WO2003064431A2 - Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them - Google Patents

Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them Download PDF

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Publication number
WO2003064431A2
WO2003064431A2 PCT/EP2003/000824 EP0300824W WO03064431A2 WO 2003064431 A2 WO2003064431 A2 WO 2003064431A2 EP 0300824 W EP0300824 W EP 0300824W WO 03064431 A2 WO03064431 A2 WO 03064431A2
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Prior art keywords
alkyl
hydroxy
alkenyl
optionally substituted
amino
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PCT/EP2003/000824
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French (fr)
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WO2003064431A3 (en
Inventor
Robert A. Daines
William Henry Miller
Neil David Pearson
Israil Pendrak
Mark Andrew Seefeld
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Glaxo Group Limited
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Priority claimed from GB0202025A external-priority patent/GB0202025D0/en
Priority claimed from GB0229819A external-priority patent/GB0229819D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to JP2003564054A priority Critical patent/JP4508650B2/en
Priority to US10/502,234 priority patent/US7109213B2/en
Priority to AU2003239302A priority patent/AU2003239302A1/en
Priority to EP20030734702 priority patent/EP1470131A2/en
Publication of WO2003064431A2 publication Critical patent/WO2003064431A2/en
Publication of WO2003064431A3 publication Critical patent/WO2003064431A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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.
  • WO99/37635 disclose piperidine and piperazine derivatives having antibacterial activity.
  • JP07179407 discloses piperidyl compounds which are useful for preventing thrombotic diseases, inhibiting tumour metastasis and accelerating wound healing.
  • This invention provides a compound of formula (1) or a pharmaceutically acceptable derivative thereof:
  • one of zl, 7?-, 7?, Z ⁇ and Z ⁇ is N, one is CR ia and the remainder are CH , or one or two of Zl, 7?-, 7?, Z ⁇ and 7 are independently CR ⁇ a and the remainder are CH;
  • R1 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 (C ⁇ __6)alkyl, acyl or (C ⁇ _6)alkylsulphonyl groups, CO H2, hydroxy, (C ⁇ _6)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C ⁇ _6)alkylsul ⁇ honyloxy; (C ⁇ _6)alkoxy-substituted(C _6)alkyl; halogen; (C ⁇ _ 6)alkyl; (C ⁇ _ ⁇ )alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (C ⁇ _6)
  • R! and R ⁇ a on adjacent positions may together form ethylenedioxy
  • R 1 is not hydrogen
  • R2 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 (C ⁇ _4)alkyl groups; carboxy; (C _ 4)alkoxycarbonyl; (C ⁇ _4)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (C2-
  • R3 is in the 2-, 3- or 4-position and is trifluoromethyl or is in the 2-position and is oxo; or R3 is in the 3-position and is fluorine or amino wherein the amino group is optionally substituted by: hydroxy; (C ⁇ _6)alkylsulphonyl; trifluoromethylsulphonyl; (C2.
  • R4 is a group -U-R ⁇ where U is selected from CO, SO2 and CH2 and
  • R5 is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (A):
  • ring (a) is aromatic or non aromatic
  • ⁇ l is C when part of an aromatic ring or CR ⁇ 4 when part of a non aromatic ring
  • X 2 is N, NR13 S O, S(O) x , CO or CR 4 when part of an aromatic or non-aromatic ring or may in addition be CR14R1 when part of a non aromatic ring;
  • X 4 is N, NR 13 , O, S(O) x , CO or CR14;
  • ⁇ 3 and X ⁇ are independently N or C;
  • ⁇ l is a 1 to 3 atom linker group each atom of which is independently selected from N, N l3 5 O, S(O) x , CO and CR* 4 when part of an aromatic or non-aromatic ring or may additionally be CRI ⁇ RI 5 w hen part of a non aromatic ring,
  • Y 2 is a 2 or 3 atom linker group completing an aromatic ring, each atom of Y 2 being independently selected from N, NR 13 , O, S(O) x , CO and CR 14 ; each of R* 4 and R 1 ⁇ is independently selected from: H; (C ⁇ _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; hydroxy(C ⁇ _4)alkyl; mercapto(C ⁇ _4)al
  • R 14 and R 15 may together represent oxo; each Rl3 is independently H; trifluoromethyl; (C ⁇ _4)alkyl optionally substituted by hydroxy, (C ⁇ _6)alkoxy, (C ⁇ _6)alkylthio, carboxy, halo or trifluoromethyl; (C2- 4)alkenyl; aryl; aryl (C ⁇ _4)alkyl; arylcarbonyl; heteroarylcarbonyl; (C ⁇ _4)alkoxycarbonyl; (C ⁇ _4)alkylcarbonyl; formyl; (C ⁇ _6)alkylsulphonyl; or aminocarbonyl wherein the amino group is optionally substituted by (C ⁇ _4)alkoxycarbonyl, (C ⁇ _4)alkylcarbonyl, (C2- 4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl, (C ⁇ _4)alkyl or (C2-4)alkenyl and optionally further substituted by (C ⁇ __4)
  • n 0 or 1 ;
  • each x is independently 0, 1 or 2
  • A is NR 1 1 , O or CR 6 R 7 and B is NR 1 1 , O, SO 2 or CR 8 R 9 and wherein: each of R ⁇ , R7, R8 and R 9 is independently selected from: hydrogen; (C ⁇ .g)alkoxy; (C _ g)alkylthio; halo; trifluoromethyl; azido; (C ⁇ _6)alkyl; (C2_6)alkenyl; C _ 6)alkoxycarbonyl; (C ⁇ _6)alkylcarbonyl; (C2_6)alkenyloxycarbonyl; (C2- g)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R 3 ; (C 6)alkylsulphonyl; (C2_6)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (C ⁇ _6)alkyl or (C2. g)alken
  • R!° is selected from (C ⁇ _4)alkyl; (C2-4)alkenyl and aryl any of which maybe optionally substituted by a group Rl2 as defined above; carboxy; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C ⁇ _6)alkyl, (C2_6)alkenyl, (C ⁇ _ 6)alkylsulphonyl, trifluoromethylsulphonyl, (C2-6)alkenylsulphonyl, (C _ 6)alkoxycarbonyl, (C ⁇ _6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2- 6)alkenylcarbonyl and optionally further substituted by (C ⁇ _6)alkyl or (C2_6)alkenyl; (C ⁇ _6)alkylsulphonyl; trifluoromethylsulphonyl; (C2_6)alkenylsulphonyl; (C ⁇ _ 6)alkoxycarbony
  • RU is hydrogen; trifluoromethyl, (C ⁇ _6)alkyl; (C2-6)alkenyl; (C ⁇ _6)alkoxycarbonyl; (C ⁇ _6)alkylcarbonyl; or aminocarbonyl wherein the amino group is optionally substituted by (C ⁇ _6)alkoxycarbonyl, (C ⁇ _6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2- 5)alkenylcarbonyl, (C ⁇ _g)alkyl or (C2-6) a lk en yl and optionally further substituted by (C 1 _ g)alkyl or (C2-6)alkenyl;
  • 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 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 the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for use in the treatment of bacterial infections in mammals.
  • 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.
  • one of i , 7?-, 7?, Z 4 and Z ⁇ 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 la and the remainder are CH.
  • Z 5 is CH, C-Cl or N
  • Z 3 is CH or CF and Z 1 , Z 2 and Z 4 are each CH, or Z 1 is N, Z 3 is CH and Z 2 and Z 4 are each CH and Z 5 is CH or C-Cl.
  • R! or R ⁇ a is substituted alkoxy it is preferably (C2_6)alkoxy substitituted by optionally N-substituted amino, guanidino or amidino, or (C ⁇ _6)alkoxy substituted by piperidyl.
  • Suitable examples of Rl and R a alkoxy include methoxy, trifluoromethoxy, n-propyloxy, iso-butyloxy, aminoethyloxy, aminopropyloxy, aminobutyloxy, aminopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy, phthalimido pentyloxy or 2-aminocarbonylprop-2-oxy.
  • R* a are independently methoxy, (C ⁇ _6)alkyl, (C ⁇ _6)alkylthio, amino(C3_5)alkyloxy, guanidino(C3_5)alkyloxy, piperidyl(C3_5)alkyloxy, nitro, fluoro or chloro; R is more preferably methoxy, fluoro or chloro.
  • R ⁇ a is more preferably H, F or Cl. Most preferably R! is methoxy. and R a is H or when Z 3 is CR ⁇ a it may be C-F or when Z 5 is CR 1 it may be C-F or C-Cl.
  • R ⁇ a is preferably hydrogen, chloro, cyano, hydroxymethyl or carboxy, most preferably hydrogen or chloro.
  • n is 0.
  • R 2 is preferably hydrogen; (C ⁇ _4)alkyl substituted with carboxy, optionally substituted hydroxy, optionally substituted aminocarbonyl, optionally substituted amino or (C ⁇ _4)alkoxycarbonyl; or (C2_4)alkenyl substituted with (C ⁇ _4)alkoxycarbonyl or carboxy. More preferred groups for R 2 are hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylallyl and carboxyallyl, most preferably hydrogen. Examples of R 3 include CF3, fluoro and oxo.
  • R 3 is amino it is preferably unsubstituted or substituted by (C ⁇ _6)alkyl or (C2_6)alkenyl.
  • R 3 is preferably in the 3- or 4-position.
  • R 3 is 3-F and more preferably it is cis to (NR 2 )R 4 .
  • n 0.
  • 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 CH2 or CO.
  • A-B is CHOH-CH 2 , NR 11 -CH 2 , NR 1 !-CO or CH 2 -CH 2 .
  • R! 1 is hydrogen or (C ⁇ _4)alkyl e.g. methyl, more preferably hydrogen.
  • U is most preferably CH2.
  • R ⁇ is an aromatic heterocyclic ring (A) having 1-4 heteroatoms of which one is N or NR 3 , more preferably an aromatic heterocyclic ring (A) having 8-11 ring atoms including 2-4 heteroatoms of which at least one is N or N in which preferably Y 2 contains 2-3 heteroatoms, one of which is S and 1-2 are N, with one N bonded to X 3 .
  • rings (A) include optionally substituted: (a and (b) aromatic lH-pyrrolo[2,3-b]-pyridin-2-yl, lH-pyrrolo[3,2-b]-pyridin-2-yl, 3H-imidazo[4,5-b]-pyrid- 2-yl, 3H-qumazolin-4-one-2-yl, benzimidazol-2-yl, benzo[l,2,3]-thiadiazol-5-yl, benzo[l,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl, benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl, imidazo[l,2-a]pyridin-2-yl, imidazo-[l,2-a]- pyrimidin-2-yl, indol-2-yl, indol-6-yl, isoquinolin-3-y
  • R ⁇ 3 whenR ⁇ 3 is optionally substituted (C ⁇ _4)alkyl, the optional substituent is other than carboxy.
  • R* is preferably H if in ring (a) or in addition (C ⁇ _4)alkyl such as methyl or isopropyl when in ring (b). More preferably, in ring (b) R ⁇ is hydrogen when NR ⁇ is bonded to X 3 and (C ⁇ _4)alkyl when NR 13 is bonded to X 5 .
  • R* 4 and R 5 are preferably independently selected from hydrogen, halo, hydroxy, (C ⁇ _4)alkyl, (C ⁇ _4)alkoxy, trifluoromethoxy, nitro, cyano, aryl(C ⁇ _4)alkoxy and (C ⁇ _ 4)alkylsulphonyl. More preferably Rl5 is hydrogen.
  • each R is selected from hydrogen, chloro, fluoro, hydroxy, methyl, methoxy, trifluoromethoxy, benzyloxy, nitro, cyano and methylsulphonyl.
  • R* 4 is selected from hydrogen, hydroxy, fluorine or nitro.
  • R 14 are substituents other than hydrogen.
  • X 4 is CR 14 and/or CR 14 is a component of Y 2 .
  • R 5 include 4,6-difluoro-indol-2-yl, lH-pyrrolo[2,3-b]- pyridin-2-yl, lH-pyrrolo[3,2-b]-pyridin-2-yl flesh 8-hydroxy-quinolin-2-yl 5 quinoxalin-2-yl, benzimidazol-2-yl, benzo[l,2,3]-thiadiazol-5-yl, benzothiophen-2-yl, 4,6-difluoro-lH- benzimidazol-2-yl, benzothiazole-5-yl and 3-(R)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin- 3-yl, [l,2,3]thiadiazolo[5,4-b]pyridin-6-yl.
  • alkyl includes groups having straight and branched chains, for instance, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t- butyl, pentyl and hexyl.
  • alkenyl' should be interpreted accordingly.
  • Halo or halogen includes fluoro, chloro, bromo and iodo.
  • Haloalkyl moieties include 1-3 halogen atoms.
  • 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; hydroxy(
  • Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.
  • suitable optional substituents in such substituted amino groups include H; trifluoromethyl; (C ⁇ _4)alkyl optionally substituted by hydroxy, (C ⁇ _6)alkoxy, (C ⁇ _6)alkylthio, halo or trifluoromethyl; (C2-4)alkenyl; aryl; aryl (C ⁇ _4)alkyl; (C ⁇ _ 4)alkoxycarbonyl; (C ⁇ _4)alkylcarbonyl; formyl; (C ⁇ _6)alkylsulphonyl; or aminocarbonyl wherein the amino group is optionally substituted by (C ⁇ _4)alkoxycarbonyl, (C ⁇ _ 4)alkylcarbonyl, (C2_4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl, (C ⁇ _4)alkyl or (C2- 4)alkenyl and optionally further substituted by (C ⁇ _4)alkoxycarbonyl, (C ⁇ _4)alkylcarbonyl, (C2_
  • Aryl groups may be optionally substituted with up to five, preferably up to three, groups selected from (C ⁇ _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; hydroxy(C ⁇ _4)alkyl; mercapto(C ⁇ _4)alkyl; (C ⁇ _4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted as for corresponding substituents in R 3 ; (C ⁇ _4)al
  • Some of the compounds of this invention maybe crystallised or recrystallised from solvents such as aqueous and organic solvents, hi such cases solvates may be formed.
  • This invention includes within its scope stoichiomexric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof.
  • Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable derivatives.
  • compositions 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 a
  • R a is hydrogen, (C . ) alkyl, (C3.7) cycloalkyl, methyl, or phenyl, R D is
  • alkylene optionally substituted with a methyl or ethyl group and R ⁇ and R e independently represent (C ⁇ _g) alkyl;
  • R ⁇ represents (C ⁇ . ) alkyl;
  • RS represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C ⁇ _g) alkyl, or (C ⁇ _6) alkoxy;
  • Q is oxygen or NH;
  • R n is hydrogen or (C ⁇ _6) alkyl;
  • R 1 is hydrogen, (C . ) alkyl optionally substituted by halogen, (C2-6) alkenyl, (C ⁇ .
  • R ) represents hydrogen, (C ⁇ _6) alkyl or (C ⁇ _g) alkoxycarbonyl; and Rk represents (C ⁇ _g) alkyl, (C ⁇ .g) alkoxy, (C ⁇ . ) 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:
  • R is hydrogen, C ⁇ _6 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 i?-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.
  • n is as defined in fo ⁇ nula (I);
  • Z ', Z 2 ', Z 3 ', Z 4 ', R 1 ' and R 3 ' are Z , Z 2 , Z 3 ,
  • Ql is NR 'R 4 ' or a group convertible thereto wherein R 2 ' and R 4 ' are R 2 and R 4 as defined in formula (I) or groups convertible thereto and Q 2 is H or R 3 ' or Q and Q 2 together form an optionally protected oxo group; and X and Y may be the following combinations:
  • X is oxirane, Y is H and n is 0;
  • COW and Y is NHR 1 1 ' or NR 1 1 'COW;
  • W is a leaving group, e.g. halo or imidazolyl
  • R x and Ry are (C ⁇ _6)alkyl
  • R z is aryl or (C ⁇ _6)alkyl
  • A' and NR 1 are A and NR 11 as defined in formula (I), or groups convertible thereto; and oxirane is:
  • R 6 , R 8 and R 9 are as defined in formula (I); and thereafter optionally or as necessary converting Q and Q 2 to NR 2 'R 4 '; converting A', Z 1 ', Z 2 ' Z 3 ', Z 4 ', Z5', R ⁇ , R 2 ', R 3 ' R 4 ' and NR 1 1' to A, Z 1 , Z 2 , Z 3 , Z 4 , z R 1 , R 2 , R 3 , R 4 and NR 1 v ; converting A-B to other A-B, interconverting R 1 , R 2 , R 3 and/or R 4 , 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 (iii) initially produces compounds of formula (I) wherein A-B is
  • Process variant (iv) initially produces compounds of formula (I) where A-B is NH-CO.
  • 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 (ix) initially produces compounds of formula (I) where A-B is CO-
  • Process variant (x) initially produces compounds of formula (I) wherein A-B is CHR 6 - NR 1 1 or NR 1 i-CHR 8 .
  • Process variant (xi) initially produces compounds of formula (I) wherein A-B is NR U '-CR 8 R 9 .
  • Process variant (xii) initially produces compounds of formula (I) wherein A-B is CR 6 R 7 - NR 1 or CR 6 R 7 -O.
  • Process variant (xiii) initially produces compounds of formula (I) where A-B is CR°R 7 -SO 2 .
  • Process variant (xiv) initially produces compounds of formula (I) wherein A-B is
  • Process variant (xv) initially produces compounds where AB is NR 11 SO2-
  • Process variant (xvi) initially produces compounds of formula (I) where A-B is NR ⁇ '-CO orNR 11 '-SO 2 and n-1.
  • Process variant (xvii) initially produces compounds of formula (I) where A-B is
  • reaction is a standard amide or urea formation reaction involving e.g.:
  • the acid and amide are preferably reacted in the presence of an activating agent such as l-(dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBT) or O-(7- azabenzotriazol-l-yl)-N,N,N'N-tetramethyluronium hexafluorophosphate (HATU); or 2.
  • EDC l-(dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole
  • A' may be, for example, protected hydroxymethylene.
  • the process variant (ii) is a standard addition reaction using methods well known to those skilled in the art.
  • the process is preferably carried out in a polar organic solvent e.g. acetonitrile in the presence of an organic base e.g. triethylamine.
  • the coupling may be effected in acetonitrile at room temperature in the presence of one equivalent of lithium perchlorate as catalyst (general method of J.E. Chateauneuf et al, J. Org. Chem., 56, 5939-5942, 1991) or more preferably with ytterbium triflate in dichloromethane.
  • an elevated temperature such as 40 - 70 °C may be beneficial.
  • the piperidine may be treated with a base, such as one equivalent of butyl lithium, and the resulting salt reacted with the oxirane in an inert solvent such as tetrahydrofuran, preferably at an elevated temperature such as 80°C.
  • Use of a chiral epoxide will afford single diastereomers.
  • mixtures of diastereomers may be separated by preparative HPLC or by conventional resolution through crystallisation of salts formed from chiral acids.
  • the process variant (iv) is a standard urea formation reaction from the reaction of an isocyanate with an amine and is conducted by methods well known to those skilled in the art (for example see March, J; Advanced Organic Chemistry, Edition 3 (John Wiley and Sons, 1985), p802-3).
  • the process is preferably carried out in a polar solvent such as ⁇ , ⁇ -dimethylformamide.
  • the process is two step: firstly a condensation using a base, preferably sodium hydride or alkoxide, sodamide, alkyl lithium or lithium dialkylamide, preferably in an aprotic solvent e.g. ether, THF or benzene; secondly, hydrolysis using an inorganic acid, preferably HC1 in aqueous organic solvent at 0-100°C.
  • a base preferably sodium hydride or alkoxide, sodamide, alkyl lithium or lithium dialkylamide, preferably in an aprotic solvent e.g. ether, THF or benzene
  • hydrolysis using an inorganic acid preferably HC1 in aqueous organic solvent at 0-100°C.
  • the reaction is carried out in the presence of a base, preferably organometallic or metal hydride e.g. NaH, lithium diisopropylamide or NaOEt, preferably in an aprotic solvent, preferably THF, ether or benzene at -78 to 25°C (analogous process in Gutswiller et al. (1978) J. Am. Chem. Soc. 100, 576).
  • a base preferably organometallic or metal hydride e.g. NaH, lithium diisopropylamide or NaOEt
  • an aprotic solvent preferably THF, ether or benzene
  • a base is preferably NaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide e.g. NaOEt, sodamide or lithium dialkylamide e.g.di- isopropylamide.
  • an analogous method is described in US 3989691 and M.Gates et. al. (1970) J. Amer.Chem.Soc, 92, 205, as well as Taylor et al. (1972) JACS 94, 6218.
  • reaction is a standard reductive alkylation using, e.g., sodium borohydride or sodium triacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagents for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p 4649).
  • sodium borohydride or sodium triacetoxyborohydride Gribble, G. W. in Encyclopedia of Reagents for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p 4649.
  • 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.
  • the hydroxy group in Y is preferably converted to an OM group where M is an alkali metal by treatment of an alcohol with a base.
  • the base is preferably inorganic such as NaH, lithium diisopropylamide or sodium.
  • X is OH
  • the hydroxy group in Y is activated under Mitsunobu conditions (Fletcher et.al. J Chem Soc. (1995), 623).
  • reaction is conducted in the presence of an organic base such as triethylamine or pyridine such as described by Fuhrman et.al., J. Amer. Chem. Soc; 67, 1245, 1945.
  • organic base such as triethylamine or pyridine
  • the reaction is an alkylation, examples of which are described in J. Med. chem. (1979) 22(10) 1171-6.
  • the compound of formula (TV) maybe prepared from the corresponding compound where X is NHR 11 ' 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 leaving group W is preferably chloro or trifluoromethylsulphonyl and the reaction is the palladium catalysed process known as the "Buchwald” reaction (J. Yin and S. L. Buchwald, Org.Lett., 2000, 2, 1101).
  • Reduction of a carbonyl group A or B to CHOH can be readily accomplished using reducing agents well known to those skilled in the art, e.g. sodium borohydride in aqueous ethanol or lithium aluminium hydride in ethereal solution. This is analogous to methods described in EP53964, US384556 and J. Gutzwiller et al, J. Amer. Chem. Soc, 1978, 100, 576.
  • the carbonyl group A or B may be reduced to CH2 by treatment with a reducing agent such as hydrazine in ethylene glycol, at e.g. 130-160°C, in the presence of potassium hydroxide.
  • a reducing agent such as hydrazine in ethylene glycol, at e.g. 130-160°C, in the presence of potassium hydroxide.
  • Reaction of a carbonyl group A or B with an organometallic reagent yields a group where R 8 is OH and R 9 is alkyl.
  • a hydroxy group on A or B may be oxidised to a carbonyl group by oxidants well known to those skilled in the art, for example, manganese dioxide, pyridinium chlorochromate or pyridinium dichromate.
  • An amide carbonyl group may be reduced to the corresponding amine using a reducing agent such as lithium aluminium hydride.
  • a hydroxy group in A or B may be converted to azido by activation and displacement e.g. under Mitsunobu conditions using hydrazoic acid or by treatment with diphenylphosphorylazide and base, and the azido group in turn may be reduced to amino by hydrogenation.
  • NR 2 'R 4 ' or halogen An example of a group Q 1 convertible to NR 2 R 4 is NR 2 'R 4 ' or halogen. Halogen may be displaced by an amine HNR 'R 4 ' by a conventional alkylation. When Q 1 Q 2 together form a protected oxo group this may be an acetal such as ethylenedioxy which can subsequently be removed by acid treatment to give a compound of formula (VI): wherein the variables are as described for formula (I)
  • Examples of groups Z 1 ', Z 2 ', Z 3 ', Z 4 ', Z 5 ' convertible to Z 1 , Z 2 , Z 3 , Z 4 and Z 5 include CR la ' where R la ' is a group convertible to R la .
  • Z 1 ', Z 2 ', Z 3 ', Z 4 ' and Z 5 ' are preferably Z 1 , Z 2 , Z 3 , Z 4 and Z5.
  • R la ', R 1 ' and R 2 ' are preferably R la , R 1 and R 2 .
  • R 1 ' is preferably methoxy.
  • R 2 ' is preferably hydrogen.
  • R 3 ' is R 3 or more preferably hydrogen, vinyl, alkoxycarbonyl or carboxy.
  • R 4 is R 4 or more preferably H or an N-protecting group such as t- butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl.
  • R ', R 2 ', R 3 ' and R 4 ' and interconversions of R 1 , R 2 R 3 and R 4 are conventional.
  • suitable conventional hydroxy protecting groups which may be removed without disrupting the remainder of the molecule include acyl and alkylsilyl groups. N-protecting groups are removed by conventional methods.
  • R 1 ' methoxy is convertible to R 1 ' hydroxy by treatment with lithium and diphenylphosphine (general method described in Ireland et al, J. Amer. Chem. Soc, 1973, 7829) or HBr.
  • Alkylation of the hydroxy group with a suitable alkyl derivative bearing a leaving group such as halide and a protected amino, piperidyl, amidino or guanidino group or group convertible thereto yields, after conversion/deprotection, R 1 alkoxy substituted by optionally N-substituted amino, piperidyl, guanidino or amidino.
  • Substituted 2-oxo-oxazolidinyl containing R 3 groups may be prepared from the corresponding aldehyde by conventional reaction with a glycine anion equivalent, followed by cyclisation of the resulting amino alcohol (M. Grauert et al, Ann. Chem., 1985, 1817; Rozenberg et al, Angew. Chem. Int. Ed. Engl., 1994, 33(1). 91).
  • the resulting 2-oxo-oxazolidinyl group contains a carboxy group which can be converted to other R 1 ⁇ groups by standard procedures.
  • Carboxy groups within R 3 may be prepared by Jones' oxidation of the corresponding alcohols CH2OH using chromium acid and sulphuric acid in water/methanol (E.R.H. Jones et al, J. Chem. Soc, 1946, 39).
  • Other oxidising agents may be used for this transformation such as sodium periodate catalysed by ruthenium trichloride (G.F. Tutwiler et al, J. Med. Chem., 1987, 50(6), 1094), chromium xrioxide- pyridine (G. Just et al, Synth. Commun., 1979, 9(7), 613), potassium permanganate (D.E. Reedich et al, J. Org.
  • the carboxy group may alternatively be formed in a two stage process, with an initial oxidation of the alcohol to the corresponding aldehyde using for instance dimethyl sulphoxide activated with oxalyl chloride (N.Cohen et al, J. Am. Chem. Soc, 1983, 105, 3661) or dicyclohexylcarbodiimide (R.M.Wengler, Angew. Chim. h t. Ed.
  • 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 acetontrile-carbontetrachloride- water solvent system (N.S.Martin et al, Tetrahedron Letters, 1988, 29(22), 2701).
  • R 3 groups containing a cyano or carboxy group may be prepared by conversion of an alcohol to a suitable leaving group such as the corresponding tosylate by reaction with para-toluenesulphonyl chloride (M.R. Bell, J. Med. Chem. ,1970, 13, 389), or the iodide using triphenylphosphine, iodine, and imidazole (G. Lange, Synth. Commun., 1990, 20, 1473).
  • the second stage is the displacement of the leaving group with cyanide anion (L.A. Paquette et al, J. Org. Chem.,1979, 44(25 . 4603; P.A. Grieco et al, J. Org.
  • R 3 cis or trans hydroxy may be introduced by the methods of van Deale et al, Drug Development Research 8:225-232 (1986) or Heterocycles 39(1), 163-170 (1994).
  • trans hydroxy a suitable method converts ⁇ -protected tetrahydropyridine to the epoxide by treatment with metachloroperbenzoic acid, followed by opening of the epoxide with a suitable amine ⁇ R 'R 4 '.
  • R 3 ' hydroxy may then be converted to optionally substituted amino via preparation of the R 3 amino derivative by standard transformations such as a Mitsunobu reaction (for eaxmple as reviewed in Misunobu, Synthesisi, (1981), 1), for example with succinimide in the presence of diethylazodicarboxylate and triphenylphosphine to give the phthalimidoethylpiperidine. Removal of the phthaloyl group, for example bytreatment with methylhydrazine, affords the R 3 amine. Optional substitution may then be introduced by standard methods for amine substitution well known to those skilled in the art.
  • R 3 4-CF3 may be introduced by the following scheme I:
  • ethyl isonipecotate (1-1) reacts with an appropriate acylating agent, preferably di-tert-butyl dicarbonate, to afford the protected derivative 1-2.
  • Typical solvents for this reaction include CH2CI2, THF, or DMF.
  • the protecting group for the amine must be compatible with subsequent chemistry, and must be readily removable when desired. Methods for the protection of amines are well-known to those of skill in the art, and are described in standard reference volumes, such as Greene "Protective Groups in Organic Synthesis” (published by Wiley-Interscience).
  • Alkylation of 1-2 can be accomplished by reaction with an appropriate base, typically LDA or LiN(TMS)2, in an aprotic solvent, usually THF or DME, followed by trapping of the enolate with an appropriate electrophile, to afford 1-3.
  • Trifluoromethyl iodide (CF31) or S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate are typically preferred as electrophilic trifluoromethylating reagents.
  • 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.
  • R 3 2-CF3 may be introduced by the following scheme JJ:
  • hnine II-l prepared in standard fashion by acid-catalyzed reaction of trifluoroacetaldehyde ethyl hemiacetal and (i?)-(+)- ⁇ -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 ZnCP). Diastereomers are best separated at this point.
  • the enone II-2 is reduced to the corresponding ketone or alcohol II-3 by reaction with L-Selectride® (lithium t ⁇ -sec- butylborohydride) in a suitable solvent, generally THF or DME, followed as necessary by subsequent oxidation of the alcohol to the ketone under standard conditions (pyridinium dichromate) and the ketone is converted to an oxime derivative under standard conditions well-known to those of skill in the art by reaction with O-methylhydroxylamine under standard conditions. Reduction of the oxime derivative under standard conditions (L1AIH4 or according to the general method of Staskun and Nan Es (J. Chem. Soc.
  • the ⁇ -methylbenzyl group of II-6 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 II-7.
  • a palladium catalyst typically palladium on activated charcoal
  • a suitable solvent usually EtOH, MeOH, EtOAc, or mixtures thereof
  • R 3 3-CF3 may be introduced by the following scheme HI:
  • the commercially-available ketone III-l is converted to the corresponding silyl enol ether III-2 by reaction with a silylating reagent, such a trimethylsilyl chloride or trimethylsilyl triflate, in the presence of an amine base, typically triethylamine, in a suitable solvent, such as diethyl ether, THF, DMF, or mixtures thereof.
  • a silylating reagent such as trimethylsilyl chloride or trimethylsilyl triflate
  • an amine base typically triethylamine
  • a suitable solvent such as diethyl ether, THF, DMF, or mixtures thereof.
  • the silyl enol ether III-2 reacts with an electrophilic trifluoromethylating reagent, such as trifluoromethyl iodide (CF31) or more preferably S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (see Jet
  • Ketone III-3 reacts with a chiral amine, for instance (i?)-(+)- ⁇ -methylbenzylamine, under standard acidic catalysis, to afford the imine derivative III-4, which can be reduced to afford amine III-5.
  • This type of reduction is typically conducted using sodium borohydride, sodium cyanoborohydride or sodium (triacetoxy)borohydride, in an appropriate solvent, such as EtOH, MeOH, THF, CH2CI2, CICH2CH2CI, or mixtures thereof. Diastereomers are best separated at this point.
  • the ⁇ -methylbenzyl group of III- 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 III-6.
  • a palladium catalyst typically palladium on activated charcoal
  • a suitable solvent usually EtOH, MeOH, EtOAc, or mixtures thereof
  • R 3 2-oxo may be introduced by the following scheme IN:
  • epoxide for instance 6-methoxy-4-(i?)- oxiranylquinoline (VT-1) or 6-methoxy-4-(- z -)-oxiranyl-[l,5]na ⁇ hthyridine, to afford the adduct IV-3.
  • 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.
  • 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.
  • a palladium catalyst typically palladium on activated charcoal
  • a suitable solvent usually EtOH, MeOH, EtOAc, or mixtures thereof
  • R 3 3-F may be introduced by the following scheme N:
  • an electrophilic fluorinating reagent preferably Selectfluor (l-chloromethyl-4-fluoro-l,4- diazabicyclo[2.2.2]octane bis(tetrafluoroborate)
  • a neutral solvent such as CH3CN
  • R 3 may be obtained by conventional conversions of hydroxy, carboxy or cyano groups.
  • Texrazoles 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 andJ. Med. Chem, 1996, 39 (11). 2219).
  • the tetrazol-5-ylaminocarbonyl group may be prepared from the corresponding carboxylic acid and 2-aminotetrazole by dehydration with standard peptide coupling agents such as l,l'-carbonyldiimidazole (P.L. Ornstein et al, J. Med Chem, 1996, 39(11), 2232).
  • the alkyl- and alkenyl-sulphonylcarboxamides are similarly prepared from the corresponding carboxylic acid and the alkyl- or alkenyl-sulphonamide by dehydration with standard peptide coupling agents such as l,r-carbonyldiimidazole (P.L. Ornstein et al, J. Med. Chem., 1996, 39(11), 2232).
  • hydroxamic acid groups are prepared from the corresponding acids by standard amide coupling reactions e.g. N.R. Patel et al, Tetrahedron, 1987, 43(22), 5375.
  • 2,4-Thiazolidinedione groups may prepared from the aldehydes by condensation with 2,4-thiazolidinedione and subsequent removal of the olefinic double bond by hydrogenation.
  • 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 a hydroxymethyl group by reduction of an ester of this acid with a suitable reducing agent such as L1AIH4.
  • An NH2 substituent on piperidine is converted to NR R 4 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, alkylation with an alkyl halide R ⁇ CH2-halide in the presence of base, acylation/reduction with an acyl derivative R ⁇ COW or reductive alkylation with an aldehyde R ⁇ CHO.
  • one of 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 (IN) and the piperidine moiety or in the presence of standard peptide coupling agents. It will be appreciated that under certain circumstances interconvertions may interfere, for example, A or B hydroxy groups in A or B and the piperidine substituent ⁇ H2 will require protection e.g. as a carboxy- or silyl-ester group for hydroxy and as an acyl derivative for piperidine NH2, during conversion of R 1 ', R 2 ', R 3 ' or R 4 ', or during the coupling of the compounds of formulae (IN) and (N).
  • Compounds of formulae (IN) and (N) are known compounds, (see for example
  • the isocyanate of formula (IN) maybe 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)].
  • the 4-amino derivatives are commercially available or may be prepared by conventional procedures from a corresponding 4-chloro or 4-trifluoromethanesulphonate derivative by treatment with ammonia (O.G. Backeberg et. al., J.
  • 4-Alkenyl compounds of formula (IN) 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 (IN) 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 3 ) 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.
  • 4-Carboxy derivatives of compounds of formula (IN) are commercially available or may be prepared by conventional procedures for preparation of carboxy heteroaromatics well known to those skilled in the art.
  • quinazolines may be prepared by standard routes as described by T.A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R.C. Elderfield.
  • These 4-carboxy derivatives maybe activated by conventional means, e.g. by conversion to an acyl halide or anhydride.
  • Pyridazines may be prepared by routes analogous to those described in
  • a 4-oxirane derivative of compounds of formula (IV) 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 the 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 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.
  • the epoxide maybe 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]naphthyridine 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-l,5-naphthyridine derivatives can be prepared from 3- ammo-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-aminoacetopheneone 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.
  • 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 CH2-halides, acyl derivative R 5 COW and R 5 SO2W 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, followed by oxidation to the aldehyde with manganese (H) dioxide.
  • the aldehydes may also be prepared from carboxylic acids in two stages by conversion to a mixed anhydride for example by reaction with isobuxyl chloroformate followed by reduction with sodium borohydride (R. j.
  • R5 heterocycles are commercially available or may be prepared by conventional methods.
  • the amines R 2 'R 4 'NH are available commercially or prepared conventionally.
  • 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.
  • the compounds of formula (I) maybe 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.
  • the pharmaceutical compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.
  • compositions may be formulated for administration by any route.
  • the compositions may be 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,
  • 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 mg/kg per day. Suitably 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.
  • the carboxylic acid (iii) (0.82g) was reacted with wobutylchloroformate and sodium borohydride to afford a semi-solid (0.12g), after chromatography on silica gel (chloroform).
  • the absolute stereochemistry was defined to be (R) by an NMR study on the Mosher's esters derived from the product obtained by reaction with 1-t-butylpiperazine.
  • Methyl benzo[l,2,3]thiadiazole-5-carboxylate (0.291g) in THF (2ml) was treated dropwise with lithium aluminium hydride (1M in THF, 0.71ml) at 0 °C. After 1.5h, additional lithium aluminium hydride (0.1ml) was added. After 0.5h the mixture was treated with 8% sodium hydroxide, ethyl acetate and sodium sulphate, filtered and evaporated. The resulting crude alcohol was dissolved in dichloromethane (3ml) and stirred with manganese (H) oxide overnight. Filtration and evaporation of solvent gave the aldehyde .
  • reaction mixture was quenched with dilute HCl, basified with sodium carbonate and evaporated.
  • the residue was diluted with water and extracted with 10% methanol in chloroform, dried (sodium sulfate), evaporated and chromatographed on silica gel
  • Enantiomer 1 (15. Og, 0.049mole) in ethanol (300ml) was hydrogenated over 20% palladium hydroxide on carbon (4 g) at 30psi for 5 h, then filtered through Celite® and evaporated.
  • the crude amine was dissolved in ethyl acetate (100 mL), saturated sodium hydrogen carbonate solution (100 mL) was added followed by benzyl chloroformate (7.6 mL, 0.53mole)and the mixture stirred vigorously for 4 h. The organic phase was separated dried and evaporated.
  • the product was dissolved in DCM (75 mL) and stirred with TFA (20 mL) for 4h then evaporated.
  • the MIC ( ⁇ g/ml) of test compounds against various organisms maybe determined: S. epidermidis CL7 , S. aureus WCUH29, S. pneumoniae 1629, S. pyogenes CN10, H. influenzae ATCC49247, E.faecalis 2, E. faecium 8, M. catarrhalis Ravisio, E, coli

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Abstract

Aminopiperidine derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man.

Description

AMINOPIPERIDINE COMPOUNDS, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
This invention relates to novel compounds, compositions containing them and their use as antibacterials.
WO99/37635, WO00/21948, WO00/21952, WO00/25227, WO00/43383, WO00/78748, WO01/07432 and WO01/07433 disclose piperidine and piperazine derivatives having antibacterial activity.
WO9717957 discloses piperidyl compounds which are haemoregulatory and stimulate haematopoesis. JP07179407 discloses piperidyl compounds which are useful for preventing thrombotic diseases, inhibiting tumour metastasis and accelerating wound healing.
We have now found a novel group of aminopiperidines which have antibacterial activity.
This invention provides a compound of formula (1) or a pharmaceutically acceptable derivative thereof:
Figure imgf000002_0001
CD wherein:
one of zl, 7?-, 7?, Z^ and Z^ is N, one is CRia and the remainder are CH , or one or two of Zl, 7?-, 7?, Z^ and 7 are independently CR^a and the remainder are CH;
R1 and R*a are independently hydrogen; hydroxy; (Cι_g)alkoxy optionally substituted by (Cι_6)alkoxy, amino, piperidyl, guanidino or amidino any of which is optionally N- substituted by one or two (Cι__6)alkyl, acyl or (Cι_6)alkylsulphonyl groups, CO H2, hydroxy, (Cι_6)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (Cι_6)alkylsulρhonyloxy; (Cι_6)alkoxy-substituted(C _6)alkyl; halogen; (Cι_ 6)alkyl; (Cι_β)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (Cι_6)alkylsulphonyl; (Cι__6)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (Ci _6)alkyl, acyl or (Cι_6)alkylsulphonyl groups; or when Z^ is CRia, R^a may instead be cyano, hydroxymethyl or carboxy;
or R! and R^a on adjacent positions may together form ethylenedioxy;
provided that when Z1, Z2, 7?, Z4 and Z5 are CRla or CH, then R1 is not hydrogen;
R2 is hydrogen, or (Cι_4)alkyl or (C2_4)alkenyl optionally substituted with 1 to 3 groups selected from: amino optionally substituted by one or two (Cι_4)alkyl groups; carboxy; (C _ 4)alkoxycarbonyl; (Cι_4)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (C2-
4)alkenylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C]__4)alkyl, hydroxy(Cι_4)alkyl, aminocarbonyl(Cι_4)alkyl, (C2-4)alkenyl, (Cι_4)alkylsulphonyl, trifluoromethylsulphonyl, (C2-4)alkenylsulphonyl, (Cj_ 4)alkoxycarbonyl, (Cι_4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl or (C2- 4)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by RlO; 3- hydroxy-3-cyclobutene-l,2-dione-4-yl; 2,4-thiazolidinedione-5-yl; tetrazol-5- ylaminocarbonyl; l,2,4-triazol-5-yl optionally substituted by RlO; 5-oxo-l,2,4-oxadiazol- 3-yl; halogen; (Cι_4)alkylthio; trifluoromethyl; hydroxy optionally substituted by (C _ 4)alkyl, (C2-4)alkenyl, (Cι_4)alkoxycarbonyl, (Cι_4)alkylcarbonyl, (C2_ 4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl; oxo; (Cι^4)alkylsulphonyl; (C2-
4)alkenylsulphonyl; or (Cι_4)aminosulphonyl wherein the amino group is optionally substituted by (Cι_4)alkyl or (C2-4)alkenyl;
R3 is in the 2-, 3- or 4-position and is trifluoromethyl or is in the 2-position and is oxo; or R3 is in the 3-position and is fluorine or amino wherein the amino group is optionally substituted by: hydroxy; (Cι_6)alkylsulphonyl; trifluoromethylsulphonyl; (C2. 6)alkenylsulphonyl; (Cι _6)alkylcarbonyl; (C2_6)alkenylcarbonyl; (Cι_6)alkoxycarbonyl; (C2-6)aikenyιoχycarbonyl; (Cι_6)alkyl; or (C2-6)aιkenyl; wherein a (Cι_6)alkyl or (C2- 5)alkenyl moiety may be optionally substituted with up to 2 groups Rl2 independently selected from: halogen; (Cι_6)alkylthio; trifluoromethyl; cyano; carboxy; tetrazolyl; 2-oxo- oxazolidinyl; 3-hydroxy-3-cyclobutene-l ,2-dione-4-yl; 2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl; l,2,4-triazol-5-yl optionally substituted by RlO; or 5-oxo- l,2,4-oxadiazol-3-yl; (Cι_6)alkoxycarbonyl; (Cι_6)alkylcarbonyl; (C2. 6)alkenyloxycarbonyl; (C2_6)alkenylcarbonyl; hydroxy optionally substituted by (C \ _ 6)alkyl, (C2-6)alkenyl, (Cι_6)alkylcarbonyl, (C2_6)alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (Cι_6)alkyl, (C2_6)alkenyl; amino optionally mono- or disubstituted by (Cι_g)alkoxycarbonyl, (Cι_6)alkylcarbonyl, (C2_ 6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (Cι_6)alkyl, (C2-6)alkenyl, (C\_ 6)alkylsulphonyl, (C2_6) lkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (Cι_6)alkyl or (C2_6)alkenyl; in addition when R^ is disubstituted with a hydroxy or amino containing substituent and carboxy containing substituent these may together form a cyclic ester or amide linkage, respectively;
R4 is a group -U-R^ where U is selected from CO, SO2 and CH2 and
R5 is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (A):
Figure imgf000004_0001
containing up to four heteroatoms in each ring in which ring (a) is aromatic or non aromatic; χl is C when part of an aromatic ring or CR^4 when part of a non aromatic ring;
X2 is N, NR13S O, S(O)x, CO or CR 4 when part of an aromatic or non-aromatic ring or may in addition be CR14R1 when part of a non aromatic ring; X4 is N, NR13, O, S(O)x, CO or CR14; χ3 and X^ are independently N or C; γl is a 1 to 3 atom linker group each atom of which is independently selected from N, N l35 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,
Y2 is a 2 or 3 atom linker group completing an aromatic ring, each atom of Y2 being independently selected from N, NR13, O, S(O)x, CO and CR14; each of R*4 and R1^ is independently selected from: H; (Cι_4)alkylthio; halo; carboxy(Cι_4)alkyl; halo(Cι_4)alkoxy; halo(Cι_4)alkyl; (Cι_4)alkyl; (C2_4)alkenyl; (Cι_ 4)alkoxycarbonyl; formyl; (Cι_4)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (C2- 4)alkenylcarbonyl; (Cι_4)alkylcarbonyloxy; (Cι_4)alkoxycarbonyl(Cι_4)alkyl; hydroxy; hydroxy(Cι_4)alkyl; mercapto(Cι_4)alkyl; (Cι_4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (C\_
4)alkylsulphonyl; (C2_4)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally mono- or di-substituted by (Cι_4)alkyl or (C2-4)alkenyl; aryl; aryl(Cι_4)alkyl; aryl(Cι_4)alkoxy or
R14 and R15 may together represent oxo; each Rl3 is independently H; trifluoromethyl; (Cι_4)alkyl optionally substituted by hydroxy, (Cι_6)alkoxy, (Cι_6)alkylthio, carboxy, halo or trifluoromethyl; (C2- 4)alkenyl; aryl; aryl (Cι_4)alkyl; arylcarbonyl; heteroarylcarbonyl; (Cι_4)alkoxycarbonyl; (Cι_4)alkylcarbonyl; formyl; (Cι_6)alkylsulphonyl; or aminocarbonyl wherein the amino group is optionally substituted by (Cι_4)alkoxycarbonyl, (Cι_4)alkylcarbonyl, (C2- 4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl, (Cι_4)alkyl or (C2-4)alkenyl and optionally further substituted by (Cι__4)alkyl or (C2-4)alkenyl;
n is 0 or 1 ;
each x is independently 0, 1 or 2
A is NR1 1, O or CR6R7 and B is NR1 1, O, SO2 or CR8R9 and wherein: each of R^, R7, R8 and R9 is independently selected from: hydrogen; (Cι.g)alkoxy; (C _ g)alkylthio; halo; trifluoromethyl; azido; (Cι_6)alkyl; (C2_6)alkenyl; C _ 6)alkoxycarbonyl; (Cι_6)alkylcarbonyl; (C2_6)alkenyloxycarbonyl; (C2- g)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (C 6)alkylsulphonyl; (C2_6)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (Cι_6)alkyl or (C2. g)alkenyl; or when n=l ^ and R8 together represent a bond and R7 and R9 are as above defined; or R" and R' or R8 and R9 together represent oxo;
provided that: when A is NRi^ B is not RH or O; when A is CO, B is not CO, O or SO2; when n is 0 and A is NR11, CR8R9 can only be CO; when A is CR6R7 and B is SO2, n is 0; when n is 0, B is not N 1 or O or R8 and R9 are not optionally substituted hydroxy or amino; when A is O, B is not NR11, O, SO2 or CO and n=l; and when A-B is CR7=CR9, n is 1
R!° is selected from (Cι_4)alkyl; (C2-4)alkenyl and aryl any of which maybe optionally substituted by a group Rl2 as defined above; carboxy; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (Cι _6)alkyl, (C2_6)alkenyl, (Cχ_ 6)alkylsulphonyl, trifluoromethylsulphonyl, (C2-6)alkenylsulphonyl, (C _ 6)alkoxycarbonyl, (Cι_6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2- 6)alkenylcarbonyl and optionally further substituted by (Cι_6)alkyl or (C2_6)alkenyl; (Cι_6)alkylsulphonyl; trifluoromethylsulphonyl; (C2_6)alkenylsulphonyl; (C\_ 6)alkoxycarbonyl; (Cι_6)alkylcarbonyl; (C2-6)aιkenyloxycarbonyl; and (C2. 6)alkenylcarbonyl; and
RU is hydrogen; trifluoromethyl, (Cι_6)alkyl; (C2-6)alkenyl; (Cι_6)alkoxycarbonyl; (Cι_6)alkylcarbonyl; or aminocarbonyl wherein the amino group is optionally substituted by (Cι_6)alkoxycarbonyl, (Cι_6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2- 5)alkenylcarbonyl, (C \ _g)alkyl or (C2-6)alkenyl and optionally further substituted by (C 1 _ g)alkyl or (C2-6)alkenyl;
or where one of R3 and R^, R7, R8 or R9 contains a carboxy group and the other contains a hydroxy or amino group they may together form a cyclic ester or amide linkage.
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 the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for use in the treatment of bacterial infections in mammals.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
Preferably one of i , 7?-, 7?, Z4 and Z^ is N, one is CR^a and the remainder are CH , or one of Z1, Z2, Z3, Z4 and Z5 is CRla and the remainder are CH.
Preferably Z5 is CH, C-Cl or N, Z3 is CH or CF and Z1, Z2 and Z4 are each CH, or Z1 is N, Z3 is CH and Z2 and Z4 are each CH and Z5 is CH or C-Cl.
When R! or R^a is substituted alkoxy it is preferably (C2_6)alkoxy substitituted by optionally N-substituted amino, guanidino or amidino, or (Cι_6)alkoxy substituted by piperidyl. Suitable examples of Rl and R a alkoxy include methoxy, trifluoromethoxy, n-propyloxy, iso-butyloxy, aminoethyloxy, aminopropyloxy, aminobutyloxy, aminopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy, phthalimido pentyloxy or 2-aminocarbonylprop-2-oxy. Preferably R! and R*a are independently methoxy, (Cι_6)alkyl, (Cι_6)alkylthio, amino(C3_5)alkyloxy, guanidino(C3_5)alkyloxy, piperidyl(C3_5)alkyloxy, nitro, fluoro or chloro; R is more preferably methoxy, fluoro or chloro. R^a is more preferably H, F or Cl. Most preferably R! is methoxy. and R a is H or when Z3 is CR^a it may be C-F or when Z5 is CR1 it may be C-F or C-Cl.
When Z^ is CR^3-, R^a is preferably hydrogen, chloro, cyano, hydroxymethyl or carboxy, most preferably hydrogen or chloro. Preferably n is 0.
R2 is preferably hydrogen; (Cι_4)alkyl substituted with carboxy, optionally substituted hydroxy, optionally substituted aminocarbonyl, optionally substituted amino or (Cι_4)alkoxycarbonyl; or (C2_4)alkenyl substituted with (Cι_4)alkoxycarbonyl or carboxy. More preferred groups for R2 are hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylallyl and carboxyallyl, most preferably hydrogen. Examples of R3 include CF3, fluoro and oxo.
When R3 is amino it is preferably unsubstituted or substituted by (Cι_6)alkyl or (C2_6)alkenyl.
R3 is preferably in the 3- or 4-position.
Most preferably R3 is 3-F and more preferably it is cis to (NR2)R4. Preferably n=0.
When A is CH(OH) the R-stereochemistry is preferred. Preferably A is NH, NCH3, CH2, CHOH, CH(NH2), C(Me)(OH) or CH(Me). Preferably B is CH2 or CO.
Preferably A-B is CHOH-CH2, NR11-CH2, NR1 !-CO or CH2-CH2. Particularly preferred are those compounds where n=0, A is H and B is CO, or A is CH2 or CHOH and B is CH2, when more preferably A is the i?-isomer of CHOH.
Preferably R! 1 is hydrogen or (Cι_4)alkyl e.g. methyl, more preferably hydrogen. U is most preferably CH2.
Preferably R^ is an aromatic heterocyclic ring (A) having 1-4 heteroatoms of which one is N or NR 3, more preferably an aromatic heterocyclic ring (A) having 8-11 ring atoms including 2-4 heteroatoms of which at least one is N or N in which preferably Y2 contains 2-3 heteroatoms, one of which is S and 1-2 are N, with one N bonded to X3.
Examples of rings (A) include optionally substituted: (a and (b) aromatic lH-pyrrolo[2,3-b]-pyridin-2-yl, lH-pyrrolo[3,2-b]-pyridin-2-yl, 3H-imidazo[4,5-b]-pyrid- 2-yl, 3H-qumazolin-4-one-2-yl, benzimidazol-2-yl, benzo[l,2,3]-thiadiazol-5-yl, benzo[l,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl, benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl, imidazo[l,2-a]pyridin-2-yl, imidazo-[l,2-a]- pyrimidin-2-yl, indol-2-yl, indol-6-yl, isoquinolin-3-yl, [l,8]-naphthyridine-3-yL oxazolo[4,5-b]-pyridin-2-yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, indan-2-yl, naphthalen-2-yl, l,3-dioxo-isoindol-2yl, benzimidazol-2-yl, benzothiophen-2-yl, 1H- benzotriazol-5-yl, lH-indol-5-yl, 3H-benzooxazol-2-one-6-yl, 3H-benzooxazol-2-thione- 6-yl, 3H-benzothiazol-2-one-5-yl, 3H-quinazolin-4-one-2-yl, 3H-quinazolin-4-one-6-yl, 4-oxo-4H-pyrido[l ,2-a]pyrimidin-3-yl, benzo[ 1 ,2,3]thiadiazol-6-yl, benzo[l,2,5]thiadiazol-5-yl, benzo[l,4]oxazin-2-one-3-yl, benzothiazol-5-yl, benzothiazol-6-yl, cinnolin-3-yl, imidazo[l,2-a]pyridazin-2-yl, imidazo[l,2-b]pyridazin- 2-yl, pyrazolo[l,5-a]pyrazin-2-yl, pyrazolo[l,5-a]pyridin-2-yl, pyrazolo [1,5 -ajpyrimidin- 6-yl, pyrazolo[5,l-c][l,2,4]xriazin-3-yl, pyrido[l,2-a]pyrimdin-4-one-2-yl, pyrido[l,2- a]pyrimidin-4-one-3-yl, quinazolin-2-yl, quinoxalin-6-yL thiazolo[3,2-a]pyrimidin-5-one- 7-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-b]pyridin-6-yl, thieno[3,2-b]pyridin-6-yl, 4- oxo-4H-pyrido[l,2-a]pyrimidin-2-yl, l-oxo-l,2-dihydro-isoquinolin-3-yl, thiazolo[4,5- b]pyridin-5-yl, [l,2,3]thiadiazolo[5,4-b]pyridin-6-yl, 2H-isoquinolin-l-one-3-yl.
(a) is non aromatic
(2S)-2,3-dihydro-lH-indol-2-yl, (2S)-2,3-dihydro-benzo[l,4]dioxine-2-yl, 3-(R,S)-3,4- dihydro-2H-benzo[l,4]thiazin-3-yl, 3-(R)-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3-yl, 2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3-yl, 3-substituted-3H-quinazolin-4-one-2-yl, 2,3- dihydro-benzo[ 1 ,4]dioxan-2-yl, 1 -oxo- 1 ,3,4,5-tetrahydrobenzo[c]azepin-2-yl.
In one aspect, whenR^3 is optionally substituted (Cχ_4)alkyl, the optional substituent is other than carboxy.
R* is preferably H if in ring (a) or in addition (Cι_4)alkyl such as methyl or isopropyl when in ring (b). More preferably, in ring (b) R^ is hydrogen when NR^ is bonded to X3 and (Cχ_4)alkyl when NR13 is bonded to X5.
R*4 and R 5 are preferably independently selected from hydrogen, halo, hydroxy, (Cχ_4)alkyl, (Cχ_4)alkoxy, trifluoromethoxy, nitro, cyano, aryl(Cχ_4)alkoxy and (Cχ_ 4)alkylsulphonyl. More preferably Rl5 is hydrogen.
More preferably each R is selected from hydrogen, chloro, fluoro, hydroxy, methyl, methoxy, trifluoromethoxy, benzyloxy, nitro, cyano and methylsulphonyl. Most preferably R*4 is selected from hydrogen, hydroxy, fluorine or nitro. Preferably 0-3 groups R14 are substituents other than hydrogen. Preferably when R14 is not hydrogen, X4 is CR14 and/or CR14 is a component of Y2. Most preferred groups R5 include 4,6-difluoro-indol-2-yl, lH-pyrrolo[2,3-b]- pyridin-2-yl, lH-pyrrolo[3,2-b]-pyridin-2-yl„ 8-hydroxy-quinolin-2-yl5 quinoxalin-2-yl, benzimidazol-2-yl, benzo[l,2,3]-thiadiazol-5-yl, benzothiophen-2-yl, 4,6-difluoro-lH- benzimidazol-2-yl, benzothiazole-5-yl and 3-(R)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin- 3-yl, [l,2,3]thiadiazolo[5,4-b]pyridin-6-yl.
When used herein, the term "alkyl" includes groups having straight and branched chains, for instance, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t- butyl, pentyl and hexyl. The term 'alkenyl' should be interpreted accordingly. Halo or halogen includes fluoro, chloro, bromo and iodo. Haloalkyl moieties include 1-3 halogen atoms.
Unless otherwise defined, the term "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(Cχ_4)alkyl; halo(Cχ_4)alkoxy; halo(Cχ_4)alkyl; (Cχ_4)alkyl; (C2_4)alkenyl; (Cχ_4)alkoxycarbonyl; formyl; (Cχ_ 4)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (C2-4)alkenylcarbonyl; (Cχ_ 4)alkylcarbonyloxy; (Cι_4)alkoxycarbonyl(Cχ_4)alkyl; hydroxy; hydroxy(Cχ_4)alkyl; mercapto(Cχ_4)alkyl; (C _4)alkoxy; nitro; cyano, carboxy; amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (Cχ_4)alkylsulphonyl; (C2_ 4)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (Cχ_4)alkyl or (C2-4)alkenyl; optionally substituted aryl, aryl(Cχ_4)alkyl or aryl(Cχ_ 4)alkoxy and oxo groups.
Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.
Where an amino group forms part of a single or fused non-aromatic heterocyclic ring as defined above suitable optional substituents in such substituted amino groups include H; trifluoromethyl; (Cι_4)alkyl optionally substituted by hydroxy, (Cχ_6)alkoxy, (Cι_6)alkylthio, halo or trifluoromethyl; (C2-4)alkenyl; aryl; aryl (Cχ_4)alkyl; (Cχ_ 4)alkoxycarbonyl; (Cχ_4)alkylcarbonyl; formyl; (Cχ_6)alkylsulphonyl; or aminocarbonyl wherein the amino group is optionally substituted by (Cχ_4)alkoxycarbonyl, (Cχ_ 4)alkylcarbonyl, (C2_4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl, (Cι_4)alkyl or (C2- 4)alkenyl and optionally further substituted by (Cχ.4)alkyl or (C2_4)alkenyl. When used herein the term "aryl", includes optionally substituted phenyl and naphthyl.
Aryl groups may be optionally substituted with up to five, preferably up to three, groups selected from (Cχ_4)alkylthio; halo; carboxy(Cχ_4)alkyl; halo(Cχ_4)alkoxy; halo(Cχ_4)alkyl; (Cχ_4)alkyl; (C2-4)alkenyl; (Cχ_4)alkoxycarbonyl; formyl; (Cχ_ 4)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (C2_4)alkenylcarbonyl; (Cχ_ 4)alkylcarbonyloxy; (Cχ_4)alkoxycarbonyl(Cχ_4)alkyl; hydroxy; hydroxy(Cι_4)alkyl; mercapto(Cχ_4)alkyl; (Cχ_4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (Cχ_4)alkylsulphonyl; (C2- 4)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (Cχ_4)alkyl or (C2-4)alkenyl; phenyl, phenyl(Cχ_4)alkyl or phenyl(Cχ_4)alkoxy The term "acyl" includes formyl and (Cχ_6)alkylcarbonyl group. Some of the compounds of this invention maybe crystallised or recrystallised from solvents such as aqueous and organic solvents, hi such cases solvates may be formed. This invention includes within its scope stoichiomexric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof.
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. Examples of 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): Ra
— C I H-O.CO.R b (i)
Rα
Rc- N<
Rc (ϋ)
CH2— ORf
(iϋ)
Figure imgf000011_0001
Figure imgf000011_0002
wherein Ra is hydrogen, (C . ) alkyl, (C3.7) cycloalkyl, methyl, or phenyl, RD is
(Cχ_6) alkyl, (Cι _g) alkoxy, phenyl, benzyl, (C3.7) cycloalkyl, (C3.7) cycloalkyloxy, (Cχ_6) alkyl (C3_γ) cycloalkyl, 1-amino (Cχ_6) alkyl, or l-(Cχ_6 alkyl)amino (Cχ.g) alkyl; or Ra and RD together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; Rc represents (C\. ) alkylene optionally substituted with a methyl or ethyl group and R^ and Re independently represent (Cχ_g) alkyl; R^ represents (C\. ) alkyl; RS represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cχ_g) alkyl, or (Cχ_6) alkoxy; Q is oxygen or NH; Rn is hydrogen or (Cχ_6) alkyl; R1 is hydrogen, (C . ) alkyl optionally substituted by halogen, (C2-6) alkenyl, (C\. ) alkoxycarbonyl, aryl or heteroaryl; or Rh and R1 together form (Cχ_6) alkylene; R) represents hydrogen, (Cχ_6) alkyl or (Cχ_g) alkoxycarbonyl; and Rk represents (Cχ_g) alkyl, (C^.g) alkoxy, (C\. ) alkoxy(Cχ_6)alkoxy or aryl.
Examples of suitable in vivo hydrolysable ester groups include, for example, acyloxy(Cχ_6)alkyl groups such as acetoxymethyl, pivaloyloxymethyl, α-acetoxyethyl, -pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop-l-yl, and
(l-aminoethyl)carbonyloxymethyl; (Cχ_6)alkoxycarbonyloxy(Cχ_6)alkyl groups, such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; di(Cι_6)alkylamino(Cι_6)alkyl especially di(Cχ_4)alkylamino(Cχ_4)alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-((Cχ.6)alkoxycarbonyl)-2-(C2-6)alkenyl groups such as
2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl; lactone groups such as phthalidyl and dimethoxyphthalidyl.
A further suitable pharmaceutically acceptable in vivo hydrolysable ester-forming group is that of the formula:
Figure imgf000012_0001
wherein R is hydrogen, Cχ_6 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. For example the invention includes compound in which an A-B group CH(OH)-CH2 is in either isomeric configuration, the i?-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.
In a further aspect of the invention there is provided a process for preparing compounds of formula (I), and pharmaceutically acceptable derivatives thereof, which process comprises:
reacting a compound of formula (IN) with a compound of formula (N):
Figure imgf000012_0002
wherein n is as defined in foπnula (I); Z ', Z2', Z3', Z4',
Figure imgf000013_0001
R1' and R3' are Z , Z2, Z3,
Z4, Z^, R1 and R3 as defined in formula (I) or groups convertible thereto;
Ql is NR 'R4' or a group convertible thereto wherein R2' and R4' are R2 and R4 as defined in formula (I) or groups convertible thereto and Q2 is H or R3' or Q and Q2 together form an optionally protected oxo group; and X and Y may be the following combinations:
(i) X is A'-COW, Y is H and n is 0;
(ii) X is CR6= R8R9, Y is H and n is O;
(iii) X is oxirane, Y is H and n is 0; (iv) X is N=C=O and Y is H and n is 0;
(v) one of X and Y is CO Ry and the other is CH2CO2Rx;
(vi) X is CHR6R7 and Y is C(=O)R9;
(viϊ) X is CR7=PRZ3 and Y is C(=O)R9 and n=l ;
(viii) X is C(=O)R7 and Y is CR9=PRZ3 and n=l ; (ix) Y is COW and X is HR11 ' or NR11 'COW and n=0 or 1 or when n=l X is
COW and Y is NHR11 ' or NR11 'COW;
(x) X is C(O=)R6 and Y is NHRl 1 ' or X is NHR11 ' and Y is C(=O)R8 and n=l ;
(xi) X is NHR111 and Y is CR8R9W and n=l ;
(xii) X is CR6R7W and Y is NHR11 ' or OH and n=l ; (xiii) X is CR6R7SO2W and Y is H and n=0;
(xiv) X is W or OH and Y is CH2OH and n=l ;
(xv) X is NHRl 1' and y is SO2W or X is NR1 l'S02W and Y is H, and n=0;
(xvi) X is NR11 'COCH2W or NR11 'SO2CH W and Y is H and n=0;
(xvii) X is W and Y is CONHR1 r;
in which W is a leaving group, e.g. halo or imidazolyl; Rx and Ry are (Cχ_6)alkyl; Rz is aryl or (Cχ_6)alkyl; A' and NR1 are A and NR11 as defined in formula (I), or groups convertible thereto; and oxirane is:
Figure imgf000013_0002
wherein R6, R8 and R9 are as defined in formula (I); and thereafter optionally or as necessary converting Q and Q2 to NR2'R4'; converting A', Z1', Z2' Z3', Z4', Z5', RΓ, R2', R3' R4' and NR11' to A, Z1, Z2, Z3, Z4, z R1, R2, R3, R4 and NR1 v; converting A-B to other A-B, interconverting R1, R2, R3 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 CHR6-CR8R9. Process variant (iii) initially produces compounds of formula (I) wherein A-B is
CR6(OH)-CR8R9.
Process variant (iv) initially produces compounds of formula (I) where A-B is NH-CO.
Process variant (v) initially produces compounds of formula (I) wherein A-B is CO-CH2 or CH2-CO.
Process variant (vi) initially produces compounds of formula (I) wherein A-B is CR6R7-CR9OH.
Process variant (vii) and (viii) initially produce compounds of formula (I) wherein A-B is CR7=CR9. Process variant (ix) initially produces compounds of formula (I) where A-B is CO-
N H orNRH-CO.
Process variant (x) initially produces compounds of formula (I) wherein A-B is CHR6- NR11 or NR1 i-CHR8.
Process variant (xi) initially produces compounds of formula (I) wherein A-B is NRU'-CR8R9.
Process variant (xii) initially produces compounds of formula (I) wherein A-B is CR6R7- NR1 or CR6R7-O.
Process variant (xiii) initially produces compounds of formula (I) where A-B is CR°R7-SO2. Process variant (xiv) initially produces compounds of formula (I) wherein A-B is
O-CH2.
Process variant (xv) initially produces compounds where AB is NR11SO2- Process variant (xvi) initially produces compounds of formula (I) where A-B is NR^'-CO orNR11'-SO2 and n-1. Process variant (xvii) initially produces compounds of formula (I) where A-B is
NRn'-CO.
In process variants (i) and (ix) the reaction is a standard amide or urea formation reaction involving e.g.:
1. Activation of a carboxylic acid (e.g. to an acid chloride, mixed anhydride, active ester, O-acyl-isourea or other species), and treatment with an amine (Ogliaruso, M.A.; Wolfe, J.F. in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp 442-8; Beckwith, A.LJ. in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The Chemistry of Amides (Ed. Zabricky, J.) (John Wiley and Sons, 1970), p 73 ff. The acid and amide are preferably reacted in the presence of an activating agent such as l-(dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBT) or O-(7- azabenzotriazol-l-yl)-N,N,N'N-tetramethyluronium hexafluorophosphate (HATU); or 2. The specific methods of: a. in situ conversion of an acid into the amine component by a modified Curtius reaction procedure (Shioiri, T., Murata, M., Hamada, Y, Chem. Pharm. Bull. 1987, 35, 2698) b. in situ conversion of the acid component into the acid chloride under neutral conditions (Nilleneuve, G. B.; Chan, T. H., Tetrahedron. Lett. 1997, 38, 6489). A' may be, for example, protected hydroxymethylene.
The process variant (ii) is a standard addition reaction using methods well known to those skilled in the art. The process is preferably carried out in a polar organic solvent e.g. acetonitrile in the presence of an organic base e.g. triethylamine.
In process variant (iii) the coupling may be effected in acetonitrile at room temperature in the presence of one equivalent of lithium perchlorate as catalyst (general method of J.E. Chateauneuf et al, J. Org. Chem., 56, 5939-5942, 1991) or more preferably with ytterbium triflate in dichloromethane. In some cases an elevated temperature such as 40 - 70 °C may be beneficial. Alternatively, the piperidine may be treated with a base, such as one equivalent of butyl lithium, and the resulting salt reacted with the oxirane in an inert solvent such as tetrahydrofuran, preferably at an elevated temperature such as 80°C. Use of a chiral epoxide will afford single diastereomers. Alternatively, mixtures of diastereomers may be separated by preparative HPLC or by conventional resolution through crystallisation of salts formed from chiral acids.
The process variant (iv) is a standard urea formation reaction from the reaction of an isocyanate with an amine and is conducted by methods well known to those skilled in the art (for example see March, J; Advanced Organic Chemistry, Edition 3 (John Wiley and Sons, 1985), p802-3). The process is preferably carried out in a polar solvent such as Ν,Ν-dimethylformamide.
In process variant (v) the process is two step: firstly a condensation using a base, preferably sodium hydride or alkoxide, sodamide, alkyl lithium or lithium dialkylamide, preferably in an aprotic solvent e.g. ether, THF or benzene; secondly, hydrolysis using an inorganic acid, preferably HC1 in aqueous organic solvent at 0-100°C. Analogous routes are described in DE330945, EP31753, EP53964 and H. Sargent, J. Am. Chem. Soc. 68, 2688-2692 (1946). Similar Claisen methodology is described in Soszko et. al., Pr.Kom.Mat. Przyr.Poznan.Tow.Przyj.Nauk., (1962), 10, 15.
In process variant (vi) the reaction is carried out in the presence of a base, preferably organometallic or metal hydride e.g. NaH, lithium diisopropylamide or NaOEt, preferably in an aprotic solvent, preferably THF, ether or benzene at -78 to 25°C (analogous process in Gutswiller et al. (1978) J. Am. Chem. Soc. 100, 576).
In process variants (vii) and (viii) if a base is used it is preferably NaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide e.g. NaOEt, sodamide or lithium dialkylamide e.g.di- isopropylamide. An analogous method is described in US 3989691 and M.Gates et. al. (1970) J. Amer.Chem.Soc, 92, 205, as well as Taylor et al. (1972) JACS 94, 6218.
In process variant (x) where X or Y is CHO the reaction is a standard reductive alkylation using, e.g., sodium borohydride or sodium triacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagents for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p 4649).
The process variants (xi) and (xii) are standard alkylation reactions well known to those skilled in the art, for example where an alcohol or amine is treated with an alkyl halide in the presence of a base (for example see March, J; Advanced Organic Chemistry, Edition 3 (John Wiley and Sons, 1985), p364-366 and p342-343). The process is preferably carried out in a polar solvent such as N,N-dimethylformamide
In process variant (xiii) 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.
In process variant (xiv) where X is W such as halogen, methanesulphonyloxy or trifluoromethanesulphonyloxy, the hydroxy group in Y is preferably converted to an OM group where M is an alkali metal by treatment of an alcohol with a base. The base is preferably inorganic such as NaH, lithium diisopropylamide or sodium. Where X is OH, the hydroxy group in Y is activated under Mitsunobu conditions (Fletcher et.al. J Chem Soc. (1995), 623). Alternatively the X=O and Y=CH2OH groups can be reacted directly by activation with dichlorocarbodiimide (DCC) (Chem. Berichte 1962, 95, 2997 or Angewante Chemie 1963 75, 377).
In process variant (xv) the reaction is conducted in the presence of an organic base such as triethylamine or pyridine such as described by Fuhrman et.al., J. Amer. Chem. Soc; 67, 1245, 1945. The
Figure imgf000016_0001
or Y=SO2W intermediates can be formed from the requisite amine e.g. by reaction with SO Cl analogously to the procedure described by the same authors Fuhrman et.al., J. Amer. Chem. Soc; 67, 1245, 1945.
In process variant (xvi) the reaction is an alkylation, examples of which are described in J. Med. chem. (1979) 22(10) 1171-6. The compound of formula (TV) maybe prepared from the corresponding compound where X is NHR11 ' 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.
In process variant (xvii) the leaving group W is preferably chloro or trifluoromethylsulphonyl and the reaction is the palladium catalysed process known as the "Buchwald" reaction (J. Yin and S. L. Buchwald, Org.Lett., 2000, 2, 1101).
Reduction of a carbonyl group A or B to CHOH can be readily accomplished using reducing agents well known to those skilled in the art, e.g. sodium borohydride in aqueous ethanol or lithium aluminium hydride in ethereal solution. This is analogous to methods described in EP53964, US384556 and J. Gutzwiller et al, J. Amer. Chem. Soc, 1978, 100, 576.
The carbonyl group A or B may be reduced to CH2 by treatment with a reducing agent such as hydrazine in ethylene glycol, at e.g. 130-160°C, in the presence of potassium hydroxide.
Reaction of a carbonyl group A or B with an organometallic reagent yields a group where R8 is OH and R9 is alkyl.
A hydroxy group on A or B may be oxidised to a carbonyl group by oxidants well known to those skilled in the art, for example, manganese dioxide, pyridinium chlorochromate or pyridinium dichromate.
A hydroxyalkyl A-B group CHR7CR9OH or CR7(OH)CHR9 maybe dehydrated to give the group CR7=CR9 by treatment with an acid anhydride such as acetic anhydride.
Methods for conversion of CR7=CR9 by reduction to CHR7CHR9 are well known to those skilled in the art, for example using hydrogenation over palladium on carbon as catalyst. Methods for conversion of CR7=CR9 to give the A-B group CR7(OH)CHR9 or CHR7CR9OH are well known to those skilled in the art for example by epoxidation and subsequent reduction by metal hydrides, hydration, hydroboration or oxymercuration.
An amide carbonyl group may be reduced to the corresponding amine using a reducing agent such as lithium aluminium hydride.
A hydroxy group in A or B may be converted to azido by activation and displacement e.g. under Mitsunobu conditions using hydrazoic acid or by treatment with diphenylphosphorylazide and base, and the azido group in turn may be reduced to amino by hydrogenation.
An example of a group Q1 convertible to NR2 R4 is NR2'R4' or halogen. Halogen may be displaced by an amine HNR 'R4' by a conventional alkylation. When Q1 Q2 together form a protected oxo group this may be an acetal such as ethylenedioxy which can subsequently be removed by acid treatment to give a compound of formula (VI):
Figure imgf000018_0001
wherein the variables are as described for formula (I)
Intermediates of formula (NI) are novel and as such form part of the invention. The ketone of formula (NI) is reacted with an amine HΝR 'R4' by conventional reductive alkylation as described above for process variant (x).
Examples of groups Z1', Z2', Z3', Z4', Z5' convertible to Z1, Z2, Z3, Z4 and Z5 include CRla' where Rla' is a group convertible to Rla. Z1', Z2', Z3', Z4' and Z5' are preferably Z1, Z2, Z3, Z4 and Z5.
Rla', R1' and R2' are preferably Rla, R1 and R2. R1' is preferably methoxy. R2' is preferably hydrogen. R3' is R3 or more preferably hydrogen, vinyl, alkoxycarbonyl or carboxy. R4 is R4 or more preferably H or an N-protecting group such as t- butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl.
Conversions of R ', R2', R3' and R4' and interconversions of R1, R2 R3 and R4 are conventional. In compounds which contain an optionally protected hydroxy group, suitable conventional hydroxy protecting groups which may be removed without disrupting the remainder of the molecule include acyl and alkylsilyl groups. N-protecting groups are removed by conventional methods.
For example R1' methoxy is convertible to R1' hydroxy by treatment with lithium and diphenylphosphine (general method described in Ireland et al, J. Amer. Chem. Soc, 1973, 7829) or HBr. Alkylation of the hydroxy group with a suitable alkyl derivative bearing a leaving group such as halide and a protected amino, piperidyl, amidino or guanidino group or group convertible thereto, yields, after conversion/deprotection, R1 alkoxy substituted by optionally N-substituted amino, piperidyl, guanidino or amidino. Substituted 2-oxo-oxazolidinyl containing R3 groups may be prepared from the corresponding aldehyde by conventional reaction with a glycine anion equivalent, followed by cyclisation of the resulting amino alcohol (M. Grauert et al, Ann. Chem., 1985, 1817; Rozenberg et al, Angew. Chem. Int. Ed. Engl., 1994, 33(1). 91). The resulting 2-oxo-oxazolidinyl group contains a carboxy group which can be converted to other R1^ groups by standard procedures. Carboxy groups within R3 may be prepared by Jones' oxidation of the corresponding alcohols CH2OH using chromium acid and sulphuric acid in water/methanol (E.R.H. Jones et al, J. Chem. Soc, 1946, 39). Other oxidising agents may be used for this transformation such as sodium periodate catalysed by ruthenium trichloride (G.F. Tutwiler et al, J. Med. Chem., 1987, 50(6), 1094), chromium xrioxide- pyridine (G. Just et al, Synth. Commun., 1979, 9(7), 613), potassium permanganate (D.E. Reedich et al, J. Org. Chem.,1985, 50(19), 3535), and pyridinium chlorochromate (D. Askin et al, Tetrahedron Lett, 1988, 29(3), 277). The carboxy group may alternatively be formed in a two stage process, with an initial oxidation of the alcohol to the corresponding aldehyde using for instance dimethyl sulphoxide activated with oxalyl chloride (N.Cohen et al, J. Am. Chem. Soc, 1983, 105, 3661) or dicyclohexylcarbodiimide (R.M.Wengler, Angew. Chim. h t. Ed. Eng., 1985, 24(2), 77), or oxidation with tetrapropylammonium perruthenate (Ley et al, J. Chem. Soc. Chem Commun., 1987, 1625). The aldehyde may then be separately oxidised to the corresponding acid using oxidising agents such as silver (U) oxide (R.Grigg et al, J. Chem. Soc. Perkinl,1983, 1929), potassium permanganate (A.Zurcher, Helv. Chim. Acta., 1987, 70 (7), 1937), sodium periodate catalysed by ruthenium trichloride (T.Sakata et al, Bull. Chem. Soc. Jpn., 1988, 61(6), 2025), pyridinium chlorochromate (RS.Reddy et al, Synth. Commun., 1988, 18(51), 545) or chromium trioxide (R.M.Coates et al, J. Am. Chem. Soc.,1982, 104, 2198).
An R3 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 acetontrile-carbontetrachloride- water solvent system (N.S.Martin et al, Tetrahedron Letters, 1988, 29(22), 2701).
Other routes to the synthesis of carboxy groups within R3 are well known to those skilled in the art.
R3 groups containing a cyano or carboxy group may be prepared by conversion of an alcohol to a suitable leaving group such as the corresponding tosylate by reaction with para-toluenesulphonyl chloride (M.R. Bell, J. Med. Chem. ,1970, 13, 389), or the iodide using triphenylphosphine, iodine, and imidazole (G. Lange, Synth. Commun., 1990, 20, 1473). The second stage is the displacement of the leaving group with cyanide anion (L.A. Paquette et al, J. Org. Chem.,1979, 44(25 . 4603; P.A. Grieco et al, J. Org. Chem., 1988, 53(16), 3658. Finally acidic hydrolysis of the nitrile group gives the desired acids (H.Rosemeyer et al, Heterocycles, 1985, 23 (10), 2669). The hydrolysis may also be carried out with base e.g. potassium hydroxide (H.Rapoport, J. Org. Chem.,1958, 23, 248) or enzymatically (T. Beard et al, Tetrahedron Asymmetry, 1993, 4 (6), 1085).
R3 cis or trans hydroxy may be introduced by the methods of van Deale et al, Drug Development Research 8:225-232 (1986) or Heterocycles 39(1), 163-170 (1994). For trans hydroxy, a suitable method converts Ν-protected tetrahydropyridine to the epoxide by treatment with metachloroperbenzoic acid, followed by opening of the epoxide with a suitable amine ΝR 'R4'. R3' hydroxy may then be converted to optionally substituted amino via preparation of the R3 amino derivative by standard transformations such as a Mitsunobu reaction (for eaxmple as reviewed in Misunobu, Synthesisi, (1981), 1), for example with succinimide in the presence of diethylazodicarboxylate and triphenylphosphine to give the phthalimidoethylpiperidine. Removal of the phthaloyl group, for example bytreatment with methylhydrazine, affords the R3 amine. Optional substitution may then be introduced by standard methods for amine substitution well known to those skilled in the art.
R3 4-CF3 may be introduced by the following scheme I:
Scheme I
Figure imgf000020_0001
Figure imgf000020_0002
(a) (Boc)2O, CH2C12; (b) LDA, then CF3-X; (c) NaOH, H2O, EtOH; (d) DPP A, Et3N, toluene, then BnOH; (e) H2, PάVC, EtOH.
Commercially-available ethyl isonipecotate (1-1) reacts with an appropriate acylating agent, preferably di-tert-butyl dicarbonate, to afford the protected derivative 1-2. Typical solvents for this reaction include CH2CI2, THF, or DMF. The protecting group for the amine must be compatible with subsequent chemistry, and must be readily removable when desired. Methods for the protection of amines are well-known to those of skill in the art, and are described in standard reference volumes, such as Greene "Protective Groups in Organic Synthesis" (published by Wiley-Interscience). Alkylation of 1-2 can be accomplished by reaction with an appropriate base, typically LDA or LiN(TMS)2, in an aprotic solvent, usually THF or DME, followed by trapping of the enolate with an appropriate electrophile, to afford 1-3. Trifluoromethyl iodide (CF31) or S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate are typically preferred as electrophilic trifluoromethylating reagents. 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. 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, generally triethylamine or diisopropylethylamine (Hunig's 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.
R3 2-CF3 may be introduced by the following scheme JJ:
Scheme II
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
7
(a) l-methoxy-3-(trimethylsilyloxy)-l,3-butadiene, ZnCl2, CH3CN; (b) separate diastereomers; (c) L-Selectride® (lithium tri-sec-butylborohydride), THF then pyridinium dichromate, CH2CI as necessary; (d) NH2OCH3,jp-TsOH, toluene; or NH2OCH3, NaOAc, EtOH; (e) L1AIH4, THF; or Al-Ni, 2N NaOH, EtOH; (f) (Boc)2O, CH2Cl2 or THF or DMF; (g) H2, Pd/C, EtOH.
hnine II-l, prepared in standard fashion by acid-catalyzed reaction of trifluoroacetaldehyde ethyl hemiacetal and (i?)-(+)-α-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 ZnCP). Diastereomers are best separated at this point. The enone II-2 is reduced to the corresponding ketone or alcohol II-3 by reaction with L-Selectride® (lithium tή-sec- butylborohydride) in a suitable solvent, generally THF or DME, followed as necessary by subsequent oxidation of the alcohol to the ketone under standard conditions (pyridinium dichromate) and the ketone is converted to an oxime derivative under standard conditions well-known to those of skill in the art by reaction with O-methylhydroxylamine under standard conditions. Reduction of the oxime derivative under standard conditions (L1AIH4 or according to the general method of Staskun and Nan Es (J. Chem. Soc. C 1966, 531)) 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 11-6. Typical solvents for this reaction include CH2CI2, THF, or DMF. The protecting group for the amine must be compatible with subsequent chemistry, and must be readily removable when desired. Methods for the protection of amines are well-known to those of skill in the art, and are described in standard reference volumes, such as Greene "Protective Groups in Organic Synthesis" (published by Wiley-Interscience). The α-methylbenzyl group of II-6 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 II-7.
R3 3-CF3 may be introduced by the following scheme HI:
Scheme HI
Figure imgf000022_0001
Figure imgf000022_0002
(a) TMSC1, Et3N, DMF; (b) CF3-X, DMF; (c) (i?)-(+)-α-methylbenzylamine,jp-TsOH, toluene; (d) NaBH , EtOH; (e) separate diastereomers; (f) H2, Pd/C, EtOH.
The commercially-available ketone III-l is converted to the corresponding silyl enol ether III-2 by reaction with a silylating reagent, such a trimethylsilyl chloride or trimethylsilyl triflate, in the presence of an amine base, typically triethylamine, in a suitable solvent, such as diethyl ether, THF, DMF, or mixtures thereof. The silyl enol ether III-2 reacts with an electrophilic trifluoromethylating reagent, such as trifluoromethyl iodide (CF31) or more preferably S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (see Jet. ett. 1990, 31, 3579-3582)), in an appropriate solvent, such as THF, DMF, or mixtures thereof, to afford the α-trifluoromethyl ketone III-3. Ketone III-3 reacts with a chiral amine, for instance (i?)-(+)-α-methylbenzylamine, under standard acidic catalysis, to afford the imine derivative III-4, which can be reduced to afford amine III-5. This type of reduction is typically conducted using sodium borohydride, sodium cyanoborohydride or sodium (triacetoxy)borohydride, in an appropriate solvent, such as EtOH, MeOH, THF, CH2CI2, CICH2CH2CI, or mixtures thereof. Diastereomers are best separated at this point. The α-methylbenzyl group of III- 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 III-6.
R3 2-oxo may be introduced by the following scheme IN:
Scheme IN
Figure imgf000023_0001
Figure imgf000023_0002
(a) NaH, THF, 0 °C to RT; (b) 10% Pd/C, H2, MeOH.
(i?,S)-4-(Dibenzylamino)piperidin-2-one (IV-2, Homo-Freidinger Lactam, prepared from (R,S)-aspartic acid according to the procedure of Weber and Gmeiner,
Synlett, 1998, 885-887) reacts with an appropriate epoxide, for instance 6-methoxy-4-(i?)- oxiranylquinoline (VT-1) or 6-methoxy-4-(-z-)-oxiranyl-[l,5]naρhthyridine, to afford the adduct IV-3. 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. 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.
R3 3-F may be introduced by the following scheme N:
Scheme N
Figure imgf000024_0001
Figure imgf000024_0002
(a) TMSC1, Et3N, DMF, 80 °C; (b) Selectflour, CH3CN; (c) benzylamine, 1,2- dichloroethane, Na(OAc)3BH; (d) separate diastereomers; (e) 10% Pd/C, H2, HCl, EtOH.
The trimethylsilyl enol ether (V-2), prepared from commercially-available N-(tert- butoxycarbonyl)piperidone (V-l) as described in Scheme HI, reacts with an electrophilic fluorinating reagent, preferably Selectfluor (l-chloromethyl-4-fluoro-l,4- diazabicyclo[2.2.2]octane bis(tetrafluoroborate), in a neutral solvent such as CH3CN, to afford the α-fluoro ketone V-3. Reductive amination of V-3 with benzylamine according to the procedures described in Schemes I and HI gives the expected 4-aminobenzyl-3- fluoro-N-(tert-butoxycarbonyl)piperidine derivatives V-4 and V-5 as a mixture of cis- and tr ws-isomers in an 8:1 ratio. These diastereomers are separable by chromatography on silica gel. The predominate cts-mixture of enantiomers is debenzylated by catalytic hydrogenation as described in Scheme H, to give the amino derivative V-6.
Other functional groups in R3 may be obtained by conventional conversions of hydroxy, carboxy or cyano groups.
Texrazoles 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 andJ. Med. Chem, 1996, 39 (11). 2219).
The 3-hydroxy-3-cyclobutene-l,2-dion-4-yl group (e.g. R.M. Soil, Bioorg. Med. Chem. Lett, 1993, 3{4), 757 and W.A. Kinney, J. Med. Chem., 1992, 35(25), 4720) can be prepared by the following sequence:- (1) a group (CH2)nCHO (n = 0,1,2) is treated with triethylamine, carbon tetrabromide-triphenylphosphine to give initially (CH2)nCH=CHBr; (2) dehydrobromination of this intermediate to give the corresponding bromoethyne derivative (CH2)nC≡CBr (for this 2 stage sequence see D. Grandjean et al, Tetrahedron Lett, 1994, 35(21), 3529); (3) palladium-catalysed coupling of the bromoethyne with 4-(l-methylethoxy)-3-(tri-n-butylstannyl)cyclobut-3-ene-l,2-dione (Liebeskind et al, J. Org. Chem., 1990, 55, 5359); (4) reduction of the ethyne moiety to - CH2CH2- under standard conditions of hydrogen and palladium on charcoal catalysis(see Howard et al, Tetrahedron, 1980, 36, 171); and finally (4) acidic hydrolysis of the methyl ethoxyester to generate the corresponding 3-hydroxy-3-cyclobutene-l,2-dione group (R.M. Soil, Bioorg. Med. Chem. Lett, 1993, 3{4), 757).
The tetrazol-5-ylaminocarbonyl group may be prepared from the corresponding carboxylic acid and 2-aminotetrazole by dehydration with standard peptide coupling agents such as l,l'-carbonyldiimidazole (P.L. Ornstein et al, J. Med Chem, 1996, 39(11), 2232). The alkyl- and alkenyl-sulphonylcarboxamides are similarly prepared from the corresponding carboxylic acid and the alkyl- or alkenyl-sulphonamide by dehydration with standard peptide coupling agents such as l,r-carbonyldiimidazole (P.L. Ornstein et al, J. Med. Chem., 1996, 39(11), 2232).
The hydroxamic acid groups are prepared from the corresponding acids by standard amide coupling reactions e.g. N.R. Patel et al, Tetrahedron, 1987, 43(22), 5375.
2,4-Thiazolidinedione groups may prepared from the aldehydes by condensation with 2,4-thiazolidinedione and subsequent removal of the olefinic 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. Polya in "Comprehensive Heterocyclic Chemistry" Edition 1, ρ762, Ed A.R. Katritzky and C.W. Rees, Pergamon Press, Oxford, 1984 and j.j. Ares et al, J. Heterocyclic Chem., 1991, 28(5), 1197).
Other substituents on R3 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 a hydroxymethyl group by reduction of an ester of this acid with a suitable reducing agent such as L1AIH4. An NH2 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, alkylation with an alkyl halide R^CH2-halide in the presence of base, acylation/reduction with an acyl derivative R^COW or reductive alkylation with an aldehyde R^CHO. Where one of R3 and R^, R7, R8 or R9 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 (IN) and the piperidine moiety or in the presence of standard peptide coupling agents. It will be appreciated that under certain circumstances interconvertions may interfere, for example, A or B hydroxy groups in A or B and the piperidine substituent ΝH2 will require protection e.g. as a carboxy- or silyl-ester group for hydroxy and as an acyl derivative for piperidine NH2, during conversion of R1', R2', R3' or R4', or during the coupling of the compounds of formulae (IN) and (N). Compounds of formulae (IN) and (N) are known compounds, (see for example
Smith et al, J. Amer. Chem. Soc, 1946, 68, 1301) or prepared analogously.
Compounds of formula (IN) where X is CR°R7SO2W maybe prepared by a route analogous to that of Ahmed El Hadri et al, J. Heterocyclic Chem., 1993, 30(3), 631. Thus compounds of formula (IN) where X is CH2SO2OH may be prepared by reacting the corresponding 4-methyl compound with Ν-bromosuccinimide, followed by treatment with sodium sulfite. The leaving group W may be converted to another leaving group W, e.g. a halogen group, by conventional methods.
The isocyanate of formula (IN) maybe 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)]. The 4-amino derivatives are commercially available or may be prepared by conventional procedures from a corresponding 4-chloro or 4-trifluoromethanesulphonate 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 (IN) 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 (IN) 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 (POCl3) or phosphorus pentachloride, PC15. A 4-chloroquinazoline is prepared from the corresponding quinazolin-4-one by reaction with phosphorus oxychloride (POCl3) or phosphorus pentachloride, PC15. 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.
Activated carboxy derivatives X=A'COW of formula (IN) maybe prepared from X=A'CO2H derivatives in turn prepared from CO2H derivatives by conventional methods such as homologation.
4-Carboxy derivatives of compounds of formula (IN) are commercially available or may be prepared by conventional procedures for preparation of carboxy heteroaromatics well known to those skilled in the art. For example, quinazolines may be prepared by standard routes as described by T.A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R.C. Elderfield. These 4-carboxy derivatives maybe activated by conventional means, e.g. by conversion to an acyl halide or anhydride. 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 Comprehensive Heterocyclic Chemistry, Volume 2, Ed A.J. Boulton and A. McKillop. A 4-oxirane derivative of compounds of formula (IV) 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.
Alternatively and preferably, 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 the art. For example, 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. (Alternatively, the same 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. For example, 5 -amino-2-methoxy pyridine can be converted to 4-hydroxy-6-methoxy-[l,5]naphthyridine using this method.
If a chiral reducing agent such as (+) or (-)-B-chlorodiisopinocamphenylborane ['DlP-chloride'] is substituted for sodium borohydride, the prochiral chloromethylketone is converted into the chiral chlorohydrin with ee values generally 85-95% [see C. Bolm et al, Chem. Ber. 125, 1169-1190, (1992)]. Recrystallisation of the chiral epoxide gives material in the mother liquor with enhanced optical purity (typically ee 95%).
The (i? -epoxide, when reacted with a piperidine derivative gives ethanolamine compounds as single diastereomers with (R)-stereochemistry at the benzylic position.
Alternatively, the epoxide maybe 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]naphthyridine 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. Similarly, 6-methoxy-l,5-naphthyridine derivatives can be prepared from 3- ammo-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)]. For example, a 2-aminoacetopheneone 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.
For compounds of formula (V), suitable amines may be prepared from the corresponding 4-substituted piperidine acid or alcohol. In a first instance, 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. For example, an acid substituted N-protected piperidine can undergo a Curtius rearrangement e.g. on treatment with diphenylphosphoryl azide and heating, and the intermediate isocyanate reacts in the presence of 2-trimethylsilylethanol to give the trimethylsilylethylcarbamate (T.L. Capson & CD. Poulter, Tetrahedron Lett, 1984, 25, 3515). This undergoes cleavage on treatment with tetrabutylammonium fluoride to give the 4-amine substituted N-protected piperidine.
In a second instance, 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. Removal of the phthaloyl group, for example by treatment with methylhydrazine, gives the amine of formula (V).
R5CH2-halides, acyl derivative R5COW and R5SO2W or aldehydes R5CHO 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, followed by oxidation to the aldehyde with manganese (H) dioxide. The aldehydes may also be prepared from carboxylic acids in two stages by conversion to a mixed anhydride for example by reaction with isobuxyl chloroformate followed by reduction with sodium borohydride (R. j. Alabaster et al., Synthesis, 598, 1989) to give the hydroxymethyl substituted heteroaromatic or aromatic and then oxidation with a standard oxidising agent such as pyridinium dichromate or manganese (H) dioxide. Acyl derivative R^COW maybe prepared by activation of the R^-acid. R5CH2-halides such as bromides maybe prepared from the alcohol R5(HH2OH by reaction with phosphorus tribromide in DCM/triethylamine. Alternatively the aldehyde R^CHO and sulphonic acid derivative R^SO2W may be generated by treatment of the R^H heterocycle with suitable reagents. For example by formylation 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)]. Reaction of a R5H heterocycle with chlorosulphonic acid gives the sulphonic acid derivative (by methods analogous to Techer et. al., C.R.Hebd. Seances Acad. Sci. Ser.C; 270, 1601, 1970)..
R5 heterocycles are commercially available or may be prepared by conventional methods.
The amines R2'R4'NH are available commercially or prepared conventionally. For example amines
Figure imgf000030_0001
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 Rla', R1', R2', R3' 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.
Further details for the preparation of compounds of formula (I) are found in the examples.
The compounds of formula (I) maybe 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.
Thus according to a further aspect of the invention there is provided 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. The pharmaceutical compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.
The composition may be formulated for administration by any route. The compositions may be 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.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, 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. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The 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 mg/kg per day. Suitably 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 β-lactam then a β-lactamase inhibitor may also be employed.
Compounds of formula (I) are active against a wide range of organisms including both Gram-negative and Gram-positive organisms.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The following examples illustrate the preparation of certain compounds of formula (I) and the activity of certain compounds of formula (I) against various bacterial organisms. EXAMPLES
Example 1. Preparation of 6-[({(3S,4i?)-3-fluoro-l-[(i?)-2-hydroxy-2-(6- methoxyquinolin-4-yl)-ethyl]piperidin-4-ylamino}methyl)]- [l,2,3]thiadiazolo[5,4- b]pyridine an 6-[({(3i<:,4S)-3-fluoro-l-[(JR)-2-hydroxy-2-(6-methoxyquinolin-4-yl) ethyl]piperidin-4-ylamino } methyl)] - [ 1 ,2,3 ] thiadiazolo [5 ,4-b]pyridine
Figure imgf000033_0001
Method A
(a) (3R, 4S) and (3S, 4i?)-4-Amino-l-tert-butoxycarbonyl-3-fluoropiperidine To a solution of the enantiomeric mixture of cw-4-benzylamino-l-tert- butoxycarbonyl-3-fluoropiperidine (prepared according to the procedures of J. Med.
Chem. 1999, 42, 2087-2104, 1.0 g, 3.2 mmole) in EtOH (40 mL) was added 3 N HCl (2.5 mL) and 10 % Pd/C (50 mg). The reaction was shaken under H2 (40 psi) on a Parr hydrogenator apparatus for 14 h, then was filtered through celite® filter medium. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3) to afford the title compound (370 mg, 53%) as a white solid: MS (ES) m/e 219 (M + H)+.
(b) [ 1 ,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxaldehyde
Figure imgf000033_0002
(i) 5-Amino-6-thioxo-l,6-dihydro-pyridine-3-carboxylic acid methyl ester
A mixture of sodium sulfide nonahydrate (2.17g) and sulfur (0.29g) was heated in boiling water (20mL) until the solution was homogeneous and added to a solution of 6- chloro-5-nitro-nicotinic acid methyl ester [prepared as described by A.H. Berrie et al. J. Chem. Soc. 2590 -2594 (1951)] (3.10g) in methanol (50mL). The mixture was boiled for 15 minutes and cooled. The resulting disulfide was collected and washed with water to give a yellow solid (2.46g). The solid (5g) in acetic acid (lOOmL) and 4M HCl in dioxan (50mL) was treated with zinc dust (12g) and the mixture was stirred at room temperature for 30 minutes, filtered and evaporated to dryness. Sodium acetate and sodium sulfate were added and the mixture was extracted with warm chloroform and chromatographed on silica gel, eluting with chloroform then methanol-chloroform to afford a yellow solid (2.3g). MS (+ve ion electrospray) m/z 185(MH+)
(ii) [l,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxylic acid methyl ester
The amine (i) (1.3 g) was suspended in 0.5 M hydrochloric acid (200mL) and cooled to -3°C. A solution of sodium nitrite (487 mg) in water (3 mL) was added dropwise over 10 minutes and the mixture was stirred for 2 hours when the solid product was collected and chromatographed on silica gel (chloroform) to afford a solid (0.90g)
MS (+ve ion electrospray) m/z 196 (MH+)
(iii) [l,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxylic acid The ester (ii) (0.94g) was hydrolysed with aqueous sodium hydroxide in tetrahydrofuran to afford a solid (0.84g).
MS (-ve ion electrospray) m/z 180 (M-H").
(iv) [ 1 ,2,3]Thiadiazolo[5,4-b]pyridin-6-yl-methanol
The carboxylic acid (iii) (0.82g) was reacted with wobutylchloroformate and sodium borohydride to afford a semi-solid (0.12g), after chromatography on silica gel (chloroform).
(v) [l,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxaldehyde
The alcohol (iv) (0.10 g) was oxidised with manganese dioxide to afford a solid
(51 mg).
MS (+ve ion electrospray in methanol) m/z 198 (MH+ for methanol adduct)
(c) (3R,42S) and (3S,4i? )-3-Fluoro-4-[([l,2,3]thiadiazolo[5,4-b]pyridine-6-ylmethyl)- amino]-piperidine
A solution of ct5-4-amino-l-tert-butoxycarbonyl-3-fluoropiperidine (la) (1.00 mmole) in CH2CI2 (5 mL) and EtOH (0.5 mL) is treated with anhydrous Na2SO4 (280 mg) and [l,2,3]thiadiazolo[5,4-b]pyridine-6-carboxaldehyde (lb) (1.10 mmole). The resulting solution is stirred at room temperature, then sodium triacetoxy borohydride (320 mg, 1.50 mmole) is added. The mixture is quenched by the addition of water (2 mL) and the volatiles removed in vacua. Purification gives the desired compound.
(d) 6-Methoxyquinoline-4-carboxylic acid
The title compound was prepared by modification of the procedure described by W.E. Doering and J.D. Chanley, J. Amer. Chem. Soc, 1946, 68, 586. A mixture of quinone (derived from quinine by reaction with potassium tert-butoxide and benzophenone in toluene) (225g, 0.70 mol), tert-butanol (1 litre) and water (10 ml) was treated with potassium tert-butoxide (170g, 1.5 mol). The mixture was stirred at 30°C, while air was bubbled through for 3 days. The mixture was diluted with diethyl ether and water and the layers separated. The aqueous phase was extracted with ethyl acetate. The combined diethyl ether and ethyl acetate extracts were dried over magnesium sulfate and evaporated to give recovered starting material (approximately lOOg). The aqueous phase was acidified to pH5 with 5M hydrochloric acid. The precipitate was collected by filtration, washed with water and methanol, then dried to give 6-methoxyquinoline-4- carboxylic acid as a yellow solid (64.6g, 46% ).
1H NMR δH (d-6 DMSO) 6.23-5.95 (IH, m), 5.34-5.06 (2H, m), 3.37-2.92 (5H, m), 2.70 (IH, m), 2.38-2.15 (3H, m), 1.94-1.52 (2H, m)
(e) [R] -2-(6-Methoxyquinolin-4-yl)oxirane A solution of 6-methoxyquinoline-4-carboxylic acid ( 1 d) ( 1 Og) in dichloromethane was heated under reflux with oxalyl chloride (5ml) and dimethylformamide (2 drops) for 1 hour and evaporated to dryness. The residue, in dichloromethane (100ml) was treated with a 2M solution of trimethylsilyldiazomethane in hexane (50ml) and stirred at room temperature for 18 hours. 5M Hydrochloric acid (150ml) was added and the solution was stirred at room temperature for 3 hours. It was basified with sodium carbonate solution, extracted with ethyl acetate and chromatographed on silica gel eluting with ethyl acetate-hexane to give the chloromethyl ketone (4.2g). A batch of the chloromethyl ketone (20g) was reduced with (+)-B- chlorodiisopinocamphenylborane (40g) in dichloromethane (400ml) at room temperature for 18 hours followed by treatment with diethanolamme (30 g) for 3 hours. The product was chromatographed on silica gel eluting with ethyl acetate-hexane to give the chloroalcohol (16.8g), which was dissolved in tetrahydrofuran (100 ml) and reacted with sodium hydroxide (2.6g) in water (13ml) for 1.5 hours. The reaction mixture was evaporated to dryness and chromatographed on silica gel eluting with ethyl acetate - hexane to give the title compound as a solid (10.4 g) (84% ee by chiral HPLC). Recrystallisation from ether-pentane gave mother-liquor (7.0 g) (90% ee). MS (+ve ion electrospray) m/z 202 (MH+)
The absolute stereochemistry was defined to be (R) by an NMR study on the Mosher's esters derived from the product obtained by reaction with 1-t-butylpiperazine.
(f) Title compounds
To an enantiomeric mixture of 3-fluoro-4-[([l,2,3]thiadiazolo[5,4-b]pyridine-6- ylmethyl)-amino]-ρiρeridine (lc) (0.33 mmole) in DMF (2 mL) is added LiClθ4 (0.33 mmole), K2CO3 (0.66 mmole), and 6-methoxy-4-(i?)-oxiranylquinoline (0.33 mmole). The reaction is heated at 90 °C for 18 h, cooled to RT and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and H2O, and the layers are separated. The aqueous phase is further extracted with ethyl acetate, and the combined organic extracts are dried over MgSO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel to give the title compounds.
Method B (g) (3R, 4S) and (3S, 4i-)-4-Benzyloxycarbonylamino-3-fluoropiperidine
(3R, 4S) and (3S, 4R)-4-Benzylamino-l-tert-butoxycarbonyl-3-fluoropiperidine [see (la)] (10.0 g) in methanol (200 mL) was hydrogenated over 20% palladium hydroxide on carbon (2.5 g) at 30psi for 7 h, then filtered through Celite and evaporated. The crude amine (7.49 g) in DCM (150 mL) and triethylamine (3.5 mL) was treated with benzyl chloroformate (4.0 mL) and the mixture stirred vigorously for 5 h.The organic phase was separated, dried, and evaporated. The product (4.27 g) was dissolved in DCM (40 mL) and stirred with TFA (8 mL) for 4h then evaporated. The residue was basified with sodium carbonate solution, extracted with 10% methanol in DCM and the extracts dried and evaporated to give a white solid (2.92 g).
(h) (R)-2-(3i?, 4S)-(4- Amino-3-fluoropiperidin- 1 -yl)- 1 -(6-methoxyquinolin-4-yl)-ethanol and (R)-2-(3S, 4R)- (4-Amino-3-fluoropiperidin-l-yl)-l-(6-methoxyquinolin-4-yl)- ethanol
The piperidine (lg) (0.63 g) and 6-methoxy-4-(R)-oxiranylquinoline (le) (0.5 g) were heated together at 85°C for 3 h, ,then allowed to cool, and the product purified on silica gel (methanol-DCM). The material obtained (0.77 g) was dissolved in ethanol (30 mL) and hydrogenated with 10% Pd/C (0.35 g) for 5h, then filtered through Celite® and evaporated to give a yellow foam (0.459 g) MS (ES) m/z 320 (M + H)+. MS (APCI-) m/z 195 ([M-H]", 50%), 165(100%)
(i) Title compounds
[l,2,3]Thiadiazolo[5,4-b]pyridin-6-yl-methanol (lb)(iv) (30 mg) in dry THF (2 mL) was treated with triethylamine (0.025 mL) and methanesulfonyl chloride (0.014 mL) to form the mesylate. After 1.5h the mixture was diluted with DMF (2 mL) and potassium carbonate (25 mg) was added followed by the amino-piperidine (lh) ((63 mg) and the mixture was stirred at room temperature for 4h, then evaporated to dryness. The residue was chromatographed on silica gel (methanol-DCM) to give the free base of the title compound (30 mg) as a 1:1 mixture of isomers. MS (ES) m/z 469 (M + H)+.
1HNMR 5H (CDC13, 250MHz), 1.80-2.05 (2H, m), 2.28-3.00 (5.5H, m), 3.15-3.30 (IH, m), 3.50 (0.5H, m), 3.91 (3H, s), 4.18 (3H, s and m), 4.90 (IH, d), 5.45 (IH, m), 7.16 (IH, s), 7.38 (IH, dd), 7.62 (IH, t), 8.05 (IH, d), 8.78 (IH, d), 8.88 (IH, d), 8.96 (IH, d). This material, as a solution in chloroform/methanol, was treated with an excess of 4M HCl in dioxan and evaporated to dryness. The solid was triturated under ether, filtered and dried under vacuum to provide the title compound as the hydrochloride salt.
Example 2. Preparation of 5-[({(3S,4i?)-3-fluoro-l-[(i-)-2-hydroxy-2-(6- methoxyquinolin-4-yl)-ethyl]piperidin-4-ylamino}methyl)]- benzo[l,2,3]thiadiazole and 5-[( {(3R,4SI)-3-fhxoro- 1 -[(i2)-2-hydroxy-2-(6-methoxyquinolin-4-yl)-ethyl]piperidin-4- ylamino} methyl)]- benzo[ 1 ,2,3]thiadiazole
Figure imgf000037_0001
(a) Benzo[ 1 ,2,3]thiadiazole-5-carboxaldehyde
Methyl benzo[l,2,3]thiadiazole-5-carboxylate (0.291g) in THF (2ml) was treated dropwise with lithium aluminium hydride (1M in THF, 0.71ml) at 0 °C. After 1.5h, additional lithium aluminium hydride (0.1ml) was added. After 0.5h the mixture was treated with 8% sodium hydroxide, ethyl acetate and sodium sulphate, filtered and evaporated. The resulting crude alcohol was dissolved in dichloromethane (3ml) and stirred with manganese (H) oxide overnight. Filtration and evaporation of solvent gave the aldehyde .
(b) Title compounds
These were prepared from amine (lh) (0.054 g) and aldehyde (2a) (0.028 g) in
DMF (5 ml) with sodium triacetoxyborohydride (0.16 g) at room temperature for 4.5 hr.
The reaction mixture was quenched with dilute HCl, basified with sodium carbonate and evaporated. The residue was diluted with water and extracted with 10% methanol in chloroform, dried (sodium sulfate), evaporated and chromatographed on silica gel
(methanol-DCM) to afford the title compound as the free base (9 mg).
LC/MS (ES) m/z 468 (M + H)+.
1H NMR δH (CDC13, 400MHz), 1.70-2.00 (2H, m), 2.20-3.60 (7H, m), 3.93 (3H, s), 4.14 (2H, s), 4.30 (IH, br s), 4.89 (IH, dd), 5.43 (IH, m), 7.19 (IH, s), 7.63 (IH, m), 7.75 (IH, dd), 8.04 (2H, m), 8.62 (IH, s), 8.76 (IH, d). This material, as a solution in chloroform/methanol, was treated with an excess of 4M HCl in dioxan and evaporated to dryness. The solid was triturated under ether, filtered and dried under vacuum to provide the title compound as the hydrochloride salt.
Example 3. Preparation of {3-Fluoro-l-[(R)-2-hydroxy-2-(6-methoxy-
[l,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-[l,2,3]thiadiazolo[5,4-b]pyridin-6- ylmethyl-amine Diastereoisomer 1 Dihydrochloride
Figure imgf000038_0001
(a) 4-Hydroxy-6-methoxy-[l,5]-naphthyridine
5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methyl propiolate (40ml, 0.44mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6g, 48%). The unsaturated ester (10.5g, 0.05mol) in warm Dowtherm A (50ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give a solid (6.26g, 70%) (b) Bromomethyl-(6-methoxy-[ 1 ,5]-naphthyridin-4-yl)-ketone
The naphthyridine (3a) (10 g, 0.057mol) in dichloromethane (200 ml) containing 2,6-lutidine (9.94 ml, 0.086mol) and 4-dimethylaminopyridine (0.07 g, 0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5 ml, 0.063mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica (dichloromethane). The triflate (13.2 g, 0.044mol) in DMF (200 ml) with triethylamine (12 ml, 0.086mol) butyl vinyl ether (22 ml, 0.17mol), palladium (H) acetate (0.97 g, 0.0044mol) and 1,3- bis(diphenylphosphino)propane (1.77 g, 0.0044mol) was heated at 60°C for 3 hours then evaporated and chromatographed on silica gel (dichloromethane) to give a yellow solid (10.7 g, 95%). This was dissolved in THF (250 ml) and water (40 ml) and treated with N-bromosuccinimide (7.4 g, 0.042 mol) for 1 hour, then evaporated and chromatographed on silica gel (dichloromethane) to give the ketone (10.42 g, 98%). (c) (R)-2-Bromo-l-(6-methoxy-[l,5]-naphthyridin-4-yl)ethanol
The ketone (3b) (6.6 g, 0.023mol) in toluene was treated with (+)-B- chlorodiisopinocamphenylborane ((+)-DIP-chloride) (12 g, 0.037mol) and stirred overnight, then diethanolamme (15 g, 0.14mol) was added and the mixture stirred for 3 hours, filtered and evaporated. Chromatography on silica gel (ethyl acetate-hexane )gave a white solid (4.73 g, 73%).
(d) (R)-2-(6-Methoxy-[l,5]-naphthyridin-4-yl)oxirane
The alcohol (3c) (4.8 g, 0.017mol) in methanol (20ml) was stirred with potassium carbonate (2.6 g, 0.019 mol) for 1 hour, then evaporated and chromatographed on silica gel (ethyl acetate-hexane-dichloromethane) to give a solid (3.14 g, 92%), (Batches typically >90% ee by chiral HPLC). MS (+ve ion electrospray) m/z 203 (MH+). (e) ct5-4-Benzylamino-l-tert-butoxycarbonyl-3-fluoropiperidine 4-Benzylamino-l-tert-butoxycarbonyl-3-fluoropiperidine was prepared according to the procedures of J. Med. Chem. 1999, 42, 2087-2104 as a mixture of isomers (approx 8:1 cis:trans, 29.8g, 0.096mole). The mixture was dissolved in DCM, extracted with 0.2M HCl, basified with Na2CO3 solution, extracted with DCM and chromatographed on silica gel to give the czs-isomer in the later fractions (15.6 g, 52%). Combined batches (32g, 0.103 mole) were separated by preparative HPLC on a Chiralpak AD column eluting with hexane: ethanol (9:1) to give faster running enantiomer [Enantiomer 1] (15.0 g, 47%, 99%ee) [ ]D +40.5° and slower running enantiomer [Enantiomer 2] (15. Og, 47%, 97%ee) [α]D -39.5°. (f) 4-Benzyloxycarbonylamino-3-fluoropiperidine Enantiomer 1 cώ-(+)-4-Benzylamino-l-tert-butoxycarbonyl-3-fluoropiperidine [(3e);
Enantiomer 1] (15. Og, 0.049mole) in ethanol (300ml) was hydrogenated over 20% palladium hydroxide on carbon (4 g) at 30psi for 5 h, then filtered through Celite® and evaporated. The crude amine was dissolved in ethyl acetate (100 mL), saturated sodium hydrogen carbonate solution (100 mL) was added followed by benzyl chloroformate (7.6 mL, 0.53mole)and the mixture stirred vigorously for 4 h. The organic phase was separated dried and evaporated. The product was dissolved in DCM (75 mL) and stirred with TFA (20 mL) for 4h then evaporated. The residue was basified with sodium carbonate solution, extracted with 10% methanol in DCM and the extracts dried and evaporated to give a white solid (12.1g, 98%), [α]D +61.1° (MeOH). (g) (R)-2-(4-Amino-3-fluoropiperidin- 1 -yl)- l-(6-methoxy-[ 1 ,5]naphthyridin-4-yl)-ethanol
Diastereoisomer 1
4-Benzyloxycarbonylamino-3-fluoropiperidine Enantiomer 1 (3f) (2.49 g) and
(R)-2-(6-Methoxy-[l,5]-naphthyridin-4-yl)oxirane (3d) (100% ee) (2.0 g) were heated together at 80-88°C for 2.5 h with 2 drops of DMF, then allowed to cool, and the product purified on silica gel (methanol-DCM) to give a solid (3.88 g). The material was dissolved in ethanol (40 mL), 1,4-cyclohexadiene (7.7 mL) was added and the solution was stirred at room temperature with 10% Pd/C (3.5 g) for 2h, then filtered through
Celite® and evaporated to give a foam (2.53 g).
LC/MS (ES) m/z 321 (M + H)+.
(h) Title compound The free base of the title compound was prepared from amine (3g) and
[l,2,3]thiadiazolo[5,4-b]pyridin-6-yl-methanol (lb)(iv) by the method of Example (li)
(41%).
LC/MS (ES) m/z 470 (M + H)+.
1H NMR δH (CDC13, 250MHz), 1.85-2.00 (2H, m), 2.28-3.00 (4H, m), 3.15 (IH, dd), 3.52 (IH, m), 4.02 (3H, s), 4.17 (2H, s), 4.30 (IH, br s), 4.90 (IH, d), 5.70 (IH, m), 7.12
(IH, d), 7.80 (IH, d), 8.23 (IH, d), 8.78 (IH, d), 8.88 (IH, d), 8.96 (IH, d).
This material, as a solution in chloroform/methanol, was treated with an excess of 4M
HCl in dioxan and evaporated to dryness. The solid was triturated under ether, filtered and dried under vacuum to provide the title compound.
DCM = dichloromethane
DMF = dimethylformamide
THF = tetrahydrofuran
Biological Activity
The MIC (μg/ml) of test compounds against various organisms maybe determined: S. epidermidis CL7 , S. aureus WCUH29, S. pneumoniae 1629, S. pyogenes CN10, H. influenzae ATCC49247, E.faecalis 2, E. faecium 8, M. catarrhalis Ravisio, E, coli
7623.
Compounds of Examples 1 and 3 have MIC's in the range 0.06-16μg/ml versus all of these organisms.

Claims

Claims
1. a compound of formula (I) or a pharmaceutically acceptable derivative thereof:
Figure imgf000041_0001
(0 wherein:
one of Z1, Z2, Z3, Z4 and Z^ is N, one is CRla and the remainder are CH , or one or two of Z1, Z2, Z3, Z4 and Z^ are independently CRla and the remainder are CH;
R1 and Rla are independently hydrogen; hydroxy; (Cχ_6)alkoxy optionally substituted by (Cχ_6)alkoxy, amino, piperidyl, guanidino or amidino any of which is optionally N- substituted by one or two (Cχ_6)alkyl, acyl or (Cχ_6)alkylsulphonyl groups, CONH2, hydroxy, (Cχ_6)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (Cχ_6)alkylsulphonyloxy; (Cχ.6)alkoxy-substituted(Cχ_6)alkyl; halogen; (Cχ_ g)alkyl; (Cχ_6)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (Cχ_6)alkylsulphonyl; (Cχ_6)aιkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (Cχ_6)alkyl, acyl or (Cχ_6)alkylsulphonyl groups;
or when Z^ is CRla, Rla may instead be cyano, hydroxymethyl or carboxy;
or R1 and Rla on adjacent positions may together form ethylenedioxy;
provided that when Z1, Z2, Z3, Z4 and Z5 are CRl a or CH, then R1 is not hydrogen;
R2 is hydrogen, or (Cχ_4)alkyl or (C2_4)alkenyl optionally substituted with 1 to 3 groups selected from: amino optionally substituted by one or two (Cχ_4)alkyl groups; carboxy; (C _ 4)alkoxycarbonyl; (Cχ_4)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (C2-
4)alkenylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (Ci_4)alkyl, hydroxy(Cι_4)alkyl, aminocarbonyl(Ci_4)alkyl, (C2-4)alkenyl, (Cχ_4)alkylsulphonyl, trifluoromethylsulphonyl, (C2-4)alkenylsulphonyl, (Cχ_ 4)alkoxycarbonyl, (Cχ_4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl or (C2- 4)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R1^; 3- hydroxy-3-cyclobutene- 1 ,2-dione-4-yl; 2,4-thiazolidinedione-5-yl; tetrazol-5- ylaminocarbonyl; l,2,4-triazol-5-yl optionally substituted by R1^; 5-oxo-l,2,4-oxadiazol- 3-yl; halogen; (Cχ_4)alkylthio; trifluoromethyl; hydroxy optionally substituted by (Cχ_ 4)alkyl, (C2_4)alkenyl, (Cχ_4)alkoxycarbonyl, (Cχ_4)alkylcarbonyl, (C2- 4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl; oxo; (Cχ_4)alkylsulphonyl; (C2- 4)alkenylsulphonyl; or (Cχ_4)aminosulphonyl wherein the amino group is optionally substituted by (Cχ_4)alkyl or (C2-4)alkenyl;
R3 is in the 2-, 3- or 4-position and is trifluoromethyl or is in the 2-position and is oxo; or R3 is in the 3-position and is fluorine or amino wherein the amino group is optionally substituted by: hydroxy; (Cχ_6)alkylsulphonyl; trifluoromethylsulphonyl; (C2- 6)alkenylsulphonyl; (Ci_6)alkylcarbonyl; (C2_6)alkenylcarbonyl; (Cχ_6)alkoxycarbonyl; (C2-6)alkenyloxycarbonyl; (Cι_6)alkyl; or (C2-6)alkenyl; wherein a (Cχ_6)alkyl or (C2- g)alkenyl moiety may be optionally substituted with up to 2 groups R12 independently selected from: halogen; (Cχ_6)alkylthio; trifluoromethyl; cyano; carboxy; tetrazolyl; 2-oxo- oxazolidinyl; 3-hydroxy-3-cyclobutene- 1 ,2-dione-4-yl; 2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl; l,2,4-triazol-5-yl optionally substituted by R1^; or 5-oxo- l,2,4-oxadiazol-3-yl; (Cχ_6)alkoxycarbonyl; (Cχ_6)alkylcarbonyl; (C2- 6)alkenyloxycarbonyl; (C2-6)alkenylcarbonyl; hydroxy optionally substituted by (Cχ_ 6)alkyl, (C2-6)alkenyl, (Cχ_6)alkylcarbonyl, (C2-6)alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (Cχ_6)alkyl, (C2_6)alkenyl; amino optionally mono- or disubstituted by (C _6")alkoxycarbonyl, (C \ _6)alkylcarbonyl, (C2- 6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (Cι_6)alkyl, (C2-6)alkenyl, (Cχ_ g)alkylsulphonyl, (C2-6)alkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (Cχ_6)alkyl or (C2-6)alkenyl; in addition when R3 is disubstituted with a hydroxy or amino containing substituent and carboxy containing substituent these may together form a cyclic ester or amide linkage, respectively;
R4 is a group -U-R5 where U is selected from CO, SO2 and CH2 and R5 is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (A):
Figure imgf000043_0001
containing up to four heteroatoms in each ring in which ring (a) is aromatic or non aromatic;
X1 is C when part of an aromatic ring or CR14 when part of a non aromatic ring; X2 is N, NR13, O, S(O)x, CO or CR14 when part of an aromatic or non-aromatic ring or may in addition be CR^R1 when part of a non aromatic ring; X4 is N, NR13, O, S(O)x, CO or CR14; X3 and χ5 are independently N or C;
Y1 is a 1 to 3 atom linker group each atom of which is independently selected from N, NR13, O, S(O)x, CO and CR14 when part of an aromatic or non-aromatic ring or may additionally be CR 4R15 when part of a non aromatic ring,
Y2 is a 2 or 3 atom linker group completing an aromatic ring, each atom of Y2 being independently selected from N, NR13, O, S(O)x, CO and CR14; each of R14 and R!5 is independently selected from: H; (Cχ_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; (Cχ_4)alkyιcarbonyl; (C2_4)alkenyloxycarbonyl; (C2- 4)alkenylcarbonyl; (Cχ_4)alkylcarbonyloxy; (Cι_4)alkoxycarbonyl(Cι_4)alkyl; hydroxy; hydroxy(Cχ_4)alkyl; mercapto(Cχ_4)alkyl; (Cχ_4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (Cχ_ 4)alkylsulphonyl; (C2_4)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally mono- or di-substituted by (Cχ_4)alkyl or (C2-4)alkenyl; aryl; aryl(Cχ_4)alkyl; aryl(C \ _4)alkoxy or
R14 and R! may together represent oxo; each R13 is independently H; trifluoromethyl; (Cχ_4)alkyl optionally substituted by hydroxy, (Cχ_6)alkoxy, (Cχ_6)alkylthio, carboxy, halo or trifluoromethyl; (C2-
4)alkenyl; aryl; aryl (Cχ_4)alkyl; arylcarbonyl; heteroarylcarbonyl; (Cι_4)alkoxycarbonyl; (Cχ_4)alkylcarbonyl; formyl; (Cχ_6)alkylsulphonyl; or aminocarbonyl wherein the amino group is optionally substituted by (Cι_4)alkoxycarbonyl, (Cχ_4)alkylcarbonyl, (C2- 4)alkenyloxycarbonyl, (C2_4)alkenylcarbonyl, (Cχ_4)alkyl or (C2_4)alkenyl and optionally further substituted by (C 1 _4)alkyl or (C2_4)alkenyl;
n is O or 1;
each x is independently 0, 1 or 2 A is NR1 !, O or CR6R7 and B is NR1 1, O, SO2 or CR8R9 and wherein: each of R° R7, R8 and R9 is independently selected from: hydrogen; (Cχ_6)alkoxy; (Cχ_ g)alkylthio; halo; trifluoromethyl; azido; (Cχ_6)alkyl; (C2-6)alkenyl; (Cχ_ g)alkoxycarbonyl; (Cχ_6)alkylcarbonyl; (C2_6)alkenyloxycarbonyl; (C2- 6)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (Cχ_6)alkylsulphonyl; (C2_6)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (Cχ_6)alkyl or (C2- 6)alkenyl; or when n=l R° and R8 together represent a bond and R7 and R9 are as above defined; or R6 and R7 or R8 and R9 together represent oxo;
provided that: when A is NR1 1, B is not NR1 1 or O; when A is CO, B is not CO, O or SO2; when n is 0 and A is NR1 * , CR8R9 can only be CO; when A is CR6R7 and B is SO2, n is 0; when n is 0, B is not NR11 or O or R8 and R9 are not optionally substituted hydroxy or amino; when A is O, B is not NR1 !, O, SO2 or CO and n=l; and when A-B is CR7=CR9, n is 1
R1^ is selected from (Cχ_4)alkyl; (C2_4)alkenyl and aryl any of which may be optionally substituted by a group R12 as defined above; carboxy; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (Cχ_6)alkyl, (C2-6)alkenyl, (Cχ_ g)alkylsulphonyl, trifluoromethylsulphonyl, (C2_6)alkenylsulphonyl, (Cχ_ 6)alkoxycarbonyl, (Cχ_6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2- g)alkenylcarbonyl and optionally further substituted by (Cχ_6)alkyl or (C2-6)alkenyl; (Cχ_6)alkylsulphonyl; trifluoromethylsulphonyl; (C2_6)alkenylsulphonyl; (Cχ_ 5)alkoxycarbonyl; (Cχ_6)alkylcarbonyl; (C2-6)alkenyloxycarbonyl; and (C2-. 6)alkenylcarbonyl; and
R1 1 is hydrogen; trifluoromethyl, (Cχ_6)alkyl; (C2_6)alkenyl; (Cχ_6)alkoxycarbonyl; (Cχ_6)alkylcarbonyl; or aminocarbonyl wherein the amino group is optionally substituted °y (Cι_6)alkoxycarbonyl, (Cμ6)alkylcarbonyl, (C2_6)alkenyloxycarbonyl, (C2_ 6)alkenylcarbonyl, (C 1 _6)alkyl or (C2-6)alkenyl and optionally further substituted by (C 1 _ 6)alkyl or (C2_6)alkenyl; or where one of R3 and R^, R7, R8 or R9 contains a carboxy group and the other contains a hydroxy or amino group they may together form a cyclic ester or amide linkage.
2. A compound according to claim 1 wherein z5 is CH, C-Cl or N, Z3 is CH or CF and Zl, Z2 and Z4 are each CH, or Z1 is N, Z3 is CH and Z2 and Z4 are each CH and Z5 is CH or C-Cl.
3. A compound according to any preceding claim wherein R1 is methoxy and Rla is H or when Z3 is CRla it may be C-F or when Z5 is CRla it may be C-F or C-Cl.
4. A compound according to any preceding claim wherein R2 is hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylallyl or carboxyallyl.
5. A compound according to any preceding claim wherein R3 is CF3, fluoro, oxo or amino unsubstituted or substituted by (Cχ_6)alkyl or (C2-6)alkenyl.
6. A compound according to any preceding claim wherein n is 0, A-B is CHOH- CH2, NR11-CH2, NR1 !-CO or CH2-CH2 and R11 is hydrogen or (Cι_4)alkyl.
7. A compound according to any preceding claim wherein U is CH2 and R5 is an aromatic heterocyclic ring (A) having 1-4 heteroatoms of which one is N or NR13, R1 is H if in ring (a) or in addition (Cχ_4)alkyl if in ring (b), R14 and Rl5 are independently selected from hydrogen, halo, hydroxy, (Cχ_4)alkyl, (Cχ_4)alkoxy, trifluoromethoxy, nitro, cyano, aryl(C \ _4)alkoxy and (C \ _4)alkylsulphonyl.
8. A compound according to any of claims 1 to 6 wherein R5 is 4,6-difluoro-indol-2- yl, lH-pyrrolo[2,3-b]-pyridin-2-yl, lH-pyrrolo[3,2-b]-pyridin-2-yl„ 8-hydroxy-quinolin- 2-yl, quinoxalin-2-yl, benzimidazol-2-yl, benzo[l,2,3]-thiadiazol-5-yl, benzothiophen-2- yl, 4,6-difluoro-lH-benzimidazol-2-yl, benzothiazole-5-yl, 3-(R)-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-3-yl or [l,2,3]thiadiazolo[5,4-b]pyridin-6-yl.
9. A compound according to claim 1 selected from:
6-[( {(3S,4i?)-3-fluoro- 1 -[(i-)-2-hydroxy-2-(6-methoxyquinolin-4-yl)-ethyl]piperidin-4- ylamino}methyl)]- [l,2,3]thiadiazolo[5,4-b]pyridine and 6-[({(3i?,4S)-3-fluoro-l-[(i-)-2- hydroxy-2-(6-methoxyquinolin-4-yl)-ethyl]piperidin-4-ylamino}methyl)]- [l,2,3]thiadiazolo[5,4-b]pyridine; 5-[({(3S,4i?)-3-fluoro-l-[(i?)-2-hydroxy-2-(6-methoxyquinolin-4-yl)-ethyl]piperidin-4- ylamino} methyl)]- benzo[l,2,3]thiadiazole and 5-[({(3i-,4S)-3-fluoro-l-[(i-)-2-hydroxy- 2-(6-methoxyquinolin-4-yl)-ethyl]piperidin-4-ylamino}methyl)]- benzo[l,2,3]thiadiazole; {3-Fluoro-l-[(R)-2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}- [l,2,3]thiadiazolo[5,4-b]pyridin-6-ylmethyl-amine Diastereoisomer 1; or a pharmaceutically acceptable derivative thereof.
10. 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 according to claim 1.
11. The use of a compound according to claim 1 , in the manufacture of a medicament for use in the treatment of bacterial infections in mammals.
12. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier.
13. A process for preparing compounds according to claim 1 , which process comprises:
reacting a compound of formula (IV) with a compound of formula (V):
Figure imgf000046_0001
(IV) (V)
wherein n is as defined in formula (I); Z1', Z2', Z3', Z4', Z5', R1? and R3' are zl, Z2, Z3, Z4, Z5, R! and R3 as defined in formula (I) or groups convertible thereto; Q! is NR2'R4' or a group convertible thereto wherein R2' and R4' are R2 and R4 as defined in formula (I) or groups convertible thereto and Q2 is H or R3' or Ql and Q2 together form an optionally protected oxo group; and X and Y may be the following combinations: (i) X is A'-COW, Y is H and n is 0; (ii) X is CR6=CR8R9, Y is H and n is 0; (iii) X is oxirane, Y is H and n is 0; (iv) X is N=C=O and Y is H and n is 0;
(v) one of X and Y is CO2Ry and the other is CH CO2Rx;
(vi) X is CHR6R7 and Y is C(=O)R9;
(vii) X is CR7=PRZ 3 and Y is C(=O)R9 and n=l ;
(viii) X is C(=O)R7 and Y is CR9=PRZ3 and n=l ;
(ix) Y is COW and X is NHRl 1 ' or NRI 1 'cow and n=0 or 1 or when n=l X is COW and Y is NHRl 1' orNRH'COW;
(x) X is C(O=)R6 and Y is NHR11 ' or X is NHR11 ' and Y is C(=O)R8 and n=l ;
(xi) X is NHR11 ' and Y is CR8R9W and n=l ;
(xii) X is CR6R7W and Y is NHR11 ' or OH and n=l ;
(xiii) X is CR6R7SO2W and Y is H and n=0;
(xiv) X is W or OH and Y is CH2OH and n=l ;
(xv) X is NHR11 ' and Y is SO2W or X is NR11 'SO2W and Y is H, and n=0;
(xvi) X is NR11 ?COCH2W or NR11 'SO2CH2W and Y is H and n=0;
(xvii) X is W and Y is CONHR11 ';
in which W is a leaving group, e.g. halo or imidazolyl; Rx and Ry are (Cχ_6)alkyl; Rz is aryl or (Cχ_6)alkyl; A' and NR 1' are A and NRI 1 as defined in formula (I), or groups convertible thereto; and oxirane is:
Figure imgf000047_0001
wherein R^, R8 and R9 are as defined in formula (I); and thereafter optionally or as necessary converting Q and Q2 to NR2'R4'; converting A', Zl', Z2', Z3', Z4', Z5', Rl', R2', R3', R4' and NR11' to A, Z1, Z2, Z3, Z4, ZΪ, R1, R2, R3, R4 and NR11'; converting A-B to other A-B, interconverting R1, R2, R3 and/or R4, and/or forming a pharmaceutically acceptable derivative thereof.
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Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002490A2 (en) * 2002-06-26 2004-01-08 Glaxo Group Limited Piperidine compounds as antibacterials
US6803369B1 (en) 2000-07-25 2004-10-12 Smithkline Beecham Corporation Compounds and methods for the treatment of neoplastic disease
EP1578743A2 (en) * 2002-12-18 2005-09-28 Glaxo Group Limited Antibacterial agents
WO2006081182A2 (en) 2005-01-25 2006-08-03 Glaxo Group Limited Antibacterial agents
WO2006081264A1 (en) 2005-01-25 2006-08-03 Glaxo Group Limited Antibacterial agents
US7141564B2 (en) 2001-05-25 2006-11-28 Smithkline Beecham P.L.C. Nitrogen-containing bicyclic heterocycles for use as antibacterials
US7186730B2 (en) 2001-05-25 2007-03-06 Smithkline Beecham P.L.C. Bicyclic nitrogen-containing heterocyclic derivatives for use as antibacterials
US7232832B2 (en) 2002-11-05 2007-06-19 Smithkline Beecham Corporation Antibacterial agents
WO2007071936A1 (en) * 2005-12-22 2007-06-28 Glaxo Group Limited Heterocyclic compounds, their preparation and their use as antibacterials
WO2007086016A1 (en) 2006-01-26 2007-08-02 Actelion Pharmaceuticals Ltd Tetrahydropyrane antibiotics
WO2007115947A1 (en) 2006-04-06 2007-10-18 Glaxo Group Limited Pyrrolo-quinoxalinone derivatives as antibacterials
WO2007122258A1 (en) * 2006-04-26 2007-11-01 Glaxo Group Limited Tryclic nitrogen containing compounds and their use as antibacterials
US7312212B2 (en) 2002-01-29 2007-12-25 Glaxo Group Limited Aminopiperidine derivatives
WO2008003690A1 (en) 2006-07-03 2008-01-10 Glaxo Group Limited Azatricyclic compounds and their use
WO2008009700A1 (en) 2006-07-20 2008-01-24 Glaxo Group Limited Derivatives and analogs of n-ethylquinolones and n-ethylazaquinolones
WO2007081597A3 (en) * 2005-10-21 2008-06-12 Glaxo Group Ltd Peri condensed tricyclic compounds useful as antibacterial agents
WO2008071964A1 (en) * 2006-12-15 2008-06-19 Astrazeneca Ab Naphthyridine bactericides
WO2008116815A2 (en) * 2007-03-23 2008-10-02 Glaxo Group Limited Compounds
WO2008128953A1 (en) * 2007-04-20 2008-10-30 Glaxo Group Limited Tricyclic nitrogen containing heterocycles as antibacterial agents
WO2008128962A1 (en) * 2007-04-20 2008-10-30 Glaxo Group Limited Tricyclic compounds as antibacterials
US7491714B2 (en) 2002-12-04 2009-02-17 Glaxo Group Limited Quinolines and nitrogenated derivatives thereof and their use as antibacterial agents
US7511035B2 (en) 2005-01-25 2009-03-31 Glaxo Group Limited Antibacterial agents
EP2080761A1 (en) 2008-01-18 2009-07-22 Glaxo Group Limited Compounds
US7566786B2 (en) 2003-05-21 2009-07-28 Glaxo Group Limited Quinoline derivatives as phosphodiesterase inhibitors
US7622481B2 (en) 2002-06-26 2009-11-24 Glaxo Group Limited Antibacterial compounds
US7648980B2 (en) 2005-01-25 2010-01-19 Glaxo Group Limited Antibacterial agents
US7655648B2 (en) 2004-08-02 2010-02-02 Glaxo Group Limited Antibacterial agents
US7691850B2 (en) 2004-06-15 2010-04-06 Glaxo Group Limited Antibacterial agents
WO2010043714A1 (en) 2008-10-17 2010-04-22 Glaxo Group Limited Tricyclic nitrogen compounds used as antibacterials
US7709496B2 (en) 2006-04-06 2010-05-04 Glaxo Group Limited Antibacterial agents
US7709472B2 (en) 2005-01-25 2010-05-04 Glaxo Group Limited Antibacterial agents
CN101778651A (en) * 2007-06-22 2010-07-14 葛兰素集团有限公司 Heterocyclic compounds for the treatment of tuberculosis
WO2010081874A1 (en) 2009-01-15 2010-07-22 Glaxo Group Limited Naphthyridin-2 (1 h)-one compounds useful as antibacterials
US7842810B2 (en) 2005-03-31 2010-11-30 Janssen Pharmaceutica, Nv Bicyclic pyrazole compounds as antibacterial agents
US7875715B2 (en) 2005-06-16 2011-01-25 Astrazeneca Ab Compounds for the treatment of multi-drug resistant bacterial infections
US8217042B2 (en) 2005-11-11 2012-07-10 Zentaris Gmbh Pyridopyrazines and their use as modulators of kinases
US8937068B2 (en) 2005-11-11 2015-01-20 Zentaris Gmbh Pyridopyrazine derivatives and their use
WO2016027249A1 (en) 2014-08-22 2016-02-25 Glaxosmithkline Intellectual Property Development Limited Tricyclic nitrogen containing compounds for treating neisseria gonorrhoea infection
WO2017029602A2 (en) 2015-08-16 2017-02-23 Glaxosmithkline Intellectual Property Development Limited Compounds for use in antibacterial applications
US9796704B2 (en) 2002-07-15 2017-10-24 Symphony Evolution, Inc. Substituted quinazolines as receptor-type kinase inhibitors
US9809549B2 (en) 2009-01-16 2017-11-07 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11124482B2 (en) 2003-09-26 2021-09-21 Exelixis, Inc. C-met modulators and methods of use

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0118238D0 (en) * 2001-07-26 2001-09-19 Smithkline Beecham Plc Medicaments
AU2003291227A1 (en) 2002-11-05 2004-06-07 Smithkline Beecham Corporation Antibacterial agents
US20070254872A1 (en) * 2004-07-08 2007-11-01 Glaxo Group Limited Antibacterial Agents
CA2643044A1 (en) * 2006-02-28 2007-09-07 Amgen Inc. Cinnoline and quinazoline derivates as phosphodiesterase 10 inhibitors
RU2008139599A (en) 2006-03-07 2010-04-20 Эррэй Биофарма Инк. (Us) Heterobicyclic pyrazole derivatives and methods for their use
US8389524B2 (en) * 2007-04-20 2013-03-05 Glaxo Group Limited Tricyclic nitrogen containing compounds as antibacterial agents

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999037635A1 (en) * 1998-01-26 1999-07-29 Smithkline Beecham Plc Quinoline derivatives as antibacterials
WO2000021948A1 (en) * 1998-10-14 2000-04-20 Smithkline Beecham Plc Naphthrydine compounds and their azaisosteric analogues as antibacterials
WO2000021952A1 (en) * 1998-10-14 2000-04-20 Smithkline Beecham Plc Quinoline derivatives and their use as antibacterial agents
WO2000043383A1 (en) * 1999-01-20 2000-07-27 Smithkline Beecham P.L.C. Piperidinylquinolines as protein tyrosine kinase inhibitors
WO2000078748A1 (en) * 1999-06-21 2000-12-28 Smithkline Beecham P.L.C. Quinoline derivatives as antibacterials
WO2001007433A2 (en) * 1999-07-23 2001-02-01 Smithkline Beecham P.L.C. Quinoline derivatives and their use as antibacterial agents
WO2001007432A2 (en) * 1999-07-23 2001-02-01 Smithkline Beecham P.L.C. Aminopiperidine derivatives as antibacterials
WO2002008224A1 (en) * 2000-07-26 2002-01-31 Smithkline Beecham P.L.C. Aminopiperidine quinolines and their azaisosteric analogues with antibacterial activity
WO2002024684A1 (en) * 2000-09-21 2002-03-28 Smithkline Beecham P.L.C. Quinoline derivatives as antibacterials
WO2002056882A1 (en) * 2001-01-22 2002-07-25 Smithkline Beecham P.L.C. Quinolines and nitrogenated derivaive thereof substituted in 4-position by a piperidine-containing moiety and their use as antibacterial agents

Family Cites Families (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1345872A (en) 1970-09-03 1974-02-06 Wyeth John & Brother Ltd Amino-and acylamino-pyridine and hydropyridine derivatives
GB1537867A (en) 1977-07-04 1979-01-04 Wyeth John & Brother Ltd Process for preparing 4-acylamino-piperidine derivatives
US4925877A (en) 1986-02-25 1990-05-15 Zaidanhojin Biseibutsu Kagaku Kenkyukai Physiologically active erbstatin analogue compounds and compositions
DE3874257T2 (en) 1987-03-11 1993-02-11 Kanegafuchi Chemical Ind HYDROXYSTYRENE DERIVATIVES.
ZA899436B (en) 1988-12-12 1990-08-29 Ciba Geigy Piperidine derivatives
MY110227A (en) * 1991-08-12 1998-03-31 Ciba Geigy Ag 1-acylpiperindine compounds.
EP0541486A1 (en) 1991-11-07 1993-05-12 Ciba-Geigy Ag Polycyclic conjugates
ATE208772T1 (en) 1993-10-01 2001-11-15 Novartis Erfind Verwalt Gmbh PHARMACOLOGICALLY ACTIVE PYRIDINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
JPH07179407A (en) 1993-11-12 1995-07-18 Green Cross Corp:The New condensed cyclic compound or its salt and its medicinal use
MX9702245A (en) 1994-11-14 1997-06-28 Warner Lambert Co 6-ARYL PYRIDO[2,3-d]PYRIMIDINES AND NAPHTHYRIDINES FOR INHIBITING PROTEIN TYROSINE KINASE MEDIATED CELLULAR PROLIFERATION.
AU700840B2 (en) 1995-04-26 1999-01-14 Kyowa Hakko Kogyo Co. Ltd. Radicicol derivatives
GB9514265D0 (en) 1995-07-13 1995-09-13 Wellcome Found Hetrocyclic compounds
WO1997017957A1 (en) 1995-11-13 1997-05-22 Smithkline Beecham Corporation Hemoregulatory compounds
US5707990A (en) 1996-01-30 1998-01-13 Ortho Pharmaceutical Corporation 2-substituted amino and thio alkyl benzoxazine antimicrobial agents
HRP970371A2 (en) 1996-07-13 1998-08-31 Kathryn Jane Smith Heterocyclic compounds
US6403610B1 (en) * 1999-09-17 2002-06-11 Aventis Pharma S.A. Quinolylpropylpiperidine derivatives, their preparation and the compositions which comprise them
FR2798656B1 (en) 1999-09-17 2004-12-17 Aventis Pharma Sa DERIVATIVES OF QUINOLYL PROPYL PIPERIDINE, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM
GB0011838D0 (en) 2000-05-17 2000-07-05 Astrazeneca Ab Chemical compounds
US6803369B1 (en) * 2000-07-25 2004-10-12 Smithkline Beecham Corporation Compounds and methods for the treatment of neoplastic disease
FR2816618B1 (en) 2000-11-15 2002-12-27 Aventis Pharma Sa HETEROCYCLYLALCOYL PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM
US6603005B2 (en) 2000-11-15 2003-08-05 Aventis Pharma S.A. Heterocyclylalkylpiperidine derivatives, their preparation and compositions containing them
GB0031086D0 (en) 2000-12-20 2001-01-31 Smithkline Beecham Plc Medicaments
GB0031088D0 (en) * 2000-12-20 2001-01-31 Smithkline Beecham Plc Medicaments
FR2822154B1 (en) 2001-03-13 2005-10-21 Aventis Pharma Sa QUINOLYL PROPYL PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM
US6602884B2 (en) * 2001-03-13 2003-08-05 Aventis Pharma S.A. Quinolylpropylpiperidine derivatives, their preparation, and compositions containing them
FR2822971A1 (en) * 2001-04-03 2002-10-04 St Microelectronics Sa SYSTEM AND METHOD FOR CONTROLLING ACCESS TO PROTECTED DATA STORED IN A MEMORY
GB0112836D0 (en) * 2001-05-25 2001-07-18 Smithkline Beecham Plc Medicaments
GB0112834D0 (en) 2001-05-25 2001-07-18 Smithkline Beecham Plc Medicaments
US20030203917A1 (en) * 2001-07-25 2003-10-30 Smithkline Beecham Corporation And Smithkline Beecham P.L.C. Compounds and methods for the treatment of neoplastic disease
GB0118238D0 (en) 2001-07-26 2001-09-19 Smithkline Beecham Plc Medicaments
EP2181996A1 (en) 2002-01-29 2010-05-05 Glaxo Group Limited Aminopiperidine derivatives
AR040335A1 (en) 2002-06-26 2005-03-30 Glaxo Group Ltd CYCLLOHEXAN OR CYCLHEXENE COMPOUND, USE OF THE SAME TO PREPARE A MEDICINAL PRODUCT, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT, PROCEDURE AND INTERMEDIATE COMPOUNDS OF UTILITY TO PREPARE SUCH COMPOUND
TW200409637A (en) 2002-06-26 2004-06-16 Glaxo Group Ltd Compounds
GB0217294D0 (en) * 2002-07-25 2002-09-04 Glaxo Group Ltd Medicaments
FR2844268B1 (en) * 2002-09-11 2004-10-22 Aventis Pharma Sa QUINOLYL PROPYL PIPERIDINE DERIVATIVES, PROCESSES AND INTERMEDIATES FOR THEIR PREPARATION, AND COMPOSITIONS CONTAINING THEM
FR2844270B1 (en) 2002-09-11 2006-05-19 Aventis Pharma Sa QUINOLYL PROPYL PIPERIDINE DERIVATIVES, THEIR PROCESS AND PREPARATION INTERMEDIATES AND THE COMPOSITIONS CONTAINING THEM
DE50312598D1 (en) 2002-10-10 2010-05-20 Morphochem Ag Komb Chemie NEW COMPOUNDS WITH ANTIBACTERIAL ACTIVITY
AU2003291227A1 (en) 2002-11-05 2004-06-07 Smithkline Beecham Corporation Antibacterial agents
EP1560821B8 (en) 2002-11-05 2010-05-19 Glaxo Group Limited Antibacterial agents
EP1567520B1 (en) 2002-12-04 2008-10-15 Glaxo Group Limited Quinolines and nitrogenated derivatives thereof and their use as antibacterial agents
TW200427688A (en) 2002-12-18 2004-12-16 Glaxo Group Ltd Antibacterial agents
US6903214B1 (en) * 2003-12-11 2005-06-07 Eastman Kodak Company Synthesis of bis(azinyl)amine-BF2 complex

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999037635A1 (en) * 1998-01-26 1999-07-29 Smithkline Beecham Plc Quinoline derivatives as antibacterials
WO2000021948A1 (en) * 1998-10-14 2000-04-20 Smithkline Beecham Plc Naphthrydine compounds and their azaisosteric analogues as antibacterials
WO2000021952A1 (en) * 1998-10-14 2000-04-20 Smithkline Beecham Plc Quinoline derivatives and their use as antibacterial agents
WO2000043383A1 (en) * 1999-01-20 2000-07-27 Smithkline Beecham P.L.C. Piperidinylquinolines as protein tyrosine kinase inhibitors
WO2000078748A1 (en) * 1999-06-21 2000-12-28 Smithkline Beecham P.L.C. Quinoline derivatives as antibacterials
WO2001007433A2 (en) * 1999-07-23 2001-02-01 Smithkline Beecham P.L.C. Quinoline derivatives and their use as antibacterial agents
WO2001007432A2 (en) * 1999-07-23 2001-02-01 Smithkline Beecham P.L.C. Aminopiperidine derivatives as antibacterials
WO2002008224A1 (en) * 2000-07-26 2002-01-31 Smithkline Beecham P.L.C. Aminopiperidine quinolines and their azaisosteric analogues with antibacterial activity
WO2002024684A1 (en) * 2000-09-21 2002-03-28 Smithkline Beecham P.L.C. Quinoline derivatives as antibacterials
WO2002056882A1 (en) * 2001-01-22 2002-07-25 Smithkline Beecham P.L.C. Quinolines and nitrogenated derivaive thereof substituted in 4-position by a piperidine-containing moiety and their use as antibacterial agents

Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6803369B1 (en) 2000-07-25 2004-10-12 Smithkline Beecham Corporation Compounds and methods for the treatment of neoplastic disease
US7186730B2 (en) 2001-05-25 2007-03-06 Smithkline Beecham P.L.C. Bicyclic nitrogen-containing heterocyclic derivatives for use as antibacterials
US7141564B2 (en) 2001-05-25 2006-11-28 Smithkline Beecham P.L.C. Nitrogen-containing bicyclic heterocycles for use as antibacterials
EP2181996A1 (en) * 2002-01-29 2010-05-05 Glaxo Group Limited Aminopiperidine derivatives
US7312212B2 (en) 2002-01-29 2007-12-25 Glaxo Group Limited Aminopiperidine derivatives
WO2004002490A3 (en) * 2002-06-26 2005-10-27 Glaxo Group Ltd Piperidine compounds as antibacterials
US7622481B2 (en) 2002-06-26 2009-11-24 Glaxo Group Limited Antibacterial compounds
US7498326B2 (en) 2002-06-26 2009-03-03 Glaxo Group Limited Compounds
WO2004002490A2 (en) * 2002-06-26 2004-01-08 Glaxo Group Limited Piperidine compounds as antibacterials
US10266518B2 (en) 2002-07-15 2019-04-23 Symphony Evolution, Inc. Solid dosage formulations of substituted quinazoline receptor-type kinase modulators and methods of use thereof
US9796704B2 (en) 2002-07-15 2017-10-24 Symphony Evolution, Inc. Substituted quinazolines as receptor-type kinase inhibitors
US7232832B2 (en) 2002-11-05 2007-06-19 Smithkline Beecham Corporation Antibacterial agents
US7491714B2 (en) 2002-12-04 2009-02-17 Glaxo Group Limited Quinolines and nitrogenated derivatives thereof and their use as antibacterial agents
EP1578743A4 (en) * 2002-12-18 2006-11-29 Glaxo Group Ltd Antibacterial agents
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US7572915B2 (en) 2003-05-21 2009-08-11 Glaxo Group Limited Quinoline derivatives as phosphodiesterase inhibitors
US7566786B2 (en) 2003-05-21 2009-07-28 Glaxo Group Limited Quinoline derivatives as phosphodiesterase inhibitors
US11124482B2 (en) 2003-09-26 2021-09-21 Exelixis, Inc. C-met modulators and methods of use
US7691850B2 (en) 2004-06-15 2010-04-06 Glaxo Group Limited Antibacterial agents
US7655648B2 (en) 2004-08-02 2010-02-02 Glaxo Group Limited Antibacterial agents
US7759340B2 (en) 2005-01-25 2010-07-20 Glaxo Group Limited Antibacterial agents
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WO2006081264A1 (en) 2005-01-25 2006-08-03 Glaxo Group Limited Antibacterial agents
WO2006081182A2 (en) 2005-01-25 2006-08-03 Glaxo Group Limited Antibacterial agents
US7511035B2 (en) 2005-01-25 2009-03-31 Glaxo Group Limited Antibacterial agents
US7648980B2 (en) 2005-01-25 2010-01-19 Glaxo Group Limited Antibacterial agents
US7592334B2 (en) 2005-01-25 2009-09-22 Glaxo Group Limited Antibacterial agents
US7605169B2 (en) 2005-01-25 2009-10-20 Glaxo Group Limited Antibacterial agents
US8242275B2 (en) 2005-03-31 2012-08-14 Janssen Pharmaceutica Nv Bicyclic pyrazole compounds as antibacterial agents
US7842810B2 (en) 2005-03-31 2010-11-30 Janssen Pharmaceutica, Nv Bicyclic pyrazole compounds as antibacterial agents
US8232391B2 (en) 2005-03-31 2012-07-31 Janssen Pharmaceutica Nv Bicyclic pyrazole compounds as antibacterial agents
US7875715B2 (en) 2005-06-16 2011-01-25 Astrazeneca Ab Compounds for the treatment of multi-drug resistant bacterial infections
US8124602B2 (en) 2005-06-16 2012-02-28 Astrazeneca Ab Compounds for the treatment of multi-drug resistant bacterial infections
WO2007081597A3 (en) * 2005-10-21 2008-06-12 Glaxo Group Ltd Peri condensed tricyclic compounds useful as antibacterial agents
US8937068B2 (en) 2005-11-11 2015-01-20 Zentaris Gmbh Pyridopyrazine derivatives and their use
US8217042B2 (en) 2005-11-11 2012-07-10 Zentaris Gmbh Pyridopyrazines and their use as modulators of kinases
US7732460B2 (en) 2005-12-22 2010-06-08 Glaxo Group Limited Heterocyclic compounds, their preparation and their use as antibacterials
WO2007071936A1 (en) * 2005-12-22 2007-06-28 Glaxo Group Limited Heterocyclic compounds, their preparation and their use as antibacterials
WO2007086016A1 (en) 2006-01-26 2007-08-02 Actelion Pharmaceuticals Ltd Tetrahydropyrane antibiotics
US7709496B2 (en) 2006-04-06 2010-05-04 Glaxo Group Limited Antibacterial agents
WO2007115947A1 (en) 2006-04-06 2007-10-18 Glaxo Group Limited Pyrrolo-quinoxalinone derivatives as antibacterials
WO2007122258A1 (en) * 2006-04-26 2007-11-01 Glaxo Group Limited Tryclic nitrogen containing compounds and their use as antibacterials
US7732461B2 (en) 2006-04-26 2010-06-08 Glaxo Group Limited Tryclic nitrogen containing compounds and their use as antibacterials
WO2008003690A1 (en) 2006-07-03 2008-01-10 Glaxo Group Limited Azatricyclic compounds and their use
WO2008009700A1 (en) 2006-07-20 2008-01-24 Glaxo Group Limited Derivatives and analogs of n-ethylquinolones and n-ethylazaquinolones
WO2008071964A1 (en) * 2006-12-15 2008-06-19 Astrazeneca Ab Naphthyridine bactericides
WO2008116815A3 (en) * 2007-03-23 2008-12-11 Glaxo Group Ltd Compounds
WO2008116815A2 (en) * 2007-03-23 2008-10-02 Glaxo Group Limited Compounds
WO2008128962A1 (en) * 2007-04-20 2008-10-30 Glaxo Group Limited Tricyclic compounds as antibacterials
WO2008128953A1 (en) * 2007-04-20 2008-10-30 Glaxo Group Limited Tricyclic nitrogen containing heterocycles as antibacterial agents
CN101778651A (en) * 2007-06-22 2010-07-14 葛兰素集团有限公司 Heterocyclic compounds for the treatment of tuberculosis
EP2080761A1 (en) 2008-01-18 2009-07-22 Glaxo Group Limited Compounds
WO2010043714A1 (en) 2008-10-17 2010-04-22 Glaxo Group Limited Tricyclic nitrogen compounds used as antibacterials
WO2010081874A1 (en) 2009-01-15 2010-07-22 Glaxo Group Limited Naphthyridin-2 (1 h)-one compounds useful as antibacterials
US11098015B2 (en) 2009-01-16 2021-08-24 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
US9809549B2 (en) 2009-01-16 2017-11-07 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US11091440B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)- N′-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide, and crystalline forms thereof for the treatment of cancer
US11091439B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11433064B2 (en) 2009-08-07 2022-09-06 Exelixis, Inc. Methods of using c-Met modulators
EP3639824A1 (en) 2014-08-22 2020-04-22 GlaxoSmithKline Intellectual Property Development Limited Tricyclic nitrogen containing compounds for treating neisseria gonorrhoea infection
WO2016027249A1 (en) 2014-08-22 2016-02-25 Glaxosmithkline Intellectual Property Development Limited Tricyclic nitrogen containing compounds for treating neisseria gonorrhoea infection
WO2017029602A2 (en) 2015-08-16 2017-02-23 Glaxosmithkline Intellectual Property Development Limited Compounds for use in antibacterial applications

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