WO2011140009A1 - Procédés d'utilisation de glycopeptides semi-synthétiques en tant qu'agents antibactériens - Google Patents

Procédés d'utilisation de glycopeptides semi-synthétiques en tant qu'agents antibactériens Download PDF

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WO2011140009A1
WO2011140009A1 PCT/US2011/034885 US2011034885W WO2011140009A1 WO 2011140009 A1 WO2011140009 A1 WO 2011140009A1 US 2011034885 W US2011034885 W US 2011034885W WO 2011140009 A1 WO2011140009 A1 WO 2011140009A1
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compound
substituted
alkoxy
alkyl
group
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PCT/US2011/034885
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English (en)
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Daniel Chu
Bing Wang
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Biomarin Pharmaceutical Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Naturally occurring and semi-synthetic glycopeptide antibiotics used to combat bacterial infections include compounds such as vancomycin, desmethylvancomycin, eremomycin, teicoplanin (complex of five compounds), dalbavancin, oritavancin, telavancin, and A82846B (LY264826) having structures A, B, C, D, E, F, G and H:
  • Staphylococcus aureus (S. aureus), a spherical bacterium, is the most common cause of staph infections.
  • S. aureus has been known to cause a range of illnesses from minor skin infections, such as pimples, impetigo, boils, cellulitis folliculitis, furuncles, carbuncles, scalded skin syndrome, abscesses, to life-threatening diseases such as pneumonia, meningitis, osteomyelitis endocarditis, toxic shock syndrome, and septicemia.
  • S. aureus is one of the most common causes of nosocomial infections, often causing postsurgical wound infections.
  • Methicillin was introduced in the late 1950s to treat infections caused by penicillin-resistant S. aureus. It has been reported previously that S. aureus isolates had acquired resistance to methicillin (methicillin-resistant S. aureus, MRSA).
  • the methicillin resistance gene (mecA) encodes a methicillin-resistant penicillin-binding protein that is not present in susceptible strains. mecA is carried on a mobile genetic element, the staphylococcal cassette chromosome mec (SCCmec), of which four forms have been described that differ in size and genetic composition.
  • SCCmec staphylococcal cassette chromosome mec
  • Vancomycin-intermediate Staphylococcus aureus and vancomycin-resistant staphylococcus aureus are specific types of antimicrobial-resistant Staph bacteria that are refractory to vancomycin treatment.
  • S. aureus isolates for which vancomycin ICs are 4-8 ⁇ g/mL ⁇ are classified as vancomycin-intermediate and isolates for which vancomycin MICs are >16 ⁇ /mL are classified as vancomycin-resistant (Clinical and Laboratory Standards Institute/NCCLS. Performance Standards for Antimicrobial Susceptibility Testing. Sixteenth informational supplement. M100-S 16. Wayne, PA: CLSI, 2006).
  • Enterococci are bacteria that are normally present in the human intestines and in the female genital tract and are often found in the environment. These bacteria sometimes cause infections. In some cases, enterococci have become resistant to vancomycin (also known as vancomycin-resistant enterococci or VRE.) Common forms of resistance to vancomycin occur in enterococcal strains that involve the acquisition of a set of genes endoding proteins that direct peptidoglycan precursors to incorporate D-Ala-D-Lac instead of D-Ala-D-Ala. The six different types of vancomycin resistance shown by enterococcus are: Van-A, Van-B, Van-C, Van-D, Van-E and Van-F.
  • Van-A VRE is resistant to both vancomycin and teicoplanin
  • Van-B VRE is resistant to vancomycin but sensitive to teicoplanin
  • Van-C is partly resistant to vancomycin, and sensitive to teicoplanin.
  • Described herein are semi-synthetic glycopeptides that have antibacterial activity. Also provided are methods for synthesis of the compounds, pharmaceutical compositions containing the compounds, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.
  • compositions formed by modification of Compound A, Compound B, Compound C or Compound H scaffolds to provide semi-synthetic glycopeptides that have antibacterial activity, as well as their pharmaceutical acceptable salts, esters, solvates, alkylated quaternary ammonium salts, stereoisomers, tautomers or prodrugs thereof, and which are used, in some embodiments, as antibacterial agents for the treatment of bacterial infections with superior microbiology and pharmacokinetic properties than currently available glycopeptide antibacterial agents.
  • a method of treating a bacterial infection in a mammal where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia comprising administering a therapeutically acceptable amount of a com X, XI, XII, XIII, or XIV:
  • RA is hydrogen, methyl, or C 2 -Ci 2 -alkyl
  • R) and R 2 are each independently selected from the group consisting of
  • R 8 , R 9 and R 10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 8 and R 10 or R 9 and R 10 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C r C 3 -alkoxy, C r C 3 - alkoxy-Ci-C 3 -alkoxy, oxo, Ci-C 3 -alkyl, halo-Ci-C 3 -alkyl, and Ci-C 3 -alkoxy-C r C 3 -alkyl; or R] and R 2 taken together with the atom to which they are attached form a substituted heteroaryl or 3-10 membered heterocycl
  • R 7 is selected from the group consisting of
  • C r Ci2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C r Ci 2 -alkoxy, Ci-C 3 -alkoxy-C C 3 -alkoxy, amino, C r Ci 2 - dialkylamino, alkenyl, alkynyl, and Ci-Ci 2 -thioalkoxy,
  • X is hydrogen or chlorine
  • Y is oxygen or NRi
  • Z is oxygen or sulfur
  • R E is halo or -OR where R is selected from the group consisting of
  • R 5 and 3 ⁇ 4 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 5 and Re taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C r C 3 -alkoxy, Ci-C 3 -alkoxy-Ci-C3-alkoxy, oxo, halo-C r Ci2-alkyl, and Ci- C 3 -alkoxy-C r C
  • R u is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
  • R 12 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or R n and Ri 2 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C 3 -alkoxy, C r C 3 -alkoxy-C r C 3 -alkoxy, oxo, CrC l2 -alkyl, substituted loweralkyl, halo-C r C i2-alkyl, amino, alkylamino, dialkylamino, and Ci-C 3 -alkoxy-Ci-Ci 2 -alkyl; or
  • R 3 is selected from the group consisting of
  • aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy;
  • R B is selected from the group consisting of
  • C r C 12 -alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C r Ci 2 -alkoxy, C r C 3 -alkoxy- C r C 3 -alkoxy, amino, C Ci 2 -alkylamino, C r C
  • C r C 12 -alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C Ci 2 -alkoxy, C C 3 -alkoxy- C r C 3 -alkoxy, amino, C]-C 12 -alkylamino, C C 12 - dialkylamino, alkenyl, alkynyl, and C r Ci 2 -thioalkoxy,
  • R 8 , R 9 and Ri 0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 8 and Rio or R 9 and R 10 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, d-C 3 -alkoxy, C r C 3 - alkoxy-CpCs-alkoxy, oxo, C r C 3 -alkyl, halo-C r C 3 -alkyl, Ci-CValkoxy-CpCs-alkyl;
  • R D is each selected from the group consisting of
  • R 8 , R 9 and Ri 0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 8 and R 10 or R 9 and R 10 taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C r C 3 -alkoxy, C1-C3- alkoxy-Ci-C 3 -alkoxy, oxo, Ci-C 3 -alkyl, halo-C r C 3 -alkyl, and Ci-C 3 -alkoxy-C r C 3 -alkyl;
  • At least two of Al , A2, and A3 are hydrogen and the other is -C(Z)-NH-R B , -C(Z)NHCHRi 5 -(CH 2 ) m -NHCONHR B ,
  • X, XI, XII, XIII, or XIV or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, in the formulation of a medicament for the treatment of a bacterial infection in a mammal where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia.
  • compositions, compounds, methods and uses described herein are described in conjunction with these embodiments, it should be understood that the compositions, compounds, methods and uses described herein are not to be limited to these embodiments. On the contrary, the compositions, compounds, methods and uses described herein cover alternatives, modifications, and equivalents as are included within the spirit and scope of the appended claims. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the
  • compositions, compounds, methods and uses described herein are optionally practiced without some or all of these specific details. Well known process operations have not been described in detail in order not to unnecessarily obscure the compositions, compounds, methods and uses described herein.
  • the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula I
  • Embodiment 1 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula II
  • Embodiment 2 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula III
  • Embodiment 3 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula IV
  • Embodiment 4 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula V
  • Embodiment 5 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula VI
  • Embodiment 6 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula VII
  • Embodiment 7 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula VIII
  • Embodiment 8 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula IX
  • Embodiment 9 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula X
  • Embodiment 10 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XI
  • Embodiment 11 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XII
  • Embodiment 12 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XIII
  • the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XIV
  • Embodiment 14 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R A is methyl and R4 is hydrogen. In embodiment, R A is hydrogen and R4 is hydrogen. In another embodiment, X is hydrogen and R4 is hydrogen. In a further embodiment, X is chlorine and R4 is hydrogen. In yet a further embodiment, R A is methyl and R4 is
  • R A is hydrogen and R4 IS CH2NHCH2PO3H2.
  • R A is hydrogen and R( is CH 2 NH-CHR 15 -(CH 2 ) M -NHS02RB, where m is 1 to 6 and R 15 is H or loweralkyl.
  • R A is hydrogen and R4 is CH 2 NR F -CHR 15 -(CH 2 ) Q -NRGS0 2 RB, where q is 2 to 4, R 15 , R F , and RQ is H or loweralkyl, R F and RQ together represents -CH 2 -.
  • R A is hydrogen and R4 is CH 2 NH- CHR 15 -(CH 2 ) P -CONHS0 2 RB, where p is 0 to 6 and R 15 is H or loweralkyl.
  • Al and A2 are both hydrogen and R4 is CH 2 NH-CHR 15 - (CH 2 ) p -CONHR B , where p is 0 to 6 and R IS is H or loweralkyl.
  • R is CH 2 NH-(CH 2 ) 2 . 6 CONHR B .
  • Al and A2 are both hydrogen and R, is CH 2 NH- CHR 15 -(CH 2 ) M -0-(CH 2 ) r NHCONHR B , where m is 1 to 6, f is 1 to 6 and R 15 is H or loweralkyl.
  • R4 is CH 2 NH-(CH 2 ) 2 -0-CH 2 -NHCONHR B .
  • Al and A2 are both hydrogen and R, is CH 2 NH-CHR 15 -(CH 2 ) p -NHCOR B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R is CH 2 NH-(CH 2 ) 2 . 6 NHCOR B .
  • Embodiment 15 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R A is hydrogen and R, is CH 2 NH- CHR 15 -(CH 2 ) p -COOH, where p is 0 to 6 and R [5 is H or loweralkyl. In yet a further embodiment, R A is methyl and R( is CH 2 NH-CHR 15 -(CH 2 ) m -NHS0 2 RB, where m is 1 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and R, is CH 2 NH- CHR 15 -(CH 2 ) p -CONHS0 2 R B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and R, is CH 2 NH- CHRi 5 -(CH 2 ) p -COOH, where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and R, is CH 2 NR F -CHR 15 -(CH 2 ) Q -NRGS0 2 R B , where q is 2 to 4, R 15 , R F , and R Q is H or loweralkyl, R F and R Q together represents -CH 2 -.
  • R A is hydrogen and Al is CONH- CHR 15 -(CH 2 ) P -NHS0 2 R B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and Al is CONH- CHR 15 -(CH 2 ) p -NHS0 2 R B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is hydrogen and Al is -CONHCHR 15 -(CH 2 ) m - NHCONHR B , where m is 1 to 6 and R [5 is H or loweralkyl.
  • R A is methyl and Al is
  • R A is hydrogen and A2 is CONH- CHR 15 -(CH 2 ) P -NHS0 2 R B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and A2 is CONH- CHR I5 -(CH2)P-NHS0 2 RB, where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is hydrogen and A2 is -CONHCHR 15 -(CH 2 ) m -NHCONHR B , where m is 1 to 6 and R !5 is H or loweralkyl.
  • R A is methyl and A2 is -CONHCHRi 5 -(CH 2 ) m -NHCONHR B , where m is 1 to 6 and Ri5 is H or loweralkyl.
  • R A is hydrogen and A3 is CONH- CHRi 5 -(CH 2 ) p -NHS0 2 R B , where p is 0 to 6 and R i5 is H or loweralkyl.
  • R A is methyl and A3 is CONH- CHR 1 5-(CH 2 ) p -NHS0 2 R B , where p is 0 to 6 and Ri 5 is H or loweralkyl.
  • R A is hydrogen and A3 is -CONHCHR 15 -(CH 2 ) m - NHCONHR B , where m is 1 to 6 and Ri 5 is H or loweralkyl.
  • R A is methyl and A3 is
  • Embodiment 16 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R 3 is selected from the group consisting of
  • R )3 and R 14 are each independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl, aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or Ri 3 and R M together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C 3 -alkoxy, Ci-C 3 -alkoxy-C r C 3 -alkoxy, oxo, C Ci 2 -alkyl, substituted loweralkyl, hal
  • Embodiment 17 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R 3 is OH. In another embodiment, R 3 is 2-adamantanamino. In yet another embodiment, R 3 is dimethylamino. In one embodiment, R 3 is dimethylaminoethylamino. In another embodiment, R 3 is N-methylpiperazino.
  • Embodiment 18 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R] and R 2 are each independently selected from the group consisting of
  • R 8 , R 9 and R 10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or
  • R 8 and Ri 0 or R 9 and Ri 0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C r C 3 -alkoxy, VC 3 - alkoxy-Ci-C 3 -alkoxy, oxo, C r C 3 -alkyl, halo-C r C 3 -alkyl, and C r C 3 -alkoxy-C C 3 -alkyl; or Ri and R 2 taken together with the atom to which they are attached form a substituted heteroaryl or 3-10 membered
  • heterocycloalkyl ring optionally having one or two hetero functionalities selected from the group consisting of -0-, -N-, -NH, -N(C r C 6 -alkyl)-, -N(aryl)-, -N(aryl- C C 6 -alkyl-)-, -N(substituted-aryl- C r C 6 -alkyl-)-, -N(heteroaryl)-,
  • n 1 or 2 and the 3-10 membered heterocycloalkyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C r C 3 -alkoxy, C C 3 -alkoxy-CrC 3 -alkoxy, oxo, C C 3 -alkyl, halo-C r C 3 -alkyl, and C r C 3 -alkoxy-Ci-C 3 -alkyl.
  • Embodiment 19 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Ri and R 2 are hydrogen.
  • R ( is C r C 12 -alkyl and R 2 is hydrogen.
  • Ri is Ci-C
  • R t is and R 2 is hydrogen.
  • Ri is C Ci 2 -alkyl substituted C r C 12 -alkoxy and R 2 is hydrogen. In another embodiment, Ri is CVCi 2 - alkyl substituted C r C 12 -thioalkoxy and R 2 is hydrogen. In yet another embodiment, Ri is C C 12 -alkyl substituted CpC ⁇ - alkylamino and R 2 is hydrogen.
  • Embodiment 20 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RE is halo or -OR where R is selected from the group consisting of
  • Ci-Ci2-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy,
  • R 5 and R are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 5 and 3 ⁇ 4 are taken together with the atom to which they are attached from a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C r C 3 -aIkoxy, Ci-C 3 -alkoxy-Ci-C 3 -alkoxy, oxo, Ci-Ci 2 -alkyl, halo-C r Ci 2 -alkyl, and C C 3 -alkoxy-C C 12 -alkyl,
  • Rn is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
  • Ri 2 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or Rn and R i2 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C 3 -alkoxy, C r C 3 -alkoxy-Ci-C 3 -alkoxy, oxo, substituted loweralkyl, halo-Ci-Ci 2 -alkyl, amino, alkylamino, dialkylamino, and Ci-C 3 -alkoxy-C r Ci 2 -alkyl.
  • Embodiment 21 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R E is -OR and R is hydrogen. In another embodiment, R E is -OR and R is C C 12 -alkyl. In one embodiment, R E is -OR and R is C r Ci 2 -alkyl substituted with aryl or substituted aryl. In a further embodiment, R E is -OR and R is substituted with aryl or substituted aryl. In one embodiment, R E is -OR and R is In another embodiment, R E is -OR and R is substituted with heteroaryl or substituted heteroaryl.
  • Embodiment 22 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R B is selected from the group consisting of
  • C r C 12 -alkyl b) C r C 12 -alkyl, c) C r C I2 -alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C r C l2 -alkoxy, C r C 3 -alkoxy- C r C 3 -alkoxy, amino, CpCn-alkylamino, C r C 12 - dialkylamino, alkenyl, alkynyl, and C r Ci 2 -thioalkoxy,
  • substituents selected from the group consisting of halogen, hydroxy, C C
  • Embodiment 23 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R B is C r C 12 -alkyl. In another embodiment, R B is C Ci 2 -alkyl substituted with aryl or substituted aryl. In yet another embodiment, R B is C Ci 2 -alkyl substituted with heteroaryl or substituted heteroaryl. In another embodiment, R B is aryl substituted with one or more halogens. In another embodiment, R B is aryl substituted one or more C Ci 2 -alkoxy.
  • R B is aryl substituted with one or more Q-Cn-alkylamino- C r C 12 -alkoxy. In another embodiment, R B is aryl substituted with one or more amino- Q-Cn-alkoxy. In another embodiment, R B is aryl substituted with one or more C Ci 2 -alkylamino. In another embodiment, R B is aryl substituted one or more C r C 12 -dialkylamino- C C 12 -alkoxy. In another embodiment, R B is aryl substituted one or more C r C Ci 2 -substituted alkyl. In another embodiment, R B is heteroaryl substituted one or more Ci-Ci 2 -alkoxy.
  • R B is heteroaryl substituted with one or more C Ci 2 -alkylamino- Ci-C 12 -alkoxy. In another embodiment, R B is heteroaryl substituted with one or more amino- C r Ci2-alkoxy. In another embodiment, R B is heteroaryl substituted with one or more C r Ci 2 -alkylamino. In another embodiment, R B is heteroaryl substituted one or more C Ci 2 -dialkylamino- C Ci 2 -alkoxy. In another embodiment, R B is heteroaryl substituted one or more C r C 12 -substituted alkyl.
  • Embodiment 24 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Rc is each selected from the group consisting of
  • R 8 , R9 and R l0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or R 8 and Ri 0 or R 9 and Ri 0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CpCValkoxy, C r C 3 - alkoxy-C r C 3 -alkoxy, oxo, Ci-C 3 -alkyl, halo-C C 3 -alkyl, and Ci-C 3 -alkoxy-C r C 3 -alkyl.
  • Embodiment 26 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R D is each selected from the group consisting of
  • Ci 2 -alkyl substituted with one or more substituents selected from the group consisting of
  • R 8 , R 9 and R 10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or R 8 and R !0 or R 9 and R !0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C C 3 -alkoxy, C r C 3 - alkoxy-CrC 3 -alkoxy, oxo, C r C 3 -alkyl, halo-C r C 3 -alkyl, and C r C 3 -alkoxy-Ci-C 3 -alkyl.
  • R D is C r Ci 2 -alkyl substituted C r C 12 -alkoxy. In a further embodiment, R D is C r C 12 -alkyl substituted C r Ci 2 -thioalkoxy. In yet a further embodiment, R D is C r Ci 2 -alkyl substituted C r C 12 -alkylamino. In yet a further embodiment, R D is alkyl.
  • Embodiment 28 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Y is oxygen and R4 is hydrogen. In another embodiment, Z is oxygen and R4 is hydrogen. In yet another embodiment, Y is NH and R4 is hydrogen. In a further embodiment, Z is sulfur and R4 is hydrogen. In yet a further embodiment, Z is oxygen and R4 is CH 2 NHCH 2 P0 3 H 2 . In one embodiment, Y is oxygen and R4 is CH 2 NHCH 2 P0 3 H 2 . In another embodiment, Y is NH and R4 is CH 2 NHCH 2 P0 3 H 2 .
  • Embodiment 29 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R] is hydrogen and R 2 is COCHR 8 NHR ]5 where R 15 is substituted arylalkyl.
  • Embodiment 30 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VII or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen. In a further embodiment of any of the aforementioned embodiments is the method of use where for the Compound of Formula (VIII) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, where Al, A2, and A3 are each hydrogen.
  • any of the aforementioned embodiments is the method or use where for the Compound of Formula (IX) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen.
  • any of the aforementioned embodiments is the method or use where for the Compound of Formula (XI) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen.
  • Embodiment 31 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula X
  • Rc is hydrogen
  • R 8 is C r C 3 alkyl.
  • R 7 is amino, amino-cycloalkyl, or C r Ci 2 alkyl.
  • Al, A2, and A3 are hydrogen and R4 is CH 2 NH- CHRi 5 -(CH 2 ) m -NHS0 2 R B or CH 2 NH-CHRi 5 -(CH 2 ) m -NHCONHR B , m is 1 to 6 and R 15 is H or loweralkyl.
  • R B is aryl substituted with one or more Ci-Ci 2 alkyl.
  • C r C 12 alkyl is selected from n-butyl, n-pentyl, n-hexyl, n-heptyl, or n-octyl.
  • R B is phenyl substituted with n-hexyl at the para position.
  • A2, A3 and R4 are hydrogen and Al is -C(Z)-NH-R B , -C(Z)NHCHRi 5 -(CH 2 ) m -NHCONHR B , C(Z)NHCHR 15 -(CH 2 ) m -R B or -C(Z)NHCHR 15 -(CH 2 ) m -NHS0 2 R B .
  • R B is C C 12 alkyl.
  • C[-C 12 alkyl is n-hexyl, n-heptyl, n-octyl, or n-nonyl.
  • Al is m is 4 or 5, R 15 is hydrogen, and R B is aryl substituted with C Ci 2 alkoxy or C r C 12 alkyl.
  • R A is methyl
  • R D is hydrogen
  • R 3 is OH
  • A2, A3 and R4 are each hydrogen.
  • Embodiment 34 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula (XIII) where R A is methyl, Rc is hydrogen and R 3 is OH.
  • R A is methyl
  • Rc is hydrogen
  • R 3 is OH.
  • Al, A2, and A3 are hydrogen and R4 is CH 2 NH-CHR l5 -(CH 2 ) m -NHS0 2 R B or CH 2 NH-CHR 15 -(CH 2 ) m -NHCONHR B , m is 1 to 6 and R 15 is H or loweralkyl.
  • R B is selected from aryl substituted with one or more C r Ci 2 alkyl, aryl substituted with one or more C r C I2 alkoxy, or aryl substituted with one or more C r Ci 2 alkylamino.
  • Embodiment 35 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is com licated skin and skin structure infection or bacterial pneumonia and the compound is of Formula II, III, VIII or IX, where Ri is hydrogen and R 2 are selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl, and said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one or more optionally substituted aryl, heteroaryl, or condensed rings, or Ri and R 2 together with the atom to which they are attached form a substituted heteroaryl or cycloheterocyclic ring which optionally contains additional heteroatom selected from the group consisting of optionally substituted O, N, and S.
  • R is hydrogen and R 2 are selected
  • Embodiment 36 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII, where R A is methyl or hydrogen and V, XI, and XIV and R B is selected from the group consisting of
  • substituents selected from the group consisting of halogen, hydroxy, C Ci 2 -alkoxy, C r Ci 2 -alkoxy- C Ci 2 -alkoxy, amino, amino-Ci-Ci 2 -alkoxy, CpCn- alkylamino, C r Ci
  • Embodiment 37 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula II - V and VIII - XI or XIII where R 7 is selected from the group consisting of
  • Ci 2 -alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Ci-C 3 -alkoxy-C C3-alkoxy, amino, C r Ci 2 -alkylamino, C r C 12 -dialkylamino, alkenyl, alkynyl,
  • Embodiment 38 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I where R E is halo or -OR where R is selected from the group consisting of
  • R 5 and e are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 5 and Re are taken together with the atom to which they are attached form a 3 - 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C r C 3 -alkoxy, C r C 3 -alkoxy-CrC 3 -alkoxy, oxo, C r Ci2-alkyl, halo-C C 12 -alkyl, and C r C3-alkoxy-C C l2 -alkyl,
  • R u is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
  • R ]2 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or R u and R 12 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C r C 3 -alkoxy, C r C 3 -alkoxy-C]-C 3 -alkoxy, oxo, C C 12 -alkyl, substituted loweralkyl, halo-C r Ci 2 -alkyl, amino, alkylamino, dialkylamino, and C r C 3 - alkoxy-C r C 12-alkyl.
  • Embodiment 39 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VII - XII where at least two of Al, A2, and A3 are hydrogen and where when two of Al, A2, and A3 are hydrogen, the other is -C(Z)-NH-R B , -C(Z)NHCHRi 5 -(CH 2 ) m -NHCONHR B , -C(Z)NHCHR 15 -(CH 2 ) m -R B or -C(Z)NHCHRi 5 -(CH 2 ) m - NHS0 2 R B where m is 1 to 6, and Ri 5 is H or loweralkyl.
  • Al and A2 are hydrogen and A3 is-C(Z)-NH-R B .
  • Al and A2 are hydrogen and A3 is -C(Z)NHCHR ]5 - (CH 2 ) m -NHS0 2 R B .
  • Al and A2 are hydrogen and A3 is -C(Z)NHCHR, 5 -(CH 2 ) m -NHCONHR B .
  • Al and A2 are hydrogen and A3 is -C(Z)NHCHRi 5 -(CH 2 ) m -R B .
  • Al and A3 are hydrogen and A2 is-C(Z)-NH-R B .
  • Al and A3 are hydrogen and A2 is -C(Z)NHCHRi5-(CH 2 ) m -NHS0 2 RB.
  • Al and A3 are hydrogen and A2 is -C(Z)NHCHRi 5 - (CH 2 ) m -NHCONHR B .
  • Al and A3 are hydrogen and A2 is -C(Z)NHCHR 15 -(CH 2 ) m -RB .
  • A2 and A3 are hydrogen and Al is-C(Z)-NH-R B .
  • A2 and A3 are hydrogen and Al is -C(Z)NHCHR 15 -(CH 2 ) m -NHS0 2 R B .
  • A2 and A3 are hydrogen and Al is -C(Z)NHCHR 15 -(CH 2 ) m -NHCONHR B .
  • A2 and A3 are hydrogen and Al is - C(Z)NHCHR 15 -(CH 2 ) m -R B .
  • Embodiment 40 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula V or XI where X is chlorine and » is hydrogen.
  • Embodiment 41 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula V or XI where X is hydrogen and R4 is hydrogen..
  • Embodiment 42 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VI where Y is oxygen and R4 is hydrogen.
  • Embodiment 43 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VI where Y is NH and R4 is hydrogen.
  • Embodiment 44 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XII where Z is oxygen and R4 is hydrogen.
  • Embodiment 45 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XII where Z is sulfur and R4 is hydrogen.
  • Embodiment 46 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where R A is methyl and R4 is hydrogen.
  • Embodiment 47 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where R A is hydrogen and R4 is hydrogen.
  • Embodiment 48 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where R A is methyl or hydrogen and R 3 is selected from the group consisting of
  • R ]3 and R, 4 are each independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl, aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or R ]3 and R M together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C 3 -alkoxy, Ci-C 3 -alkoxy-Ci-C 3 -alkoxy, oxo, C r Ci2-alkyl, substituted loweralkyl
  • Embodiment 49 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where R A is methyl or hydrogen and R4 is selected from the group consisting of
  • aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy,
  • Embodiment 50 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula XIII or XIV where R4 is selected from the group consisting of hydrogen, CH 2 NH-CHR 15 -(CH 2 ) m -NHS0 2 R B , where m is 1 to 6 and R 15 is H or loweralkyl, hydrogen, CH 2 NH-CHR 15 -(CH 2 ) m -NHCONHR B , where m is 1 to 6 and R L5 is H or loweralkyl, CH 2 NR F -CHR 15 -(CH 2 ) q -NR G S0 2 R B where q is 2 to 4 and R L5 is H or loweralkyl, or CH 2 NH-CHR 15 -(CH 2 ) m -0- (CH 2 ) r NHS0 2 R B , where m is 1 to 6 and f
  • Embodiment 51 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is selected from Compound (23). Compound (24). Compound (25). Compound (26). Compound (27). Compound (28). Compound (29). Compound (30). Compound (31). Compound (32). Compound (33). Compound (34). Compound (47). Compound (49).
  • Compound (201) Compound (202). Compound (203). Compound (204). Compound (205). Compound (206). Compound (207). Compound (208). Compound (209). Compound (210). Compound (211). Compound (212). Compound (213).
  • Embodiment 52 In a further embodiment of any embodiments 1-31, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the bacterial strain is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137. In a further embodiment, the method or use is where the bacterial strain is Staphylococcus aureus 2E5 CFU ATCC 13709 and the compound is
  • the method or use is where the bacterial strain is methicillin-resistant Staphylococcus aureus VL-137 and the compound is
  • a method of treating a bacterial infection in a mammal where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137 comprising administering a therapeutically acceptable amount of a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV as described in the Summary of the Invention or in any of embodiments 1-52 as a pharmaceutical composition comprising the Compound of any of Formula I-XIV together with a pharmaceutically acceptable carrier.
  • a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV as described in the Summary of the Invention or in any of embodiments 1-52 as a pharmaceutical composition comprising the Compound of any of Formula I-XIV together with a pharmaceutically acceptable carrier, for treating a bacterial infection in a mammal where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL- 137.
  • a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV as described in the Summary of the Invention or in any of embodiments 1-52 as a pharmaceutical composition
  • a pharmaceutical composition comprising the Compound of any of Formula I-XIV together with a pharmaceutically acceptable carrier, in the formulation of a medicment for the treatment of a bacterial infection in a mammal where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137.
  • articles of manufacture comprising packaging material, a compound of any of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII or Formula XIV as described in the Summary of the Invention or in any of embodiments 1-52 which is effective for treatment, prevention or amelioration of one or more symptoms of a bacterial- mediated disease or condition where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable acyl glucuroide metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for treatment, prevention or amelioration of one or more symptoms of a bacterial-mediated disease
  • Embodiment 53 In another embodiment is a method of treating a gram-positive bacterial infection in a mammal comprising f
  • [0078] is use of a compound (303). (309). or (311). for treating a mammal having a gram-positive bacterial infection.
  • [0079] is use of a compound (303). (309). or (311). in the formulation of a medicament for the treatment of a mammal having a gram-positive bacterial infection.
  • Embodiment 54 In an further embodiment of embodiment 53, the method or use is that where the infection is bacteremia, complicated intra-abdominal infection, complicated skin and skin structure infection, or bacterial pneumonia.
  • a futher embodiment is that where the infection is complicated skin and skin structure infection or bacterial pneumonia.
  • a further embodiment is that where t he bacterium to be treated is resistant or refractory to a beta-lactam antibiotic, vancomycin, desmethylvancomycin, eremomycin, teicoplanin, dalbavancin, oritavancin, telavancin, or A82846B
  • Embodiment 55 A further embodiment of any of the embodiments in embodiments 53 and 54 is that where the compound is administered as a pharmaceutical composition which comprises a therapeutically effective amount of a compound, together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the bacterium is a Gram-positive bacteria.
  • the Gram-positive bacterium is S. aureus.
  • the S. aureus is resistant or refractory to a beta-lactam antibiotic.
  • the beta-lactam antibiotic belongs to the class of penicillins.
  • the beta-lactam antibiotic is methicillin.
  • the subject has a methicillin-resistant S. aureus bacteria.
  • the beta-lactam antibiotic is flucloxacillin.
  • a method for treating a subject having a dicloxacillin-resistant bacteria comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to dicloxacillin.
  • a method for treating a subject having a methicillin-resistant bacteria comprising administering compound (303). (309).
  • the subject is screened for methicillin-resistant bacteria.
  • the subject screening is performed through a nasal culture.
  • the methicillin-resistant bacteria is detected by swabbing the nostril(s) of the subject and isolating the bacteria.
  • Real-time PCR and/or Quantitative PCR is employed to determine whether the subject has a methicillin- resistant bacteria.
  • a method for treating a subject having a first-generation cephalosporin-resistant bacteria comprising administering compound (303). (309), or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a first-generation cephalosporin.
  • the bacteria is resistant to a first-generation cephalosporin.
  • the bacteria is resistant to cefacetrile.
  • the bacteria is resistant to cefadroxil.
  • the bacteria is resistant to cefalexin.
  • the bacteria is resistant to cefaloglycin.
  • the bacteria is resistant to cefalonium. In another embodiment, the bacteria is resistant to cefaloridine. In yet another embodiment, the bacteria is resistant to cefalotin. In a further embodiment, the bacteria is resistant to cefapirin. In yet a further embodiment, the bacteria is resistant to cefatrizine. In one embodiment, the bacteria is resistant to cefazaflur. In another embodiment, the bacteria is resistant to cefazedone. In yet another embodiment, the bacteria is resistant to cefazolin. In a further embodiment, the bacteria is resistant to cefradine. In yet a further embodiment, the bacteria is resistant to cefroxadine. In one embodiment, the bacteria is resistant to ceftezole.
  • the bacteria is resistant to a second-generation cephalosporin.
  • the bacteria is resistant to cefaclor.
  • the bacteria is resistant to cefonicid.
  • the bacteria is resistant to cefprozil.
  • the bacteria is resistant to cefuroxime.
  • the bacteria is resistant to cefuzonam.
  • the bacteria is resistant to cefmetazole.
  • the bacteria is resistant to cefotetan.
  • the bacteria is resistant to cefoxitin.
  • a method for treating a subject having a third-generation cephalosporin-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a third-generation cephalosporin.
  • the bacteria is resistant to a third-generation cephalosporin.
  • the bacteria is resistant to cefcapene.
  • the bacteria is resistant to cefdaloxime.
  • the bacteria is resistant to cefdinir.
  • the bacteria is resistant to cefditoren.
  • the bacteria is resistant to cefixime. In another embodiment, the bacteria is resistant to cefmenoxime. In yet another embodiment, the bacteria is resistant to cefodizime. In a further embodiment, the bacteria is resistant to cefotaxime. In yet a further embodiment, the bacteria is resistant to cefpimizole. In one embodiment, the bacteria is resistant to cefpodoxime. In another embodiment, the bacteria is resistant to cefteram. In yet another embodiment, the bacteria is resistant to ceftibuten. In a further embodiment, the bacteria is resistant to ceftiofur. In yet a further embodiment, the bacteria is resistant to ceftiolene. In one embodiment, the bacteria is resistant to ceftizoxime. In another embodiment, the bacteria is resistant to ceftriaxone. In yet another embodiment, the bacteria is resistant to cefoperazone. In yet a further embodiment, the bacteria is resistant to ceftazidime.
  • a method for treating a subject having a fourth-generation cephalosporin-resistant bacteria comprising administering compound (303), (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a fourth-generation cephalosporin.
  • the bacteria is resistant to a fourth-generation cephalosporin.
  • the bacteria is resistant to cefclidine.
  • the bacteria is resistant to cefepime.
  • the bacteria is resistant to cefluprenam.
  • the bacteria is resistant to cefoselis.
  • the bacteria is resistant to cefozopran.
  • the bacteria is resistant to cefpirome.
  • the bacteria is refractory to cefquinome.
  • a method for treating a subject having a carbapenem-resistant bacteria comprising administering compound (303), (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a carbapenem.
  • the bacteria is resistant to a carbapenem.
  • a method for treating a subject having a imipenem-resistant bacteria comprising administering compound (303). (309).
  • a method for treating a subject having a meropenem-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to imipenem.
  • a method for treating a subject having a meropenem-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to meropenem.
  • a method for treating a subject having a ertapenem -resistant bacteria comprising administering compound (303). (309).
  • a method for treating a subject having a faropenem-resistant bacteria comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to faropenem.
  • a method for treating a subject having a doripenem -resistant bacteria comprising administering compound (303). (309).
  • a method for treating a subject having a panipenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to doripenem.
  • a method for treating a subject having a panipenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to panipenem.
  • a method for treating a subject having a biapenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where
  • Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus
  • MIC minimum inhibitory concentration
  • a common method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of the antibiotic, that are then inoculated with the bacterial isolate of interest. The MIC of an antibiotic is determined from the tube with the lowest concentration that shows no turbidity (no growth).
  • [0091] in one aspect is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacterial infection comprises a vancomycin-intermediate Staphylococcus aureus bacterium.
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • [0092] in another aspect is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacterial infection comprises a vancomycin-resistant
  • the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of between about 16 ⁇ / ⁇ ⁇ ,. In another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about > 16 ⁇ g/mL. In yet another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about 20 ⁇ / ⁇ ⁇ . In a further embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about 25 ⁇ g/mL.
  • conditions treated by the compounds described herein include, but are not limited to, endocarditis, osteomyelitis, neningitis, skin and skin structure infections, genitourinary tract infections, abscesses, and necrotizing infections.
  • the compounds disclosed herein are used to treat conditions, such as, but not limited to, diabetic foot infections, decubitus ulcers, burn infections, animal or human bite wound infections, synergistic- necrotizing gangrene, necrotizing fascilitis, intra-abdominal infection associated with breeching of the intestinal barrier, pelvic infection associated with breeching of the intestinal barrier, aspiration pneumonia, and post-operative wound infections.
  • the conditions listed herein are caused by, contain, or result in the presence of VISA and/or VRSA.
  • a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococci has developed resistance to vancomycin.
  • the subject has been previously treated with vancomycin for a sustained period of time.
  • the subject has been hospitalized.
  • the subject has a weakened immune system such as patients in Intensive Care Units or in cancer or transplant wards.
  • the subject has undergone surgical procedures such as, for example, abdominal or chest surgery.
  • the subject has been colonized vith VRE.
  • the subject has a medical device such that an infection has developed.
  • the medical device is a urinary catheter or central intravenous (IV) catheter.
  • [0097] in another embodiment is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococcus has Van-A resistance.
  • [0098] in another embodiment is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococcus has Van-B resistance.
  • [0099] in another embodiment is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococcus has Van-C resistance.
  • [00 00] in another aspect, is use of a compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, for treating a subject having a vancomycin- resistant enterococci.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
  • substituted alkyl refers to alkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylamino, dialkylamino, hydroxy, aryl, heteroaryl, alkenyl or alkynyl group.
  • alkenyl refers to unsaturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between two and twenty carbon atoms by removal of a single hydrogen atom.
  • cycloalkyl refers to a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound containing between three and twenty carbon atoms by removal of a single hydrogen atom.
  • substituted cycloalkyl refers to cycloalkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylamino, dialkylamino, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups.
  • cycloalkenyl refers to a monovalent group derived from a monocyclic or bicyclic unsaturated carbocyclic ring compound containing between three and twenty carbon atoms by removal of a single hydrogen atom.
  • C r C 3 -alkyl refers to saturated, straight- or branched- chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, one and six, and one and twelve carbon atoms, respectively, by removal of a single hydrogen atom.
  • Examples of Ci-C 3 -alkyl radicals include methyl, ethyl, propyl and isopropyl.
  • C C 6 -alkyl radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl.
  • Ci-Ci 2 -alkyl radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl , n-hexyl. N-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-docecyl.
  • loweralkyl refers to Ci-Ci2-alkyl as defined above.
  • substituted loweralkyl refers to C r Ci 2 -alkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylamino, dialkylamino, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups.
  • C 3 -Ci 2 -cycloalkyl denoted a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by removal of a single hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.
  • Ci-C 3 -alkoxy refers to the C C 3 -alkyl group and Ci-C 6 -alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • C C 6 -alkoxy radicals include, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
  • loweralkylamino refers to Ci-Ci2-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
  • loweralkylamino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, propylamino and decylamino.
  • oxo denotes a group where two hydrogen atoms on a single carbon atom in an alkyl group as defined above are replaced with a single oxygen atom (i.e. a carbonyl group).
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like and is optionally un- substituted or substituted (including bicyclic aryl groups) with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, Ci-Ci2-alkoxy, thioalkoxy, C r C 12 -thioalkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • substituted aryl groups include tetrafluorophenyl and pentafluoroph
  • substituted aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like substituted (including bicyclic aryl groups) with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, C r Ci 2 -alkoxy, thioalkoxy, C r Ci 2 -thioalkoxy, alkoxyalkylalkoxy, aryloxy, amino, aminoalkyl, aminoalkylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylalkoxy, dialkylamino, dialkylaminoalkyl,
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • arylalkyl refers to an aryl group as defined above attached to the parent molecular moiety through an alkyl group where the alkyl group is of one to twelve carbon atoms.
  • substituted arylalkyl refers to a substituted aryl group as defined above attached to the parent molecular moiety through an alkyl group where the alkyl group is of one to twelve carbon atoms.
  • alkylaryl refers to an alkyl group as defined above attached to the parent molecular moiety through an aryl group.
  • halo and "halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • alkylamino refers to a group having the structure -NHR' where R' is alkyl, as previously defined.
  • alkylamino include methylamino, ethylamino, iso-propylamino, and the like.
  • dialkylamino refers to a group having the structure -NHR'R" where R' and R" are independently selected from alkyl, as previously defined. Additionally, R' and R" taken together optionally be -(CH 2 ) k - where k is an integer of from 2 to 6. Examples of dialkylamino include dimethylamino, diethylamino, methylpropylamino, piperidino, and the like.
  • haloalkyl denotes an alkyl group, as defined above, having one, two or three halogen atoms attached thereto and is exemplified by such group as chloromethyl, bromoethyl , trifluoromethyl, and the like.
  • alkoxycarbonyl represents as ester group; i.e. an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like.
  • thioalkoxy refers to an alkyl group previously defined attached to the parent molecular moiety through a sulfur atom.
  • carboxamide refers to a group of formula -CONHR'R" where R' and R" are independently selected from hydrogen, alkyl, substituted loweralkyl, or R' and R" taken together optionally be -(CH 2 ) k - where k is an integer of from 2 to 6.
  • heteroaryl refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring of which at least one atom of the cyclic or bicyclic ring is selected from optionally substituted S, O, and N; zero, one or two ring atoms are additional heteroatoms independently selected from optionally substituted S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, naphthyridinyl;
  • substituted heteroaryl refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring of which at least one atom of the cyclic or bicyclic ring is selected from optionally substituted S, O, and N; zero, one or two ring atoms are additional heteroatoms independently selected from optionally substituted S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, naphthyridiny
  • heterocycloalkyl refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which includes aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring.
  • heterocycloalkyl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms optionally be oxidized and the nitrogen heteroatom optionally be quaternized.
  • heterocycloalkyl rings include, but not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • heteroarylalkyl refers to a heteroaryl group as defined above attached to the parent molecular moiety through an alkylene group where the alkylene group is of one to four carbon atoms.
  • Protecting group refers to an easily removable group which is known in the art to protect a functional group, for example, a hydroxyl, ketone or amine, against undesirable reaction during synthetic procedures and to be selectively removable. Examples of such protecting groups are known, cf., for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991).
  • hydroxy-protecting groups include, but not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, ethers such as methoxymethyl, and esters including acetyl, benzoyl, and the like.
  • ketone protecting groups include, but not limited to, ketals, oximes, O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, 1-isopropoxycyclohexyl oxime, and the like.
  • amine protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc) and carbobenzyloxy (Cbz).
  • a term "protected-hydroxy” refers to a hydroxy group protected with a hydroxy protecting group, as defined above.
  • amino acid refers to amino acids having D or L stereochemistry, and also refers to synthetic, non-natural amino acids having side chains other than those found in the 20 common amino acids.
  • Non-natural amino acids are commercially available or are optionally prepared according to US 5,488,131 and references therein.
  • Amino acids are optionally further substituted to contain modifications to their amino, carboxy, or side-chain groups. These modifications include the numerous protecting group commonly used in peptide synthesis (T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York, 1991).
  • substituted heteroaryl refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with CI, Br, F, I, OH, CN, C C 12 - alkoxy, C r C 12 -alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • any one substituent is optionally an aryl, heteroaryl, or heterocycloalkyl group.
  • substituted heterocycloalkyl refers to a heterocycloalkyl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with CI, Br, F, I, OH, CN, C r C, 2 - alkyl, C Ci 2 -alkoxy, C r C 12 -alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • any one substituent is optionally aryl, heteroaryl, or heterocycloalkyl group.
  • phenolic regioiosmer refers to either of the three possible isomers of a compound having the same molecular weight with the substituent attached to one of the phenolic alcohols of the glycopeptide derivatives illustrated by either structure (A), (B) or (C).
  • stereoisomer refers to either of two forms of a compound having the same molecular formula and having their constituent atoms attached in the same order, but having different arrangement if their atoms in space about an asymmetric center. If asymmetric centers exist in the described compounds, except where otherwise noted, the compounds described herein include the various stereoisomers and mixtures thereof. Accordingly, except where otherwise noted, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation is present.
  • tautomer refers to either of the two forms of a chemical compound that exhibits tautomerism, which is the ability of certain chemical compounds to exist as a mixture of two interconvertible isomers in equilibrium via proton transfer.
  • the keto and enol forms of carbonyl compounds are examples of tautomers. They are interconvertible in the presence of traces of acids and bases via a resonance stabilized anion, the enolate ion.
  • salts refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference for this purpose.
  • the salts are prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base function with a suitable organic acid.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other documented methodologies such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other documented methodologies such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • solvate refers to a compound formed by salvation, the combination of solvent molecules with molecules or ions of solute composed of a compound described herein.
  • pharmaceutically acceptable solvate refers to those solvates which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lover animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • alkylated quaternary ammonium salt refers to a compound formed by alkylation of the nitrogen atom of the primary, secondary or tertiary amine of the molecule with alkyl halide to form alkyl quaternary ammonium salt.
  • prodrugs refers to those prodrugs of the compounds described herein which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds described herein.
  • prodrug refers to compounds that are transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for this purpose.
  • a "beta-lactam antibiotic” includes, but is not limited to, penicillin, methicillin, dicloxacillin, flucloxacillin, first generation cephalosporins (such as cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, and ceftezole), second generation cephalosporins (such as cefaclor, cefonicid, cefprozil, cefuroxime, cefuzonam, cefmetazole, cefotetan, and cefoxitin), third generation cephalosporins (such as cefcapene, cefdaloxime, cefdinir, cefditoren, cefixime, cefmenoxime,
  • the semi-synthetic glycopeptides described herein are based on hydrolysis of the disaccharide moiety of the amino acid-4 of the parent glycopeptide to monosaccharide; conversion of the monosaccharide to the amino-sugar; acylation of the amino substituent on the amino-substituted sugar moiety on these scaffolds with certain acyl groups; and conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides.
  • Key reaction is the treatment of properly protected intermediate compound with isocyanate or carrying a Hofmann degradation of the primary amide of the 3 rd amino acid asparagines with phenyl-bis-trifluoroacetate to give the primary amine.
  • the compounds described herein are made, for example, by coupling the amino-sugar moiety of functionalized or unfunctionalized glycopeptides from the above scaffolds with the appropriate acyl and/or amino groups under amide formation conditions and conversion of the acid moiety on the macrocyclic ring of the resulting glycopeptide derivative to certain substituted amides; or a combination of an alkylation modification of the substituent on the amino-substituted sugar moiety on this scaffold with certain alkyl groups or acylation modification of the amino substituent on the amino-substituted sugar moiety on this scaffold with certain acyl groups, a-amino acid or ⁇ -amino acids or derivatives thereof, and conversion of the acid moiety on the macrocyclic ring of this scaffold to certain substituted amides.
  • the compounds described herein are made, for example, by chemical modifications of the Compound A, Compound B, Compound H and Compound C scaffolds.
  • the semi-synthetic glycopeptides described herein are made by chemical modification of Compound A, Compound B, Compound H and Compound C or of the monosaccharide of the about glycopeptides made by subjecting the appropriate protected glycopeptide to a Mannich reaction with formaldehyde and an amine followed by de-protection.
  • synthesis of compounds also involves the use of protecting or blocking groups in order to maximize yields, minimize unwanted side products, or improve purification.
  • the semi-synthetic glycopeptides of the compounds described herein are made, for example, by modifying Compound A, Compound B, Compound H and Compound C scaffolds.
  • the glycopeptide starting material is optionally unsubstituted or substituted at the 7 th amino acid at the 4' position of the phenyl ring with CH2NHCH2PO3H2, or aminoloweralkyl as defined herein.
  • compound of Formulas I-XIV, described herein are made by where R A is hydrogen or methyl, X is chlorine or hydrogen, R 3 is alkoxy, 2-adamantanamino, or loweralkylamino, or R4 is hydrogen or properly protected CH 2 NHCH 2 P0 3 H2, or Boc-aminoloweralkyl, or PG is nitrogen protecting group by a technique selected from the group consisting of,
  • R, R h R 2 , R 3 , R4, R A , RB, RC, 3 ⁇ 4>, Al, A2, A3, X , Y, and Z are as defined herein.
  • the semi-synthetic glycopeptides described herein are made, for example, by modifying Compound A, Compound B, Compound H or Compound C scaffolds.
  • These natural glycopeptide starting materials are optionally unsubstituted or substituted at R4 with CH2NHCH2PO3H2, or aminoloweralkyl as defined herein.
  • Substitutions at R4 are introduced, for example, via a Mannich reaction where the glycopeptide is treated with an amine and formaldehyde under basic conditions (for example, as described in The Journal of Antibiotics, Vol. 50, No. 6, p. 509-513).
  • compositions described herein comprise a therapeutically effective amount of a compound described herein formulated together with one or more pharmaceutically acceptable carriers.
  • a pharmaceutically acceptable carrier As used herein, the term
  • “pharmaceutically acceptable carrier” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar;
  • buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants are also present in the composition, according to the judgment of the formulator.
  • compositions described herein are administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray, or a liquid aerosol or dry powder formulation for inhalation.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms optionally contain inert diluents 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, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions optionally also include adjuvants such as wetting agents,
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions are formulated using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation are optionally a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that are optionally employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are optionally employed as a solvent or suspending medium.
  • any bland fixed oil is optionally employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations are sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which is dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • biodegradable polymers examples include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared, for example, by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which are optionally prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acety
  • compositions of a similar type are optionally employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules are prepared, for example, with coatings and shells such as enteric coatings and other documented coatings. They optionally contain opacifying agents and also are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which are used include polymeric substances and waxes.
  • compositions of a similar type are optionally employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds are optionally in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules are optionally prepared with coatings and shells such as enteric coatings, release controlling coatings and other documented coatings.
  • the active compound is admixed, for example, with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms optionally comprise additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms optionally comprise buffering agents. They optionally contain opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as required. Ophthalmic formulations, ear drops, and the like are also contemplated.
  • the ointments, pastes, creams and gels optionally contain, in addition to an active compound described herein, 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.
  • 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.
  • compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder.
  • Liquid aerosol formulations are nebulized, for example, predominantly into particle sizes that are delivered to the terminal and respiratory bronchioles where bacteria reside in patients with bronchial infections, such as chronic bronchitis and pneumonia.
  • Pathogenic bacteria are commonly present throughout airways down to bronchi, bronchioli and lung parenchema, particularly in terminal and respiratory bronchioles. During exacerbation of infection, bacteria can also be present in alveoli.
  • Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
  • Aerosolized formulations described herein are delivered, for example, using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of a aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ⁇ . Further, the formulation preferably has balanced osmolality ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the compounds described herein to the site of the infection. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
  • an aerosol forming device such as a jet, vibrating porous plate or ultrasonic nebulizer
  • Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ⁇ . Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ⁇ range.
  • a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • a variety of suitable devices are available, including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California),
  • Compounds described herein are formulated, for example, for use as topical powders and sprays that contain, in addition to the compounds described herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays optionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms made, for example, by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers are optionally used to increase the flux of the compound across the skin.
  • the rate is controlled, for example, by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound described herein, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound described herein is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds and compositions described herein will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors known in the medical arts.
  • the total daily dose of the compounds described herein administered to a human or other mammal in single or in divided doses is in amounts, for example, from about 0.01 to about 50 mg/kg body weight or more usually from about 0.1 to about 25 mg kg body weight.
  • Single dose compositions contain, for example, such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens described herein comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of the compound(s) described herein per day in single or multiple doses.
  • LiN(TMS)2 for lithium bis(trimethylsilyl)amide
  • MCPBA for /Meta-chloroperbenzoic acid
  • MeOH for methanol
  • MsCl for methanesulfonyl chloride
  • NaHMDS or NaN(TMS)2 for sodium bis(trimethylsilyl)amide
  • MTBE for methyl tert-butyl ether
  • NMO for N-methylmorpholine N-oxide
  • pNZ-OSu for 2,5-dioxopyrrolidin-l-yl 4-nitrobenxyl carbonate
  • Boc for tert- W 201 butoxycarbonyl group
  • pNZ or p-nitrocarbobenzyloxy for carbo-(4-nitro)benzyloxy group
  • PE for petroleum ether
  • SOCl 2 for thionyl chloride
  • PPTS for pyridium -toluene sulfonate
  • Pd(OAc) 2 for palladium (II) acetate
  • PPh 3 for triphenylphosphine
  • Py for pyridine
  • TFA for trifluoroacetic acid
  • TEA for triethylamine
  • THF for tetrahydrofuran
  • TMSC1 for trimethylsilyl chloride
  • TMSCF 3 for trimethyl(trifluoromethyl)-silane

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Abstract

La présente invention concerne des procédés d'utilisation de glycopeptides semi-synthétiques de formules I-XIV ayant une activité antibactérienne.
PCT/US2011/034885 2010-05-04 2011-05-03 Procédés d'utilisation de glycopeptides semi-synthétiques en tant qu'agents antibactériens WO2011140009A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8420650B2 (en) 2008-08-06 2013-04-16 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US8735392B2 (en) 2010-10-21 2014-05-27 Biomarin Pharmaceutical Inc. Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt
WO2017140269A1 (fr) 2016-02-19 2017-08-24 中国科学院上海药物研究所 Composé à cycle hétérocyclique nitrique à six éléments amino substitué, sa préparation et son utilisation
US9926303B2 (en) 2010-02-08 2018-03-27 Medivation Technologies Llc Processes of synthesizing dihydropyridophthalazinone derivatives
US10493078B2 (en) 2010-02-03 2019-12-03 Medivation Technologies Llc Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency
CN111073457A (zh) * 2019-12-31 2020-04-28 沈阳顺风新材料有限公司 一种环保长效抗菌涂料及其制备方法

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WO2009085562A1 (fr) * 2007-12-26 2009-07-09 Lead Therapeutics, Inc. Nouveaux glycopeptides semi-synthétiques comme agents antibactériens
WO2010065174A1 (fr) * 2008-12-05 2010-06-10 Lead Therapeutics, Inc. Nouveaux glycopeptides semi-synthétiques comme agents antibactériens

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WO2008140973A1 (fr) * 2007-05-08 2008-11-20 Lead Therapeutics, Inc. Glycopeptides semi-synthétiques à activité antibactérienne
WO2009085562A1 (fr) * 2007-12-26 2009-07-09 Lead Therapeutics, Inc. Nouveaux glycopeptides semi-synthétiques comme agents antibactériens
WO2010065174A1 (fr) * 2008-12-05 2010-06-10 Lead Therapeutics, Inc. Nouveaux glycopeptides semi-synthétiques comme agents antibactériens

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HEGDE S S ET AL: "PHARMACODYNAMICS OF TELAVANCIN (TD-6424), A NOVEL BACTERICIDAL AGENT, AGAINST GRAM-POSITIVE BACTERIA", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, WASHINGTON, DC, US, vol. 48, no. 8, 1 August 2004 (2004-08-01), pages 3043 - 3050, XP009048268, ISSN: 0066-4804, DOI: 10.1128/AAC.48.8.3043-3050.2004 *
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8420650B2 (en) 2008-08-06 2013-04-16 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US8999987B2 (en) 2008-08-06 2015-04-07 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US9820985B2 (en) 2008-08-06 2017-11-21 Medivation Technologies Llc Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US10543209B2 (en) 2008-08-06 2020-01-28 Medivation Technologies Llc Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US10780088B2 (en) 2008-08-06 2020-09-22 Medivation Technologies Llc Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US11364241B2 (en) 2008-08-06 2022-06-21 Medivation Technologies Llc Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US10493078B2 (en) 2010-02-03 2019-12-03 Medivation Technologies Llc Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency
US9926303B2 (en) 2010-02-08 2018-03-27 Medivation Technologies Llc Processes of synthesizing dihydropyridophthalazinone derivatives
US8735392B2 (en) 2010-10-21 2014-05-27 Biomarin Pharmaceutical Inc. Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt
US10189837B2 (en) 2010-10-21 2019-01-29 Medivation Technologies Llc Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt
WO2017140269A1 (fr) 2016-02-19 2017-08-24 中国科学院上海药物研究所 Composé à cycle hétérocyclique nitrique à six éléments amino substitué, sa préparation et son utilisation
CN111073457A (zh) * 2019-12-31 2020-04-28 沈阳顺风新材料有限公司 一种环保长效抗菌涂料及其制备方法

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