Patent Grant
8933012
This application is a U.S. national stage of International Application No. PCT/JP2007/060673 filed May 25, 2007.
The invention relates to a glycopeptide antibiotic derivative and a pharmaceutical formulation comprising such derivative.
The claimed invention was made by or on behalf of the parties to a joint research agreement, within the meaning of 35 U.S.C. § 100(h) and 37 C.F.R § 1.9(e), which was in effect on or before the date the claimed invention was made, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement. The parties of the joint research agreement are (1) “National University Corporation Nagoya University” of Aichi, Japan, and (2) “Shionogi & Co., Ltd.” of Osaka, Japan.
Glycopeptide antibiotics, which have a complex polycyclic peptide structure, are produced in various microorganism and effective to most gram-positive bacteria as an antimicrobial. In recent years, there are emergences of drug-resistant strains such as penicillin-resistant, cephalosporin-resistant, and serious problems of infections with multidrug resistant and methicillin-resistant Staphylococcus aureus (MRSA) has been raised in clinical practice. Glycopeptide antibiotics, such as vancomycin, are effective typically to these resistant strains, and vancomycin has been a drug as an ultimate tool for infections with MRSA and other resistant strains.
In certain strains, however, there is growing concern of emergence of resistance to vancomycin, such as vancomycin-resistant enterococci (VRE). VRE has a different mechanism and degree of resistance, depending on the gene type of a resistance-related gene such as Van A, B, C, D, E, G. For example, teicoplanin, which is a glycopeptide antibiotic as with vancomycin, is effective to Van B type VRE. On the other hand, effective glycopeptide antibiotic has not been released for Van A type VRE, while clinical measures to fight such resistant strain is especially needed. Furthermore, Staphylococcus aureus that has acquired the resistance of VRE (VRSA) has been discovered recently. Therefore, need for development of glycopeptide derivative having improved activity and/or selectivity exists. Many vancomycins and other glycopeptide derivatives have been known in the art. See, e.g., references as follows.
The invention relates to a novel glycopeptide antibiotic derivative that has an increased and improved property compared with that of conventional glycopeptide antibiotics. Certain glycopeptide derivatives of the invention, particularly vancomycin derivatives, show an increased antimicrobial activity compared with vancomycin itself.
The invention provides:
or a pharmaceutically acceptable salt or solvate thereof,
wherein
wherein R3 is alkylene; and
The present invention also relates to a pharmaceutical composition comprising the compound of the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, preferably an antimicrobial drug.
The glycopeptide antibiotic derivative of the invention, a pharmaceutically acceptable salt, or solvate thereof shows an antimicrobial activity against various microorganisms such as staphylococcus including MRSA, streptococcus, pneumococcus and enterococcus. The compound is also effective against vancomycin-resistant strains thereof, particularly vancomycin-resistant enterococcus (VRE) and vancomycin-resistant staphylococcus aureus (VRSA). Thus, the compound is useful in the treatment or prevention of various bacterial infectious diseases such as meningitis, sepsis, pneumonia, arthritis, peritonitis, bronchitis, empyema and the like. The more preferred compound of the invention is highly water-soluble and shows good pharmacokinetics and/or is safe with respect to toxicity.
In order to describe the compound of the invention, the terms as used herein have the following meaning solely or in combination with other terms as used herein.
The term “lower alkyl” refers to a saturated straight or branched hydrocarbon mono radical having 1 to 6 carbons, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, N-hexyl, isohexyl.
The term “linking group” in the definition for X1, X2 and X3 refers to a linking group that comprises a hetero atom selected from the group consisting of —N═, ═N—, —NR1— (wherein R1 is hydrogen or lower alkyl), —O—, —S—, —SO— and —SO2— selected from the group, and includes for example —S—S—, —NR1CO—, —NR1O—, —NR1S—, —OSO2—, —OCO—, —SO2NR1—, etc.
The term “alkylene” refers to a saturated straight or branched hydrocarbon diradical having 1 to 6 carbons, and includes for example methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene or hexamethylene, etc. A saturated straight or branched alkylene having one to four carbon atoms, such as methylene, ethylene, trimethylene or tetramethylene is preferred. Preferred is methylene.
The term “alkenylene” refers to an unsaturated straight or branched hydrocarbon diradical of 2 to 6 carbons, having one or more double bond in the above “alkylene”, and includes for example vinylene, propenylene or butenylene. A straight chain alkenylene of 2 or 3 carbons, such as vinylene or propenylene, is preferred.
The term “optionally substituted alkylene or alkenylene” refers to alkylene or alkenylene having 1 to 5 substituents, preferably 1 to 3 substituents, wherein said substituent is selected from the group consisting of: optionally substituted alkyl (e.g., methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (e.g., carbamoylmethyl), mono- or di-alkylcarbamoylalkyl (e.g., dimethylcarbamoylethyl), hydroxyalkyl, heterocyclealkyl (e.g., morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonylalkyl (e.g., ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- or di-alkylaminoalkyl (e.g., dimethylamminioethyl) etc), alkoxyalkyl (e.g., methoxyethyl, ethoxymethyl, ethoxyethyl, i-propoxyethyl etc), acyl (e.g., formyl, optionally substituted alkylcarbonyl (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, methoxyethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, ethoxycarbonylmethylcarbonyl, alkoxyalkylcarbonyl (e.g., methoxyethylcarbonyl), alkylcarbamoylalkylcarbonyl (e.g., methylcarbamoylethylcarbonyl), alkoxycarbonylacetyl etc), optionally substituted arylcarbonyl (e.g., benzoyl, toluoyl etc)), optionally substituted aralkyl (e.g., benzyl, 4-F-benzyl etc), hydroxy, optionally substituted alkylsulfonyl (e.g., methanesulfonyl, ethanesulphonyl, isopropylsulphonyl, 2,2,2-trifluoroethanesulphonyl, benzylsulphonyl, methoxyethylsulphonyl etc), arylsulfonyl optionally substituted with alkyl or halo (e.g., benzenesulfonyl, toluenesulfonyl, 4-fluorobenzenesulfonyl), cycloalkyl (e.g., cyclopropyl etc), aryl optionally substituted with alkyl (e.g., 4-methylphenyl etc), alkylaminosulphonyl (e.g., methylaminosulphonyl, dimethylamminiosulphonyl etc), alkylaminocarbonyl (e.g., dimethylaminocarbonyl etc), alkoxycarbonyl (e.g., ethoxycarbonyl etc), cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclohexylcarbonyl etc), optionally substituted sulfamoyl (e.g., sulfamoyl, methylsulfamoyl, dimethylsulfamoyl etc), alkylcarbonylamino (e.g., methylcarbonylamino), heterocycle (e.g., morpholino, tetrahydropyranyl), optionally substituted amino (e.g., mono- or di-alkylamino (such as dimethylamminio), formylamino).
Thus, “optionally substituted alkylene or alkenylene optionally interrupted by one or more same or different heteroatomic group” refers to alkylene or alkenylene optionally substituted and optionally interrupted by one or more same or different of a heteroatom-containing group selected from the group consisting of —N═, ═N—, —NR1— (wherein R1 is hydrogen or lower alkyl), —O—, —S—, —SO— and —SO2—. In this regard, “interrupted” means the presence of a heteroatomic group between carbon atoms composing such alkylene or alkenylene or between said carbon atom and Ar1, Y or Ar2. For example, —O—CH2—, —CH2—O—, —CH2—O—CH2—, CH2—NH—CH2—, —O—CH2—O—, —CH2—O—CH2—NH—CH2—, CH2—N═CH—, —CH2—O—CH═N—CH2—, and —O—CH═CH—, —CH═CH—O—, —CH═CH—O—CH2—, CH2—NH—CH═CH—, —O—CH═CH—O—, or —(CH2—O)—Ar1—(O—CH2—O)—Y—(O—CH2)—Ar2, etc. are exemplified. Also, in the case that alkylene is substituted with oxo, —CO— is preferably exemplified.
X1 is preferably C1-C3 alkylene.
X2 is preferably a single bond, C1-C3 alkylene, O or NH, more preferably, single bond or NH.
Y is preferably, —NHCO—, —CONH—, —NMeCO—, —CONMe- or a radical as follows:
X3 is preferably a single bond, C1-C3 alkylene, C2-C3 alkenylene, O or NH, more preferably a single bond, CH2, or CH═CH.
Ar1 and Ar2 are each a carbocycle or a heterocycle that may be substituted or unsaturated.
The term “optionally unsaturated carbocycle” in the definition for Ar1 and Ar2 refers to a cycloalkyl of 3-10 carbons or a cycloalkenyl or aryl of 3-10 carbons.
The term “cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Cycloalkyl of 3-6 carbon atoms, such as cyclopentyl, cyclohexyl, is preferred.
The term “cycloalkenyl” includes, for example, cyclopropenyl (e.g., 1-cyclopropenyl), cyclobutenyl (e.g., 1-cyclobutenyl), cyclopentenyl (e.g., 1-cyclopentene-1-yl, 2-cyclopentene-1-yl, 3-cyclopentene-1-yl), cyclohexenyl (e.g., 1-cyclohexene-1-yl, 2-cyclohexene-1-yl, 3-cyclohexene-1-yl), cycloheptenyl (e.g., 1-cycloheptenyl), cyclooctenyl (e.g., 1-cyclooctenyl). Particularly, 1-cyclohexene-1-yl, 2-cyclohexene-1-yl, 3-cyclohexene-1-yl are preferred.
The term “aryl” refers to a monocyclic aromatic hydrocarbon group (phenyl) and a polycyclic aromatic hydrocarbon group (e.g., 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl etc). Phenyl or naphthyl (e.g., 1-naphthyl, 2-naphthyl) is preferred.
The term “optionally unsaturated heterocycle” in the definition for Ar1 and Ar2 means a heterocycle or a heteroaryl.
The term “heterocycle” refers to a five- to eight-membered nonaromatic heterocyclic group having at least one N, O or S atom within the ring, the ring being optionally substituted at a substitutable position. Examples are 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolindinyl, 2-pyrrolindinyl, 3-pyrrolindinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolynyl, 3-pyrazolynyl, 4-pyrazolynyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl etc. The “a nonaromatic heterocyclic group” may be saturated or unsaturated so long as it is not aromatic.
The term “heteroaryl” refers to a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group. The monocyclic aromatic heterocyclic group is that optionally substituted at a substitutable position and derived from a 5-8 membered aromatic ring that may contain one to four O, S, and/or N atoms within the ring. The condensed aromatic heterocyclic group is that optionally substituted at a substitutable position and wherein a 5-8 membered aromatic ring containing one to four O, S, and/or N atoms within the ring is condensed with one to four 5-8 membered aromatic carbocycles or another 5-8 membered aromatic hetero ring.
The “heteroaryl” includes, for example, furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (e.g., 3-furazanyl), pyrazinyl (e.g., 2-pyrazinyl), oxadiazolyl (e.g., 1,3,4-oxadiazole-2-yl), benzofuryl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl), benzthienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), benzimidazolyl (e.g., 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzoxazolyl, quinoxalyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), puryl, pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (e.g., 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenazinyl (e.g., 1-phenazinyl, 2-phenazinyl) or phenothiazinyl (e.g., 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl), etc.
The carbocycle and/or heterocycle in Ar1 and Ar2 also include those wherein an aromatic ring is condensed with a nonaromatic ring.
As obvious from the definition of RA, Ar1 is a divalent group, and therefore, a carbon atom or a hetero atom, which constitutes the carbocycle or heterocycle as described above as a monovalent substituent, should further be involved with additional linkage to another group.
Substituent for “a carbocycle or heterocycle which is optionally substituted and may have an unsaturated bond” in the definition for Ar1 and Ar2 include lower alkyl, hydroxy lower alkyl, optionally substituted lower alkoxy (example of substituent: hydroxy, phenyloxy, optionally substituted heterocycle (preferably 5-6 membered ring), lower alkoxy, optionally substituted amino (example of substituent: lower alkyl, lower alkenyl, cyano, phenyl), optionally substituted lower alkoxy lower alkyl (example of substituent: hydroxy, lower alkoxy, optionally substituted heterocycle (preferably 5-6 membered ring)), cycloalkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted aryloxy lower alkyl, optionally substituted aryloxycarbonyl, lower alkoxycarbonyl, nitro, hydroxy, carboxy, lower alkoxycarbonyl, cyano, oxo, carboxy lower alkenyl, SO2-cyclic amino (preferably 5-6 membered ring), lower alkylsulfonylamino, optionally substituted amino (example of substituent: lower alkyl, lower alkoxy, acyl (e.g., lower alkylcarbonyl, amino lower alkylcarbonyl, lower alkylamino lower alkylcarbonyl), heterocycle (preferably 5-6 membered ring)), optionally substituted amino lower alkyl, optionally substituted carbamoyl (example of substituent: lower alkyl, CN, OH), optionally substituted carbamoyloxy, halo, lower alkyl halide, lower alkoxy halide, lower alkylthio halide, lower alkylcarbonyl halide, heterocyclo lower alkyl, heterocyclo lower alkoxy, cycloalkyl lower alkoxy, optionally substituted aralkyloxy, optionally substituted heteroaryl (preferably 5-6 membered ring), optionally substituted heteroaryl-lower alkyl, optionally substituted heteroaryl-lower alkyloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycle lower alkyloxy, optionally substituted heterocyclecarbonyl lower alkenyl, optionally substituted heterocycleamino, optionally substituted aryl, and optionally substituted heterocyclecarbonyl lower alkenyl, SCO2R, OC(═S)OR, OC(═O)SR, C(═S)OR, SC(═O)SR, SC(═S)SR, OC(═S)NH2, SC(═O)NH2, SC(═S)NH2, OC(═S)NHR, SC(═O)NHR, SC(═S)NHR, OSO2NHR, OSO2NHPh, OC(═S)NR2, SC(═O)NR2, SC(═S)NR2, C(═S)NH2, C(═S)NHR, C(═S)NR2 (R is lower alkyl), CONHCN, CONHOH, etc. The optionally substituted amino as described above is for example amino, mono- or di-lower alkylamino, phenylamino, N-alkyl-n-phenylamino, mono- or di-lower alkoxy lower alkylamino, mono- or di-hydroxy lower alkylamino lower alkoxycarbonylamino, lower alkylcarbamoylamino, lower alkylcarbonylamino, NHC(═O)SR, NHC(═S)OR, NHC(═S)SR, NHC(═S)R, NH(CH2)2OH, N[(CH2)2OH]2 (R is lower alkyl), optionally substituted heterocycleamino (substituent: lower alkyl), optionally substituted acetylamino (example of substituent: optionally substituted heterocycle (substituent: e.g., lower alkyl), amino, alkylamino), etc. The substituent of the above optionally substituted aryl, aralkyl, heteroaryl, heterocycle includes, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, heterocycle (preferably 5-6 membered ring), cyano, etc.
The substituent for “carbocycle or heterocycle which may have an unsaturated bond” in the definition for Ar1 and Ar2 is, more specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, vinyl, allyl, propargyl, OH, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, vinyloxy, allyloxy, propargyloxy, benzyloxy, 2,3,4-picolyloxy, furfuryloxy, thiophenemethyloxy, imidazolylmethyloxy, pyrazolylmethyloxy, triazolylmethyloxy, thiazolylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, phenylethyloxy, 2,3,4-pyridylethyloxy, furylethyloxy, thiopheneethyloxy, imidazolylethyloxy, pyrazolylethyloxy, triazolylethyloxy, thiazolylethyloxy, oxazolylethyloxy, isoxazolylethyloxy, cyclopropylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, tetrahydropyran-4-ylmethyloxy, [1,3]dioxolan-2-ylmethyloxy, OCO2Me, NHCO2Me, OCONHMe, NHCONHMe, NHCOMe, CONH2, CONHMe, CONMe2, OCONHPh, SCO2Me, OC(═S)OMe, OC(═O)SMe, C(═S)OMe, SC(═O)SMe, SC(═S)SMe, NHC(═O)SMe, NHC(═S)OMe, NHC(═S)SMe, OC(═S)NH2, SO2NH2, SO2Me, SC(═O)NH2, SC(═S)NH2, OC(═S)NHMe, SC(═O)NHMe, SC(═S)NHMe, OSO2NHMe, OSO2NHPh, OC(═S)NMe2, SC(═O)NMe2, SC(═S)NMe2, NHC(═S)Me, C(═S)NH2, C(═S)NHMe, C(═S)NMe2, NO2, NH2, NHMe, NMe2, NHEt, NEt2, NH(CH2)2OH), N[(CH2)2OH]2, piperazinyl, 4-alkylpiperadino (e.g., 4-methylpiperadino), piperidinyl, morpholino, F, Cl, Br, CF3, OCF3, OCH2CF3, CN, oxo, etc.
Ar1 or Ar2 may contain preferably one to three of these substituents.
One preferred embodiment of Ar1 is optionally substituted phenylene. Preferred substituent on phenylene include halo, hydroxy, hydroxy lower alkyl, optionally substituted lower alkoxy, optionally substituted amino (substituent: e.g., lower alkyl, heterocycle, heterocycle lower alkyl, lower alkoxy lower alkyl, hydroxy lower alkyl, lower alkylsulfonyl), optionally substituted amino lower alkyl, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, phenylene optionally substituted with optionally substituted heterocycle lower alkyl, optionally substituted carbamoyl (substituent: e.g., lower alkyl), optionally substituted carbamoyl lower alkenyl. Preferred heterocycle is a heterocycle optionally substituted with lower alkyl (e.g., morpholino, piperadino, piperidino), pyridyl etc.
One preferred embodiment of Ar1 is optionally substituted 5 to 7-membered heterocycle containing one to two N atoms. Preferred substituent on the heterocycle includes lower alkyl, oxo, halo, amino lower alkyl, mono- or di-lower alkylamino lower alkyl, lower alkoxy lower alkyl, and oxo is especially preferred.
One preferred embodiment of Ar2 is aryl or heterocycle optionally substituted with one or more substituent selected from the group consisting of halo, mono-, di- or tri-halogenated lower alkyl, mono-, di-, tri- or tetra-halogenated lower alkoxy, mono-, di-, tri- or tetra-halogenated lower alkylthio, mono- or di-lower alkylamino, cycloalkylmethyloxy, optionally substituted benzyloxy, lower alkoxycarbonylamino, nitro, heterocycle (e.g., morpholino, piperadino, piperidino, pyrrolidino optionally substituted independently with lower alkyl etc.), optionally substituted acetylamino, optionally substituted lower alkoxy, acyl (e.g., optionally substituted lower alkylcarbonyl), and optionally substituted lower alkyloxycarbonyl. Particularly, substituted phenyl (substituent: halo, halogenated lower alkoxy) is preferred.
The term “aralkyloxy” refers to a group wherein oxygen atom is substituted the above “alkyl” substituted with the above “aryl” and, for example, benzyloxy, diphenylmethyloxy, triphenylmethyloxy, phenetyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy, etc.
The term “lower alkoxy” refers to a group wherein O atom is substituted with the above “lower alkyl”, and for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. Particularly, methoxy, ethoxy are preferred.
The term “aryloxy” refers to a group wherein O atom is substituted with the above “aryl”.
The term “optionally substituted amino” is an amino substituted or unsubstituted.
The term “optionally substituted carbamoyl” is a carbamoyl substituted or unsubstituted.
For substituents of “optionally substituted amino” and “optionally substituted carbamoyl” include, optionally substituted alkyl (e.g., methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (e.g., carbamoylmethyl), mono- or di-alkylcarbamoylalkyl (e.g., dimethylcarbamoylethyl), hydroxyalkyl, heterocyclealkyl (e.g., morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonylalkyl (e.g., ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- or di-alkylaminoalkyl (e.g., dimethylamminioethyl) etc), alkoxyalkyl (e.g., methoxyethyl, ethoxymethyl, ethoxyethyl, i-propoxyethyl etc), acyl (e.g., formyl, optionally substituted alkylcarbonyl (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, methoxyethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, ethoxycarbonylmethylcarbonyl, alkoxyalkylcarbonyl (e.g., methoxyethylcarbonyl), alkylcarbamoylalkylcarbonyl (e.g., methylcarbamoylethylcarbonyl), alkoxycarbonylacetyl etc), optionally substituted arylcarbonyl (e.g., benzoyl, toluoyl etc)), optionally substituted aralkyl (e.g., benzyl, 4-F-benzyl etc), hydroxy, optionally substituted alkylsulfonyl (e.g., methanesulfonyl, ethanesulphonyl, isopropylsulphonyl, 2,2,2-trifluoroethanesulphonyl, benzylsulphonyl, methoxyethylsulphonyl etc), arylsulfonyl optionally substituted with alkyl or halo (e.g., benzenesulfonyl, toluenesulfonyl, 4-fluorobenzenesulfonyl), cycloalkyl (e.g., cyclopropyl etc), aryl optionally substituted with alkyl (e.g., 4-methylphenyl etc), alkylaminosulphonyl (e.g., methylaminosulphonyl, dimethylamminiosulphonyl etc), alkylaminocarbonyl (e.g., dimethylaminocarbonyl etc), alkoxycarbonyl (e.g., ethoxycarbonyl etc), cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclohexylcarbonyl etc), optionally substituted sulfamoyl (e.g., sulfamoyl, methylsulfamoyl, dimethylsulfamoyl etc), alkylcarbonylamino (e.g., methylcarbonylamino), heterocycle (e.g., morpholino, tetrahydropyranyl), optionally substituted amino (e.g., mono- or di-alkylamino (e.g., dimethylamminio), formylamino), etc. It may be mono- or di-substituted with the above substituent.
The amino group of “optionally substituted amino” and “optionally substituted carbamoyl” may be substituted with alkylene such as trimethylene, tetramethylene, pentamethylene, and may form a ring optionally containing O and/or S atom together with the nitrogen atom of the amino group.
For the amino group of “optionally substituted amino” and “optionally substituted carbamoyl”, the two substituents of the amino group may be taken together with a nitrogen atom to which they are attached to form a nitrogen containing heterocycle that may contain S and/or O atom within the ring, preferably 5- to 7-membered and preferably saturated, and said ring may be substituted with oxo, lower alkyl or hydroxy etc. The ring may be substituted at S atom with oxo. For example, 5- or 6-membered rings such as piperidino, piperadino, morpholino, pyrrolidino, thiazinan-2-yl, 2-oxopiperidino, 2-oxopyrrolidino, 1,1-dioxido-1,2-thiazinan-2-yl, 4-hydroxymorpholino are preferred.
Substituent of “optionally substituted aryl” and “optionally substituted heteroaryl” is as defined above for “optionally substituted amino group”.
Ar1 especially preferred in the present invention is selected from the following groups:
Ar2 is preferably aryl optionally substituted, specifically phenyl optionally substituted. Ar2 especially preferred in the present invention is selected from the following groups:
Preferred embodiments of the group of the formula: —X1—Ar1—X2—Y—X3—Ar2 for RA are as follows:
In one embodiment of the invention, RB is a group of the formula —NHNRXRY. For RX, it can be hydrogen, lower alkyl, etc. For RY, it can be hydrogen, optionally substituted lower alkyl, lower alkylcarbonyl, C(═NH)NH2, CSNH2, COCONH2, CN, optionally substituted heterocyclic group, or optionally substituted carbamoyl etc. Preferred substituent of the lower alkyl can be OH, CN, lower alkoxy, amino, ═O, halogen, heterocyclic group etc., and preferably —OH. The heterocyclic group in “optionally substituted heterocyclic group” can be a group as recited above for “heterocycle” and “heteroaryl”, and preferably five- or six-membered heterocyclic group such as morpholinyl, imidazoyl, tetrahydropyranyl. Substituent for “optionally substituted heterocycle” includes hydroxy, amino, carboxy, lower alkyl, amino lower alkyl, quaternary ammonium lower alkyl. The lower alkyl group on the quaternary ammonium radical may be substituted with a substituted alkyl (substituent: carboxy, hydroxy, quaternary ammonium). Substituent for “optionally substituted carbamoyl” includes alkyl (e.g., methyl, ethyl, dimethyl, etc.), alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl etc.), alkoxyalkyl (e.g. ethoxymethyl, ethoxyethyl etc.), acyl (e.g., formyl, acetyl, benzoyl, toluoyl etc.), aralkyl (e.g. benzyl etc.), hydroxy, alkylsulfonyl (e.g., methanesulfonyl, ethanesulphonyl etc.), SO2NH2, arylsulfonyl optionally substituted with alkyl (e.g., benzenesulfonyl, toluenesulfonyl), cycloalkyl (e.g., cyclopropyl etc.), alkylene (e.g., trimethylene, tetramethylene, pentamethylene), aryl optionally substituted with alkyl (e.g., phenyl, trityl etc.). RY especially preferred is optionally substituted lower alkyl, or lower alkylcarbonyl.
In further embodiment of the invention, RB is a group of the formula —NRZORW. For RZ, it can be hydrogen, lower alkyl etc. For RW, it can be hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted heterocyclic group, optionally substituted heterocyclic carbonyl, or optionally substituted carbamoyl. Substituent for “optionally substituted lower alkyl” includes OH, a lower alkoxy, optionally substituted amino, ═O, halogen, SO3H, optionally substituted carbamoyl, heterocyclic group, etc. For such heterocyclic group, it can be as recited above for “heterocycle” and “heteroaryl”, and preferably five- or six-membered heterocyclic group such as morpholinyl, imidazoyl, tetrahydropyranyl. Substituent for “optionally substituted heterocycle” and “optionally substituted heterocyclic carbonyl” includes hydroxy, amino, carboxy, amino lower alkyl, quaternary ammonium lower alkyl. The lower alkyl group for the quaternary ammonium radical may be substituted further with a substituted alkyl (substituent: carboxy, hydroxy, quaternary ammonium radical). Substituent for “optionally substituted lower alkenyl” includes OH, CN, lower alkoxy, amino, ═O, halogen, NH3, etc. Substituent for “optionally substituted amino” and “optionally substituted carbamoyl” includes alkyl (e.g., methyl, ethyl, dimethyl etc.), alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl etc.), alkoxyalkyl (e.g., ethoxymethyl, ethoxyethyl etc.), acyl (e.g., formyl, acetyl, benzoyl, toluoyl etc.), aralkyl (e.g., benzyl etc.), hydroxy, CN, alkylsulfonyl (e.g., methanesulfonyl, ethanesulphonyl etc.), SO2NH2, arylsulfonyl optionally substituted with alkyl (e.g., benzenesulfonyl, toluenesulfonyl), cycloalkyl (e.g., cyclopropyl etc.), alkylene (e.g., trimethylene, tetramethylene, pentamethylene), aryl optionally substituted with alkyl (e.g., phenyl, trityl etc.). For the amino group of “optionally substituted amino”, the two substituents of the amino group may be taken together with a nitrogen atom to which they are attached to form a nitrogen containing heterocycle that may contain S atom within the ring, which may be substituted with oxo.
Preferred embodiments of the group of the formula: —NHNRXRY for RB are as follows:
Preferred embodiments of the group of the formula: —NRZORW for RB are as follows:
RC is selected from the group consisting of the following (3-1)-(3-4):
RC is preferably hydrogen or optionally substituted alkyl. Substituent for such optionally substituted alkyl is preferably —NHR5 as described above or substituents of the optionally substituted alkyl as defined for R5.
RD is selected from the group consisting of the following (4-1)-(4-6):
Especially preferred compounds of the invention are exemplified as follows:
Another preferred compounds are Compound 200 to Compound 232, as described in the following Examples.
The present invention encompasses the compounds described above, a pharmaceutically acceptable salt and solvate thereof. Any theoretically available tautomer and geometric isomer of such compound are also within the scope of the present invention.
The term “pharmaceutically acceptable” means harmless with respect to the prevention and the treatment.
Pharmaceutically acceptable salts of a compound of the present invention include, as basic salts, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts, meglumine salt, diethanolamine salt or ethylenediamine salt; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benethamine salt; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts or lysine salts. Acid salts include, for example, inorganic acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tartrates, malates, citrates, or ascorbates; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts such as aspartates or glutamates.
Furthermore, various solvates of a compound of the present invention, for example, monosolvate, disolvate, monohydrate or dihydrate are also within the scope of the present invention.
(2) General Procedure
Below is described a representative procedure for the production of a compound of the invention. The preparation of the compound is not intend to limit to such procedure, and of course, can be conducted by another procedure.
The compound of the invention may be synthesized using vancomycin or its known derivative as a starting material, by chemical modification of the amino moiety (RA) at the amino sugar, or the C terminal (RB), the resorcinol moiety (RC), or the methylamino moiety at the N terminal (RD). Such chemical modification can be conducted according to the procedure, for example, as disclosed in Japanese Patent Publication No. 7-258289, WO00/39156, Japanese Patent Publication No. 2001-163898. Specifically, it may be conducted in the following manner.
1) Modification of RA Moiety
Specifically, the Schiff base formation is conducted in a polar solvent such as dimethylformamide or methanol or mixture thereof, optionally under inert atmosphere such as nitrogen or argon gas and optionally in the presence of a base, at a temperature between about 25° C. and about 100° C. Preferably, the reaction is conducted at room temperature to 100° C., preferably about 60° C. to about 80° C., for about 30 minute to 2 hours. The base used in the reaction is, for example, alkylamine (e.g., diisopropylethylamine, etc).
The intermediate Schiff base, preferably without purification, may be reduced with a hydrogenated metal complex or subjected to a catalytic reduction. For such hydrogenated metal complex, a metal borohydride, such as sodium borohydride or sodium cyanoborohydride, may be used. The catalytic reduction may be conducted using hydrogen in the presence of homogeneous or heterogeneous catalysis such as Crabtree catalyst, Wilkinson catalyst, palladium on carbon, platinum on carbon or rhodium on carbon. The reduction reaction is conducted at about 25° C. to about 100° C. for about 1 to 24 hours. Preferably, the reaction is conducted in the above solvent, using an excessive amount (e.g., 3-5 equiv) of sodium cyanoborohydride at about 60° C. to about 80° C.
2) Modification of RB Moiety
Typically, the carboxylic acid moiety at the C terminal of the vancomycin skeleton may be amidated using an appropriate reagent according to a conventional procedure to provide a different amido derivative wherein RB=—NHNRXRY or —NRZORW.
When RB is a group of the formula —NHNRXRY, a compound of the formula NH2NRXRY (wherein RX and RY are as defined above) can be used to react in an appropriate solvent (dimethylformamide (DMF) etc.) with the carboxyl group at the C terminal of the vancomycin skeleton, in the presence of benztriazole-1-yl-oxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), diisopropyl ethyl amine (DIPEA), etc.
When RB is a group of the formula —NRZORW, a compound of the formula NHRZORV (wherein RZ is as defined above and RV is a hydroxy protecting group or RW as defined above) can be used to react in an appropriate solvent (dimethylformamide (DMF) etc.) with a carboxyl group at the C terminal of the vancomycin skeleton, in the presence of benztriazole-1-yl-oxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), diisopropyl ethyl amine (DIPEA), etc.
The reagents used in the above reactions are commercially available or can be prepared readily according to procedures well known in the art using reagents as commercially available.
The amindation can be conducted preferably in a solvent such as dimethylformamide, etc. at room temperature or under heating for several minutes to several hours.
3) Modification of RC Moiety
Typically, vancomycin as a starting material may be subjected to alkylation of the resorcinol moiety, according to a conventional procedure.
4) Modification of RD Moiety
Typically, vancomycin as a starting material may be subjected to N-alkylation of the methylamine moiety at the N-terminal, according to a conventional procedure.
(3) Pharmaceutical Composition
The invention also provides a pharmaceutical formulation comprising a novel glycopeptide derivative of the invention. Thus, the glycopeptide compound in a form of pharmaceutically acceptable salt may be formulated preferably for oral or parenteral administration for therapeutic and prophylactic treatment of bacterial infection.
For oral administration, the compounds of the present invention can be used in any form of usual formulations, for example, formulations in a solid form such as tablets, powders, granules, capsules; formulations in a liquid form such as aqueous formulation; oily suspension; syrup or elixir. For parenteral administration, the compounds of the invention can be used in a form of aqueous or oily suspending injection, or nose drops. In the preparation of such formulation, conventional excipients, binding agents, lubricants, aqueous solvents, oleaginous solvents, emulsifying agents, suspending agents, preservatives, stabilizers, and the like can be optionally used. Oral formulations or intravenous injection is preferred for use as an antimicrobial drug.
The formulation of the invention may be prepared by combining (for example, admixing) a therapeutically effective amount of a compound of the invention with a pharmaceutically acceptable carrier or diluent. The formulation of the invention may be prepared in accordance with a procedure known in the art using ingredients well-known and easily available.
For the preparation of a pharmaceutical composition according to the present invention, an active ingredient is admixed or diluted with a carrier, or they are contained in a carrier in the form of capsule, sacheier, paper, or another container. In case that a carrier is served as a diluent, the carrier is a solid, semi-solid, or liquid material which functions as a medium. Accordingly, a formulation according to the present invention may be prepared in a form of tablet, pill, powder, intraoral formulation, elixir, suspension, emulsion, solution, syrup, aerosol (solid in liquid medium), and ointment. Such a formulation may contain up to 10% of an active compound. It is preferred to formulate the compound of the invention prior to administration thereof.
Any suitable carrier well known to those skilled in the art may be used for the present formulation. Such carrier may be in a form of solid, liquid or mixture thereof in the formulation. For instance, the compound of the invention is dissolved into an aqueous solution of 4% dextrose/0.5% sodium citrate for intravenous injection. Solid formulation can be powder, tablet, and capsule. Solid carrier can be one or more of material(s) that also serves as a fragrant, a lubricant, a dissolving agent, a suspending agent, a binder, a tablet disintegrator or a capsule. A tablet for oral administration contains a suitable excipient such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, etc., together with a disintegrator such as corn starch, alginic acid, etc. and/or a binder such as gelatin, acacia, etc. and a lubricant such as magnesium stearate, stearic acid, talc, etc.
For powder formulation, the carrier can be a finely-divided solid to be blended with an active ingredient that has been finely-divided. In a tablet, an active ingredient has been admixed in a suitable ratio with a carrier having required binding property and solidified in a desired shape and size. Powder and tablet formulations contain about 1% to about 99% by weight of the active ingredient, which is a novel compound of the invention. Example for a suitable solid carrier is magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methyl cellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter.
A liquid formulation can be suspension, emulsion, syrup, or elixir. An active ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier such as sterile water, a sterile organic solvent, or a mixture thereof. Often, the active ingredient may be dissolved in a suitable organic solvent such as propylene glycol aqueous solution. Other compositions may be prepared by dispersing a finely-divided active ingredient in an aqueous starch, sodium carboxylmethylcellulose solution or suitable oil.
For oral administration, daily dosage of the compound of the invention can be between approximately 0.1-7000 mg, preferably approximately 0.5-2000 mg, for an adult, while such dosage varies depending on the administration route therefor, age, body weight and conditions of the patient, and disease in the patient. The dosage may be divided for administration. In case of parenteral administration, the daily dosage for an adult can be between approximately 0.1-1000 mg, preferably approximately 0.5-500 mg.
The present invention is further explained by the following Examples, which are not intended to limit the scope of the present invention in any way.
Preparation of Compound 1
(Step 1)
Cytosine (a, 51 g, 0.46M), 2-bromo-1,1-dimethoxyethane (93 g, 0.55M) and potassium carbonate (127 g, 0.92M) were suspended in N,N-dimethylformamide (250 mL) and the mixture was stirred vigorously for 21 hours at 130° C. After the reaction mixture was cooled to room temperature, precipitate was filtered and washed with N,N-dimethylformamide (300 mL) and diethylether (300 mL). The obtained powder was extracted with hot ethanol (3×500 mL), followed by removing the solvent in vacuo to afford 30.4 g of the desired compound 4-amino-1-(2,2-diethoxy-ethyl)-1H-pyrimidin-2-one (b) (yield 33%, brown crystal).
(Step 2)
P-chloro cinnamic acid (1.84 g, 10 mM), 4-amino-1-(2,2-diethoxyethyl)-1H-pyrimidin-2-one (b, 3.00 g, 15 mM), 1-hydroxybenztriazolemonohydrate (2.30 g, 15 mM) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.90 g, 15 mM) were suspended in N,N-dimethylformamide (20 mL) and stirred at 70° C. for 5 hours. After the reaction mixture was cooled to room temperature, water (20 mL) was added and stirred at room temperature. The crystal precipitated from the reaction mixture was filtered to afford 2.48 g of the desired compound (E)-3-(4-chlorophenyl)-N-[1-(2,2-diethoxyethyl)-2-oxo-1,2-dihydropyrimidin-4-yl]-acrylamide (c) (yield 68%, colorless crystal).
(Step 3)
(E)-3-(4-chloro-phenyl)-N-[1-(2,2-diethoxy-ethyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-acrylamide (c, 2.48 g, 6.8 mM) was dissolved in trifluoroacetic acid (37 mL) and stirred at room temperature for 4.5 hours. Trifluoroacetic acid was removed in vacuo, and toluene (40 mL) was added to remove the solvent in vacuo. The residual solid was added with ethyl acetate (15 mL) and 5% aqueous sodium bicarbonate (15 mL) and stirred at room temperature. The precipitated crystal was filtered to afford 2.28 g of the desired compound (E)-3-(4-chloro-phenyl)-N-[1-(2,2-dihydroxy-ethyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-acrylamide (d) (yield 100%, colorless crystal).
(Step 4)
Vancomycin hydrochloride (42.1 g, 28.3 mM) and benztriazole-1-yl-oxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (7.36 g, 14.2 mM) were suspended in N,N-dimethylformamide (400 mL), and a solution of hydroxylammonium chloride (3.94 g, 56.7 mM) and diisopropylethylamine (14.8 mL, 85 mM) in N,N-dimethylformamide (10 mL) was added to the suspension and stirred at room temperature for 30 minutes.
The reaction mixture is added to ethyl acetate (3 L), and the precipitate was filtered. The powder thus obtained was purified by ODS column chromatography to afford 16.2 g of the desired vancomycin derivative having a modification at the C-terminal (f) (titer 0.8, yield 31%, colorless powder).
(Step 5)
The vancomycin derivative having a modification at the C-terminal prepared in the above Step 4 (f, 1.78 g, F=0.8, 0.96 mM) and (E)-3-(4-chlorophenyl)-N-[1-(2,2-dihydroxyethyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-acrylamide (d, 0.37 g, 1.2 mM) prepared in the above Step 3 were suspended in N,N-dimethylformamide (27 mL), and diisopropylethylamine (0.33 mL, 1.9 mM) was added to the suspension and stirred at 70° C. for 3.5 hours.
The mixture was cooled on ice and added with trifluoroacetic acid (0.14 mL, 1.9 mM), sodium cyanoborohydride (90 mg, 1.44 mM) and methanol (9 mL) and stirred at room temperature for 5 hours. To the reaction mixture, 5% aqueous sodium chloride (200 mL) was added, and the precipitate was filtered. The precipitate was washed with acetonitrile (23 ml) and filtered. The obtained powder was purified by ODS column chromatography to afford 330 mg of the desired compound (Compound 1) (titer 0.8, yield 16%, colorless powder).
[M+H]+=1764
Anal calcd. for C81H88Cl3N13O26.11.1H2O.2.4HCl: C, 47.38%; H, 5.53%; N, 8.87%; Cl, 9.32%. Found: C, 47.35%; H, 5.52%; N, 8.97%; Cl, 9.32%.
Preparation of Compound 2
(Step 1)
3-amino benzyl alcohol (18.85 g, 0.15 mol) was dissolved in 190 mL of tetrahydrofuran. After cooling on ice, 29 mL of diisopropyl ethylamine was added dropwise, and a solution of 4-trifluoromethoxy benzoyl chloride (g) (24 mL, 0.15 mol) in tetrahydrofuran (30 mL) was added dropwise with maintaining the temperature bellow 10° C. The mixture was then stirred at room temperature for 10 hours. The mixture was pored into ice water (900 mL), extracted with 900 mL of ethyl acetate, and followed by dryness on anhydrous magnesium sulfate. After the desiccant agent was removed by filtration, the filtrate was concentrated in vacuo. The crude solid obtained was dissolved in acetone and added with 15 g of activated carbon. After standing for 10 minutes at room temperature, the mixture was filtered to remove the activated carbon, and the filtrate was concentrated in vacuo. The obtained crude solid was subjected to recrystallization from diisopropyl ether afforded 42.08 g of the titled compound (N-(3-hydroxymethylphenyl)-4-trifluoromethoxy-benzamide: h) as colorless crystal (yield 90%).
(Step 2)
51.22 g of N-(3-hydroxymethylphenyl)-4-trifluoromethoxybenzamide (h, 0.164 mol) as prepared in Step 1 was dissolved in 100 mL of tetrahydrofuran. To the mixture, 102.4 g of manganese dioxide was added and stirred at room temperature for 36 hours. The mixture was filtered using Hyflo Super-Cel to remove manganese dioxide, and the filter residue was rinsed with acetone (1.0 L). The obtained yellow filtrate was added with activated carbon (20 g) and left stand for 10 minutes at room temperature. After the activated carbon was filtered off to concentrate the filtrate in vacuo, recrystallization of the obtained crude solid from acetone-hexane afforded 46.05 g of the titled compound (i) as colorless crystal (yield 91%).
(Step 3)
40 g of vancomycin hydrochloride (j, 26.9 mmol) and 8.32 g of N-(3-formylphenyl)-4-trifluoromethoxybenzamide (26.9 mmol) were dissolved in dimethylformamide (800 mL), and molecular sieves 3 Å (80 g) was suspended in the solution. After the mixture was stirred at room temperature for 30 minutes, diisopropylethylamine (9.37 mL) was added and stirred at room temperature for 4 hours. The mixture was added with methanol (800 mL), trifluoroacetic acid (5 mL) dropwise slowly, and sodium cyanoborohydride (3.76 g), and stirred at room temperature for 2 hours. Molecular sieves were removed by filtration through a cotton-plugged funnel, and methanol was removed in vacuo from the filtrate, which was then pored into ethyl acetate. The precipitate was collected by filtration, and the obtained crude solid was rinsed with 10% saline to remove sodium cyanoborohydride. The crude solid was purified by reverse phase column chromatography to afford 18.78 g of the titled compound (j) as a colorless solid (yield 40%).
(Step 4)
1.97 g (1.13 mmol) of the compound (j) as prepared in Step 3, 706 mg (1.36 mmol) of benztriazole-1-yl-oxy-tris-(pyrrolidino)phosphonium hexafluoro phosphate, and 199 mg (1.47 mmol) of benztriazole-1-ol were dissolved in 40 mL of dimethylformamide, and the mixture was stirred at room temperature for 1.5 hours. Diisopropylethylamine (0.59 mL) and ethylhydrazine (170 mg) were then added sequentially at room temperature, and the reaction mixture was stirred at the same temperature for 24 hours. The mixture was added dropwise to 400 mL of ethyl acetate, and the precipitate formed was collected by filtration and purified by reverse phase column chromatography to afford 1.30 g of the titled compound (Compound 2) as colorless solid (yield 64%).
[M+H]+=1783
Anal calcd. for C83H91Cl2F3N12O25.11H2O.2.3HCl: C, 48.24%; H, 5.62%; N, 8.13%; Cl, 7.38%; F, 2.76%. Found: C, 48.33%; H, 5.51%; N, 8.15%; Cl, 7.39%; F, 2.69%.
Preparation of Compound 3
(Step 1)
5-bromo-pyridine-3-carbaldehyde (k) (11.98 g), p-toluenesulfonic acid (1.23 g) and ethyleneglycol (39.98 g) were dissolved in 200 mL of toluene, and the mixture was heated under reflux for 3 hours with dehydration using a Dean Stark trap. The reaction mixture was poured into 5% aqueous NaHCO3, and extracted with toluene and subsequently worked up according to conventional procedure to afford 13.82 g of the titled compound (5-bromo-5-[1,3]dioxolan-2-yl-pyridine: m) as a brown oil (yield 93%).
(Step 2)
5-bromo-5-[1,3]dioxolan-2-yl-pyridine (m) (1.15 g) prepared in Step 1 and copper sulfate (II) (0.25 g) were suspended in 28% ammonia water and subjected to reaction in a microwave reactor (Emrys Optimizer, Amersham BioSciences) at 150° C. for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, and subsequently worked up according to conventional procedure to afford 0.696 g of the titled compound (5-[1,3]dioxolan-2-yl-pyridine-3-ylamine: n) as a yellow oil (yield 84%).
(Step 3)
8.75 g of 5-[1,3]dioxolan-2-yl-pyridine-3-ylamine (n) prepared in Step 2 and pyridine (5.00 g) were dissolved in 100 mL of tetrahydrofuran, and 3,5-dichloro-benzoyl chloride (12.14 g) was added dropwise to the mixture over 0.5 hour. After the mixture was stirred for 15 minutes at room temperature, it was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the residue. The obtained residue was dissolved in a mixed solution of 2N hydrochloric acid (100 mL)-tetrahydrofuran (100 mL) and stirred at 60° C. for 8 hours. After tetrahydrofuran was removed in vacuo, the reaction mixture was neutralized by 2N sodium hydroxide. The precipitate was collected by filtration to afford 12.74 g of the titled compound (3,5-dichloro-N-(5-formyl-pyridine-3-yl)-benzamide: p) as a colorless powder (yield 82%).
(Step 4)
Vancomycin hydrochloride (7.43 g) prepared in Step 3,3,5-dichloro-N-(5-formyl-pyridine-3-yl)-benzamide (p) (1.475 g) and diisopropyl ethylamine (1.29 g) were suspended in dimethylformamide (50 mL)-methanol (50 mL) and stirred at room temperature for 2 hours. To the reaction mixture, trifluoroacetic acid (1.37 g) and sodium cyanoborohydride (0.628 g) were added sequentially at room temperature and stirred for 1 hours at this temperature. After methanol was removed in vacuo, the mixture was poured into ethyl acetate and filtered to collect the precipitate, which was then washed with 10% aqueous NaCl. The obtained residue was purified by reverse phase column chromatography to afford 2.73 g (yield 32%) of the titled compound (q).
(Step 5)
The compound (q) (14.40 g) prepared in Step 4, benztriazole-1-yl-oxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (6.09 g) were dissolved in dimethylformamide (100 mL) and stirred for 0.5 hour at room temperature. Diisopropyl ethyl amine (5.38 g) and 2-hydrazino ethanol (1.27 g) were added sequentially at room temperature and stirred for 1 hour at this temperature. The reaction mixture was poured into ethyl acetate and filtered to collect the precipitate, which was then purified by reverse phase column chromatography to afford 8.57 g of the titled compound (Compound 3) (yield 58%).
[M+H]+=1786
Anal calcd. for C81H89Cl4N13O25.11.2H2O.2.4HCl: C, 46.87%; H, 5.53%; N, 8.77%; Cl, 10.93%. Found: C, 46.88%; H, 5.41%; N, 8.75%; Cl, 10.84%.
Preparation of Compound 4
(Step 1)
Under nitrogen gas stream, 50 g of 2-piperidine-4-ylethanol (r) (0.387 mol) was dissolved in tetrahydrofuran (1 L), and after ice cooling, 78.6 g of 1-isocyanate-4-trifluoromethoxy-benzene (0.387 mol) was added dropwise to keep the mixture at the temperature bellow 10° C. and then stirred at this temperature for 1 hour. The mixture was concentrated in vacuo to achieve ⅓ of the total volume. The residue was added with diisopropyl ether and stirred for 5 minutes, and then filtered to collect the precipitate, which was rinsed with diisopropyl ether and dried to afford 120.1 g of the titled compound (4-(2-hydroxyethyl)-piperazine-1-carboxylic acid (4-trifluoromethoxyphenyl) amide: s) as colorless crystal (yield 93%).
(Step 2)
4-(2-hydroxyethyl)-piperazine-1-carboxylic acid (4-trifluoromethoxyphenyl)-amide (s) (8.0 g, 24.1 mmol) was suspended in dichloromethane (80 mL). After ice cooling, 8.38 mL of diisopropylethylamine (48.1 mmol) and 10.1 mL of dimethylsulfoxide (72.3 mmol) were added sequentially. Sulfur trioxidepyridine complex (7.66 g, 48.1 mmol) was then added portionwise to keep the temperature bellow 10° C., and the mixture was stirred for 10 minutes. Water (80 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract layer was washed sequentially with saturated sodium bicarbonate and saturated saline, and dried on anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated in vacuo to afford 10.6 g of the titled compound (4-(2-oxo-ethyl)-piperidin-1-carboxylic acid (4-trifluoromethoxy-phenyl)amide: t) as yellow crude solid. Titer was 0.65, and the yield was 87%, as confirmed by 1H-NMR spectroscopic analysis.
(Step 3)
Vancomycin hydrochloride (20.8 g, 14 mmol) and 4-(2-oxoethyl)-piperidin-1-carboxylic acid (4-trifluoromethoxyphenyl)amide (t) (6.94 g, 21 mmol) prepared in Step 2 were dissolved in dimethylformamide (208 mL), and diisopropylethylamine (9.37 mL) was added to the mixture and stirred at room temperature for 75 minutes. To the mixture, trifluoroacetic acid (4.3 mL) was added slowly dropwise over 10 minutes. The mixture was then added with methanol (208 mL) and further sodium cyanoborohydride (1.76 g) and stirred at room temperature for 3 hours. Methanol was removed in vacuo, and the residue was poured into 2.0 L of ethyl acetate. The precipitate was collected by filtration, and the obtained crude solid was rinsed with 10% saline to remove sodium cyanoborohydride. The crude solid was purified by reverse phase column chromatography to afford 10.19 g of the titled compound (u) (yield 41%).
(Step 4)
The compound (u) as prepared in Step 3 (485 mg, 0.275 mmol), benztriazole-1-yl-oxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (200 mg, 0.385 mmol) and benztriazole-1-ol (38 mg, 0.289 mmol) were dissolved in dimethylformamide (8 mL), and the mixture was stirred at room temperature for 1.5 hours. Diisopropyl ethylamine (0.24 mL) and o-(tetrahydro-2H-pyran-2-yl)hydroxylamine (64 mg, 0.55 mmol) were added sequentially at room temperature, and the mixture was stirred at this temperature for 1.5 hours. The mixture was poured into 60 mL of diethylether, and the precipitate was collected by filtration. The crude solid thus obtained was dissolved in a mixed solvent of acetonitrile (8 mL) and 0.5N hydrochloric acid (6 mL), and the mixture was stirred at room temperature for 1.5 hours. The mixture was subjected to purification by reverse phase column chromatography to afford 202 mg of the titled compound (Compound 4) as colorless solid (yield 41%).
[M+H]+=1777
Anal calcd. for C81H93Cl2F3N12O26.11.3H2O2.2.0HCl: C, 47.34%; H, 5.77%; Cl, 6.90%; F, 2.77%; N, 8.18%. Found: C, 47.42%; H, 5.77%; Cl, 6.85%; F, 2.64%; N, 8.21%.
The following compounds were prepared in a similar manner as described in the above Examples.
Compound 5
[M+H]+=1828
Anal calcd. for C81H89Cl4N15O26.11.2H2O.1.7HCl: C, 46.45%; H, 5.44%; N, 10.03%; Cl, 9.65%. Found: C, 46.48%; H, 5.34%; N, 9.77%; Cl, 9.69%.
Compound 6
[M+H]+=1860
Anal calcd. for C84H94Cl2F3N13O2810.0H2O.2.5HCl: C, 47.30%; H, 5.51%; N, 8.54%; Cl, 7.48%; F, 2.67%. Found: C, 47.24%; H, 5.42%; N, 8.67%; Cl, 7.50%; F, 2.70%.
Compound 7
[M+H]+=1814
Anal calcd. for C82H91Cl4N13O26.10.4H2O.2.2HCl: C, 47.26%; H, 5.51%; N, 8.74%; Cl, 10.55%. Found: C, 47.25%; H, 5.38%; N, 8.78%; Cl, 10.62%.
Compound 8
[M+H]+=1813
Anal calcd. for C82H92Cl4N14O25.10.4H2O.2.4HCl: C, 47.12%; H, 5.55%; N, 9.38%; Cl, 10.85%. Found: C, 47.07%; H, 5.49%; N, 9.44%; Cl, 10.83%.
Compound 9
[M+H]+=1862
Anal calcd. for C85H91Cl4N15O25.12.7H2O.2.4HCl: C, 46.81%; H, 5.49%; N, 9.63%; Cl, 10.40%. Found: C, 46.75%; H, 5.19%; N, 9.78%; Cl, 10.46%.
Compound 10
[M+H]+=1853
Anal calcd. for C83H92Cl4N16O25.13.7H2O.1.8HCl: C, 45.98%; H, 5.63%; N, 10.34%; Cl, 9.48%. Found: C, 45.96%; H, 5.34%; N, 10.44%; Cl, 9.55%.
Compound 11
[M+H]+=1871
Anal calcd. for C84H94Cl4N14O27.10.0H2O.1.9HCl: C, 47.52%; H, 5.50%; N, 9.24%; Cl, 9.85%. Found: C, 47.50%; H, 5.47%; N, 9.29%; Cl, 9.87%.
Compound 12
[M]+=1884
Anal calcd. for C85H98Cl5N15O26.12.1H2O.2.4HCl: C, 45.81%; H, 5.64%; N, 9.43%; Cl, 11.77%. Found: C, 45.78%; H, 5.59%; N, 9.62%; Cl, 11.69%.
Compound 13
[M+H]+=1971
Anal calcd. for C88H102Cl4N16O26S.12.1H2O.3.1HCl: C, 45.86%; H, 5.65%; N, 9.72%; Cl, 10.92%; S, 1.39%. Found: C, 45.80%; H, 5.53%; N, 9.79%; Cl, 10.98%; S, 1.42%.
Compound 14
[M+H]+=1805
Anal calcd. for C82H91Cl3N16O25.11.9H2O.2.8HCl: C, 46.38%; H, 5.58%; N, 10.55%; Cl, 9.68%. Found: C, 46.50%; H, 5.51%; N, 10.09%; Cl, 9.71%.
Compound 15
[M+H]+=1846
Anal calcd. for C84H90Cl3N15O27.10.3H2O.2.3HCl: C, 47.65%; H, 5.37%; N, 9.92%; Cl, 8.87%. Found: C, 47.64%; H, 5.30%; N, 9.94%; Cl, 8.90%.
Compound 16
[M+H]+=1763
Anal calcd. for C81H89Cl3N14O25.10.9H2O.2.6HCl: C, 47.31%; H, 5.56%; N, 9.54%; Cl, 9.66%. Found: C, 47.30%; H, 5.56%; N, 9.66%; Cl, 9.68%.
Compound 17
[M+H]+=1821
Anal calcd. for C83H91Cl3N14O27.9.9H2O.2.2HCl: C, 47.89%; H, 5.47%; N, 9.42%; Cl, 8.86%. Found: C, 47.92%; H, 5.45%; N, 9.31%; Cl, 8.92%.
Compound 18
[M+H]+=1839
Anal calcd. for C83H90Cl3FN14O27.9.6H2O.2.3HCl: C, 47.52%; H, 5.36%; N, 9.35%; Cl, 8.96%; F, 0.91%. Found: C, 47.52%; H, 5.40%; N, 9.18%; Cl, 8.94%; F, 1.09%.
Compound 19
[M+H]+=1814
Anal calcd. for C82H91Cl4N13O26.9.5H2O.2.3HCl: C, 47.54%; H, 5.46%; N, 8.79%; Cl, 10.78%. Found: C, 47.53%; H, 5.41%; N, 8.79%; Cl, 10.82%.
Compound 20
[M+H]+=1913
Anal calcd. for C86H96Cl4N14O28.10.1H2O.2.0HCl: C, 47.59%; H, 5.49%; N, 9.03%; Cl, 9.80%. Found: C, 47.62%; H, 5.43%; N, 8.84%; Cl, 9.74%.
Compound 21
[M+H]+=1813
Anal calcd. for C82H92Cl4N14O25.11.1H2O.2.2HCl: C, 47.00%; H, 5.60%; N, 9.36%; Cl, 10.49%. Found: C, 47.01%; H, 5.51%; N, 9.29%; Cl, 10.51%.
Compound 22
[M+H]+=1807
Anal calcd. for C83H93Cl3N14O26.10.5H2O.2.3HCl: C, 47.88%; H, 5.63%; N, 9.42%; Cl, 9.02%. Found: C, 47.90%; H, 5.50%; N, 9.39%; Cl, 9.04%.
Compound 23
[M+H]+=1816
Anal calcd. for C84H92Cl3N15O25.9.3H2O.2.8HCl: C, 48.33%; H, 5.47%; N, 10.06%; Cl, 9.85%. Found: C, 48.32%; H, 5.42%; N, 9.77%; Cl, 9.93%.
Compound 24
[M+H]+=1899
Anal calcd. for C86H98Cl4N14O27.10.8H2O.3.0HCl: C, 46.83%; H, 5.60%; N, 8.89%; Cl, 11.25%. Found: C, 46.84%; H, 5.55%; N, 8.94%; Cl, 11.20%.
Compound 25
[M+H]+=1871
Anal calcd. for C85H98Cl4N14O26.11.0H2O.3.0HCl: C, 46.81%; H, 5.68%; N, 8.99%; Cl, 11.38%. Found: C, 46.77%; H, 5.71%; N, 9.03%; Cl, 11.48%.
Compound 26
[M+H]+=1799
Anal calcd. for C81H90Cl4N14O25.10.3H2O.2.5HCl: C, 46.81%; H, 5.49%; N, 9.44%; Cl, 11.09%. Found: C, 46.82%; H, 5.52%; N, 9.51%; Cl, 11.06%.
Compound 27
[M+H]+=1829
Anal calcd. for C82H92Cl4N14O26.10.4H2O.2.7HCl: C, 46.52%; H, 5.50%; N, 9.26%; Cl, 11.22%. Found: C, 46.53%; H, 5.42%; N, 9.26%; Cl, 11.19%.
Compound 28
[M+H]+=1843
Anal calcd. for C82H90Cl4N14O27.9.8H2O.2.3HCl: C, 46.77%; H, 5.36%; N, 9.31%; Cl, 10.61%. Found: C, 46.75%; H, 5.46%; N, 9.33%; Cl, 10.61%.
Compound 29
[M+H]+=1827
Anal calcd. for C81H90Cl4N16O25.10.6H2O.2.6HCl: C, 45.99%; H, 5.42%; N, 10.59%; Cl, 11.06%. Found: C, 45.98%; H, 5.37%; N, 10.33%; Cl, 11.13%.
Compound 30
[M+H]+=1887
Anal calcd. for C84H94Cl4N14O28.9.4H2O.2.4HCl: C, 47.00%; H, 5.41%; N, 9.14%; Cl, 10.57%. Found: C, 46.98%; H, 5.38%; N, 9.29%; Cl, 10.64%.
Compound 31
[M+H]+=1871
Anal calcd. for C84H94Cl4N14O27.10.3H2O.2.4HCl: C, 47.00%; H, 5.49%; N, 9.14%; Cl, 10.57%. Found: C, 46.99%; H, 5.36%; N, 9.26%; Cl, 10.64%.
Compound 32
[M+H]+=1838
Anal calcd. for C83H91Cl4N15O25.9.0H2O.2.4HCl: C, 47.69%; H, 5.37%; N, 10.05%; Cl, 10.86%. Found: C, 47.67%; H, 5.33%; N, 10.27%; Cl, 10.88%.
Compound 33
[M+H]+=1857
Anal calcd. for C83H92Cl4N14O27.9.8H2O.2.4HCl: C, 46.94%; H, 5.41%; N, 9.23%; Cl, 10.68%. Found: C, 46.96%; H, 5.40%; N, 9.17%; Cl, 10.57%.
Compound 34
[M+H]+=1887
Anal calcd. for C85H95Cl2F3N14O28.10.2H2O.2.3HCl: C, 47.35%; H, 5.50%; N, 9.09%; Cl, 7.07%; F, 2.64%. Found: C, 47.38%; H, 5.54%; N, 9.09%; Cl, 7.09%; F, 2.53%.
Compound 35
[M+H]+=1869
Anal calcd. for C84H93Cl2F3N16O26.11.2H2O.3.2HCl: C, 46.09%; H, 5.46%; N, 10.24%; Cl, 8.42%; F, 2.60%. Found: C, 46.11%; H, 5.43%; N, 10.35%; Cl, 8.34%; F, 2.41%.
Compound 36
[M+H]+=1837
Anal calcd. for C83H92Cl3FN16O25.11.6H2O.3.1HCl: C, 46.13%; H, 5.52%; N, 10.37%; Cl, 10.01%; F, 0.88%. Found: C, 46.10%; H, 5.46%; N, 10.48%; Cl, 10.02%; F, 0.90%.
Compound 37
[M+H]+=1855
Anal calcd. for C84H94Cl3FN14O27.10.9H2O.2.0HCl: C, 47.45%; H, 5.58%; N, 9.22%; Cl, 8.34%; F, 0.89%. Found: C, 47.45%; H, 5.54%; N, 9.26%; Cl, 8.43%; F, 0.94%.
Compound 38
[M+H]+=1800
Anal calcd. for C81H89Cl4N13O26.11.0H2O.2.2HCl: C, 46.75%; H, 5.48%; N, 8.75%; Cl, 10.56%. Found: C, 46.71%; H, 5.42%; N, 8.81%; Cl, 10.52%.
Compound 39
[M+H]+=1784
Anal calcd. for C81H89Cl3FN13O26.11.9H2O.2.1HCl: C, 46.84%; H, 5.58%; N, 8.77%; Cl, 8.71%; F, 0.91%. Found: C, 46.79%; H, 5.57%; N, 8.96%; Cl, 8.76%; F, 0.95%.
Compound 40
[M+H]+=1783
Anal calcd. for C81H90Cl3FN14O25.12.6H2O.2.7HCl: C, 46.10%; H, 5.63%; N, 9.29%; Cl, 9.58%; F, 0.90%. Found: C, 46.10%; H, 5.48%; N, 9.36%; Cl, 9.63%; F, 0.92%.
Compound 41
[M+H]+=1852
Anal calcd. for C83H89Cl3FN15O27.12.6H2O.2.1HCl: C, 46.20%; H, 5.43%; N, 9.74%; Cl, 8.38%; F, 0.88%. Found: C, 46.15%; H, 5.32%; N, 9.99%; Cl, 8.34%; F, 0.92%.
Compound 42
[M+H]+=1796
Anal calcd. for C82H89Cl3FN13O26.11.5H2O.2.1HCl: C, 47.31%; H, 5.52%; N, 8.75%; Cl, 8.69%; F, 0.91%. Found: C, 47.30%; H, 5.48%; N, 8.80%; Cl, 8.65%; F, 0.96%.
Compound 43
[M+H]+=1855
Anal calcd. for C83H90Cl4N14O27.10.4H2O.2.1HCl: C, 46.99%; H, 5.36%; N, 9.24%; Cl, 10.19%. Found: C, 46.96%; H, 5.32%; N, 9.26%; Cl, 10.16%.
Compound 44
[M+H]+=1811
Anal calcd. for C82H90Cl3FN14O26.10.4H2O.2.2HCl: C, 47.34%; H, 5.47%; N, 9.42%; Cl, 8.86%; F, 0.91%. Found: C, 47.32%; H, 5.42%; N, 9.36%; Cl, 8.89%; F, 0.98%.
Compound 45
[M+H]+=1812
Anal calcd. for C81H89Cl3FN15O26.11.0H2O.2.2HCl: C, 46.50%; H, 5.45%; N, 10.04%; Cl, 8.81%; F, 0.91%. Found: C, 46.14%; H, 5.47%; N, 10.78%; Cl, 8.78%; F, 0.88%.
Compound 46
[M+H]+=1792
Anal calcd. for C84H99Cl2N13O27.10.1H2O.2.0HCl: C, 49.25%; H, 5.96%; N, 8.89%; Cl, 6.92%. Found: C, 49.13%; H, 5.91%; N, 9.35%; Cl, 6.91%.
Compound 47
[M+H]+=1788
Anal calcd. for C84H95Cl2N13O27.10.5H2O23HCl: C, 48.91%; H, 5.78%; N, 8.83%; Cl, 7.39%. Found: C, 48.75%; H, 5.75%; N, 9.44%; Cl, 7.48%.
Compound 48
[M+H]+=1820
Anal calcd. for C84H99Cl2N15O27.10.3H2O.2.0HCl: C, 48.50%; H, 5.89%; N, 10.10%; Cl, 6.82%. Found: C, 48.33%; H, 5.82%; N, 10.64%; Cl, 6.89%.
Compound 49
[M+H]+=1816
Anal calcd. for C84H95Cl2N15O27.10.2H2O.2.4HCl: C, 48.30%; H, 5.68%; N, 10.06%; Cl, 7.47%. Found: C, 48.16%; H, 5.64%; N, 10.57%; Cl, 7.46%.
Compound 50
[M+H]+=1813
Anal calcd. for C82H92Cl3FN14O26.9.5H2O.2.4HCl: C, 47.49%; H, 5.51%; N, 9.46%; Cl, 9.23%; F, 0.92%. Found: C, 47.40%; H, 5.48%; N, 10.09%; Cl, 9.25%; F, 0.96
Compound 51
[M+H]+=1840
Anal calcd. for C82H89Cl3FN15O27.13.0H2O.2.2HCl: C, 45.67%; H, 5.48%; N, 9.74%; Cl, 8.55%; F, 0.88%. Found: C, 45.70%; H, 5.45%; N, 9.72%; Cl, 8.46%; F, 0.88%.
Compound 52
[M+H]+=1797
Anal calcd. for C82H92Cl3FN14O25.12.5H2O.2.7HCl: C, 46.40%; H, 5.68%; N, 9.24%; Cl, 9.52%; F, 0.90%. Found: C, 46.37%; H, 5.64%; N, 9.38%; Cl, 9.38%; F, 0.90%.
Compound 53
[M+H]+=1823
Anal calcd. for C82H90Cl3FN16O25.9.5H2O.2.4HCl: C, 47.27%; H, 5.39%; N, 10.76%; Cl, 9.19%; F, 0.91%. Found: C, 47.13%; H, 5.23%; N, 11.20%; Cl, 9.25%; F, 0.85%.
Compound 54
[M+H]+=1840
Anal calcd. for C84H93Cl3FN13O27.10.6H2O.2.4HCl: C, 47.58%; H, 5.54%; N, 8.59%; Cl, 9.03%; F, 0.90%. Found: C, 47.56%; H, 5.48%; N, 8.68%; Cl, 9.04%; F, 0.99%.
Compound 55
[M+H]+=1827
Anal calcd. for C82H90Cl4N14O26.10.6H2O.2.0HCl: C, 47.05%; H, 5.45%; N, 9.37%; Cl, 10.16%. Found: C, 47.05%; H, 5.31%; N, 9.39%; Cl, 10.08%.
Compound 56
[M+H]+=1784
Anal calcd. for C81H89Cl3FN13O26.10.6H2O.2.1HCl: C, 47.38%; H, 5.51%; N, 8.87%; Cl, 8.80%; F, 0.93%. Found: C, 47.37%; H, 5.42%; N, 9.02%; Cl, 8.82%; F, 0.98%.
Compound 57
[M+H]+=1812
Anal calcd. for C81H89Cl3FN15O26.10.2H2O.2.2HCl: C, 46.82%; H, 5.41%; N, 10.11%; Cl, 8.87%; F, 0.91%. Found: C, 46.81%; H, 5.35%; N, 10.16%; Cl, 8.83%; F, 0.96%.
Compound 58
[M+H]+=1811
Anal calcd. for C81H90Cl3FN16O25.11.9H2O.3.2HCl: C, 45.37%; H, 5.50%; N, 10.45%; Cl, 10.25%; F, 0.89%. Found: C, 45.39%; H, 5.47%; N, 10.32%; Cl, 10.28%; F, 0.86%.
Compound 59
[M+H]+=1797
Anal calcd. for C82H92Cl3FN14O25.11.1H2O.2.2HCl: C, 47.37%; H, 5.64%; N, 9.43%; Cl, 8.87%; F, 0.91%. Found: C, 47.34%; H, 5.64%; N, 9.58%; Cl, 8.89%; F, 0.97%.
Compound 60
[M+H]+=1822
Anal calcd. for C83H91Cl3FN15O25.9.9H2O.2.2HCl: C, 47.87%; H, 5.47%; N, 10.09%; Cl, 8.85%; F, 0.91%. Found: C, 47.80%; H, 5.39%; N, 10.22%; Cl, 8.91%; F, 0.98%.
Compound 61
[M+H]+=1955
Anal calcd. for C88H102Cl3FN16O26S.11.2H2O.3.2HCl: C, 46.44%; H, 5.65%; N, 9.85%; Cl, 9.66%; F, 0.83; S, 1.41%. Found: C, 46.36%; H, 5.63%; N, 10.01%; Cl, 9.69%; F, 0.90; S, 1.37%.
Compound 62
[M+H]+=1769
Anal calcd. for C80H88Cl3FN14O25.11.3H2O.2.6HCl: C, 46.43%; H, 5.51%; N, 9.48%; Cl, 9.59%; F, 0.92%. Found: C, 46.37%; H, 5.36%; N, 9.64%; Cl, 9.54%; F, 1.11%.
Compound 63
[M+H]+=1845
Anal calcd. for C85H96Cl2N14O28.10.4H2O.2.6HCl: C, 48.27%; H, 5.69%; N, 9.27%; Cl, 7.71%. Found: C, 48.25%; H, 5.65%; N, 9.45%; Cl, 7.75%.
Compound 64
[M+H]+=1829
Anal calcd. for C83H93Cl2F3N14O26.9.8H2O.2.3HCl: C, 47.67%; H, 5.54%; N, 9.38%; Cl, 7.29%; F, 2.73%. Found: C, 47.64%; H, 5.59%; N, 9.43%; Cl, 7.30%; F, 2.71%.
Compound 65
[M+H]+=1843
Anal calcd. for C82H91Cl2F3N16O26.11.0H2O.2.9HCl: C, 45.84%; H, 5.44%; N, 10.43%; Cl, 8.09%; F, 2.65%. Found: C, 46.05%; H, 5.49%; N, 9.62%; Cl, 8.09%; F, 2.41%.
Compound 66
[M+H]+=1860
Anal calcd. for C82H90Cl2F3N15O26S.10.8H2O.1.9HCl: C, 46.34%; H, 5.38%; N, 9.88%; Cl, 6.51%; F, 2.68%; S, 1.51%. Found: C, 46.41%; H, 5.30%; N, 9.42%; Cl, 6.50%; F, 2.87%; S, 1.22%.
Compound 67
[M+H]+=1872
Anal calcd. for C83H90Cl2F3N15O28.11.2H2O.2.1HCl: C, 46.33%; H, 5.36%; N, 9.76%; Cl, 6.75%; F, 2.65%. Found: C, 46.31%; H, 5.31%; N, 9.77%; Cl, 6.75%; F, 2.51%.
Compound 68
[M+H]+=1811
Anal calcd. for C82H90Cl4N14O25.11.4H2O.2.7HCl: C, 46.52%; H, 5.50%; N, 9.26%; Cl, 11.22%. Found: C, 46.54%; H, 5.53%; N, 9.30%; Cl, 11.18%.
Compound 69
[M+H]+=1841
Anal calcd. for C83H92Cl4N14O26.11.3H2O.2.9HCl: C, 46.31%; H, 5.50%; N, 9.11%; Cl, 11.36%. Found: C, 46.28%; H, 5.39%; N, 9.21%; Cl, 11.38%.
Compound 70
[M+H]+=1883
Anal calcd. for C86H98Cl4N14O26.10.9H2O.3.3HCl: C, 46.90%; H, 5.63%; N, 8.90%; Cl, 11.75%. Found: C, 46.85%; H, 5.54%; N, 8.96%; Cl, 11.79%.
Compound 71
[M+H]+=1839
Anal calcd. for C82H90Cl4N16O25.11.1H2O.3.2HCl: C, 45.64%; H, 5.39%; N, 10.38%; Cl, 11.83%. Found: C, 45.76%; H, 5.37%; N, 9.92%; Cl, 11.86%.
Compound 72
[M+H]+=1911
Anal calcd. for C87H98Cl4N14O27.11.8H2O.3.5HCl: C, 46.36%; H, 5.59%; N, 8.70%; Cl, 11.80%. Found: C, 46.36%; H, 5.49%; N, 8.73%; Cl, 11.78%.
Compound 73
[M+H]+=1880
Anal calcd. for C84H89Cl4N15O27.11.0H2O.2.0HCl: C, 46.85%; H, 5.29%; N, 9.76%; Cl, 9.88%. Found: C, 46.88%; H, 5.36%; N, 9.61%; Cl, 9.86%.
Compound 74
[M+H]+=1862
Anal calcd. for C83H89Cl4F2N13O26.10.7H2O.2.2HCl: C, 46.64%; H, 5.31%; N, 8.52%; Cl, 10.28%; F, 1.78%. Found: C, 46.60%; H, 5.33%; N, 8.68%; Cl, 10.26%; F, 1.48%.
Compound 75
[M+H]+=1812
Anal calcd. for C82H89Cl4N13O26.11.6H2O.2.2HCl: C, 46.82%; H, 5.48%; N, 8.66%; Cl, 10.45%. Found: C, 46.82%; H, 5.43%; N, 8.65%; Cl, 10.46%.
Compound 76
[M+H]+=1856
Anal calcd. for C84H93Cl4N13O27.10.3H2O.2.6HCl: C, 47.17%; H, 5.48%; N, 8.51%; Cl, 10.94%. Found: C, 47.17%; H, 5.48%; N, 8.63%; Cl, 10.90%.
Compound 77
[M+H]+=1857
Anal calcd. for C83H92Cl4N14O27.10.2H2O.3.0HCl: C, 46.31%; H, 5.40%; N, 9.11%; Cl, 11.53%. Found: C, 46.36%; H, 5.48%; N, 9.01%; Cl, 11.48%.
Compound 78
[M+H]+=1795
Anal calcd. for C83H100Cl2N14O27.11.5H2O.2.4HCl: C, 47.67%; H, 6.04%; N, 9.38%; Cl, 7.46%. Found: C, 47.67%; H, 5.91%; N, 9.47%; Cl, 7.47%.
Compound 79
[M+H]+=1891
Anal calcd. for C87H97Cl3N14O28.11.2H2O.2.4HCl: C, 47.88%; H, 5.63%; N, 8.99%; Cl, 8.77%. Found: C, 47.84%; H, 5.64%; N, 9.15%; Cl, 8.75%.
Compound 80
[M+H]+=1806
Anal calcd. for C82H90Cl3N15O26.10.6H2O.2.2HCl: C, 47.37%; H, 5.50%; N, 10.10%; Cl, 8.87%. Found: C, 47.36%; H, 5.49%; N, 9.95%; Cl, 8.85%.
Compound 81
[M+H]+=1831
Anal calcd. for C84H93Cl3N16O25.10.2H2O.3.2HCl: C, 47.29%; H, 5.51%; N, 10.50%; Cl, 10.30%. Found: C, 47.31%; H, 5.62%; N, 10.49%; Cl, 10.28%.
Compound 82
[M+H]+=1849
Anal calcd. for C86H99Cl3N14O26.12.2H2O.3.2HCl: C, 47.22%; H, 5.83%; N, 8.96%; Cl, 10.05%. Found: C, 47.20%; H, 5.75%; N, 9.07%; Cl, 10.07%.
Compound 83
[M+H]+=1865
Anal calcd. for C85H95Cl3N14O28.11.0H2O.2.4HCl: C, 47.42%; H, 5.59%; N, 9.11%; Cl, 8.89%. Found: C, 47.44%; H, 5.52%; N, 9.03%; Cl, 8.96%.
Compound 84
[M+H]+=1877
Anal calcd. for C87H99Cl3N14O27.11.5H2O.3.1HCl: C, 47.51%; H, 5.73%; N, 8.92%; Cl, 9.83%. Found: C, 47.53%; H, 5.70%; N, 9.10%; Cl, 9.78%.
Compound 85
[M+H]+=1791
Anal calcd. for C83H93Cl3N14O25.11.5H2O.2.1HCl: C, 48.00%; H, 5.73%; N, 9.44%; Cl, 8.71%. Found: C, 48.01%; H, 5.67%; N, 9.39%; Cl, 8.66%.
Compound 86
[M+H]+=1835
Anal calcd. for C84H93Cl3N14O27.10.8H2O.2.2HCl: C, 47.77%; H, 5.57%; N, 9.29%; Cl, 8.73%. Found: C, 47.73%; H, 5.52%; N, 9.38%; Cl, 8.66%.
Compound 87.
[M+H]+=1849
Anal calcd. for C85H95Cl3N14O27.11.8H2O.2.4HCl: C, 47.46%; H, 5.67%; N, 9.12%; Cl, 8.90%. Found: C, 47.45%; H, 5.56%; N, 9.19%; Cl, 8.84%.
Compound 88
[M+H]+=1778
Anal calcd. for C82H90Cl3N13O26.11.5H2O.2.3HCl: C, 47.55%; H, 5.61%; N, 8.79%; Cl, 9.07%. Found: C, 47.51%; H, 5.57%; N, 9.01%; Cl, 9.12%.
Compound 89
[M+H]+=1849
Anal calcd. for C85H95Cl3N14O27.11.4H2O.2.2HCl: C, 47.78%; H, 5.66%; N, 9.18%; Cl, 8.63%. Found: C, 47.75%; H, 5.60%; N, 9.29%; Cl, 8.66%.
Compound 90
[M]+=1862
Anal calcd. for C86H99Cl4N15O26.13.2H2O.2.0HCl: C, 46.71%; H, 5.81%; N, 9.50%; Cl, 9.62%. Found: C, 46.69%; H, 5.78%; N, 9.59%; Cl, 9.65%.
Compound 91
[M+H]+=1777
Anal calcd. for C82H91Cl3N14O25.12.1H2O.3.1HCl: C, 46.68%; H, 5.65%; N, 9.29%; Cl, 10.25%. Found: C, 46.65%; H, 5.68%; N, 9.42%; Cl, 10.32%.
Compound 92
[M+H]+=1834
Anal calcd. for C83H90Cl3N15O27.11.8H2O.2.2HCl: C, 46.83%; H, 5.48%; N, 9.87%; Cl, 8.66%. Found: C, 46.81%; H, 5.48%; N, 9.86%; Cl, 8.67%.
Compound 93
[M+H]+=1792
Anal calcd. for C83H92Cl3N13O26.10.8H2O.2.5HCl: C, 47.93%; H, 5.63%; N, 8.76%; Cl, 9.38%. Found: C, 47.94%; H, 5.60%; N, 8.77%; Cl, 9.43%.
Compound 94
[M+H]+=1822
Anal calcd. for C84H94Cl3N13O27.11.6H2O.2.5HCl: C, 47.50%; H, 5.68%; N, 8.57%; Cl, 9.18%. Found: C, 47.45%; H, 5.55%; N, 8.66%; Cl, 9.21%.
Compound 95
[M+H]+=1805
Anal calcd. for C83H91Cl3N14O26.12.5H2O.2.3HCl: C, 47.11%; H, 5.63%; N, 9.27%; Cl, 8.88%. Found: C, 47.13%; H, 5.51%; N, 9.25%; Cl, 8.87%.
Compound 96
[M+H]+=1770
Anal calcd. for C80H87Cl3FN13O26.11.9H2O.2.2HCl: C, 46.50%; H, 5.51%; N, 8.81%; Cl, 8.92%; F, 0.92%. Found: C, 46.47%; H, 5.42%; N, 8.86%; Cl, 8.88%; F, 0.94%.
Compound 97
[M+H]+=1827
Anal calcd. for C82H90Cl3FN14O27.11.7H2O.2.3HCl: C, 46.38%; H, 5.49%; N, 9.23%; Cl, 8.85%; F, 0.89%. Found: C, 46.37%; H, 5.33%; N, 9.24%; Cl, 8.83%; F, 0.95%.
Compound 98
[M+H]+=1785
Anal calcd. for C80H88Cl4N14O25.12.6H2O.2.6HCl: C, 45.55%; H, 5.53%; N, 9.30%; Cl, 11.09%. Found: C, 45.53%; H, 5.49%; N, 9.45%; Cl, 11.05%.
Compound 99
[M+H]+=1883
Anal calcd. for C86H98Cl3FN14O27.11.6H2O.3.5HCl: C, 46.49%; H, 5.66%; N, 8.83%; Cl, 10.37%; F, 0.86%. Found: C, 46.46%; H, 5.65%; N, 9.23%; Cl, 10.43%; F, 0.92%.
Compound 100
[M+H]+=1897
Anal calcd. for C86H96Cl3FN14O28.10.9H2O.2.3HCl: C, 47.40%; H, 5.55%; N, 9.00%; Cl, 8.62%; F, 0.87%. Found: C, 47.23%; H, 5.52%; N, 9.30%; Cl, 8.55%; F, 0.90%.
Compound 101
[M+H]+=1855
Anal calcd. for C85H98Cl3FN14O26.11.4H2O.3.2HCl: C, 46.85%; H, 5.74%; N, 9.00%; Cl, 10.09%; F, 0.87%. Found: C, 46.57%; H, 5.83%; N, 9.30%; Cl, 10.18%; F, 0.89%.
Compound 102
[M+H]+=1868
Anal calcd. for C83H88Cl4N15O27.11.8H2O.1.9HCl: C, 46.34%; H, 5.32%; N, 9.77%; Cl, 9.72%. Found: C, 46.32%; H, 5.33%; N, 10.03%; Cl, 9.65%.
Compound 103
[M+H]+=1786
Anal calcd. for C80H87Cl4N13O26.11.1H2O.2.7HCl: C, 46.04%; H, 5.40%; N, 8.73%; Cl, 11.38%. Found: C, 45.90%; H, 5.38%; N, 9.32%; Cl, 11.31%.
Compound 104
[M+H]+=1791
Anal calcd. for C83H93Cl3N14O25.12.1H2O.2.2HCl: C, 47.67%; H, 5.75%; N, 9.38%; Cl, 8.82%. Found: C, 47.63%; H, 5.75%; N, 9.53%; Cl, 8.80%.
Compound 105
[M+H]+=1820
Anal calcd. for C84H99Cl2N15O27.11.3H2O.1.7HCl: C, 48.34%; H, 5.95%; N, 10.07%; Cl, 6.28%. Found: C, 48.35%; H, 5.95%; N, 10.24%; Cl, 6.23%.
Compound 106
[M+H]+=1796
Anal calcd. for C84H103Cl2N13O27.11.4H2O.2.3HCl: C, 48.34%; H, 6.19%; N, 8.73%; Cl, 7.30%. Found: C, 48.35%; H, 6.13%; N, 8.85%; Cl, 7.30%.
Compound 107
[M+H]+=1823
Anal calcd. for C83H93Cl3N14O27.11.8H2O.2.2HCl: C, 47.07%; H, 5.65%; N, 9.26%; Cl, 8.70%. Found: C, 47.05%; H, 5.50%; N, 9.34%; Cl, 8.62%.
Compound 108
[M+H]+=1858
Anal calcd. for C84H95Cl4N13O27.11.5H2O.2.1HCl: C, 47.05%; H, 5.65%; N, 8.49%; Cl, 10.09%. Found: C, 46.99%; H, 5.66%; N, 8.76%; Cl, 10.16%.
Compound 109
[M+H]+=1828
Anal calcd. for C83H93Cl3FN13O27.11.9H2O.1.9HCl: C, 47.16%; H, 5.66%; N, 8.61%; Cl, 8.22%; F, 0.90%. Found: C, 47.13%; H, 5.55%; N, 8.79%; Cl, 8.22%; F, 1.20%.
Compound 110
[M+H]+=1782
Anal calcd. for C83H101Cl2N13O27.11.5H2O.2.3HCl: C, 48.05%; H, 6.14%; N, 8.78%; Cl, 7.35%. Found: C, 47.98%; H, 6.20%; N, 9.13%; Cl, 7.33%.
Compound 111
[M+H]+=1752
Anal calcd. for C82H99Cl2N13O26.11.7H2O.2.2HCl: C, 48.17%; H, 6.14%; N, 8.91%; Cl, 7.28%. Found: C, 48.16%; H, 6.06%; N, 8.83%; Cl, 7.24%.
Compound 112
[M+H]+=1841
Anal calcd. for C83H92Cl3FN14O27.11.9H2O.2.0HCl: C, 46.79%; H, 5.57%; N, 9.20%; Cl, 8.32%; F, 0.89%. Found: C, 46.81%; H, 5.51%; N, 9.20%; Cl, 8.28%; F, 0.90%.
Compound 113
[M+H]+=1828
Anal calcd. for C83H93Cl3FN13O27.10.6H2O.2.4HCl: C, 47.28%; H, 5.57%; N, 8.64%; Cl, 9.08%; F, 0.90%. Found: C, 47.22%; H, 5.48%; N, 8.78%; Cl, 9.02%; F, 0.95%.
Compound 114
[M+H]+=1811
Anal calcd. for C81H90Cl3FN16O25.11.8H2O.2.8HCl: C, 45.72%; H, 5.51%; N, 10.53%; Cl, 9.66%; F, 0.89%. Found: C, 45.65%; H, 5.41%; N, 10.62%; Cl, 9.73%; F, 0.90%.
Compound 115
[M+H]+=1841
Anal calcd. for C83H92Cl3FN14O27.10.1H2O.2.1HCl: C, 47.44%; H, 5.48%; N, 9.33%; Cl, 8.60%; F, 0.90%. Found: C, 47.28%; H, 5.37%; N, 9.63%; Cl, 8.59%; F, 1.16%.
Compound 116
[M+H]+=1827
Anal calcd. for C82H90Cl3FN14O27.11.5H2O.2.5HCl: C, 46.30%; H, 5.47%; N, 9.22%; Cl, 9.17%; F, 0.89%. Found: C, 46.27%; H, 5.36%; N, 9.38%; Cl, 9.24%; F, 0.94%.
Compound 117
[M+H]+=1786
Anal calcd. for C82H90Cl2F3N13O25.10.0H2O.2.4HCl: C, 47.97%; H, 5.52%; N, 8.87%; Cl, 7.60%; F, 2.78%. Found: C, 47.98%; H, 5.39%; N, 8.98%; Cl, 7.61%; F, 2.82%.
Compound 118
[M+H]+=1811
Anal calcd. for C83H89Cl2F3N14O25.10.7H2O.2.3HCl: C, 47.76%; H, 5.44%; N, 9.40%; Cl, 7.30%; F, 2.73%. Found: C, 47.75%; H, 5.24%; N, 9.41%; Cl, 7.29%; F, 2.77%.
Compound 119
[M+H]+=1786
Anal calcd. for C82H90Cl2F3N13O25.10.3H2O.2.4HCl: C, 47.84%; H, 5.53%; N, 8.85%; Cl, 7.58%; F, 2.77%. Found: C, 47.80%; H, 5.45%; N, 8.92%; Cl, 7.53%; F, 2.87%.
Compound 120
[M+H]+=1802
Anal calcd. for C82H90Cl2F3N13O26.10.5H2O.2.3HCl: C, 47.47%; H, 5.50%; N, 8.78%; Cl, 7.35%; F, 2.75%. Found: C, 47.46%; H, 5.40%; N, 8.88%; Cl, 7.37%; F, 2.68%.
Compound 121
[M+H]+=1872
Anal calcd. for C86H96Cl2F3N13O27.11.4H2O.3.6HCl: C, 46.77%; H, 5.59%; N, 8.25%; Cl, 8.99%; F, 2.58%. Found: C, 46.73%; H, 5.45%; N, 8.37%; Cl, 8.97%; F, 2.66%.
Compound 122
[M+H]+=1817
Anal calcd. for C83H91Cl2F3N12O27.10.8H2O.2.7HCl: C, 47.26%; H, 5.51%; N, 7.97%; Cl, 7.90%; F, 2.70%. Found: C, 47.25%; H, 5.43%; N, 8.03%; Cl, 7.94%; F, 2.76%.
Compound 123
[M+H]+=1759
Anal calcd. for C80H85Cl2F3N12O26.10.0H2O.3.1HCl: C, 46.83%; H, 5.31%; N, 8.19%; Cl, 8.81%; F, 2.78%. Found: C, 46.81%; H, 5.26%; N, 8.23%; Cl, 8.82%; F, 2.76%.
Compound 124
[M+H]+=1801
Anal calcd. for C82H90Cl4N12O26.9.9H2O.3.0HCl: C, 47.14%; H, 5.44%; N, 8.05%; Cl, 11.88%. Found: C, 47.11%; H, 5.36%; N, 8.30%; Cl, 11.83%.
Compound 125
[M+H]+=1759
Anal calcd. for C80H86Cl4N12O25.11.5H2O.2.2HCl: C, 46.99%; H, 5.48%; N, 8.22%; Cl, 10.75%. Found: C, 46.96%; H, 5.36%; N, 8.33%; Cl, 10.72%.
Compound 126
[M+H]+=1770
Anal calcd. for C81H89Cl4N13O24.11.9H2O.2.4HCl: C, 46.95%; H, 5.60%; N, 8.79%; Cl, 10.95%. Found: C, 46.92%; H, 5.49%; N, 8.86%; Cl, 11%.
Compound 127
[M+H]+=1786
Anal calcd. for C81H89Cl4N13O25.11.3H2O.2.1HCl: C, 47.08%; H, 5.55%; N, 8.81%; Cl, 10.46%. Found: C, 47.03%; H, 5.52%; N, 8.98%; Cl, 10.40%.
Compound 128
[M+H]+=1785
Anal calcd. for C80H86Cl4N14O25.10.6H2O.3.0HCl: C, 46.07%; H, 5.33%; N, 9.40%; Cl, 11.90%. Found: C, 46.04%; H, 5.20%; N, 9.47%; Cl, 11.89%.
Compound 129
[M+H]+=1866
Anal calcd. for C82H90Cl4N12O28S1.8.5H2O.2.6HCl: C, 46.60%; H, 5.23%; N, 7.95%; Cl, 11.07%; S, 1.52%. Found: C, 46.57%; H, 5.45%; N, 8.22%; Cl, 11.11%; S, 1.31%.
Compound 130
[M+H]+=1856
Anal calcd. for C85H95Cl4N13O26.13.4H2O.3.1HCl: C, 46.17%; H, 5.69%; N, 8.24%; Cl, 11.38%. Found: C, 46.12%; H, 5.58%; N, 8.39%; Cl, 11.44%.
Compound 131
[M+H]+=1743
Anal calcd. for C79H84Cl4N12O25.10.6H2O.2.3HCl: C, 47.01%; H, 5.37%; N, 8.33%; Cl, 11.07%. Found: C, 47.03%; H, 5.33%; N, 8.23%; Cl, 11.08%.
Compound 132
[M+H]+=1865
Anal calcd. for C81H90Cl4N14O27S1.9.5H2O.2.3HCl: C, 45.88%; H, 5.29%; N, 9.25%; Cl, 10.53%; S, 1.51%. Found: C, 45.93%; H, 5.27%; N, 9.12%; Cl, 10.46%; S, 1.33%.
Compound 133
[M+H]+=1800
Anal calcd. for C81H87Cl4N13O26.10.9H2O.2.4HCl: C, 46.68%; H, 5.38%; N, 8.74%; Cl, 10.89%. Found: C, 46.67%; H, 5.41%; N, 8.81%; Cl, 10.92%.
Compound 134
[M+H]+=1814
Anal calcd. for C82H89Cl4N13O26.10.2H2O.2.3HCl: C, 47.30%; H, 5.41%; N, 8.75%; Cl, 10.73%. Found: C, 47.26%; H, 5.34%; N, 8.87%; Cl, 10.75%.
Compound 135
[M+H]+=1828
Anal calcd. for C83H91Cl4N13O26.10.8H2O.2.4HCl: C, 47.23%; H, 5.49%; N, 8.63%; Cl, 10.75%. Found: C, 47.26%; H, 5.34%; N, 8.87%; Cl, 10.75%.
Compound 136
[M+H]+=1825
Anal calcd. for C82H86Cl4N14O26.10.6H2O.2.3HCl: C, 46.89%; H, 5.26%; N, 9.34%; Cl, 10.63%. Found: C, 46.91%; H, 5.27%; N, 9.38%; Cl, 10.59%.
Compound 137
[M+H]+=1784
Anal calcd. for C81H87Cl4N13O25.11H2O.2.2HCl: C, 47.16%; H, 5.43%; N, 8.83%; Cl, 10.66%. Found: C, 47.13%; H, 5.39%; N, 8.99%; Cl, 10.68%.
Compound 138
[M+H]+=1757
Anal calcd. for C80H86Cl4N12O25.10.6H2O.2.3HCl: C, 47.28%; H, 5.43%; N, 8.27%; Cl, 10.99%. Found: C, 47.26%; H, 5.34%; N, 8.37%; Cl, 11.04%.
Compound 139
[M+H]+=1770
Anal calcd. for C81H89Cl4N13O24.11.1H2O.2.8HCl: C, 46.94%; H, 5.54%; N, 8.79%; Cl, 11.63%. Found: C, 46.89%; H, 5.41%; N, 8.87%; Cl, 11.65%.
Compound 140
[M+H]+=1785
Anal calcd. for C80H86Cl4N14O25.11.8H2O.2.8HCl: C, 45.75%; H, 5.39%; N, 9.34%; Cl, 11.48%. Found: C, 45.72%; H, 5.26%; N, 9.43%; Cl, 11.45%.
Compound 141
[M+H]+=1743
Anal calcd. for C79H84Cl4N12O25.11.2H2O.2.3HCl: C, 46.76%; H, 5.40%; N, 8.28%; Cl, 11.01%. Found: C, 46.73%; H, 5.32%; N, 8.37%; Cl, 11.06%.
Compound 142
[M+H]+=1825
Anal calcd. for C82H86Cl4N12O26.12.0H2O.1.8HCl: C, 46.74%; H, 5.35%; N, 9.31%; Cl, 9.76%. Found: C, 46.84%; H, 5.25%; N, 9.22%; Cl, 9.81%.
Compound 143
[M+H]+=1772
Anal calcd. for C81H87Cl2F3N12O26.11.6H2O.2.0HCl: C, 47.35%; H, 5.50%; N, 8.18%; Cl, 6.90%; F, 2.77%. Found: C, 47.29%; H, 5.32%; N, 8.38%; Cl, 6.91%; F, 2.66%.
Compound 144
[M+H]+=1759
Anal calcd. for C80H85Cl2F3N12O26.11.0H2O.2.3HCl: C, 47.09%; H, 5.40%; N, 8.24%; Cl, 7.47%; F, 2.79%. Found: C, 47.07%; H, 5.33%; N, 8.31%; Cl, 7.44%; F, 2.74%.
Compound 145
[M+H]+=1802
Anal calcd. for C82H90Cl2F3N13O26.11.7H2O.2.5HCl: C, 46.82%; H, 5.55%; N, 8.66%; Cl, 7.58%; F, 2.71%. Found: C, 46.81%; H, 5.46%; N, 8.71%; Cl, 7.50%; F, 2.63%.
Compound 146
[M+H]+=1801
Anal calcd. for C81H87Cl2F3N14O26.12.6H2O.2.2HCl: C, 46.16%; H, 5.47%; N, 9.30%; Cl, 7.06%; F, 2.70%. Found: C, 46.15%; H, 5.29%; N, 9.40%; Cl, 7.06%; F, 2.65%.
Compound 147
[M+H]+=1815
Anal calcd. for C82H88Cl2F3N13O27.9.8H2O.2.4HCl: C, 47.36%; H, 5.33%; N, 8.76%; Cl, 7.50%; F, 2.74%. Found: C, 47.30%; H, 5.23%; N, 8.85%; Cl, 7.49%; F, 2.68%.
Compound 148
[M+H]+=1741
Anal calcd. for C80H86Cl3F1N12O25.11.9H2O.3.1HCl: C, 46.45%; H, 5.50%; N, 8.13%; Cl, 10.46%; F, 0.92%. Found: C, 46.42%; H, 5.32%; N, 8.23%; Cl, 10.37%; F, 1.11%.
Compound 149
[M+H]+=1747
Anal calcd. for C82H89Cl3N12O25.12.0H2O.2.3HCl: C, 48.07%; H, 5.67%; N, 8.20%; Cl, 9.17%. Found: C, 48.04%; H, 5.54%; N, 8.27%; Cl, 9.23%.
Compound 150
[M+H]+=1776
Anal calcd. for C83H92Cl3N13O25.11.3H2O.2.5HCl: C, 48.09%; H, 5.69%; N, 8.78%; Cl, 9.41%. Found: C, 48.08%; H, 5.66%; N, 8.97%; Cl, 9.33%.
Compound 151
[M+H]+=1733
Anal calcd. for C81H87Cl3N12O25.12.0H2O.2.3HCl: C, 47.81%; H, 5.61%; N, 8.26%; Cl, 9.23%. Found: C, 47.78%; H, 5.56%; N, 8.31%; Cl, 9.18%.
Compound 152
[M+H]+=1797
Anal calcd. for C83H89Cl2F3N12O26.10.6H2O.2.7HCl: C, 47.74%; H, 5.45%; N, 8.05%; Cl, 7.98%; F, 2.73%. Found: C, 47.70%; H, 5.37%; N, 8.22%; Cl, 8.00%; F, 2.70%.
Compound 153
[M+H]+=1796
Anal calcd. for C83H90Cl2F3N13O25.11.5H2O.2.7HCl: C, 47.40%; H, 5.54%; N, 8.66%; Cl, 7.92%; F, 2.71%. Found: C, 47.32%; H, 5.49%; N, 8.86%; Cl, 7.92%; F, 2.61%.
Compound 154
[M+H]+=1826
Anal calcd. for C84H92Cl2F3N13O26.11.4H2O.2.6HCl: C, 47.42%; H, 5.56%; N, 8.56%; Cl, 7.66%; F, 2.68%. Found: C, 47.41%; H, 5.42%; N, 8.71%; Cl, 7.60%; F, 2.63%.
Compound 155
[M+H]+=1783
Anal calcd. for C82H87Cl2F3N12O26.11.1H2O.2.4HCl: C, 47.53%; H, 5.43%; N, 8.11%; Cl, 7.53%; F, 2.75%. Found: C, 47.37%; H, 5.51%; N, 8.41%; Cl, 7.61%; F, 2.63%.
Compound 156
[M+H]+=1725
Anal calcd. for C79H84Cl3FN12O25.10.4H2O.2.2HCl: C, 47.57%; H, 5.41%; N, 8.43%; Cl, 9.24%; F, 0.95%. Found: C, 47.51%; H, 5.40%; N, 8.73%; Cl, 9.16%; F, 1.00%.
Compound 157
[M+H]+=1739
Anal calcd. for C80H86Cl3FN12O25.9.2H2O.2.2HCl: C, 48.36%; H, 5.41%; N, 8.46%; Cl, 9.28%; F, 0.96%. Found: C, 48.30%; H, 5.67%; N, 8.72%; Cl, 9.37%; F, 0.97%.
Compound 158
[M+H]+=1768
Anal calcd. for C81H89Cl3FN13O25.11.1H2O.2.3HCl: C, 47.37%; H, 5.57%; N, 8.87%; Cl, 9.15%; F, 0.93%. Found: C, 47.38%; H, 5.49%; N, 8.90%; Cl, 9.12%; F, 0.98%.
Compound 159
[M+H]+=1767
Anal calcd. for C80H86Cl3FN14O25.11.6H2O.2.1HCl: C, 46.77%; H, 5.46%; N, 9.54%; Cl, 8.80%; F, 0.92%. Found: C, 46.74%; H, 5.20%; N, 9.56%; Cl, 8.83%; F, 0.99%.
Compound 160
[M+H]+=1782
Anal calcd. for C81H87Cl3FN13O26.13.0H2O.2.2HCl: C, 46.36%; H, 5.53%; N, 8.68%; Cl, 8.79%; F, 0.91%. Found: C, 46.34%; H, 5.39%; N, 8.79%; Cl, 8.81%; F, 0.97%.
Compound 161
[M+H]+=1807
Anal calcd. for C82H95Cl2F3N12O27.9.4H2O.2.2HCl: C, 47.85%; H, 5.68%; Cl, 7.23%; F, 2.77%; N, 8.17%. Found: C, 48.18%; H, 5.72%; Cl, 7.16%; F, 2.92%; N, 7.78%.
Compound 162
[M+H]+=1820
Anal calcd. for C83H98Cl2F3N13O26.12.0H2O.2.7HCl: C, 46.66%; H, 5.88%; Cl, 7.80%; F, 2.67%; N, 8.52%. Found: C, 46.71%; H, 5.75%; Cl, 7.76%; F, 2.64%; N, 8.64%.
Compound 163
[M+H]+=1915
Anal calcd. for C83H99Cl2F3N14O29S.9.2H2O.2.1HCl: C, 46.17%; H, 5.58%; Cl, 6.73%; F, 2.64%; N, 9.08%; S, 1.49%. Found: C, 46.11%; H, 5.64%; Cl, 6.73%; F, 2.52%; N, 9.23%; S, 1.29%.
Compound 164
[M+H]+=1789
Anal calcd. for C82H96Cl4N12O25.11.5H2O.2.9HCl: C, 46.80%; H, 5.84%; Cl, 11.62%; N, 7.99%. Found: C, 46.84%; H, 5.81%; Cl, 11.65%; N, 8.21%.
Compound 165
[M+H]+=1802
Anal calcd. for C83H99Cl4N13O24.11.5H2O.3.6HCl: C, 46.52%; H, 5.91%; Cl, 12.57%; N, 8.50%. Found: C, 46.54%; H, 5.80%; Cl, 12.55%; N, 8.61%.
Compound 166
[M+H]+=1805
Anal calcd. for C83H97Cl2F3N12O26.11.5H2O.3.0HCl: C, 46.95%; H, 5.84%; Cl, 8.35%; F, 2.68%; N, 7.92%. Found: C, 47.07%; H, 5.85%; Cl, 8.31%; F, 2.42%; N, 8.06%.
Compound 167
[M+H]+=1818
Anal calcd. for C84H100Cl2F3N13O25.12.5H2O.3.2HCl: C, 46.68%; H, 5.98%; Cl, 8.53%; F, 2.64%; N, 8.42%. Found: C, 46.69%; H, 5.91%; Cl, 8.50%; F, 2.40%; N, 8.54%.
Compound 168
[M+H]+=1913
Anal calcd. for C84H101Cl2F3N14O28S.11.7H2O.2.9HCl: C, 45.22%; H, 5.75%; Cl, 7.79%; F, 2.55%; N, 8.79%; S, 1.44%. Found: C, 45.19%; H, 5.64%; Cl, 7.84%; F, 2.32%; N, 8.94%; S, 1.42%.
Compound 169
[M+H]+=1791
Anal calcd. for C82H95Cl2F3N12O26.11.5H2O.2.1HCl: C, 47.43%; H, 5.83%; Cl, 7.00%; F, 2.74%; N, 8.10%. Found: C, 47.52%; H, 5.86%; Cl, 6.93%; F, 2.59%; N, 8.47%.
Compound 170
[M+H]+=1899
Anal calcd. for C83H99Cl2F3N14O28S.10.0H2O.2.0HCl: C, 46.29%; H, 5.66%; Cl, 6.58%; F, 2.65%; N, 9.10%; S, 1.49%. Found: C, 46.12%; H, 5.72%; Cl, 6.65%; F, 2.46%; N, 9.10%; S, 1.40%.
Compound 171
[M+H]+=1859
Anal calcd. for C84H95Cl2F3N14O27.11.0H2O.2.1HCl: C, 47.25%; H, 5.62%; Cl, 6.81%; F, 2.67%; N, 9.18%. Found: C, 47.07%; H, 5.65%; Cl, 6.87%; F, 2.50%; N, 9.47%.
Compound 172
[M+H]+=1793
Anal calcd. for C81H93Cl2F3N12O27.11.3H2O.2.1HCl: C, 46.89%; H, 5.72%; Cl, 7.01%; F, 2.75%; N, 8.10%. Found: C, 46.96%; H, 5.71%; Cl, 6.91%; F, 2.70%; N, 8.06%.
Compound 173
[M+H]+=1807
Anal calcd. for C81H95F3Cl2N14O26.3.1HCl.10H2O: C, 46.29%; H, 5.66%; N, 9.33%; Cl, 8.60%; F, 2.71%. Found: C, 46.18%; H, 5.64%; N, 9.34%; F, 2.71%; Cl, 8.56%.
Compound 174
[M+H]+=1920
Anal calcd. for C86H102F3Cl2N15O28.3.2HCl.10H2O: C, 46.56%; H, 5.69%; N, 9.47%; Cl, 8.31%; F, 2.57%. Found: C, 46.45%; H, 5.70%; N, 9.36%; F, 2.67%; Cl, 8.34%.
Compound 175
[M+H]+=1835
Anal calcd. for C81H95F3Cl2N16O26.3.0HCl.13H2O: C, 44.62%; H, 5.73%; N, 10.28%; Cl, 8.13%; F, 2.61%. Found: C, 44.79%; H, 5.63%; N, 10.38%; F, 2.57%; Cl, 8.19%.
Compound 176
[M+H]+=1820
Anal calcd. for C82H98F3Cl2N15O25.2.2HCl.12H2O: C, 46.50%; H, 5.91%; N, 9.92%; Cl, 7.03%; F, 2.69%. Found: C, 46.33%; H, 5.72%; N, 9.91%; F, 11.51%; Cl, 7.11%.
Compound 177
[M+H]+=1820
Anal calcd. for C82H98F3Cl2N15O25.4HCl.11H2O: C, 45.48%; H, 5.77%; N, 9.70%; Cl, 9.82%; F, 2.63%. Found: C, 45.46%; H, 5.76%; N, 9.80%; F, 2.64%; Cl, 9.74%.
Compound 178
[M+H]+=1851
Anal calcd. for C83H99F3Cl2N14O27.3HCl.11H2O: C, 46.15%; H, 5.79%; N, 9.08%; Cl, 8.21%; F, 2.64%. Found: C, 46.13%; H, 5.76%; N, 9.22%; F, 2.59%; Cl, 8.28%.
Compound 179
[M+H]+=1906
Anal calcd. for C86H104F3Cl2N15O27.4HCl.12H2O: C, 45.51%; H, 5.86%; N, 9.26%; Cl, 9.37%; F, 2.51%. Found: C, 45.60%; H, 5.90%; N, 9.41%; F, 2.59%; Cl, 9.55%.
Compound 180
[M+H]+=1915
Anal calcd. for C83H99F3Cl2N14O29S.2.2HCl 11.5H2O: C, 45.23%; H, 5.68%; N, 8.90%; Cl, 6.76%; F, 2.59%; S, 1.45%. Found: C, 45.21%; H, 5.72%; N, 8.84%; F, 2.78%; Cl, 6.75%; S, 1.46%.
Compound 181
[M+H]+=1915
Anal calcd. for C82H99F3Cl2N16O28S.3.2HCl.10H2O: C, 44.49%; H, 5.56%; N, 10.12%; Cl, 8.33%; F, 2.57%; S, 1.45%. Found: C, 44.61%; H, 5.54%; N, 10.01%; F, 2.70%; Cl, 8.24%; S, 1.47%.
Compound 182
[M+H]+=1793
Anal calcd. for C80H93F3Cl2N14O26.3HCl.11.8H2O: C, 45.40%; H, 5.70%; N, 9.26%; Cl, 8.38%; F, 2.69%. Found: C, 45.30%; H, 5.67%; N, 9.14%; F, 2.60%; Cl, 8.28%.
Compound 183
[M+H]+=1791
Anal calcd. for C80H94Cl4N14O25.2.4HCl.10.5H2O: C, 46.41%; H, 5.72%; N, 9.47%; Cl, 10.96%. Found: C, 46.24%; H, 5.72%; N, 9.32%; Cl, 10.96%.
Compound 184
[M+H]+=1804
Anal calcd. for C81H97Cl4N15O24.2.7HCl.11H2O: C, 46.26%; H, 5.83%; N, 9.99%; Cl, 11.29%. Found: C, 46.19%; H, 5.77%; N, 9.94%; Cl, 11.31%.
Compound 185
[M+H]+=1779
Anal calcd. for C80H91F3Cl2N12O27.2.1HCl.11.3H2O: C, 46.63%; H, 5.66%; N, 8.16%; Cl, 7.05%; F, 2.77%. Found: C, 46.83%; H, 5.52%; N, 8.51%; F, 2.70%; Cl, 7.03%.
Compound 186
[M+H]+=1765
Anal calcd. for C79H89F3Cl2N12O27.2HCl.11H2O: C, 46.57%; H, 5.59%; N, 8.25%; Cl, 6.96%; F, 2.80%. Found: C, 46.41%; H, 5.57%; N, 8.30%; F, 2.90%; Cl, 6.94%.
Compound 187
[M+H]+=1822
Anal calcd. for C81H92F3Cl2N13O28.2.1HCl.11H2O: C, 46.36%; H, 5.58%; N, 8.68%; Cl, 6.93%; F, 2.72%. Found: C, 46.59%; H, 5.46%; N, 8.91%; F, 2.67%; Cl, 7.01%.
Compound 188
[M+H]+=1850
Anal calcd. for C82H96F3Cl2N15O28.3.1HCl.12H2O: C, 44.83%; H, 5.65%; N, 9.56%; Cl, 8.23%; F, 2.59%. Found: C, 44.92%; H, 5.47%; N, 9.81%; F, 2.55%; Cl, 8.27%.
Compound 189
[M+H]+=1807
Anal calcd. for C80H91F3Cl2N14O27.2.1HCl.11.5H2O: C, 45.92%; H, 5.59%; N, 9.37%; Cl, 6.95%; F, 2.72%. Found: C, 45.95%; H, 5.57%; N, 9.51%; F, 2.71%; Cl, 6.97%.
Compound 190
[M+H]+=1792
Anal calcd. for C81H94F3Cl2N13O26.3HCl.11H2O: C, 46.30%; H, 5.71%; N, 8.67%; Cl, 8.44%; F, 2.71%. Found: C, 46.28%; H, 5.73%; N, 8.76%; F, 2.67%; Cl, 8.30%.
Compound 191
[M+H]+=1835
Anal calcd. for C81H91F3Cl2N14O28.2HCl.11.5H2O: C, 45.96%; H, 5.52%; N, 9.26%; Cl, 6.70%; F, 2.69%. Found: C, 45.92%; H, 5.43%; N, 9.42%; F, 2.68%; Cl, 6.78%.
Compound 192
[M+H]+=1863
Anal calcd. for C82H95F3Cl2N16O27.3HCl 12.5H2O: C, 44.78%; H, 5.64%; N, 10.19%; Cl, 8.06%; F, 2.59%. Found: C, 44.80%; H, 5.58%; N, 10.24%; F, 2.45%; Cl, 8.07%.
Compound 193
[M+H]+=1887
Anal calcd. for C81H95F3Cl2N14O29S.2HCl.10H2O: C, 45.42%; H, 5.51%; N, 9.16%; Cl, 9.62%; F, 2.66%. Found: C, 45.33%; H, 5.50%; N, 9.19%; F, 2.64%; Cl, 6.62%.
Compound 194
[M+H]+=1803
Anal calcd. for C82H98Cl4N14O24.11.6H2O.2.8HCl: C, 46.53%; H, 5.90%; N, 9.26%; Cl, 11.39%. Found: C, 46.50%; H, 5.68%; N, 9.27%; Cl, 11.29%.
Compound 195
[M+H]+=1846
Anal calcd. for C82H95Cl4N15O26.12.3H2O.2.9HCl: C, 45.26%; H, 5.67%; N, 9.66%; Cl, 11.24%. Found: C, 45.26%; H, 5.37%; N, 9.72%; Cl, 11.17%.
Compound 196
[M+H]+=1858
Anal calcd. for C83H95Cl4N15O26.10.8H2O.1.5HCl: C, 47.25%; H, 5.64%; N, 9.96%; Cl, 9.24%. Found: C, 47.136; H, 5.34%; N, 9.94%; Cl, 9.19%.
Compound 197
[M+H]+=1898
Anal calcd. for C83H99Cl4N13O28S.16.2H2O.1.7HCl: C, 44.18%; H, 5.95%; N, 8.07%; Cl, 8.96%; S, 1.42%. Found: C, 44.20%; H, 5.88%; N, 8.14%; Cl, 8.92%; S, 1.33%.
Compound 198
[M+H]+=1858
Anal calcd. for C83H95Cl4N15O26.9.9H2O.2.1HCl: C, 47.12%; H, 5.57%; N, 9.93%; Cl, 10.22%. Found: C, 47.13%; H, 5.55%; N, 9.91%; Cl, 10.21%.
Compound 199
[M+H]+=1803
Anal calcd. for C82H98Cl4N14O24.11.3H2O.3.7HCl: C, 45.94%; H, 5.84%; N, 9.15%; Cl, 12.73%. Found: C, 45.85%; H, 5.74%; N, 9.32%; Cl, 12.78%.
Compound 200
[M+H]+=1790
Anal calcd. for C81H95Cl4N13O25.10.4H2O.2.7HCl: C, 46.81%; H, 5.75%; N, 8.76%; Cl, 11.43%. Found: C, 46.86%; H, 5.82%; N, 8.57%; Cl, 11.50%.
Compound 201
[M+H]+=1818
Anal calcd. for C81H95Cl4N15O25.11H2O.3HCl: C, 45.72%; H, 5.68%; N, 9.87%; Cl, 11.66%. Found: C, 45.74%; H, 5.62%; N, 9.96%; Cl, 11.69%.
Compound 202
[M+H]+=1818
Anal calcd. for C81H95Cl4N15O25.10.7H2O.2.8HCl: C, 45.99%; H, 5.68%; N, 9.93%; Cl, 11.4%. Found: C, 45.98%; H, 5.6%; N, 9.95%; Cl, 11.33%.
Compound 203
[M+H]+=1840
Anal calcd. for C82H95Cl4F2N13O25.9.2H2O.2.7HCl: C, 46.75%; H, 5.55%; N, 8.64%; Cl, 11.28%; F, 1.80%. Found: C, 46.83%; H, 5.61%; N, 8.60%; Cl, 11.29%; F, 1.23%.
Compound 204
[M+H]+=1790
Anal calcd. for C81H95Cl4N13O25.18.6H2O.3.1HCl: C, 43.42%; H, 6.09%; N, 8.13%; Cl, 11.23%. Found: C, 43.30%; H, 6.03%; N, 8.71%; Cl, 11.17%.
Compound 205
[M+H]+=1776
Anal calcd. for C80H93Cl4N13O25.10.2H2O.2.9HCl: C, 46.46%; H, 5.67%; N, 8.81%; Cl, 11.83%. Found: C, 46.41%; H, 5.68%; N, 8.97%; Cl, 11.90%.
Compound 206
[M+H]+=1889
Anal calcd. for C86H104Cl4N14O26.10.7H2O.3.9HCl: C, 46.39%; H, 5.85%; N, 8.81%; Cl, 12.58%. Found: C, 46.28%; H, 5.83%; N, 9.42%; Cl, 12.60%.
Compound 207
[M+H]+=1803
Anal calcd. for C82H98Cl4N14O24.12.1H2O.3.6HCl: C, 45.71%; H, 5.88%; N, 9.10%; Cl, 12.50%. Found: C, 45.67%; H, 5.78%; N, 9.14%; Cl, 12.50%.
Compound 208
[M+H]+=1783
Anal calcd. for C83H91Cl2F3N12O25.11H2O.2.7HCl: C, 47.90%; H, 5.60%; N, 8.08%; Cl, 8.01%; F, 2.74%. Found: C, 48.00%; H, 5.51%; N, 8.13%; Cl, 8.05%; F, 2.74%.
Compound 209
[M+H]+=1770
Anal calcd. for C82H88Cl2F3N11O26.9H2O.2HCl: C, 49.08%; H, 5.42%; N, 7.68%; Cl, 7.07%; F, 2.84%. Found: C, 49.02%; H, 5.39%; N, 7.79%; Cl, 7.00%; F, 2.83%.
Compound 210
[M+H]+=1867
Anal calcd. for C88H99Cl2F3N12O26.9H2O.2.9HCl: C, 49.47%; H, 5.66%; N, 7.87%; Cl, 8.13%; F, 2.67%. Found: C, 49.54%; H, 5.67%; N, 7.95%; Cl, 8.16%; F, 2.92%.
Compound 211
[M+H]+=1823
Anal calcd. for C86H95Cl2F3N12O26.10H2O.2.6HCl: C, 49.20%; H, 5.65%; N, 8.01%; Cl, 7.77%; F, 2.71%. Found: C, 49.33%; H, 5.60%; N, 8.08%; Cl, 7.86%; F, 2.67%.
Compound 212
[M+H]+=1784
Anal calcd. for C83H90Cl2F3N11O26.9H2O.2.0HCl: C, 49.34%; H, 5.49%; N, 7.63%; Cl, 7.02%; F, 2.82%. Found: C, 49.19%; H, 5.42%; N, 7.65%; Cl, 7.07%; F, 2.88%.
Compound 213
[M+H]+=1756
Anal calcd. for C81H86Cl2F3N11O26.5H2O.2HCl: C, 50.66%; H, 5.14%; N, 8.02%; Cl, 7.38%; F, 2.97%. Found: C, 50.63%; H, 5.19%; N, 8.20%; Cl, 7.40%; F, 2.88%.
Compound 214
[M+H]+=1797
Anal calcd. for C84H93Cl2F3N12O25.10H2O.2.4HCl: C, 48.83%; H, 5.63%; N, 8.13%; Cl, 7.55%; F, 2.76%. Found: C, 48.99%; H, 5.58%; N, 8.40%; Cl, 7.60%; F, 2.76%.
Compound 215
[M+H]+=1784
Anal calcd. for C83H90Cl2F3N11O26.9H2O.2HCl: C, 49.34%; H, 5.49%; N, 7.63%; Cl, 7.02%; F, 2.82%. Found: C, 49.13%; H, 5.53%; N, 7.68%; Cl, 7.06%; F, 2.76%.
Compound 216
[M+H]+=1797
Anal calcd. for C84H93Cl2F3N12O25.10H2O.2.5HCl: C, 48.74%; H, 5.62%; N, 8.12%; Cl, 7.71%; F, 2.75%. Found: C, 48.78%; H, 5.60%; N, 8.33%; Cl, 7.78%; F, 2.68%.
Compound 217
[M+H]+=1770
Anal calcd. for C82H88Cl2F3N11O26.10H2O.2HCl: C, 48.65%; H, 5.48%; N, 7.61%; Cl, 7.00%; F, 2.82%. Found: C, 48.68%; H, 5.40%; N, 7.73%; Cl, 7.06%; F, 2.71%.
Compound 218
[M+H]+=1798
Anal calcd. for C82H88Cl2F3N13O26.10H2O.2.1HCl: C, 47.90%; H, 5.40%; N, 8.86%; Cl, 7.07%; F, 2.77%. Found: C, 47.95%; H, 5.37%; N, 9.10%; Cl, 7.17%; F, 2.72%.
Compound 219
[M+H]+=1823
Anal calcd. for C84H91Cl2F3N14O25.10H2O.3HCl: C, 47.72%; H, 5.44%; N, 9.28%; Cl, 8.38%; F, 2.70%. Found: C, 47.54%; H, 5.49%; N, 9.45%; Cl, 8.39%; F, 2.55%.
Compound 220
[M+H]+=1817
Anal calcd. for C83H90Cl2F4N12O26.12.0H2O.2.7HCl: C, 46.73%; H, 5.51%; N, 7.88%; Cl, 7.81%; F, 3.56%. Found: C, 46.70%; H, 5.53%; N, 7.92%; Cl, 7.88%; F, 3.48%.
Compound 221
[M+H]+=1803
Anal calcd. for C83H89Cl3N14O26.15.9H2O.2.5HCl: C, 45.67%; H, 5.69%; N, 8.98%; Cl, 8.93%. Found: C, 45.71%; H, 5.51%; N, 8.87%; Cl, 8.96%.
Compound 222
[M+H]+=1828
Anal calcd. for C83H87Cl2F4N13O26.18.0H2O.3.2HCl: C, 43.91%; H, 5.60%; N, 8.02%; Cl, 8.12%; F, 3.35%. Found: C, 43.87%; H, 5.15%; N, 8.01%; Cl, 8.03%; F, 3.24%.
Compound 223
[M+H]+=1844
Anal calcd. for C83H87Cl2F4N13O27.13.0H2O.2.1HCl: C, 46.23%; H, 5.38%; N, 8.44%; Cl, 6.74%; F, 3.52%. Found: C, 46.19%; H, 5.20%; N, 8.44%; Cl, 6.73%; F, 3.52%.
Compound 224
[M+H]+=1801
Anal calcd. for C83H90Cl2F4N12O25.12.6H2O.2.3HCl: C, 47.17%; H, 5.60%; N, 7.95%; Cl, 7.21%; F, 3.60%. Found: C, 47.16%; H, 5.44%; N, 7.91%; Cl, 7.21%; F, 3.48%.
Compound 225
[M+H]+=1799
Anal calcd. for C83H91Cl2F3N12O26.11.1H2O.2.3HCl: C, 47.83%; H, 5.59%; N, 8.06%; Cl, 7.31%; F, 2.73%. Found: C, 47.87%; H, 5.64%; N, 8.03%; Cl, 7.36%; F, 2.69%.
Compound 226
[M+H]+=1826
Anal calcd. for C83H88Cl2F3N13O27.10.3H2O.2.2HCl: C, 47.62%; H, 5.34%; N, 8.70%; Cl, 7.11%; F, 2.72%. Found: C, 47.69%; H, 5.46%; N, 8.66%; Cl, 7.06%; F, 2.58%.
Compound 227
[M+H]+=1797
Anal calcd. for C83H89Cl2F3N12O26.11.1H2O.1.8HCl: C, 48.30%; H, 5.52%; N, 8.14%; Cl, 6.53%; F, 2.76%. Found: C, 48.41%; H, 5.55%; N, 7.62%; Cl, 6.53%; F, 2.53%.
Compound 228
[M+H]+=1757
Anal calcd. for C85H98Cl2N12O25.11.2H2O.2.2HCl: C, 50.03%; H, 6.06%; N, 8.24%; Cl, 7.30%. Found: C, 49.98%; H, 6.00%; N, 8.39%; Cl, 7.32%.
Compound 229
[M+H]+=1801
Anal calcd. for C83H90Cl2F4N12O25.11.9H2O.3.0HCl: C, 46.88%; H, 5.54%; N, 7.90%; Cl, 8.34%; F, 3.57%. Found: C, 46.93%; H, 5.49%; N, 7.68%; Cl, 8.40%; F, 3.34%.
Compound 230
[M+H]+=1826
Anal calcd. for C83H88Cl2F3N13O27.10.0H2O.2.2HCl: C, 47.75%; H, 5.32%; N, 8.72%; Cl, 7.13%; F, 2.73%. Found: C, 47.72%; H, 5.32%; N, 8.92%; Cl, 7.06%; F, 2.71%.
Compound 231
[M+H]+=1828
Anal calcd. for C83H87Cl2F4N13O26.10.2H2O.1.7HCl: C; 48.04%; H, 5.30%; N, 8.77%; Cl, 6.32%; F, 3.66%. Found: C, 48.33%; H, 5.44%; N, 7.83%; Cl, 6.37%; F, 3.22%.
Compound 232
[M+H]+=1784
Anal calcd. for C85H95Cl2N13O26.10.8H2O.1.9HCl: C, 49.81%; H, 5.83%; N, 8.88%; Cl, 6.75%. Found: C, 49.91%; H, 5.75%; N, 8.39%; Cl, 6.79%.
In Vitro Assay of Antimicrobial Activity
Method
For several compounds of the invention, minimal inhibitory concentration (MIC) was determined by the microdilution method using cation adjusted Mueller-Hinton broth well known in the art.
Results
The compounds of the invention showed a strong antimicrobial activity against various bacteria, including vancomycin-resistant strains. In particular, the compound of Example 4 showed MIC=4 μg/mL against vancomycin-resistant enterococcus E. faecalis SR7914 (VanA), and MIC=0.5 μg/mL against methicillin-resistant Staphylococcus aureus S. aureus SR3637 (H-MRSA).
The compounds of the invention were tested for water solubility and toxicity.
The compounds of the invention showed good water solubility. Also, in a single-dose intravenous toxicity screening test in mouse (dosage: 30 mg/kg), the compound of the invention (e.g., the compound of Example 2 (Compound 2) etc.) showed good histological findings in kidney etc., as compared with its corresponding compound having —COOH at the C-terminal.
Formulations
It is to be noted that the following Formulations 1 to 8 are mere illustration, but not intended to limit the scope of the invention. The term “active ingredient” means the compounds of the invention, a tautomer, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
Formulation 1
Hard gelatin capsules are prepared using of the following ingredients:
Formulation 2
A tablet is prepared using of the following ingredients:
The components are blended and compressed to form tablets each weighing 665 mg.
Formulation 3
An aerosol solution is prepared containing the following components:
The active compound is mixed with ethanol and the admixture added to a portion of the propellant 22, cooled to −30° C. and transferred to filling device. The required amount is then fed to stainless steel container and diluted with the reminder of the propellant. The valve units are then fitted to the container.
Formulation 4
Tablets, each containing 60 mg of active ingredient, are made as follows.
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve, and the mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the admixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Formulation 5
Capsules, each containing 80 mg of active ingredient, are made as follows:
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
Formulation 6
Suppository, each containing 225 mg of active ingredient, are made as follows:
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
Formulation 7
Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are made as follows:
The active ingredient is passed through a No. 45 U.S. sieve, and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
Formulation 8
An intravenous formulation may be prepared as follows:
The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 mL per minute.
Industrial Applicability
The glycopeptide derivatives of the invention, pharmaceutically acceptable salts and solvates thereof are useful in the medical treatment and show a biological activity, including antimicrobial activity. Accordingly, the present invention provides a method for the treatment of infections diseases, particularly diseases caused by gram-positive microbial in animal, and the compounds of the invention is particularly useful in the treatment of infections with methicillin resistant staphylococcus. The compound is also useful for the treatment of infections with enterococcus including vancomycin-resistant enterococcus (VRE). Example of such disease includes severe infections with staphylococcus such as staphylococcal endocarditis and staphylococcal sepsis.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2006-147008 | May 2006 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2007/060673 | 5/25/2007 | WO | 00 | 8/27/2008 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2007/138999 | 12/6/2007 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 6455669 | Judice et al. | Sep 2002 | B1 |
| 6498238 | Kim et al. | Dec 2002 | B1 |
| 6699836 | Kahne et al. | Mar 2004 | B2 |
| 20030068669 | Thorson | Apr 2003 | A1 |
| 20040259228 | Thorson | Dec 2004 | A1 |
| 20050239689 | Thorson | Oct 2005 | A1 |
| 20050266523 | Thorson | Dec 2005 | A1 |
| 20080097078 | Arimoto et al. | Apr 2008 | A1 |
| Number | Date | Country |
|---|---|---|
| 0 201 251 | Dec 1986 | EP |
| 0 273 727 | Jul 1988 | EP |
| 0 301 785 | Feb 1989 | EP |
| 0 435 503 | Dec 1990 | EP |
| 0 667 353 | Aug 1995 | EP |
| 1 016 670 | Jul 2000 | EP |
| 1 031 576 | Aug 2000 | EP |
| 1 818 340 | Aug 2007 | EP |
| 01-240196 | Sep 1989 | JP |
| 04-108800 | Apr 1992 | JP |
| 2000-302687 | Oct 2000 | JP |
| 2001-163898 | Jun 2001 | JP |
| 2003-026725 | Jan 2003 | JP |
| 2006-503015 | Jan 2006 | JP |
| 9303060 | Feb 1993 | WO |
| 9630401 | Oct 1996 | WO |
| 0004044 | Jan 2000 | WO |
| 0039156 | Jul 2000 | WO |
| 0042067 | Jul 2000 | WO |
| 0059528 | Oct 2000 | WO |
| 0069893 | Nov 2000 | WO |
| 0181372 | Nov 2001 | WO |
| 0181373 | Nov 2001 | WO |
| 03018608 | Mar 2003 | WO |
| 2004019970 | Mar 2004 | WO |
| 2004044222 | May 2004 | WO |
| 2005018743 | Mar 2005 | WO |
| 2005034856 | Apr 2005 | WO |
| 2006003456 | Jan 2006 | WO |
| 2006057288 | Jun 2006 | WO |
| WO 2006057303 | Jun 2006 | WO |
| 2006093933 | Sep 2006 | WO |
| 2006094082 | Sep 2006 | WO |
| Entry |
|---|
| Vippagunta, S.R., Brittain, H.G., Grant, D.J.W. (2001) Crystalline solids. Advanced Drug Delivery Reviews, vol. 48, pp. 3-26. |
| Morissette, S.L., Almarsson, Ö., Peterson, M.L., Remenar, J.F., Read, M.J., Lemmo, A.V., Ellis, S., Cima, M.J., Gardner, C.R. (2004) High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Advanced Drug Delivery Reviews, vol. 56, pp. 275-300. |
| Parenti, F., Cavalleri, B. (1990) Novel Glycopeptide Antibiotics of the Dalbaheptide Group. Drugs of the Future, vol. 15, No. 1, p. 57-72. |
| Trani, A., Malabarba, A., Ferrari, P., Pallanza, Berti, M., Ciabatti, R. (1990) Carboxyhydrazides of the Aglycone of Teicoplanin Synthesis and Antibacterial Activity. The Journal of Antibiotics, vol. XLIII, No. 11, p. 1471-1481. |
| M. N. Preobrazhenskaya et al.,“Patents on Glycopeptides of the Vancomycin Family and Their Derivatives as Antimicrobials: Jan. 1999-Jun. 2003”, Expert Opin. Ther. Patents, vol. 14, No. 2, pp. 141-173, 2004. |
| J. F. Barrett, “Recent Developments in Glycopeptide Antibacterials”, Current Opinion in Investigational Drugs, vol. 6, No. 8, pp. 781-790, 2005. |
| Reyes et al., “Efficacy of Telavancin (TD-6424), A Rapidly Bactericidal Lipoglycopeptide with Multiple Mechanisms of Action, in a Murine Model of Pneumonia Induced by Methicillin-Resistant Staphylococcus aureus”, Antimicrobial Agents and Chemotherapy, vol. 49, No. 10, pp. 4344-4346, Oct. 2005. |
| J. L. Pace et al., “Glycopeptides: Update on an Old Successful Antibiotic Class”, Biochemical Pharmacology, vol. 71, No. 7, pp. 968-980, Mar. 2006. |
| O. Yoshida et al., “Novel Semi-Synthetic Glycopeptide Antibiotics Active Against Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Enterococci (VRE): Doubly-Modified Water-Soluble Derivatives of Chloroorienticin B”, Bioorganic & Medicial Chemistry Letters, vol. 12, pp. 3027-3031, 2002. |
| J. K. Judice et al., “Semi-Synthetic Glycopeptide Antibacterials”, Bioorganic & Medicinal Chemistry Letters, vol. 13, pp. 4165-4168, 2003. |
| Griffith et al.; “‘Sweetening’ Natural Products via Glycorandomization”; Current Opinion in Biotechnology; c. 2005; vol. 16; p. 622-30. |
| Lu et al.; “Characterization of a Regiospecific Epivancosaminyl Transferase GtfA and Enzymatic Reconstitution of the Antibiotic Chloroeremomycin”; Proceedings of the National Academy of Sciences; c. Mar. 2004; vol. 101, No. 13; p. 4390-4395. |
| Oberthür et al.; “A systematic Investigation of the Synthetic Utility of Glycopeptide Glycosyltransferases”; Journal of the American Chemical Society; c. 2005; vol. 127; p. 10747-10752. |
| Mulichak et al.; “Structure of the UDP—Glucosyltransferase GtfB that Modifies the Heptapeptide Aglycone in the Biosynthesis of Vancomycin Group Antibiotics”; Structure; c. Jul. 2001; vol. 9; p. 547-557. |
| Cooper et al.; “Reductive Alkylation of Glycopeptide Antibiotics: Synthesis and Antibacterial Activity”; The Journal of Antibiotics; c. 1996; vol. 49, No. 6; p. 575-581. |
| Shi et al.; “Catalysis of Carbamate Hydrolysis by Vancomycin and Semisynthetic Derivatives”; Journal of the American Chemical Society; c. 1993; vol. 115; p. 6482-6486. |
| Sundram et al.; “General and Efficient Method for the Solution- and Solid-Phase Synthesis of Vancomycin Carboxamide Derivatives”; Journal of Organic Chemistry; c. 1995; vol. 60; p. 1102-1103. |
| Pavlov et al.; “A New Type of Chemical Modification of Glycopeptides, Antibiotics, Aminomethylated Derivatives of Eremomycin and Their Antibacterial Activity”; The Journal of Antibiotics; c. 1997; vol. 50, No. 6; p. 509-513. |
| Malabarba et al.; “Structural Modifications of Glycopeptide Antibiotics”; Medicinal Research Reviews; c. 1997; vol. 17, No. 1; p. 69-137. |
| Allen et al.; “The Role of Hydrophobic Side Chains as Determinants of Antibacterial Activity of Semisynthetic Glycopeptide Antibiotics”; The Journal of Antibiotics; c. 1997; vol. 50; No. 8; p. 677-684. |
| Rodriguez et al.; “Novel Glycopeptide Antibiotics: N-Alkylated Derivatives Active Against Vancomycin-Resistant Enterococci”; The Journal of Antibiotics; c. Jun. 1998; vol. 51, No. 6; p. 560-569. |
| Fu et al.; “Antibiotic Optimization Via in vitro Glycorandomization”; Nature Biotechnology; c. Dec. 2003; vol. 21, No. 12; p. 1467-1469. |
| Melançon, III et al.; “Glyco-Stripping and Glyco-Swapping”; Acs Chemical Biology; c. Sep. 2006; vol. 1, No. 8; p. 499-504. |
| Balzarini et al.; “Inhibition of Feline (FIPV) and Human (SARS) Coronavirus by Semisynthetic Derivatives of Glycopeptide Antibiotics”; Antiviral Research; c. 2006; vol. 72; p. 20-33. |
| Maffioli et al.; “Synthesis and Antibacterial Activity of Alkyl Derivatives of the Glycopeptide Antibiotic A40926 and Their Amides”; Bioorganic & Medicinal Chemistry Letters; c. 2005; vol. 15; p. 3801-3805. |
| Fu et al.; “Diversifying Vancomycin via Chemoenzymatic Strategies”; Organic Letters; c. 2005; vol. 7, No. 8; p. 1513-1515. |
| Kruger et al.; “Tailoring of Glycopeptide Scaffolds by the Acyltransferases from the Teicoplanin and A-40,926 Biosynthetic Operons”; Chemistry & Biology; c. Jan. 2005; vol. 12, p. 131-140. |
| Ritter et al.; “A Programmable One-Pot Oligosaccharide Synthesis for Diversifying the Sugar Domains of Natural Products: A Case Study of Vancomycin”; Angewandte Chemie Int. Ed.; c. 2003; vol. 42; p. 4657-4660. |
| Balzarini et al.; “Antiretroviral Activity of Semisynthetic Derivatives of Glycopeptide Antibiotics”; The Journal of Medicinal Chemistry; c. 2003; vol. 46; p. 2755-2764. |
| Chen et al.; “Structural Requirements for VanA Activity of Vancomycin Analogues”; Tetrahedron; c. 2002; vol. 58; p. 6585-6594. |
| Blizzard et al.; “Antibacterial Activity of G6-Quaternary Ammonium Derivatives of a Lipophilic Vancomycin Analogue”; Bioorganic & Medicinal Chemistry Letters; c. 2002; vol. 12; p. 849-852. |
| Nicolaou et al.; “Solid- and Solution-Phase Synthesis of Vancomycin and Vancomycin Analogues with Activity Against Vancomycin-Resistant Bacteria”; Chemistry-A European Journal; c. 2001; vol. 7, No. 17; p. 3798-3823. |
| Kerns et al.; “The Role of Hydrophobic Substituents in the Biological Activity of Glycopeptide Antibiotics”; The Journal of the American Chemical Society; c. 2000; vol. 122; p. 12608-12609. |
| Pavlov et al.; “Synthesis and Antibacterial Activity of Derivatives of the Glycopeptide Antibiotic A-40926 N-alkylated at the Aminoglucuronyl Moiety”; The Journal of Antibiotics; c. 1998; vol. 51, No. 5; p. 525-527. |
| Nagarajan; “Structure-Activity Relationships of Vancomycin-Type Glycopeptide Antibiotics”; The Journal of Antibiotics; c. 1993, vol. 46, No. 8; p. 1181-1195. |
| Hubbard et al.; “Vancomycin Assembly: Nature's Way”; Angewandte Chemie; c. 2003; vol. 42, No. 7; p. 730-765. |
| Parenti et al.; “Proposal to Name the Vancomycin-Ristocetin Like Glycopeptides as Dalbaheptides”; The Journal of Antibiotics; c. Dec. 1989; vol. 42, No. 12, p. 1882-1883. |
| Rao et al.; “Studies Directed Toward the Synthesis of Vancomycin and Related Cyclic Peptides”; Chemical Review; c. 1995; vol. 95; p. 2135-2167. |
| Nicolaou et al.; “Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics”; Angewandte Chemie; c. 1999; vol. 38; p. 2096-2152. |
| Van Bambeke et al.; “Glycopeptide Antibiotics from Conventional Molecules to New Derivatives”; Drugs; c. 2004; vol. 64, No. 9; p. 913-936. |
| Kahne et al.; “Glycopeptide and Lipoglycopeptide Antibiotics”; Chemical Review; c. 2005; vol. 105; p. 425-448. |
| Gerhard et al.; “The Role of the Sugar and Chlorine Substituents in the Dimerization of Vancomycin Antibiotics”; The Journal of the American Chemical Society; c. 1993; vol. 115; p. 232-237. |
| Ward et al.; “Oritavancin—an Investigational Glycopeptide Antibiotic”; Expert Opinion Investigating Drugs; c. 2006; vol. 15, No. 4; p. 417-429. |
| Williams et al.; “The Vancomycin Group of Antibiotics and the Fight Against Resistant Bacteria”; Angewandte Chemie; c. 1999; vol. 38; p. 1172-1193. |
| Malabarba et al.; “Glycopeptide Resistance in Multiple Antibiotic-Resistant Gram-Positive Bacteria: A Current Challenge for Novel Semi-Synthetic Glycopeptide Derivatives”; European Journal of Medicinal Chemistry; c. 1997; vol. 62; p. 459-478. |
| Nagarajan et al.; “The Structural Relationships of A82846B and Its Hydrolysis Products with Chloroorienticins A, B and C”; The Journal of Antibiotics; c. Sep. 1989; vol. 42, No. 9; p. 1438-1440. |
| Salas et al.; “Engineering the Glycosylation of Natural Products in Actinomycetes”; Trends in Microbiology; c. 2007; vol. 15, No. 5; p. 219-232. |
| Thayer et al.; “Vancomycin Analogues Containing Monosaccharides Exhibit Improved Antibiotic Activity: A Combined One-Pot Enzymatic Glycosylation and Chemical Diversification Strategy”; Chemistry—An Asian Journal; c. 2006; vol. 1; p. 445-452. |
| Supplementary European Search Report dated Dec. 28, 2011 in corresponding European Application No. 07 74 4107. |
| Number | Date | Country | |
|---|---|---|---|
| 20090286717 A1 | Nov 2009 | US |
