2440523 A1 EP2440523 A1 EP 2440523A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substituted
- unsubstituted
- group
- acid
- antimicrobial
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 230000000845 anti-microbial effect Effects 0.000 title claims abstract description 106
- 150000001875 compounds Chemical class 0.000 title claims abstract description 96
- 239000004599 antimicrobial Substances 0.000 title claims abstract description 89
- 230000035515 penetration Effects 0.000 title claims abstract description 43
- 239000000203 mixture Substances 0.000 title claims description 103
- 229940002612 prodrug Drugs 0.000 title abstract description 19
- 239000000651 prodrug Substances 0.000 title abstract description 19
- 230000004888 barrier function Effects 0.000 claims abstract description 41
- 239000003814 drug Substances 0.000 claims abstract description 38
- 229940079593 drug Drugs 0.000 claims abstract description 38
- -1 2- oxo-1 -imidazolidinyl Chemical group 0.000 claims description 82
- 238000000034 method Methods 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 47
- 125000003118 aryl group Chemical group 0.000 claims description 46
- 239000002253 acid Substances 0.000 claims description 45
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 44
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 41
- 229910052794 bromium Inorganic materials 0.000 claims description 34
- 229910052731 fluorine Inorganic materials 0.000 claims description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- 229910052801 chlorine Inorganic materials 0.000 claims description 33
- 229910052740 iodine Inorganic materials 0.000 claims description 33
- 229910052760 oxygen Inorganic materials 0.000 claims description 33
- 229910052717 sulfur Inorganic materials 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 150000002148 esters Chemical class 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 229910052721 tungsten Inorganic materials 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 26
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 125000003282 alkyl amino group Chemical group 0.000 claims description 23
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims description 23
- 239000002132 β-lactam antibiotic Substances 0.000 claims description 23
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 23
- 125000000304 alkynyl group Chemical group 0.000 claims description 22
- 238000012360 testing method Methods 0.000 claims description 22
- 150000001350 alkyl halides Chemical class 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 241000233866 Fungi Species 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 241000894006 Bacteria Species 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- 125000004414 alkyl thio group Chemical group 0.000 claims description 16
- 125000003277 amino group Chemical group 0.000 claims description 15
- 239000003937 drug carrier Substances 0.000 claims description 15
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- 244000005700 microbiome Species 0.000 claims description 15
- 210000000056 organ Anatomy 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 241000700605 Viruses Species 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 125000005647 linker group Chemical group 0.000 claims description 13
- 239000002207 metabolite Substances 0.000 claims description 13
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 11
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 229910003204 NH2 Inorganic materials 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 230000000149 penetrating effect Effects 0.000 claims description 9
- 208000013223 septicemia Diseases 0.000 claims description 9
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 claims description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 210000002784 stomach Anatomy 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 7
- 201000009906 Meningitis Diseases 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 208000002193 Pain Diseases 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 239000010452 phosphate Substances 0.000 claims description 7
- 150000003141 primary amines Chemical group 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- 208000004429 Bacillary Dysentery Diseases 0.000 claims description 6
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 6
- 208000007764 Legionnaires' Disease Diseases 0.000 claims description 6
- 206010024229 Leprosy Diseases 0.000 claims description 6
- 229910004845 P(O) Inorganic materials 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 206010035664 Pneumonia Diseases 0.000 claims description 6
- 206010039438 Salmonella Infections Diseases 0.000 claims description 6
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 6
- 210000004556 brain Anatomy 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 201000001371 inclusion conjunctivitis Diseases 0.000 claims description 6
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 210000004185 liver Anatomy 0.000 claims description 6
- 210000004072 lung Anatomy 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 206010039447 salmonellosis Diseases 0.000 claims description 6
- 201000005113 shigellosis Diseases 0.000 claims description 6
- 239000005711 Benzoic acid Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 235000010233 benzoic acid Nutrition 0.000 claims description 5
- 230000002496 gastric effect Effects 0.000 claims description 5
- 208000014674 injury Diseases 0.000 claims description 5
- 210000003734 kidney Anatomy 0.000 claims description 5
- 210000000214 mouth Anatomy 0.000 claims description 5
- 210000001331 nose Anatomy 0.000 claims description 5
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 5
- 125000005009 perfluoropropyl group Chemical group FC(C(C(F)(F)F)(F)F)(F)* 0.000 claims description 5
- 210000000664 rectum Anatomy 0.000 claims description 5
- 210000002345 respiratory system Anatomy 0.000 claims description 5
- 238000012216 screening Methods 0.000 claims description 5
- 150000003335 secondary amines Chemical group 0.000 claims description 5
- 150000003512 tertiary amines Chemical group 0.000 claims description 5
- 150000003952 β-lactams Chemical class 0.000 claims description 5
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 4
- 206010068172 Anal pruritus Diseases 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- 206010012735 Diarrhoea Diseases 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- 208000009544 Pruritus Ani Diseases 0.000 claims description 4
- 208000027418 Wounds and injury Diseases 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 235000001014 amino acid Nutrition 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- 210000001072 colon Anatomy 0.000 claims description 4
- 230000006378 damage Effects 0.000 claims description 4
- 210000001198 duodenum Anatomy 0.000 claims description 4
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 4
- 210000001508 eye Anatomy 0.000 claims description 4
- 210000000232 gallbladder Anatomy 0.000 claims description 4
- 210000002216 heart Anatomy 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- 210000000936 intestine Anatomy 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 210000000496 pancreas Anatomy 0.000 claims description 4
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 4
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- LWEXAPVESMZHFG-NRFANRHFSA-N (2s)-2,6-diamino-n-hexadecylhexanamide Chemical compound CCCCCCCCCCCCCCCCNC(=O)[C@@H](N)CCCCN LWEXAPVESMZHFG-NRFANRHFSA-N 0.000 claims description 3
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 claims description 3
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
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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
- C07D499/46—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with acyclic hydrocarbon radicals or such radicals substituted by carbocyclic or heterocyclic rings, attached to the carboxamido radical
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- C07D499/00—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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- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/62—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by sulfur atoms
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- C07D499/00—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
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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
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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
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- C07—ORGANIC CHEMISTRY
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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
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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—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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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C07D501/00—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
- C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
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- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D503/12—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6
- C07D503/14—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, attached in position 3
- C07D503/16—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical
- C07D503/18—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical by oxygen atoms
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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
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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
- C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic 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
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
Definitions
- This invention relates to the field of pharmaceutical compositions capable of penetrating one or more biological barriers and methods of using the pharmaceutical compositions for preventing, diagnosing and/or treating conditions or diseases in humans and animals that are treatable by antimicrobials and antimicrobial- related compounds.
- the invention also relates to methods of using the pharmaceutical compositions for screening new drug candidates and methods of using the pharmaceutical compositions for diagnosing a condition in a biological subject.
- Antimicrobials are substances that kill or inhibit the growth of microorganisms such as bacteria, fungi, or protozoans, as well as destroying viruses.
- the main classes of antimicrobials include, for example, antibiotics that treat bacterial- related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiprotozoals that treat protozoans-related conditions.
- Beta-lactam antibiotics are a class of antibiotics that comprise a four- member ring beta-lactam nucleus in their molecular structures. Over a hundred thousand of beta-lactam antibiotics have been prepared by partial or total chemical synthesis (L. A. Mitscher, et al., Antibiotic and Antimicrobial Drugs, in D. F. Smith, Ed., Handbook of Stereoisomers: Therapeutic Drugs, Boca Raton, FL, CRC Press, 1989; R.B. Morin and M. Gorman Eds., Chemistry and Biology of Beta-lactam Antibiotics, Volumes 1-3, New York, Academic Press, 1982; and A.LDemain and N.A.
- beta- lactam antibiotics include penicillin derivatives, cephalospotrins, monobactams, carbapenems, beta-lactamase inhibitors, sulfonamide and quinolones.
- a wide variety of antimicrobial are administered through Intravenous infusion, intramuscular injection, subcutaneous, buccal, oral, and rectal routes.
- Oral administration has disadvantage of poor absorption of the antibiotics from the Gl tract.
- Intravenous, subcutaneous and intramuscular routes are not only painful, but also require administration by trained individuals and may incur other risks such as needle injury, infection, and other trauma.
- Topical drug delivery has several advantages. This method avoids inactivation of a drug caused by first pass metabolism in the liver and gastro-intestinal tract. It also provides local delivery of appropriate concentrations of a drug to the intended site of action without systemic exposure. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) indicated that an additional problem associated with oral medications, is that the concentration levels which must be achieved in the bloodstream must be significant in order to effectively treat distal areas of pain, inflammation, or infection. These levels are often much higher than would be necessary if the drugs were accurately delivered to the particular site of pain or injury. For most of antimicrobials, topical administration cannot deliver an effective therapeutic level.
- compositions that are capable of being delivered efficiently and effectively to the action site of a condition (e.g., a disease) to prevent, reduce or treat conditions as well as minimize adverse side effects.
- a condition e.g., a disease
- One aspect of the invention is directed to a high penetration prodrug
- HPP high penetration composition
- HPC high penetration composition
- a functional unit of a HPP or HPC comprises a moiety of a parent drug, wherein the efficient and effective delivery of the parent drug to a biological subject and/or transportation of the parent drug across one or more biological barriers are/is desired.
- a functional unit may be hydrophilic, lipophilic, or amphiphilic (i.e., both hydrophilic and lipophilic).
- the lipophilic nature of a function unit may be inherent or achieved by converting the hydrophilic moieties of a functional unit to lipophilic moieties.
- a carboxyl group, amino group, guanidine group or other hydrophilic group of a functional unit is protected with an alkyl, aryl, or heteroaryl ester or amide group to make the HPP or HPC more lipophilic.
- a functional unit of a HPP or HPC comprises a moiety of an antimicrobial or an antimicrobial-related compound.
- An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans, as well as destroying viruses.
- An antimicrobial-related compound is a compound comprising an antimicrobial structure, an antimicrobial metabolite, or an agent that can be metabolized into an antimicrobial or antimicrobial metabolite after a HPP or HPC penetrates one or more biological barriers.
- An antimicrobial-related compound further includes a compound that is an analog or mimic of an antimicrobial or an antimicrobial metabolite, or an agent that can be metabolized into an analogue or mimic of an antimicrobial or an antimicrobial metabolite, after a HPP or HPC penetrates one or more biological barriers.
- Examples of antimicrobials include, for example, antibiotics that treat bacterial-related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiprotozoals that treat protozoans-related conditions.
- antibiotics include, without limitation, beta-lactam antibiotics, sulfonamides and quinolones.
- beta-lactam antibiotics include, but are not limited to, penicillin derivatives, cephalosporins, penems, monobactams, carbapenems, beta-lactamase inhibitors and combinations thereof.
- penicillin derivatives include, but are not limited to, aminopenicillins (e.g. amoxicillin, ampicillin, and epicillin); carboxypenicillins (e.g. carbenicillin, ticarcillin, and temocillin); ureidopenicillins (e.g.
- azlocillin, piperacillin and mezlocillin azlocillin, piperacillin and mezlocillin); mecillinam, sulbenicillin, benzathine penicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), penicillin O (allylmercaptomethylpenicillinic), procaine penicillin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, hetacillin, becampicillin, metampicillin, talampicillin, co-amoxiclav (amoxicillin plus clavulanic acid), and piperacillion.
- sulbenicillin benzathine penicillin
- penicillin G benzylpenicillin
- penicillin V phenoxymethylpenicillin
- penicillin O allylmercaptomethylpenicillinic
- procaine penicillin oxacillin, methicillin,
- cephalosporins include, but are not limited to, cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime and cefpirome.
- penems include, without limitation, faropenem.
- monobactams include, without limitation, aztreonam and tigemonam.
- carbapenems include, but are not limited to, biapenem,-doripenem, ertapenem,-imipenem,-meropenem,-and panipenem.
- beta-lactamase inhibitors include, but are not limited to, tazobactam ([2S- (2alpha,3beta,5alpha)]-3-Methyl-7-oxo-3-(1 H-1 ,2,3-triazoM -ylmethyl)-4-thia-1 - azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium salt), sulbactam (2S,5f?)- 3,3-dimethyl-7-oxo-4-thia-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium), and clavulanic acid ((2f?,5f?,Z)-3-(2-hydroxyethylidene)-7-ox
- antibiotics include, without limitation, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4-nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(3- pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-( ⁇ /-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1 ,4-dienecarboxylic acid), 1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3-carboxylic acid, nalidixic acid (1-ethyl-7-methyl-4-oxo-[1 ,8]naphthyridine-3-carboxylic acid),
- sulfonamides include, without limitation, sulfaisodimidine, sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfadimethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, xipamide, dichlorphenamide, dorzolamide, acetazolamide, ethoxzolamide, sultiame, zonisamide, mafenide, celecoxib, darunavir, probenecid, sulfasalazine, and sumatriptan.
- Examples of quinolones include, without limitation, cinoxacin, flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin, ecinofloxacin, delafloxacin and nalidixic acid.
- antivirals examples include, without limitation, rifampicin, zanamivir and oseltamivir.
- antifungals include, without limitation, polyene antifungals
- imidazole antifungals e.g. miconazole, ketoconazloe, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole
- triazoles antifungals e.g.
- thiazole antifungals e.g. abafungin
- allyamines e.g. terbinafine, amorolfine, naftifine and butenafine
- echinocandins e.g. anidulafungin, caspofungin and micafungin
- antiprotozoals include, without limitation, elornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and tinidazole.
- a transportational unit of a HPP or HPC comprises a protonatable amine group that is capable of facilitating or enhancing the transportation or crossing of the HPP or HPC through one or more biological barriers.
- the protonatable amine group is substantially protonated at the pH of the biological barriers through which a HPP or HPC penetrates.
- the amine group can be reversibly protonated or deprotonated.
- a linker covalently links the functional unit to the transportational unit of a HPP and comprises a bond that is capable of being cleaved after the HPP penetrates across one or more biological barriers.
- the cleavable bond comprises, for example, a covalent bond, an ether, a thioether, an amide, an ester, a thioester, a carbonate, a carbamate, a phosphate or an oxime bond.
- a HPP or HPC of an antimicrobial or antimicrobial-related compound comprises one or two primary, secondary or tertiary amine groups that exist in the protonated form at physiological pH.
- the HPP or HPC comprises one primary, secondary or tertiary amine group that exists in the protonated form at physiological pH.
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least one HPP or HPC of an antimicrobial or antimicrobial-related compound and a pharmaceutically acceptable carrier.
- Another aspect of the invention relates to a method for penetrating a biological barrier using a HPP or HPC of an antimicrobial or antimicrobial-related compound.
- Another aspect of the invention relates to a method for diagnosing the onset, development, or remission of a condition in a biological subject by using a HPP or HPC of an antimicrobial or antimicrobial-related compound.
- the HPP (or HPC) or the functional unit thereof is detectable.
- the HPP or the functional unit of the HPP is inherently detectable, labeled with, or conjugated to, a detectable marker.
- Another aspect of the invention relates to a method for screening functional units, linkers, or transportational units for desired characteristics.
- Another aspect of the invention relates to a method for preventing, ameliorating, or treating a condition in a biological subject by administering to the subject a composition in accordance with the invention.
- the method relates to treating a condition in a subject treatable by antimicrobials or antimicrobial-related compounds by administering to the subject a therapeutically effective amount of a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof.
- conditions treatable by the method include, without limitation, pain, injuries and microorganism related conditions.
- Microoranism related conditions are conditions that are caused by microorganisms such as bacteria, fungi, protozoans and viruses.
- Bacteria-related conditions conditions caused by bacteria (bacteria-related conditions), conditions caused by protozoa (protozoa-related conditions), conditions caused by fungi (fungi-related conditions) and conditions caused by virus (virus-related conditions).
- Bacteria-related conditions include, for example, infections (e.g.
- anorectum and pruritus ani respiratory infections, upper respiratory tract infections, urinary tract infections, nosocomial infections, pseudomonas infection, Coagulase-positive staphylococcal infections (e.g. skin infection, toxinoses, acute infective endocarditis, septicemia, necrotizing pneumonia), infections of implanted prostheses, opportunistic infections with septicemia and pneumonia), plague (e.g.
- anthrax e.g. cutaneous anthrax, pulmonary anthrax and gastrointestinal antrax
- lyme diseases brucellosis, whooping cough, acute enteritis, psittacosis, nongonococcal urethritis, trachoma, inclusion conjunctivitis of the newborn, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, diarrhea, meningitis in infants, hemorrhagic colitis, hemolytic-uremic syndrome, tularemia, pneumonia, bronchitis, peptic ulcer, legionnaire's disease, Pontiac fever, leptospirosis, listeriosis, leprosy, turberculosis, mycoplasma pneumonia, gonorrhea, ophthalmia neonatorum, septic arthritis, meningococcal disease,
- anthrax e.g
- Protozoa related conditions include, for example, malaria, sleeping sickness, and toxoplasmosis.
- Fungi related conditions include, for example, aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, histoplasmosis, paracoccidiomycosis, sporotrichosis, and zygomycosis.
- Virus related conditions include, for example, influenza, yellow fever and AIDS.
- a pharmaceutical composition of a HPP or HPC is administrated to a biological subject via various routes including, but not limited to, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteral routes.
- a pharmaceutical composition of a HPP or HPC is administered orally, transdermal ⁇ , topically, subcutaneously and/or parenterally.
- a therapeutically effective amount of a HPP or HPC can be administered locally to a site of condition at a high concentration which results in a lower overall dosage than systemic administration.
- the advantages of the invention also include, for example, avoidance of systematic administration, reduction of adverse effects (e.g., pain of injection, gastrointestinal/renal effects, and other side effects), and possible novel treatments due to high local concentration of a HPP, HPC or active agent.
- the advantages further include, for example, systematic administration of a HPP or HPC to a biological subject to achieve faster and more efficient bioavailability, penetration of biological barriers (e.g., the blood brain barrier and the blood milk barrier) which have been difficult to cross, and new indications as a result of passing through biological barriers.
- biological barriers e.g., the blood brain barrier and the blood milk barrier
- Figure 1a1 Cumulative amounts of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl ester hydrochloride (A), allylmercaptomethylpenicillinic acid 2- dimethylaminoethyl ester hydrochloride (B), 6-(2,6-dimethoxybenzamido)penicillinic acid 2-dipropylaminoethyl ester hydrochloride (C), 6-(5-methyl-3-phenyl-2-isoxazoline-4- carboxamido)penicillinic acid 4-piperidineethyl ester hydrochloride (D), 6-[3-(o- chlorophenyl)-5-methyl-4-isoxazolecarboxamido]penicillinic acid 3-piperidine ethyl ester hydrochloride (E), 6-[3-(2,6-dichlorophenyl)-5-methyl-4- isoxazolecarboxamido]penicillinic acid 1-piper
- Figure 1a2 Cumulative amounts of 6-[D(-)- ⁇ - aminophenylacetamidopenicillinic acid ethyl ester hydrochloride (A), D- ⁇ -[(imidazolidin- 2-on-1-yl)carbonylamino]benzylpenicillin 2-pyrrolidinemethyl ester hydrochloride (B), 6R-[2-[3-(methylsulfonyl)-2-oxo-1-imidazolidinecarboxamido]-2- phenylacetamido]penicillinic acid 1-pyrrolidineethyl ester hydrochloride (C), 6-D(-)- ⁇ -(4- ethyl-2,3-dioxo-1 -piperazinylcarbonylamino)- ⁇ -phenylacetamidopenicillinic acid 2- diethylaminoethyl ester hydrochloride (D), 7-(2-thienylacetamido)cephalosporanic acid 2-diethy
- Figure 1a3 Cumulative amounts of 7-[(hydroxyphenylacetyl)amino]-3-
- Figure 1a4 Cumulative amounts of 3-[(acetyloxy)methyl]-7-[[(2- acetylamino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (A), 7-[[(2-acetylamino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (B), 7-[[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-acetoxyphenyl)ace
- Figure 1 b Cumulative amounts of [2S-(2alpha,3beta,5alpha)]-3-Methyl-
- HPP high penetration prodrug
- HPC high penetration composition
- One aspect of the invention is directed to a high penetration prodrug
- HPP high penetration prodrug
- HPP high penetration composition
- HPC high penetration composition
- a functional unit of a HPP or HPC which comprises a moiety of a parent drug has the properties of: 1 ) the delivery of the parent drug or the HPP/HPC into a biological subject and/or the transportation of the parent drug across a biological barrier are/is desired, 2) the HPP/HPC is capable of penetrating or crossing a biological barrier, and 3) the HPP/HPC is capable of being cleaved so as to turn the moiety of a parent drug into the parent drug or a metabolite of the parent drug.
- a functional unit may be hydrophilic, lipophilic, or amphiphilic (hydrophilic and lipophilic).
- the lipophilic moiety of the functional unit may be inherent or achieved by converting one or more hydrophilic moieties of the functional unit to lipophilic moieties.
- a lipophilic moiety of a functional unit is produced by converting one or more hydrophilic groups of the functional unit to lipophilic groups via organic synthesis. Examples of hydrophilic groups include, without limitation, carboxylic, hydroxyl, thiol, amine, phosphate/phosphonate, guanidine and carbonyl groups.
- Lipophilic moieties produced via the modification of these hydrophilic groups include, without limitation, ethers, thioethers, esters, thioesters, carbonates, carbamates, amides, phosphates and oximes.
- a functional unit is lipophilicized by acetylation or acylation(alkanoylation).
- a functional unit is lipophilicized by esterification.
- a parent drug of a HPP or HPC is selected from the group consisting of an antimicrobial and antimicrobial-related compound.
- the moiety of an antimicrobial or antimicrobial-related compound can be further converted to a lipophilic moiety as described supra.
- Antimicrobials are substances that kill or inhibit the growth of microorganisms such as bacteria, fungi, or protozoans, as well as destroying or inhibit the growth of viruses.
- the main classes of antimicrobials include, for example, antibiotics that treat bacterial-related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiparastics that treat parasite-related conditions.
- An antimicrobial-related compound is a compound comprising an antimicrobial structure, an antimicrobial metabolite, or an agent that can be metabolized into an antimicrobial or antimicrobial metabolite after a HPP or HPC penetrates one or more biological barriers.
- An antimicrobial-related compound further includes a compound that is an analog or mimic of an antimicrobial or an antimicrobial metabolite, or an agent that can be metabolized into an analog or mimic of an antimicrobial or an antimicrobial metabolite, after a HPP or HPC penetrates one or more biological barriers.
- antimicrobials include, for example, antibiotics that treat bacterial-related conditions, antivirals that treat viral-related conditions, antifungals that treat fungal-related conditions and antiprotozoals that treat protozoans-related conditions.
- antibiotics include, without limitation, beta-lactam antibiotics, sulfonamides and quinolones.
- Beta-lactam antibiotics are well known in the art and are used in connection with various conditions.
- a beta-lactam antibiotics refers to a compound that comprises a beta-lactam nucleus.
- beta-lactam antibiotics include, but are not limited to, penicillin derivatives, cephalosporins, penems, monobactams, carbapenems, beta- lactamase inhibitors and combinations thereof.
- penicillin derivatives include, but are not limited to, aminopenicillins (e.g. amoxicillin, ampicillin, and epicillin), carboxypenicillins (e.g. carbenicillin, ticarcillin, and temocillin), ureidopenicillins (e.g.
- azlocillin, piperacillin and mezlocillin mecillinam
- sulbenicillin benzathine penicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), penicillin O (allylmercaptomethylpenicillinic), procaine penicillin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, hetacillin, becampicillin, metampicillin, talampicillin, co-amoxiclav (amoxicillin plus clavulanic acid), and piperacillion.
- cephalosporins include, but are not limited to, cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime and cefpirome.
- penems include, without limitation, faropenem.
- monobactams include, without limitation, aztreonam and tigemonam.
- carbapenems include, but are not limited to, biapenerrvdoripenem, ertapenem,-imipenem,-meropenem,-and panipenem.
- beta-lactamase inhibitors include, but are not limited to, tazobactam ([2S- (2alpha,3beta,5alpha)]-3-Methyl-7-oxo-3-(1 H-1 ,2,3-triazoM -ylmethyl)-4-thia-1 - azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide sodium salt), sulbactam ((2S,5R)-3,3-dimethyl-7-oxo-4-thia-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4- dioxide sodium), and clavulanic acid ((2f?,5f?,Z)-3-(2-hydroxyethylidene)-7-oxox
- antibiotics include, without limitation, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4- nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(3-pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-( ⁇ /-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1 ,4- dienecarboxylic acid), 1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3- carboxylic acid, and nalidixic acid (1-ethyl-7-methyl-4-oxo-[1 ,8]naphthyridine-3- carboxylic acid),
- sulfonamides include, without limitation, sulfaisodimidine, sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfadimethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, xipamide, dichlorphenamide, dorzolamide, acetazolamide, ethoxzolamide, sultiame, zonisamide, mafenide, celecoxib, darunavir, probenecid, sulfasalazine, and sumatriptan.
- Examples of quinolones include, without limitation, cinoxacin, flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin, ecinofloxacin, delafloxacin and nalidixic acid.
- antivirals include, without limitation, rifampicin, zanamivir and oseltamivir.
- antifungals include, without limitation, polyene antifungals
- imidazole antifungals e.g. miconazole, ketoconazloe, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole
- triazoles antifungals e.g.
- thiazole antifungals e.g. abafungin
- allyamines e.g. terbinafine, amorolfine, naftifine and butenafine
- echinocandins e.g. anidulafungin, caspofungin and micafungin
- antiprotozoals include, without limitation, elornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and tinidazole.
- a functional unit of a HPP of an antimicrobial or antimicrobial-related compound comprises a moiety having a structure of Structure F-1 :
- Structure F-1 including stereoisomers and pharmaceutically acceptable salts thereof.
- W is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, the protonatable amine group, pharmaceutically acceptable substituted and unsubstituted primary amine groups, Structure Wa, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18:
- Z is selected from the group consisting of CH 2 , S, SO, SO 2 , NH, NR 6 , CHCH 3 , CHCH 2 CH 3 , CHR 6 , R 6 , -C(O)-, and O;
- AA represents any amino acids; each m and n is independently selected from the group of O and integer, e.g. O, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, ...;
- HA is selected from the group consisting of nothing, and pharmaceutically acceptable acid, e.g. hydrochloride hydrobromide, hydroiodide, nitric acid , sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid and pamoic acid;
- pharmaceutically acceptable acid e.g. hydrochloride hydrobromide, hydroiodide, nitric acid , sul
- R1-R3 are independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues;
- X 4 is selected from the group consisting of nothing, N, CH, and CYi;
- Yi, Y31, Y2, Y32, Y3, and Y 4 are independently selected from the group consisting of H, OH, OW, OC(O)W, L 1 -L 4 -L 2 -W, OC(O)CH 3 , CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , R 6 , SO 3 R 6 , CH 2 OR 6 , CH 2 OC(O)R 6 , CH 2 C(O)OR 8 , OCH 3 , OC 2 H 5 , OR 6 , CH 3 SO 2 , R 6 SO 2 , CH 3 SO 3 , R 6 SO 3 , NO 2 , CN, CF 3 , OCF 3 , CH 2 (CH 2 ) n NR 5 R 6 , CH 2 (CH 2 ) n OR 6, CH(C(O)NH 2 )NHR 6 , CH 2 C(O)NH 2, F, Br, I, Cl, CHOHC(O)NHCH 2 C(O)
- L 2 is selected from the group consisting of nothing, O, S, -0-L 3 -, -S-L 3 -, -N(L 3 )-, -
- a functional unit of a HPP or HPC of an antimicrobial or antimicrobial-related compound comprises a moiety having a structure selected from the group consisting of Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38
- L-31 is defined the same as Li as supra
- L 32 is defined the same as L 2 as supra
- L 34 is defined the same as L 4 as supra
- a functional unit of a HPP of a antimicrobial and antimicrobial-related compound comprises a moiety having a structure of Structure F-1 , Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38, Structure Structure FP
- Ri is selected from the group consisting of H, C1-C20 alkyl, C1-C20 alkyloxyl, d- C 2 O alkenyl, CrC 20 alkynyl, aryl, and heteroaryl;
- R 2 is selected from the group consisting of H, C r C 20 alkyl, C r C 20 alkyloxy, C r C 20 alkenyl, CrC 20 alkynyl, aryl, and heteroaryl residues;
- R 3 is selected from the group consisting of H, CrC 20 alkyl, CrC 20 alkyloxy, d- C 20 alkenyl, CrC 20 alkynyl, aryl and heteroaryl residues;
- X 2 is selected from the group consisting of nothing, H, CH 2 (CH 2 ) n OR 8 , Cl, F, Br, I, NO 2 , CN, CF 3 , C 2 F 5 , C 3 F 7 , OCF 3 , OC 2 F 5 , NH 2 , NHR 6 , CH 3 , C 2 H 5 , R 6 , C(O)NH 2 , CH 2 OC(O)NH 2 , CH 2 C(O)OR 5 , CH 2 (CH 2 ) n N(CH 3 ) 2 , CH 2 (CH 2 ) n SO 3 R 5 , C 1-8 alkyl, C 1-8 alkylthio, C 1-8 alkylamino, and C 1-8 alkyloxyl;
- X 3 is selected from the group consisting of nothing, H, N 3 , SO 3 W, F, Cl, Br, OH, OCH 3 , OR 6 , CH 3 , R 6 , C(O)OW, OW, and I;
- X 4 is selected from the group consisting of nothing, N, CH, and CY 1 ;
- any CH 2 groups may be replaced with O, S, NR 6 or any other pharmaceutically acceptable groups .
- pharmaceutically acceptable salt means those salts of compounds of the invention that are safe for application in a subject.
- Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention.
- Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1 ,11- methylene-bis-(2-hydroxy-3-naphthoate)) salts.
- Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
- alkyl means a branched or unbranched, saturated or unsaturated, monovalent or multivalent hydrocarbon group, including saturated alkyl groups, alkenyl groups and alkynyl groups.
- alkyl examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl,
- cycloalkyl means an alkyl which contains at least one ring and no aromatic rings.
- examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
- the hydrocarbon chain contains 1 to 30 carbons.
- the hydrocarbon group contains 1 to 20 carbons.
- the hydrocarbon group contains 1 to 12 carbons.
- heterocycloalkyl means a cycloalkyl wherein at least one ring atom is a non-carbon atom.
- non-carbon ring atom include, but are not limited to, S, O and N.
- alkoxyl means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more oxygen atoms.
- alkoxyl include, but are not limited to, -CH 2 -OH, -OCH 3 , -O-R e , -R e -OH, - R e i-O-Re2-, wherein R e , R e i and R ⁇ 2 can be the same or different alkyl, cycloalkyl or heterocycloalkyl.
- alkyl halide means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more halogen atoms, wherein the halogen atoms can be the same or different.
- halogen means fluorine, chlorine, bromine or iodine.
- alkyl halide examples include, but are not limited to, -R e -F, -R e -CI, -R e -Br, -R e -I, -Re(F)-, -Re(CI)-, -Re(Br)- and -R e (l)-, wherein R e is an alkyl, cycloalkyl or heterocycloalkyl.
- alkylthio means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more sulfur atoms.
- alkylthio include, but are not limited to, -CH 2 -SH, -SCH 3 , -S-R e , -Re-SH, - R e i-S-Re2-, wherein R e , R e i and R ⁇ 2 are the same or different alkyl, cycloalkyl or heterocycloalkyl.
- alkylamino means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more nitrogen atoms.
- alkylamino include, but are not limited to, -CH 2 -NH, -NCH 3 , - N(Rei)-Re2, -N-Re, -Re-NH 2 , -R 61 -N-Re 2 and -R e -N(Rei )-R ⁇ 2 wherein R e , R e i and R e2 are the same or different alkyl, cycloalkyl or heterocycloalkyl.
- alkylcarbonyl means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more carbonyl groups.
- perfluoroalkyl means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more fluoro group, including, without limitation, perfluoromethyl, perfluoroethyl, perfluoropropyl.
- aryl means a chemical structure comprising one or more aromatic rings.
- the ring atoms are all carbon.
- one or more ring atoms are non- carbon, e.g. oxygen, nitrogen, or sulfur ("heteroaryl").
- aryl examples include, without limitation, phenyl, benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyhdazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl, furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl, thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxolyl, quanidino and benzothiazolyl.
- a transportational unit of a HPP comprises a protonatable amine group that is capable of facilitating the transportation or crossing of the HPP through one or more biological barriers (e.g., > about 20 times, > about 50 times, > about 100 times, > about 300 times, > about 500 times, > about 1 ,000 times faster than the parent drug).
- the protonatable amine group is substantially protonated at a physiological pH.
- the amine group can be reversibly protonated.
- a transportational unit may or may not be cleaved from the functional unit after the penetration of HPP through one or more biological barriers.
- a functional unit may also contain one or more transportational units, especially for antimicrobials and antimicrobial-related compounds that have at least a free amino group.
- the protonatable amine group is selected from the group consisting of pharmaceutically acceptable substituted and unsubstituted primary amine groups, pharmaceutically acceptable substituted and unsubstituted secondary amine groups, and pharmaceutically acceptable substituted and unsubstituted tertiary amine groups.
- the protonatable amine group is selected from the group consisting of pharmaceutically acceptable substituted and unsubstituted primary amine groups, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18 as defined supra, including stereoisomers and pharmaceutically acceptable salts thereof.
- a linker covalently linking a functional unit and a transportational unit of a HPP comprises a bond that is capable of being cleaved after the HPP penetrates across one or more BBs.
- the cleavable bond comprises, for example, a covalent bond, an ether, thioether, amide, ester, thioester, carbonate, carbamate, phosphate or oxime bond.
- a HPP of a antimicrobials and antimicrobial- related compound has the following Structure L-1 :
- F is a functional unit of a HPP of an antimicrobial or antimicrobial-related compound.
- Examples of F include Structure F-1 , Structure FP-1 , Structure FP-2, Structure FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure FP-11 , Structure FP-12, Structure FP-13, Structure FP-14, Structure FP-15, Structure FP-16, Structure FP-17, Structure FP-18, Structure FP-19, Structure FP-20, Structure FP-21 , Structure FP-22, Structure FP-23, Structure FP-24, Structure FP-25, Structure FP-26, Structure FP-27, Structure FP-28, Structure FP-29, Structure FP-30, Structure FP-31 , Structure FP-32, Structure FP-33, Structure FP-34, Structure FP-35, Structure FP-36, Structure FP-37, Structure FP-38, Structure FP-39, Structure FP-40, Structure
- T is a transportational unit of a HPP of an antimicrobial or antimicrobial-related compound.
- T is selected from the group consisting of the protonatable amine group, pharmaceutically acceptable substituted and unsubstituted primary amine groups, pharmaceutically acceptable substituted and unsubstituted secondary amine groups, and pharmaceutically acceptable substituted and unsubstituted tertiary amine groups, Structure W-1 , Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11 , Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18 as defined supra; and
- a HPP or HPC of antimicrobial or antimicrobial- related compound comprises a structure selected from the group consisting of Structure P-1 , Structure P-2, Structure P-3, Structure P-4, Structure P-5, Structure P-6, Structure P-7, Structure P-8, Structure P-9, Structure P-10, Structure P-11 , Structure P-12, Structure P-13, Structure P-14, Structure P-15, Structure P-16, Structure P-17, Structure P-18, Structure P-19, Structure P-20, Structure P-21 , Structure P-22, Structure P-23, Structure P-24, Structure P-25, Structure P-26, Structure P-27, Structure P-28, Structure P-29, Structure P-30, Structure P-31 , Structure P-32, Structure P-33, Structure P-34, Structure P-35, Structure P-36, Structure P-37, Structure P-38, Structure P-39, Structure P-40, Structure P-41 , Structure P-42, Structure P-43, Structure P-44, Structure P-45, Structure P-46, Structure P-47, Structure P-
- X 46 , X 7 , Yi , Y2, Y31 , Y32, Y3, Y4, Z, AA, HA, R, R 8 , and Rn-R 16 are defined the same as supra.
- compositions comprising HPPs
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least one HPP of an antimicrobial or antimicrobial-related compound and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a HPP from one location, body fluid, tissue, organ (interior or exterior), or portion of the body, to another location, body fluid, tissue, organ, or portion of the body.
- Each carrier is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients, e.g., a HPP, of the formulation and suitable for use in contact with the tissue or organ of a biological system without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- Some examples of materials which can serve as pharmaceutically- acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium
- compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
- the pharmaceutically acceptable carrier is an aqueous carrier, e.g. buffered saline and the like.
- the pharmaceutically acceptable carrier is a polar solvent, e.g. acetone and alcohol.
- the concentration of HPP in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the biological system's needs.
- the concentration can be 0.0001 % to 100%, 0.001 % to 50%, 0.01 % to 30%, 0.1 % to 20%, 1 % to 10% wt.
- compositions of the invention can be administered for prophylactic, therapeutic, and/or hygienic use.
- Such administration can be topical, mucosal, e.g., oral, nasal, vaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, via inhalation, ophthalmic and other convenient routes.
- the pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration.
- unit dosage forms suitable for oral administration include powder, tablets, pills, capsules and lozenges and for transdermal administration include solution, suspension and gel.
- a typical pharmaceutical composition for transdermal, oral, and intravenous administrations would be about 10 ⁇ 10 g to about 100 g, about 10 ⁇ 10 g to about 10 ⁇ 3 g, about 10 ⁇ 9 g to about 10 ⁇ 6 g, about 10 ⁇ 6 g to about 100 g, about 0.001 g to about 100 g, about 0.01 g to about 10 g, or about 0.1 g to about 1 g per subject per day. Dosages from about 0.01 mg, up to about 100 g, per subject per day may be used. Actual methods for preparing parenterally administrable compositions will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington: The Science and Practice of Pharmacy 21st ed., Mack Publishing Company, Easton, Pa. (2005).
- Another aspect of the invention relates to a method of using a composition of the invention in penetrating one or more biological barriers in a biological subject.
- the method comprises a step of administering to a biological subject a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof.
- a HPP exhibits more than about 20 times or higher, 50 times or higher, > about 100 times or higher, > about 200 time higher, >about 300 times or higher, >about 500 times or higher, >about 1 ,000 times or higher penetration rate through one or more biological barriers than its parent drug.
- biological barrier refers to a biological layer that separates an environment into different spatial areas or compartments, which separation is capable of modulating (e.g. restricting, limiting, enhancing or taking no action in) the passing through, penetrating or translocation of substance or matter from one compartment/area to another.
- the different spatial areas or compartments as referred to herein may have the same or different chemical or biological environment(s).
- the biological layer as referred herein includes, but is not limited to, a biological membrane, a cell layer, a biological structure, an inner surface of subjects, organisms, organs or body cavities, an external surface of subjects, organisms, organs or body cavities, or any combination or plurality thereof.
- a biological membrane examples include a lipid bilayer structure, eukaryotic cell membrane, prokaryotic cell membrane, and intracellular membrane (e.g., nucleus or organelle membrane, such as membrane or envelope of Golgi apparatus, rough and smooth endoplasmic reticulum (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosome, nucleus, chloroplasts, plastids, peroxisomes or microbodies).
- the lipid bilayer referred to herein is a double layer of lipid-class molecules, including, but not limited to, phospholipids and cholesterol.
- lipids for bilayer are amphiphilic molecules consisting of polar head groups and non- polar fatty acid tails.
- the bilayer is composed of two layers of lipids arranged so that their hydrocarbon tails face one another to form an oily core held together by the hydrophobic effect, while their charged heads face the aqueous solutions on either side of the membrane.
- the lipid bilayer may contain one or more embedded protein and/or sugar molecule(s).
- Examples of a cell layer include a lining of eukaryotic cells (e.g., epithelium, lamina intestinal and smooth muscle or muscularis mucosa (in gastrointestinal tract)), a lining of prokaryotic cells (e.g., surface layer or S-layer which refers to a two dimensional structure monomolecular layer composed of identical proteins or glycoproteins, specifically, an S-layer refers to a part of a cell envelope commonly found in bacteria and archaea), a biofilm (a structured community of microorganisms encapsulated within a self-developed polymeric matrix and adherent to a living or inert surface), and a plant cell layer (e.g., empidermis).
- the cells may be normal cells or pathological cells (e.g. disease cells, cancer cells).
- Examples of biological structures include structures sealed by tight or occluding junctions that provide a barrier to the entry of toxins, bacteria and viruses, e.g. the blood milk barrier and the blood brain barrier (BBB).
- BBB blood brain barrier
- the biological structure may also include a mixture of cells, proteins and sugars (e.g. blood clots).
- Examples of the inner surface of subjects, organisms, organs or body cavities include buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa and endometrium (the mucosa of the uterus, inner layer of the wall of a pollen grain or the inner wall layer of a spore), or a combination or plurality thereof.
- Examples of the external surface of subjects, organisms, organs or body cavities include capillaries (e.g. capillaries in the heart tissue), mucous membranes that are continuous with skin (e.g. such as at the nostrils, the lips, the ears, the genital area, and the anus), outer surface of an organ (e.g. liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, anorectum and pruritus ani), skin, cuticle (e.g.
- a biological barrier further includes a sugar layer, a protein layer or any other biological layer, or a combination or plurality thereof.
- skin is a biological barrier that has a plurality of biological layers.
- a skin comprises an epidermis layer (outer surface), a demis layer and a subcutaneous layer.
- the epidermis layer contains several layers including a basal cell layer, a spinous cell layer, a granular cell layer, and a stratum corneum.
- the cells in the epidermis are called keratinocytes.
- the stratum corneum (“horny layer”) is the outmost layer of the epidermis, wherein cells here are flat and scale-like (“squamous”) in shape. These cells contain a lot of keratin and are arranged in overlapping layers that impart a tough and oilproof and waterproof character to the skin's surface.
- Another aspect of the invention relates to a method of using a composition of the invention in diagnosing a condition in a biological system.
- the method comprises the following steps:
- the HPP (or the agent cleaved from the HPP) aggregates in the site of action where a condition occurs.
- the presence, location or amount of the functional unit of the HPP is also detected.
- the onset, development, progress, or remission of a condition (e.g., infection) associated is also determined.
- the HPP is labeled with or conjugated to a detectable agent.
- the HPP is prepared to include radioisotopes for detection.
- detectable agents are available which can be generally grouped into the following categories:
- Radioisotopes such as 35 S, 14 C, 13 C, 15 N, 125 I, 3 H, and 131 I.
- the diagnostic agent can be labeled with the radioisotope using the techniques known in the art and radioactivity can be measured using scintillation counting; in addition, the diagnostic agent can be spin labeled for electron paramagnetic resonance for carbon and nitrogen labeling.
- Fluorescent agents such as BODIPY, BODIPY analogs, rare earth chelates (europium chelates), fluorescein and its derivatives, FITC, 5,6 carboxyfluorescein, rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin, green fluorescent protein, yellow fluorescent protein, red fluorescent protein and Texas Red. Fluorescence can be quantified using a fluorometer.
- luciferases e.g., firefly luciferase and bacterial luciferase
- luciferin 2,3-dihydrophthalazinediones
- malate dehydrogenase urease
- peroxidase such as horseradish peroxidase (HRPO)
- HRPO horseradish peroxidase
- alkaline phosphatase ⁇ - galactosidase
- glucoamylase lysozyme
- saccharide oxidases e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase
- heterocyclic oxidases such as uricase and xanthine oxidase
- lactoperoxidase lactoperoxidase
- microperoxidase and the like.
- enzyme-substrate combinations include, for example: (i) Horseradish peroxidase (HRPO) with hydrogen peroxidase as a substrate, wherein the hydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylene diamine (OPD) or 3, 3', 5,5'- tetramethyl benzidine hydrochloride (TMB)); (ii) alkaline phosphatase (AP) with para- Nitrophenyl phosphate as chromogenic substrate; and (iii) ⁇ -D-galactosidase ( ⁇ -D-GaI) with a chromogenic substrate (e.g., p-nitrophenyl- ⁇ -D-galactosidase) or fluorogenic substrate 4-methylumbelliferyl- ⁇ - D-galactosidase.
- HRPO Horseradish peroxidase
- OPD orthophenylene diamine
- TMB 3, 3', 5,5'- t
- the detectable agent is not necessarily conjugated to the diagnostic agent but is capable of recognizing the presence of the diagnostic agent and the diagnostic agent can be detected.
- the HPP of the invention can be provided in a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing the diagnostic assay.
- the kit will include substrates and cofactors required by the enzyme (e.g., a substrate precursor which provides the detectable chromophore or fluorophore).
- substrates and cofactors required by the enzyme e.g., a substrate precursor which provides the detectable chromophore or fluorophore
- other additives may be included such as stabilizers, buffers (e.g., a block buffer or lysis buffer) and the like.
- the relative amounts of the various reagents may be varied widely to provide for concentrations in solution of the reagents which substantially optimize the sensitivity of the assay.
- the reagents may be provided as dry powders, usually lyophilized, including excipients which on dissolution will provide a reagent solution having the appropriate concentration.
- Another aspect of the invention relates to a method of screening a HPP for a desired character.
- the method comprises: covalently linking a test functional unit to a transportational unit through a linker to form a test composition (or covalently linking a functional unit to a test transportational unit through a linker, or covalently linking a functional unit to a transportational unit through a test linker)
- test composition has the desired nature or character.
- a desired character may include, for example, 1 ) the ability of a test functional unit to form a high penetration composition or convert back to a parent drug, 2) the penetration ability and/or rate of a test composition, 3) the efficiency and/or efficacy of a test composition, 4) the transportational ability of a test transportational unit, and 5) the cleavability of a test linker.
- Another aspect of the invention relates to a method of using a composition of the invention in treating a condition in a biological system.
- the method comprises administrating the pharmaceutical composition to the biological system.
- treating means curing, alleviating, inhibiting, or preventing.
- treat means cure, alleviate, inhibit, or prevent.
- treatment means cure, alleviation, inhibition or prevention.
- biological system means an organ, a group of organs that work together to perform a certain task, an organism, or a group of organisms.
- organ as used herein means an assembly of molecules that function as a more or less stable whole and has the properties of life, such as animal, plant, fungus, or micro-organism.
- animal means a eukaryotic organism characterized by voluntary movement.
- animals include, without limitation, vertebrata (e.g. human, mammals, birds, reptiles, amphibians, fishes, marsipobranchiata and leptocardia), tunicata (e.g. thaliacea, appendiculaha, sorberacea and ascidioidea), articulata (e.g. insecta, myriapoda, malacapoda, arachnida, pycnogonida, merostomata, Crustacea and annelida), gehyrea (anarthropoda), and helminthes (e.g. rotifera).
- vertebrata e.g. human, mammals, birds, reptiles, amphibians, fishes, marsipobranchiata and leptocardia
- tunicata e.g. thaliacea, appendiculaha, sorberacea and ascidio
- plant as used herein means organisms belonging to the kindom Plantae.
- plant include, without limitation, seed plants, bryophytes, ferns and fern allies.
- seed plants include, without limitation, cycads, ginkgo, conifers, gnetophytes, angiosperms.
- bryophytes include, without limitation, liverworts, hornworts and mosses.
- ferns include, without limitation, ophioglossales (e.g. adders-tongues, moonworts, and grape-ferns), marattiaceae and leptosporangiate ferns.
- fern allies include, without limitation, lycopsida (e.g. clubmosses, spikemosses and quillworts), psilotaceae (e.g. lycopodiophyta and whisk ferns) and equisetaceae (e.g. horsetails).
- lycopsida e.g. clubmosses, spikemosses and quillworts
- psilotaceae e.g. lycopodiophyta and whisk ferns
- equisetaceae e.g. horsetails.
- fungus as used herein means a eukaryotic organism that is a member of the kingdom Fungi. Examples of fungus include, without limitation, chytrids, blastocladiomycota, neocallimastigomycota, zygomycota, glomeromycota, ascomycota and basidiomycota.
- microorganism as used herein means an organism that is microscopic (e.g. with length scale of micrometer). Examples of microorganism include, without limitation, bacteria, fungi, archaea, protists and microscopic plants (e.g. green algae) and microscopic animals (e.g. plankton, planarian and amoeba).
- Some examples of the conditions the method can treat include conditions that can be treated by the parent drug of the HPP.
- Another aspect of the invention relates to a method of using HPPs of antimicrobials or antimicrobial-related compounds, or pharmaceutical compositions thereof in treating a condition in a biological system or subject by administrating a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof to the biological system or subject.
- Antimicrobials and antimicrobial-related compounds can be used to regulate a wide range of biological processes in a biological system. Conditions that are related to such biological processes are treatable by the corresponding antimicrobials or antimicrobial-related compounds, and therefore treatable by HPPs/HPCs of the antimicrobials or antimicrobial-related compounds, and a pharmaceutical composition thereof.
- Such conditions include, but are not limited to, pain, injuries and microorganism related conditions.
- Microoranism related conditions are conditions that are caused by microorganisms such as bacteria, fungi, protozoans and viruses. For example, conditions caused by bacteria (bacteria-related conditions), conditions caused by protozoa (protozoa-related conditions), conditions caused by fungi (fungi-related conditions) and conditions caused by virus (virus-related conditions).
- Bacteria-related conditions include, for example, infections (e.g. infection condition in an organ such as liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, anorectum and pruritus ani, respiratory infections, upper respiratory tract infections, urinary tract infections, nosocomial infections, pseudomonas infection, Coagulase-positive staphylococcal infections (e.g.
- cutaneous anthrax, pulmonary anthrax and gastrointestinal antrax lyme diseases, brucellosis, whooping cough, acute enteritis, respiratory infection, psittacosis, nongonococcal urethritis, trachoma, inclusion conjunctivitis of the newborn, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, diarrhea, meningitis in infants, hemorrhagic colitis, hemolytic-uremic syndrome, tularemia, pneumonia, bronchitis, peptic ulcer, legionnaire's disease, Pontiac fever, leptospirosis, listeriosis, leprosy, turberculosis, mycoplasma pneumonia, gonorrhea, ophthalmia neonatorum, septic arthritis, meningococcal disease, waterhouse-friderichsen syndrome, Rocky mountain spotted
- Protozoa related conditions include, for example, malaria, sleeping sickness, and toxoplasmosis.
- Fungi related conditions include, for example, aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycois, cryptococcosis, histoplasmosis, paracoccidiomycosis, sporotrichosis, and zygomycosis.
- Virus related conditions include, for example, influenza, yellow fever and
- a method of treating a condition in a subject amelioratable or treatable with antimicrobials or antimicrobial-related compounds comprises administering a therapeutic effective amount of a HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof to the subject.
- a HPP or a pharmaceutical composition thereof can be administered to a biological system by any administration route known in the art, including without limitation, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteral administration.
- the pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration.
- a parenteral administration refers to an administration route that typically relates to injection which includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intra cardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and/or intrasternal injection and/or infusion.
- a HPP or a pharmaceutical composition thereof can be given to a subject in the form of formulations or preparations suitable for each administration route.
- the formulations useful in the methods of the invention include one or more HPPs, one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic ingredients.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration.
- the amount of a HPP which can be combined with a carrier material to produce a pharmaceutically effective dose will generally be that amount of a HPP which produces a therapeutic effect.
- Methods of preparing these formulations or compositions include the step of bringing into association a HPP with one or more pharmaceutically acceptable carriers and, optionally, one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association a HPP with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
- Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non- aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a HPP as an active ingredient.
- a compound may also be administered as a bolus, electuary, or paste.
- the HPP is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1 ) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarding agents, such as paraffin, (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting
- pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1 ) fillers or extenders, such as star
- the pharmaceutical compositions may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered antimicrobials or peptidomimetic moistened with an inert liquid diluent.
- Tablets, and other solid dosage forms such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of a HPP therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
- compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
- These compositions may also optionally contain pacifying agents and may be of a composition that they release the HPP(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
- embedding compositions which can be used include polymeric substances and waxes.
- the HPP can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adjuvants such as wetting agents, e
- Suspensions in addition to the HPP, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more HPPs with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
- Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
- Formulations for the topical or transdermal or epidermal or dermal administration of a HPP composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
- the ointments, pastes, creams and gels may contain, in addition to the HPP composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to the HPP composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
- a HPP or a pharmaceutical composition thereof can be alternatively administered by aerosol. This can be accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the HPPs.
- a nonaqueous (e. g., fluorocarbon propellant) suspension could be used.
- Sonic nebulizers can also be used.
- An aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers.
- the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
- Transdermal patches can also be used to deliver HPP compositions to a target site.
- Such formulations can be made by dissolving or dispersing the agent in the proper medium.
- Absorption enhancers can also be used to increase the flux of the peptidomimetic across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the peptidomimetic in a polymer matrix or gel.
- Ophthalmic formulations are also contemplated as being within the scope of this invention.
- Formulations suitable for parenteral administration comprise a HPP in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacterostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- aqueous and nonaqueous carriers examples include water, ethanol, polyols (e. g., such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
- polyols e. g., such as glycerol, propylene glycol, polyethylene glycol, and the like
- vegetable oils such as olive oil
- injectable organic esters such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- Formulations suitable for parenteral administration may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
- Injectable depot forms are made by forming microencapsule matrices of a HPP or in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the HPP to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the HPP in liposomes or microemulsions which are compatible with body tissue.
- a HPP of an antimicrobial or antimicrobial- related compound, or a pharmaceutical composition thereof is delivered to a disease or tumor action site in a therapeutically effective dose.
- the precise amount of the pharmaceutically effective dose of a HPP that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon, for example, the activity, the particular nature, pharmacokinetics, pharmacodynamics, and bioavailability of a particular HPP, physiological condition of the subject (including race, age, sex, weight, diet, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), the nature of pharmaceutically acceptable carriers in a formulation, the route and frequency of administration being used, and the severity or propensity of a disease caused by pathogenic target microbial organisms, to name a few.
- Amtimicrobials e.g. antibiotics
- antimicrobial-related compounds are often hydrophilic and are difficult to penetrate skin membrane barrier. When antimicrobials or antimicrobial-related compounds are taken orally, they may be inactivated by first pass metabolism. In the case of injection, administration of antimicrobials and amtimicrobial-related compounds is painful and may require frequent and costly office visits.
- a HPP or HPC of the invention is capable of crossing one or more biological barriers
- the HPP or HPC can be administered locally (e.g., topically or transdermally) to reach a location where a condition occurs without the necessity of a systematic administration (e.g., oral or parenteral administration).
- a local administration and penetration of a HPP or HPC allows the HPP or HPC to reach the same level of local concentration of an agent or drug with much less amount or dosage of HPP or HPC in comparison to a systematic administration of a parent agent or drug; alternatively, a higher level of local concentration which may not be afforded in the systematic administration, or if possible, requires significantly higher dosage of an agent in the systematic administration.
- the high local concentration of the HPP/HPC or its parent agent if being cleaved enables the treatment of a condition more effectively or much faster than a systematically delivered parent agent and the treatment of new conditions that may not be previously possible or observed.
- the local administration of the HPP or HPC may allow a biological subject to reduce potential suffering from a systemic administration, e.g., adverse reactions associated with the systematic exposure to the agent, gastrointestinal/renal effects. Additionally, the local administration may allow the HPP or HPC to cross a plurality of biological barriers and reach systematically through, for example, general circulation and thus avoid the needs for systematic administration (e.g., injection) and obviate the pain associated with the parenteral injection.
- a HPP/HPC or a pharmaceutical composition according to the invention can be administered systematically (e.g., orally or parenterally).
- the HPP/HPC or the active agent (e.g., drug or metabolite) of the HPP/HPC may enter the general circulation with a faster rate than the parent agent and gain faster access to the action site a condition.
- the HPP/HPC can cross a biological barrier (e.g., blood brain barrier and blood milk barrier) which has not been penetrated if a parent agent is administered alone and thus offer novel treatment of conditions that may not be previously possible or observed.
- HPPs/HPCs of antimicrobials or antimicrobial-related compounds in the invention demonstrated high penetration rate through a biological barrier (e.g., > about 10 times, > about 50 times, >about 100 times, >about 200 times, >about 300 times, > about 1000 times higher than if the antimicrobials or antimicrobial- related compounds are administered alone).
- a biological barrier e.g., > about 10 times, > about 50 times, >about 100 times, >about 200 times, >about 300 times, > about 1000 times higher than if the antimicrobials or antimicrobial- related compounds are administered alone.
- No or few adverse side effects were observed from the subjects that took antimicrobial HPP/HPC, while side effects (such as nausea) were observed from the subjects that took the parent antimicrobials at the similar dosage.
- HPP/HPC or a pharmaceutical composition according to the invention can penetrate one or more biological barriers, such as biofilm, cell wall of bacteria, fungi and other microorganisms, at much higher rate and can overcome the drug resistance.
- Example 1 Preparation of a HPP from a parent drug.
- T is a transportational unit of a HPP of an antimicrobial or antimicrobial-related compound.
- T is selected from the group consisting of W and R6 as defined supra.
- a HPP having Structure L-1 is prepared according to organic synthesis by reacting the parent compounds or derivatives of the parent compounds having Structure D (e.g. acid halides, mixed anhydrides of the parent compounds, etc.):
- W c is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy;
- F, l_i, L 2 , L 4 and T are defined as supra.
- T is a transportational unit of a HPP of an antimicrobial or antimicrobial-related compound.
- T is selected from the group consisting of W and Re as defined supra;
- M is selected from the group consisting of Na, K, or other metal.
- W N is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy.
- the obtained protected HPP may be further partially or completely deprotected to render a partially protected HPP or an unprotected HPP respectively.
- HPPs of an antimicrobial or antimicrobial-related compound can be synthesized by similar procedures.
- HPPs of antimicrobials and antimicrobial-related compounds have higher in vitro penetration rates across human skin comparing to their parent drugs.
- a test compound (2 ml_, 10% in 0.2 M phosphate buffer, pH 7.4) was added to the sample chamber of a Franz cell.
- the receiving chamber contained 10 ml of 0.2 M phosphate buffer which was stirred at 600 rpm.
- the amount of the tested compound penetrating the skin was determined by high-performance liquid chromatography (HPLC) method.
- HPLC high-performance liquid chromatography
- the results were shown in Figures 1a1 , 1a2, 1a3, 1a4, 1 b, and 1c.
- Apparent flux values of the tested compounds calculated from the slopes in the Figures 1a1 , 1a2, 1a3 and 1 a4 were summarized in Table 1a.
- Apparent flux values of the tested compounds calculated from the slopes in the Figures 1 b and 1c are summarized in Tables 1 b and 1c respectively.
- parent drugs that showed a apparent flux value equal to or less than 1 ⁇ g /cm 2 /h were considered as not detectable for penetrating across the skin tissue.
- parent compounds e.g. penicillin V, penicillin O
- their HPPs had detectable apparent flux values.
- their HPPs had higher detectable apparent flux values. Therefore the HPPs of antimicrobials or antimicrobial-related compounds showed a higher penetration rate (340-600 times higher) across the skin tissue comparing to their parent compounds.
- Example 3 In vivo penetration rate of HPPs through skin and/or blood-brain barrier
- mice After 2 hours, the mice were killed. 5 ml of methanol was added to 1 g of homogenized blood, liver, kidney, muscle, or brain. The samples were centrifuged for 5 min and analyzed by HPLC (Table 2). No drug was detected for the mice treated with only the parent drug (methicillin, oxacillin, and cloxacillin). The results showed that these prodrugs have high pentration rate of blood- brain barrier while the respective parent drugs were not able to penetrate the skin.
- HPPs of antimicrobials or antimicrobial-related compounds penetrate cell wall of bacteria faster than that of their parent drugs.
- 1-piperidineethyl ester hydrochloride penicillin V-PEE
- penicillin V penicillin V
- 6-(2,6- dimethoxybenzamido)penicillinic acid 2-pyrrolidinemethyl ester hydrochloride
- methicillin-PME methicillin
- 7-[[(2-acetylamino-4- thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 2-diethylaminoethyl ester hydrochloride (ceftizoxime-DEE), or ceftizoxime) was added into 100 ml of E. coli suspension and stirred for 3 minutes.
- Table 4 The amount of antibiotics and their HPPs entered cells of E. CoIi.
- HPPs of antimicrobials or antimicrobial-related compounds converted to the parent antimicrobials or antimicrobial-related compounds quickly in good yield in human plasma.
- a HPP of antimicrobial or antimicrobial-related compound (10 mg) was dissolved in 0.1 ml of 0.2M pH 7.4 phosphate buffer. 1 ml of human plasma, preheated to 37 ° C, was added into the mixture. The mixture was kept in a water bath at 37 ° C, and at every 2 min intervals 0.2 ml of samples were withdrawn and added to 0.4 ml of methanol to precipitate the plasma protein. The samples were centrifuged for 5 min and analyzed by HPLC. The results showed that most of the HPPs of antimicrobials or antimicrobial-related compounds were converted back to the parent antimicrobials or antimicrobial-related compounds (Table 5).
- MICs Minimum inhibitory concentrations of the antimicrobials and their pro-drugs were assessed according to Jennifer M. Andrews, Journal of Antimicrobial Chemotherapy 48, suppl. S1 , 5-16 (2001 ). The results (Tables 6a-6c) showed that the HPPs of antimicrobials were able to overcome ⁇ -lactam resistance in methicillin- resistant Staphylococcus aureus (MRSA) according to Minimum inhibitory concentrations (MICs).
- MRSA methicillin- resistant Staphylococcus aureus
- Example 8 Treatment of clinical mastitis using HPPs of beta-lactam antibiotics or related compounds.
- Example 9 Anti-M. tuberculosis activity of the pro-drugs of antimicrobial drugs.
- group B was the treated group with isoniazid/moxifoxacin/pyrazinamide (0.18/0.22/1.2mmol/kg, were given orally) for 45 days
- group C was the treated group with isoniazid/moxifoxacin/pyrazinamide (0.18/0.22/1.2mmol/kg, were given orally) for 90 days
- group D was the treated group with N-(N-methyl-phenylalanyl)isoniazid (pro- isoniazid, made from N-methylphenylalanine and isoniazid, were given tansdermally)/ 1- cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo [4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo- quinoline-3-carboxylic acid butyl ester(pro-moxifoxacin)/pyrazinoic acid N, N- diethylamin
- mice were held for an additional 90 days without treatment and then sacrificed to determine the proportion with negative lung cultures indicating cure.
- the results showed that the pro-drugs were superior to their parent drugs and they can be used transdermal ⁇ (Tables 9a and 9b).
- Example 10 Treatment of tuberculosis in adults (reduced dosage for child).
- Example 12 Treatment of ear infection.
- Example 13 Treatment of lower respiratory tract infection in adults (reduced dosage for child).
- Example 14 Treatment of upper respiratory tract infection in adults (reduced dosage for child).
- Example 16 Treatment of meningitis in adults (reduced dosage for child).
- Example 17 Treatment of diarrheal diseases (reduced dosage for child).
- Example 18 Treatment of breast infection.
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US12/482,373 US20100040548A1 (en) | 2006-12-10 | 2009-06-10 | High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds |
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PCT/CN2010/073743 WO2010142241A1 (en) | 2009-06-10 | 2010-06-10 | High penetration compositions or prodrugs of antimicrobials and antimicrobial-related compounds |
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US8476425B1 (en) | 2012-09-27 | 2013-07-02 | Cubist Pharmaceuticals, Inc. | Tazobactam arginine compositions |
US8809314B1 (en) | 2012-09-07 | 2014-08-19 | Cubist Pharmacueticals, Inc. | Cephalosporin compound |
US9724353B2 (en) | 2011-09-09 | 2017-08-08 | Merck Sharp & Dohme Corp. | Methods for treating intrapulmonary infections |
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CN104540504A (en) * | 2012-01-18 | 2015-04-22 | 苏州泰飞尔医药有限公司 | High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions |
US20140274993A1 (en) | 2013-03-15 | 2014-09-18 | Cubist Pharmaceuticals, Inc. | Ceftolozane-tazobactam pharmaceutical compositions |
EP3100732A1 (en) | 2013-03-15 | 2016-12-07 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
CN105143174B (en) * | 2013-03-15 | 2021-01-12 | 苏州泰飞尔医药有限公司 | Novel high-penetration medicine for treating Parkinson's disease and medicine composition thereof |
US9872906B2 (en) | 2013-03-15 | 2018-01-23 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
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CN108396007B (en) * | 2018-03-15 | 2021-07-23 | 东北农业大学 | Method for in-vitro construction of three-dimensional model of blood and milk barrier of dairy cow |
CN118556043A (en) * | 2022-01-17 | 2024-08-27 | 苏州泰飞尔医药有限公司 | Treatment of signs, symptoms and/or complications of viral, bacterial, protozoal and/or fungal infections by highly penetrating prodrugs |
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US9724353B2 (en) | 2011-09-09 | 2017-08-08 | Merck Sharp & Dohme Corp. | Methods for treating intrapulmonary infections |
US10028963B2 (en) | 2011-09-09 | 2018-07-24 | Merck Sharp & Dohme Corp. | Methods for treating intrapulmonary infections |
US8809314B1 (en) | 2012-09-07 | 2014-08-19 | Cubist Pharmacueticals, Inc. | Cephalosporin compound |
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US8685957B1 (en) | 2012-09-27 | 2014-04-01 | Cubist Pharmaceuticals, Inc. | Tazobactam arginine compositions |
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BRPI1012905A2 (en) | 2017-09-12 |
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JP6707512B2 (en) | 2020-06-10 |
HK1178537A1 (en) | 2014-05-09 |
WO2010142241A1 (en) | 2010-12-16 |
CN105566213B (en) | 2019-11-12 |
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KR20120034721A (en) | 2012-04-12 |
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CA2764376C (en) | 2021-05-04 |
JP2012529443A (en) | 2012-11-22 |
KR102102972B1 (en) | 2020-04-22 |
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JP2018048197A (en) | 2018-03-29 |
MX366035B (en) | 2019-06-25 |
AU2010257905A1 (en) | 2012-02-02 |
AU2017200897B2 (en) | 2018-10-04 |
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