WO2007027599A1 - 9-aminocarbonylsubstituted derivatives of glycylcyclines - Google Patents

9-aminocarbonylsubstituted derivatives of glycylcyclines Download PDF

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WO2007027599A1
WO2007027599A1 PCT/US2006/033516 US2006033516W WO2007027599A1 WO 2007027599 A1 WO2007027599 A1 WO 2007027599A1 US 2006033516 W US2006033516 W US 2006033516W WO 2007027599 A1 WO2007027599 A1 WO 2007027599A1
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Prior art keywords
amino
oxy
carbonyl
butyl
methyl
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PCT/US2006/033516
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French (fr)
Inventor
Phaik-Eng Sum
Tarek Suhayl Mansour
David Brian How
Darrin William Hopper
Matthew Douglas Vera
Joshua James Sabatini
Jaechul Shim
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Wyeth
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Priority to JP2008529162A priority Critical patent/JP2009507793A/en
Priority to EP06790037A priority patent/EP1919879A1/en
Priority to AU2006285043A priority patent/AU2006285043A1/en
Priority to BRPI0615300-3A priority patent/BRPI0615300A2/en
Priority to CA002620600A priority patent/CA2620600A1/en
Publication of WO2007027599A1 publication Critical patent/WO2007027599A1/en
Priority to IL189796A priority patent/IL189796A0/en
Priority to NO20081103A priority patent/NO20081103L/en

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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
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    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
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    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to 9-aminocarbonylsubstituted derivatives of glycylcyclines which are useful as antibiotic agents and exhibit antibacterial activity against a wide spectrum of organisms including organisms which are resistant to tetracyclines and other antibiotics.
  • Tetracyclines inhibit protein synthesis by binding to the 3OS subunit of the bacterial ribosome preventing binding of aminoacyl RNA (Chopra, Handbook of Experimental Pharmacology, Vol. 78, 317-392, Springer-Verlag, 1985). Resistance to tetracyclines has emerged among many clinically important microorganisms which limit the utility of these antibiotics. There are two major mechanisms of bacterial resistance to tetracyclines: a) energy-dependent efflux of the antibiotic mediated by proteins located in the cytoplasmic membrane which prevents intracellular accumulation of tetracycline (S. B.
  • ribosomal protection mediated by a cytoplasmic protein which interacts with the ribosome such that tetracycline no longer binds or inhibits protein synthesis
  • the efflux mechanism of resistance is encoded by resistance determinants designated tetA-tetL. They are common in many Gram-negative bacteria (resistance genes Class A-E), such as Enterobacteriaceae, Pseudomonas, Haemophilus and Aeromonas, and in Gram- positive bacteria (resistance genes
  • Class K and L such as Staphylococcus, Bacillus and Streptococcus.
  • the ribosomal protection mechanism of resistance is encoded by resistance determinants designated TetM, N and O, and is common in Staphylococcus, Streptococcus, Campylobacter, Gardnerella, Haemophilus and Mycoplasma (A. A. Salyers, B. S. Speers and N. B. Shoemaker, MoI. Microbiol, 4:151-156 1990).
  • a particularly useful tetracycline compound is 7-(dimethylamino)- 6-demethyl- 6-deoxytetracycline, known as minocycline (see U.S. Pat. No. 3,148,212, U.S. Pat. No. RE 26,253 and U.S. Pat. No. 3,226,436 discussed below).
  • minocycline 7-(dimethylamino)- 6-demethyl- 6-deoxytetracycline
  • tetB efflux in gram-negative bacteria
  • tetK efflux in Staphylococcus
  • strains carrying tetM are resistant to minocycline.
  • Duggar U.S. Pat. No. 2,482,055, discloses the preparation of Aureomycin.RTM. by fermentation which have antibacterial activity.
  • Growich et al. U.S. Pat. No. 3,007,965, disclose improvements to the fermentation preparation.
  • Beereboom et al. U.S. Pat. No. 3,043,875 discloses tetracycline derivatives Boothe et al., U.S. Pat. No. 3,148,212, reissued as U.S. Pat. No. RE 26,253, and Petisi et al., U.S. Pat. No. 3,226,436, discloses tetracycline derivatives which are useful for treating bacterial infections. Blackwood et al., U.S.
  • Pat. No. 3,200,149 discloses tetracycline derivatives which possess microbiological activity.
  • Petisi et al., U.S. Pat. No. 3,338,963 discloses tetracycline compounds which have broad-spectrum antibacterial activity.
  • Bitha et al., U.S. Pat. No. 3,341 ,585 discloses tetracycline compounds which have broad-spectrum antibacterial activity.
  • Shu, U.S. Pat. No. 3,360,557 discloses 9- hydroxytetracyclines which have been found to possess antibacterial activity.
  • Zambrano, U.S. Pat. No. 3,360,561 discloses a process for preparing 9-nitrotetracyclines.
  • Martell et al., U.S. Pat. No. 3,518,306 discloses tetracyclines which possess in vivo antibacterial activity.
  • the present invention provides such antibiotics.
  • This invention is concerned with 9-aminocarbonylsubstituted derivatives of glycylcyclines represented by Formula I which have antibacterial activity; with methods of treating infectious diseases in humans and other animals when administering these new compounds; with pharmaceutical preparations containing these compounds; and with novel processes for the production of compounds of Formula I.
  • A is a moiety or is absent
  • R- I is selected from hydrogen, -OH, amino, -NR 7 R 8 , halogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)- aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl
  • R 2 is selected from hydrogen, halogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyi, alkoxy
  • R 3 is the moiety Rg
  • R 4 is selected from hydrogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, al
  • R 5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, aikyl, haloalkyl
  • R 6 is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms) ⁇ aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alky
  • R 7 and R 8 are each independently H or alkyl of 1 to 12 carbon atoms or R 7 and R 8 when optionally taken together with the nitrogen atom to which each is attached form a 3 to 8 membered heterocyclyl ring;
  • R 9 is aralkyl of 7 to 16 carbon atoms optionally substituted or alkyl of 1 to 12 carbon atoms;
  • R 10 is H or alkyl of 1 to 12 carbon atoms;
  • An embodiment of this invention provides compounds of Formula I wherein Ri is - NR 7 R 8 , R 7 is hydrogen, R 8 is methyl, ethyl, n-propyl, n-butyl, 1-methylethyl, 1- methylpropyl, 2-methylpropyl or 1 ,1-dimethylethyl or a pharmaceutically acceptable salt thereof.
  • R 1 is -NR 7 R 8
  • R 7 is methyl or ethyl
  • R 8 is methyl, ethyl, n-propyl, 1-methylethyl, n-propyl, 1-methylpropyl, or 2-methylpropyl or a pharmaceutically acceptable salt thereof.
  • R 1 is -NR 7 R 8 , R 7 and Ra are taken together with the nitrogen atom to which each is attached form a 3 to 8 membered heterocyclyl ring or a pharmaceutically acceptable salt thereof.
  • Another embodiment of this invention provides compounds of Formula I wherein R 2 is H or a pharmaceutically acceptable salt thereof.
  • a further embodiment of this invention provides compounds of Formula I wherein A is absent or a pharmaceutically acceptable salt thereof.
  • a further embodiment of this invention provides compounds of Formula I wherein R 3 is a moiety
  • a further additional embodiment of this invention provides compounds of Formula wherein R 3 is a moiety
  • An embodiment of this invention provides compounds of Formula I wherein R 3 is a moiety
  • R 6 and R 10 are H or a pharmaceutically acceptable salt thereof.
  • R 6 and R 10 are H or a pharmaceutically acceptable salt thereof.
  • a further embodiment of this invention provides compounds of Formula I wherein R 3 is R 9 or a pharmaceutically acceptable salt thereof.
  • An additional embodiment of this invention provides compounds of Formula I wherein A is the moiety
  • R 3 is the moiety
  • R 5 is aryl of 6 carbon atoms or a pharmaceutically acceptable salt thereof.
  • R 3 is the moiety
  • R 4 is 1 ,1-dimethylethyl
  • R 5 is aryl of 6 carbon atoms or a pharmaceutically acceptable salt thereof.
  • A is a moiety
  • R 4 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, and aryloxy wherein said aryl and aryloxy is optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl;
  • R 5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, and aryloxy wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, diaikylamino,
  • R 6 is hydrogen
  • R 7 and R 8 are each independently H or alkyl of 1 to 12 carbon atoms
  • R 9 is aralkyl of 7 to 16 carbon atoms optionally substituted or alkyl of 1 to 12 carbon atoms;
  • R 4 is selected from hydrogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, aikenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino
  • R 5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, aryloxy and N-(aikyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl,
  • R 6 is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alky
  • Rio is H or alkyl of 1 to 12 carbon atoms
  • R 11 is H, benzyl optionally substituted with nitro or a moiety of the formula
  • Ri 2 is alkyl of 1 to 6 carbon atoms.
  • the compounds having Formula Il are useful as chemical intermediates for making the compounds having formula I and the pharmaceutically acceptable salt thereof wherein: A is a moiety
  • R 3 is the moiety
  • R 4 and R 5 are as defined above.
  • An embodiment of the invention provides compounds of Formula Il wherein R 4 is t- butyl, R 5 is alkyl of 1 to 6 carbon atoms, and R 11 is benzyl optionally substituted with nitro.
  • R 4 is alkyl of 1 to 6 carbon atoms
  • R 5 is phenyl optionally substituted
  • R 11 is benzyl optionally substituted with nitro.
  • An embodiment of the invention provides compounds of Formula Il wherein R 5 is alkyl of 1 to 6 carbon atoms, R 4 is t-butyl and Ri 1 is H.
  • a further embodiment of the invention provides compounds of Formula Il wherein R 5 is alkyl of 1 to 6 carbon atoms, R 4 is t-butyl, Q is -OR 11 , R 11 is and R 12 is alkyl of 1 to 6 carbon atoms.
  • Another embodiment of the invention provides compounds of Formula Il wherein R 6 and R 10 are H.
  • Additional embodiments of the invention are the following specifically preferred compounds of Formula Il or pharmaceutically acceptable salts thereof.
  • a further embodiment of the invention is the following specifically preferred compound of Formula Il or pharmaceutically acceptable salts thereof.
  • alkyl means a straight or branched alkyl moiety of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alk
  • alkyl is a moiety of 1 to 6 carbon atoms. In other embodiments of the invention alkyl is a moiety of 1 to 3 carbon atoms. In other embodiments of the invention alkyl is 1 ,1-dimethylethyl also termed t-butyl. In some embodiments of the invention when alkyl is a methyl group wherein optional substitution is two independent phenyl rings. Non-limiting examples of alkyl are methyl, ethyl, n- propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1 ,1- dimethylethyl.
  • alkenyl means a straight or branched carbon chain of 2 to 12 carbon atoms having at least one site of unsaturation optionally independently substituted with 1 to 3 substituents selected from the group optionally independently substituted with 1 to 3 substituents selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH 3 -C(O)-NH-, aral
  • alkoxy refers to alkyl-O- wherein alkyl is hereinbefore defined.
  • Non limiting examples include: methoxy and ethoxy.
  • aryl means an aromatic moiety having 6, 10 or 14 carbon atoms preferably 6 to 10 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH 3 - C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl.
  • aryl is phenyl or naphthyl optionally substituted with 1 to 3 substituents.
  • aralkyl as used herein of 7 to 16 carbon atoms means an alkyl substituted with an aryl group in which the aryl and alkyl group are as defined herein.
  • Non- limiting exemplary aralkyl groups include benzyl and phenethyl and the like.
  • Perhaloalkyl as used herein means an alkyl moiety of 1 to 6 carbon atoms in which each hydrogen atom is substituted with a halogen atom, an exemplary example is trifluoromethyl.
  • Phenyl as used herein refers to a 6-membered carbon aromatic ring.
  • alkynyl includes both straight chain and branched moieties containing 2 to 12 carbon atoms having at least one carbon to carbon triple bond optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alky! of 1 to 12 carbon atoms, hydroxyl, and alkoxy of 1 to 12 carbon atoms.
  • halogen or halo means F, Cl, Br or I.
  • cycloalkyl means a saturated monocyclic ring having from 3 to 6 carbon atoms. Exemplary cycloalkyl rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment of the invention cycloalkyl is a moiety of 5 or 6 carbon atoms.
  • aroyl means an aryl-C(O)- group in which the aryl group is as previously defined.
  • Non-limiting examples include benzoyl and naphthoyl.
  • heteroaryl means an aromatic heterocyclic, monocyclic ring of 5 or 6 ring atoms containing 1 to 4 heteroatoms independently selected from O, N and S or bicyclic aromatic rings of 8 to 20 ring atoms containing 1 to 4 heteroatoms independently selected from O, N and S.
  • Heteroaryl rings may optionally be substituted with 1 to 3 substitutents independently selected from the group alkyl, halogen, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, - CH 2 OCOCH 3 and carboxy.
  • Non-limiting heteroaryl moieties optionally substituted include: furanyl, benzofuranyl, benzothienyl, thienyl, pyridinyl, quinolinyl, tetrazolyl, imidazo, thiazolyl and the like.
  • aralkyl refers to an aryl group
  • alkyl refers to the alkyl group as defined above
  • aryloxy refers to a arylO- group.
  • heteroarylcarbonyl means a heteroaryl-C(O)- group in which the heteroaryl group is as previously defined.
  • heterocyclyl as used herein represents a saturated ring of 3 to 8 ring atoms containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments of the invention a saturated ring of 5 or 6 ring atoms is preferred. Representative examples are pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
  • alkylheterocyclyl means an alkyl-heterocyclyl group in which the alkyl and heterocyclyl group are independently previously defined. Non-limiting exemplary alkylheterocyclyl groups include moieties of the formulae:
  • the present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
  • Proton sponge is [1 ,8-bis(dimethylamino)naphthalene, N,N,N',N'-tetramethyl-1 ,8- naphthalenediamine].
  • Alkali metal carbonate includes lithium, potassium and sodium carbonate.
  • DMPU is 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone.
  • N-butyl-glycylcycline (N-bu-glycyl) is
  • N-propyl-glycylcycline N-prop-glycyl
  • the compounds of this invention may be prepared according to the following schemes: (1 ) from commercially available starting materials or: (2) from known starting materials which can be prepared as described in literature procedures or: (3) from new intermediates described in the schemes and experimental procedures.
  • acyloxy intermediate 8 is shown in Scheme 1. Reaction of amine R 4 NH 2 , preferably t-butylamine, with ester 1 provides the substituted amino ester 2. Preparation of the intermediate 4 is accomplished by using Proton Sponge as base to effect the acylation of substituted amino ester 2 with chloromethyl chloroformate 3. Treatment of intermediate 4 with the tetrabutylammonium salt 5 of carboxylic acids gives the benzyl protected acyloxy intermediate 6.
  • the benzyl protecting group is removed by catalytic reduction to give carboxylic acid 7 which is activated to a mixed anhydride with chloroformate ClCO 2 Ri 2 where Ri 2 is alkyi of 1 to 6 carbon atoms, for example iso-butyl chloroformate to give acyloxycarbamate intermediate 8.
  • silyl esters may optionally be used in place of the benzyl ester of intermediate 4, treating with the appropriate carboxylic acid followed by deblocking the silyl ester with tetrabutylammonium fluoride or magnesium bromide to afford carboxylic acid 7.
  • carboxylic acid 7 may be activated through the use of coupling agents not limited to di-t-butyl dicarbonate (BoC 2 O); e.g., benzotriazole-1-yl- oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (also known asBop); benzotriazole-1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (also known as PyBop); 0-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate (HBTU); Bromotris-pyrollidino-phosphonium hexafluorophosphate; 2- Chloro-N-methylpyridinium iodide (CMPI); dicyclohexylcarbodiimide (DCC); 1 ,3- diisopropylcarbodiimide (DIG); 1
  • Additional acyloxy carbamate compounds may be synthesized via routes as shown in Schemes 3 and 4.
  • Treatment of chloromethyl chloroformate 3 with ethanethiol in the presence of triethylamine (TEA) gives carbonothioate 11.
  • Compound 12 is prepared by reacting carbonothioate 11 with carboxylic acid tetrabutylammonium salt 5 in tetrahydrofuran. Chlorination of compound 12 with sulfuryl chloride in the presence of catalytic amount of boron trifluoroetherate affords chloro intermediate 13 (using the methods described in M. Folkmann and FJ. Lund, Synthesis, December 1990, 1159- 1166).
  • acyloxycarbamates 16 and 17 where R 4 is preferably n- butyl or n-propyl are synthesized by treatment of either 14 or 15 where R 4 is preferably n-butyl or n-propyl with the chloro intermediate 13 to give acyloxycarbamates 16 and 17 respectively.
  • R 4 n-propyl
  • carbamates of glycylcycline where R 4 is preferably propyl 18 may also be prepared by reaction with chloro intermediate 19 in the presence of an alkali metal carbonate preferably sodium carbonate, and DMPU in acetonitrile to afford preferred compounds (21 and 22),
  • R 4 is preferably propyl
  • compounds of Formula I may generally be prepared by removal of the benzyl protecting group from benzyl protected acyloxy intermediate 24 to give carboxylic acid 25 which is activated to a mixed anhydride with a chloroformate CICO 2 R 12 where R 12 is alkyl of 1 to 6 carbon atoms, for example iso- butyl chloroformate to give acyloxycarbamate intermediate 26. Further reaction of 7,8-disubstituted-9-aminotetracycline 9 with acyloxycarbamate mixed anhydride intermediate 26 in the presence of triethylamine and DMPU affords compounds of Formula (I).
  • Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformations proposed. This may necessitate judgement as to the order of synthetic steps, protecting groups, if required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions. Such restrictions to the substituents which are compatible with the reaction conditions will be apparent to one skilled in the art.
  • the compounds of the hereinbefore described schemes have center of asymmetry.
  • the compounds may, therefore, exist in at least two and often more stereoisomeric forms.
  • the present invention encompasses all stereoisomers of the compounds whether free from other stereoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixture of enantiomers as well as the diastereomeric mixture of isomers.
  • the absolute configuration of any compound may be determined by conventional X-ray crystallography.
  • the compounds of the invention may be obtained as metal complexes such as aluminum, calcium, iron, magnesium, manganese and complex salts; inorganic and organic salts and corresponding Mannich base adducts using methods known to those skilled in the art (Richard C. Larock, Comprehensive Organic Transformations, VCH Publishers, 411-415, 1989).
  • the compounds of the invention are obtained as inorganic salts such as hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric or sulfate; or organic salts such as acetate, benzoate, citrate, cysteine or other amino acids, fumarate, glycolate, maleate, succinate, tartrate alkylsulfonate or arylsulfonate.
  • the salt formation occurs with the C(4)- dimethylamino group.
  • the salts are preferred for oral and parenteral administration. Standard Pharmacological Test Procedures
  • Antimicrobial susceptibility testing The in vitro activities of the antibiotics are determined by the broth microdilution method as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (1).
  • NCCLS National Committee for Clinical Laboratory Standards
  • MHBII Mueller-Hinton Il broth
  • Microtiter plates containing serial dilutions of each antimicrobial agent are inoculated with each organism to yield the appropriate density (10 ⁇ CFU/ml) in a 100 //I final volume. The plates are incubated for 18 - 22 hours at 35 0 C in ambient air.
  • the minimal inhibitory concentration for all isolates is defined as the lowest concentration of antimicrobial agent that completely inhibits the growth of the organism as detected by the unaided eye.
  • Tables I-XIII are representative compounds of Formula I which were evaluated against a panel of 40 selected gram-positive and gram-negative bacteria strains by pre-incubation in water, mouse serum or human serum. Representative compounds were first incubsted in mouse serum for an hour prior to the in vitro testing against a panel of selected gram-positive and gram-negative bacteria strains. All compounds were also pre-incubated in water for an hour prior to testing as control. Representative compounds of Formula I were incubated in human serum prior to MIC determination. Representative compounds of Formula I which demonstrated in vivo activity were further subjected to various stability tests. A summary of the in vitro testing data of representative examples of Formula I are shown in Table 1.
  • Table 2 and 5 Expanded in vitro data of selected examples (87 and 27) are shown in Table 2 and 5 respectively. MICs of representative examples of Formula I are further shown in Tables 3 and 4.
  • Table 6 presents in vitro and in vivo activity of representative examples of compounds of Formula I against Staph, aureus Smith in mice.
  • Table 7 presents in vivo (oral, iv) and in vitro (MIC) activity of representative examples of compounds of Formula I against E. coli in mice .
  • Table 8 presents in vivo (oral, iv) and in vitro (MIC) activity of representative examples of compounds of Formula I, against Staph aureus Smith in mice.
  • Table 9 presents in vitro (MIC) activity of representative examples of compounds of Formula I against E.
  • Table 10 presents in vivo single oral dose (SOD) and single intravenous dose (SIV) ED 50 data for representative examples of compounds of Formula I against Staph. Smith and E. CoIi #311 in mammals.
  • Example 1 Serum Water Serum Water erurr i Water Serum Water Example 1 Example 1 Example 2 Example 2 simple i 3 Example 3 Example 4 Example 4
  • Example 1 Example 1 Example 2 Example 2 Exampie 3 Example 3 Example 4 Exar ⁇ r. )le
  • Example 5 Example 5 Example 5 Example 6 Example 6 Example 7 Example 7 Example 8 Example 8
  • Example 5 Example 5 Example 5 Example 6 Example 6 Example 7 Example 7 Example 8 Example 8
  • Example 5 Example 5 Example 5 Example 6 Example 6 Example 7 Example 7 Example 8 Example 8
  • Example 9 Example 9 Example 10 Example 10 Example 11 Example 11 Example 12 Example 12
  • E. coli GC 4560 0.25 1 0.12 0.12 0.12 0.12 0.25 1
  • Example 9 Example Example 10 10 Example 11 11 Example 12 Example 12
  • Example 9 Example 9 Example 10 Example 10 Example 11 Example 11 Example 12 Example 12
  • Example 13 Example 13 Example 13 Example 14 Example 14 Example 15 Example 15 Example 16 Example 16
  • Example 13 Example 13 Example 14 Example ⁇ A ⁇ Example 15 Example 15 Example 16 Example 1 ⁇
  • Example 13 Example 13 Example 13 Example 14 Example 14 Example 15 Example 15 Example 16 Example 16
  • E. faecal is GC 4555 2 4 2 8 4 8 4 8
  • Example 16 Mouse Serum Water Serum Water Serum Water Mouse Serum Water Example 13 Example 13 e 14 Example 14 Example 15 Example 15 Example 16 Example 16
  • Example 21 Example : Example 22 Example 22 Example 23 Example 23 Example 24 Example 24
  • Example 21 Example 22 22 Example 23 Example 23 Example 24 Example 24
  • Example 25 Example 25 Example 25 Example 26 Example 26 Example 27 Example 27 Example 28 Example 28
  • Example 25 Example 25 Example 25 Example 26 Example 26 Example 27 Example 27 Example 28 Example 28
  • E. faecium GC 2243 0.50 1 1 2 0.12 0.25 0.25 0.25
  • Example 25 Exampl Iee 2255 Example 26 26 Example 27 27 Example 2
  • Example 42 Example 42 Example 42 Example 42 Example 43 Example 43 Example 43 44 Example 44 Example 44
  • Example 42 Example 42 Example 42 Example 42 Example 43 Example 43 Example 43 44 Example 44 Example 44
  • Example 42 '. Example 42 Example 42 Example 43 Example 43 44 Example 44 • Example 44
  • E. faecal is GC 4555 4 2 4 32 0.50 8 4 2 4
  • Example 48 Example 48 Example 48 Example 49 Example 49 Example 49 Example 50 Example 50 Example 50
  • Example 48 Example 48 Example 48 Example 49 Example 49 Example 49 Example 50 Example 50 Example 50
  • Example 51 Example 51 Example 51 Example 51 Example 52 Example 52 Example 52 Example 53 Example 53 Example 53
  • Example 51 Example 51 Example 51 Example 52 Exampl Iee 5522 Example 52 Example .' Example 53 Example 53
  • Example 51 EExxaammppllee i 5. 511 EExxaammppllee 55 11 5522 Example 52 Example 52 53 Example 53 Example 53
  • Example 58 Example 58 Example 58 Example 59 Example 59 Example 60 Example 60
  • Example 58 Example 58 Example 58 Example 59 Example 59 Example 60 Example 60
  • Example 61 Example 61 Example 61 Example 61 Example 62 Example 62 Example 62 Example 63 Example 63 Example 63

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Abstract

This invention provides compounds of Formula (I) having the structure where R1, R2, R3 and A are defined in the specification or a pharmaceutically acceptable salt thereof useful as antibacterial agents. Compounds according to Formula (II): where Q, R4, R5, and R6 and A are defined in the specification are useful as chemical intermediates.

Description

9-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES
This application claims priority from U.S. Application No.60/713,112 filed August 31 , 2005 the entire disclosure of which is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to 9-aminocarbonylsubstituted derivatives of glycylcyclines which are useful as antibiotic agents and exhibit antibacterial activity against a wide spectrum of organisms including organisms which are resistant to tetracyclines and other antibiotics.
BACKGROUND OF THE INVENTION
Since 1947 a variety of tetracycline antibiotics have been synthesized and described for the treatment of infectious diseases in man and animals. Tetracyclines inhibit protein synthesis by binding to the 3OS subunit of the bacterial ribosome preventing binding of aminoacyl RNA (Chopra, Handbook of Experimental Pharmacology, Vol. 78, 317-392, Springer-Verlag, 1985). Resistance to tetracyclines has emerged among many clinically important microorganisms which limit the utility of these antibiotics. There are two major mechanisms of bacterial resistance to tetracyclines: a) energy-dependent efflux of the antibiotic mediated by proteins located in the cytoplasmic membrane which prevents intracellular accumulation of tetracycline (S. B. Levy, et al., Antimicrob. Agents Chemotherapy 33, 1373-1374 (1989); and b) ribosomal protection mediated by a cytoplasmic protein which interacts with the ribosome such that tetracycline no longer binds or inhibits protein synthesis (A. A. Salyers, B. S. Speers and N. B. Shoemaker, MoI. Microbiol, 4:151- 156, 1990). The efflux mechanism of resistance is encoded by resistance determinants designated tetA-tetL. They are common in many Gram-negative bacteria (resistance genes Class A-E), such as Enterobacteriaceae, Pseudomonas, Haemophilus and Aeromonas, and in Gram- positive bacteria (resistance genes
Class K and L), such as Staphylococcus, Bacillus and Streptococcus. The ribosomal protection mechanism of resistance is encoded by resistance determinants designated TetM, N and O, and is common in Staphylococcus, Streptococcus, Campylobacter, Gardnerella, Haemophilus and Mycoplasma (A. A. Salyers, B. S. Speers and N. B. Shoemaker, MoI. Microbiol, 4:151-156 1990).
A particularly useful tetracycline compound is 7-(dimethylamino)- 6-demethyl- 6-deoxytetracycline, known as minocycline (see U.S. Pat. No. 3,148,212, U.S. Pat. No. RE 26,253 and U.S. Pat. No. 3,226,436 discussed below). However, strains harboring the tetB (efflux in gram-negative bacteria) mechanism, but not tetK (efflux in Staphylococcus) are resistant to minocycline. Also, strains carrying tetM (ribosomal protection) are resistant to minocycline.
Duggar, U.S. Pat. No. 2,482,055, discloses the preparation of Aureomycin.RTM. by fermentation which have antibacterial activity. Growich et al., U.S. Pat. No. 3,007,965, disclose improvements to the fermentation preparation. Beereboom et al., U.S. Pat. No. 3,043,875 discloses tetracycline derivatives Boothe et al., U.S. Pat. No. 3,148,212, reissued as U.S. Pat. No. RE 26,253, and Petisi et al., U.S. Pat. No. 3,226,436, discloses tetracycline derivatives which are useful for treating bacterial infections. Blackwood et al., U.S. Pat. No. 3,200,149 discloses tetracycline derivatives which possess microbiological activity. Petisi et al., U.S. Pat. No. 3,338,963 discloses tetracycline compounds which have broad-spectrum antibacterial activity. Bitha et al., U.S. Pat. No. 3,341 ,585 discloses tetracycline compounds which have broad-spectrum antibacterial activity. Shu, U.S. Pat. No. 3,360,557 discloses 9- hydroxytetracyclines which have been found to possess antibacterial activity. Zambrano, U.S. Pat. No. 3,360,561 discloses a process for preparing 9-nitrotetracyclines. Martell et al., U.S. Pat. No. 3,518,306 discloses tetracyclines which possess in vivo antibacterial activity.
In U.S. Pat. No. 5,021 ,407 a method of overcoming the resistance of tetracycline resistant bacteria is disclosed. The method involves utilizing a blocking agent compound in conjunction with a tetracycline type antibiotic. This patent does not disclose novel tetracycline compounds which themselves have activity against resistant organisms. Described in U.S. Pat. No. 5,494,903 are 7-substituted-9- substitutedamino-6-demethyl-6-deoxytetracyclines which have broad spectrum antibacterial activity.
Despite the advances being made to overcome the resistance of tetracycline resistant bacteria, there remains a need for newer and better antibiotics to overcome the increasing incidence of resistance. The present invention provides such antibiotics.
In summary, none of the above patents teach or suggest the novel derivatives of glycylcyclines of this application.
SUMMARY OF THE INVENTION
This invention is concerned with 9-aminocarbonylsubstituted derivatives of glycylcyclines represented by Formula I which have antibacterial activity; with methods of treating infectious diseases in humans and other animals when administering these new compounds; with pharmaceutical preparations containing these compounds; and with novel processes for the production of compounds of Formula I.
In accordance with the present invention, there is provided compounds represented by Formula (I);
Figure imgf000004_0001
(I)
wherein:
A is a moiety
Figure imgf000004_0002
or is absent;
R-I is selected from hydrogen, -OH, amino, -NR7R8, halogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)- aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyi, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, and alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy;
R2 is selected from hydrogen, halogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyi, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3- C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryi and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-
C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, and alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy;
R3 is the moiety Rg,
Figure imgf000006_0001
R4 is selected from hydrogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3- C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy, aryl of 6, 10 or 14 carbon atoms said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, N-(alkyl of 1 to 12 carbon atoms)-aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl of 7 to 13 carbon atoms optionally substituted, SR3, heteroaryl optionally substituted and heteroarylcarbonyl optionally substituted;
R5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, aikyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3- C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl, -CH2(CO)OCH2aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted, heteroaryl optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, aikynyl of 2 to 12 carbon atoms optionally substituted, cycloalkyl 3 to 6 ring atoms, aryl-CH=CH-, cycloalkyl-alkyl; and adamantyl;
R6 is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)~aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3- C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, and cycloalkyl of 3 to 6 carbon atoms;
R7 and R8 are each independently H or alkyl of 1 to 12 carbon atoms or R7 and R8 when optionally taken together with the nitrogen atom to which each is attached form a 3 to 8 membered heterocyclyl ring;
R9 is aralkyl of 7 to 16 carbon atoms optionally substituted or alkyl of 1 to 12 carbon atoms; R10 is H or alkyl of 1 to 12 carbon atoms;
or a pharmaceutically acceptable salt thereof.
An embodiment of this invention provides compounds of Formula I wherein Ri is - NR7R8 , R7 is hydrogen, R8 is methyl, ethyl, n-propyl, n-butyl, 1-methylethyl, 1- methylpropyl, 2-methylpropyl or 1 ,1-dimethylethyl or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention provides compounds of Formula I wherein R1 is -NR7R8, R7 is methyl or ethyl, R8 is methyl, ethyl, n-propyl, 1-methylethyl, n-propyl, 1-methylpropyl, or 2-methylpropyl or a pharmaceutically acceptable salt thereof. A further embodiment of this invention provides compounds of Formula I wherein R1 is -NR7R8 , R7 and Ra are taken together with the nitrogen atom to which each is attached form a 3 to 8 membered heterocyclyl ring or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention provides compounds of Formula I wherein R2 is H or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention provides compounds of Formula I wherein A is a moiety
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention provides compounds of Formula I wherein A is absent or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention provides compounds of Formula I wherein R3 is a moiety
Figure imgf000009_0002
or a pharmaceutically acceptable salt thereof. A further additional embodiment of this invention provides compounds of Formula wherein R3 is a moiety
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof.
An embodiment of this invention provides compounds of Formula I wherein R3 is a moiety
Figure imgf000010_0002
and R6 and R10 are H or a pharmaceutically acceptable salt thereof.
An additional embodiment of this invention provides compounds of Formula I wherein R3 is a moiety
Figure imgf000011_0001
and R6 and R10 are H or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention provides compounds of Formula I wherein R3 is R9 or a pharmaceutically acceptable salt thereof.
An additional embodiment of this invention provides compounds of Formula I wherein A is the moiety,
Figure imgf000011_0002
R3 is the moiety
Figure imgf000011_0003
R5 is aryl of 6 carbon atoms or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention provides compounds of Formula I wherein A is the moiety
10
Figure imgf000012_0001
R3 is the moiety ,
Figure imgf000012_0002
R4 is 1 ,1-dimethylethyl and
R5 is aryl of 6 carbon atoms or a pharmaceutically acceptable salt thereof.
An additional embodiment of this invention provides compounds of Formula I
wherein:
A is a moiety
Figure imgf000012_0003
Figure imgf000012_0004
R2 is hydrogen; R3 is the moiety
Figure imgf000013_0001
R4 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, and aryloxy wherein said aryl and aryloxy is optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl;
R5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, and aryloxy wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, diaikylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl, -CH2(CO)OCH2aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl, heteroaryl optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, cycloalkyl 3 to 6 ring atoms, aryl-CH=CH-, cycloalkyl-alkyl; and adamantyl;
R6 is hydrogen;
R7 and R8 are each independently H or alkyl of 1 to 12 carbon atoms;
R9 is aralkyl of 7 to 16 carbon atoms optionally substituted or alkyl of 1 to 12 carbon atoms;
or a pharmaceutically acceptable salt thereof.
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 2-methylpropanoate,
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(buty!)amino]carbonyl}oxy)methyl 4-methoxybenzoate,
({[(2-{[(7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 -tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyi)amino]carbonyl}oxy)methyl 4-methylbenzoate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(buty!)amino]carbonyl}oxy)methyl 4-fluorobenzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,1 Oa, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-methylbenzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-methoxybenzoate,
({^-{[(SaR.βaSys.iOaS^g-CaminocarbonylHy-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yi]amino}-2- oxoethyl)(propyi)amino]carbonyl}oxy)methyl cyclobutanecarboxylate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propy!)amino]carbonyl}oxy)methyl 4-fluorobenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a, 11- tetrahydroxy-10,12-dioxo-5, 5a,6,6a,7, 10,10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl pivalate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 2-methylpropanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10,10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyi)amino]carbonyl}oxy)methyl phenylacetate, ({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-δ.δa.θ.θa.T.10.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyi)amino]carbonyl}oxy)methyl phenylacetate,
({[(2-{[(5aR,6aSI7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methy! pivalate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 I8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amiπo]carbonyl}oxy)methyl heptanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl cyclobutanecarboxylate,
({^-{[(SaR.eaSJS.10aS^θ^aminocarbonylHy-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl heptanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonylH,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 4-tert-butylbenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 1 ,1 '-biphenyl-4-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(anninocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a!12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 3,5-dimethylbenzoate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahyclrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 1 ,1'-biphenyl-4-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10,10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 3,5-dimethylbenzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-δ.δa.e.βaJ.10JOa.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-tert-butylbenzoate,
1 -({[(2-{[(7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyi}oxy)ethy! acetate,
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethy)amino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7, 10, 10a112-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl cyclohexanecarboxyiate,
({[(2-{[(7S,10aS)-9-(aminocarbony))-4,7-bis(dimethy!amino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10/i0a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl cyclohexanecarboxyiate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 3,3-dimethylbutanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 3,3-dimethylbutanoate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylannino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 2,2-dimethylbutanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamlno)-1 ,8,10aI11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethy))(butyl)amino]carbonyl}oxy)methyl cyclopentylacetate,
({[(2-{[(5aR,6aSI7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10aI11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl adamantane-1-carboxylate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl cyclopentylacetate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl adamantane-1-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,3-dimethylbutanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-tert-butylbenzoate,
({^-{[(SaR.eaSJS.10aS^Θ-Caminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,2-dimethylbutanoate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-methylpropanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a>7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methy! cyclopentanecarboxylate,
(^-{[(δaR.θaS.ZS.10aS^-Caminocarbonyl)-4,7-bis(dimethylaminoJ-i .β.iOa.H- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-methylbenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbony!)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-y)]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyi heptanoate, and
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethy)amino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-methoxybenzoate.
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
benzyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl(propyl)carbamate,
ethyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-δ.δa.θ.δaJJO.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl(propyl)carbamate, and isobutyl 2-{[(5aR,6aS,7SI10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-
1 ,8, 10a, 1 1 -tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2- yl]amino}-2-oxoethyl(propyl)carbamate.
Additional further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a111 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl thiophene-2-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 , 8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl thiophene-2-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a, 11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl thiophene-3-carboxylate,
({^-{[(SaR.δaSJS.10aSJ-θ-laminocarbonyl)-4,7-bis(dimethylaminol-i .δ.iOa.H- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methy! thiophene-3-carboxylate,
({^-{[(δaR.eaSJS.10aSJ-θ^aminocarbonylMJ-bisfdimethylaminoJ-i .δJOa.i i- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 2-furoate, and
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 2-furoate.
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof: ({[(2-{[(5aRI6aS,7SI10aS)-9-(aminocarbonyl)-4>7-bis(dimethylamino)-1 f8I10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl propionate,
({[(2-{[(5aR,6aS,7SI10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclohexanecarboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,5-dimethylbenzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5, 5a,6,6a, 7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-fluorobenzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5, 5a,6,6a, 7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3-methylbutanoate,
({^-{[(SaR.eaSJSJ OaS^Θ-Caminocarbonyl)-4,7-bis(dimethylamino^tδ.iOa.i i- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclopentylacetate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(trifiuoromethyl)benzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclopropanecarboxylate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(climethylamino)-1 I8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7,10.10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl adamantane-1-carboxylate,
butyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyI)-4,7-bis(dimethylamino)-1 , 8,1 Oa, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethy I (tert-butyl)ca rbamate ,
isobutyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)- 1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octa hydrotetracen-2- yl]amino}-2-oxoethyl(tert-butyl)carbamate,
methyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 , 8,10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl(tert-butyl)carbamate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethy!)(tert-butyl)amino]carbonyl}oxy)methy! pentanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclobutanecarboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-δ^a.δ.δaJ.I O.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3-cyclohexylpropanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-δ,δa,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl (4-fluorophenoxy)acetate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(atninocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclohexylacetate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,1Oa1H- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyi 2,6-dimethylbenzoate,
({[(2-{[(5aR,6aS,7S!10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl phenylacetate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,δ,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-buty!)amino]carbonyl}oxy)methyl pivalate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5, 5a,6,6a,7, 10,10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 ,1 '-biphenyl-4-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 -naphthoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-naphthoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-δ.δa.θ.θaJ.IC10a.12-octahydrotetracen-2-y^annino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,6-difluorobenzoate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4)7-bis(dimethylamino)-1 ,8,10a,11- tetrahyciroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-fluorobenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-(trifluoromethyl)benzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethy!amino)-1 ,8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 , 1 '-biphenyl-2-carboxylate,
({^-{[(δaR.θaSJS.10aS^Θ-laminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,4,6-trimethylbenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyi)(tert-butyl)amino]carbonyl}oxy)methyl 4-isopropoxybenzoate,
({^-{[(δaR^aSJS^OaS^Θ-lanninocarbonylHy-bis(dimethylaminoVi .δJOa.i i- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,4,5-trimethoxybenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,5-dimethoxybenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbony!}oxy)methyl (2E)-3-phenylprop-2-enoate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa112-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl [3,5- bis(trifluoromethy!)phenyl]acetate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(heptyloxy)benzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10,10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methy! 2-(2-phenylethyl)benzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(dodecyloxy)benzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(acetylamino)benzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a112-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl anthracene-9-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-buty!)amino]cεrbonyl}oxy)methyl 4-benzoylbenzoate, and
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2~yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl diphenylacetate. Additional further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 4-fluorobenzoate,
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-δ,δa,6,6a,7,10,10a,12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 3,5-dimethylbenzoate,
[({[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-6,δa,6, 6a, 7, 10,1 Oa, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl pivalate,
[({[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-δ,δa,6,6a,7,10,10a,12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 3,3-dimethylbutanoate,
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2- yi]amino}carbonyl)oxy]methyl 2,2-dimethylbutanoate,
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino^i .δ.iOa.H- tetrahydroxy-10,12-dioxo-δ,δa,6,6a,7,10,1 Oa, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 2-ethylbutanoate,
[({[(δaR;6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a,11 - tetrahydroxy-10,12-dioxo-δ,δa,6,6a,7, 10, 10a, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl thiophene-2-carboxylate, [({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl cyclopentylacetate, and
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10^-dioxo-S.δa.δ.δaJ.10.10a.12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 4-tert-butylbenzoate.
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 H-indole-2-carboxyiate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl nicotinate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5, 5a, 6, 6a, 7, 10,10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl isonicotinate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5, 5a, 6, 6a,7, 10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-pyrrolidin-1-ylbenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3-methyi-1 -benzofuran-2-carboxylate, ({[(2-{[(5aR,6aSI7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- σxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 -methyl-1 H-indole-3-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 , 8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- σxoethyl)(tert-butyl)amino]cεrbonyl}oxy)methyl quinoline-2-carboxylate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 -benzofuran-2-carboxylate, and
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,1 Oa, 11 - tetrahydroxy-10,12-dioxo-5,5a,6, 6a, 7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl-1 -methyl-1 H-pyrrole-2- carboxylate.
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
(5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl 2-{[(7S,10aR)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino}-2-oxoethyl(propyl)carbamate,
(5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl 2-{[(7S,10aS)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 ,8, 10a, 11 -tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12- octahydrotetracen-2-yl]amino}-2-oxoethyl(butyl)carbamate,
(2-oxo-5-phenyl-1 ,3-dioxol-4-yl)methyl 2-{[(7R,10aS)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 , 8,10a, 11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a, 12- octahydrotetracen-2-yl]amino}-2-oxoethyl(propyl)carbamate, [5-(4-methoxyphenyl)-2-oxo-1 , 3-d ioxol-4-yl] methyl 2-{[(7S, 10aS)-9-(aminocarbonyl)- 4,7-bis(dimethylamino)-1,8,10a,11-tetrahyclroxy-10,12-dioxo-5,5a)6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino}-2-oxoethyl(propyl)carbamate,
(2-oxo-5-phenyl-1 ,3-dioxol-4-yl)methyl 2-{[(7S,10aS)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 ,8,1 Oa, 11 -tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10, 10a, 12- octahydrotetracen-2-yl]amino}-2-oxoethyl(butyl)carbamate and
[5-(4-methoxyphenyl)-2-oxo-1 ,3-dioxol-4-yl]methyl 2-{[(7S, 10aS)-9-(aminocarbonyl)- 4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino}-2-oxoethyl(butyl)carbamate.
An additional embodiment of this invention are compounds represented by Formula
(H):
Figure imgf000029_0001
(II)
wherein:
R4 is selected from hydrogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, aikenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkyiamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3- C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkyiamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyi and phenyl, alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy, aryl of 6, 10 or 14 carbon atoms said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkyiamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, N-(alkyl of 1 to 12 carbon atoms)-aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkyiamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl of 7 to 13 carbon atoms optionally substituted, SR3, heteroaryl optionally substituted and heteroarylcarbonyl optionally substituted;
R5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, aryloxy and N-(aikyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkyiamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3- C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl, -CH2(CO)OCH2aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted, heteroaryl optionally substituted, aryi of 6, 10 or 14 carbon atoms optionally substituted, alkynyl of 2 to 12 carbon atoms optionally substituted, cycloalkyl 3 to 6 ring atoms, aryl-CH=CH-, cycloalkyl-alkyl; and adamantyl;
R6 is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3- C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, and cycloalkyl of 3 to 6 carbon atoms;
Rio is H or alkyl of 1 to 12 carbon atoms;
Q iS -OR11, Cl, Br or I;
R11 is H, benzyl optionally substituted with nitro or a moiety of the formula
Figure imgf000031_0001
Ri2 is alkyl of 1 to 6 carbon atoms. The compounds having Formula Il are useful as chemical intermediates for making the compounds having formula I and the pharmaceutically acceptable salt thereof wherein: A is a moiety
Figure imgf000032_0001
and R3 is the moiety
Figure imgf000032_0002
where R4 and R5 are as defined above.
An embodiment of the invention provides compounds of Formula Il wherein R4 is t- butyl, R5 is alkyl of 1 to 6 carbon atoms, and R11 is benzyl optionally substituted with nitro.
Another embodiment of the invention provides compounds of Formula Il wherein R4 is alkyl of 1 to 6 carbon atoms, R5 is phenyl optionally substituted and R11 is benzyl optionally substituted with nitro.
An embodiment of the invention provides compounds of Formula Il wherein R5 is alkyl of 1 to 6 carbon atoms, R4 is t-butyl and Ri1 is H.
A further embodiment of the invention provides compounds of Formula Il wherein R5 is alkyl of 1 to 6 carbon atoms, R4 is t-butyl, Q is -OR11, R11 is
Figure imgf000033_0001
and R12 is alkyl of 1 to 6 carbon atoms.
Another embodiment of the invention provides compounds of Formula Il wherein R6 and R10 are H.
Further embodiments of the invention provides the following specifically preferred compounds of Formula Il or pharmaceutically acceptable salts thereof.
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4-tert- butylbenzoate,
({[[2-(benzyIoxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2,2- dimethylbutanoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2- methylpropanoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl cyclopentanecarboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4-methylbenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl heptanoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl propionate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl cyclohexanecarboxylate, ({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 3,5- dimethylbenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4-fluorobenzoate,
({[[2-(benzy!oxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 3- methylbutanoate,
benzyl N-(tert-butyl)-N-({[(cyclopentylacetyl)oxy]methoxy}carbonyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl A- (trifluoromethyl)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl cyclopropanecarboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl adamantane-1- carboxylate,
({[[2-(benzyloxy)-2-oxoethy!](tert-butyl)amino]carbonyl}oxy)methyl pentanoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl cyclobutanecarboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 3- cyclohexylpropanoate,
benzyl N-(tert-butyl)-N-[({[(4-fluorophenoxy)acetyl]oxy}methoxy)carbonyl]glycinate,
benzyl N-(tert-butyl)-N-({[(cyclohexylacetyl)oxy]methoxy}carbonyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2,6- dimethylbenzoate, benzyl N-(tert-butyl)-N-({[(phenylacetyl)oxy]methoxy}carbonyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl pivalate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1-benzofuran-2- carboxylate, i
({[[2-(benzyloxy)-2-oxoethyi](tert-butyi)amino]carbonyl}oxy)methyl 1 -methyl- 1 H- pyrrole-2-carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1 , 1 '-biphenyl-4- carboxylate,
({[[2-(ben2yloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl A- methoxybenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1 H-indole-2- carboxylate,
benzyl N-(tert-butyl)-N-({[(diphenylacetyl)oxy]methoxy}carbonyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1-naphthoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2-naphthoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1 -methyl-1 H- indole-3-carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl quinoline-2- carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl nicotinate, ({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl isonicotinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2,6- difluorobenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2-fluorobenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2- (trifiuoromethyl)benzoate,
({[[2-(benzyloxy)-2-oxoethy!](tert-butyl)amino]carbonyl}oxy)methyl 4-(1 H-pyrrol-1- yl)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1 , 1 '-biphenyl-2- carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2,4,6- trϊmethylbenzoate,
({[[2-(benzyloxy)-2-oxoethy!](tert-butyl)amino]carbony!}oxy)methyl 4- isopropoxybenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbony!}oxy)methyl 3,4,5- trimethoxybenzoate,
({[[2-(benzyloxy)-2-oxoethy!3(tert-butyl)amino]carbonyl}oxy)methyl 3,5- dimethoxybenzoate,
3-phenyl-acrylic acid (benzyloxycarbonylmethyl-tert-butyl-carbamoyloxy)-methyl ester, ({[[2-(benzyloxy)-2-oxoethyl}(tert-butyl)amino]carbonyl}oxy)methyl 3-methyl-1- benzofuran-2-carboxylate,
benzyl N-{[({[3,5-bis(trifluorornethyl)phenyl]acetyl}oxy)methoxy]carbonyl}-N-(tert- butyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carboπyl}oxy)methyl 4- (heptyloxy)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2-(2- phenylethyl)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- (dodecyloxy)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- (acetylamino)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl anthracene-9- carboxylate and
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- benzoylbenzoate.
Additional embodiments of the invention are the following specifically preferred compounds of Formula Il or pharmaceutically acceptable salts thereof.
N-(tert-butyl)-N-({[(4-tert-butylbenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-{[(isobutyryloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-({[(cyclopentylcarbonyl)oxy]methoxy}carbonyl)glycine, N-(tert-butyl)-N-({[(4-methylbenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-{[(heptanoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-{[(propionyloxy)methoxy]carbonyl}gIycine,
N-(tert-butyl)-N-({[(cyclohexylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(3,5-dimethylbenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(4-fluorobenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-buty!)-N-({[(3-methylbutanoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(cyclopentylacetyl)oxy]methoxy}carbonyI)glycine,
N-(tert-butyl)-N-[({[4-(trifluoromethyl)benzoyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-({[(cyclopropylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-^i-adamantylcarbonyOoxyJmethoxyJcarbonyO-N-^ert-buty^glycine,
N-(tert-butyl)-N-{[(pentanoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-({[(cyclobutylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyI)-N-({[(3-cycIohexylpropanoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-[({[(4-fluorophenoxy)acetyl]oxy}methoxy)carbonyl]glycine
N-(tert-butyl)-N-({[(cyclohexylacetyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(2,6-dimethylbenzoyl)oxy]methoxy}carbonyl)glycine, N-(tert-butyl)-N-({[(phenylacetyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(2,2-dimethylpropanoyl)oxy]methoxy}carbonyl)glycine,
N-({[(1-benzofuran-2-ylcarbonyl)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine,
N-(tert-butyl)-N-[({[(1-methyl-1 H-pyrrol-2-yl)carbonyl]oxy}methoxy)carbonyl]glycine,
N-({[(1 ,1'-biphenyl-4-ylcarbonyl)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine,
N-(tert-butyl)-N-({[(4-methoxybenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(1 H-indol-2-ylcarbonyl)oxy]methoxy}carbonyi)glycine,
N-(tert-butyl)-N-({[(diphenylacety!)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-{[(1-naphthoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-{[(2-naphthoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-[({[(1-methyl-1 H-indol-3-yl)carbonyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-({[(quinolin-2-ylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(pyridin-3-ylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-{[(isonicotinoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-({[(2,6-difluorobenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(2-fluorobenzoyl)oxy]methoxy}carbonyl)glycine, N-(tert-butyl)-N-[({[2-(trifluoromethyl)benzoyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-({[(4-pyrrolidin-1-ylbenzoyl)oxy]methoxy}carbonyl)glycine,
N-({[(1 , 1 '-biphenyl-2-ylcarbony!)oxy]methoxy}carbonyl)-N-(tert-butyl)g!ycine,
N-(tert-butyl)-N-({[(mesitylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(4-isopropoxybenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(3,4,5-trimethoxybenzoyi)oxy]methoxy}carbonyl)glycine1
N-(tert-butyl)-N-({[(3,5-dimethoxybenzoyl)oxy]methoxy}carbonyl)g!ycine,
N-(tert-butyl)-N-[({[(2E)-3-phenylprop-2-enoyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-[({[(3-methyl-1-benzofuran-2- yl)carbonyl]oxy}methoxy)carbonyl]glycine,
N-{[({[3,5-bis(trifluoromethyl)phenyl]acetyl}oxy)methoxy]carbonyl}-N-(tert- butyl)glycine,
N-(tert-butyl)-N-[({[4-(heptyioxy)benzoyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-[({[2-(2-phenylethyl)benzoyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-[({[4-(dodecyloxy)benzoyl]oxy}methoxy)carbonyl]glycine,
N-[({[4-(acetylamino)beπzoyl]oxy}methoxy)carbonyl]-N-(tert-butyl)glycine,
N-({[(9-anthrylcarbonyl)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine and
N-({[(4-benzoylbenzoy!)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine A further embodiment of the invention is the following specifically preferred compound of Formula Il or pharmaceutically acceptable salts thereof.
3,3-Dimethyl-butyric acid [tert-butyl-(2-isobutoxycarbonyloxy-2-oxo-ethyl)- carbamoyloxy)-methyl ester.
Definitions
For the compounds of the invention defined above and referred to herein, unless otherwise noted, the following terms are defined:
The term alkyl means a straight or branched alkyl moiety of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl. In some embodiments of the invention alkyl is a moiety of 1 to 6 carbon atoms. In other embodiments of the invention alkyl is a moiety of 1 to 3 carbon atoms. In other embodiments of the invention alkyl is 1 ,1-dimethylethyl also termed t-butyl. In some embodiments of the invention when alkyl is a methyl group wherein optional substitution is two independent phenyl rings. Non-limiting examples of alkyl are methyl, ethyl, n- propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1 ,1- dimethylethyl.
The term alkenyl means a straight or branched carbon chain of 2 to 12 carbon atoms having at least one site of unsaturation optionally independently substituted with 1 to 3 substituents selected from the group optionally independently substituted with 1 to 3 substituents selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl. In some embodiments of the invention alkenyl is a vinyl moiety CH2=CH-.
As used herein the term alkoxy refers to alkyl-O- wherein alkyl is hereinbefore defined. Non limiting examples include: methoxy and ethoxy.
As used herein the term aryl means an aromatic moiety having 6, 10 or 14 carbon atoms preferably 6 to 10 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3- C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl. In particular, aryl is phenyl or naphthyl optionally substituted with 1 to 3 substituents.
The term aralkyl as used herein of 7 to 16 carbon atoms means an alkyl substituted with an aryl group in which the aryl and alkyl group are as defined herein. Non- limiting exemplary aralkyl groups include benzyl and phenethyl and the like.
Perhaloalkyl as used herein means an alkyl moiety of 1 to 6 carbon atoms in which each hydrogen atom is substituted with a halogen atom, an exemplary example is trifluoromethyl.
Phenyl as used herein refers to a 6-membered carbon aromatic ring.
As used herein the term alkynyl includes both straight chain and branched moieties containing 2 to 12 carbon atoms having at least one carbon to carbon triple bond optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alky! of 1 to 12 carbon atoms, hydroxyl, and alkoxy of 1 to 12 carbon atoms.
As used herein the term halogen or halo means F, Cl, Br or I. As used herein the term cycloalkyl means a saturated monocyclic ring having from 3 to 6 carbon atoms. Exemplary cycloalkyl rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment of the invention cycloalkyl is a moiety of 5 or 6 carbon atoms.
The term aroyl means an aryl-C(O)- group in which the aryl group is as previously defined. Non-limiting examples include benzoyl and naphthoyl.
The term heteroaryl means an aromatic heterocyclic, monocyclic ring of 5 or 6 ring atoms containing 1 to 4 heteroatoms independently selected from O, N and S or bicyclic aromatic rings of 8 to 20 ring atoms containing 1 to 4 heteroatoms independently selected from O, N and S. Heteroaryl rings may optionally be substituted with 1 to 3 substitutents independently selected from the group alkyl, halogen, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, - CH2OCOCH3 and carboxy. Non-limiting heteroaryl moieties optionally substituted include: furanyl, benzofuranyl, benzothienyl, thienyl, pyridinyl, quinolinyl, tetrazolyl, imidazo, thiazolyl and the like.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, aralkyl refers to an aryl group, and alkyl refers to the alkyl group as defined above. Also, aryloxy refers to a arylO- group.
The term heteroarylcarbonyl means a heteroaryl-C(O)- group in which the heteroaryl group is as previously defined.
The term heterocyclyl as used herein represents a saturated ring of 3 to 8 ring atoms containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments of the invention a saturated ring of 5 or 6 ring atoms is preferred. Representative examples are pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like. The term alkylheterocyclyl means an alkyl-heterocyclyl group in which the alkyl and heterocyclyl group are independently previously defined. Non-limiting exemplary alkylheterocyclyl groups include moieties of the formulae:
Figure imgf000045_0001
Some of the compounds of Formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For instance, compounds of Formula (I) which exist as tautomers are depicted below:
Figure imgf000045_0002
The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
Proton sponge is [1 ,8-bis(dimethylamino)naphthalene, N,N,N',N'-tetramethyl-1 ,8- naphthalenediamine].
Alkali metal carbonate includes lithium, potassium and sodium carbonate.
DMPU is 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone. N-butyl-glycylcycline (N-bu-glycyl) is
Figure imgf000046_0001
N-propyl-glycylcycline (N-prop-glycyl) is
Figure imgf000046_0002
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compounds of this invention may be prepared according to the following schemes: (1 ) from commercially available starting materials or: (2) from known starting materials which can be prepared as described in literature procedures or: (3) from new intermediates described in the schemes and experimental procedures.
The synthesis of acyloxy intermediate 8 is shown in Scheme 1. Reaction of amine R4NH2, preferably t-butylamine, with ester 1 provides the substituted amino ester 2. Preparation of the intermediate 4 is accomplished by using Proton Sponge as base to effect the acylation of substituted amino ester 2 with chloromethyl chloroformate 3. Treatment of intermediate 4 with the tetrabutylammonium salt 5 of carboxylic acids gives the benzyl protected acyloxy intermediate 6. The benzyl protecting group is removed by catalytic reduction to give carboxylic acid 7 which is activated to a mixed anhydride with chloroformate ClCO2Ri2 where Ri2 is alkyi of 1 to 6 carbon atoms, for example iso-butyl chloroformate to give acyloxycarbamate intermediate 8. In an alternate route, silyl esters may optionally be used in place of the benzyl ester of intermediate 4, treating with the appropriate carboxylic acid followed by deblocking the silyl ester with tetrabutylammonium fluoride or magnesium bromide to afford carboxylic acid 7. Optionally, carboxylic acid 7 may be activated through the use of coupling agents not limited to di-t-butyl dicarbonate (BoC2O); e.g., benzotriazole-1-yl- oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (also known asBop); benzotriazole-1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (also known as PyBop); 0-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate (HBTU); Bromotris-pyrollidino-phosphonium hexafluorophosphate; 2- Chloro-N-methylpyridinium iodide (CMPI); dicyclohexylcarbodiimide (DCC); 1 ,3- diisopropylcarbodiimide (DIG); 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC); or Carbonyl diimidazole. SCHEME 1
Figure imgf000048_0001
As shown in Scheme 2, reaction of activated acyloxycarbamate intermediate 8 with Z.S-disubstituted-θ-aminotetracycline 9 in the presence of triethylamine and DMPU gives acyloxycarbamate 10.
Scheme 2
Figure imgf000049_0001
triethylamine, DMPU, room temperature, 1 hr
Figure imgf000049_0002
10
Additional acyloxy carbamate compounds may be synthesized via routes as shown in Schemes 3 and 4. Treatment of chloromethyl chloroformate 3 with ethanethiol in the presence of triethylamine (TEA) gives carbonothioate 11. Compound 12 is prepared by reacting carbonothioate 11 with carboxylic acid tetrabutylammonium salt 5 in tetrahydrofuran. Chlorination of compound 12 with sulfuryl chloride in the presence of catalytic amount of boron trifluoroetherate affords chloro intermediate 13 (using the methods described in M. Folkmann and FJ. Lund, Synthesis, December 1990, 1159- 1166).
Scheme 3
Figure imgf000050_0001
13
As further seen in Scheme 4 acyloxycarbamates 16 and 17 where R4 is preferably n- butyl or n-propyl are synthesized by treatment of either 14 or 15 where R4 is preferably n-butyl or n-propyl with the chloro intermediate 13 to give acyloxycarbamates 16 and 17 respectively.
Scheme 4
Figure imgf000050_0002
14 R4 = n-Butyl
15 R4 = n-propyl DMPU
Figure imgf000050_0003
17 R4 = n-propyl As shown in Scheme 5, carbamates of glycylcycline where R4 is preferably propyl 18 may also be prepared by reaction with chloro intermediate 19 in the presence of an alkali metal carbonate preferably sodium carbonate, and DMPU in acetonitrile to afford preferred compounds (21 and 22),
Scheme 5
Figure imgf000051_0001
18
Na2CO3/ CH3CN/ DMPL)
-^Y" 19
Figure imgf000051_0002
21 22
R4 is preferably propyl
Scheme 6
Figure imgf000052_0001
triethylamine, DMPU, room temperature, 1 hr
Figure imgf000052_0002
13
Figure imgf000052_0003
As shown in Scheme 6, reaction of chloro intermediate 13 with 7,8-disubstituted-9- aminotetracycline 9 in the presence of triethylamine and DMPU gives carbamate 23.
As further shown in Scheme 7, compounds of Formula I may generally be prepared by removal of the benzyl protecting group from benzyl protected acyloxy intermediate 24 to give carboxylic acid 25 which is activated to a mixed anhydride with a chloroformate CICO2R12 where R12 is alkyl of 1 to 6 carbon atoms, for example iso- butyl chloroformate to give acyloxycarbamate intermediate 26. Further reaction of 7,8-disubstituted-9-aminotetracycline 9 with acyloxycarbamate mixed anhydride intermediate 26 in the presence of triethylamine and DMPU affords compounds of Formula (I).
Figure imgf000053_0001
Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformations proposed. This may necessitate judgement as to the order of synthetic steps, protecting groups, if required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions. Such restrictions to the substituents which are compatible with the reaction conditions will be apparent to one skilled in the art.
Some of the compounds of the hereinbefore described schemes have center of asymmetry. The compounds may, therefore, exist in at least two and often more stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds whether free from other stereoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixture of enantiomers as well as the diastereomeric mixture of isomers. The absolute configuration of any compound may be determined by conventional X-ray crystallography.
The compounds of the invention may be obtained as metal complexes such as aluminum, calcium, iron, magnesium, manganese and complex salts; inorganic and organic salts and corresponding Mannich base adducts using methods known to those skilled in the art (Richard C. Larock, Comprehensive Organic Transformations, VCH Publishers, 411-415, 1989). Preferably, the compounds of the invention are obtained as inorganic salts such as hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric or sulfate; or organic salts such as acetate, benzoate, citrate, cysteine or other amino acids, fumarate, glycolate, maleate, succinate, tartrate alkylsulfonate or arylsulfonate. In all cases, the salt formation occurs with the C(4)- dimethylamino group. The salts are preferred for oral and parenteral administration. Standard Pharmacological Test Procedures
Methods for in Vitro Antibacterial evaluation
The minimum inhibitory concentration (MIC)
Antimicrobial susceptibility testing. The in vitro activities of the antibiotics are determined by the broth microdilution method as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (1). Mueller-Hinton Il broth (MHBII)(BBL Cockeysville, MD) is the medium employed in the testing procedures. Microtiter plates containing serial dilutions of each antimicrobial agent are inoculated with each organism to yield the appropriate density (10^ CFU/ml) in a 100 //I final volume. The plates are incubated for 18 - 22 hours at 350C in ambient air. The minimal inhibitory concentration for all isolates is defined as the lowest concentration of antimicrobial agent that completely inhibits the growth of the organism as detected by the unaided eye.
1. NCCLS. 2000. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standards: M7-A5, vol. 20.
National Committe for Clinical Laboratory Standards, Wayne, PA.
Standard Pharmacological Test Procedures
Presented in Tables I-XIII are representative compounds of Formula I which were evaluated against a panel of 40 selected gram-positive and gram-negative bacteria strains by pre-incubation in water, mouse serum or human serum. Representative compounds were first incubsted in mouse serum for an hour prior to the in vitro testing against a panel of selected gram-positive and gram-negative bacteria strains. All compounds were also pre-incubated in water for an hour prior to testing as control. Representative compounds of Formula I were incubated in human serum prior to MIC determination. Representative compounds of Formula I which demonstrated in vivo activity were further subjected to various stability tests. A summary of the in vitro testing data of representative examples of Formula I are shown in Table 1. Expanded in vitro data of selected examples (87 and 27) are shown in Table 2 and 5 respectively. MICs of representative examples of Formula I are further shown in Tables 3 and 4. Table 6 presents in vitro and in vivo activity of representative examples of compounds of Formula I against Staph, aureus Smith in mice. Table 7 presents in vivo (oral, iv) and in vitro (MIC) activity of representative examples of compounds of Formula I against E. coli in mice . Table 8 presents in vivo (oral, iv) and in vitro (MIC) activity of representative examples of compounds of Formula I, against Staph aureus Smith in mice. Table 9 presents in vitro (MIC) activity of representative examples of compounds of Formula I against E. CoIi in human serum and water and also also against Staph in human serum and water. Table 10 presents in vivo single oral dose (SOD) and single intravenous dose (SIV) ED50 data for representative examples of compounds of Formula I against Staph. Smith and E. CoIi #311 in mammals.
TABLE I
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF
FORMULA I MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse Mouse Mouse
Serum Water Serum Water erurr i Water Serum Water Example 1 Example 1 Example 2 Example 2 simple i 3 Example 3 Example 4 Example 4
E. coli GC 2236 1 16 4 32 1 >64 1 64 E. coli GC 2231 1 64 4 64 2 >64 1 64 E. coli GC 2235 0.50 16 2 64 1 >64 1 64 E. coli GC 2232 0.50 16 2 64 2 >64 1 64 E. coli GC 2233 1 16 1 64 1 >64 1 64 E. coli GC 2234 0.50 16 1 64 1 >64 1 64 E. coli GC 2270 0.50 16 1 64 1 >64 1 64 E. coli GC 2271 0.50 16 1 64 1 >64 0.50 64 E. coli GC 2272 1 16 1 64 1 >64 1 64 E. coli GC 4559 1 32 1 64 2 >64 2 >64 E. coli GC 4560 0.50 2 0.25 4 0.50 32 0.25 8 E. coli GC 6465 8 >64 8 64 8 >64 4 >64 E. coli GC 3226 1 32 4 64 2 >64 2 64 E. coli GC 2203 0.50 16 2 64 1 >64 1 64 E. coli GC 1073 1 32 4 64 2 >64 1 >64 Salmonella spp. GC 235 1 64 8 >64 >64 >64
TABLE I (Cont)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF G LYCYLCYC LI N ES
OF FORMULA I MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse Mouse Mouse
Serum Water Serum Water Serum Water Serum Water Example
1 Example 1 Example 2 Example 2 Example 3 Example 3 Example 4 Example 4 M C
Salmonella spp. GC 566 2 64 8 >64 4 >64 4 >64
S. cholerasius GC 1355 8 >64 >64 >64 16 >64 8 >64
S. typhimurium GC 2172 4 >64 >64 >64 8 >64 4 >64
P. aeruginosa GC 2214 32 >64 >64 >64 32 >64 32 >64
S. aureus GC 1131 1 4 2 4 2 4 1 4
S. aureus GC 6466 1 1 1 2 1 4 0.50 2
S. aureus GC 6467 4 4 4 8 4 32 2 8
S. aureus GC 1079 2 4 8 8 32 1 4
S. aureus GC 4536 2 4 2 4 2 4 1 4
S. aureus GC 2216 1 4 2 4 1 4 0.50 4
S. aureus GC 6335 4 8 8 2 8 1 4
S. aureus GC 6469 2 8 2 4 4 32 16
M C
57
M C
TABLE I (Cont)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF
FORMULA I MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse Mouse Mouse
Serum Water Serum Water Serum Water Serum Water
Example 1 Example 1 Example 2 Example 2 Exampie 3 Example 3 Example 4 Exarπr. )le
S. epidermidis GC 4935 2 8 8 8 4 8 2 4
E. faecalis GC 4555 1 4 2 4 1 8 1 8
E. faecalis GC 2265 1 4 4 8 2 32 8
E. faecalis GC 2267 2 8 4 4 2 32 1 8
E. faecalis GC 2242 1 4N ( C 4 4 2 16 1 4
E. faecium GC 4556 1 4 4 8 2 16 1 4
E. faecium GC 2243 1 1 4 1 4 0.50 2
S. pneumoniae* GC
4465 0.50 0.25 0.50 0.25 0.12 0.25 <0.06 0.12
S. pneumoniae+ GC 5
Figure imgf000059_0001
0 c. albicans GC 3066 >64 >64 >64 >64 >64 >64 >64 >64
58
CM TABLE Il
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Serum Water Mouse Serum Water Mouse Serum Water Mouse Serum Water
Example 5 Example 5 Example 6 Example 6 Example 7 Example 7 Example 8 Example 8
E. coli GC 2236 2 16 2 8 0.25 2 1 32
E. coli GC 2231 2 64 2 64 2 16 2 >64
E. coli GC 2235 1 16 1 8 0.50 4 1 16
E. coli GC 2232 2 32 2 32 0.50 4 1 32
E. coli GC 2233 2 32 2 16 0.50 4 1 32
E. coli GC 2234 1 32 1 16 1 4 1 32
E. coli GC 2270 1 16 1 8 0.50 4 1 64
E. coli GC 2271 1 16 1 8 0.50 4 1 32
E. coli GC 2272 1 32 1 16 0.50 4 1 32
E. coli GC 4559 2 32 2 16 1 8 1 64
E. coli GC 4560 0.50 4 0.25 2 0.25 0.50 0.50 4
E. coli GC 6465 8 >64 4 >64 16 >64 8 >64
E. coli GC 3226 2 32 2 16 0.50 8 2 64
E. coli GC 2203 1 32 2 16 0.50 4 1 32
E. coli GC 1073 2 32 2 16 0.50 8 1 32 Salmonella spp. GC 235 2 32 2 16 2 8 4 64 Salmonella spp. GC 566 4 64 4 64 1 16 4 >64
TABLE Il (Cont)
ANTIBACTERIAL ACTIVITY OF 9-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse Mouse
Serum Water Serum Water Serum Water Mouse Serum Water
Example 5 Example 5 Example 6 Example 6 Example 7 Example 7 Example 8 Example 8
S. cholerasius GC
1355 16 >64 16 >64 16 >64 32 >64
S. typhimurium GC
2172 8 >64 8 >64 >64 8 >64
P. aeruginosa GC
2214 32 >64 32 >64 16 >64 32 >64
S. aureus GC 1131 0.50 1 0.50 1 1 1 1 2
S. aureus GC 6466 0.25 0.50 0.25 1 0.50 0.50 0.50 1
S. aureus GC 6467 2 4 2 4 4 4 4 8
S. aureus GC 1079 2 2 2 4 1 4 2 4
S. aureus GC 4536 1 1 0.50 2 1 1 0.50 2
S. aureus GC 2216 0.50 2 0.50 2 0.50 0.50 0.50 4
S. aureus GC 6335 0.50 1 0.50 2 1 1 1 4
S. aureus GC 6469 2 4 2 4 2 4 2 8
S. epidermidis GC
4935 1 2 1 8
TABLE Ii (Cont)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
MouseSerum Water Serum Water Mouse Serum Water Mouse Serum Water
Example 5 Example 5 Example 6 Example 6 Example 7 Example 7 Example 8 Example 8
E. faecalis GC 4555 1 4 1 4 0.50 1 0.50 8
E. faecalis GC 2265 2 4 2 4 1 2 2 8
E. faecalis GC 2267 2 4 1 4 1 2 2 8
E. faecalis GC 2242 1 2 1 2 1 1 1 4
E. faecium GC 4556 1 2 1 2 0.50 1 1 4
E. faecium GC 2243 0.50 1 0.50 2 0.25 0.12 0.25 2
S. pneumoniae* GC
4465 <0.06 0.12 0.12 0.25 0.25 0.12 <0.06 0.25
S. pneumoniae+ GC
4465 2 4 2 2 4 2 1 4
S. pyogenes GC
4563 0.12 0.25 0.25 0.25 0.25 0.25 0.12 0.50
S. agalactiae GC
4564 0.50 0.50 0.50 0.50 0.25 0.50 0.25 0.50 c. albicans GC 3066 >64 >64 >64 >64 >64 >64 >64 >64
TABLE III
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Serum Water Mouse Serum Water Mouse Serum Water Mouse Serum Water
Example 9 Example 9 Example 10 Example 10 Example 11 Example 11 Example 12 Example 12
E. coli GC 2236 1 8 0.50 8 0.50 8 1 16
E. coli GC 2231 2 64 2 32 2 64 2 64
E. coli GC 2235 0.50 4 0.25 4 0.25 4 1 16
E. coli GC 2232 1 8 0.50 8 1 16 0.50 32
E. coli GC 2233 0.50 4 0.50 8 0.25 8 1 32
E. coli GC 2234 0.50 8 0.50 8 0.50 16 1 16
E. coli GC 2270 0.50 4 0.50 8 0.50 8 0.50 32
E. coli GC 2271 0.50 8 0.25 8 0.25 4 0.50 16
E. coli GC 2272 0.50 8 0.50 8 0.25 4 1 16
E. coli GC 4559 1 8 0.50 16 0.50 32 1 64
E. coli GC 4560 0.25 1 0.12 0.12 0.12 0.12 0.25 1
E. coli GC 6465 4 >64 8 >64 8 >64 8 >64
E. coli GC 3226 2 16 0.50 16 0.50 >64 2 64
E. coli GC 2203 0.50 4 0.50 8 0.25 16 1 32
E. coli GC 1073 1 - 8 0.50 16 0.50 16 1 64
Salmonella spp. GC 235 1 8 0.50 32 0.50 64 1 64
Salmonella spp. GC 566 2 64 2 >64 2 >64 4 >64
S. cholerasius GC 1355 64 >64 16 >64 32 >64 16 >64
TABLE III (Cont)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Serum Water Mouse Serum Water Mouse Serum Water Mouse Serum Water
Example Example
Example 9 Example Example 10 10 Example 11 11 Example 12 Example 12
S. typhimurium GC 2172 8 >64 4 >64 4 >64 4 >64
P. aeruginosa GC 2214 16 >64 16 >64 16 >64 32 >64
S. aureus GC 1131 <0.06 0.25 0.12 0.12 0.25 0.25 1 2
S. aureus GC 6466 0.12 0.12 0.12 0.12 0.25 0.25 0.50 1
S. aureus GC 6467 1 2 2 2 4 4 4 16
S. aureus GC 1079 2 1 0.50 1 2 4 2 8
S. aureus GC 4536 0.50 0.50 0.25 0.50 0.50 0.50 1 2
S. aureus GC 2216 0.25 0.50 0.25 0.50 0.50 0.50 1 4
S. aureus GC 6335 0.25 0.50 0.25 0.50 1 1 1 2
S. aureus GC 6469 1 2 1 2 4 4 4 16
S. epidermidis GC 4935 0.25 1 0.50 1 1 2 4 8
E. faecalis GC 4555 0.50 2 0.50 1 0.50 1 0.50 4
TABLE III (Cont)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF G LYCYLCYC LI N ES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse
MouseSerum Water Mouse Serum Water Serum Water Serum Water
Example 9 Example 9 Example 10 Example 10 Example 11 Example 11 Example 12 Example 12
E. faecalis GC
2265 1 2 1 1 2 4 2 8
E. faecalis GC
2267 1 2 1 2 2 2 2 8
E. faecalis GC
2242 0.50 1 0.25 0.50 0.25 0.50 2 4
E. faecium GC
4556 0.25 0.50 0.25 0.50 0.25 0.50 1 4
E. faecium GC
2243 0.25 0.50 <0.06 0.12 0.12 0.25 0.50 4
S. pneumoniae*
GC 4465 <0.06 <0.06 <0.06 <0.06 <0.06 <0.06 <0.06 0.12
S. pneumoniae+
GC 4465 2 2 1 1 2 2 4 8
S. pyogenes GC
4563 <0.06 <0.06 <0.06 <0.06 <0.06 <0.06 0.12 0.25
S. agalactiae GC
4564 0.12 0.25 <0.06 0.12 <0.06 <0.06 0.25 0.25 c. albicans GC
3066 >64 >64 >64 >64 >64 >64 >64 >64
TABLE IV
ANTIBACTERIAL ACTIVITY OF 9-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse
Serum Water Mouse Serum Water Serum Water Mouse Serum Water
Example
13 Example 13 Example 14 Example 14 Example 15 Example 15 Example 16 Example 16
E. coli GC 2236 2 8 >64 >64 >64 64 64 >64
E. coli GC 2231 2 16 >64 >64 >64 >64 >64 >64
E. coli GC 2235 2 8 32 64 32 32 16 64
E. coli GC 2232 2 8 >64 >64 >64 >64 >64 >64
E. coli GC 2233 2 8 >64 >64 >64 >64 >64 >64
E. coli GC 2234 1 8 >64 >64 >64 >64 >64 >64
E. coli GC 2270 1 8 >64 >64 64 64 >64 >64
E. coli GC 2271 2 8 >64 >64 64 64 >64 >64
E. coli GC 2272 2 8 >64 >64 >64 >64 >64 >64
E. coli GC 4559 4 16 >64 >64 >64 >64 >64 >64
E. coli GC 4560 1 4 4 4 1 1 2 4
E. coli GC 6465 8 >64 >64 >64 >64 >64 >64 >64
E. coli GC 3226 2 16 >64 >64 >64 >64 64 >64
E. coli GC 2203 2 8 32 64 32 64 16 64
E. coli GC 1073 2 16 >64 >64 >64 >64 >64 >64
Salmonella spp. GC 235 2 16 >64 >64 >64 >64 >64 >64
TABLE IV (Cont)
Mouse Serum Water Mouse Serum Water Mouse Serum Water Mouse Serum Water
Example 13 Example 13 Example 14 Example ΛA \ Example 15 Example 15 Example 16 Example 1ι
Salmonella spp. GC 566 8 64 >64 >64 >64 >64 >64 >64 S. cholerasius GC 1355 16 >64 >64 >64 >64 >64 >64 >64
TABLE IV (Cont)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF G LYCYLCYC LI N ES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
Mouse Serum Water Mouse Serum Water Serum Water Mouse Serum Water
Example 13 Example 13 Example 14 Example 14 Example 15 Example 15 Example 16 Example 16
S. typhimurium GC
2172 8 64 >64 >64 >64 >64 >64 >64
P. aeruginosa GC
2214 32 >64 >64 >64 >64 >64 >64 >64
S. aureus GC 1131 2 2 1 2 2 4 2 4
S. aureus GC 6466 1 2 2 8 2 4 4 8
S. aureus GC 6467 4 8 2 4 16 16 8 8
S. aureus GC 1079 4 4 1 2 2 4 2 4
S. aureus GC 4536 1 2 2 2 2 4 2 4
S. aureus GC 2216 2 4 2 4 2 4 2 4
S. aureus GC 6335 2 4 1 4 4 4 4 4
S. aureus GC 6469 4 8 2 4 4 8 4 8
S. epidermidis GC
4935 4 8 8 8 16 16 8 8
E. faecal is GC 4555 2 4 2 8 4 8 4 8
TABLE IV (Cont)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
Mouse Serum Water Serum Water Serum Water Mouse Serum Water Example 13 Example 13 e 14 Example 14 Example 15 Example 15 Example 16 Example 16
E. faecalis GC 2265 4 8 2 8 8 8 4 8
E. faecalis GC 2267 4 8 2 8 8 8 4 8
E. faecalis GC 2242 4 8 2 8 8 8 8 8
E. faecium GC 4556 2 8 4 8 8 8 4 8
E. faecium GC 2243 2 4 2 4 8 8 4 8
S. pneumoniae* GC
4465 0.50 0.50 2 4 2 2 4 4
S. pneumoniae* GC
4465 8 8 4 4 4 4 8 8
S. pyogenes GC
4563 0.50 1 2 4 2 2 4 8
S. agalactiae GC
4564 1 2 16 16 8 8 16 16 c. albicans GC 3066 >64 >64 >64 >64 >64 >64 >64 >64
TABLE V
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Serum Water serum Water Mouse Serum Water Mouse Serum Water Example 21 Example 21 322 Example 22 Example 23 Example 23 Example 24 Example 24
E. coii GC 2236 1 >64 2 >64 2 >64 1 >64
E. coli GC 2231 1 >64 2 >64 2 >64 2 >64
E. coli GC 2235 0.50 >64 1 >64 1 >64 0.50 >64
E. coli GC 2232 1 >64 2 >64 1 >64 0.50 >64
E. coli GC 2233 1 >64 2 >64 2 >64 1 >64
E. coli GC 2234 0.50 >64 1 >64 1 >64 0.50 >64
E. coli GC 2270 1 >64 1 >64 1 >64 0.50 >64
E. coli GC 2271 0.50 >64 1 >64 1 >64 0.50 >64
E. coli GC 2272 1 >64 1 >64 1 >64 1 >64
E. coli GC 4559 1 >64 2 >64 2 >64 1 >64
E. coli GC 4560 0.25 >64 0.50 >64 0.50 8 0.25 64
E. coli GC 6465 4 >64 8 >64 4 >64 8 >64
E. coli GC 3226 >64 8 >64 8 >64 1 >64
E. coli GC 2203 0.50 >64 1 >64 1 >64 0.50 >64
E. coli GC 1073 1 >64 2 >64 1 >64 1 >64
Salmonella spp. GC 235 2 >64 2 >64 2 >64 1 >64
Salmonella spp. GC 566 4 >64 4 >64 4 >64 2 >64
S. cholerasius GC 1355 16 >64 16 >64 16 >64 32 >64
TABLE V (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
Serum Water Mouse Serum Water Mouse Serum Water Mouse Serum Water
Example 21 Example : Example 22 Example 22 Example 23 Example 23 Example 24 Example 24
S. typhimurium GC 2172 4 >64 8 >64 4 >64 8 >64
P. aeruginosa GC 2214 >64 >64 >64 >64 >64 >64 16 >64
S. aureus GC 1131 1 64 1 4 1 2 1 2
S. aureus GC 6466 1 64 0.50 2 0.25 0.50 0.25 0.50
S. aureus GC 6467 4 >64 4 >64 4 8 4 >64
S. aureus GC 1079 4 >64 2 32 2 4 2 64
S. aureus GC 4536 2 32 1 2 1 2 1 4
S. aureus GC 2216 1 64 1 4 1 4 0.50 4
S. aureus GC 6335 2 64 2 8 2 4 2 16
S. aureus GC 6469 4 >64 4 64 4 4 4 >64
S. epidermidis GC 4935 2 64 2 16 2 4 2 16
E. faecalis GC 4555 1 64 2 64 1 4 1 64
E. faecalis GC 2265 1 64 2 64 1 4 2 32
E. faecalis GC 2267 2 64 4 64 2 8 4 64
E. faecalis GC 2242 2 32 2 32 2 4 2 4
E. faecium GC 4556 2 64 2 64 2 4 1 32
E. faecium GC 2243 0.50 8 1 8 0.50 4 0.50 2
S. pneumoniae* GC 4465 0.25 0.50 0.50 1 0.12 0.12 <0.06 <0.06
TABLE V (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse Mouse Mouse
Serum Water Serum Water Serum Water Serum Water
Example Example
Example 21 21 Example 22 22 Example 23 Example 23 Example 24 Example 24
S. pneumoniae+
GC 4465 4 4 4 16 4 8 2 1
S. pyogenes GC
4563 0.25 0.12 0.50 1 0.12 0.25 <0.06 <0.06
S. agalactiae GC
4564 0.50 8 1 8 0.25 0.25 0.50 8 c. albicans GC
3066 >64 >64 >64 >64 >64 >64 >64 >64
TABLE Vl
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Serum Water Mouse Serum Water Mouse Serum Water Mouse Serum Water
Example 25 Example 25 Example 26 Example 26 Example 27 Example 27 Example 28 Example 28
E. coli GC 2236 2 64 2 >64 0.50 64 0.50 >64
E. coli GC 2231 2 >64 4 >64 1 >64 1 >64
E. coli GC 2235 1 32 1 64 0.50 64 0.50 >64
E. coli GC 2232 1 >64 1 >64 0.50 64 0.50 >64
E. coli GC 2233 2 32 2 >64 0.50 64 0.50 >64
E. coli GC 2234 1 >64 1 >64 0.50 64 0.25 >64
E. coli GC 2270 1 >64 1 >64 0.50 64 0.50 >64
E. coli GC 2271 1 32 1 >64 0.50 64 0.25 >64
E. coli GC 2272 2 64 2 64 0.50 32 0.50 >64
E. coli GC 4559 2 >64 2 >64 0.50 >64 0.50 >64
E. coli GC 4560 0.50 2 0.50 8 0.25 1 0.25 >64
E. coli GC 6465 8 >64 8 >64 4 >64 8 >64
E. coli GC 3226 2 >64 2 >64 0.50 >64 0.50 >64
E. coli GC 2203 1 >64 1 >64 0.50 >64 0.50 >64
E. coli GC 1073 2 >64 2 >64 0.50 >64 0.50 >64
Salmonella spp. GC 235 2 >64 2 >64 1 >64 0.50 >64
Salmonella spp. GC 566 4 >64 4 >64 1 >64 2 >64
S. cholerasius GC 1355 32 >64 32 >64 16 >64 16 >64
TABLE Vl (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Serum Water Mouse Serum Water Mouse Serum Water Mouse Serum Water
Example 25 Example 25 Example 26 Example 26 Example 27 Example 27 Example 28 Example 28
S. typhimurium GC 2172 8 >64 16 >64 4 >64 8 >64
P. aeruginosa GC 2214 32 >64 32 >64 8 >64 16 >64
S. aureus GC 1131 0.50 0.50 0.50 0.50 0.12 0.25 0.50 32
S. aureus GC 6466 0.25 0.25 0.25 0.25 0.12 0.25 0.50 4
S. aureus GC 6467 2 2 1 4 2 2 4 64
S. aureus GC 1079 1 2 1 2 1 2 2 64
S. aureus GC 4536 0.50 0.50 0.25 0.50 0.12 0.12 0.50 32
S. aureus GC 2216 0.50 1 0.50 0.50 0.25 0.25 0.50 32
S. aureus GC 6335 0.50 0.50 0.50 1 0.25 0.50 1 16
S. aureus GC 6469 2 4 1 2 1 2 4 64
S. epidermidis GC 4935 1 2 1 2 0.25 1 1 32
E. faecalis GC 4555 1 2 1 4 0.25 1 0.25 64
E. faecalis GC 2265 2 2 2 8 1 2 2 64
E. faecalis GC 2267 2 4 2 4 1 2 2 64
E. faecalis GC 2242 2 2 2 4 0.50 0.50 0.50 4
E. faecium GC 4556 1 4 1 4 0.50 1 0.50 32
E. faecium GC 2243 0.50 1 1 2 0.12 0.25 0.25 0.25
S. pneumoniae* GC 4465 0.12 0.25 0.25 0.25 <0.06 <0.06 <0.06 <0.06
TABLE Vl (CONT)
ANTIBACTERIAL ACTIVITY OF 9-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF G LYCYLCYC LI N ES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
Mouse Serum Water Mouse Serum Water Mouse Serum Water Serum Water
Example Example
Example 25 Exampl Iee 2255 Example 26 26 Example 27 27 Example 2
S. pneumoniae+
GC 4465 4 4 4 4 1 2 2 0.50
S. pyogenes GC
4563 0.12 0.25 0.25 0.25 <0.06 <0.06 <0.06 <0.06
S. agalactiae GC
4564 0.50 0.50 1 2 0.12 0.12 0.25 0.50 c. albicans GC
3066 >64 >64 >64 >64 >64 >64 >64 >64
TABLE VII
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse Human
Water Mouse Serum Mouse Serum Water Serum Human Serum Water Serum Serum
Example
Example 42 Example 42 Example 42 Example 43 Example 43 Example 43 44 Example 44 Example 44
E. coli GC 2236 >64 4 >64 >64 0.50 >64 >64 2 >64
E. coli GC 2231 >64 4 >64 >64 0.50 >64 >64 2 >64
E. coli GC 2235 >64 4 >64 >64 0.25 >64 >64 2 >64
E. coli GC 2232 >64 4 >64 >64 0.50 >64 >64 2 >64
E. coli GC 2233 >64 4 >64 >64 0.50 >64 >64 2 >64
E. coli GC 2234 >64 4 >64 >64 0.25 >64 >64 2 >64
E. coli GC 2270 >64 4 >64 >64 0.25 >64 >64 2 >64
E. coli GC 2271 >64 4 >64 >64 0.25 >64 >64 2 >64
E. coli GC 2272 >64 4 >64 >64 0.50 >64 >64 2 >64
E. coli GC 4559 >64 8 >64 >64 0.50 >64 >64 4 >64
E. coli GC 4560 8 2 8 32 <0.06 16 4 2 4
E. coli GC 6465 >64 16 >64 >64 2 >64 >64 8 >64
E. coli GC 3226 >64 16 >64 >64 1 >64 >64 4 >64
E. coli GC 2203 >64 8 >64 >64 0.50 >64 >64 2 >64
E. coli GC 1073 >64 8 >64 >64 0.50 >64 >64 4 >64
Salmonella spp. GC 235 >64 16 >64 >64 0.50 >64 >64 4 >64
Salmonella spp. GC 566 >64 32 >64 >64 2 >64 >64 8 >64
TABLE VII (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse Human
Water Mouse Serum Mouse Serum Water Serum Human Serum Water Serum Serum
Example
Example 42 Example 42 Example 42 Example 43 Example 43 Example 43 44 Example 44 Example 44
S. cholerasιusGC1355 >64 64 >64 >64 4 >64 >64 16 >64
S. typhimurium GC
2172 >64 64 >64 >64 2 >64 >64 8 >64
P. aeruginosa GC 2214 >64 >64 >64 >64 16 >64 >64 >64 >64
S. aureus GC 1131 4 2 2 64 1 16 4 2 2
S. aureus GC 6466 4 2 4 64 0.50 16 2 2 2
S. aureus GC 6467 8 4 4 >64 0.50 32 4 2 2
S. aureus GC 1079 4 2 4 64 1 32 4 2 2
S. aureus GC 4536 8 2 4 32 1 16 4 2 2
S. aureus GC 2216 4 2 2 64 0.50 32 2 2 2
S. aureus GC 6335 4 2 4 64 1 64 4 2 4
S. aureus GC 6469 4 2 4 >64 1 32 4 2 2
TABLE VII (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Mouse Human
Water Mouse Serurr ) Mouse Serurr i Water Serum Human Serum Water Serum Serum
Example
Example 42 '. Example 42 Example 42 Example 43 Example 43 Example 43 44 Example 44 • Example 44
S. epidermidis GC 4935 8 4 4 32 2 4 4 2 4
E. faecal is GC 4555 4 2 4 32 0.50 8 4 2 4
E. faecalis GC 2265 8 2 4 32 0.50 8 4 2 2
E. faecalis GC 2267 4 2 4 32 0.50 4 4 2 4
E. faecalis GC 2242 8 4 4 16 0.50 4 4 2 4
E. faecium GC 4556 8 2 4 16 0.50 8 4 2 4
E. faecium GC 2243 4 2 4 0.25 0.12 0.25 4 2 4
S. pneumoniae* GC
4465 4 2 4 0.50 <0.06 1 2 1 2
S. pneumoniae+ GC
4465 8 4 8 2 2 2 4 4 4
S. pyogenes GC 4563 4 2 4 <0.06 <0.06 <0.06 2 1 4
S. agaiactiae GC 4564 8 2 8 2 <0.06 2 4 1 4 c. albicans GC 3066 >64 >64 >64 >64 >64 >64 >64 >64 >64
TABLE VlII
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
Water Serum Human Serum Water Mouse Serum Human Serum Water Mouse Serum Human Serum
Example 45 Example 45 Example 45 Example 46 Example 46 Example 46 Example 47 Example 47 Example 47
E. coli GC 2236 16 1 4 64 0.50 4 >64 1 32
E. coli GC 2231 32 1 4 64 0.50 4 >64 1 32
E. coli GC 2235 16 0.50 4 64 0.50 4 >64 1 16
E. coli GC 2232 16 1 4 64 0.50 4 >64 1 16
E. coli GC 2233 16 1 4 64 0.50 4 >64 0.50 16
E. coli GC 2234 16 0.50 4 64 0.50 4 >64 1 16
E. coli GC 2270 32 0.50 4 >64 0.50 4 >64 0.50 16
E. coli GC 2271 16 0.50 4 64 0.50 4 >64 1 16
E. coli GC 2272 16 1 8 64 1 4 >64 1 16
E. coli GC 4559 64 1 8 >64 1 8 >64 2 64
E. coli GC 4560 2 0.25 0.50 4 0.50 1 16 1 4
E. coli GC 6465 >64 2 16 >64 2 16 >64 2 >64
E. coli GC 3226 64 1 8 >64 1 16 >64 2 32
E. coli GC 2203 32 0.50 4 >64 0.50 8 >64 1 32
E. coli GC 1073 64 1 8 >64 1 8 >64 2 32
Salmonella spp. GC 235 >64 1 8 >64 1 16 >64 2 64
Salmonella spp. GC 566 >64 2 32 >64 2 16 >64 4 >64
TABLE VIII (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
Water Serum Human Serum Water Mouse Serum Human Serum Water Mouse Serum Human Serum
Example 45 Example 45 Example 45 Example 46 Example 46 Example 46 Example 47 Example 47 Example 47
S. cholerasius GC 1355 >64 4 32 >64 2 32 >64 4 >64
S. typhimurium GC 2172 >64 2 32 >64 2 32 >64 4 >64
P. aeruginosa GC 2214 >64 16 >64 >64 16 >64 >64 32 >64
S. aureus GC 1131 1 0.50 0.50 0.50 0.50 0.50 2 1 2
S. aureus GC 6466 0.50 0.25 0.25 0.25 0.25 0.25 2 1 1
S. aureus GC 6467 2 1 1 1 1 0.50 4 1 2
S. aureus GC 1079 1 0.50 0.12 0.50 0.50 0.50 2 1 2
S. aureus GC 4536 1 0.50 0.50 0.50 0.50 0.50 4 1 1
S. aureus GC 2216 1 1 0.50 1 0.50 0.50 2 1 1
S. aureus GC 6335 2 1 0.50 1 1 0.50 2 1 2
S. aureus GC 6469 1 1 0.50 1 1 0.50 4 1 2
S. epidermidis GC 4935 2 1 1 2 1 1 4 2 4
TABLE VIII (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
Water Serum Human Serum Water Mouse Serum Human Serum Water Mouse Serum Human Serum
Example 45 Example 45 Example 45 Example 46 Example 46 Example 46 Example 47 Example 47 Example 47
E. faecalis GC 4555 2 1 2 2 0.50 0.50 4 1 4
E. faecalis GC 2265 4 0.50 1 2 0.50 1 4 1 4
E. faecalis GC 2267 2 0.50 1 2 0.50 1 4 1 4
E. faecalis GC 2242 2 1 1 1 0.50 4 1 4
E. faecium GC 4556 2 1 1 1 0.50 1 4 1 4
E. faecium GC 2243 2 0.50 1 0.50 0.25 0.25 2 0.50 2
S. pneumoniae* GC 4465 0.50 0.25 0.25 0.12 0.12 0.12 0.50 0.25 0.50
S. pneumoniae+ GC 4465 4 2 2 1 1 1 4 2 2
S. pyogenes GC 4563 0.50 0.25 0.25 0.25 0.12 0.25 0.25 0.12 0.25
S. agalactiae GC 4564 0.50 0.25 0.50 0.25 0.25 0.25 1 0.50 1 c. albicans GC 3066 >64 >64 >64 >64 >64 >64 >64 >64 >64
TABLE IX
ANTIBACTERIAL ACTIVITY OF Θ-AIVIINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Water Mouse Serum Human Serum Water Mouse Serum Human Serum Water Mouse Serum Human Serum
Example 48 Example 48 Example 48 Example 49 Example 49 Example 49 Example 50 Example 50 Example 50
E. coli GC 2236 64 0.25 16 16 0.50 32 1 8
E. coli GC 2231 64 0.50 16 16 0.50 64 1 8
E. coli GC 2235 32 0.25 16 8 0.50 4 32 1 4
E. coli GC 2232 64 0.25 16 16 0.50 4 32 1 8
E. coli GC 2233 64 0.25 16 8 0.25 4 32 1 8
E. coli GC 2234 64 0.50 16 16 0.25 4 64 1 8
E. coli GC 2270 64 0.50 16 16 0.50 4 32 1 8
E. coli GC 2271 32 0.25 8 0.25 4 32 1 4
E. coli GC 2272 64 0.25 8 8 0.50 2 32 1 4
E. coli GC 4559 >64 0.25 32 16 0.50 8 64 2 16
E. coli GC 4560 2 0.12 1 1 0.12 0.50 4 0.50 2
E. coli GC 6465 >64 2 >64 >64 2 32 >64 2 16
E. coli GC 3226 >64 0.50 32 16 0.50 32 1 8
E. coli GC 2203 64 0.25 16 8 0.25 4 32 1 8
E. coli GC 1073 64 0.50 32 32 0.50 8 32 2 8
Salmonella spp. GC 235 >64 0.50 32 32 1 16 >64 2 32
Salmonella spp. GC 566 >64 2 >64 64 2 32 >64 4 32
S. cholerasius GC 1355 >64 4 >64 >64 4 64 >64 4 64
TABLE IX (CONT)
ANTIBACTERIAL ACTIVITY OF 9-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
Water Mouse Serum Human Serum Water Serum Human Serum Water Mouse Serum Human Serum
Example 48 Example 48 Example 48 Example 49 Example 49 Example 49 Example 50 Example 50 Example 50
S. typhimuπum GC 2172 >64 4 >64 >64 4 32 >64 4 32
P. aeruginosa GC 2214 >64 16 >64 >64 32 >64 >64 32 >64
S. aureus GC 1131 0.25 0.25 0.25 0.50 0.50 0.50 1 0.50 0.50
S. aureus GC 6466 0.12 0.12 0.12 0.12 0.12 0.12 0.25 0.25 0.25
S. aureus GC 6467 2 1 0.50 2 1 1 2 0.25 0.25
S. aureus GC 1079 1 0.25 0.25 0.50 0.50 0.50 2 0.50 0.50
S. aureus GC 4536 0.25 0.25 0.25 0.25 0.25 0.25 0.50 0.25 0.25
S. aureus GC 2216 0.50 0.25 0.25 0.50 0.25 0.25 2 1 0.50
S. aureus GC 6335 2 2 2 2 1 1 1 1 1
S. aureus GC 6469 1 0.50 1 1 1 1 2 1 1
S. epidermidis GC 4935 1 0.50 0.50 2 1 1 4 2 2
E. faecalis GC 4555 2 0.12 4 4 0.25 0.50 4 1 2
TABLE IX (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Human Mouse Human Mouse Human
Water Mouse Serum Serum Water Serum Serum Water Serum Serum
Example Example Example Example 48 Example 48 Example 48 49 49 Example 49 50 Example 50 Example 50
E. faecalis GC 2265 2 0.50 1 2 0.50 1 4 1 2
E. faecalis GC 2267 2 0.50 1 4 0.50 1 4 1 2
E. faecalis GC 2242 1 0.50 1 2 0.50 1 2 1 1
E. faecium GC 4556 1 0.50 1 2 0.50 1 2 1 1
E. faecium GC 2243 0.50 0.25 0.25 0.50 0.25 0.25 0.50 0.25 0.25
S. pneumoniae* GC 4465 0.12 0.12 0.12 0.12 0.12 0.12 <0.06 <0.06 <0.06
S. pneumoniae+ GC 4465 0.25 0.25 0.25 1 1 1 0.50 0.50 0.50
S. pyogenes GC 4563 0.12 0.12 0.12 0.12 0.12 0.12 0.25 0.12 0.12
S. agalactiae GC 4564 0.12 0.12 0.12 0.25 0.12 0.12 0.25 0.25 0.25 c. albicans GC 3066 >64 >64 >64 >64 >64 >64 >64 >64 >64
TABLE X
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Water Mouse Serum Human Serum i Water Mouse Serum Human Serum Water Mouse Serum Human Serum
Example 51 Example 51 Example 51 Example 52 Example 52 Example 52 Example 53 Example 53 Example 53
E. coli GC 2236 >64 2 32 8 1 8 32 1 16
E. coli GC 2231 >64 2 32 16 1 8 64 1 16
E. coli GC 2235 >64 1 32 4 0.50 4 32 0.50 8
E. coli GC 2232 >64 2 32 8 0.50 4 32 0.50 8
E. coli GC 2233 >64 2 32 8 0.50 8 32 1 16
E. coli GC 2234 >64 1 32 8 0.50 4 16 0.50 8
E. coli GC 2270 >64 1 32 4 0.50 4 32 1 8
E. coli GC 2271 >64 1 32 4 0.50 4 16 0.50 8
E. coli GC 2272 >64 2 32 4 0.50 4 16 0.25 8
E. coli GC 4559 >64 2 32 8 1 8 32 1 16
E. coli GC 4560 32 1 8 2 0.25 2 2 0.50 2
E. coli GC 6465 >64 4 32 64 2 16 >64 4 32
E. coli GC 3226 >64 2 64 16 1 16 32 1 16
E. coli GC 2203 >64 2 32 8 0.50 8 32 1 16
E. coli GC 1073 >64 2 64 4 1 8 32 1 16
Salmonella spp. GC 235 >64 2 64 16 1 16 64 2 64
Salmonella spp. GC 566 >64 4 64 64 2 32 >64 2 32
S. cholerasius GC 1355 >64 8 >64 >64 4 >64 >64 8 64
S. typhimurium GC 2172 >64 8 64 64 4 64 >64 4 64
TABLE X (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse
Water Serum Human Serum Water Mo Serum Human Serum Water Mouse Serum Human Serum
Example 51 Example 51 Example 51 Example 52 Exampl Iee 5522 Example 52 Example .' Example 53 Example 53
P. aeruginosa GC
2214 >64 64 >64 >64 64 >64 >64 64 >64
S. aureus GC 1131 1 0.50 0.50 2 0.50 1 1 1 1
S. aureus GC 6466 1 0.25 0.25 2 0.50 1 0.50 0.50 0.50
S. aureus GC 6467 2 0.50 1 4 0.50 4 2 1 1
S. aureus GC 1079 2 0.50 1 2 0.50 1 1 0.50 0.50
S. aureus GC 4536 1 0.50 0.50 2 0.50 0.50 1 0.25 0.50
S. aureus GC 2216 1 0.50 0.50 4 0.50 1 1 0.50 0.50
S. aureus GC 6335 1 0.50 0.50 4 1 2 1 0.50 0.50
S. aureus GC 6469 2 1 1 4 0.50 2 2 1 1
S. epidermidis GC
4935 4 2 2 4 1 4 2 1 2
E. faecalis GC 4555 16 1 8 4 0.50 2 2 0.50 2
E. faecalis GC 2265 8 1 4 4 1 4 4 1 0.50
E. faecalis GC 2267 16 2 4 4 0.50 4 4 0.50 2
TABLE X (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Human Human Mouse Human
Water Serum Serum Water Mouse Serum Serum Water Serum Serum
Example Example
Example 51 EExxaammppllee i 5. 511 EExxaammppllee 55 11 5522 Example 52 Example 52 53 Example 53 Example 53
E. faecalis GC
2242 8 2 4 4 0.50 4 2 0.50 2 E. faecium GC
4556 8 2 8 4 0.50 2 2 0.50 2
E. faecium GC
2243 4 1 4 1 0.25 1 0.50 0.25 0.25 S. pneumoniae*
GC 4465 1 0.50 0.12 <0.06 0.25 0.12 0.12 0.25
S. pneumoniae+
GC 4465 1 1 2 2 1 4 2 2 1
S. pyogenes
GC 4563 2 0.50 2 0.25 0.12 0.25 0.25 0.12 0.25
S. agalactiae
GC 4564 2 1 4 0.50 0.12 0.50 0.50 <0.06 0.50 c. albicans GC
3066 >64 >64 >64 >64 >64 >64 >64 >64 >64
TABLE Xl
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Water Mouse Serum Human Serum Water Mouse Serum Human Serum Water Mouse Serum Human Serum
Example 58 Example 58 Example 58 Example 59 Example 59 Example 59 Example 60 Example 60 Example 60
E. coli GC 2236 >64 >64 >64 >64 >64 >64 >64 >64 >64
E. coli GC 2231 >64 >64 >64 >64 >64 >64 >64 >64 >64
E. coli GC 2235 >64 >64 >64 >64 >64 >64 >64 64 64
E. coli GC 2232 >64 >64 >64 >64 >64 >64 >64 >64 >64
E. coli GC 2233 >64 >64 >64 >64 >64 >64 >64 >64 >64
E. coli GC 2234 >64 >64 >64 >64 >64 >64 >64 >64 >64
E. coli GC 2270 >64 >64 >64 >64 >64 >64 >64 >64 >64
E. coli GC 2271 >64 >64 >64 >64 >64 >64 >64 64 64
E. coli GC 2272 >64 >64 >64 >64 64 >64 64 32 32
E. coli GC 4559 >64 >64 >64 >64 64 >64 >64 >64 >64
E. coli GC 4560 4 4 4 4 4 4 2 1 1
E. coli GC 6465 >64 >64 >64 >64 32 >64 >64 >64 >64
E. coli GC 3226 >64 >64 >64 >64 >64 >64 >64 >64 >64
E. coli GC 2203 >64 >64 >64 >64 >64 >64 >64 >64 >64
E. coli GC 1073 >64 >64 >64 >64 >64 >64 >64 >64 >64
Salmonella spp. GC 235 >64 >64 >64 >64 >64 >64 >64 >64 >64
Salmonella spp. GC 566 >64 >64 >64 >64 >64 >64 >64 >64 >64
S. cholerasius GC 1355 >64 >64 >64 >64 >64 >64 >64 >64 >64
S. typhimurium GC 2172 >64 >64 >64 >64 >64 >64 >64 >64 >64
TABLE Xl (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Water Mouse Serum Human Serum Water Mouse Serum Human Serum Water Mouse Serum Human Serum
Example 58 Example 58 Example 58 Example 59 Example 59 Example 59 Example 60 Example 60 Example 60
P. aeruginosa GC 2214 >64 >64 >64 >64 >64 >64 >64 >64 >64
S. aureus GC 1131 4 2 4 4 4 4 8 2 2
S. aureus GC 6466 4 2 4 8 4 4 8 4 4
S. aureus GC 6467 4 2 4 4 4 4 8 4 4
S. aureus GC 1079 8 2 4 8 4 2 4 2 2
S. aureus GC 4536 4 2 4 4 4 4 4 2 2
S. aureus GC 2216 4 2 4 4 4 4 4 2 2
S. aureus GC 6335 4 4 4 4 4 4 8 8 8
S. aureus GC 6469 4 2 4 4 4 4 4 2 2
S. epidermidis GC 4935 8 4 4 4 4 4 16 8 8
E. faecalis GC 4555 8 4 4 4 4 4 4 4 2
E. faecalis GC 2265 4 4 4 4 4 4 8 8 4
E. faecalis GC 2267 4 2 4 4 4 4 8 8 4
E. faecalis GC 2242 4 2 4 4 2 4 8 8 4
E. faecium GC 4556 4 2 4 4 4 4 4 4 4
E. faecium GC 2243 4 2 4 4 4 8 4 2 2
S. pneumoniae* GC 4465 2 2 4 4 4 4 2 1 1
S. pneumoniae* GC 4465 8 4 4 8 4 8 4 4 2
S. pyogenes GC 4563 4 4 4 4 4 4 2 1 0.50
S. agalactiae GC 4564 8 8 16 8 8 8 4 4 4 c. albicans GC 3066 >64 >64 >64 >64 >64 >64 >64 >64 >64
TABLE XII
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Water Mouse Serum Human Serum Water Mouse Serum Human Serum Water Mouse Serum Human Serum
Example 61 Example 61 Example 61 Example 62 Example 62 Example 62 Example 63 Example 63 Example 63
E. coli GC 2236 16 0.50 4 4 0.50 8 >64 1 >64
E. coli GC 2231 32 1 8 8 0.50 4 >64 1 >64
E. coli GC 2235 16 0.50 4 4 0.50 2 >64 0.50 >64
E. coli GC 2232 16 0.50 4 8 1 2 >64 1 >64
E. coli GC 2233 16 1 8 8 2 4 >64 1 >64
E. coli GC 2234 16 0.50 8 8 1 2 >64 1 64
E. coli GC 2270 16 0.50 4 8 0.50 2 >64 0.50 64
E. coli GC 2271 16 0.50 4 4 1 2 >64 0.50 >64
E. coli GC 2272 8 0.50 4 8 1 4 >64 1 >64
E. coli GC 4559 64 1 8 16 1 8 >64 2 >64
E. coli GC 4560 1 0.25 1 0.50 0.25 0.50 16 0.50 2
E. coli GC 6465 >64 1 32 >64 2 8 >64 2 >64
E. coli GC 3226 32 0.50 8 8 1 4 >64 1 >64
E. coli GC 2203 32 0.50 8 16 1 4 >64 1 >64
E. coli GC 1073 32 0.50 8 16 0.50 4 >64 2 >64 Salmonella spp. GC 235 >64 1 16 >64 1 8 >64 1 >64 Salmonella spp. GC 566 >64 1 32 >64 1 16 >64 1 >64
S. cholerasius GC 1355 >64 2 64 >64 2 32 >64 2 >64
TABLE XII (CONT)
ANTIBACTERIAL ACTIVITY OF 9-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Water Mouse Serum Human Serum Water Mouse Serum Human Serum Water Mouse Serum Human Serum
Example 61 Example 61 Example 61 Example 62 Examp )llee 6622 Example 62 Example 63 Example 63 Example 63
S. typhimurium GC
2172 >64 1 64 >64 2 16 >64 >64
P. aeruginosa GC
2214 >64 8 >64 >64 16 >64 >64 32 >64
S. aureus GC 1131 0.50 0.50 0.50 0.50 0.50 0.50 4 1 1
S. aureus GC 6466 0.50 0.50 0.50 0.25 0.50 0.50 2 0.50 1
S. aureus GC 6467 1 0.50 0.50 0.50 1 0.50 16 2 4
S. aureus GC 1079 1 0.25 0.50 0.50 1 0.50 8 1 2
S. aureus GC 4536 0.50 0.50 0.50 0.50 0.50 0.50 4 1 1
S. aureus GC 2216 1 0.50 0.50 0.50 0.50 0.50 4 1 1
S. aureus GC 6335 1 0.50 1 0.50 1 0.50 4 1 1
S. aureus GC 6469 2 0.50 0.50 1 1 0.50 16 1 2
S. epidermidis GC
4935 1 0.50 1 0.50 0.50 0.50 4 2 2
E. faecalis GC 4555 2 1 2 1 1 0.50 4 1 2
E. faecalis GC 2265 2 0.50 2 1 0.50 0.50 8 1 2
E. faecalis GC 2267 2 0.50 2 1 0.50 0.50 16 1 2
E. faecalis GC 2242 2 0.50 2 0.50 0.50 0.50 1 1 1
TABLE XII (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF G LYCYLCYC LI N ES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
Mouse Human Mouse Human Mouse Human
Water Serum Serum Water Serum Serum Water Serum Serum
Example Example
Example 61 Example 61 Example 61 62 Example 62 Example 62 63 Example 63 Example 63
E. faecium GC
4556 2 0.50 2 1 1 1 0.50 1 4
E. faecium GC
2243 0.50 0.25 1 0.50 0.50 0.50 0.50 0.25 0.25
S. pneumoniae*
GC 4465 0.12 0.12 0.25 0.12 0.12 0.12 0.12 0.12 0.12
S. pneumoniae+
GC 4465 0.50 0.50 0.50 0.50 1 0.50 0.50 0.50 0.50
S. pyogenes GC
4563 0.50 0.25 0.25 0.25 0.25 0.12 0.12 0.12 0.12
S. agalactiae GC
4564 0.25 0.25 0.50 0.25 0.25 0.12 0.25 0.25 0.25 c. albicans GC
3066 >64 >64 >64 >64 >64 >64 >64 >64 >64
TABLE XIII
ANTIBACTERIAL ACTIVITY OF 9-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF GLYCYLCYCLINES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
MouseSerum Water MouseSerum Water MouseSerum Water MouseSerum Water
Example 108 Example 108 Example 109 Example 109 Example 109 Example 109 Example 110 Example 110
E. coli GC 2236 0.50 2 0.50 1 0.50 2 1 2
E. coli GC 2231 2 4 0.50 1 1 2 4 8
E. coli GC 2235 0.50 1 0.25 0.50 0.50 1 0.50 1
E. coli GC 2232 1 2 0.50 1 0.50 2 1 2
E. coli GC 2233 0.50 1 0.25 0.50 1 2 0.50 1
E. coli GC 2234 0.50 2 0.12 0.25 0.25 2 1 2
E. coli GC 2270 0.50 1 0.25 0.50 0.25 2 1 1
E. coli GC 2271 0.50 0.50 0.12 0.25 0.25 1 1 2
E. coli GC 2272 0.25 0.50 0.25 0.25 0.50 2 1 1
E. coli GC 4559 0.50 1 0.12 0.25 1 2 2 2
E. coli GC 4560 0.12 0.25 <0.06 <0.06 0.25 0.25 0.25 0.50
E. coli GC 6465 8 64 1 4 4 16 64 >64
E. coli GC 3226 0.50 1 0.50 1 1 4 2 4
E. coli GC 2203 0.50 1 0.50 1 0.50 2 1 4
E. coli GC 1073 0.50 2 0.50 1 1 4 2 8 Salmonella spp. GC 235 1 4 1 2 1 4 4 8 Salmonella spp. GC 566 1 8 2 4 2 4 16 32
S. cholerasius GC 1355 32 64 8 32 8 32 >64 >64
TABLE XIII (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF G LYCYLCYC LI N ES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
MouseSerum Water MouseSerum Water MouseSerum Water MouseSerum Water
Example 108 Example 108 Example 109 Example 109 Example 109 Example 109 Example 110 Example 110
S. typhimurium GC
2172 4 32 16 4 16 64 >64
P. aeruginosa GC
2214 16 32 16 ->64 32 >64 >64 >64
S. aureus GC 1131 0.25 0.50 1 2 1 4 2 4
S. aureus GC 6466 0.50 1 0.50 1 0.50 4 1 2
S. aureus GC 6467 2 8 2 4 2 8 32 >64
S. aureus GC 1079 2 4 2 4 2 8 16 16
S. aureus GC 4536 0.50 1 1 2 1 4 4 4
S. aureus GC 2216 0.50 1 1 2 0.50 8 2 4
S. aureus GC 6335 1 2 2 4 1 4 8 8
S. aureus GC 6469 0.25 1 1 2 2 8 32 32
S. epidermidis GC
4935 1 2 2 4 8 4 8
E. faecalis GC
4555 0.50 0.50 0.50 1 0.50 1 1 2
E. faecalis GC
2265 1 2 1 2 1 8 4
TABLE XIII (CONT)
ANTIBACTERIAL ACTIVITY OF Θ-AMINOCARBONYLSUBSTITUTED DERIVATIVES OF G LYCYLCYC LI N ES OF FORMULA I
MINIMAL INHIBITORY CONCENTRATION MIC(UG/ML)
MouseSeru MouseSeru MouseSeru
MouseSerum Water r m Water m Water m Water Example Example Example Example pie 108 109 Example 109 109 109 110 Example 110
E. faecalis GC
2267 1 2 1 2 1 4 8 4
E. faecalis GC
2242 0.50 1 1 1 1 2 1 1
E. faecium GC
4556 0.50 1 1 2 1 2 1 2
E. faecium GC
2243 0.50 0.50 0.50 0.50 0.50 1 0.50 0.50
S. pneumoniae*
GC 4465 0.12 0.12 <0.06 0.12 <0.06 0.25 0.25 0.12
S. pneumoniae+
GC 4465 1 2 1 1 1 2 4 2
S. pyogenes
GC 4563 0.12 0.12 <0.06 0.12 0.12 0.25 0.12 <0.06
S. agalactiae
GC 4564 0.12 0.12 0.12 0.25 <0.06 0.25 0.25 0.25 c. albicans GC
3066 >64 >64 >64 >64 >64 >64 >64 >64
Table 1. In vitro activity (MIC)a of representative examples of formula
Figure imgf000096_0001
a Range of MIC (minimum inhibitory concentration) for E. coli and Staph., including MRSA which are selected from those E. coli and Staph., presented in Tables I -X III. Table 1 (Cont)
Minimum inhibitory concentration MICa (μg/ml)
E.coli E.coli Staph Staph
Ex (Mouse
Number Serum) (Water) (Mouse Serum) (Water)
34 0.5-1 4-16 0.25-4 0.25-4
35 4-8 8-64 2-4 2-4
36 2-8 8-32 2-4 4-16
37 2-4 4-32 1-4 2-4
38 0.5-4 64->64 0.5-2 1-8
39 1-4 16-32 1-4 2-16
40 1-2 16->64 0.25-2 0.25-2
41 0.5-4 16-64 0.5-4 1-8
42 4-16 >64 2-4 4-8
43 0.25-2 >64 0.5-2 32->64
44 2-8 >64 2 2-4
45 0.5-2 16->64 0.25-1 0.5-2
46 0.5-2 64->64 0.25-1 0.25-2
47 0.5-2 >64 1-2 2-4
48 0.25-2 32->64 0.12-2 0.12-2
49 0.25-2 8->64 0.12-1 0.12-2
50 1-2 32-64 0.25-2 0.25-4
51 1-2 >64 0.25-2 1-4
52 0.5-1 4-16 0.5-1 2-4
53 0.25-1 16-64 0.25-1 0.5-2
54 0.5-1 >64 0.5-2 1-4
55 0.5-8 64->64 1-2 2-8
56 0.25-2 8>64 0.25-1 1-4
57 0.5-4 >64 0.5-2 4-16
58 >64 >64 2-4 4-8
59 32->64 >64 4 4-8
60 32->64 64->64 2-8 4-16
61 0.5-1 8->64 0.25-0.5 0.5-2
62 0.5-2 4->64 0.5-1 0..25-1
63 0.5-2 >64 0.5-2 2-16
64 <0.12 O.12 - 1 O.12 - 0.25 O.12 - 0.5
<0.12 -
65 0.5 16 O.12 - 0.5 <0.12 - 1
66 >128 >128 1-16 2-16
O.12 -
67 0.25 8-32 O.12 - 0.25 <0.12 - 1
68 O.12 - 1 2-8 O.12 - 0.25 O.12 - 1 a Range of MIC (minimum inhibitory concentration) for E. coli and Staph., including
MRSA which are selected from those E Ξ. coli and Staph ., presented in Tables I-Xlll
Figure imgf000098_0001
Figure imgf000099_0002
a Range of MIC (minimum inhibitory concentration) for E. coli and Staph., including MRSA which are selected from those E. coli and Staph., presented in Tables I-XIII.
Table 2. In vitro activity (MIC) of Example 87.
Example 87
Figure imgf000099_0001
water Mouse serum Human serum
E. coli, tet(A-D), efflux >64 0.25-0.5 >64
E. coli, tet (M1S1O) Tet >64 0.25-0.5 >64
(M)
E. coli (susceptible) >64 0.5 >64
E. coli (IMP) 32 <0.06 16
S. aureus, tet (M) 64 0.5 16
S. aureus, tet (K), 64 1 32 efflux
S. aureus 32 1 16
(susceptible)8
Enterococcus spp. 0.25-32 0.12-0.5 0.25-8
Streptococcus spp. 0.5-2 <0.06 1-2
C. albicans >64 >64 >64
Strain used for the in vivo testing Representative examples of compounds of Formula I were further evaluated for oral efficacy, stability in physiological pH in mouse serum and human plasma.
Table 3. In vitro activity (MlCf of representative examples of compounds of Formula
Minimum inhibitory concentration (MIC), μg/ml_
Ex. No. E. coli E. coli Staph. Staph, (water)
(mouse (water) (mouse serum) serum)
1 0.5-1 16-64 1-4 1-8
2 1-4 32-64 1-8 2-8
3 1-2 >64 1-4 4-32
4 0.5-2 64->64 0.5-2 2-16
12 0.5-2 16-64 0.5-4 1-16
13 1-4 8-16 1-4 2-8
17 0.5-2 32-64 1-4 2-32
18 0.5-2 4-8 1-4 1-4
20 0.5-2 >64 1-4 64->64
21 0.5-8 >64 1-4 32->64
22 1-8 >64 0.5-4 2->64
23 1-8 >64 0.25-4 0.5-8
29 0.5-1 >64 0.25-2 1-4
30 0.5-1 32->64 0.25-2 1-8
34 0.5-1 4-16 0.25-4 0.25-4
36 2-8 8-32 2-4 4-16
38 0.5-4 64->64 0.5-2 1-8
39 1-4 16-32 1-4 2-16
a Range of MIC (minimum inhibitory concentration) for E. coli and Staph., including MRSA which are selected from those E. coli and Staph., presented in Tables I-XIII.
Table 4. In vitro activity (MIC)a of representative examples of compounds of Formula
Minimum inhibitory concentration (MIC), μg/m L
Ex. No. E. coli E. coli Staph. Staph, (water)
(mouse (water) (mouse serum) serum)
5 1-2 16-64 0.25-2 0.5-4
6 1-2 8-64 0.5-2 1-4
7 0.25-2 2-16 0.5-4 0.5-4
8 1-2 16->54 0.5-4 1-8
9 0.5-2 4-64 0.06-1 0.12-2
10 0.25-2 4-32 0.25-2 0.12-2
11 0.25-2 4->64 0.25-4 0.25-4
19 0.5-2 32->64 0.5-4 1-8
24 0.5-2 >64 0.25-4 0.5->64
25 1-2 32->64 0.25-2 0.5-4
26 1-4 64->64 0.25-1 0.25-4
27 0.5-1 32->64 0.12-2 0.12-2
28 0.25-1 >64 0.5-4 4-64
31 0.5-1 16->64 0.25-2 0.5-4
33 0.5-2 32->64 0.12-2 0.12-2
35 4-8 8-64 2-4 2-4
40 1-2 16->64 0.25-2 0.25-2
41 0.5-4 16-64 0.5-4 1-8 a Range of MIC (minimum inhibitory concentration) for E. coli and Staph. including MRSA which are selected from those E. coli and Staph., presented in Tables I-XIII.
Table 5. In vitro activity (MIC) of Example 27
Example 27
Figure imgf000102_0001
water Mouse serum Human serum
E. coli, tet(A-D), 64->64 0.5-1 4-16 efflux
E. coli, tet 0.5 0.5 4-8
(M1S1O) Tet (M)
E. coli 0.5 0.5 16
(susceptible)
E. coli (IMP) 0.25 0.25 0.5
S. aureus, tet (M) 0.12 0.12 0.25
S. aureus, tet (K), 1 1 1 efflux
S. aureus 0.12 0.12 0.5
(susceptible)8
Enterococcus 0.12-1 0.12-1 0.5-2 spp.
Streptococcus O.06- <0.06-0.12 0.12-2 spp. 0.12
C. albicans >64 >64 >64 a Strain used for in vivo testing
Representative examples of compounds of Formula I were tested for the oral efficacy using S. aureus Smith in mice. The summary of in vivo and in vitro activities of selected compounds are listed in Table 6.
Table 6. In vitro and in vivo activity of representative examples of compounds of Formula I against Staph, aureus Smith in mice.
ED50 mg/kg (Staph μg/ml_ (Staph aureus aureus Smith) Smith)
Ex. No. SODb SIVC MICa
42 5.68 1.43 8
44 4 0.75 4
45 5.9 0.66 1
47 14 1.2 4
48 10.1 1.1 0.25
49 16 0.92 0.25
50 16.88 1.65 0.5
52 10.69 1.29 2
53 5.08 0.73 1
54 8.4 0.83 0.5
87 12.82 0.83 32 a MIC (minimum inhibitory concentration) b SOD (Single oral dose) c SIV (Single intravenous dose)
Representative examples of compounds of Formula I were tested in vivo against gram-negative bacteria (E. coli) in mice. Results of the tests (MIC, oral and IV) are list in Table 7.
Table 7. In vivo (oral, iv) and in vitro (MIC)a activity of representative examples of compounds of Formula I against E. coli in mice .
ED50 mg/kg (E. μg/mL (E. coli) coli)
Ex. No. SODb SIVC MIC
5 >64 3.17 >64
42 30.3 3.1 >64
44 42.8 2.85 >64
45 64 1.8 64
48 29.8 1.7 >64
49 49 2.2 64
50 29.8 1.7 >64
52 43.7 3.78 8
53 46.88 2.25 32
54 29.2 2.16 >64
87 60.4 3.6 >64
a MIC (minimum inhibitory concentration) b SOD (Single oral dose) c SIV (Single intravenous dose)
Test results of in vivo activity are shown in Table 8 for representative examples of compounds of Formula I .
Table 8. In vivo (oral, iv) and in vitro (MIC)a activity of representative examples of compounds of Formula I, against Staph aureus Smith in mice .
ED50 mg/kg (Staph μg/mL (Staph aureus aureus Smith) Smith)
Ex. No. SODb SlV0 MIC
1 4.7 0.6 4
5 8.51 0.5 1
19 8.05 0.31 1
26 8.79 0.43 0.5
27 3.9 0.44 0.12
28 6.61 0.6 32
33 4.91 0.48 0.12
35 3.5 0.43 4
36 5.15 0.84 8
38 5.3 0.6 2
40 4.65 0.39 0.5 a MIC (minimum inhibitory concentration) b SOD (Single oral dose) c SIV (Single intravenous dose)
Table 9
Minimum inhibitory concentration (MIC), //g/mL
Ex No. E.coli E.coli Staph Staph
(Human Serum) (Water) (Human Serum) (Water)
4 8-32 32->64 0.5-4 2-8
19 8-32 16->64 0.12-1 0.25-4
27 4-16 64->64 0.25-2 0.5-4
42 >64 >64 2-4 4-8
43 >64 >64 4-64 32->64
44 >64 >64 2-4 2-4
45 4-16 16->64 0.12-1 0.5-2
46 4-16 64->64 0.25-1 0.25-2
47 16->64 >64 1-4 2-4
48 8->64 32->64 0.12-2 0.12-2
49 4-32 8->64 0.12-1 0.12-2
50 4-16 32-64 0.25-2 0.25-4
51 32-64 >64 0.25-2 1-4
52 4-16 4-16 0.5-4 2-4
53 8-16 16-64 0.5-2 0.5-2
54 16-32 >64 0.5-2 1-4
55 32->64 64->64 1-4 2-8
56 4-32 8->64 0.25-2 1-4
57 >64 >64 1-8 4-16
58 >64 >64 4 4-8
59 >64 >64 2-4 4-8
60 32->64 64->64 2-8 4-16
61 4-32 8->64 0.5-1 0.5-2
62 2-8 4->64 0.5 0.25-1
63 64->64 >64 1-4 2-16
102 64->64 >64
105 64>64 8->64
Figure imgf000107_0001
Table 10 (cont)
ED50 (mg/kg ) ED50 mg/kg IV - RAT PO - RAT
Staph Smith E. coli #31 1 2 mg/kg 20 mg/kg
Ex. No. SOD SIV SOD SIV Cmax AUC T1/2 Cmax AUC |%BA
23 19.01 0.47
24 27 0.59
25 15.71 0.56
26 8.79 0.43
27 3.9 0.44 >32 >2
28 6.61 0.6 >32 >2
29 13.67 0.43
30 15.1 0.41
31 11.11 0.31
32 7.7 0.56
33 4.91 0.45
34 12.86 0.71
35 3.5 0.43
36 5.15 0.84
37 4.1 0.55
38 5.3 0.6
39 13.3 0.6
40 4.65 0.39
41 11.3 0.83
42 I 5.68 1.43 30.3 3.1 4.1 1.6 5.1 0.22 0.64 8.1
43 12.82 0.83 60.4 3.6
44 4 0.75 42.8 2.85 6.5 2.4 3.5 0.05 0.27 2.3
45 5.9 0.66 64 1.8
Figure imgf000109_0001
O
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
When the compounds of the invention are employed as antibacteriais, they can be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight. An effective amount of compound from 2.0 mg/kg of body weight to 100.0 mg/kg of body weight may be administered one to five times per day via any typical route of administration including but not limited to oral, parenteral (including subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques), topical or rectal, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as com, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
The present invention further provides a method of treating bacterial infections in warm-blooded animals including man, which comprises providing to the afflicted warm-blooded animals an antibacterially effective amount of a compound or a pharmaceutical composition of a compound of the invention.
The invention will be more fully described in conjunction with the following specific examples which are not to be construed as limiting the scope of the invention.
Reference Compound 1
(Tert-butyl-chloromethoxycarbonyl-amino)-acidic acid benzyl ester.
Figure imgf000115_0001
To a solution of tert-butylamino-acetic acid benzyl ester in dichloromethane is added two equivalents of [1 ,8-bis(dimethylamino)naphthalene, N,N,N',N'-tetramethyl-1 ,8- naphthalenediamine]. The reaction mixture is than cooled in an ice bath and one equivalent of chloromethyl chloroformate is added. The reaction is then warm to room temperature and continue to stir for 24 hr. It is then washed with water and then brine.
Reference Compound 2
3,3-Dimethyl-butyric acid (benzy[oxycarbonylmethyl-tert-butyl-carbamoyloxy)-methyl ester
Figure imgf000115_0002
Tert-butylacetic acid and 1.0 M tetrabutylammonium hydroxide in methanol is stirred for an hour, methanol is removed and THF is added. To this solution is then added benzyl N-(tert-butyl)-N-[(chIoromethoxy)carbonyl]glycinate and stirred at room temperature for 24 hr. Solvent is removed and residue is diluted with ether, then washed with water, then brine. It is dried over magnesium sulfate, filtered and solvent removed. MS (ESI) m/z 394.25
Reference Compounds 3-55 (Table A)
Substantially following the method described in detail hereinabove in Reference Compound 2 using (tert-butyl-chloromethoxycarbonyl-amino)-acidic acid benzyl ester from Reference Compound 1 and the appropriate carboxylic acid, the reference compounds 3-55 of this invention listed below in Table A are prepared.
Table A
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Reference Compound 56
3,3-Dimethyl-butyric (tert-butyl-carboxymethyl-carbamoyloxy)-methyl ester.
Figure imgf000123_0001
The product from Reference Compound 2, 10% palladium on carbon in ethyl acetate is hydrogenated in a Parr shaker at ca. 40 psi for about an hour. The catalyst is filtered and solvent removed to give the corresponding carboxylic acid product of the example MS(ESI) m/z 394.25.
Reference Examples 57-108 (Table B)
Substantially following the method described in detail hereinabove in Reference Compound 56 the reference compounds 57-108 of this invention listed below in Table B are prepared using the appropriate benzyl esters of Reference Compounds 3-55.
Table B
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Reference Compound 109
3,3-Dimethyl-butyric acid [tert-butyl-(2-isobutoxycarbonyloxy-2-oxo-ethyI)- carbamoyloxy)-methyl ester.
Figure imgf000135_0001
To a solution of Reference Compound 56 in dichloromethane at room temperature is added 1.2 equivalent of [1 ,8-bis(dimethylamino)naphthalene, N,N,N',N'-tetramethyl- 1 ,8-naphthalenediamine] and 0.95 equivalent of iso-butylchloroformate. The reaction is stirred for 24 hour, diluted with dichloromethane, washed with dilute HCI, brine, then water. It is dried with sodium sulfate. Solvent removed and the product is used in the next step without further purification.
Reference Compound 110 3,3-Dimethylbutyric acid ethylsulfanylcarbonyloxymethyl ester
Figure imgf000135_0002
To a solution of t-butylacetic acid (0.025 mol, 3 g) in methanol is added tetrabutylammonium hydroxide (I M/methanol, 25 ml). The mixture is stirred for 1 h and the solvent removed to a residue. The residue is dissolved in 150 ml of methylene chloride and 150 ml of water and a solution of O-chloromethyl S-ethyl carbonothioate (0.025 mol, 3.85 f) in 50 ml of methylene chloride added. The mixture is stirred at room temperature for 24 h. The methylene chloride layer is separated, washed with water, brine and dried over sodium sulfate. The solvent is removed under vacuo and the residue stirred in 300 ml of ether for 24 h. The resulting white solid is filtered, the solid discarded and the solvent removed from the filtrate to give 6 g of a crude oil.
Reference Compound 111
Figure imgf000136_0001
To a stirred solution of 3,3-dimethylbutyric acid ethylsulfanylcarbonyloxymethyl ester (Reference Compound 110) (0.025 ml, 6 g) in methylene chloride at -2O0C (dry ice/carbon tetrachloride) is added sulfuryl chloride ().O25 mol, 3.5 g). After 10 min, 0.1 ml of boron trifluoride etherate is added. The mixture is stirred at O0C for 1 h, at room temperature for 30 min. The volatiles are removed by distillation to yield 4.9 g of the desired acid chloride.
Following the procedure of Reference Compound 111 the corresponding acid chloride used in Examples 112 to 120 was prepared.
Reference Compound 112 benzyl N-(butoxycarbonyl)-N-(tert-butyl)glycinate
Figure imgf000136_0002
Reference Compound 113 benzyl N-(tert-butyl)-N-(isobutoxycarbonyl)glycinate
Figure imgf000137_0001
Reference Compound 114 benzyl N-(tert-butyl)-N-(methoxycarbonyl)glycinate
Figure imgf000137_0002
Reference Compound 115 N-(butoxycarbonyl)-N-(tert-butyl)glycine
Figure imgf000137_0003
Reference Compound 116 N-(tert-butyl)-N-(isobutoxycarbonyl)glycine
Figure imgf000138_0001
Reference Compound 117 N-(tert-butyl)-N-(methoxycarbonyl)glycine
Figure imgf000138_0002
Reference Compound 118 isobutoxycarbonyl N-(butoxycarbonyl)-N-(tert-butyl)glycinate
Figure imgf000138_0003
Reference Compound 119 isobutoxycarbonyl N-(tert-butyl)-N-(isobutoxycarbonyl)glycinate
Figure imgf000139_0001
Reference compound 120 isobutoxycarbonyl N-(tert-butyl)-N-(methoxycarbonyl)glycinate
Figure imgf000139_0002
Reference Compound 121 (5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate
Figure imgf000139_0003
The product of the Reference Example was prepared using the conditions described by R. Sakamoto et al, Chem. Pharm. Bull. 32(6), 2241-2248(1984).
Reference Compound 122 4-nitrophenyl (2-oxo-5-phenyl-1 ,3-dioxol-4-yl)methyl carbonate
Figure imgf000140_0001
The product of the Reference Example was prepared using the conditions described by R. Sakamoto et al, Chem. Pharm. Bull. 32(6), 2241-2248(1984).
Reference Compound 123
[5-(4-methoxyphenyl)-2-oxo-1 ,3-dioxol-4-yl]methyl 4-nitrophenyl carbonate
Figure imgf000140_0002
The product of the Reference Example was prepared using the conditions described by R. Sakamoto et al, Chem. Pharm. Bull. 32(6), 2241-2248(1984). Reference Compound 124
4-tert-butyl-10,10-dimethyl-3,6-dioxo-2,7-dioxa-4-aza-10-silaundec-1 -yl (2E)-3- phenylacrylate
Figure imgf000141_0001
Trans-cinnamic acid (23.1 mmol) and 1.0 M tetrabutylammonium hydroxide (22.2 mmol) in methanol are stirred for one hour, and the methanol is removed. THF is added. To this solution is added 2-(trimethylsilyl)ethyl 2-(tert- butyl((chloromethoxy)carbonyl)amino)-acetate (18.5 mmol) and the mixture is stirred at room temperature for 24 hr. The solvent is removed and the residue is diluted with ether. The resulting solution is washed with water and brine. The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 5.01 g (61%) MS (ESI) m/z 436.3.
Using substantially the same procedure as described above for Reference Compound 124 the following reference compounds were prepared from the appropriate carboxylic acids:
Reference Compound 125
4-tert-butyl-10,10-dimethyl-3,6-dioxo-2,7-dioxa-4-aza-10-silaundec-1 -yl anthracene-
9-carboxylate
Figure imgf000141_0002
MS (ESI) m/z 510.3 Reference Compound 126
4-tert-butyl-10,10-dimethyl-3,6-dioxo-2,7-dioxa-4-aza-10-silaundecyl 4- benzoylbenzoate
MS (ESI) m/z 536.2
Example 1
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 2-methylpropanoate
Figure imgf000142_0001
To a solution of n-Butylglycylcycline in acetonitrile/DMPA (1 :5), sodium carbonate is added. The reaction mixture is stirred for 5 min and propanoic acid, 2-methyl- [(chlorocarbonyl)oxy]methyl ester prepared according to the methods described in M. Folkmann and F.J. Lund, Synthesis, December 1990, 1159-1166, is added. Stirring is continued for about 30 to 45 minute (or monitored by MS (ES)). Upon completion of the reaction, 0.5 mL of methanol is added and the mixture poured slowly into a mixture of isopropanol and ether. 1.0M HCI in ether is added and the solid is filtered. The solid is dissolved in water and is extracted with methylene chloride to give the product of the Example. MS (ESI) m/z 730.28 (M+H); Following the procedure of Example 1 , and the corresponding acid chloride prepared by methods described in M. Folkmann and F.J. Lund, Synthesis, December 1990, 1159-1166 and N-butylglycylcycline or N-propylglycylcycline the following Examples 2-41 are prepared.
Example 2
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 4-methoxybenzoate
Figure imgf000143_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl 4-methoxybenzoate and N-butylglycylcycline to give the product of the Example. Example 3
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethyIamino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 4-methylbenzoate
Figure imgf000144_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyi)oxy]methyl 4-methylbenzoate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 778.3 ((M+H)+);
Example 4
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethyIamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-0110X0-5,53,6,63,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 4-fluorobenzoate
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxyjmethyl 4-fluorobenzoate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 782.3 ((M+H)+);
Example 5
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-methylbenzoate
Figure imgf000146_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl 4-methylbenzoate and N-propylglycylcycline to give the product of the Example. MS (ESI) m/z 764.3 ((M+H)+);
Example 6
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-methoxybenzoate
Figure imgf000146_0002
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl 4-methoxybenzoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 780.3 ((M+H)+); Example 7
({[(2-{[(5aR,6aSI7S)10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10aI11- tetrahydroxy-10,12-dioxo-S.δa.e.θaJJ O.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl cyclobutanecarboxylate
Figure imgf000147_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl cyclobutanecarboxylate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 728.3 ((M+H)+);
Example 8
({[(2-{[(5aRI6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-fluorobenzoate
Figure imgf000147_0002
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxyjmethyl 4-fIuorobenzoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 768.3 ((M+H)+);
Example 9
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,1 Oa, 1 1 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl pivalate
Figure imgf000148_0001
The title compound is prepared by the procedure of Example 1 , using Propanoic acid, 2,2-dimethyh [(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 730.3 ((M+HVi ); Example 10
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 2-methylpropanoate
Figure imgf000149_0001
The title compound is prepared by the procedure of Example 1 , using propanoic acid, 2-methyl-,[(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 716.3 ((M+H)+);
Example 11
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl phenylacetate
Figure imgf000149_0002
The title compound is prepared by the procedure of Example 1 , using benzeneacetic acid, [(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 764.3 ((M+H)+
Example 12
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl phenylacetate
Figure imgf000150_0001
The title compound is prepared by the procedure of Example 1 , using using benzeneacetic acid, [(chlorocarbonyl)oxy]methyl ester and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 778.3 ((M+H)+);
Example 13
({[(2-{[(5aRI6aS,7SI10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8f10af11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl pivalate
Figure imgf000151_0001
The title compound is prepared by the procedure of Example 1 , using propanoic acid, 2,2-dimethyl-, [(chlorocarbonyl)oxy]methyl ester and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 744.3 ((M+H)+);
Example 14
benzyl 2-{[(5aR,6aS, 7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1, 8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethy!(propyl)carbamate
Figure imgf000151_0002
The title compound is prepared by the procedure of Example 1 , using benzyl chloroformate and N-propylglycylcycline in the presence of sodium carbonate and DMPU in acetonitrile to give the product of the Example.
MS (ESI) m/z 706.3 ((M+H)+);
HRMS: calcd for C36H43N5O10 • HCI, 741.2777; found (ESI), 706.31133;
Example 15
ethyl 2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a111 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl(propyl)carbamate
Figure imgf000152_0001
The title compound is prepared by the procedure of Example 1 , using ethyl chloroformate and N-propylglycylcycline in the presence of sodium carbonate and DMPU in acetonitrile to give the product of the Example.
MS (ESI) m/z 644.3 ((M+H)+);
HRMS: calcd for C31H4IN5O10 ■ HCI, 679.2620; found (ESI+), 644.29398; Example 16
isobutyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-
1 ,8, 10a, 11 -tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2- yl]amino}-2-oxoethyl(propyl)carbamate
Figure imgf000153_0001
The title compound is prepared by the procedure of Example 1 , using isobutyl chloroformate and N-propylglycylcycline in the presence of sodium carbonate and DMPU in acetonitrile to give the product of the Example.
MS (ESI) m/z 672.3 ((M+H)+);
MS (ESI) m/z 336.9 ((M+2H)2+);
HRMS: calcd for C33H45N5O10 • HCI, 707.2933; found (ESI+), 672.32618
Example 17
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10 J Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl heptanoate
Figure imgf000154_0001
The title compound is prepared by the procedure of Example 1 , using heptanoic acid, [(chlorocarbonyl)oxy]methyl ester and N-butylglycylcycline to give the product of the Example.
MS (ESI+) m/z 772.2 (M+H);
HRMS: calcd for C38H53N5O12 • 2.00 HCI, 843.3224; found (ESI+), 772.37696;
Example 18
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl cyclobutanecarboxylate
Figure imgf000154_0002
The title compound is prepared by the procedure of Example 1 , using
[(chlorocarbonyl)oxy]methyl cyclobutanecarboxylate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 742.3 ((M+H)+); HRMS: calcd for C36H47N5Oi2 ' 2.00 HCI, 813.2755; found (ESI+), 742.32898; Example 19
({^-{[(SaR.eaS.ZS.10aSJ-θ-Caminocarbonyl)-4,7-bis(dimethylaminoJ-i .δ.i Oa.H- tetrahydroxy-10,12-0110X0-5,53,6,63,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl heptanoate
Figure imgf000155_0001
The title compound is prepared by the procedure of Example 1 , using Heptanoic acid, [(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 758.4 ((M+H)+);
HRMS: calcd for C37H5IN5O12 • HCI, 793.3301 ; found (ESI+), 758.36175;
Example 20
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 4-tert-butylbenzoate
Figure imgf000155_0002
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl 4-tert-butylbenzoate and N-butylglycylcycline to give the product of the Example.
MS (ESI+) m/z 820.2 (M+H);
HRMS: calcd for C42H53N5O12 • HCI, 855.3458; found (ESl+), 820.37684;
Example 21
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-010X0-5,53,6,63,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 1 ,1'-biphenyl-4-carboxylate
Figure imgf000156_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl biphenyl-4-carboxylate and N-butylglycylcycline to give the product of the Example. MS (ESI) m/z 840.3 ((M+H)+);
HRMS: caicd for C44H49N5O12 ■ HCI, 875.3145; found (ESI+), 840.34337;
Eample 22
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8I10aI11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 3,5-dimethylbenzoate
Figure imgf000157_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl 3,5-dimethylbenzoate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 792.3 ((M+H)+);
HRMS: calcd for C40H49N5O12 • 2.00 HCI, 863.2911 ; found (ESI+), 792.34378;
Example 23
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl thiophene-2-carboxylate
Figure imgf000158_0001
The title compound is prepaied by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl thiophene-2-carboxylate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 770.1 ((M+H)+);
HRMS: calcd for C36H43N5O12S ■ HCI, 805.2396; found (ESI+), 770.27084;
Example 24
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 1 , 1 '-biphenyl-4-carboxylate
Figure imgf000158_0002
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl biphenyI-4-carboxylate and N-propylglycylcycline to give the product of the Example.
MS (ES!) m/z 826.4 ((M+H)+);
MS (ESI) m/z 414 ((M+2H)2+);
HRMS: calcd for C43H47N5O12 • HCI, 861.2988; found (ESI+), 826.32782;
Example 25
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl thiophene-2-carboxylate
Figure imgf000159_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl thiophene-2-carboxylate and N-propylglycylcycline to give the product of the Example. MS (ESI) m/z 756.3 ((M+H)+);
MS (ESI) m/z 378.9 ((M+2H)2+);
HRMS: calcd for C35H4IN5O12S • HCI, 791.2239; found (ESI+), 756.2532;
Example 26
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 3,5-dimethylbenzoate
Figure imgf000160_0001
The title compound is prepared by the procedure of Example 1 , using
[(chlorocarbonyl)oxy]methyl 3,5-dimethylbenzoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 778.3 ((M+H)+);
HRMS: calcd for C39H47N5O12 ' HCI, 813.2988; found (ESI+), 778.32984;
Example 27
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-S.Sa.θ.βaJ.10.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl thiophene-3-carboxylate
Figure imgf000161_0001
The title compound is prepared by the procedure of Example 1 , using
[(chlorocarbonyl)oxyjmethyl thiophene-3-carboxylate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 756.3 ((M+H)+);
HRMS: calcd for C35H41N5O12S • HCI, 791.2239; found (ESI+), 756.2547;
Example 28
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8I10aI11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-tert-butylbenzoate
Figure imgf000162_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl 4-tert-butylbenzoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 806.4 ((M+H)+); MS (ESI) m/z 403.9 ((M+2H)2+); HRMS: calcd for C41H5IN5O12 • HCI, 841.3301 ; found (ESI+), 806.36024;
Example 29
({[(2-{[(5aR,6aS7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 I8,10aI11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl thiophene-3-carboxylate
Figure imgf000163_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl thiophene-3-carboxylate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 770.3 ((M+H)+);
HRMS: calcd for C36H43N5O12S HCI, 805.2396; found (ESI+), 770.27028;
Example 30
({^-{[(δaR.eaSJS.10aS^Θ-Caminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 2-furoate
Figure imgf000164_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl 2-furoate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 752.2 ((M-H)-);
HRMS: calcd for C36H43N5O13 • HCI, 789.2624; found (ESI+), 754.29242;
Example 31
({[(2-{[(5aR,6aS,7SI10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 2-furoate
Figure imgf000165_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl 2-furoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 740.19 (M+H);
Example 32
1-({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)ethyl acetate
Figure imgf000165_0002
The title compound is prepared by the procedure of Example 1 , using 1- [(chlorocarbonyl)oxy]ethyl acetate and N-butylglycylcycline to give the product of the Example. MS (ESI) m/z 716.14 (M+H);
HRMS: calcd for C34H45N5O12, 715.3065; found (ESI+), 716.31469;
Example 33
({[(2-{[(7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 -tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl cyclohexanecarboxylate
Figure imgf000166_0001
The title compound is prepared by the procedure of Example 1 , using cyclohexanecarboxylic acid, [(chlorocarbonyl)oxy]methyl ester d N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 756.08 (M+H);
HRMS: calcd for C37H49N5O12, 755.3378; found (ESI+), 756.34507;
Example 34
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethyIamino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl cyclohexanecarboxylate
Figure imgf000167_0001
The title compound is prepared by the procedure of Example 1 , using cyclohexanecarboxylic acid, [(chlorocarbonyl)oxy]methyl ester and N- butylglycylcycline to give the product of the Example.
MS (ESI) m/z 70.64 (M+H);
HRMS: calcd for C38H5IN5O12 • HCI, 805.3301 ; found (ESI+), 770.36093;
Example 35
({^-{[(δaR.eaSyS.10aSJ-θ^aminocarbonylH.Z-bis(dimethylaminoJ-i .δ.iOa.i i- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 3,3-dimethylbutanoate
Figure imgf000167_0002
The title compound is prepared by the procedure of Example 1 , using butanoic acid, 3,3-dimethyl-, [(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example. MS m/z 00-304761 LMS;
HRMS: calcd for C36H49N5O12 • HCI, 779.3145; found (ESI+), 744.34539;
Example 36
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 3,3-dimethylbutanoate
Figure imgf000168_0001
The title compound is prepared by the procedure of Example 1 , using Butanoic acid, 3,3-dimethyl-, [(chlorocarbonyl)oxy]methyl ester and N-butylglycylcycline to give the product of the Example.
MS m/z 00-304762LMS;
HRMS: calcd for C37H51N5O12 • HCI, 793.3301 ; found (ESI+), 758.36071 ;
Example 37
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 2,2-dimethylbutanoate
Figure imgf000169_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl 2,2-dimethylbutanoate and N-propylglycylcycline to give the product of the Example.
MS m/z 00-304763LMS;
HRMS: calcd for C36H49N5O12 • HCI, 779.3145; found (ESI+), 744.3452;
Example 38
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,1Oa1H- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl cyclopentylacetate
Figure imgf000169_0002
The title compound is prepared by the procedure of Example 1 , using
[(chlorocarbonyl)oxy]methyl cyclopentylacetate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 770.7 (M+H);
HRMS: calcd for C38H5IN5O12 ' HCI, 805.3301 ; found (ESI+), 770.36062; Example 39
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl adamantane-1 -carboxylate
Figure imgf000170_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl adamantane-1 -carboxylate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 822.9 (M+H);
HRMS: calcd for C42H55N5O12 • HCI, 857.3614; found (ESI+), 822.39184;
Example 40
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl cyclopentylacetate
Figure imgf000170_0002
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methy! cyclopentylacetate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 754.2 ((M-H)-);
HRMS: calcd for C37H49N5Oi2 ■ HCI, 791.3145; found (ESI+), 756.34433;
Example 41
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl adamantane-1-carboxylate
Figure imgf000171_0001
The title compound is prepared by the procedure of Example 1 , using [(chlorocarbonyl)oxy]methyl adamantane-1-carboxylate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 808.8 (M+H);
HRMS: calcd for C4iH53N5O12 ■ HCI, 843.3458; found (ESI+), 808.37604;
Example 42
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,3-dimethylbutanoate
Figure imgf000172_0001
To a solution of 9-amino-minocycline monosulfate (0.0055 mol, 3.135g, 1 equivalent) in a mixture of 12 ml of acetonitrile and 50 ml of DMPU is added 1.66 g (3 equivalents)of triethylamine and Reference Compound 109 (0.012 mole, 4.88g), 3,3-Dimethyl-butyric acid [tert-butyl-(2-isobutoxycarbonyloxy-2-oxo-ethyl)- carbamoyloxy)-methyl ester. The reaction is stirred at room temperature for 2 hour, 1 mL methanol is added, stirred for 5 min. and the mixture is poured onto a mixture of 500 ml of ether and 100 ml of isopropanol. Solid is collected and purified by extraction to give 1.5 g of the product of the Example.
MS (ESI) m/z 758.55 (M+H);
HRMS: calcd for C37H51N5O12 ' HCI, 793.3301 ; found (ESI+), 758.36201 ;
Example 43
Prepared according to Scheme Il
({[(2-{[(5aR,6aS, 7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 , 8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-tert-butylbenzoate
Figure imgf000173_0001
Reference Compound 57 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 820.37 (M+H);
HRMS: calcd for C42H53N5O12 • HCI, 855.3458; found (ESI+), 820.37574;
Example 44
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,2-dimethylbutanoate
Figure imgf000173_0002
The title compound is prepared by reacting the product of the reaction of N-(tert- butyl)-N-({[(2,2-dimethylbutanoyl)oxy]methoxy}carbonyl)glycine using the conditions of Reference Compound 109 with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 758.63 (M+H); HRMS: calcd for C37H51N5Oi2 " HCI, 793.3301 ; found (ESI+), 758.36119; Example 45
Prepared according to Scheme 2 ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-methylpropanoate
Figure imgf000174_0001
Reference Compound 58 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 730.38 (M+H);
HRMS: calcd for C35H47N5O12 HCI, 765.2988; found (ESI+), 730.33002;
Example 46
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10,10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclopentanecarboxylate
Figure imgf000175_0001
Reference Compound 59 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 754.09 ((M-H)-);
HRMS: calcd for C37H49N5O12 " HCI, 791.3145; found (ESI+), 378.67644;
Example 47
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-methylbenzoate
Figure imgf000175_0002
Reference Compound 60 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example. MS (ESI) m/z 778.34 (M+H);
HRMS: calcd for C39H47N5O12, 777.3221 ; found (ESI+), 778.33065;
Example 48
Prepared according to Scheme Il
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl heptanoate
Figure imgf000176_0001
Reference Compound 61 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 772.45 (M+H);
HRMS: calcd for C38H53N5O12 ■ HCI, 807.3458; found (ESI+), 772.37695;
Example 49
Prepared according to Scheme Il
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-IC^-dioxo-δ.δa.e.eaJ.10.I Oa.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl propionate
Figure imgf000177_0001
Reference Compound 62 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 716.3 (M+H); HRMS: calcd for C34H45N5O12 • HCI, 751.2832; found (ESI+), 716.31461 ;
Example 50
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclohexanecarboxylate
Figure imgf000177_0002
Reference Compound 63 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example. MS (ESI) m/z 770.36 (M+H);
HRMS: calcd for C38H5iN5O12 • HCI, 805.3301 ; found (ESI-), 768.34546;
Example 51
Prepared according to Scheme 2
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,5-dimethylbenzoate
Figure imgf000178_0001
Reference Compound 64 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 792.32 (M+H);
HRMS: calcd for C40H49N5O12 • HCI, 827.3145; found (ESI+), 792.34613;
Example 52
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)aminojcarbonyl}oxy)methyl 4-fluorobenzoate
Figure imgf000179_0001
Reference Compound 65 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 782.3 (M+H); HRMS: calcd for C38H44FN5O12 ' HCI, 817.2737; found (ESI+), 782.30406
Example 53
Prepared according to Scheme 2 ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4)7-bis(dimethylamino)-1 ,8,10a>11- tetrahydroxy-IC^-dioxo-δ.δa.δ.θaJ.10.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3-methylbutanoate
Figure imgf000179_0002
Reference Compound 66 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example. MS (ESI) m/z 744.37 (M+H);
HRMS: calcd for C36H49N5Oi2 HCI, 779.3145; found (ESI+), 744.34481 ;
Example 54
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-Z-yOamino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclopentylacetate
Figure imgf000180_0001
Reference Compound 67 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 770.4 (M+H);
HRMS: calcd for C38H5IN5O12 HCI, 805.3301 ; found (ESI+), 770.35888;
Example 55
Prepared according to Scheme 2
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(trifluoromethyl)benzoate
Figure imgf000181_0001
Reference Compound 68 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 832.2 (M+H);
MS (ESI) m/z 416.6 (M+2H);
HRMS: calcd for C39H44F3N5O12 • HCI, 867.2705; found (ESI+), 832.30055;
Example 56
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclopropanecarboxylate
Figure imgf000181_0002
Reference Compound 69 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 728.34 (M+H);
HRMS: calcd for C35H45N5O12 • HCI, 763.2832; found (ESI+), 728.31289; Example 57
Prepared according to Scheme 2
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-δ.δa.δ.δaJJO.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl adamantane-1-carboxylate
Figure imgf000182_0001
Reference Compound 70 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 822.5 (M+H);
HRMS: calcd for C42H55N5O12 HCI, 857.3614; found (ESI+), 822.39237
Example 58
butyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl(tert-butyl)carbamate
Figure imgf000182_0002
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(butoxycarbonyl)- N-(tert-butyl)glycinate Reference Example 118 to give the product of the example.
MS (ESI) m/z 686.4 (M+H);
HRMS: calcd for C34H47N5O10 ■ HCI, 721.3090; found (ESI+), 686.34079;
Example 59
isobutyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-
1 ,8, 10a, 11 -tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2- yl]amino}-2-oxoethyl(tert-butyl)carbamate
Figure imgf000183_0001
The title compound is prepaied by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(tert-butyl)-N- (isobutoxycarbonyl)glycinate, Reference Example 119 to give the product of the example.
MS (ESI) m/z 686.3 (M+H); MS (ESI) m/z 1371.7 (2M+H);
HRMS: calcd for C34H47N5O10 ■ HCI, 721.3090; found (ESI-), 684.32433;
Example 60
methyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 , 8,1 Oa, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl(tert-butyl)carbamate
Figure imgf000184_0001
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(tert-butyl)-N- (methoxycarbonyl)glycinate Reference Example 120 to give the product of the example.
MS (ESI) m/z 644.3 (M+H); MS (ESI) m/z 322.6 (M+2H); HRMS: calcd for C31H41N5O10 ' HCI, 679.2620; found (ESI-), 642.27736;
Example 61
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl pentanoate
Figure imgf000184_0002
Reference Compound 71 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example. MS (ESI) m/z 742 (M-H);
HRMS: calcd for C36H49N5O12 • HCI, 779.3145; found (ESI+), 744.34613;
Example 62
Prepared according to Scheme Il
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-ylJamino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclobutanecarboxylate
Figure imgf000185_0001
Reference Compound 72 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 742.4 (M+H);
Example 63
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3-cyclohexylpropanoate
Figure imgf000185_0002
Reference Compound 73 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocyciine using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 796.4 (M-H);
Example 64
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10J2-dioxo-5,5a,6,6aJJ0,10aJ2-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl (4-fluorophenoxy)acetate
Figure imgf000186_0001
Reference Compound 74 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 812.4 (M+H); MS (ESI) m/z 406.7 (M+2H); HRMS: calcd for C39H46FN5Oi3 • HCI, 847.2843; found (ESI+), 812.31518;
Example 65
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a112-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclohexylacetate
Figure imgf000187_0001
Reference Compound 75 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 782.2 (M-H);
HRMS: calcd for C39H53N5O12 • HCI, 819.3458; found (ESI+), 784.37621 ;
Example 66
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,6-dimethylbenzoate
Figure imgf000187_0002
Reference Compound 76 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 790.4 (M-H);
HRMS: calcd for C40H49N5O12 • HCI, 827.3145; found (ESI+), 792.34423; Example 67
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl phenylacetate
Figure imgf000188_0001
Reference Compound 77 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 778.3 (M+H);
HRMS: calcd for C39H47N5O12 • HCI, 813.2988; found (ESI+), 778.3299;
Example 68
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl pivalate
Figure imgf000188_0002
Reference Compound 78 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example. MS (ESI) m/z 744.5 (M+H);
HRMS: calcd for C36H49N5O12 • HCI, 779.3145; found (ESI+), 744.34434;
Example 69
Prepared according to Scheme Il
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1-benzofuran-2-carboxylate
Figure imgf000189_0001
Reference Compound 79 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 804.4 (M+H); MS (ESI) m/z 402.7 (M+2H);
HRMS: calcd for C40H45N5O13 ' HCI, 839.2781 ; found (ESI+), 804.30779;
Example 70
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 -benzofuran-2-carboxylate
Figure imgf000189_0002
Reference Compound 80 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 767.4 (M+H);
HRMS: calcd for C37H46N6O12, 766.3174; found (ESI+), 767.32406;
Example 71
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 ,1'-biphenyl-4-carboxyiate
Figure imgf000190_0001
Reference Compound 81 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 838.2 (M-H); MS (ESI) m/z 113 (TFA-H); HRMS: calcd for C44H49N5O12 • HCI, 875.3145; found (ESI+), 840.34496; Example 72
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-methoxybenzoate
Figure imgf000191_0001
Reference Compound 82 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 792.3 (M-H); HRMS: calcd for C39H47N5O13 HCI, 829.2937; found (ESI+), 794.32511 ;
Example 73
Prepared according to Scheme Il ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 H-indole-2-carboxylate
Figure imgf000191_0002
Reference Compound 83 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocyciine using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 803.4 (M+H);
HRMS: calcd for C40H46N6O12 ■ HCI, 838.2941 ; found (ESI+), 803.32375;
Example 74
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8>10a,11- tetrahydroxy-10,12-0110X0-5,53,6,63,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl diphenylacetate
Figure imgf000192_0001
Reference Compound 84 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 852.4 (M-H);
HRMS: calcd for C45H5IN5O12 ' HCI, 889.3301 ; found (ESI-), 852.3463;
Example 75
Prepared according to scheme 6
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-δ.δa^.θaJJO.10a.12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl thiophene-2-carboxylate
Figure imgf000193_0001
The title compound is prepared by the procedure of Example 42, using
[(chlorocarbonyl)oxy]methyl thiophene-2-carboxylate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 655.2 (M-H); HRMS: calcd for C30H32N4OnS • HCI, 692.1555; found (ESI+), 657.18613;
Example 76
Prepared according to scheme 6 [({[(5aR,6aS,7S,10aS)-9-(aminocarbonyI)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 4-fluorobenzoate
Figure imgf000193_0002
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 4-fluorobenzoate in place of the Reference Compound 109 to give the product of the example. MS (ESI) m/z 667.2 (M-H);
HRMS: calcd for C32H33FN4Oi-I • HCI, 704.1897; found (ESI+), 669.22024;
Example 77
Prepared according to scheme 6
[({[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-010X0-5,58,6,63,7,10,10a,12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 3,5-dimethylbenzoate
Figure imgf000194_0001
The title compound is prepared by the procedure of Example 42, using
[(chlorocarbonyl)oxy]methyl 3,5-dimethylbenzoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 679.2 (M+H); HRMS: calcd for C34H38N4O11 • HCI, 714.2304; found (ESI+), 679.26076;
Example 78
Prepared according to scheme 6 [({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl pivalate
Figure imgf000195_0001
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl pivalate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 631.2 (M+H);
HRMS: calcd for C30H38N4O11 • HCI, 666.2304; found (ESI+), 631.26094;
Example 79
Prepared according to scheme 6
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-δ.δa.δ.βay.iOjiOa.12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 3,3-dimethylbutanoate
Figure imgf000195_0002
The title compound is prepared by the procedure of Example 42, using
[(chlorocarbonyl)oxy]methyl 3,3-dimethylbutanoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 643.3 (M-H); HRMS: calcd for C31H40N4O11 • HCI, 680.2460; found (ESI+), 645.27632; Example 80
Prepared according to scheme 6
[({[(5aR,6aSI7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 I8,10a,11- tetrahydroxy-10,12^0X0-5,58,6,63,7, 10,1 Os, 12-oct3hydrotetracen-2- yl]amino}carbonyl)oxy]methyl 2,2-dimethylbutanoate
Figure imgf000196_0001
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 2,2-dimethylbutanoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 645.2 (M+H);
HRMS: calcd for C3IH40N4On • HCI, 680.2460; found (ESI+), 645.27637;
Example 81
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 -naphthoate
Figure imgf000196_0002
Reference Compound 85 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 812.5 (M-H);
HRMS: calcd for C42H47N5O12 ■ HCI, 849.2988; found (ESI+), 814.33029;
Example 82
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-naphthoate
Figure imgf000197_0001
Reference Compound 86 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 812.5 (M-H);
HRMS: calcd for C42H47N5O12 • HCI, 849.2988; found (ESI+), 814.33004;
Example 83
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1-methyl-1 H-indole-3-carboxylate
Figure imgf000198_0001
Reference Compound 87 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 815.5 (M-H);
HRMS: calcd for C4IH48N6Oi2 ' HCI, 852.3097; found (ESI-), 815.32484;
Example 84
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl quinoline-2-carboxylate
Figure imgf000198_0002
Reference Compound 88 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 813.5 (M-H);
HRMS: calcd for C41H46N6O12 • HCI, 850.2941 ; found (ESI+), 815.32509; Example 85 Prepared according to scheme 6
[({[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 2-ethylbutanoate
Figure imgf000199_0001
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 2-ethylbutanoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 643.4 (M-H); MS (ESI) m/z 1287.7 (2M-H);
HRMS: calcd for C3IH40N4O11 HCI, 680.2460; found (ESI+), 645.27618;
Example 86 Prepared according to scheme 6
[({[(5aRI6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8I10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10,1 Oa112-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl cyclopentylacetate
Figure imgf000200_0001
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl cyclopentylacetate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 655.3 (M-H);
MS (ESI) m/z 1311.7 (2M-H);
HRMS: calcd for C32H40N4O11 • HCI, 692.2460; found (ESI+), 657.27572;
Example 87 Prepared according to scheme 6
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-010X0-5,58,6,63,7,10,1 Oa, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 4-tert-butylbenzoate
Figure imgf000201_0001
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 4-tert-butylbenzoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 705.1 (M-H);
MS (ESI) m/z 1410.9 (2M-H);
HRMS: calcd for C36H42N4On HCI, 742.2617; found (ESI+), 707.29336;
Example 88
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl nicotinate
Figure imgf000201_0002
Reference Compound 89 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 763.5 (M-H);
HRMS: calcd for C37H44N6O12 HCI, 800.2784; found (ESI+), 765.30896; Example 89
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl isonicotinate
Figure imgf000202_0001
Reference Compound 90 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
HRMS: calcd for C37H44N6O12 • HCI, 800.2784; found (ESI+), 765.3117;
Example 90
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,6-difluorobenzoate
Figure imgf000202_0002
Reference Compound 91 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 798.2 (M-H);
HRMS: caicd for C38H43F2N5O12 • HCI, 835.2643; found (ESI+), 800.29464; Example 91
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10J2-dioxo-5,5aA6aJJ0J0aJ2-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-fluorobenzoate
Figure imgf000203_0001
Reference Compound 92 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 780 (M-H);
HRMS: calcd for C38H44FN5O12 • HCI, 817.2737; found (ESI+), 782.30558;
Example 92
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-(trifluoromethyl)benzoate
Figure imgf000203_0002
Reference Compound 93 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycIine using the conditions of Example 42 to give the product of the Example.
HRMS: calcd for C39H44F3N5Oi2 " HCI, 867.2705; found (ESI+), 832.30026;
Example 93
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,53,6,68,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-pyrrolidin-1-ylbenzoate
Figure imgf000204_0001
Reference Compound 94 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 833.4 (M+H);
HRMS: calcd for C42H52N6O12 • HCI, 868.3410; found (ESI-), 831.3565;
Example 94
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 , 1 '-biphenyl-2-carboxylate
Figure imgf000205_0001
Reference Compound 95 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycIine using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 838.4 (M-H);
HRMS: calcd for C44H49N5O12 • HCI, 875.3145; found (ESI+), 840.34553;
Example 95
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,1 Oa111- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,4,6-trimethylbenzoate
Figure imgf000205_0002
Reference Compound 96 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 804.5 (M-H);
HRMS: calcd for C41H5-IN5O12 • HCI, 841.3301 ; found (ESI+), 806.36101 ; Example 96
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10110a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-isopropoxybenzoate
Figure imgf000206_0001
Reference Compound 97 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 820.2 (M-H);
HRMS: calcd for C41H51N5O13 ' HCI, 857.3250; found (ESI-), 820.34117;
Example 97
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,4,5-trimethoxybenzoate
Figure imgf000206_0002
Reference Compound 98 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 852.2 (M-H);
HRMS: calcd for C41H51N5O15 ' HCI, 889.3148; found (ESI+), 854.34728;
Example 98
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,5-dimethoxybenzoate
Figure imgf000207_0001
Reference Compound 99 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 822.1 (M-H);
HRMS: calcd for C40H49N5O14, 824.3349; found (ESI+), 824.3351 ;
Example 99
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl (2E)-3-phenylprop-2-enoate
Figure imgf000208_0001
Reference Compound 100 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 788.3 (M-H);
HRMS: calcd for C40H47N5O12 HCI, 825.2988; found (ESI+), 790.33068;
Example 100
({[(2-{[(5aR>6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3-methyl-1-benzofuran-2-carboxylate
Figure imgf000208_0002
Reference Compound 101 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 816.5 (M-H);
HRMS: calcd for C4-IH47N5O13 HCI, 853.2937; found (ESI+), 818.3234; Example 101
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-I O,12-dioxo-δ.δa.δ.θaJ.10.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl [3,5-bis(trifluoromethyl)phenyl]acetate
Figure imgf000209_0001
Reference Compound 102 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 912 (M-H); HRMS: calcd for C41H45F6N5O12 ■ HCI, 949.2736; found (ESI+), 914.30367;
Example 102
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(heptyloxy)benzoate
Figure imgf000209_0002
Reference Compound 103 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 876.1 (M-H);
HRMS: calcd for C45H59N5O13 ' HCI, 913.3876; found (ESI+), 878.41791 ;
Example 103
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-(2-phenylethyl)benzoate
Figure imgf000210_0001
Reference Compound 104 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 866.5 (M-H); HRMS: calcd for C46H53N5O12 ' HCI, 903.3458; found (ESI), 868.37357; Example 104
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-0110X0-5,53,6,63,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(dodecyloxy)benzoate
Figure imgf000211_0001
Reference Compound 105 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 946.7 (M-H);
HRMS: calcd for C50H69N5O13 • HCI, 983.4659; found (ESI-), 946.48106;
Example 105
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 , 8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(acetylamino)benzoate
Figure imgf000211_0002
Reference Compound 106 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 819.1 (M-H);
HRMS: calcd for C40H48N6O13 • HCI, 856.3046; found (ESI-), 819.32051 ;
Example 106 ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,ba,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl anthracene-9-carboxylate
Figure imgf000212_0001
Reference Compound 107 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 864.3 (M+H);
HRMS: calcd for C46H49N5O12 • HCI, 899.3145; found (ESI-), 862.32855;
Example 107
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-benzoylbenzoate
Figure imgf000213_0001
Reference Compound 108 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 866.3 (M-H);
HRMS: calcd for C45H49N5O13 • HCI, 903.3094; found (ESI-), 866.32405;
Example 108
(5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl 2-{[(7S, 10aR)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 ,8, 10a, 11 -tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12- octahydrotetracen-2-yl]amino}-2-oxoethyl(propyl)carbamate
Figure imgf000213_0002
To a solution of 107 mg (0.166 mmol)of N-propyl-glycylcycline (N-prop-glycyl) in DMPU (2 ml) is added 5 equivalents of sodium carbonate (95 mg, 0.9 mmol) followed by 2 equivalents of (5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate (95 mg, 0.33 mmol) Reference Compound 121 and stirring for 2 hr at room temperature. The reaction mixture is filtered through diatomaceous earth and the filtrate added to a mixture of (1 :4)(20 ml) etheπisopropyl alcohol and HCI (1 M in ether) is added and the formed solid filtered, redissolved in water, the pH adjusted to about 2 and extracted with methylene chloride to give 15 mg of the product of the Example.
MS (ESI) m/z 728.5 (M+H); MS (ESI) m/z 364.8 (M+2H); HRMS: calcd for C34H41N5O13, 727.2701 ; found (ESI+), 728.27606;
Example 109
(5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl 2-{[(7S,10aS)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino}-2-oxoethyl(butyl)carbamate
Figure imgf000214_0001
The title compound is prepared by the procedure of Example 108, using N-butyi- glycylcycline (N-bu-glycyl) and (5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate Reference Compound 121to give the product of the Example. MS (ESI) m/z 742.3 ((M+H)+);
Example 110
(2-oxo-5-phenyl-1 ,3-dioxol-4-yl)methyl 2-{[(7R,10aS)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 ,8, 10a, 11 -tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12- octahydrotetracen-2-yl]amino}-2-oxoethyl(propyl)carbamate
Figure imgf000215_0001
The title compound is prepared by the procedure of Example 108, using N-propyl- glycylcycline (N-prop-glycyl) and 4-nitrophenyl (2-oxo-5-phenyl-1 ,3-dioxol-4- yl)methyl carbonate Reference Compound 122 to give the product of the Example.
MS (ESI) m/z 790.3 ((M+H)+);
HRMS: calcd for C39H43N5O13, 789.2857; found (ESI+), 790.29243;
Example 111
[5-(4-methoxyphenyl)-2-oxo-1 ,3-dioxol-4-yl]methyl 2-{[(7S,10aS)-9-(aminocarbonyl)- 4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino}-2-oxoethyl(propyl)carbamate
Figure imgf000215_0002
The title compound is prepared by the procedure of Example 108, using N-propyl- glycylcycline (N-prop-glycyl) and [5-(4-methoxyphenyl)-2-oxo-1 ,3-dioxol-4-yl]methyl 4-nitrophenyl carbonate Reference Compound 123 to give the product of the Example.
MS (ES!) m/z 820.3 ((M+H)+);
Example 112
(2-oxo-5-phenyl-1 ,3-dioxol-4-yl)methyl 2-{[(7S,10aS)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino}-2-oxoethyl(butyl)carbamate
Figure imgf000216_0001
The title compound is prepared by the procedure of Example 108, using N-butyl- glycylcycline (N-bu-glycyl) and 4-nitrophenyl (2-oxo-5-phenyl-1 ,3-dioxol-4-yl)methyl carbonate Reference Compound 122 to give the product of the Example.
MS (ESI) m/z 804.12 (M+H); MS (ESI) m/z 402.58 (M+2H); HRMS: calcd for C40H45N5O13, 803.3014; found (ESI+), 804.30946;
Example 113
[5-(4-methoxyphenyl)-2-oxo-1 ,3-dioxol-4-yl]methyl 2-{[(7S,10aS)-9-(aminocarbonyl)- 4,7-bis(dimethylamino)-1 ,8, 10a, 11 -tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10110a, 12- octahydrotetracen-2-yl]amino}-2-oxoethyl(butyl)carbamate
Figure imgf000217_0001
The title compound is prepared by the procedure of Example 108, using N-butyl- glycylcycline (N-bu-glycyl) and [5-(4-methoxyphenyl)-2-oxo-1 ,3-dioxol-4-yl]methyl 4- nitrophenyl carbonate Reference Compound 123 to give the product of the Example.

Claims

WHAT IS CLAIMED IS:
1. A compound represented by Formula (I);
Figure imgf000218_0001
(I)
wherein:
A is a moiety
Figure imgf000218_0002
or is absent;
R1 is selected from hydrogen, -OH, amino, -NR7R8, halogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)- aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-ary! may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of
N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aryloxy, heterocyclyl and phenyl, and alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy;
R2 is selected from hydrogen, halogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3- C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, and alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy;
R3 is the moiety R9,
Figure imgf000220_0001
R4 is selected from hydrogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy, aryl of 6, 10 or 14 carbon atoms said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, N-(alkyl of 1 to 12 carbon atυms)-aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl of 7 to 13 carbon atoms optionally substituted, SR3, heteroaryl optionally substituted and heteroarylcarbonyl optionally substituted;
R5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxy!, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl, -CH2(CO)OCH2aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted, heteroaryl optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, alkynyl of 2 to 12 carbon atoms optionally substituted, cycloalkyl 3 to 6 ring atoms, aryl-CH=CH-, cycloalkyl-alkyl; and adamantly;
R6 is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N- cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, and cycloalkyl of 3 to 6 carbon atoms;
R7 and R8 are each independently H or alkyl of 1 to 12 carbon atoms or R7 and R8 when optionally taken together with the nitrogen atom to which each is attached form a 3 to 8 membered heterocyclyl ring;
R9 is aralkyl of 7 to 16 carbon atoms optionally substituted or alkyl of 1 to 12 carbon atoms;
R-io is H or alkyl of 1 to 12 carbon atoms;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R1 is -NR7R8 , R7 is hydrogen, R8 is methyl, ethyl, n-propyl, n-butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl or 1 ,1- dimethylethyl or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 , wherein R1 is -NR7R8, R7 is methyl or ethyl, R8 is methyl, ethyl, n-propyl, 1-methylethyl, n-propyl, 1-methylpropyl, or 2-methylpropyl or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 , wherein R1 is -NR7R8 , R7 and R8 are taken together with the nitrogen atom to which each is attached form a 3 to 8 membered heterocyclyl ring or a pharmaceutically acceptable salt thereof.
5. A compound according to any one of claims 1 to 5, wherein R2 is H or a pharmaceutically acceptable salt thereof.
6. A compound according to any one of claims 1 to 5, wherein A is a moiety
Figure imgf000223_0001
or a pharmaceutically acceptable salt thereof.
7. A compound according to any one of claims 1 to 5, wherein A is absent or a pharmaceutically acceptable salt thereof.
8. A compound according to any one of claims 1 to 7, wherein R3 is a moiety
Figure imgf000223_0002
or a pharmaceutically acceptable salt thereof.
9. A compound according to any one of claims 1 to 7, wherein R3 is a moiety
Figure imgf000223_0003
or a pharmaceutically acceptable salt thereof.
10. A compound according to any one of claims 1 to 7, wherein R3 is a moiety
Figure imgf000224_0001
and R6 and R-J0 are H or a pharmaceutically acceptable salt thereof.
11. A compound according to any one of claims 1 to 7, wherein R3 is a moiety
Figure imgf000224_0002
and R6 and R10 are H or a pharmaceutically acceptable salt thereof.
12. A compound according to any one of claims 1 to 7, wherein R3 is Rg or a pharmaceutically acceptable salt thereof.
13. A compound according to claim 1 , wherein A is the moiety,
Figure imgf000224_0003
R3 is the moiety
Figure imgf000225_0001
R5 is aryl of 6 carbon atoms or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 1 , wherein A is the moiety
Figure imgf000225_0002
R3 is the moiety
Figure imgf000225_0003
R4 is 1 ,1-dimethylethyl and
R5 is aryl of 6 carbon atoms or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 1 , wherein A is a moiety
Figure imgf000226_0001
R1 is -NR7R8;
R2 is hydrogen; R3 is the moiety
Figure imgf000226_0002
R4 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, and aryloxy wherein said aryl and aryloxy is optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl;
R5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, and aryloxy wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)-, CH3-C(O)-NH-, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl, -CH2(CO)OCH2aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl, heteroaryl optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, cycloalkyl 3 to 6 ring atoms, aryl-CH=CH-, cycloalkyl-alkyl; and adamantyl;
R6 is hydrogen;
R7 and R8 are each independently H or alkyl of 1 to 12 carbon atoms;
Rg is aralkyl of 7 to 16 carbon atoms optionally substituted or alkyl of 1 to 12 carbon atoms;
or a pharmaceutically acceptable salt thereof.
16. A compound according to claim 1 , selected from the group or pharmaceutically acceptable salts thereof
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 2-methylpropanoate, ({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8)10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yi]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 4-methoxybenzoate,
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 4-methylbenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-S.Sa.e.θaJ.10.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 4-fluorobenzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a, 11- tetrahydroxy-10,12-dioxo-S.δa.δ.δaJ.10JOa.12-octahydrotetracen-2-yllamino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-methylbenzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,1 Oa, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-methoxybenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-ylJamino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl cyclobutanecarboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-fluorobenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl pivalate, ({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 2-methylpropanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dinnethylamino)-1 ,8,10a,11- tetrahydroxy-10, 12-dioxo~5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl phenylacetate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl phenylacetate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl pivalate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl heptanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl cyclobutanecarboxylate,
({[(2-{[(5aRI6aS,7S,10aS)-9- (aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl heptanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamJno)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 4-tert-butylbenzoate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyi)amino]carbonyl}oxy)methyl 1 ,1'-biphenyl-4-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 3,5-dimethylbenzoate,
(^-{[(SaR.eaSJS.10aS^Θ-Caminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10, ^-dioxo-δ.Sa.θ.δaJ.10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 1 ,1'-biphenyl-4-carboxylate,
({[(2-{[(53R,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetr3hydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]3mino}-2- oxoethyl)(propyl)3mino]carbonyl}oxy)methyl 3,5-dimethylbenzoate,
({[(2-{[(53R,6aS,7S, lOaSJ-θ-Caminocarbonyl)-4,7-bis(dimethylamino^i , 8,103,11 - tetrahydroxy-10,12-dioxo-5,5a,6,63,7,10,10a,12-octahydrotetr3cen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 4-tert-butylbenzoate,
1 -({[(2-{[(7S, 10aS^g-Caminocarbonyl)-4,7-bis(dimethylannino)-! ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,63,7,10,103,12-oct3hydrotetr3cen-2-yl]amino}-2- oxoethyl)(butyl)3mino]c3rbonyl}oxy)ethyl scetste,
({[(2-{[(7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethy[3mino)-1 ,8,10a,11-tetrahydroxy- 10,12-dioxo-5,5a,6,6a,7,10, 10a, 12-oct3hydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)3mino]c3rbonyl}oxy)methyl cyclohexsnecsrboxylste,
({[(2-{[(7S,1 θ3S)-9-(aminocarbonyl)-4,7-bis(dimethyl3mino)-1 ,8, 103,11 -tetrahydroxy- 10,12-dioxo-5, 5s, 6,63,7, 10, 10a, 12-octahydrotetr3cen-2-yl]amino}-2- oxoethyl)(butyl)amino]c3rbonyl}oxy)methyl cyclohexsnecarboxylate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 3,3-dimethylbutanoate,
({[(2-{[(5aRI6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 I8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 3,3-dimethylbutanoate,
({[(2-{[(5aR,6aSI7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylannino)-1 ,8,10a>11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methy! 2,2-dimethylbutanoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl cyclopentylacetate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yllamino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl adamantane-1-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl cyclopentylacetate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl adamantane-1-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,3-dimethylbutanoate, ({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-0110X0-5,53,6,63,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-tert-butylbenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,2-dimethylbutanoate,
({^-{[(SaR.esSJS.10sSJ-θ^aminocsrbonyl)-4,7-bis(dimethylaminoJ-I .S.10a.i i- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-methylpropanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,63,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclopentanecarboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-methylbenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl heptanoate, and
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-methoxybenzoate.
17. A compound according to claim 1 selected from the group
benzyl 2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylarnino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl(propyl)carbamate, ethyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 , 8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl(propyl)carbamate, and
isobutyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)- i .δ.iOa.H-tetrahydroxy-10.IZ-dioxo-δ.Sa.e.eaJ.10.10a.12-octahydrotetracen-2- yl]amino}-2-oxoethyl(propyl)carbamate, or pharmaceutically acceptable salts thereof.
18. A compound according to claim 1 selected from the group
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,58,6,63,7, 10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl thiophene-2-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl thiophene-2-carboxylate,
({^-{[(SaR.eaSJS.10aS^Θ-CaminocarbonylHy-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl thiophene-3-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl thiophene-3-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(butyl)amino]carbonyl}oxy)methyl 2-furoate, and ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10^-dioxo-S.δa.θ.θay.iO.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(propyl)amino]carbonyl}oxy)methyl 2-furoate,
or pharmaceutically acceptable salts thereof.
19. A compound according to claim 1 selected from the group
({[(2-{[(5aR,6aS,7SI10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8I10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl propionate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclohexanecarboxylate,
({[(2-{[(5aR)6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 I8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,5-dimethylbenzoate,
({^{[(δaR.βaSJS.10aSJ-θ^aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-fluorobenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3-methylbutanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclopentylacetate, ({[(2-{[(5aRI6aSI7S,10aS)-9-(aminocarbonyl)-4f7-bis(dimethylamino)-1, 8,1 Oa1H- tetrahydroxy-10,12-dioxo-5, 5a, 6, 6a, 7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(trifluoromethyl)benzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10, 12^10X0-5,53,6,68,7,10110a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl cyclopropanecarboxylate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dinnΘthylannino)-1 ,8,1 Oa, 11 - tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl adamantane-1-carboxylate,
butyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,1 Oa, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl(tert-butyl)carbamate,
isobutyl 2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)- 1 ,8, 10a, 11 -tetrahydroxy-10,12-dioxo-5,5a, 6,6a, 7, 10, 10a, 12-octahydrotetracen-2- yl]amino}-2-oxoethyl(tert-butyl)carbamate,
methyl 2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,58,6,63,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl(tert-butyl)carbamate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl pentanoate,
({^-{[(δaR.eaSJS.10aSJ-θ^aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-buty!)amino]carbonyl}oxy)methyl cyclobutanecarboxylate, ({[(2-{[(5aR,6aS,7SI10aS)-9-(aminocarbonyl)-4,7-bis(climethylamino)-1 ,8,1 Oa111 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3-cyclohexylpropanoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,1Oa1H- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl (4-fluorophenoxy)acetate,
({[(2-{[(5aR,6aS)7S,10aS)-9-(aminocarbonyl)-4)7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]c3rbonyl}oxy)methyl cyclohexylacetate,
({[(2-{[(53R,63S,7S,1θ3S)-9-(3minocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrshydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,6-dimethylbenzo3te,
({[(2-{[(5aR,6aS,7S,103S)-9-(3minoc3rbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrshydroxy-I O,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl phenylacetate,
({[(2-{[(53R,63S,7S,103S)-9-(3minoc3rbonyl)-4,7-bis(dimethyl3mino)-1 , 8,103,11 - tetr3hydroxy-10,12-dioxo-5,53,6,63,7,10,103,12-oct3hydrotetr3cen-2-yl]3mino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl pivalate,
({[(2-{[(53R,63S,7S, 103S)-9-(3minocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrshydroxy-10,12-dioxo-5, 5a, 6, 63,7, 10,103,12-oct3hydrotetr3cen-2-yl]3mino}-2- oxoethyl)(tert-butyl)3mino]c3rbonyl}oxy)methyl 1 , 1 '-biphenyl-4-c3rboxyl3te,
({[(2-{[(53R,63S,7S, 1θ3S)-9-(3minoc3rbonyl)-4,7-bis(dimethylamino)-1 , 8, 103,11- tetr3hydroxy-10,12-dioxo-5,53,6,63,7,10,10a,12-octahydrotetr3cen-2-yl]3mino}-2- oxoethyl)(tert-butyl)3mino]c3rbonyl}oxy)methyl 1 -naphthoate, ({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-naphthoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methy! 2,6-difluorobenzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-fluorobenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-(trifluoromethyl)benzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 ,1'-biphenyl-2-carboxylate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2,4,6-trimethylbenzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10, 12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-isopropoxybenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethy[amino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5, 5a, 6, 6a, 7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,4,5-trimethoxybenzoate, ({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3,5-dimethoxybenzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-I O,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yllamino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl (2E)-3-phenylprop-2-enoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl [3,5- bis(trifluoromethyl)phenyl]acetate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(heptyloxy)benzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 2-(2-phenylethyl)benzoate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(dodecyloxy)benzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-(acetylamino)benzoate,
({[(2-{[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylaπnino)-1 ,8, 10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl anthracene-9-carboxylate, ({C(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-benzoylbenzoate, and
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]c?.i"bonyl}oxy)methyl diphenylacetate.
20. A compound according to claim 1 selected from the group
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-δ.δa.θ.δaJ.10.10a.12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 4-fluorobenzoate,
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5, 58,6,68,7,10,1 Oa, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 3,5-dimethylbenzoate,
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl pivalate,
[({[(5aR,6aS,7S, 10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8, 10a, 11 - tetrahydroxy-10,12-dioxo-S.δa.δ.eaJ.10.10a.12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 3,3-dimethylbutanoate,
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-I Oj^-dioxo-δ.δa.β.δay.iO.10a.12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 2,2-dimethylbutanoate,
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 2-ethylbutanoate, [({[(5aR,6aS,7S,10aS)-9-(anninocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12^0X0-5,58,6,63,7, 10,1 Oa, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl thiophene-2-carboxylate,
[({[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,Z, 10, 10a, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl cyclopentylacetate, and
[({[(5aRI6aS,ZS,10aS)-9-(aminocarbonyl)-4,Z-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2- yl]amino}carbonyl)oxy]methyl 4-tert-butylbenzoate or pharmaceutically acceptable salts thereof.
21. A compound according to claim 1 selected from the group
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,53,6,63,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 H-indole-2-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl nicotinate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl isonicotinate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 , 8,10a, 11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 4-pyrrolidin-1 -ylbenzoate, (^-{[(δaR.eaS.TS.10aSJ-θ-Caminocarbonyl)-4,7-bis(dimethylaminoVi .δ.iOa.i i- tetrahydroxy-10,12-dioxo-S.Sa.θ.δaJ.I O.10a.12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 3-methyl-1-benzofuran-2-carboxylate,
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1 -methyl-1 H-indole-3-carboxylate,
(^-{[(δaR.eaS.ZS.I OaSJ-θ^aminocarbonylH.y-bis(dimethylamlnoϊ-i .β.iOa.H- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a112-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl quinoline-2-carboxylate,
({[(2-{[(δaR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl 1-benzofuran-2-carboxylate, and
({[(2-{[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethy!amino)-1 ,8,10a,11- tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]amino}-2- oxoethyl)(tert-butyl)amino]carbonyl}oxy)methyl-1 -methyl-1 H-pyrrole-2- carboxylate or pharmaceutically acceptable salts thereof.
22. A compound according to claim 1 selected from the group
(δ-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl 2-{[(7S,10aR)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 , 8, 10a, 11 -tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,1 Oa, 12- octahydrotetracen-2-yl]amino}-2-oxoethyl(propyl)carbamate,
(5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl 2-{[(7S, 10aS)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 ,8, 10a, 11 -tetrahydroxy-10,12-dioxo-5,5a,6,6a,7, 10, 10a, 12- octahydrotetracen-2-yl]amino}-2-oxoethyl(butyl)carbamate, (2-oxo-5-phenyl-1 ,3-dioxol-4-yl)methyl 2-{[(7R,10aS)-9-(aminocarbonyl)-4,7- bis(dimethy!amino)-1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino^-oxoethyKpropyOcarbamate,
[5-(4-methoxyphenyl)-2-oxo-1 , 3-d ioxol-4-yl] methyl 2-{[(7S,10aS)-9-(aminocarbonyl)- 4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino}-2-oxoethyl(propyl)carbamate,
(2-oxo-5-phenyl-1 ,3-dioxol-4-yl)methyl 2-{[(7S,10aS)-9-(aminocarbonyl)-4,7- bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino}-2-oxoethyl(butyl)carbamate and
[5-(4-methoxyphenyl)-2-oxo-1 ,3-dioxol-4-yl]methyl 2-{[(7S,10aS)-9-(aminocarbonyl)- 4,7-bis(dimethylamino)-1 ,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12- octahydrotetracen-2-yl]amino}-2-oxoethyl(butyl)carbamate
or pharmaceutically acceptable salts thereof.
23. A pharmaceutical composition comprising a compound according to anyone of claims 1 to 22, in association with a pharmaceutically acceptable carrier.
24. A method for the prevention, treatment or control of bacterial infections in warm-blooded animals which comprises providing to said warm-blooded animals an antibacterially effective amount of a compound according to anyone of claims 1 to 22, or a pharmaceutically acceptable salt thereof.
25. Use of a compound according to any one of claims 1 to 22 for the preparation of a medicament for the treatment of bacterial infections.
26. A compound according to Formula (II):
Figure imgf000243_0001
wherein R4, R5, R6, and R10 are as defined in claim 1 , and
Q iS -OR11, Cl, Br, or I;
R11 is H, benzyl optionally substituted with nitro or a moiety of the formula
Figure imgf000243_0002
and R12 is alkyl of 1 to 6 carbon atoms.
27. A compound according to claim 26 wherein R4 is t-butyl, R5 is alkyl of 1 to 6 carbon atoms, and R11 is benzyl optionally substituted with nitro.
28. A compound according to claim 26 wherein R4 is alkyl of 1 to 6 carbon atoms, R5 is phenyl optionally substituted and R11 is benzyl optionally substituted with nitro.
29. A compound according to claim 26 wherein R5 is alkyl of 1 to 6 carbon atoms, R4 is t-butyl and Ri1 is H.
30. A compound according to claim 26 wherein R5 is alkyl of 1 to 6 carbon atoms, R4 is t-butyl, Q is
Figure imgf000244_0001
and R12 is alkyl of 1 to 6 carbon atoms.
31. A compound according to anyone of claims 26 to 30 wherein R6 and Ri0 are H.
32. A compound according to claim 26 selected from the group
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4-tert- butylbenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2,2- dimethylbutanoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2- methylpropanoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl cyclopentanecarboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4-methylbenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl heptanoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl propionate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl cyclohexanecarboxylate, ({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 3,5- dimethylbenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4-fluorobenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 3- methylbutanoate,
benzyl N-(tert-butyl)-N-({[(cyclopentylacetyl)oxy]methoxy}carbonyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- (trifluoromethyl)benzoate,
({[[2-(benzyloxy)-2-oxoethyl3(tert-butyl)amino]carbonyl}oxy)methyl cyclopropanecarboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl adamantane-1- carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl pentanoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl cyclobutanecarboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 3- cyclohexyipropanoate,
benzyl N-(tert-butyl)-N-[({[(4-fluorophenoxy)acetyl]oxy}methoxy)carbonyl]glycinate,
benzyl N-(tert-butyl)-N-({[(cyclohexylacetyl)oxy]methoxy}carbonyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2,6- dimethylbenzoate, benzyl N-(tert-butyl)-N-({[(phenylacetyl)oxy]methoxy}carbonyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl pivalate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1-benzofuran-2- carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1 -methyl-1 H- pyrrole-2-carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1 ,T-biphenyl-4- carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- methoxybenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1 H-indole-2- carboxylate,
benzyl N-(tert-butyl)-N-({[(diphenylacetyl)oxy]methoxy}carbonyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1-naphthoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2-naphthoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1 -methyl-1 H- indole-3-carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl quinoline-2- carboxylate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl nicotinate, ({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl isonicotinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2,6- difiuorobenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2-fluorobenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2- (trifluoromethyl)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4-(1 H-pyrrol-1 - yl)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 1 , 1 '-biphenyl-2- carboxylate,
({[[2-(benzyIoxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2,4,6- trimethyibenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- isopropoxybenzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 3,4,5- trimethoxybenzoate,
({[[2-(benzyloxy)-2-oxoethy!}(tert-butyl)amino3carbonyl}oxy)methyl 3,5- dimethoxybenzoate,
3-phenyl-acrylic acid (benzyloxycarbonylmethyl-tert-butyl-carbamoyloxy)-methyl ester, ({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 3-methyl-1- benzofuran-2-carboxylate,
benzyl N-{[({[3,5-bis(trifluoromethyl)phenyl]acetyl}oxy)methoxy]carbonyl}-N-(tert- butyl)glycinate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- (heptyloxy)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 2-(2- phenylethyl)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- (dodecyloxy)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- (acetylamino)benzoate,
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl anthracene-9- carboxylate and
({[[2-(benzyloxy)-2-oxoethyl](tert-butyl)amino]carbonyl}oxy)methyl 4- benzoylbenzoate.
33. A compound according to claim 26 selected from the group:
N-(tert-butyl)-N-({[(4-tert-butylbenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-{[(isobutyryloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-({[(cyclopentylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(4-methylbenzoyl)oxy]methoxy}carbonyl)glycine, N-(tert-butyl)-N-{[(heptanoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-{[(propionyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-({[(cyclohexylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(3,5-dimethylbenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(4-fluorobenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(3-methylbutanoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(cyclopentylacetyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-[({[4-(trifluoromethyl)benzoyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-({[(cyclopropylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-({[(1-adamantylcarbonyl)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine,
N-(tert-butyl)-N-{[(pentanoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-({[(cyclobutylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(3-cyclohexylpropanoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(cyclohexylacetyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(2,6-dimethyibenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(phenylacetyl)oxy]methoxy}carbonyl)glycine, N-(tert-butyl)-N-({[(2,2-dimethylpropanoyl)oxy]methoxy}carbonyl)glycine,
N-({[(1-benzofuran-2-ylcarbonyl)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine,
N-(tert-butyl)-N-[({[(1-methy!-1H-pyrrol-2-yl)carbonyl]oxy}methoxy)carbonyl]glycine,
N-({[(1,1'-biphenyl-4-ylcarbonyl)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine,
N-(tert-butyl)-N-({[(4-methoxybenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(1 H-indol-2-ylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(diphenylacetyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-{[(1-naphthoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-{[(2-naphthoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-[({[(1 -methyl-1 H-indol-3-yl)carbonyl]oxy}methoxy)carbonyi]glycine,
N-(tert-butyl)-N-({[(quinolin-2-ylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(pyridin-3-ylcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-{[(isonicotinoyloxy)methoxy]carbonyl}glycine,
N-(tert-butyl)-N-({[(2,6-difluorobenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(2-fluorobenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-[({[2-(trifluoromethyl)benzoyl]oxy}methoxy)carbonyl]glycine, N-(tert-butyl)-N-({[(4-pyrrolidin-1-ylbenzoyl)oxy]methoxy}carbonyl)glycine,
N-({[(1 ,1'-biphenyl-2-ylcarbonyl)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine,
N-(tert-butyl)-N-({[(mesityIcarbonyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(4-isopropoxybenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(3,4,5-trimethoxybenzoyl)oxy]nnethoxy}carbonyl)glycine,
N-(tert-butyl)-N-({[(3,5-dimethoxybenzoyl)oxy]methoxy}carbonyl)glycine,
N-(tert-butyl)-N-[({[(2E)-3-phenylprop-2-enoyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-[({[(3-methyl-1-benzofuran-2- yl)carbonyl]oxy}methoxy)carbonyl]glycine,
N-{[({[3,5-bis(trifluoromethyl)phenyl]acetyl}oxy)methoxy]carbonyl}-N-(tert- butyl)glycine,
N-(tert-butyl)-N-[({[4-(heptyloxy)benzoyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-[({[2-(2-phenylethyl)benzoyl]oxy}methoxy)carbonyl]glycine,
N-(tert-butyl)-N-[({[4-(dodecyloxy)benzoyl]oxy}methoxy)carbonyl]glycine,
N-[({[4-(acetylamino)benzoyl]oxy}methoxy)carbonyl]-N-(tert-butyl)glycine,
N-({[(9-anthrylcarbonyl)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine and
N-({[(4-benzoylbenzoyl)oxy]methoxy}carbonyl)-N-(tert-butyl)glycine.
34. A compound according to claim 26 which is 3,3-Dimethyl-butyric acid [tert-butyl-(2-isobutoxycarbonyloxy-2-oxo-ethyl)- carbamoyloxy)-methyl ester.
35. A method for the preparation of compounds represented by Formula (I);
Figure imgf000252_0001
(I)
wherein:
R3O - A - CO- represents
Figure imgf000252_0002
and R1, R2, R4, R5, R6, and R-|Oare as defined in claim 1
or a pharmaceutically acceptable salt thereof comprising the step of:
a. reacting an activated acyloxycarbamate intermediate of the formula
Figure imgf000252_0003
where R4, R5, R6, and Ri0 are as defined in claim 1 and Ri2 is as defined in claim 26 with a Z.δ-disubstituted-θ-aminotetracycline of the formula
Figure imgf000253_0001
where R1, and R2 are as defined in claim 1 in the presence of 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone and triethylamine to afford a compound of Formula (I) and, if desired, b. converting the compound of Formula (I) into a pharmaceutically acceptable salt thereof.
36. A method for the preparation of compounds represented by Formula (I);
Figure imgf000253_0002
(I)
wherein:
R3O - A - CO- represents
Figure imgf000253_0003
and R1, R2, R4, Rs, Rε, and R10 are as defined in claim 1or a pharmaceutically acceptable salt thereof comprising:
reacting an amine of the formula
Figure imgf000254_0001
wherein R1, R2, R4, Rs, Re, and R10 are as defined in claim 1 with a chloro intermediate of the formula
R5γo>coγcι 0 R RIO0 in the presence of an alkali metal carbonate, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone and acetonitrile to afford a compound of the formula
Figure imgf000254_0002
or a pharmaceutically acceptable salt thereof and, if desired, converting the compound of Formula (I) into a pharmaceutically acceptable salt thereof.
37. A method for the preparation of compounds represented by Formula (I);
Figure imgf000254_0003
(I) wherein:
R3O - A - CO- represents
Figure imgf000255_0001
and R1, R2, R4, R5, Re, and R10 are as defined in claim 1or a pharmaceutically acceptable salt thereof comprising the step of:
reacting a compound of the formula
Figure imgf000255_0002
wherein R-i, R2, and R4 are as defined in claim 1 with a chloro intermediate of the formula
Figure imgf000255_0003
wherein R5 is as defined in claim 1 in the presence of an alkali metal carbonate, and 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone in acetonithle to give a compound of Formula I
Figure imgf000255_0004
and, if desired, converting the compound of Formula (I) into a pharmaceutically acceptable salt thereof.
38. A method for the preparation of a compound represented by Formula (I);
Figure imgf000256_0001
(I)
wherein:
R3O - A - CO- represents
Figure imgf000256_0002
and R1, R2, R5, R6, and R10 are as defined in claim 1 or a pharmaceutically acceptable salt thereof comprising the step of:
reacting a 7,8-disubstituted-9-aminotetracycline of the formula
Figure imgf000256_0003
with a chloro intermediate of the formula
Rδ γ°>τoγcι o /\ o
R, R 10 where R1, R2, R5, R6, and R10 are as defined in claim 1 in the presence of triethylamine and 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)~ pyrimidinone to afford a compound of the formula
Figure imgf000257_0001
or a pharmaceutically acceptable salt thereof and, if desired, converting the compound of Formula (I) into a pharmaceutically acceptable salt thereof.
39. A method for the preparation of a compound represented by Formula (I);
Figure imgf000257_0002
(I)
wherein:
A, R1, R2, and R3 are as defined in claim 1 or a pharmaceutically acceptable salt thereof comprising :
reacting a carboxylic acid of the formula
Figure imgf000257_0003
where A, and R3 are as defined above with a chloroformate CICO2R12 where Ri2 is alkyl of 1 to 6 carbon atoms in the presence of 1 ,8-bis(dimethylamino)naphthalene in methylene chloride to give a mixed anhydride of the formula
Figure imgf000258_0001
Mixed anhydride
and reacting said mixed anhydride with a Z.δ-disubstituted-θ-aminotetracycline of the formula
Figure imgf000258_0002
where R1, and R2 are as defined above in the presence of triethylamine and 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone to afford a compound of Formula (I)
Figure imgf000258_0003
(i)
or a pharmaceutically acceptable salt thereof and, if desired, converting the compound of Formula (I) into a pharmaceutically acceptable salt thereof.
PCT/US2006/033516 2005-08-31 2006-08-29 9-aminocarbonylsubstituted derivatives of glycylcyclines WO2007027599A1 (en)

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AU2006285043A AU2006285043A1 (en) 2005-08-31 2006-08-29 9-aminocarbonylsubstituted derivatives of glycylcyclines
BRPI0615300-3A BRPI0615300A2 (en) 2005-08-31 2006-08-29 compound; pharmaceutical composition; method for the preparation, treatment or control of bacterial infections in warm-blooded animals; use of a compound; and method for preparing compounds represented by formula (i)
CA002620600A CA2620600A1 (en) 2005-08-31 2006-08-29 9-aminocarbonylsubstituted derivatives of glycylcyclines
IL189796A IL189796A0 (en) 2005-08-31 2008-02-26 9-aminocarbonylsubstituted derivatives of glycylcyclines
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010008886A2 (en) * 2008-06-24 2010-01-21 Teva Pharmaceutical Industries Ltd. Processes for preparing prodrugs of gabapentin and intermediates thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1393350B1 (en) * 2009-03-16 2012-04-20 Antibioticos Spa TIGECYCLINE PREPARATION PROCESS
KR101156666B1 (en) * 2010-09-17 2012-06-15 대한민국(농촌진흥청장) Novel compound and Antibiotic Composition comprising the same
CN109507309A (en) * 2018-10-22 2019-03-22 重庆中邦科技有限公司 The gas chromatography analysis method of triethylamine and isopropanol in recycling design

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5442059A (en) * 1992-08-13 1995-08-15 American Cyanamid Company 9-[(substituted glycyl)amido)]-6-demethyl-6-deoxytetracyclines
US5494903A (en) * 1991-10-04 1996-02-27 American Cyanamid Company 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
US5607691A (en) * 1992-06-12 1997-03-04 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
US5639742A (en) * 1993-04-02 1997-06-17 Lee; Ving Jick 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines
WO2001074761A1 (en) * 2000-03-31 2001-10-11 Trustees Of Tufts College 7-and 9-carbamate, urea, thiourea, thiocarbamate, and heteroaryl-amino substituted tetracycline compounds
WO2002072031A2 (en) * 2001-03-14 2002-09-19 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds as synergistic antifungal agents

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2482055A (en) * 1948-02-11 1949-09-13 American Cyanamid Co Aureomycin and preparation of same
US3007965A (en) * 1959-02-13 1961-11-07 American Cyanamid Co New tetracyclines produced by streptomyces aureofaciens
US3043875A (en) * 1959-10-22 1962-07-10 Pfizer & Co C Halogenated tetracycline derivatives and processes for their preparation
FR1430859A (en) * 1960-05-23 1966-05-25
US3338963A (en) * 1960-10-28 1967-08-29 American Cyanamid Co Tetracycline compounds
US3148212A (en) * 1961-12-22 1964-09-08 American Cyanamid Co Reductive alkylation process
US3360557A (en) * 1963-05-10 1967-12-26 American Cyanamid Co 9-hydroxytetracyclines and a process of preparing same
USRE26253E (en) * 1963-05-17 1967-08-15 And z-alkylamino-g-deoxytetracycline
US3341585A (en) * 1966-05-06 1967-09-12 American Cyanamid Co Substituted 7-and/or 9-amino-6-deoxytetracyclines
US3360561A (en) * 1967-06-19 1967-12-26 American Cyanamid Co Nitration of tetracyclines
US3518306A (en) * 1968-02-19 1970-06-30 American Cyanamid Co 7- and/or 9-(n-nitrosoalkylamino)-6-demethyl-6-deoxytetracyclines
US4806529A (en) * 1982-11-18 1989-02-21 Trustees Of Tufts College, Tufts University Tetracycline activity enhancement
ATE211128T1 (en) * 1991-10-04 2002-01-15 American Cyanamid Co 7-SUBSTITUTED-9-SUBSTITUTED AMINO-6-DEMETHYL-6-DEOXY-TETRACYCLINE
NZ508493A (en) * 1998-05-01 2002-06-28 Kyoto Pharma Ind Carbapenem derivatives, utilization thereof and intermediate compounds of the same
WO2002100347A2 (en) * 2001-06-11 2002-12-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
WO2004064728A2 (en) * 2003-01-16 2004-08-05 Paratek Pharmaceuticals, Inc. Use of specific tetracycline compounds in therapy
MXPA05013915A (en) * 2003-06-17 2006-07-03 Vicuron Pharm Inc Novel lincomycin derivatives possessing antimicrobial activity.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5494903A (en) * 1991-10-04 1996-02-27 American Cyanamid Company 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
US5607691A (en) * 1992-06-12 1997-03-04 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
US5442059A (en) * 1992-08-13 1995-08-15 American Cyanamid Company 9-[(substituted glycyl)amido)]-6-demethyl-6-deoxytetracyclines
US5639742A (en) * 1993-04-02 1997-06-17 Lee; Ving Jick 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines
WO2001074761A1 (en) * 2000-03-31 2001-10-11 Trustees Of Tufts College 7-and 9-carbamate, urea, thiourea, thiocarbamate, and heteroaryl-amino substituted tetracycline compounds
WO2002072031A2 (en) * 2001-03-14 2002-09-19 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds as synergistic antifungal agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
P.-E SUM ET AL: "Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines", JOURNAL OF MEDICINAL CHEMISTRY., vol. 37, no. 1, 1994, USAMERICAN CHEMICAL SOCIETY. WASHINGTON., pages 184 - 188, XP002417786 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010008886A2 (en) * 2008-06-24 2010-01-21 Teva Pharmaceutical Industries Ltd. Processes for preparing prodrugs of gabapentin and intermediates thereof
WO2010008886A3 (en) * 2008-06-24 2010-04-15 Teva Pharmaceutical Industries Ltd. Processes for preparing prodrugs of gabapentin and intermediates thereof

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