EP1888597A2 - Agents antibacteriens - Google Patents

Agents antibacteriens

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Publication number
EP1888597A2
EP1888597A2 EP06755883A EP06755883A EP1888597A2 EP 1888597 A2 EP1888597 A2 EP 1888597A2 EP 06755883 A EP06755883 A EP 06755883A EP 06755883 A EP06755883 A EP 06755883A EP 1888597 A2 EP1888597 A2 EP 1888597A2
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EP
European Patent Office
Prior art keywords
compound
substituted
unsubstituted
mmol
formula
Prior art date
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EP06755883A
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German (de)
English (en)
Inventor
Michael Robert Barbachyn
Paul Joseph Dobrowolski
Susan Elizabeth Hagen
Tycho Heinar Heimbach
Alexander Ross Hurd
Timothy Allen Johnson
Dennis Joseph Mcnamara
James Craig Ruble
Debra Ann Sherry
Lisa Marie Thomasco
Peter Laurence Toogood
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Publication of EP1888597A2 publication Critical patent/EP1888597A2/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • antibacterial compounds Described herein are antibacterial compounds, their use as antibacterial agents, pharmaceutical compositions containing these compounds, and methods for their preparation.
  • Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years and undoubtedly will increase in the near future. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections pose an increasing burden for health care systems worldwide. Strategies to address these issues emphasize enhanced surveillance of drug resistance, increased monitoring and improved usage of antimicrobial drugs, professional and public education, development of new drugs, and assessment of alternative therapeutic modalities.
  • R 1 is a substituted or unsubstituted thiadiazole
  • R 2 and R 3 are independently H or substituted or unsubstituted Ci. 6 alkyl
  • R 8 and R 9 are independently H, substituted or unsubstituted C 1 ⁇ alkyl or R 8 and R 9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;
  • X and Y are independently H, halo, substituted or unsubstituted Ci- 6 alkyl, -OR 6 , a substituted or unsubstituted ether, or a substituted or unsubstituted amine; [0006] with the proviso that the compound is not rel-(2R,4S,4aS)-1 ,2,4,4a-Tetrahydro-2,4- dimethyl-8-[5-(methylthio)-1 , 3,4-th iadiazol-2-yl]spiro[[1 ,4]oxazino[4,3-a]quinoline-5(6H),5'(2'H)-pyrimidine]- 2 ⁇ 4',6'(1H3 ⁇ )-trione.
  • Forms of the compounds can include salts, such as pharmaceutically acceptable salts, solvates, hydrates or prodrugs of the described compounds.
  • the described compounds can also be part of a pharmaceutical composition, which can additionally include a pharmaceutically acceptable carrier, diluent or excipient.
  • Such compounds and compositions exhibit antibacterial activity and can be used accordingly.
  • X, Y or both can be a substituted or unsubstituted ether.
  • R 4 and R 5 can be H.
  • R 4 and R 5 can also independently be ethers.
  • independently X, Y or both can be a substituted or unsubstituted amine.
  • the group can independently have the formula -(CH 2 ) m NR 8 R 9 and each m, R 8 and R 9 is independent of any other m, R 8 and R 9 values at other positions.
  • the ring can be a monocyclic ring system, for example containing three to eight ring atoms, or the ring system can be a bi- or polyheterocyclic ring system.
  • one or more ring atoms, in addition to the N to which R 8 and R 9 are attached can be selected from non-carbon atoms, for example N, O or S.
  • Ri is one of the following:
  • ⁇ indicates a point of attachment
  • Rn, R 12 and Ri 3 are independently H 1 substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aminoalkyl, an amino acid residue or a peptide residue.
  • amino acid residues include alanine, aspartic acid, glycine, glutamic acid, histidine, lysine or valine.
  • X is H, Y is H or both X and Y are H.
  • X is F, Y is F or both X and Y are F.
  • R 2 and R 3 can be methyl.
  • X can be -OH or -OR 6 , and in some instances R 6 will be methyl or ethyl.
  • X can be an ether or an amine.
  • m in R 7 is 0, for example where R 7 is -CO 2 E, -NR 8 Rg, -PO 3 (Rn) 2 ,
  • R 7 groups can be found in the exemplified compounds. In certain compounds R 7 is H or methyl. [0016] In some embodiments R 4 and R 5 are the same, for example where both are H.
  • R 4 and R 5 can be -OH, -(CH 2 ) m OH, -CH 2 OH, -CH 2 OAc, -CH 2 OCH 3 , -CH 2 O(CH 2 ) 2 OCH 3 .
  • R 4 or R 5 can also be substituted or unsubstituted -(CH 2 ) m aryl or -O(CH 2 ) m aryl, such as substituted or unsubstituted benzyl or substituted or unsubstituted -Obenzyl.
  • R 4 and R 5 can also be -CH 2 OPO 3 H 2 .
  • the heterocyclic ring when R 8 and R 9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring, the heterocyclic ring can have three, four, five, six, seven, eight or more ring members and include one, two, three or more heteroatoms, such as N, O or S.
  • Specific examples of such heterocyclic rings include morpholine and piperazine or a substituted piperazine.
  • R 11 , R 12 or R 13 can be an amino acid residue.
  • amino acids examples include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • Other amino acids include gamma-aminobutyric acid (GABA), carnitine, ornithine, citrulline, homocysteine, hydroxyproline, hydroxylysine, and sarcosine.
  • GABA gamma-aminobutyric acid
  • the amino acids can be in the L- or D- configuration.
  • R 11 , R 12 or R 13 can be a peptide residue, which can be C- or N-linked.
  • Peptides are amino acids linked together via peptide bonds and can be straight-chained or branched.
  • Suitable peptides can include dipeptides, tripeptides, tetrapeptides or more in which the amino acid residues making up the peptide can be the same or different.
  • (R p ) 2 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring.
  • oxygen atoms can be connected
  • each E or ether independently has the formula
  • each E or ether independently has the formula -[(CH 2 ) p O(CH 2 ) p ] q CH 3 where each p is independently 0, 1 , 2, 3 or 4 and each q is independently 1 , 2, 3 or 4.
  • X and Y are F
  • R 2 and R 3 are methyl
  • R 4 and R 5 are
  • R 7 can be methyl.
  • m is 1 or 2.
  • X and Y are F
  • R 2 and R 3 are methyl
  • m is 1 or 2.
  • X is H
  • Y is F
  • R 2 and R 3 are methyl
  • m is 1 or 2.
  • R can include H, such as in aldehydes, a hydrocarbon, such as in a ketone, -NR 8 R 9 , such as in an amide, -OR 6 such as in a carboxylic acid or ester, -0OCR 2 , such as in an acyl anhydride or a halo, such as in an acyl halide.
  • alkenyl group can optionally be substituted, for example where 1 , 2, 3, 4, 5, 6, 7, 8 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR 8 R 9 .
  • alkyl refers to hydrocarbon chains, for example Ci. 6 chains, that do not contain heteroatoms.
  • the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • the phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CHg) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CHg) 2 , -CH 2 C(CHa) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CHg) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CHg) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3
  • the phrase includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
  • Alkyl groups can be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound.
  • An alkyl group can optionally be substituted, for example where 1, 2, 3, 4, 5, 6 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR 8 R 9 .
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical, generally having from two to ten carbon atoms.
  • alkynyl refers to straight and branched chain hydrocarbon groups, such as those described with respect to alkyl groups as described herein, except that at least one triple bond exists between two carbon atoms. Examples include -C ⁇ C(H), -C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -C(H 2 )C ⁇ C(H), -C(H) 2 C ⁇ C(CH 3 ), and -C(H) 2 CsC(CH 2 CH 3 ) among others.
  • alkynyl group can optionally be substituted, for example where 1 , 2, 3, 4, 5, 6, 7, 8 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR 8 R 9 .
  • a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR 8 R 9 .
  • aminoalkyl refers to an alkyl group as above attached to an amino group, which can ultimately be a primary, secondary or tertiary amino group.
  • An example of an amino alkyl group is the -NR 8 Rg where one or both of R 8 and R 9 is a substituted or unsubstituted C-i.
  • R 8 and R 9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring.
  • Specific aminoalkyl groups include -NHCH 3 , -IM(CH 3 ).,, -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 ,-N(CH 2 CH 3 ) 2 , -NHCH 2 CH 2 CH 3 , -N(CH 2 CH 2 CH 3 ) 2 , and the like.
  • Additional aminoalkyl groups include:
  • aminoalkyl group can optionally be substituted with 1 , 2, 3, 4 or more non-hydrogen substituents, for example where each substituent is independently selected from the group consisting of halogen, cyano, hydroxy, Ci. 6 alkyl, C 1 ⁇ alkoxy, Cr 2 alkyl substituted with one or more halogens, Cr ⁇ alkoxy substituted with one or more halogens, -C(O)R 6 , -C(O)OR 6 , -S(O) n R 6 and -NR 8 R 9 .
  • substituents may be the same or different and may be located at any position of the ring that is chemically permissible.
  • aryl refers to cyclic or polycyclic aromatic rings, generally having from 5 to
  • the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example.
  • the phrase "unsubstituted aryl” includes groups containing condensed rings such as naphthalene. Unsubstituted aryl groups can be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound. Substituted aryl groups include methoxyphenyl groups, such as para-methoxyphenyl.
  • Substituted aryl groups include aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, alkynyl group or a heteroatom containing group as described herein. This includes bonding arrangements in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyl group to define a fused ring system (e.g. dihydronaphthyl or tetrahydronaphthyl).
  • the phrase "substituted aryl” includes, but is not limited to tolyl, and hydroxyphenyl among others.
  • An aryl moiety can optionally be substituted with 1 , 2, 3, 4 or more non-hydrogen substituents, for example where each substituent is independently selected from the group consisting of halogen, cyano, hydroxy, Ci. 6 alkyl, C 1 ⁇ alkoxy, Cr 2 alkyl substituted with one or more halogens, Cr 2 alkoxy substituted with one or more halogens, -C(O)R 6 , -C(O)OR 6 , -S(O) n R 6 and - NR 8 R 9 .
  • substituents may be the same or different and may be located at any position of the ring that is chemically permissible.
  • cycloalkyl refers to cyclic hydrocarbon chains, generally having from 3 to 12 carbon atoms, and includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as described herein.
  • the phrase also includes polycyclic alkyl groups such as, but not limited to, adamantly, norbornyl, and bicyclo[2.2.2]octyl and such rings substituted with straight and branched chain alkyl groups as described herein.
  • Cycloalkyl groups can be saturated or unsaturated and can be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound.
  • a cycloalkyl group can be optionally substituted, for example where 1 , 2, 3, 4 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 1 ⁇ alkoxy, C r ⁇ alkyl substituted with one or more halogens, Cr 2 alkoxy substituted with one or more halogens, -C(O)R 6 , -C(O)OR 6 , -S(O) n R 6 and -NR 8 R 9 .
  • Ethers as used herein, generically encompass monoethers, polyethers, straight chain ethers, branched ethers and cyclic ethers.
  • Straight chain ethers can have the structure -[(CH 2 ) p O(CH 2 ) p ] q CH 3 where each p is independently 0, 1 , 2, 3, 4, 5 or 6 and q is 1 , 2, 3, 4, 5 or 6.
  • Branched ethers can have the formula -[(CV 2 ) p O(CV 2 ) p ] q CH 3 where each V is independently H or another
  • Cyclic ethers can have the formula where p and q are as above and ⁇ JVW > indicates a point of attachment.
  • ether compounds there are -dimethyl ether, -methyl ethyl ether, -methoxy ethyl ether, -diethyl ether, -methyl t-butyl ether, -methyl cellosolve, - ethylene glycol dimethyl ether, -diethylene glycol dimethyl ether, -triethylene glycol dimethyl ether, -tetraethylene glycol dimethyl ether, -tetrahydrofuran, -1 ,4-dioxane, and the like.
  • halo refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group in which at least one, for example 1 , 2, 3,
  • haloalkyls include chloromethyl, difluoromethyl, trifluoromethyl, 1-fluro-2-chloro-ethyl, 5-fluoro-hexyl, 3-difluro-isopropyl, 3- chloro-isobutyl, etc.
  • heterocyclyl or “heterocyclic ring” refers to aromatic, nonaromatic, saturated and unsaturated ring compounds including monocyclic, bicyclic, and polycyclic ring compounds, including fused, bridged, or spiro systems, such as, but not limited to, quinuclidyl, containing 1 , 2, 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, P and S.
  • Unsubstituted heterocyclyl groups include condensed heterocyclic rings such as benzimidazolyl.
  • heterocyclyl groups include: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1 ,2,4-triazolyl, 1 H-1 ,2,3-triazolyl, 2H- 1 ,2,3-triazolyl etc.), tetrazolyl, (e.g.
  • saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; saturated 3 to 8 membered rings containing 1 to 3 oxygen atoms such as, but not limited to, tetrahydrofuran; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g.
  • saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g.
  • unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g.
  • saturated 3 to 8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g.
  • unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as; but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms, and 1 to 2 sulfur atoms such as 1 ,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl.
  • Heterocyclyl group also include those described herein in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones).
  • heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1 ,1 -dioxide.
  • Heterocyclyl groups can contain 5 or 6 ring members.
  • heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1 ,2,3- triazole, 1 ,2,4-triazole, tetrazole, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazoie, quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
  • a heterocyclyl group can be optionally substituted, for example where 1 , 2, 3, 4 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, C 1 ⁇ a'M.
  • Heterocyclyl groups include heteroaryl groups as a subgroup.
  • heteroaryl refers to a monovalent aromatic ring radical, generally having 5 to 10 ring atoms, containing 1 , 2, 3, or more heteroatoms independently selected from S, O, or N.
  • heteroaryl also includes bicyclic groups in which the heteroaryl ring is fused to a benzene ring, heterocyclic ring, a cycloalkyl ring, or another heteroaryl ring.
  • heteroaryl examples include 7-benzimidazolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, benzothiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, furanyl, furyl, imidazolyl, indolyl, indazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiophenyl, triazolyl and the like.
  • Heteroaryl rings can also be optionally fused to one or more of another heterocyclic ring(s), heteroaryl ring(s), aryl ring(s), cycloalkenyl ring(s), or cycloalkyl rings.
  • a heteroaryl group can be optionally substituted, for example where 1 , 2, 3, 4 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, Ci- 6 alkoxy, d- 2 alkyl substituted with one or more halogens, Cr 2 alkoxy substituted with one or more halogens, -C(O)R 6 , -C(O)OR 6 , -S(O) n R 6 and -NR 8 R 9 .
  • heterocyclyloxy refers to a group in which an oxygen atom is bound to a ring atom of a heterocyclyl group as described herein.
  • a “pharmaceutically acceptable” means suitable for use in mammals.
  • a “pharmaceutically acceptable salt” includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid.
  • the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia.
  • salts of organic bases the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine.
  • the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid.
  • the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • salts of basic amino acids the instant invention includes, for example, arginine, lysine and ornithine.
  • Acidic amino acids include, for example, aspartic acid and glutamic acid.
  • pharmaceutically acceptable salts are described in Berge, S. M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1 19.
  • a "prodrug” is a compound that can be transformed in vivo into an active therapeutic compound, such as a compound described herein. Transformation of the prodrug compound can be accomplished chemically, enzymatically, or by action with other endogenous materials, e.g. amino acids, peptides and proteins. Prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S.
  • prodrugs can include esters and amides of polar groups, such as carboxylate groups.
  • prodrugs can include esters and amides of polar groups, such as carboxylate groups.
  • protected with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wilts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999) which can be added or removed using the procedures set forth therein.
  • Examples of protected hydroxyl groups include silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxym ethyl ether, tetrahydropyranyl ethers, 1 -ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but not limited to
  • protected amine groups include amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others.
  • protected sulfhydryl groups include thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • a "salt" is intended to refer to all salt forms of a compound, including salts suitable for use in industrial processes, such as the preparation of the compound, and pharmaceutically acceptable salts.
  • Substituted refers to a group in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen atom. In some instances the bond will also be replaced by non-carbon atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, heterocyclylamine, (alkyl)(heterocyclyl)amine, (aryl)(heterocyclyl)amine, or diheterocyclylamine groups, isonitrile, N-oxides, imides, and enamines; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, ester groups, and heterocyclyloxy groups; a silicon atom in groups such as in trialkylsilyl groups,
  • Substituted alkyl groups and substituted cycloalkyl groups also include groups in which one or more bonds to one or more carbon or hydrogen atoms are replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl, and ether groups; nitrogen in groups such as imines, oximes and hydrazones.
  • Substituted cycloalkyl, substituted aryl, substituted heterocyclyl and substituted heteroaryl also include rings and fused ring systems which can be substituted with alkyl groups as described herein.
  • Substituted arylalkyl groups can be substituted on the aryl group, on the alkyl group, or on both the aryl and aikyl groups.
  • substituents for substitution include one or more, for example one, two or three, groups independently selected from halogen, -OH, -C 1-6 alkyl, C 1 ⁇ alkoxy, trifluoromethoxy, -S(O) n C 1 . 6 alkyl, amino, haloalkyl, thiol, cyano, -OR 10 and -NR 8 R 9 , and trifluoromethyl.
  • Treating means an alleviation of symptoms associated with an infection, halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the infection.
  • Treatment can also include administering the pharmaceutical formulations of the present invention in combination with other therapies.
  • the compounds and pharmaceutical formulations of the present invention can be administered before, during, or after surgical procedure and/or radiation therapy.
  • the compounds of the invention can also be administered in conjunction with other antibacterial drugs.
  • compounds described herein can be provided ex vivo or produced in vivo, for example where a prodrug of a compound is administered.
  • reference to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • compound B can be obtained from compound A by forming a thiadiazole side chain precursor from the carboxylic acid moiety.
  • the thiadiazole side chain precursor can then be cyclized to the desired thiadiazole, as described in more detail in the following reactions, and the alcohol can be deprotected to obtain compound C.
  • thiadiazole ring formation can occur directly from compound A, particularly for compounds containing sulfide and sulfone substituted 1 ,3,4-thiadiazoles, using the appropriate reagents as described below.
  • compound A can be prepared at least as follows, particularly where
  • X is H and Y is F:
  • reaction, OPro 2 is a carbonyl protecting group, such as a cyclic acetal, which can be formed by reaction of a carbonyl with 1 ,2-ethanediol or propane-1 ,3-diol in the presence of an acid catalyst. Typical halo atoms include bromine.
  • the carbonyl deprotection can be performed by acid deprotection in THF.
  • the carbonyl can be reduced, such as by using sodium borohydride in the presence of methanol.
  • the resulting alcohol can be protected utilizing art-known methods and groups, for example a trialkyl silyl ether such as t-butyldiphenyl silyl ether (TBDPS), and the halo group can be substituted by a carboxylation to give compound A.
  • TDPS t-butyldiphenyl silyl ether
  • the carboxylation can be achieved by performing a halogen metal exchange reaction followed by reacting the product with a carbonyl donor.
  • the halogen metal exchange reaction can include can include contacting the compound with a strong base, such as alkyl lithium, or a Grignard reagent in a non-protic organic solvent.
  • Compound A can also be produced according to the following synthetic scheme, particularly when both X and Y are F:
  • ring coupling can be achieved by the use of a base, such as lithium hexamethyldisilazide (LiHDMS), Et 3 N, or the like. Similar to the preceding reaction, the carbonyl can be reduced, such as by using sodium borohydride and I 2 . The resulting alcohol can be protected utilizing art- known methods and groups, for example a trialkyl silyl ether such as t-butyldiphenyl silyl ether (TBDPS), and the halo group can be displaced by a carboxylation reaction to give compound A.
  • a base such as lithium hexamethyldisilazide (LiHDMS), Et 3 N, or the like.
  • the carbonyl can be reduced, such as by using sodium borohydride and I 2 .
  • the resulting alcohol can be protected utilizing art- known methods and groups, for example a trialkyl silyl ether such as t-butyldiphenyl silyl ether (TBDPS), and
  • compound A is modified to add the thiadiazole side chain precursor by converting the starting carboxylic acid into a ketone via the Weinreb amide using Grignard chemistry.
  • a non-limiting example of this chemistry is shown in Example 2, steps 1 and 2.
  • Reaction with tosyl hydrazine to generate a hydrazone, followed by treatment with thionyl chloride produces the 1 ,2,3-thiadiazole as shown.
  • compound A where n is 1 may be obtained from compound A where n is 0 by adding a carbon to the carboxyl side chain.
  • the carboxlic acid is converted to an acid chloride using oxalyl chloride then treated with trimethylsilyl-diazomethane and methanol resulting in homologation to a methyl ester as follows:
  • the carboxyl group of compound A is converted to an amide which is converted to a thioamide.
  • the thiadiazole of compound C is then formed from the thioamide of compound B by cyclization with the appropriate reagents, as described in more detail in the examples.
  • Pro 3 represents a protecting group, for example an amine protecting group such as a tert-butoxycarbonyl (BOC) group.
  • BOC tert-butoxycarbonyl
  • the carboxyl group of compound A is converted to a protected hydrazide which is converted to a thiohydrazide similar to the thioamide conversion described herein.
  • the thiohydrazide is deprotected and cyclized to a thiadiazole, for example by using an acylating agent.
  • reaction to form Il can occur in an aqueous or organic solvent.
  • temperatures for this reaction will be about 60 to about 180 0 C, for example from about 80 to 180 0 C, 100 to 140 0 C or 140 to 180 0 C, and can occur from about 2 to about 24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
  • solvents that can be used include DMSO, methanol, isopropanol, butanol, toluene and water.
  • temperatures can range from about 80 0 C to about 120 0 C.
  • reaction times can range from about 5 to 24 h.
  • the method can also involve (b) reacting a compound of formula V with a compound of formula Vl, optionally in a non-protic organic solvent and/or in the presence of a base, to make the compound of formula III:
  • the base when present, can be an organic or inorganic base.
  • compound Vl can act as a base.
  • the reaction will take place at a temperature of about 20 to about 100 0 C, for example from about 40 to 100 0 C, 60 to 80 0 C or 80 to 100 0 C.
  • This reaction can also be performed alone to provide the compound of formula III.
  • solvents that can be used include acetonitrile and dimethylformamide.
  • Temperature ranges for the reaction can also be about 70 to 90 0 C
  • Bases that can be used in the reaction include triethylamine, diisopropylethylamine or potassium carbonate. Reaction times can range from about 2 to 24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
  • Compound V can be made by:
  • reaction Ha is hydrogen or a halogen, for example bromine. Ha can also be chlorine or iodine.
  • (c)(i) can include contacting the compound of formula VII with a strong base, such as alkyl lithium.
  • (c)(i) can include contacting the compounds of formula VII with a Grignard reagent in a non-protic organic solvent. These reactions typically occur at a temperature from about -78 to about 50 °C, for example from about -78 to about 0 0 C.
  • the carbonyl donor can include one or more of dimethylformamide, N-formylmorpholine, or para- nitrophenylformate. Examples of reaction times can be from about 1 to about 18 hours, for example 2, 4, 6, 8, 10, 12, 14, 16 or 18 hours.
  • Compound V can also be synthesized by (c) oxidizing a compound of formula VIII to make the compound of formula V:
  • X IX is a halogen, such as iodine. Accordingly, compound IX is made by reacting compounds X and Xl. This coupling reaction can also be performed with reverse polarity wherein the boron is attached to R 1 and the halogen is attached to compound X at the position indicated by B' (see structure XII below). In general, the coupling reaction can be performed under standard Suzuki cross-coupling conditions employing 0.01- 0.1 equivalents of a palladium catalyst with appropriate ligands, such as Pd(PPh 3 ) 4 or Pd(dppf) Cl 2 , in an organic solvent or solvent mixture containing organic solvents, such as toluene and an alcohol, and water.
  • a palladium catalyst with appropriate ligands, such as Pd(PPh 3 ) 4 or Pd(dppf) Cl 2
  • organic solvent or solvent mixture such as toluene and an alcohol, and water.
  • the reaction can be performed in the presence of a base such as potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate or sodium acetate for example, at temperatures, e.g. from about 20 to 120 0 C for about 2 to 24 h.
  • a base such as potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate or sodium acetate for example, at temperatures, e.g. from about 20 to 120 0 C for about 2 to 24 h.
  • This route can also be used to make compounds of formula III when a trans-morpholine compound is used in the reaction.
  • Compounds III or IX can be used to make compound of formula I or Il according to the methods described herein.
  • Compound X can be made by reacting compound XII to provide compound X:
  • Conversion of compounds XII to compound X can be performed by reaction with a borane such as for example, bis(pinacolato)diboron, under palladium catalysis employing a palladium(ll) or palladium(o) species with appropriate ligands, for example Pd(PPh 3 )4, Pd(dppf)CI 2 , Pd(PCy) 2 CI 2 , in an organic solvent such as tetrahydrofuran, methyl-tetrahydrofuran, or toluene, and in the presence of an inorganic base such as, for example, potassium acetate, potassium phosphate, sodium carbonate, cesium carbonate.
  • the reaction typically proceeds at elevated temperatures from 80 to 120 0 C over about 12 h to 5 days.
  • compound XII can be made by reacting compounds XIII and XIV:
  • the method can involve (a) reacting a compound of formula XIV with a compound of formula XIII, optionally in a non-protic organic solvent and/or in the presence of a base, to make the compound of formula XII.
  • the base can be an organic or inorganic base.
  • compound XII can act as a base.
  • the reaction will take place at a temperature of about 20 to about 100 0 C, for example from about 40 to 100 0 C, 60 to 80 0 C or 80 to 100 0 C.
  • Compound XIV can be made from compound XV as follows:
  • compound XIV can be made by:
  • reaction, Ha is hydrogen.
  • reaction, (b)(i) can include contacting the compound of formula XV with a strong base, such as alkyl lithium. These reactions typically occur at a temperature from about -78 to about 50 0 C.
  • the carbonyl donor can include one or more of dimethylformamide, N-formylmorpholine, or para-nitrophenylformate.
  • R 14 is a halogen, such as bromine or iodine, boronic acid, a boronate ester, such
  • the base when present, can be an organic or inorganic base. In some instances compound Vl can act as a base. Typically, the reaction will take place at a temperature of about 20 to about 100 0 C, for example from about 40 to 100 0 C, 60 to 80 0 C or 80 to 100 0 C. Examples of solvents that can be used include acetonitrile and dimethylformamide. Temperatures ranges for the reaction can also be about 70 to 90 0 C. Bases that can be used in the reaction include triethylamine, dirsopropylethylam ine or potassium carbonate. Reaction times can range from about 2 to 24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
  • compound XVII can be used to make compound XVII where R 14 is boronic acid or a boronate ester using the same reaction as set forth for making compound X.
  • compound XVII can also be used to make the compound of formula III by coupling compound XVII with a compound of formula RrB', where B' is
  • the compound of formula III can also be produced when Ru is boronic acid, a boronate ester, by reaction compound XVII with compound Xl (R r halo) by the method set forth for making compound IX described herein.
  • this coupling reaction can be performed under standard Suzuki cross-coupling conditions employing 0.01- 0.1 or more equivalents of a palladium catalyst with appropriate ligands, such as Pd(PPh 3 ) 4 or Pd(dppf) Cl 2 , in an organic solvent or solvent mixture containing organic solvents, such as toluene and an alcohol, and water.
  • the reaction can be performed in the presence of a base, such as potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate or sodium acetate for example, at temperatures, e.g. from about 20 to 120 0 C for about 2 to 24 h.
  • Compound III can then be used to produce compounds of Formula Il as described herein.
  • Compound XVIII can be made by:
  • Ha is hydrogen or a halogen, for example bromine. Ha can also be chlorine or iodine.
  • (c)(i) can include contacting the compound of formula VII with a strong base, such as alkyl lithium.
  • (c)(i) can include contacting the compounds of formula W
  • the carbonyl donor can include one or more of tetrahydrofuran, diethylether, dimethylformamide, N- formylmorpholine, or para-nitrophenylformate. Examples of reaction times can be from about 1 to about 18 hours, for example 2, 4, 6, 8, 10, 12, 14, 16 or 18 hours.
  • Compound XVIII can also be synthesized by (c) oxidizing a compound of formula VIII to make the compound of formula XVIII:
  • compositions that can be prepared by mixing one or more compounds described herein, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, to treat or ameliorate a variety of bacterial infections.
  • a therapeutically effective dose or amount refers to that amount of one or more compounds described herein sufficient to result in amelioration of symptoms of the infection.
  • the pharmaceutical compositions of the instant invention can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, emulsifying or levigating processes, among others.
  • compositions can be in the form of, for example, granules, powders, tablets, capsule syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the instant compositions can be formulated for various routes of administration, for example, by oral administration, by transmucosal administration, by rectal administration, or subcutaneous administration as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection.
  • the compound or compounds of the instant invention can also be administered in a local rather than a systemic fashion, such as injection as a sustained release formulation.
  • the following dosage forms are given by way of example and should not be construed as limiting the instant invention.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive or excipient such as a starch or other additive.
  • Suitable additives or excipients are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methyl cellulose, hydroxypropylmethyl- cellulose, and/or polyvinylpyrrolidone.
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Additionally, dyestuffs or pigments can be added for identification. Tablets and pills can be further treated with suitable coating materials known in the art.
  • Liquid dosage forms for oral administration can be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, slurries and solutions, which can contain an inactive diluent, such as water.
  • Pharmaceutical formulations can be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents can be added for oral or parenteral administration.
  • suspensions can include oils.
  • oils include peanut oil, sesame oil, cottonseed oil, corn oil, olive oil and mixtures of oils.
  • Suspension preparation can also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations can include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water can also be used in suspension formulations.
  • the pharmaceutical formulations can be a spray or aerosol containing and appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailablity modifiers and combinations of these.
  • a propellant for an aerosol formulation can include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
  • the compound or compounds of the instant invention are conveniently delivered in the form of an aerosol spray presentation from a nebulizer or the like.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Generally, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the pharmaceutical formulation can be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection can be in ampoules or in multi-dose containers.
  • the pharmaceutical formulations can be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum.
  • Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils can also be employed in the preparation of formulations of the soft gelatin type and suppositories.
  • suspension formulations which can also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxym ethyl cellulose, as well as buffers and preservatives.
  • suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxym ethyl cellulose, as well as buffers and preservatives.
  • the formulations of the invention can be designed for to be short-acting, fast-releasing, long-acting, and sustained-releasing.
  • the pharmaceutical formulations can also be formulated for controlled release or for slow release.
  • compositions can also comprise, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants can employ known materials such as silicones and biodegradable polymers.
  • the compositions can contain, for example, from about 0.1% by weight, to about 90% or more by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit can contain, for example, from about 5 to 500 mg or more of the active ingredient.
  • the dosage as employed for adult human treatment can range, for example, from about 10 to 3000 mg per day, depending on the route and frequency of administration. [00111] Specific dosages can be adjusted depending on conditions of infection, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention. Generally, the total daily dose can typically range from about 0.1 mg/kg/day to about 500 mg/kg/day in single or in divided doses. Typically, dosages for humans can range from about 10 mg to about 3000 mg per day, in a single or multiple doses.
  • a therapeutically effective dose or amount can vary depending upon the route of administration and dosage form.
  • Some compositions of the instant invention provide a formulation that exhibits a high therapeutic index.
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD 50 and ED 50 .
  • the LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 can be determined by standard pharmaceutical procedures in animal cell cultures or experimental models.
  • the invention provides methods of treating or preventing a bacterial infection in a subject, such as a mammal, e.g., a human or non-human mammal, comprising administering an effective amount of one or more compounds described herein to the subject.
  • Suitable subjects that can be treated include domestic or wild animals, companion animals, such as dogs, cats and the like; livestock, including horses, cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example monkeys, such as rhesus monkeys and cynomolgus (also known as crab-eating or long-tailed) monkeys, marmosets, tamarins, chimpanzees, macaques and the like; and rodents, such as rats, mice, gerbils, guinea pigs and the like.
  • the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier.
  • the compounds described herein can be used for the treatment or prevention of infectious disorders caused by a variety of bacterial organisms, including infections by pathogenic bacterial species.
  • infections by pathogenic bacterial species examples include Gram positive and Gram negative aerobic and anaerobic bacteria, such as Staphylococci, e.g. S. aureus; Enterococci, e.g. E. faecalis; Streptococci, e.g. S. pyogenes and S. pneumoniae; Escherichia species, e.g. E. coli, including enterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic and enteroaggregative E. coli strains; Haemophilus, e.g. H.
  • influenza e.g. M. tuberculosis
  • M. avian-intracellulare M. kansasii, M. bovis
  • M. africanum M. genavense
  • M. leprae M. xenopi
  • M. simiae M. scrofulaceum
  • M. malmoense M. celatum
  • M. abscessus M. chelonae
  • M. szulgai M. gordonae, M. haemophilum, M. fortuni and M. marinum
  • Corynebacteria e.g. C.
  • Vibrio species e.g. V. cholerae
  • Campylobacter species e.g. C. jejuni
  • Helicobacter species e.g. H. pylori
  • Pseudomonas species e.g. P. aeruginosa
  • Legionella species e.g. L. pneumophila
  • Treponema species e.g. T. pallidum
  • Borrelia species e.g. B. burgdorferi
  • Listeria species e.g. L monocytogenes
  • Bacillus species e.g. B. cereus
  • Bordatella species e.g. B.
  • Clostridium species e.g. C. perfringens, C. tetani, C. difficile and C. botulinum
  • Neisseria species e.g. N. meningitidis and N. gonorrhoeae
  • Chlamydia species e.g. C. psittaci, C. pneumoniae and C. trachomatis
  • Rickettsia species e.g. R. rickettsii and R. prowazekii
  • Shigella species e.g. S. sonnei
  • Salmonella species e.g. S. typhimurium
  • Yersinia species e.g. Y. enterocolitica and Y. pseudotuberculosis
  • Klebsiella species e.g. K. pneumoniae
  • Mycoplasma e.g. M. pneumoniae.
  • Infections that can be treated with the described compounds include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients. These infections can be treated in hospital or community settings via various routes of administration as described herein.
  • one or more of the present compounds or compositions can be administered to an individual deemed to be at risk for developing a microbial infection.
  • Individuals at risk for developing a microbial infection include individuals who have been exposed to a particular microorganism, such as a pathogenic bacterial species; individuals having a compromised immune system, such as individuals suffering from an immunodeficiency disease or taking immunocompromising medication; and individuals having a history of repeated or chronic infection, such as children who have repeated infections of the middle ear.
  • Another embodiment provides a method of killing or preventing the growth of bacteria that includes contacting a bacteria with either a non-therapeutic amount or a therapeutically effective amount of one or more of the present compounds. Such methods can occur in vivo or in vitro.
  • In vitro contact can involve a screening assay to determine the efficacy of the one or more compounds against selected bacteria at various amounts or concentrations.
  • In vivo contact with a therapeutically effective amount of the one or more compounds can involve treatment or prophylaxis of a bacterial infection in the animal in which the contact occurs.
  • the effect of the one or more compounds on the bacteria and/or host animal can also be determined or measured.
  • ail isomers e.g. stereoisomers, diastereoisomers, epimers, geometrical isomers
  • ail isomers e.g. stereoisomers, diastereoisomers, epimers, geometrical isomers
  • the present invention also covers the individual isomers of the compounds represented by the formulas herein as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • Stereoisomeric mixtures e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a known manner by means of suitable separation methods.
  • Diastereomeric mixtures for example can be separated into their individual diastereomers by means of fraction crystallization, chromatography, solvent distribution, and similar procedures. This separation can take place either at the level of one of the starting compounds or in a compound of formula I itself.
  • Enantiomers can be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomerically pure chiral acid, or by means of chromatography, for example by HPLC, using chiral chromatographic media.
  • the compounds described herein can exhibit the phenomenon of tautomerism. As the chemical structures sometimes only represent one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form of the represented structure. [00120]
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • Step 1 1-[3-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5- fluoro-phenyl]-ethanone.
  • Steps 2-4 [2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-[1 ,2,3]thiadiazol-4-yl-phenyl]- methanol.
  • steps 1-4 was followed using 1-[3-(fert-butyl-diphenyl- silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro-phenyl]-ethanone to provide the compound (0.188 g) as a colorless oil.
  • Step 5 part 1 : 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-[1 ,2,3]thiadiazol-4-yl- benzaldehyde.
  • the procedure of Example 10, step 5 was followed except the residue following the filtration was purified by column chromatography to provide the compound (0.154 g) as an oil.
  • Step 6, part 2 Compound 1.
  • the procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with isopropanol (IPA) (2 x 1 mL) providing the compound (0.148 g) as a beige solid.
  • IPA isopropanol
  • Step 1 5-(fe/t-Butyl-diphenyl-silanyloxymethyi)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-N-methoxy-N-methyl-benzamide.
  • a solution of 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6- dimethyl-morpholin-4-yl)-2,3-difluoro-benzoic acid (10.0 g, 19 mmol) in CH 2 CI 2 (50 mL) at 0 °C was treated with CDI (3.76 g, 23.2 mmol).
  • Step 2 1-[5-(ferf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-ethanone.
  • Step 3 and Step 4 parts 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-
  • the filter cake was washed with EtOH (2 x 10 ml) and dried to provide a white solid (2.0 g, 2.8 mmol).
  • the white solid (0.50 g, 0.71 mmol) was dissolved in SOCI ⁇ (5 mL) at rt and stirred for 30 min. The solution was quenched carefully with water (50 mL) and extracted with EtOAc (50 mL). The organics were dried over Na 2 SO 4 and concentrated. The residue was dissolved in HCI (10 mL of a 4M solution in dioxane) and stirred overnight. The solution was diluted with water (75 ml) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na 2 SO 4 and concentrated.
  • Step 4, part 3 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-[1 ,2,3]thiadiazol-4-yl- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.088 g) as a yellow oil.
  • Step 5 Compound 2.
  • the procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt.
  • the filter cake was washed with IPA (2 x 1 mL) providing the compound (0.070 g) as a beige solid, mp: >260 0 C;
  • Step 1 Performed as set forth in Step 1 of Example 2.
  • Step 2 1-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-propan-1-one.
  • the Grignard addition procedure of Example 2, step 2 was followed using ethylmagnesium bromide to provide the compound (1.78 g) as a colorless oil.
  • Step 3 and Step 4 parts 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5- methyl-[1 ,2,3]thiadiazol-4-yl)-phenyl]-methanol.
  • steps 1-4 was followed to provide the compound (0.340 g) as a pale yellow oil.
  • Step 4, part 3 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,2,3]thiadiazol-
  • Step 1 Performed as set forth in Step 1 of Example 2.
  • Step 2 1-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-2-phenyl-ethanone.
  • the Grignard addition procedure of Example 2, step 2 was followed using benzylmagnesium bromide to provide the compound (1.92 g) as a colorless oil.
  • Step 3 and Step 4 parts 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5- phenyl-[1 ,2,3]thiadiazol-4-yl)-phenyl]-methanol.
  • steps 1-4 was followed to provide the compound (0.371 g) as a beige solid.
  • Step 4, part 3 2-(2,6-Dimethyl-mo ⁇ holin-4-yl)-3,4-difluoro-5-(5-phenyl-[1 ,2,3]thiadiazol-
  • Step 5 Compound 6.
  • the procedure of Example 10, step 6 was followed except the reaction was concentrated and the residue was purified by column chromatography to provide the compound (0.296 g) as a yellow foam.
  • Step 1 [5-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-acetic Acid Methyl Ester.
  • Step 2 part 1 : 2-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-
  • Steps 3 and 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-[1 ,2,3]thiadiazol-5-yl- phenyl]-methanol.
  • a solution of [5-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)- 2,3-difluoro-phenyl]-acetaldehyde (0.375 g, 0.70 mmol) in CH 2 CI 2 (5 mL) at -78 0 C was treated with tosyl hydrazide (0.130 g, 0.70 mmol).
  • Step 5 part 1 : 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-[1 ,2,3]thiadiazol-5-yl- benzaldehyde.
  • the procedure of Example 10, step 5 was followed except the residue following the filtration was purified by column chromatography to provide the compound (0.100 g) as an oil.
  • Step 5 part 2: Compound 7.
  • Step 1 Preparation of 5-(ferf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-
  • Step 2 Preparation of 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-
  • Step 4 parts 1 and 2: Preparation of 2-(2,6-Dimethylmorpholin-4-yI)-3,4-difIuoro-5-(3- methyl-1 ,2,4-thiadiazol-5-yl)benzaldehyde.
  • Step 4, part 3 Compound 8. A solution of 2-(2,6-dimethylmorpholin-4-yl)-3,4-difluoro-5-
  • Steps 1 and 2 were performed as set forth in Example 8, steps 1 and 2.
  • Step 3 4-(6-(tert-Butyl-diphenyl-silyloxymethyl)-2,3-difluoro-4-(1 ,2,4-thiadiazol-5- yl)phenyl]-2,6-dimethylmorpholine.
  • dimethyl acetamide-dimethylacetal 0.2 ml, 1.5 mmol
  • DMF-DMA dimethyl acetamide-dimethylacetal
  • Step 4 parts 1 and 2: Preparation of 2-(2,6-Dimethylmorpholin-4-yl)-3,4-difluoro-5-(1 ,2,4- thiadiazol-5-yl)benzaldehyde.
  • a solution of 4-(6-(tert-butyl-diphenyI-silyloxymethyl)-2,3-difluoro-4-(1 ,2,4- thiadiazol-5-yl)phenyl]-2,6-dimethylmorpholine (0.26 g, 0.45 mmol) in MeOH (1 ml) was treated with 4M HCI in dioxane (2 ml) and stirred at room temperature for 3 hours. TLC analysis shows no starting material.
  • Step 1 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-benzoylj-hydrazinecarboxylic Acid terf-Butyl Ester.
  • Step 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- phenyl]-methanol.
  • a solution of 4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl-thiobenzoic acid hydrazide hydrochloride (0.80 g, 2.2 mmol) in THF (20 mL) at rt was treated with diisopropylethylamine (1.14 mL, 6.5 mmol) followed by acetyl choride (0.23 mL, 3.26 mmol).
  • Step 6 Compound 10. A stirring slurry of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-
  • Step 1 Preparation of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-benzoic acid.
  • a stirred solution of 2,3,4-trifluorobenzoic acid (Aldrich, 890 g, 5.05 mol) in tetrahydrofuran (5 L) was cooled to - 78°C.
  • a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (5.56 L) was added dropwise to the reaction at such a rate that the reaction temperature did not rise above -65°C. Stirring was continued at -78°C for 45 min.
  • Step 2 Preparation of 4-[6-(tert-Butyl-diphenyl-silanyloxymethyl)-2,3-difluoro-phenyl]-2,6- dimethyl-morpholine.
  • Step 3 Preparation of 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-
  • Steps 4 and 5 A solution of 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl- morpholin-4-y!-2,3-difluoro-benzoic acid (20.0 g, 37 mmol) in CH 2 CI 2 (100 mL) was treated with carbonyldiimidazole (7.2 g, 44 mmol). The resulting solution was stirred for 30 min, acetic hydrazide (3.3 g, 44 mmol) was added followed by diisopropylethylamine (5.7 g, 44 mmol) and the solution was stirred at rt for 5h. The reaction was poured into sat.
  • the solution was diluted with water (100 mL) and extracted with CH 2 CI 2 (3 x 100 mL). The combined organics were dried over Na 2 SO 4 and concentrated. The residue was treated with HCI (50 mL of a 4M solution in dioxane) and stirred overnight. The solution was diluted with water (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organics were dried over Na 2 SO 4 .
  • Step i 2-Bromo-3,4,5-trifluorobenzaldehyde.
  • a 3-L 4-neck flask was dried by heating with a hot air gun to 94-95 °C. After cooling to room temperature, 74.48 g (1.47 mol) diisopropylamine was added and dissolved in 600 ml dry THF. The solution was cooled to -75 0 C and n-butyllithium (2.5 M in hexane, 320 ml) was added dropwise over 70 min while maintaining the temperature between -75 to - 60 °C. The mixture was allowed to warm to -10.4 0 C to 0.2 0 C for 13 min.
  • Step 2 3-Bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde. 2-Bromo-
  • 3,4,5-trifluorobenzaldehyde (133.15 g, 0.56 mol) was dissolved in 1000 ml dry acetonitrile. Triethylamine (118.65 ml, 0.85 mol) was added, followed by cis-2,6-dimethylmorpholine (71.64 g, 0.62 mol), and 125 ml additional acetonitrile. The mixture was refluxed for 24 hours, then cooled to room temperature, and poured into 1500 ml saturated sodium bicarbonate solution. The phases were separated and the aqueous phase extracted 2 x 500 ml ethyl acetate. The combined organic portions were washed 2 x 500 ml brine and then dried over magnesium sulfate.
  • Methyltetrahydrofuran (3300 ml) was added. The mixture was mechanically stirred as it was evacuated until bubbling stopped. The reactants were flushed with argon, then evacuated and flushed with argon again. Argon was then bubbled through the mixture for 2 h 16 min. The mixture was then evacuated until bubbling ceased, then flushed with argon, evacuated, and flushed with argon again. The mixture was heated to reflux for 4.7 days, when NMR indicated that all 3-bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde had been consumed.
  • Step 4 2-lodo-5-methyl-[1 ,3,4]thiadiazole (2.0 g) was slurried in CH 3 CN (30 ml) and
  • Steps 1 to 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-phenyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol.
  • the procedure set forth in Example 10, steps 1 to 4 was followed using benzoyl chloride as the acylating reagent to provide the compound (0.150 g) as an orange solid.
  • Step 5 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-phenyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.120 g) as a yellow solid.
  • Steps 1 to 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-trifluoromethyl-
  • Step 5 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-trifluoromethyl-[1 ,3,4]thiadiazol-
  • Step 5 2-(2,6-Dimethyl-morpholin-4-yI)-3,4-difluoro-5-(5-acetoxymethyl-[1 ,3,4]thiadiazol-
  • Steps 1 to 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-([1 ,3,4]thiadiazol-2-yl)- phenylj-methanol.
  • the procedure set forth in Example 10, steps 1 to 4 was followed using formic acid as the acylating reagent except the reaction was heated to reflux for 3h to provide the compound (0.120 g) as a green oil.
  • Step 5 2-(2,6-Dimethyl-mo ⁇ holin-4-yl)-3,4-difluoro-5-([1 ,3,4]thiadiazol-2-yl)- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.069 g) as a yellow oil.
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- phenylj-methanol.
  • steps 1 to 4 was followed using propionyl chloride as the acylating reagent to provide the compound (0.231 g).
  • Step 2 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.200 g) as a yellow solid.
  • Step 3 Compound 15.
  • Step 1 parts 1 and 2: 3- ⁇ 5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl- phenyl]-[1,3,4]thiadiazoi-2-yl ⁇ -propionic Acid Methyl Ester.
  • steps 1 to 4 was followed using 3-chlorocarbonyl-propionic acid methyl ester as the acylating reagent to provide the compound (0.495 g).
  • Step 2 Compound 17.
  • the procedure of Example 10, step 6 was followed providing the compound (0.250 g).
  • Step 1 parts 1 and 2: 5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl- phenyl]-[1,3,4]thiadiazole-2-carboxylic Acid Methyl Ester.
  • steps 1 to 4 was followed using chloromethyloxalate as the acylating reagent to provide the compound (0.120 g).
  • Step 1 part 3: 5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-formyl-phenyl]-
  • Step 2 Compound 18.
  • the procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with IPA (2 x 1 ml_) providing the compound (0.085 g) as a yellow solid, mp: >260 0 C;
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-(pyridin-4-yl)-t1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol.
  • steps 1 to 4 was followed using isonicotinoyl chloride hydrochloride as the acylating reagent to provide the compound (0.370 g).
  • Step 2 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-(pyridin-4-yl)-[1 ,3,4]thiadiazol-2- yl)-benzaldehyde.
  • the procedure of Example 10, step 5 was followed except for the reaction was heated to reflux for 30 min. Normal work-up provided the compound (0.095 g) as a yellow solid.
  • Step 3 Compound 19. The procedure of Example 10, step 6 was followed except the residue was crystallized from MeOH (2 mL) to provide the compound (0.090 g).
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-cyclopropyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol.
  • steps 1 to 4 was followed using cyclopropanecarbonyl chloride as the acylating reagent to provide the compound (0.315 g).
  • Step 2 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-cyclopropyl -[1 ,3,4]thiadiazol-2- yl)-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.245 g) as a yellow solid.
  • 1H NMR (400 MHz, CDCI 3 ) ⁇ 1.2 (m, 10 H), 2.4 (m, 1 H) 3.1 (m, 4 H), 3.8 (m, 2 H), 8.5 (d, J 7.6 Hz, 1 H), 10.1 (s, 1 H); MS (APCI + ) m/z 380 (MH + ).
  • Step 3 Compound 20.
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-isoxazol-5-yl)-[1 ,3,4]thiadiazol-
  • Step 2 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-isoxazol-5-yl-[1 ,3,4]thiadiazol-2- yl)-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.150 g) as an orange solid.
  • Step 3 Compound 21.
  • the procedure of Example 10, step 6 was followed except following the IPA reflux overnight, the residue was refluxed in n-BuOH for 5 h.
  • Concentration and crystallization from MeCN (4 mL) provided the compound (0.070 g) as an orange/brown solid, mp: >260 0 C;
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-fluoromethyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol.
  • steps 1 to 4 was followed using fluoroacetyl chloride as the acylating reagent to provide the compound (0.200 g).
  • Step 2 2-(2,6-Dimethyl-mor ⁇ holin-4-yl)-3,4-difluoro-5-(5-fluoromethyl-[1 ,3,4]thiadiazol-2- yl)-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.115 g) as a yellow solid.
  • Step 3 Compound 22.
  • the procedure of Example 10, step 6 was followed except the residue was crystallized from MeOH (2 mL) to provide the compound (0.038 g).
  • Step 1 [5-(5-Chloromethyl-[1 ,3,4]thiadiazol-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-phenyrj-methanol.
  • steps 1 to 4 was followed using chloroacetyl chloride as the acylating reagent to provide the compound (1.04 g).
  • Step 2 5-(5-Chloromethyl-[1 ,3,4]thiadiazol-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.145 g) as a yellow oil.
  • Step 3 Compound 23.
  • the procedure of Example 10, step 6 was followed to provide the compound (0.077 g).
  • Step i [5-[5-(2-Chloro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-phenyl]-methanol.
  • steps 1 to 4 was followed using 2- chlorobenzoyl chloride as the acylating reagent to provide the compound (0.860 g).
  • Step 2 5-[5-(2-Chloro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.690 g) as a yellow solid.
  • Step 3 Compound 24.
  • the procedure of Example 10, step 6 was followed to provide the compound (0.037 g).
  • Step 1 [5-[5-(2-Fluoro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-phenyl]-methanol.
  • steps 1 to 4 was followed using 2- fluorobenzoyl chloride as the acylating reagent to provide the compound (0.278 g).
  • Step 2 5-[5-(2-Fluoro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.079 g) as a yellow solid.
  • Step 3 Compound 25.
  • the procedure of Example 10, step 6 was followed to provide the compound (0.036 g).
  • Step 3 (S)-[5-[5-(2,2-Dimethyl-[1 ,3]dioxolan-4-yl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl- morpholin-4-yl)-3,4-difluoro-phenyl]-methanol.
  • Step 4 part 1 (S)-5-[5-(2,2-Dimethyl-[1 ,3]dioxolan-4-yl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6- dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde.
  • step 5 was followed except for the concentrated residue following filtration was purified by column chromatography to provide the compound (0.470 g).
  • Example 10 The procedure of Example 10, step 6 was followed except the reaction was concentrated to a residue that was purified by column chromatography to provide the compound (0.525 g) as a mixture of diastereomers.
  • Step 5 Compound 27.
  • a solution of compound 26 (0.32 g, 0.58 mmol) in THF (10 ml.) was treated with 1 N HCI (10 ml_). The reaction was stirred overnight at rt, heated to reflux for 2 h and cooled to rt. The reaction was diluted with water (50 ml_) and extracted with EtOAc (50 ml). The combined organics were dried over Na 2 SO 4 and concentrated. Purification by column chromatography provided the compound (0.220 g) as a mixture of diastereomers.
  • Step 1 A suspension of rel-(2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-2',4',6'-trioxo-
  • Step 2 Compound 28.
  • Steps 1 and 2 [5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-3-fluoro-phenyl]-methanol.
  • a solution of 4-(4-bromo-2-[1 ,3]dioxolan-2-yl-6-fluoro-phenyl)-2,6-dimethyl-morpholine (5.0 g, 14 mmol) in THF (100 ml_) was treated with 1M HCI (3 mL) and stirred for 5 h at rt.
  • the reaction was diluted with EtOAc (250 mL) and sat. NaHCO 3 (150 mL) was added. The organics were separated and washed with sat.
  • Step 3 4-[4-Bromo-2-(fert-butyl-diphenyl-silanyloxymethyl)-6-fluoro-phenyl]-2,6-dimethyl- morpholine.
  • Step 4 3-(ferf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro- benzoic Acid.
  • Step 5 3-(t ⁇ rt-Butyl-diphenyl-siIanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yI)-5-fluoro- benzoyl]-hydrazinecarboxylic Acid terf-Butyl Ester.
  • a suspension of 3-(terf-butyl-diphenyl- silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro-benzoic acid (1.72 g, 3.3 mmol) in DMF (8 ml_) was treated with triethylamine (0.460 mL, 3.3 mmol) and HATU (1.5 g, 4.0 mmol).
  • Step 6 3-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro- thiobenzoyl]-hydrazinecarboxylic Acid terf-Butyl Ester.
  • Step 7 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- phenyl]-methanol.
  • 3-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro- thiobenzoyl]-hydrazinecarboxylic acid terf-butyl ester (1.25 g, 1.92 mmol) was treated with HCI (12 mL of a 4 M solution in dioxane) and the resulting solution was stirred for 4h at rt and concentrated.
  • Step 8 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.180 g) as a yellow solid.
  • Step 9 Compound 35.
  • the procedure of Example 10, step 6 was followed except the residue was crystallized from MeOH (4 mL) to provide the compound (0.149 g) as a solid, mp: >260 0 C;
  • Steps 1 and 2 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methylsulfanyl-
  • Step 3a 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methylsulfanyl-
  • Triethylamine (0.404 mL, 2.90 mmol) was added and the solution was allowed to warm to rt. The reaction was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na 2 SO 4 and concentrated. Purification by column chromatography provided the compound (0.160 g) as a pale yellow solid.
  • Step 4 Compound 36.
  • Steps 1 and 2 were performed as set forth in Example 36, steps 1 and 2.
  • Step 3b 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methanesulfonyl-
  • Step 1 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-methoxy-5-(5-methyl-[1 ,3,4]thiadiazol-
  • Steps 1 and 2 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-hydroxy-5-(5-methyl-
  • Step 3 Compound 41.
  • the procedure of Example 10, step 6 was followed except the reaction was heated for an additional day in MeOH.
  • the reaction mixture was filtered at rt.
  • the filter cake was washed with MeOH (1 mL) providing the compound (0.050 g) as a beige solid.
  • Step i 5-Bromo-2,3,4-trifluoro-benzoic acid.
  • Steps 2 and 3 2-(5-Bromo-2,3,4-trifluoro-phenyl)-5-methyl-[1 ,3,4]thiadiazole.
  • Step 4 2,3,4-Trifluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde.
  • Step 5 K 2 CO 3 was added to a vigorously stirred mixture of 2R,6R-(trans)-dimethyl- morpholine (from BASF) in acetone (100 ml). Benzyl bromide was added dropwise to the mixture resulting in an exothermic reaction. The reaction was allowed to cool and stirred 18 h at rt. A majority of the acetone was removed under vacuum and portioned with water (100 ml) and EtOAc (100 ml). The aqueous layer was extracted with EtOAc (100 ml), dried over Na 2 SO 4 and concentrated. The product was distilled under reduced pressure at 120 °C (75-80 at 0.5 torr) providing a colorless oil of 4-Benzyl-2R,6R- (trans)-dimethyl-morpholine.
  • Step 6 Compound 42.
  • Steps 1 and 2 2-Methyl-5-(2,3,4-trifluoro-phenyl)-[1 ,3,4]thiadiazole.
  • the procedure set forth in Example 10 was followed using 2,3,4-trifluoro-benzoic acid to provide the compound (20.5 g).
  • 1 H NMR (400 MHz, CDCI 3 ) ⁇ 2.8 (s, 3 H), 7.1 (m, J 9.0, 9.0, 6.9, 2.0 Hz, 1 H), 8.1 (m, 1 H); MS (APCI + ) m/z 231 (MH + ).
  • Step 3 2,3,4-Trifluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde.
  • a solution of diisopropylamine (9.8 ml_, 70 mmol THF (100 mL) at -78 0 C treated with n-BuLi (44 ml_ of a 1.6 M solution in hexanes).
  • the solution was stirred for 5 min and a solution of 2-Methyl-5-(2,3,4-trifluoro- phenyl)-[1 ,3,4]thiadiazole (6.43 g, 28 mmol) in THF (100 mL) was added dropwise.
  • Compound 42 can then be made by treating 5-bromo-3,4-difluoro-2-((2R,6R)(trans)- dimethyl-morpholin-4-yl)-benzaldehyde according to the procedure set forth in 10 B, steps 3 and 4.
  • Compound 56 Compound 55 (0.3 g, 0.53 mmol) was dissolved in 50% MeOH/THF (50 ml), 5 wt% of PdBaSO 4 (0.1 g) was added and the mixture was subjected to 50 psi of hydrogen for 34 hrs The mixture was filtered to remove the catalyst and concentrated by rotoevaporation. The residue was purified by column chromatography to provide the title compound as white solids (91 mg).
  • N-(4- methoxybenzyl)urea (3.81 g, 21.1 mmol) and malonic acid (2.55 g, 24.5 mmol) were dissolved in acetic acid (8 ml) and heated at 70 0 C for 1 hr. The reaction mixture was cooled to room temperature, acetic acid (5 ml) was added and the resulting mixture was heated at 90 °C for 2 hrs. The reaction was cooled and concentrated by rotoevaporation and the resulting solids were recrystallized from ethanol to provide the title compound as white solids (3.1 g).
  • Steps 1 and 2 A flame-dried round-bottom flask was charged with Rieke magnesium
  • the reaction mixture was then cooled again to 23 0 C, poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • the crude dithioester was dissolved in EtOH (15 mL) and hydrazine monohydrate was added (0.24 mL, 4.92 mmol). The resulting solution was stirred at 23 0 C for 1 h.
  • the reaction mixture was concentrated onto silica gel and purified by silica gel chromatography (Biotage, 40 g SiO 2 , 50% EtOAc/Hex to 5% MeOH/CH 2 CI 2 ) to afford 150 mg of thiohydrazide.
  • Steps 3 and 4 A mixture of thiohydrazide (63.9 mg, 0.19 mmol) and acetyl chloride (20 ⁇ L, 0.26 mmol) in dry THF (2 mL) was heated to reflux for 1 h. 1 M HCI (0.75 mL) was added and the heating was continued for 1 h. The reaction mixture was cooled to 23 0 C, diluted with CH 2 CI 2 , washed with 10% Na 2 CO 3 (2 x 10 mL). The organic extract was washed with brine, dried (Na 2 SOzO, filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 12 g SiO 2 , 40% EtOAc/Hex) to afford 33.6 mg of thiadiazole aldehyde.
  • Step 5 A mixture of aldehyde (32.4 mg, 0.10 mmol) and barbituric acid in MeOH (2 mL) was heated to reflux for 18 hr. The solution was concentrated and the residue was purified by silica gel chromatography (Biotage 12 g SiO 2 , 50% EtOAc/Hex to 100% EtOAc) to afford 23.4 mg of compound 59: IR (diffuse reflectance) 2340 (w), 2048 (w), 1915 (w), 1754, 1727 (s), 1704 (s), 1610 (s), 1523, 1442, 1414, 1377, 1372, 1354 (s), 1338, 1245 cm '1 .
  • Compound 60 was prepared according to Example 59, except that methoxy acetyl chloride was used as the acetyl chloride.
  • Compound 60 IR (diffuse reflectance) 2350 (w), 2338 (w), 2052 (W), 1996 (w), 1990 (w), 1727 (s), 1710 (s), 1699 (s), 1608, 1447, 1439, 1429, 1415, 1354, 1338 cm " 1 .
  • HRMS (ESl) calcd for C 21 H 23 N 5 O 5 S +H 1 458.1498, found 458.1498.
  • Compound 62 was prepared according to Example 59, except that ethyl oxalyl chloride was used as the acetyl chloride.
  • Compound 62 IR (diffuse reflectance) 2352 (w), 2334 (w), 1957 (w), 1920 (W), 1915 (W), 1716 (s), 1607, 1414, 1396, 1393, 1351 , 1332, 1306, 1279, 1242 cm "1 .
  • HRMS (ESI) calcd for C 22 H 23 N 5 O 6 S +H 1 486.1447, found 486.1451.
  • Anal. Calcd for C 22 H 23 N 5 OeS 1 C, 54.42; H, 4.77; N, 14.42; S, 6.60. Found: C, 53.44; H, 4.84; N, 14.24; S, 6.35.
  • Compound 63 was prepared according to Example 59, except that the following acetyl chloride was produced as follows and used:
  • Compound 63 IR (diffuse reflectance) 2481 (w), 2372 (w), 2347 (w), 2281 (w), 2048 (w),
  • Step 1 To a suspension of acid (636.1 mg, 0.70 mmol) in THF (15 mL) was added
  • Step 2 A mixture of the Boc-hydrazide (620 mg, 1.27 mmol), solid Na 2 HCO 3 (373.4 mg,
  • Step 3 part 1 : A mixture of Boc-thiohydrazide in 4 N HCI/dioxane was stirred at 23 0 C for
  • Step 3, part 2 To a mixture of the thiohydrazide (52.3 mg, 0.13 mmol) in THF (2 mL) was added 3,4-difluorbenzoyl chloride (17 ⁇ L, 0.136 mmol). The reaction was stirred at 23 0 C for 1 h. Concentrated HCI (2 drops) was added and the stirring was continued for 30 min. The formed solid precipitate was filtered, rinsed with Et 2 O and dried to afford 65.8 mg of compound 65.
  • Staphylococcus aureus SA-1 (UC-76) and H. influenzae HI-3542. Incubations were at 35°C. Stock bacterial cultures were maintained on Tryptic Soy Agar containing 5% Sheep Blood (BD, Becton Dickinson Microbiology Systems, Cockeysville, Maryland), anaerobes were maintained on Anaerobic Blood Agar plates - CDC Formulation (BD), and fastidious organisms were maintained on Chocolate Agar Il Plates (BD). Specific conditions of handling are listed below.
  • WalkAway 40 SI Instrument (Dade Behring, West Sacramento, California). This device utilizes an automated incubator, reader, and computer to assess for identification purposes the biochemical reactions carried out by each organism. Using this machine, organism identification (confirmation) and an initial antibiogram was generated for each strain.
  • Standardized Organism lnocula Frozen stock cultures were used as the initial source of organisms for performing microbroth dilution MIC testing. Stock cultures were passed on their standard growth medium for at least 1 growth cycle (18 24 hours) prior to their use.
  • Test Compound (Drug) Preparation Compounds were solubilized in DMSO. Drug stock solutions were prepared on the day of testing. Drugs were weight corrected for assay content where necessary.
  • BioMek FX robot Beckman Coulter Inc., Fullerton, CA
  • 10 of the remaining 11 wells each of which contained 100 ⁇ L of the appropriate solvent/diluent.
  • Row 12 contained solvent/diluent only and served as the control.
  • 200 ⁇ L of an 8 ⁇ g/mL stock was added to duplicate rows of a 96-well plate. Serial two-fold dilutions were made as described above.
  • BioMek FX robot were either used immediately or frozen at -70°C until use.
  • NCCLS document M7-A6 ⁇ ISBN 1-56238-486-4 ⁇ , NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2003.
  • the range C 1 -C 6 includes the subranges C 2 -C 6 , C 3 -C 6 , C 3 - C 5 , C 4 -C 6 , etc., as well as Ci (methl), C 2 (ethyl), C 3 (propyl), C 4 (butyl), C 5 (pentyl) and C 6 (hexyl) individually.
  • Ci methl
  • C 3 propyl
  • C 4 butyl
  • C 5 (pentyl) and C 6 (hexyl) individually individually.
  • all language such as “up to,” “at least,” “greater than,” “less than,” “more than,” “or more” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés antibactériens, des méthodes pour fabriquer ces composés, des compositions pharmaceutiques contenant ces composés et des méthodes de traitement d'infections bactériennes faisant appel aux composés et aux compositions pharmaceutiques de l'invention.
EP06755883A 2005-05-09 2006-04-27 Agents antibacteriens Withdrawn EP1888597A2 (fr)

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US67918505P 2005-05-09 2005-05-09
PCT/IB2006/001276 WO2006120563A2 (fr) 2005-05-09 2006-04-27 Agents antibacteriens

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EP1888597A2 true EP1888597A2 (fr) 2008-02-20

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DOP2006000268A (es) 2005-12-22 2007-07-31 Pfizer Prod Inc Agentes antibacterianos
AU2008272693A1 (en) * 2007-07-02 2009-01-08 Astrazeneca Ab 3-spiropyrimidinetrione-quinoline derivatives and their use as antibacterial agents
JP2010533701A (ja) 2007-07-16 2010-10-28 アストラゼネカ アクチボラグ 抗菌剤として使用のスピロ縮合バルビツール酸誘導体
CA2736335C (fr) * 2008-10-14 2017-05-09 Astrazeneca Ab Composes heteroaromatiques spirocycliques fusionnes pour traiter les infections bacteriennes
US9040528B2 (en) 2008-10-14 2015-05-26 Astrazeneca Ab Chemical compounds 542
CN102417505B (zh) * 2011-08-29 2014-07-09 南开大学 含甲基-1，2，3-噻二唑的四氮唑类化合物及其制备方法和用途
CN102633745B (zh) * 2012-04-05 2014-06-18 南开大学 一类α-甲氧亚氨基-4-甲基-1,2,3-噻二唑-5-甲基羧酸酯衍生物及其制备方法和用途
CN102603670A (zh) * 2012-04-05 2012-07-25 南开大学 一类4-(4-甲基-1，2，3-噻二唑-5-基)-3-烯-2-酮衍生物及其制备方法和用途
CN102633746A (zh) * 2012-04-05 2012-08-15 南开大学 含5-甲基-1,2,3-噻二唑的双酰肼衍生物及其制备方法和用途
US8952149B2 (en) * 2012-09-26 2015-02-10 Zoetis Llc Tricyclic tetrahydroquinoline antibacterial agents
US8889671B2 (en) * 2013-01-23 2014-11-18 Astrazeneca Ab Compounds and methods for treating bacterial infections
SG11201609404SA (en) 2014-05-29 2016-12-29 Entasis Therapeutics Ltd Fused, spirocyclic heteroaromatic compounds for the treatment of bacterial infections
CN108101860B (zh) * 2018-02-08 2021-11-23 苏州敬业医药化工有限公司 顺式-2，6-二甲基吗啉的制备方法
CN113429493B (zh) * 2021-06-29 2022-06-17 吉祥三宝高科纺织有限公司 一种非释放型高分子抗菌防螨剂的制备方法

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US7208490B2 (en) * 2002-10-07 2007-04-24 Pharmacia & Upjohn Company Llc Tricyclic tetrahydroquinoline antibacterial agents

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WO2006120563A2 (fr) 2006-11-16
CA2606847A1 (fr) 2006-11-16
WO2006120563A3 (fr) 2007-04-12

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