Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/02—Halogenated hydrocarbons
  • A61K31/025—Halogenated hydrocarbons carbocyclic
  • A61K31/03—Halogenated hydrocarbons carbocyclic aromatic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• This invention relates to novel compounds, compositions containing them and their use as antibacterials.
• WOOl/07432, WOOl/07433, WO02/08224, WO02/24684, WO02/50040, WO02/56882, WO02/96907, PCT/EP02/05708, WO03010138, WO01/25227, WO0240474 and WO0207572 disclose cyclohexane, piperidine and piperazine derivatives having antibacterial activity.
• This invention provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof:
• R- - is an optionally substituted bicyclic carbocyclic or heterocyclic ring system of structure:
• each ring in which: at least one of rings (x) and (y) is aromatic; one of ⁇ 4 and Z ⁇ is C or N and the other is C; Z 3 is N, NR 13 , O, S(O) x , CO, CR 1 or CR!R la ; ⁇ and Z 2 are independantly a 2 or 3 atom linker group each atom of which is independently selected from N, NR 13 , O, S(O) x , CO, CR 1 and CR*R la ; such that each ring is independently substituted with 0-3 groups R! and/or R i a ;
• one of Z 1 , Z2, Z 3 , Z 4 and Z 5 is N, one is CR ⁇ a and the remainder are CH , or one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is CR l a and the remainder are CH;
• R! and R ⁇ a are independently hydrogen; hydroxy; (C ⁇ _g)alkoxy optionally substituted by (C ⁇ _6)alkoxy, amino, piperidyl, guanidino or amidino any of which is optionally N- substituted by one or two (Ci _g)alkyl, acyl or (Ci _6)alkylsulphonyl groups, CON ⁇ 2, hydroxy, (Ci _ ⁇ )alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (Ci _6)alkylsulphonyloxy; (Ci _6)alkoxy-substituted(C ⁇ _6)alkyl; hydroxy (Ci _ 6)alkyl; halogen; (Ci _6)alkyl; (C ⁇ _6)alkylthio; trifiuoromethyl; trifluoromethoxy; cyano; carboxy;
• RA when RA is optionally substituted quinolin-4-yl: it is unsubstituted in the 6-position; or it is substituted by at least one hydroxy (C ⁇ _g)alkyl, cyano or carboxy group at the
• Rl and R ia together represent (Ci _2)alkylenedioxy; (ii) when R ⁇ is optionally substituted quinazolin-4-yl, cinnolin-4-yl, l,5-naphthyridin-4- yl, l,7-naphthyridin-4-yl or l,8-naphthyridin-4-yl: it is substituted by at least one hydroxy (C ⁇ _6)alkyl, cyano or carboxy group at the 2-, 5-, 6-, 7- or 8-position as available; or it is substituted by at least one trifluoromethoxy group; or
• 2 is hydrogen, or (C ⁇ _4)alkyl or (C2-4)alkenyl optionally substituted with 1 to 3 groups selected from: amino optionally substituted by one or two (Ci _4)alkyl groups; carboxy; (Ci . 4)alkoxycarbonyl; (C ⁇ _4)alkylcarbonyl; (C2_4)alkenyloxycarbonyl; (C2- 4)alkenylcarbonyl; ammocarbonyl wherein the amino group is optionally substituted by hydroxy, (C ⁇ _4)alkyl, hydroxy(C ⁇ _4)alkyl, aminocarbonyl(C ⁇ _4)alkyl, (C2-4)alkenyl, (Ci _4)alkylsulphonyl, trifluoromethylsulphonyl, (C2-4)alkenylsulphonyl, (Ci _ 4)alkoxycarbonyl, (C ⁇ _4)alkylcarbonyl, (C2_4)alkenyloxycarbonyl or
• R 3 is hydrogen
• R 3 is in the 2-, 3- or 4-position and is: trifiuoromethyl; carboxy; (C ⁇ _6)alkoxycarbonyl; (C2-6) a lkenyloxycarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (Ci . 6) a lkyl 5 hydroxy(C ⁇ _g)alkyl, aminocarbonyl(C ⁇ _g)alkyl, (C2-6) a lkenyl, (C 1 _ g)alkylsulphonyl, trifluoromethylsulphonyl, (C2_6)alkenylsulphonyl, (Ci .
• R 3 is in the 2-position and is oxo; or R 3 is in the 3-position and is fluorine, amino optionally substituted by a group selected from hydroxy, (C ⁇ _6)alkylsulphonyl, trifluoromethylsulphonyl, (C2-6) a lkenylsulphonyl, (C ⁇ _6)alkylcarbonyl, (C2-6) a lkenylcarbonyl, (C ⁇ _g)alkoxycarbonyl, (C2- g)alkenyloxycarbonyl, (Ci _6)alkyl and (C2_6) lkenyl, wherein a (C ⁇ _g)alkyl or (C2- g)alkenyl moiety may be optionally substituted with up to 2 groups R ⁇ , or hydroxy optionally substituted as described above for R 2 hydroxy; in addition when R 3 is disubstituted with a hydroxy or amino containing substituent and carboxy containing substituent these may together form a
• U is selected from CO, SO2 and CH2 and
• R5 is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (A):
• X 2 is N, NR 3 , O, S(O) x , CO or CR ⁇ 4 when part of an aromatic or non-aromatic ring or may in addition be CR X 4R15 when part of a non aromatic ring;
• X 3 and X ⁇ are independently N or C;
• ⁇ l is a 0 to 4 atom linker group each atom of which is independently selected from N, NR , O, S(O) x , CO and CR ⁇ 4 when part of an aromatic or non-aromatic ring or may additionally be CRI ⁇ RI 5 when part of a non aromatic ring;
• n 0 and AB is NRHCO, CO-CR 8 R 9 , CR 6 R 7" CO, NHR 1 !S02, CR 6 R 7 -SO 2 or CR6R 7_ CR 8 R 9 , provided that R 8 and R 9 are not optionally substituted hydroxy or amino and R6 and R 8 do not represent a bond: or n is 1 and AB is NR 1 !CO, CO-CR 8 R 9 , CR 6 R 7 -CO, NR 11 SO 2 , CONRl 1, CR 6 R 7 " CR 8 R 9 , 0-CR 8 R 9 orNR n -CR 8 R 9 ;
• R ⁇ and R 7 , and R 8 and R 9 are not both optionally substituted hydroxy or amino; and wherein: each of R ⁇ , R 7 , R 8 and R 9 is independently selected from: H; (C ⁇ _g)alkoxy; (C ⁇ _ g)alkylthio; halo; trifiuoromethyl; azido; (Ci _6)alkyl; (C2-6) a lkenyl; (Ci _ g)alkoxycarbonyl; (C ⁇ _6)alkylcarbonyl; (C2_6) a lkenyloxycarbonyl; (C2- 6)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R 3 ; (Ci _6)alkylsulphonyl; (C2_6)alkenylsulphonyl; or (Ci _ 6)aminosulphonyl wherein the amino group is optionally substituted by (Ci .
• RIO is selected from (C ⁇ _4)alkyl; (C2_4)alkenyl and aryl any of which may be optionally substituted by a group R i2 as defined above; carboxy; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (Ci _6)alkyl, (C2-6)alkenyl, (Ci _ g)alkylsulphonyl, trifluoromethylsulphonyl, (C2_6) a lkenylsulphonyl, (Ci .
• This invention also provides a method of treatment of bacterial infections in mammals, particularly in man, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable derivative thereof.
• the invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
• R-A- is not indole or benzofuran.
• Z 2 is three atoms long.
• Z 4 and 7? are both carbon.
• Preferably is three atoms long with carbon joined to 7? and with R on the carbon atom j oined to Z 3 .
• R ⁇ is aromatic and ring (y) is fused benzene.
• ring (y) is fused pyridin-4-yl (7?- is three atoms long, the atom attached to 7? in 7?- is nitrogen and the remainder and Z 4 and 7 are carbon), 7 ⁇ - is two or three atoms long and Z 3 is a heteroatom such as O or S.
• rings include optionally substituted isoquinolin-5-yl, quinolin-8-yl, thieno[3,2-b]pyridin-7-yl, 2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl, quinoxalin-5-yl, isoquinolin-8-yl, [l,6]-naphthyridin-4-yl, l,2,3,4-tetrahydroquinoxalin-5- yl and l,2-dihydroisoquinoline-8-yl.
• RA is optionally 2-substituted- quinolin-8-yl or optionally 3-substituted-quinoxalin-5-yl.
• RI 3 in rings (x) and (y) is preferably H or (C ⁇ .g)alkyl.
• R! or R ⁇ a is substituted alkoxy it is preferably (C2_g)alkoxy substitituted by optionally N-substituted amino, or (C ⁇ .6)alkoxy substituted by piperidyl.
• Suitable examples of R* and R i a alkoxy include methoxy, trifluoromethoxy, n-propyloxy, iso- butyloxy, aminoethyloxy, aminopropyloxy, aminobutyloxy, aminopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy or 2-aminocarbonylprop-2-oxy.
• R! and R a are independently hydrogen, (C ⁇ _4)alkoxy, (C ⁇ _ 4)alkylthio, (Ci _4)alkyl, amino(C3_5)alkyloxy, nitro, cyano, carboxy, hydroxymethyl or halogen; more preferably hydrogen, methoxy, methyl, cyano, halogen or amino(C3_ 5)alkyloxy.
• Ring R ⁇ - is preferably substituted by one group R* .
• R is H, methoxy, methyl, cyano or halogen and R* a is H.
• Halogen is preferably chloro or fluoro.
• n is 0.
• R 3 include hydrogen; optionally substituted hydroxy; optionally substituted amino; halogen; (Ci _4)alkoxycarbonyl; (Ci .4) alkyl; ethenyl; optionally substituted l-hydroxy-(Cj_4) alkyl; optionally substituted aminocarbonyl; carboxy(C ⁇ _4)alkyl; optionally substituted aminocarbonyl(C ⁇ _4)alkyl; cyano(C ⁇ _4)alkyl; optionally substituted 2-oxo-oxazolidinyl and optionally substituted 2-oxo- oxazolidinyl(C ⁇ _4alkyl).
• R 3 groups are hydrogen; CONH2; 1_ hydroxyalkyl e.g. CH 2 OH, CH(OH)CH 2 CN; CH 2 CO 2 H; CH 2 CONH ; CONHCH 2 CONH 2 ; 1,2-dihydroxyalkyl e.g. CH(OH)CH 2 OH; CH 2 CN; 2-oxo- oxazolidin-5-yl, 2-oxo-oxazolidin-5-yl(C ⁇ _4alkyl); optionally substituted hydroxy; optionally substituted amino; and halogen, in particular fluoro.
• R 3 is hydrogen, hydroxy or fluoro.
• R 3 is preferably in the 3- or 4-position. When R 3 is in the 3-position, preferably it is trans to (NR2)R4 nd nas p stereochemistry or is cis to NR2R4 and has S stereochemistry.
• CR 6 R 7 is CH 2 , CHOH, CH(NH 2 ), C(Me)(OH) or CH(Me) and CR 8 R 9 is CH 2 -
• A is CH(OH) the R-stereochemistry is preferred.
• A is NH, NCH3, CH 2 , CHOH, CH(NH 2 ), C(Me)(OH) or CH(Me).
• B is CH 2 or CO.
• R 1 is hydrogen or (C ⁇ _4)alkyl e.g. methyl, more preferably hydrogen.
• the heterocyclic ring (A) has ring (a) aromatic selected from optionally substituted benzo and pyrido and ring (b) non aromatic and Y ⁇ has 3-5 atoms, more preferably 4 atoms, including a heteroatom bonded to X ⁇ selected from O, S or N ⁇ 3 , where R ⁇ 3 is other than hydrogen, and NHCO bonded via N to X 3 , or O bonded to X 3 .
• the ring (a) preferably contains aromatic nitrogen, and more preferably ring (a) is pyridine. Examples of rings (A) include optionally substituted:
• R i3 is preferably H if in ring (a) or in addition (Ci _4)alkyl such as methyl or isopropyl when in ring (b). More preferably, in ring (b) R ⁇ 3 is H when NR* 3 is bonded to X 3 and (C ⁇ _4)alkyl when NR 13 is bonded to X 5 .
• heterocyclic as used herein includes optionally substituted aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or C-substituted by, for example, up to three groups selected from (Ci _4)alkylthio; halo; carboxy(C ⁇ _4)alkyl; halo(C ⁇ _4)alkoxy; halo(C ⁇ _4)alkyl; (C ⁇ _4)alkyl; (C2-4)alkenyl; (C ⁇ 4)alkoxycarbonyl; formyl; (C ⁇ _ 4)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (C2-4)alkenylcarbonyl; (C ⁇ _ 4)alkylcarbonyloxy; (C ⁇ _4)alkoxycarbonyl(C ⁇ _4)alkyl; hydroxy;
• suitable optional substituents in such substituted amino groups include H; trifiuoromethyl; (C ⁇ _4)alkyl optionally substituted by hydroxy, (Ci _g)alkoxy, (C ⁇ _6)alkylthio, halo or trifiuoromethyl; (C2_4)alkenyl; aryl; aryl (C ⁇ _4)alkyl; (C ⁇ _ 4)alkoxycarbonyl; (Ci _4)alkylcarbonyl; formyl; (Ci _g)alkylsulphonyl; or aminocarbonyl wherein the amino group is optionally substituted by (Ci _4)alkoxycarbonyl, (Ci .
• aryl includes optionally substituted phenyl and naphthyl.
• Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
• This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
• Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable derivatives.
• Pharmaceutically acceptable derivatives of the above-mentioned compounds of formula (I) include the free base form or their acid addition or quaternary ammonium salts, for example their salts with mineral acids e.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, or organic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic, p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid or tartaric acids.
• Compounds of formula (I) may also be prepared as the N-oxide.
• Compounds of formula (I) having a free carboxy group may also be prepared as an in vivo hydrolysable ester. The invention extends to all such derivatives.
• Suitable pharmaceutically acceptable in vivo hydrolysable ester- forming groups include those forming esters which break down readily in the human body to leave the parent acid or its salt. Suitable groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v): R ⁇
• R a is hydrogen, (Ci . ⁇ ) alkyl, (C3.7) cycloalkyl, methyl, or phenyl
• R ⁇ is (Cl-6) alkyl, (C ⁇ .g) alkoxy, phenyl, benzyl, (C3.7) cycloalkyl, (03.7) cycloalkyloxy, (Ci _g) alkyl (03.7) cycloalkyl, 1-amino (C ⁇ . ⁇ ) alkyl, or l-(C ⁇ _6 alkyl)amino (Cj.g) alkyl; or R a and R° together form a 1,2-phenylene group optionally substituted by one or two methoxy groups;
• R c represents (Ci _g) alkylene optionally substituted with a methyl or ethyl group and R ⁇ and R e independently represent (C ⁇ _g) alkyl;
• Rf represents (Ci .g) alkyl;
• R ⁇
• R ⁇ is hydrogen or (C ⁇ _g) alkyl
• R 1 is hydrogen, (Ci _g) alkyl optionally substituted by halogen, (C2-6) alkenyl, (C . ) alkoxycarbonyl, aryl or heteroaryl; or R n and R 1 together form (C ⁇ _6) alkylene
• RJ represents hydrogen, (Ci _g) alkyl or (Ci .5) alkoxycarbonyl
• Rk represents (Ci _g) alkyl, (Ci _g) alkoxy, (C ⁇ _g) alkoxy(C ⁇ _6)alkoxy or aryl.
• Suitable in vivo hydrolysable ester groups include, for example, acyloxy(C ⁇ _6)alkyl groups such as acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop-l-yl, and
• a further suitable pharmaceutically acceptable in vivo hydrolysable ester-forming group is that of the formula:
• Rk is hydrogen, Ci _g alkyl or phenyl.
• R is preferably hydrogen.
• Compounds of formula (I) may also be prepared as the corresponding N-oxides.
• Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
• the invention includes all such forms, in particular the pure isomeric forms.
• the invention includes compound in which an A-B group CH(OH)-CH2 is in either isomeric configuration, the R-isomer is preferred.
• the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
• a process for preparing compounds of formula (I), and pharmaceutically acceptable derivatives thereof which process comprises reacting a compound of formula (TV) with a compound of formula (V):
• n is as defined in formula (I);
• Z 1 ', 7? , , and R 3 ' are Z 1 , 7 , Z 3 , R 1 , and R 3 as defined in formula (I) or groups convertible thereto;
• Z4 and Z ⁇ are as defined in formula (I);
• Q 1 is NR2'R4' or a group convertible thereto wherein R ⁇ ' and R4' are R ⁇ and R as defined in formula (I) or groups convertible thereto and Q2 is H or R ' or Q! and Q ⁇ together form an optionally protected oxo group; (i) X is A'-COW, Y is H and n is 0;
• one of X and Y is CO2Ry and the other is CH 2 CO 2 R x ;
• COW and Y is NHR 1 1 ', NCO or NRl 1 'COW;
• X is W or OH and Y is CH 2 OH and n is 1 ;
• X is NHR 1 1 ' and Y is SO 2 W or X is NR 11 'SO 2 W and Y is H, and n is 0; (xvi) X is W and Y is CONHR 1 v ;
• R x and Ry are (C ⁇ _5)alkyl;
• R z is aryl or (C ⁇ _g)alkyl;
• A' and NR 1 ⁇ are A and NR 1 as defined in formula (I), or groups convertible thereto; and oxirane is:
• R", R 8 and R 9 are as defined in formula (I); and thereafter optionally or as necessary converting Q and Q to NR2'R4'; converting A', Z 1 * , Z2', Z 3 ', Rl', R2', R 3 ', R4' and NR 1 1 ' ⁇ A, Z 1 , Z2 Z 3 , R 1 , R2, R3, R4 and NR 11 ; converting A-B to other A-B, interconverting R 1 , R2, R 3 and/or R4, and/or forming a pharmaceutically acceptable derivative thereof.
• Process variant (i) initially produces compounds of formula (I) wherein A-B is A'- CO.
• Process variant (ii) initially produces compounds of formula (I) wherein A-B is CHR 6 -CR 8 R 9 .
• Process variant (v) initially produces compounds of formula (I) wherein A-B is CO-CH 2 or CH 2 -CO.
• Process variant (vi) initially produces compounds of formula (I) wherein A-B is CR 6 R 7 -CR 9 OH.
• Process variant (vii) and (viii) initially produce compounds of formula (I) wherein
• process variant (xii) the reaction is an alkylation, examples of which are described in J. Med. chem. (1979) 22(10) 1171-6.
• the compound of formula (IV) maybe prepared from the corresponding compound where X is NHR 1 ⁇ by acylation with an appropriate derivative of the acid WCH2COOH such as the acid chloride or sulphonation with an appropriate derivative of the sulphonic acid WCH2SO3H such as the sulphonyl chloride.
• the reaction is a standard sulphonamide formation reaction well known to those skilled in the art. This may be e.g. the reaction of a sulphonyl halide with an amine.
• R 3 vinyl can be chain extended by standard homologation, e.g. by conversion to hydroxyethyl followed by oxidation to the aldehyde, which is then subjected to a Wittig reaction. Opening an epoxide-containing R 3 ' group with cyanide anion yields a CH(OH)- CH 2 CN group.
• R 3 CO2H group may also be prepared from oxidative cleavage of the corresponding diol, CH(OH)CH2OH, using sodium periodate catalysed by ruthenium trichloride with an acetonitrile-carbontetrachloride-water solvent system (V.S.Martin et al, Tetrahedron Letters, 1988, 29(22), 2701).
• the ethyl ester of 1-3 is hydrolyzed using aqueous base, for example, LiOH in aqueous THF or NaOH in aqueous methanol or ethanol, and the intermediate carboxylate salt is acidified with a suitable acid, for instance TFA or HCl, to afford the carboxylic acid 1-4.
• aqueous base for example, LiOH in aqueous THF or NaOH in aqueous methanol or ethanol
• a suitable acid for instance TFA or HCl
• Curtius-type rearrangement of 1-4 gives an intermediate isocyanate, which typically is not isolated, but rather is reacted in situ with an appropriate alcohol, such as benzyl alcohol, to give 1-5.
• Diphenylphosphoryl azide in the presence of an amine base is the preferred reagent combination for effecting the Curtius-type rearrangement of 1-4, but more classical conditions, such as formation of the acid chloride, reaction with azide anion, and warming of the acyl azide, can also be used.
• the benzyloxycarbonyl group in 1-5 is removed by hydrogenolysis in the presence of a palladium catalyst, typically palladium on activated charcoal, in a suitable solvent, usually EtOH, MeOH, EtOAc, or mixtures thereof, to give amine 1-6.
• Imine II-l prepared in standard fashion by acid-catalyzed reaction of trifluoroacetaldehyde ethyl hemiacetal and (R)-(+)- ⁇ -methylbenzylamine, reacts with a silyloxydiene, for example l-methoxy-3-(trimethylsilyloxy)-l,3-butadiene, in a Diels- Alder reaction to afford piperidone II-2.
• the reaction is conducted in a neutral solvent such as CH3CN, THF, or CH2CI2, and oftentimes is mediated by a Lewis acid such as ZnCl2- Diastereomers are best separated at this point.
• the enone II-2 is reduced to the corresponding ketone II-3 by reaction with L-Selectride® in a suitable solvent, generally THF or DME, and the ketone is converted to an oxime derivative under standard conditions well-known to those of skill in the art.
• Reduction of the oxime derivative under standard conditions gives a mixture of diastereomeric amines from which the amine II-5 can be isolated.
• the amine is protected with an appropriate protecting group, preferably a tert-butyl carbamate (see Scheme I), to afford II-6.
• the reaction is mediated by a strong base, preferably sodium hydride, which is used to deprotonate IV-2, and is typically conducted in a polar, aprotic solvent, such as THF, DMF, or mixtures thereof.
• a strong base preferably sodium hydride
• a polar, aprotic solvent such as THF, DMF, or mixtures thereof.
• the benzyl groups in IV-3 are removed by hydrogenolysis in the presence of a palladium catalyst, typically palladium on activated charcoal, in a suitable solvent, usually EtOH, MeOH, EtOAc, or mixtures thereof, to give amine IV-4.
• an electrophilic fluorinating reagent preferably S electfluorTM ( 1 -chloromethyl-4-fluoro- 1 ,4- diazabicyclo[2.2.2]octane bis(tetrafluoroborate)
• R 3 may be obtained by conventional conversions of hydroxy, carboxy or cyano groups.
• Tetrazoles are conveniently prepared by reaction of sodium azide with the cyano group (e.g. F. Thomas et al, Bioorg. Med. Chem. Lett., 1996, 6(6), 631; K. Kubo et al, J. Med. Chem., 1993, 36, 2182) or by reaction of azidotri-n-butyl stannane with the cyano group followed by acidic hydrolysis (P.L. Ornstein, J. Org. Chem., 1994, 59, 7682 and J. Med. Chem, 1996, 39 (11 , 2219).
• the 3-hydroxy-3-cyclobutene-l,2-dion-4-yl group e.g. R.M. Soil, Bioorg. Med.
• the tetrazol-5-ylaminocarbonyl group maybe prepared from the corresponding carboxylic acid and 2-aminotetrazole by dehydration with standard peptide coupling agents such as l,l'-carbonyldiimidazole (P.L. Omstein et al, J. Med Chem, 1996, 39(11), 2232).
• 2,4-Thiazolidinedione groups may prepared from the aldehydes by condensation with 2,4-thiazolidinedione and subsequent removal of the olefmic double bond by hydrogenation.
• the preparation of 5-oxo-l,2,4-oxadiazoles from nitriles is decribed by Y. Kohara et al, Bioorg. Med. Chem. Lett., 1995, 5(17), 1903.
• l,2,4-Triazol-5-yl groups may be prepared from the corresponding nitrile by reaction with an alcohol under acid conditions followed by reaction with hydrazine and then an R ⁇ -substituted activated carboxylic acid (see J.B.
• R 3 alkyl or alkenyl may be interconverted by conventional methods, for example hydroxy may be derivatised by esterification, acylation or etherification. Hydroxy groups may be converted to halogen, thiol, alkylthio, azido, alkylcarbonyl, amino, aminocarbonyl, oxo, alkylsulphonyl, alkenylsulphonyl or aminosulphonyl by conversion to a leaving group and substitution by the required group or oxidation as appropriate or reaction with an activated acid, isocyanate or alkoxyisocyanate.
• Primary and secondary hydroxy groups can be oxidised to an aldehyde or ketone respectively and alkylated with a suitable agent such as an organometallic reagent to give a secondary or tertiary alcohol as appropriate.
• a carboxylate group may be converted to an hydroxymethyl group by reduction of an ester of this acid with a suitable reducing agent such as lithium aluminium hydride.
• ⁇ -2 substituent on piperidine is converted to NR R4 by conventional means such as amide or sulphonamide formation with an acyl derivative R ⁇ COW or R ⁇ SO2W, for compounds where U is CO or SO2 or, where U is CH2, by alkylation with an alkyl halide R ⁇ C ⁇ -halide in the presence of base, acylation/reduction with an acyl derivative R ⁇ COW or reductive alkylation with an aldehyde R ⁇ CHO.
• R 3 and R° R 7 , R 8 or R 9 contains a carboxy group and the other contains a hydroxy or amino group they may together form a cyclic ester or amide linkage. This linkage may form spontaneously during coupling of the compound of formula (IV) and the piperidine moiety or in the presence of standard peptide coupling agents.
• the isocyanate of formula (TV) may be prepared conventionally from a 4-amino derivative such as 4-amino-quinoline, and phosgene, or phosgene equivalent (eg triphosgene) or it may be prepared more conveniently from a 4-carboxylic acid by a "one- pot" Curtius Reaction with diphenyl phosphoryl azide (DPP A) [see T. Shiori et al. Chem. Pharm. Bull. 35, 2698-2704 (1987)].
• DPP A diphenyl phosphoryl azide
• the 4-amino derivatives are commercially available or may be prepared by conventional procedures from a corresponding 4-chloro or 4-trifluoromethanesulpl ⁇ onate derivative by treatment with ammonia (O.G. Backeberg et. al., J. Chem Soc, 381, 1942) or propylamine hydrochloride (R. Radinov et. al., Synthesis, 886, 1986).
• 4- Alkenyl compounds of formula (JV) may be prepared by conventional procedures from a corresponding 4-halogeno-derivative by e.g. a Heck synthesis as described in e.g. Organic Reactions, 1982, 27, 345.
• 4-Halogeno derivatives of compounds of formula (TV) are commercially available, or may be prepared by methods known to those skilled in the art.
• a 4-chloroquinoline is prepared from the corresponding quinolin-4-one by reaction with phosphorus oxychloride (POCl ) or phosphorus pentachloride, PC1 5 .
• a 4-chloroquinazoline is prepared from the corresponding quinazolin-4-one by reaction with phosphorus oxychloride (POCl 3 ) or phosphorus pentachloride, PC1 5 .
• a quinazolinone and quinazolines may be prepared by standard routes as described by T. A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R.C. Elderfield.
• Pyridazines may be prepared by routes analogous to those described in Comprehensive Heterocyclic Chemistry, Volume 3, Ed A.J. Boulton and A. McKillop and napthyridines may be prepared by routes analogous to those described in
• a 4-oxirane derivative of compounds of formula (JV) is conveniently prepared from the 4-carboxylic acid by first conversion to the acid chloride with oxalyl chloride and then reaction with trimethylsilyldiazomethane to give the diazoketone derivative. Subsequent reaction with 5M hydrochloric acid gives the chloromethylketone. Reduction with sodium borohydride in aqueous methanol gives the chlorohydrin which undergoes ring closure to afford the epoxide on treatment with base, e.g. potassium hydroxide in ethanol-tetrahydrofuran.
• 4-oxirane derivatives can be prepared from bromomethyl ketones which can be obtained from 4-hydroxy compounds by other routes well known to those skilled in he art.
• hydroxy compounds can be converted to the corresponding 4-trifluoromethanesulphonates by reaction with trifluoromethanesulphonic anhydride under standard conditions (see K. Ritter, Synthesis, 1993, 735).
• Conversion into the corresponding butyloxyvinyl ethers can be achieved by a Heck reaction with butyl vinyl ether under palladium catalysis according to the procedure of W. Cabri et al, J. Org. Chem, 1992, 57 (5), 1481.
• the equivalent intermediates can be attained by Stille coupling of the trifluoromethanesulphonates or the analaogous chloro derivatives with (l-ethoxyvinyl)tributyl tin, (T. R. Kelly, J. Org. Chem., 1996, 61, 4623).)
• the alkyloxyvinyl ethers are then converted into the corresponding bromomethylketones by treatment with N-bromosuccinimide in aqueous tetrahydrofuran in a similar manner to the procedures of J. F. W. Keana, J. Org. Chem., 1983, 48, 3621 and T. R. Kelly, J. Org. Chem., 1996, 61, 4623.
• the 4-hydroxyderivatives can be prepared from an aminoaromatic by reaction with methylpropiolate and subsequent cyclisation, analogous to the method described in N. E. Heindel et al, J. Het. Chem., 1969, 6, 77.
• 5 -amino-2-methoxy pyridine can be converted to 4-hydroxy-6-methoxy-[l,5]naphthyridine using this method.
• a chiral reducing agent such as (+) or (-)-B-chlorodiisopinocamphenylborane
• the epoxide may be prepared from the 4-carboxaldehyde by a Wittig approach using trimethylsulfonium iodide [see G.A. Epling and K-Y Lin, J. Het. Chem., 1987, 24, 853-857], or by epoxidation of a 4-vinyl derivative.
• 4-Hydroxy-l,5-naphthyridines can be prepared from 3-aminopyridine derivatives by reaction with diethyl ethoxymethylene malonate to produce the 4-hydroxy-3- carboxylic acid ester derivative with subsequent hydrolysis to the acid, followed by thermal decarboxylation in quinoline (as for example described for 4-Hydroxy- [l,5]naphthyridine-3-carboxylic acid, J. T. Adams et al., J.Amer.Chem.Soc, 1946, 68, 1317).
• a 4-hydroxy-[l,5]naphtl ⁇ yridine can be converted to the 4-chloro derivative by heating in phosphorus oxychloride, or to the 4-methanesulphonyloxy or 4- trifluoromethanesulphonyloxy derivative by reaction with methanesulphonyl chloride or trifluoromethanesulphonic anhydride, respectively, in the presence of an organic base.
• a 4-amino 1,5-naphthyridine can be obtained from the 4-chloro derivative by reaction with n-propylamine in pyridine.
• 6-methoxy- 1,5-naphthyridine derivatives can be prepared from 3-amino-6- methoxypyridine.
• 1,5-Naphthyridines may be prepared by other methods well known to those skilled in the art (for examples see P.A. Lowe in “Comprehensive Heterocyclic Chemistry” Volume 2, p581 -627, Ed A.R. Katritzky and C.W. Rees, Pergamon Press, Oxford, 1984).
• the 4-hydroxy and 4-amino-cinnolines may be prepared following methods well known to those skilled in the art [see A.R. Osborn and K. Schofield, J. Chem. Soc. 2100 (1955)].
• a 2-aminoacetophenone is diazotised with sodium nitrite and acid to produce the 4-hydroxycinnoline with conversion to chloro and amino derivatives as described for 1,5-naphthyridines.
• R ⁇ groups where the ring (y) is 4-pyridyl are available by the sequence described below, starting from an aromatic or heterocyclic amine (1), with at least one free CH position adjacent to the amine. Reaction with Meldrum's acid and trimethyl orthformate in ethanol at reflux affords the corresponding 2,2-dimethyl-5-phenylaminomethylene- [l,3]dioxane-4,6-dione derivatives (2).
• Activation of the quinolone species related to (3) into the corresponding 4- quinolyl bromides (4) can be accomplished with phosphorous oxybromide or more preferably phosphorous tribromide in N,N-dimethylformamide (see M. Schstoff et al, Synlett, 1997, (9), 1096 and K. Gould et al, J. Med., Chem., 1988, 31 (7), 1445).
• the corresponding chlorides (5) are available by using phosphoryl oxychloride (for instance C. W. Wright et al, J. Med., Chem., 2001, 44 (19), 3187).
• the quinolone species maybe activated to the corresponding 1,1,1- trifluoro-methanesulfonic acid quinolin-4-yl esters (6) by the action of agents such as triflic anhydride or more preferably N-trifluoromethanesulphonimide (see for example M. Alvarez et al, Tet 2000, 56 (23) 3703; M. Alvarez et al, Eur. J. Org., Chem., 2000, (5), 849; J. Joule et al, Tet, 1998, 54 (17), 4405; J. K. Stille et al, J.A.C.S., 1988, 110 (12), 4051).
• agents such as triflic anhydride or more preferably N-trifluoromethanesulphonimide
• R A 3- methoxyquinoxaline-5-yl derivatives may be obtained from 3-oxoquinoxalin-5-yl prepared by the general methods of F.J.Wolf et al., J.A.C.S. 1949, 71, 6, using a suitable methylating agent such as trimethylsilyl(diazomethane).
• the corresponding 1,2,3,4- tetrahydro-quinoxalin-5-yl maybe prepared by reduction with a suitable reducing agent such as sodium cyanoborohydride in the presence of an acid such as acetic acid.
• the isoquinolin-8-yl system can be prepared from the appropriately substituted benzylamine by cyclocondensation with diethoxy-acetaldehyde (see, for example, K. Kido and Y. Watanabe, Chemical & Pharmaceutical Bulletin, 35(12), 4964-6; 1987).
• 8-bromo-isoquinoline prepared by the method of F.T.Tyson, J.A.C.S., 1939, 61, N. Briet et al, Tetrahedron (2002), 58(29), 5761-5766 or W.D. Brown, et al., Synthesis (2002), (1), 83-86.
• 183 can be subjected to N-oxidation and rearrangement to give 8-bromo-2H-isoquinolin-l-one. This can be N-methylated to give 8-bromo-2-methyl-2H-isoquinolin-l-one, an appropriate intermediate for the 2-methyl-l- oxo- 1 ,2-dihydroisoquinolin-8-yl system.
• the l-methoxy-isoquinolin-8-yl system can also be obtained from the 8- bromoisoquinoline-N-oxide above by rearrangement with methyl chloroformate to give 8-bromo-l-methoxy-isoquinoline, an appropriate intermediate for the 1-methoxy- isoquinolin-8-yl system.
• suitable amines may be prepared from the corresponding 4-substituted piperidine acid or alcohol.
• an N-protected piperidine containing an acid bearing substituent can undergo a Curtius rearrangement and the intermediate isocyanate can be converted to a carbamate by reaction with an alcohol. Conversion to the amine may be achieved by standard methods well known to those skilled in the art used for amine protecting group removal.
• an acid substituted N-protected piperidine can undergo a Curtius rearrangement e.g.
• an N-protected piperidine containing an alcohol bearing substituent undergoes a Mitsunobu reaction (for example as reviewed in Mitsunobu, Synthesis, (1981), 1), for example with succinimide in the presence of diethyl azodicarboxylate and triphenylphosphine to give the phthalimidoethylpiperidine.
• a Mitsunobu reaction for example as reviewed in Mitsunobu, Synthesis, (1981), 1
• succinimide in the presence of diethyl azodicarboxylate and triphenylphosphine to give the phthalimidoethylpiperidine.
• diethyl azodicarboxylate diethyl azodicarboxylate and triphenylphosphine
• R 5 CH 2 -halides, acyl derivative R 5 COW and R 5 SO 2 W or aldehydes R 5 CHO are commercially available or are prepared conventionally.
• the aldehydes may be prepared by partial reduction of the R ⁇ -ester with lithium aluminium hydride or di- isobutylaluminium hydride or more preferably by reduction to the alcohol, with lithium aluminium hydride or sodium borohydride or lithium triethylborohydride (see Reductions by theAlumino- and Borohydr ides in Organic Synthesis, 2nd ed., Wiley, N.Y., 1997; JOC, 3197, 1984; Org. Synth.
• the aldehydes may also be prepared from carboxylic acids in two stages by conversion to a mixed carbonate for example by reaction with isobutyl chloro formate followed by reduction with sodium borohydride (R. J.
• R ⁇ COW may be prepared by activation of the R ⁇ -ester.
• R5CH2-halides such as bromides may be prepared from the alcohol R ⁇ C ⁇ OH by reaction with phosphorus tribromide in DCM/triethylamine.
• the aldehyde R ⁇ CHO and sulphonic acid derivative R ⁇ SO2W may be generated by treatment of the R ⁇ H heterocycle with suitable reagents.
• benzoxazinones or more preferably their N-methylated derivatives can be formylated with hexamine in either trifluoroacetic acid or methanesulfonic acid, in a modified Duff procedure [O. I. Petrov et al. Collect. Czech. Chem. Commun. 62, 494-497 (1997)].
• 4- Methyl-4H-benzo[l,4]oxazin-3-one may also be formylated using dichloromethyl methyl ether and aluminium chloride giving exclusively the 6-formyl derivative. Reaction of a R ⁇ H heterocycle with chlorosulphonic acid gives the sulphonic acid derivative (by methods analogous to Techer et. al., C.RHebd. Seances Acad. Sci. Ser.C; 270, 1601, 1970).
• the aldehyde R ⁇ CHO may be generated by conversion of an R ⁇ halogen or sulphonyloxy derivative into an olefin with subsequent oxidative cleavage by standard methods. For example, reaction of a bromo derivative under palladium catalysis with trans-2-phenylboronic acid under palladium catalysis affords a styrene derivative which upon ozonolysis affords the required R ⁇ CHO (Stephenson, G. R., Adv. Asymmetric Synth. (1996), 275-298. Publisher: Chapman & Hall, London).
• R ⁇ H heterocycles are commercially available or may be prepared by conventional methods.
• a nitrophenol may be alkylated with for example ethyl bromoacetate and the resulting nitro ester reduced with Fe in acetic acid (alternatively Zn/AcOH/HCl or H 2 /Pd C or H 2 /Raney Ni).
• the resulting amine may undergo spontaneous cyclisation to the required benzoxazinone, or cyclisation may be induced by heating in acetic acid.
• a nitrophenol may be reduced to the aminophenol, which is reacted with chloroacetyl chloride [method of X. Huang and C.
• 2-oxo-2,3-dihydro-lH-pyrido[3,4-b][l,4]thiazine- 7-carbaldehyde may be accessed from 5-fluoro-2-picoline (E. J. Blanz, F. A. French, J. R. DoAmaral and D. A. French, J. Med. Chem. 1970, 13, 1124-1130) by constructing the thiazinone ring onto the pyridyl ring then functionalising the methyl substituent.
• the dioxin analogue of this aza substitution patern, 2,3-dihydro-[l,4]dioxino[2,3-c]pyridine- 7-carbaldehyde is accessible from Kojic acid by aminolysis from pyrone to pyridone then annelating the dioxin ring.
• Other aza substitution patterns with pyrido thiazin-3 -one, pyridooxazin-3-one, and pyridodioxin ring systems are also accessible.
• Ortho- aminothiophenols may be conveniently prepared and reacted as their zinc complexes [see for example V. Taneja et al Chem. Ind. 187 (1984)].
• Benzoxazolones may be prepared from the corresponding aminophenol by reaction with carbonyl diimidazole, phosgene ot triphosgene. Reaction of benzoxazolones with diphosporus pentasulfide affords the corresponding 2-thione.
• Thiazines and oxazines can be prepared by reduction of the corresponding thiazinone or oxazinone with a reducing agent such as lithium aluminium hydride.
• amines R2'R 'NH are available commercially or prepared conventionally.
• amines may be prepared from a bromomethyl derivative by reaction with sodium azide in dimethylformamide (DMF), followed by hydrogenation of the azidomethyl derivative over palladium-carbon.
• An alternative method is to use potassium phthalimide/DMF to give the phthalimidomethyl derivative, followed by reaction with hydrazine in DCM to liberate the primary amine.
• Conversions of R l a ', R 1 ', R ', R 3 ' and R4' may be carried out on the intermediates of formulae (IV), and (V) prior to their reaction to produce compounds of formula (I) in the same way as described above for conversions after their reaction.
• the compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I).
• Libraries of compounds of formula (I) may be prepared by a combinatorial "split and mix” approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
• a compound library comprising at least 2 compounds of formula (I) or pharmaceutically acceptable derivatives thereof.
• Novel intermediates of formulae (IV) and (V) are also part of this invention.
• the antibacterial compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibacterials.
• compositions of the invention include those in a form adapted for oral, topical or parenteral use and maybe used for the treatment of bacterial infection in mammals including humans.
• the composition may be formulated for administration by any route.
• the compositions maybe in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
• the topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
• the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl >-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
• Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
• fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
• the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
• the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
• agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum.
• the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
• Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
• the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
• the dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mgkg per day.
• the dosage is from 5 to 20 mg/kg per day. No toxicological effects are indicated when a compound of formula (I) or a pharmaceutically acceptable derivative thereof is administered in the above-mentioned dosage range.
• the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibacterials. If the other antibacterial is a ⁇ -lactam then a ⁇ -lactamase inhibitor may also be employed.
• This mixture of regioisomers was chromatographed (preparative HPLC) on Lichrosphere silica gel 60A; 12 u,100 mm ID x 250 mm L; 70:30:0.5 hexanes:THF:diethylamine; 500 mL/min; uv detection 254 nm; 4.5 g mixture per injection.
• Enamine (4b) (22.9 g) was added portionwise to refluxing Dowtherm A (45 mL) over 3 minutes. After a further 3 minutes at reflux the mixture was cooled to room temperature. Ethyl acetate/hexane (10 mL/20 mL) was added and a black solid isolated by filtration. This residue was dissolved in hot methanol (400 mL) and filtered through Keiselguhr. Water (800 mL) was added and the mixture stored at 5°C overnight. Filtration and drying afforded a pale yellow solid (10.3 g, 61%). MS (APCI-) m/z 281 [M-H] "
• the ketone (5i) (2.83g, 10.07mmol) was partially dissolved in methanol (50mL).
• the reaction mixture was cooled down to 0°C before sodium borohydride (0.78g, 20.6mmol) was added portionwise..
• the reaction mixture was stirred at 0°C for 1 hour. More sodium borohydride was added (0.14g) and the new reaction mixture was stirred for a further 20 minutes.
• Cesium carbonate (7.5g, 20mmol) was then added and the reaction mixture was allowed to reach room temperature. Stirring at room temperature was continued for 3 days until total conversion to epoxide.
• the mixture was diluted with water and extracted several times with dichloromethane.
• the free base was prepared as in Example 5 from amine (51) (30mg, O.lmmol) and aldehyde (6c) (16mg, 0.1 mmol).
• Triflate (2c) (2.50 g, 8.14 mmol) was dissolved in DMF (25 mL). After subsequent addition of butyl vinyl ether (4.21 mL, 32.55 mmol), palladium acetate (0.182 g, 0.81 mmol), l,3-bis(diphenylphosphino)propane (0.334 g, 0.81 mmol), and N,N- diisopropylethylamme (4.25 mL, 24.4 mmol), the reaction was heated to 60°C and stirred for 18 hours. The solution was then cooled to ambient temperature and poured into a saturated NaHCO3 solution. The solution was then extreacted with EtOAc and washed with water (3X). The organic layer was then dried over Na j SO ⁇ filtered, and the solvent removed under reduced pressure yielding an oil (2.80 g, >100% crude). ⁇ MS (+ve ion electrospray) m/z 258 (MH+).
• the ketone (8c) (0.25 g, 0.627 mmol) was dissolved in tetrahydrofuran (10 mL) and the solution cooled to 0°C.
• NaBH 4 (0.024 g, 0.627 mmol) was added and the solution stirred at 0°C for 2 hours and allowed to warm to ambient temperature overnight.
• the reaction was not complete, and thus another equivalent of NaBH 4 (0.024 g, 0.627 mmol) was added at 0°C.
• the solution was allowed to warm to ambient temperature and was stirred for 3 more hours.
• the reaction was quenched with saturated NaHCO 3 solution and diluted with ethyl acetate.
• the trihydrochloride salt of amine (9b) (0.36 mmol, 180mg) was dissolved in 3mL of 1:1 dichloromethane:methanol and treated with sodium bicarbonate (1.8 mmol, 152mg) and carbaldehyde (2o) (0.36 mmol, 70mg) and stirred overnight.
• the suspension was treated with sodium triacetoxyborohydride (0.54 mmol, 114mg) and stirred overnight.
• the resulting reaction mixture was diluted with dichloromethane and poured into saturated aqueous sodium bicarbonate.
• the dihydrochloride salt (lOe) (1.4 mmol, 650mg) was dissolved in 3mL methanol and diluted with 9mL dichloromethane. The solution was treated with triethylamine (7.1 mmol, 0.99mL) and aldehyde (lj) (1.4 mmol, 253mg) and stirred overnight. The resulting solution was treated with sodium borohydride (1.4 mmol, 54mg) and stirred two hours. The reaction mixture was diluted with chloroform and poured into saturated aqueous sodium bicarbonate solution.
• Examples 1, 5, 6, 7, 8, 11, 13 have an MIC ⁇ 2 ⁇ g/ml versus all these organisms.
• Examples 4, 10, 12 have an MIC ⁇ 16 ⁇ g/ml versus all these organisms.
• Example 9 has an MIC ⁇ 16 ⁇ g/ml versus some of these organisms.

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