WO2001034573A1 - Composes - Google Patents

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WO2001034573A1
WO2001034573A1 PCT/SE2000/002192 SE0002192W WO0134573A1 WO 2001034573 A1 WO2001034573 A1 WO 2001034573A1 SE 0002192 W SE0002192 W SE 0002192W WO 0134573 A1 WO0134573 A1 WO 0134573A1
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Prior art keywords
methyl
sulfanyl
ylsulfanyl
benzimidazol
methylphenyl
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PCT/SE2000/002192
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English (en)
Inventor
Joseph Abedi
Daniel Carcanague
Thomas Kühler
Youe-Kong Shue
Mark Wuonola
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Astrazeneca Ab
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Priority to AU17464/01A priority Critical patent/AU1746401A/en
Publication of WO2001034573A1 publication Critical patent/WO2001034573A1/fr

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
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    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds which have anti-Helicobacter pylori activity, i.e., compounds which can be administered to a mammalian patient therapeutically to treat Helicobacter pylori infection in the patient.
  • the invention also relates to pharmaceutical formulations, use of a compound of the invention in the manufacture of a medicament, and processes for preparing the compounds.
  • Helicobacter pylori is a gram negative bacterium which infects the human gastric mucosa. Infection with the bacterium causes inflammation of the gastric mucosa. Peptic ulceration of the duodenum or stomach can develop as well as adenocarcinomas or lymphomas of the stomach wall.
  • Omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl]-lH-benzimidazole) is active against Helicobacter pylon (see Vogt, K and Hahn, H (1998), "Bactericidal Activity of Lansoprazole and Omeprazole against Helicobacter pylori in vitro", Drug Res. 48(1), No. 6, 694-697), and is labile towards rearrangement in acidic media.
  • Omeprazole is a sulfoxide.
  • This sulfoxide is labile towards rearrangement in acidic media and the rearrangement gives an intermediate, which is a potent proton pump inhibitor.
  • the parent compound does not persist in the acidic environment of the stomach.
  • Compounds related to omeprazole, where the sulphur atom is unoxidized are also active against Helicobacter pylori. However, these related compounds can undergo metabolic oxidation in vivo to give the corresponding sulfoxide, analagous to omeprazole, and have a propensitiy towards rearrangement in acidic media in vivo [J. Med. Chem. 1988, 41, 1777-1788].
  • Analogues which are potent against Helicobacter pylon, but not acid labile and thus stable in acidic media are desirable. Such analogues could be administered to a mammalian patient therapeutically to treat Helicobacter pylori infection.
  • the present invention provides compounds of formula I or pharmaceutically acceptable salts or solvates thereof which are active against Helicobacter pylori, but lack the pyridine nitrogen of omeprazole and its analogues which is necessary for rearrangement in acidic media.
  • the compounds of the invention are more stable in acid media.
  • Formula I is as follows:
  • X is S; SO 2 ; NH; N(C, -6 alkyl); O or CH 2 ;
  • Y is C,. 6 alkyl; O(C 3-8 cycloalkyl); O(C ⁇ - 6 alkyl); Hal; CHal 3 , CHHal 2 , CH 2 Hal, OCHal 3 , OCHHal 2 or OCH 2 Hal , wherein Hal represents halogen; NRR', wherein R and R' independently represent H or C ⁇ _ 8 alkyl, or NRR' represents an optionally substituted C 3 .
  • R is an optionally substituted mono- or bi-cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; R 3 is H; C ⁇ -6 alkyl; optionally substituted C .
  • R 5 is H; C ⁇ _ 8 alkyl; optionally substituted C 3 . 8 cycloalkyl optionally fused to a benzo ring; (C ⁇ -8 alkyl)aryl wherein the aryl is C 6 - ⁇ o and optionally substituted; optionally substituted C 6- i 0 aryl; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or
  • the structure -NR 4 R 5 represents a C 3 . 8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C 6-1 o ring structure, -NR 4 R 5 being optionally substituted;
  • the invention also relates to pharmaceutical formulations, use of a compound of the invention in the manufacture of a medicament, processes for preparing the compounds and intermediates for use in such processes.
  • a compound of the invention in the manufacture of a medicament
  • processes for preparing the compounds and intermediates for use in such processes are outlined.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof
  • X represents S; SO ; NH; O or CH 2 .
  • X represents N(C ⁇ _ 6 alkyl), more preferably N-methyl or N(C 2 . alkyl).
  • Y represents (preferably C 2-4 alkyl, and most preferably methyl); O(C 3 . 8 cycloalkyl), preferably O-cyclopropyl, or O-cyclobutyl or O-cyclopentyl; O(C ⁇ _ 6 alkyl), preferably Omethyl or O(C 2 .
  • Hal preferably Cl or F; CHal 3 , CHHal 2 , CH 2 Hal, OCHal 3 , OCHHal 2 or OCH 2 Hal , wherein Hal represents halogen (preferably F); NRR', wherein R and R' independently represent H or C ⁇ _ 8 alkyl (preferably methyl or C 2 - 6 alkyl or C 2-4 alkyl) , or NRR' represents an optionally substituted C 3 . 8 , preferably C 3-6 , heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR" or COR", R" representing H or C t-6 alkyl (preferably methyl, ethyl); or CH 2 OH.
  • R 1 represents -(CH 2 ) a -CH 3 or -((CH 2 ) b O) c -CH 3 .
  • R 2 represents an optionally substituted mono- or bi-cyclic 5-, 6-, 7-, 8-, 9- or 10- membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S.
  • the heterocycle are benzimidazolyl (preferably benzimidazol-2-yl), imidazolyl (preferably imidazol-2-yl), oxadiazolyl (preferably 1,3,4- oxadiazol-2-yl), pyrimidinyl (preferably pyrimidin-2-yl), tetrazolyl (preferably 1,2,3,4- tetrazol-5-yl), pyridinyl (preferably pyridin-2-yl or pyridin-4-yl), thiazolyl (preferably 1,3- thiazol-2-yl), pyridineimidazolyl (preferably pyridineimidazol-2-yl), benzoxazolyl (preferably l,3-benzoxazol-2-yl), ind
  • NRR' represents an optionally substituted C 3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S;
  • R" represents . ⁇ alkylene (preferably d or C 2 ) and R"' represents C ⁇ . 6 alkyl (preferably Ci or C 2 ).
  • R 2 represents
  • Q is CH or N
  • Q ' is NH. O or S;
  • W is CH or N; W is CH or N; and R 8 represents C ⁇ -6 alkyl (preferably C 2- alkyl, and most preferably methyl); O(C -8 cycloalkyl), preferably O-cyclopropyl, or O-cyclobutyl or O-cyclopentyl; O(C ⁇ . 6 alkyl), preferably Omethyl or O(C 2 . 4 alkyl); Hal, preferably Cl or F; CHal 3 , CHHal 2 , CH 2 Hal, OCHal 3 , OCHHah or OCH 2 Hal, wherein Hal represents halogen (preferably F); NRR', wherein R and R' independently represent H or C[. 8 alkyl (preferably methyl or C 2 .
  • NRR' represents an optionally substituted C 3-8 , preferably C 3-6 , heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR 9 or COR 9 , R 9 representing H or C ⁇ . 6 alkyl (preferably methyl, ethyl); or CH 2 OH.
  • R 3 represents H; C ⁇ -6 alkyl; optionally substituted C 3 . 8 , preferably C 3-6 , cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C 5 . ⁇ 0 aromatic ring structure (e.g., phenyl) optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or an optionally substituted 5- to 10- membered mono- or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N and S.
  • aromatic ring structure e.g., phenyl
  • R 3 represents H; C ⁇ -6 alkyl; optionally substituted C 3 . 8 , preferably C 3-6 , cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C 5 . ⁇ 0 aromatic ring structure (e.g., phenyl) optionally containing 1,
  • the cycloalkyl contains heteroatoms and is selected from morpholinyl (4-morpholinyl), piperazinyl (preferably 1-piperazinyl), tetrazolyl (preferably l,2,3,4-tetrazol-2-yl), imidazolyl (e.g., 1-imidazolyl) and triazolyl (e.g., l-(l,2,4-triazolyl)).
  • morpholinyl 4-morpholinyl
  • piperazinyl preferably 1-piperazinyl
  • tetrazolyl preferably l,2,3,4-tetrazol-2-yl
  • imidazolyl e.g., 1-imidazolyl
  • triazolyl e.g., l-(l,2,4-triazolyl)
  • Preferred examples of the C ⁇ -6 alkyl are preferably C 2 . 4 alkyl, methyl and butyl (e.g., isobutyl).
  • heterocyclic ring structure examples include imidazopyridazine (more preferably 6-imidazo[l,2-b]pyridazine) and imidazolyl (more preferably 1-imidazolyl).
  • imidazopyridazine more preferably 6-imidazo[l,2-b]pyridazine
  • imidazolyl more preferably 1-imidazolyl
  • at least one (e.g., one, two or three) substituents may be provided independently selected from C ⁇ -6 alkyl (preferably C 2 . 4 alkyl, more preferably methyl) and nitro.
  • the heterocyclic ring structure is selected from imidazopyridazine (more preferably 6-imidazo[l,2-b]pyridazine) and imidazolyl (more preferably 1-imidazolyl).
  • imidazopyridazine more preferably 6-imidazo[l,2-b]pyridazine
  • imidazolyl more preferably 1-imidazolyl
  • at least one (e.g., one, two or three) substituents may be provided independently selected from C ⁇ -6 alkyl (preferably C 2- alkyl, more preferably methyl) and nitro.
  • R 4 and R 5 either: (i) R 4 is H; C ⁇ -8 alkyl; optionally substituted C 3-8 cycloalkyl optionally fused to a benzo ring; Z 2 -(C ⁇ .
  • the aryl is phenyl.
  • Z 2 -(d. 8 alkyl)aryl represents Z 2 -(C ⁇ _ 8 alkyl)benzodioxol.
  • R 4 where a heterocyclic ring structure is mentioned, this is selected from furyl (e.g., 2-furyl), tetrahydrofuranyl (e.g., tetrahydro-2-furanyl), thienyl (e.g., 2-thienyl), morpholinyl (e.g., 4- morpholinyl), isoxazolyl (e.g., 4-isoxazolyl or 5-isoxazolyl), dioxoimidazolidinyl (e.g., 2,5- dioxoimidazolidinyl), pyrazinyl, dioxotetrahydropurinyl (e.g., 2,6-dioxo-l,2,3,6-tetrahydro- purin-7-yl), benzofuranyl (e.g., 2-benzofuranyl), pyridyl (e.g., 2-pyridyl or 3-pyrid
  • the aryl is optionally fused to a heterocyclic ring structure selected from furan, tetrahydrofuran, thiophene, morpholine, isoxazole, dioxoimidazolidine (e.g., 2,5-dioxoimidazolidine), pyrazine, dioxotetrahydropurine (e.g., 2,6- dioxo-l,2,3,6-tetrahydro-purine), benzofuran, pyridine, quinoline, pyrrolidine, piperazine, imidazopyridazine (e.g., imidazo[l,2-£]pyridazine) and tetrazole (e.g., 1,2,3,4-tetrazole).
  • dioxoimidazolidine e.g., 2,5-dioxoimidazolidine
  • pyrazine e.g., dioxotetrahydropur
  • the C 3 . 8 cycloalkyl is selected from cyclopropyl C 4-6 cycloalkyl and cyclopentyl.
  • the cycloalkyl, aryl, heterocycle or heterocyclic ring structure at least one (e.g., one, two or three) substituents may be provided independently selected from
  • the C -8 heterocyclic ring is preferably selected from piperidinyl (e.g., 1- piperidinyl), piperazinyl (e.g., 1-piperazinyl), morpholinyl (e.g., 4-morpholinyl) and tetrazolyl (e.g., l,2,3,4-tetrazol-2-yl).
  • the C6- ⁇ 0 ring structure is selected from cyclohexyl and a benzo ring.
  • R 6 and R 7 either: (i) R 6 is H; C ⁇ . ⁇ ?alkyl; optionally substituted C 3-8 cycloalkyl optionally fused to a benzo ring; optionally substituted (C ⁇ _ 8 alkyl)aryl wherein the aryl is C 6 - ⁇ 0 ; optionally substituted (C ⁇ .
  • the structure -NR 6 R 7 represents a C 3-8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C 6- ⁇ 0 ring structure, -NR 6 R 7 being optionally substituted.
  • C ⁇ _ ⁇ 2 alkyl is selected from C ⁇ . 8 alkyl, C 2 . 6 alkyl, methyl, propyl (e.g., isopropyl), butyl (e.g., isobutyl or tert-butyl), pentyl and adamantyl (e.g., 1- adamantyl).
  • the alkyl is selected from C 2 .
  • benzofuryl e.g., benzofur-2-yl
  • furyl e.g., 2- furyl
  • tetrahydrofuranyl e.g., tetrahydro-2-furanyI
  • thienyl e.g., 2-thienyl
  • morpholinyl e.g., 4-morpholinyl
  • isoxazolyl e.g., 4-isoxazolyl or 5-isoxazolyl
  • dioxoimidazolidinyl e.g., 2,5-dioxoimidazolidinyl
  • pyrazinyl dioxotetrahydropurinyl (e.g., 2,6-dioxo-l,2,3,6- tetrahydro-purin-7-yl)
  • benzofuranyl e.g., 2-benzo
  • the C 3 . 8 cycloalkyl is selected from cyclopropyl C -6 cycloalkyl and cyclopentyl.
  • at least one (e.g., one, two or three) substituents may be provided independently selected from C ⁇ . 6 alkyl (preferably C 2-4 alkyl, more preferably methyl); phenyl; OCF ; OCHF 2 ; -O(C,.
  • the C 3 . 8 heterocyclic ring is preferably selected from piperidinyl (e.g., 1- piperidinyl), piperazinyl (e.g., 1-piperazinyl), morpholinyl (e.g., 4-morpholinyl) and tetrazolyl (e.g., l,2,3,4-tetrazol-2-yl).
  • the C 6 - ⁇ oring structure is selected from cyclohexyl and a benzo ring.
  • at least one (e.g., one, two or three) substituents may be provided independently selected from C 1-6 alkyl (preferably C 2 .
  • 6 alkyl 6 alkyl
  • -S(C,. 8 alkyl) preferably -S-methyl, -S-ethyl or -S(C 3-6 alkyl
  • OH hydroxy
  • halogen e.g., F, Cl or Br
  • a represents 1, 2, 3, 4 or 5 (preferably 1 or 2); each b independently represents 1, 2, 3, 4 or 5 (preferably 1 or 2); c represents 1, 2, 3, 4 or 5 (preferably 1 or 2); c' represents 1, 2, 3, 4 or 5 (preferably 1 or 2); d represents 1, 2, 3, 4 or 5 (preferably 1 or 2); each e independently represents 1, 2, 3, 4 or 5 (preferably 1 or 2); f represents 1, 2, 3, 4 or 5 (preferably 1 or 2); and g represents zero or represents 1, 2, 3, 4 or 5 (preferably 1 or 2).
  • an alkyl substituent may be linear or branched.
  • the substituent can be selected from C ⁇ . 6 alkyl (preferably C 2 . alkyl, and most preferably methyl); O(C 3 - 8 cycloalkyl), preferably O- cyclopropyl, or O-cyclobutyl or O-cyclopentyl; O(C
  • NRR' represents an optionally substituted C 3 . 8 , preferably C 3-6 , heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR" or COR", R" representing H or C ⁇ -6 alkyl (preferably methyl, ethyl); or CH 2 OH.
  • at least one (e.g., one, two or three) substituents may be provided independently selected from C ⁇ . 6 alkyl (preferably C 2-4 alkyl, more preferably methyl); phenyl; OCF 3 ; OCHF 2 ; -O(C ⁇ .
  • Y is C,. 6 alkyl, O(C,. 6 alkyl), Hal; CHal 3 , CHHal 2 , CH 2 Hal, OCHal 3 , OCHHal 2 or OCH 2 Hal.
  • R 3 is C ⁇ -6 alkyl; optionally substituted C 3 . 8 cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted Cs-ioaromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or an optionally substituted 5- to 10-membered mono- or bi-cyclic heterocyclic ring structure ' containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S per cycle.
  • R 6 and R 7 either: (i) R 6 is H; C ⁇ _ ⁇ alkyl; optionally substituted C 3 . 8 cycloalkyl optionally fused to a benzo ring; optionally substituted (C ⁇ . 8 alkyl)aryl wherein the aryl is C 6- ⁇ o; optionally substituted (C ⁇ -8 alkyl)R, where R represents a mono- or bi-cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S per cycle; or R represents a mono-, bi- or tri-cyclic C - ⁇ 3 cycloalkyl; optionally substituted C 6 . ⁇ 0 aryl; an optionally substituted mono- or bi-cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1,
  • R 7 is H; or (ii) the structure -NR 6 R 7 represents a C 3 . 8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S per cycle; -NR 6 R 7 being optionally substituted.
  • X is S or O;
  • R 3 is optionally substituted C 3-8 cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C 5 . ⁇ 0 aromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or an optionally substituted 5- to 10-membered mono- or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N and S.
  • R 1 is selected from -iso- u,
  • R represents
  • Q isCHorN; Q'isNH, OorS;
  • W isCHorN; W isCHorN; and
  • R 8 is C,. 6 alkyl; O(C 3-8 cycloalkyl); O(C ⁇ _ 6 alkyl); Hal; CHal 3 , CHHal 2 , CH 2 Hal, OCHal 3 , OCHHal 2 or OCH 2 Hal, wherein Hal represents halogen; NRR', wherein R and R ' independently represent H or C ⁇ _ 8 alkyl, or NRR' represents an optionally substituted C -8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S; H; COOR 9 or COR 9 , R 9 representing H orC ⁇ . 6 alkyl;orCH 2 OH.
  • Preferred compounds are selected from compounds II, III, IV and V
  • Mass spectral molecular ion data are reported in units of m/z (mass/charge) in Daltons.
  • the compounds of formula I can be prepared by a process comprising any one of steps (a) to (h) as follows:
  • R , 10 represents (CH 2 )d Or -(CH 2 )f.,-O-(CH 2 ) e - and R represents H or C ⁇ -6 alkyl; or (b) reacting compound VII with R -NCO
  • R , 10 represents a bond, (CH 2 ) d ⁇ r-(CH 2 ) f -O-(CH ) e -; or
  • L 1 represents a leaving group and R 10 represents (CH 2 ) d Or-(CH 2 ) f -O-(CH 2 ) e -; or
  • R , 10 represents (CH 2 ) ⁇ r -(CH 2 ) f . r O-(CH 2 ) e -.
  • protecting groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups.
  • the preparation of the compounds of formula (I) may involve, at an appropriate stage, the addition and subsequent removal of one or more protecting groups.
  • the compounds of the present invention have an -Helicobacter pylori activity, i.e., they can be administered to a mammalian patient therapeutically to treat Helicobacter pylori infection in the patient and/or to prevent such infection.
  • a further advantage of compounds of the invention is that they are particularly selective for Helicobacter pylori.
  • Methyl 2- ⁇ [3-(chloromethyl)-2-methylphenyl]sulfanyI ⁇ acetate Methyl 2- ⁇ [3-(hydroxymethyl)-2-methylphenyl]sulf anyl ⁇ acetate, 4.4 g was dissolved in 220 mL methylene chloride, treated with thionyl chloride, 5 mL, and stirred at room temp, for 4 hours. The solvents were evaporated to yield 4.3 g of methyl 2- ⁇ [3-(chloromethyl)-2- methylphenyl sulfanyl ⁇ acetate as a slightly brown oil.
  • Methyl 2-( ⁇ 3-[( lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl ⁇ sulfanyl)acetate 0.68 g, was dissolved in 14 mL MeO ⁇ and treated with excess LiO ⁇ dissolved in 2 mL ⁇ 2 O for 1 h. The solvents were evaporated and the residue was partitioned between 100 mL 5% ⁇ a 2 CO 3 and 100 mL EtOAc. The aq layer was collected and the pH was adjusted to about 4 with 4M HCl. The aq layer was extracted with a 2: 1 ethyl acetate/THF mixture.
  • Compound 113 can be prepared by a similar scheme by using 2-methyl-5-nitro-lH- imidazole in place of morpholine.
  • Compound 114 can be prepared by a similar scheme by using lH-triazole in place of morpholine.
  • 2-Mercaptobenzimidazole 2 g was dissolved in a solution of 10 mL water, 30 mL methanol, and 0.53 g NaOH, and cooled on an ice bath. A solution of 3.2 g of methyl 2- [3-(chloromethyl)-2-methylphenoxy]acetate in 50 mL methanol was added and the reaction was stirred at room temp, for 6 hours. The solvents were evaporated and the residue was partitioned between 600 mL CH 2 C1 2 and 300 mL of 5% Na 2 CO 3 , the org.
  • Methyl 2- ⁇ 3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenoxy ⁇ acetate 0.68 g, was dissolved in 14 mL MeO ⁇ and treated with excess LiO ⁇ dissolved in 2 mL ⁇ 2 O for 1 h. The solvents were evaporated and the residue was partitioned between 100 mL 5% Na 2 CO 3 and 100 L EtOAc The aq layer was collected and the pH was adjusted to about 4 with 4M HCl. The aq layer was extracted with a 2: 1 ethyl acetate/THF mixture.
  • 2-Mercaptobenzimidazole 2 g was dissolved in a solution of 10 mL water, 30 mL methanol, and 0.53 g NaOH, and cooled on an ice bath. A solution of 3.2 g l-(chloromethyl)- 3-isobutoxy-2-methylbenzene in 50 mL methanol was added and the reaction was stirred at room temp, for 6 hours. The solvents were evaporated and the residue was partitioned between 600 mL CH 2 C1 2 and 300 mL of 5% Na 2 CO 3 , the org. layer was collected, dried over Na 2 SO and evaporated to give 3.1 g 2-[(3-isobutoxy-2-methylbenzyl)sulfanyl]-lH- benzimidazole as a light yellow solid.
  • Compound 105 can be made by a similar scheme by using 2-mercaptoindole in place of 2-mercaptobenzimidazole.
  • Compound 110 can be made by a similar scheme by using 2-mercaptobenzothiazole in place of 2-mercaptobenzimidazole.
  • N-bromosuccinimide 0.47 g was dissolved in 20 mL methylene chloride and cooled to 0 °C. Dimethylsulfide, 0.213 mL, was added slowly and the mixture was stirred for 30 minutes at 0 °C. A solution of 0.42 g [3-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethoxy)-2- chlorophenyljmethanol in 5 mL methylene chloride was added, and the reaction was allowed to proceed at RT for 2 h. The mixture was concentrated to give crude ⁇ 2-[3-(bromomethyl)-2- chlorophenoxy]ethoxy ⁇ (tert-butyl)dimethylsilane, 0.56 g, used in the next step without any further purification.
  • Compound 107 can be prepared by a similar scheme by replacing 2-[2-(2- methoxyethoxy)ethoxy]ethyl methanesulfonate with 3,6,9,12,15-pentaoxahexadec-l-yl methanesulfonate.
  • Compound 109 can be prepared by a similar scheme by replacing 2-[2-(2- methoxyethoxy)ethoxy]ethyl methanesulfonate with 3,6,9, 12,15-pentaoxahexadec-l-yl methanesulfonate.
  • Compound 112 can be prepared by a similar scheme by replacing 2-[2-(2- methoxyethoxy)ethoxy]ethyl methanesulfonate with isobutyl bromide.
  • Compound 115 can be prepared by a similar scheme by replacing 2-[2-(2- methoxyethoxy)ethoxy]ethyl methanesulfonate with 3,6,9, 12, 15-pentaoxahexadec-l-yl methanesulfonate. and 2-mercaptobenzimidazole replaced with 5-carboethoxy-2- mercaptobenzimidazole.
  • Compound 116 can be prepared by a similar scheme by replacing 2-[2-(2- methoxyethoxy)ethoxy]ethyl methanesulfonate with 3,6,9, 12, 15-pentaoxahexadec-l-yl methanesulfonate, and 2-mercaptobenzimidazole replaced with 5-(propan-l-one)-2- mercaptobenzimidazole.
  • Compound 117 can be prepared by a similar scheme by replacing 2-[2-(2- methoxyethoxy)ethoxy]ethyl methanesulfonate with 3,6,9, 12, 15-pentaoxahexadec-l-yl methanesulfonate, and 2-mercaptobenzimidazole replaced with 5-amino-2- mercaptobenzimidazole.
  • Compound 118 can be prepared by a similar scheme by replacing 2-[2-(2- methoxyethoxy)ethoxy]ethyl methanesulfonate with 3, 6,9, 12, 15-pentaoxahexadec-l-yl methanesulfonate, and 2-mercaptobenzimidazole replaced with 5-(hydroxymethyl)-2- mercaptobenzimidazole.
  • Table 1 shows which compounds can be made by each of Schemes 1 to 14 or by schemes that are similar to schemes 1 to 14, but differ in one or more reagents as will be readily apparent to the skilled person taking into account the final compound. Table 1
  • microdilution assay tests the anti-H. pylori activity of compounds. In this assay,
  • MICs Minimum Inhibitory Concentrations
  • ATCC 43504 H pylori strains
  • the tests were performed in 24-well microtiter plates in which the medium, the inoculum, and the antibiotic solutions were distributed in the wells.
  • Serial dilutions were prepared in 24-well plates containing a total volume of 2 mL medium per well. Cultures were resuspended in Brucella broth (OD 600 of 0.6) and 50 ⁇ l of these cultures were inoculated into each well to give a final concentration of 10 7 cells per mL (OD 60 o of less than 0.03, which is the same as that of the non-inoculated control).
  • the plates were then incubated for two days and the amount of growth recorded (OD 600 ) with a plate reader (Molecular Devices, Sunnyvale, California).
  • the plates were incubated in a controlled microaerophilic atmosphere (5% O2, 10% CO 2 and 85% N 2 ) that assured optimal growth of the bacterial strains and high reproducibility of results.
  • the MIC was defined as the lowest concentration of antibiotic resulting in complete inhibition of growth.
  • MIC values ⁇ 10 ⁇ g/mL are indicative of an ⁇ -Helicobacter pylori activity.
  • Compounds according to the invention were tested in this assay and give MIC values in this range.
  • Standard agar dilution protocols were used to determine the effect of compounds of the invention on panels of Gram negative and Gram positive bacteria.
  • the invention relates in one aspect to a compound of formula I for use as a medicament.
  • the compound can be provided as part of a pharmaceutical formulation which alo includes a pharmaceutically acceptable diluent or carrier (e.g., water).
  • the formulation may be in the form of tablets, capsules, granules, powders, syrups, emulsions (e.g., lipid emulsions), suppositories, ointments, creams, drops, suspensions (e.g., aqueous or oily suspensions) or solutions (e.g., aqueous or oily solutions).
  • the formulation may include one or more additional substances independently selected from stabilising agents, wetting agents, emulsfying agents, buffers, lactose, sialic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter and ethylene glycol.
  • the formulation may contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents.
  • the compound is preferably orally administered to a patient, but other routes of administration are possible, such as parenteral or rectal administration.
  • parenteral or rectal administration For intravenous, subcutaneous or intra-muscular administration, the patient may receive a daily dose of 5 mgkg "1 to 20 mgkg "1 of the compound, the compound being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intra-muscular dose may be given by means of a bolus injection. Alternatively, the intravenous dose may be given by continuous infusion over a period of time. Alternatively, the patient may receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • a suitable pharmaceutical formulation is one suitable for oral administration in unit dosage form, for example as a tablet or capsule, which contains between lOOmg and lg of the compound of the invention.
  • compound X a pharmaceutically acceptable salt or solvate thereof
  • Buffers e.g., pharmaceutically acceptable co-solvents (e.g., polyethylene glycol, propylene glycol, glycerol or EtOH) or complexing agents such as hydroxy-propyl ⁇ cyclodextrin may be used to aid formulation.
  • pharmaceutically acceptable co-solvents e.g., polyethylene glycol, propylene glycol, glycerol or EtOH
  • complexing agents such as hydroxy-propyl ⁇ cyclodextrin may be used to aid formulation.
  • Another aspect of the invention relates to the use of a compound of formula I, in the manufacture of a medicament, for the therapeutic and/or prophylactic treatment of Helicobacter pylori infection in a mammalian host, e.g. a human.
  • therapeutic treatment we mean the eradication or suppression of a pre-existing Helicobacter pylori infection in the host.
  • a method of therapeutically treating or preventing Helicobacter pylori infection in a mammal comprising administering (e.g., orally) to the mammal a compound of formula I or a pharmaceutical formulation as described above.
  • a mammal e.g., a human
  • administering e.g., orally
  • a compound of formula I or a pharmaceutical formulation as described above.

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Abstract

L'invention concerne des composés de la formule (I) ayant une activité anti-Helicobacter pylori.
PCT/SE2000/002192 1999-11-09 2000-11-08 Composes WO2001034573A1 (fr)

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WO2004020415A1 (fr) * 2002-08-27 2004-03-11 Astrazeneca Ab 2,5-dioxoimidazolidine-4-yl acetamides et analogues servant d'inhibiteurs de la metalloproteinase mmp12.
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6964975B2 (en) * 2000-02-18 2005-11-15 Kirin Beer Kabushiki Kaisha Isoxazole and thiazole compounds and use thereof as medicine
US7132434B2 (en) 2001-11-07 2006-11-07 Astrazeneca Ab Metalloproteinase inhibitors
US7368465B2 (en) 2001-03-15 2008-05-06 Astrazeneca Ab Metalloproteinase inhibitors
US7648992B2 (en) 2004-07-05 2010-01-19 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
US7655664B2 (en) 2004-12-17 2010-02-02 Astrazeneca Ab Hydantoin derivatives as metalloproteinase inhibitors
US7700604B2 (en) 2004-12-17 2010-04-20 Astrazeneca Ab Hydantoin derivatives as metalloproteinase inhibitors
JP2011502983A (ja) * 2007-11-01 2011-01-27 アキュセラ インコーポレイテッド 眼の疾患及び障害治療用のアミン誘導体化合物
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
CN110156752A (zh) * 2019-05-28 2019-08-23 沈阳药科大学 2-[(吡啶-2-基甲基)硫基]-1h-苯并咪唑类化合物及应用
US11970489B1 (en) 2023-10-23 2024-04-30 King Faisal University 4-[(substituted 1H-benzimidazol-2-ylsulfanyl)methyl]-6-substituted-2H-chromen-2-ones as larvicidal agents

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EP0204215A1 (fr) * 1985-05-24 1986-12-10 G.D. Searle & Co. [(1H-benzimidazol-yl-2-sulfonyl)méthyl]-2-benzèneamines
EP0251536A1 (fr) * 1986-06-24 1988-01-07 FISONS plc Benzimidazoles, leur préparation, formulation et utilisation comme inhibiteurs de sécrétion d'acide gastrique
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Cited By (23)

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USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US7399772B2 (en) 1996-01-04 2008-07-15 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6964975B2 (en) * 2000-02-18 2005-11-15 Kirin Beer Kabushiki Kaisha Isoxazole and thiazole compounds and use thereof as medicine
US7368465B2 (en) 2001-03-15 2008-05-06 Astrazeneca Ab Metalloproteinase inhibitors
US6818642B2 (en) 2001-05-18 2004-11-16 Altana Pharma Ag Benzylaminopyrimidines
WO2002094832A1 (fr) * 2001-05-18 2002-11-28 Altana Pharma Ag Nouvelles benzylaminopyrimidines
US7132434B2 (en) 2001-11-07 2006-11-07 Astrazeneca Ab Metalloproteinase inhibitors
US7662845B2 (en) 2002-08-27 2010-02-16 Astrazeneca Ab 2,5-Dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12
US7354940B2 (en) 2002-08-27 2008-04-08 Astrazeneca Ab 2,5-dioxoimidazolidin-4-yl acetamines and analogues as inhibitors of metalloproteinase mmp12
WO2004020415A1 (fr) * 2002-08-27 2004-03-11 Astrazeneca Ab 2,5-dioxoimidazolidine-4-yl acetamides et analogues servant d'inhibiteurs de la metalloproteinase mmp12.
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US7648992B2 (en) 2004-07-05 2010-01-19 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
US7700604B2 (en) 2004-12-17 2010-04-20 Astrazeneca Ab Hydantoin derivatives as metalloproteinase inhibitors
US7655664B2 (en) 2004-12-17 2010-02-02 Astrazeneca Ab Hydantoin derivatives as metalloproteinase inhibitors
JP2011502983A (ja) * 2007-11-01 2011-01-27 アキュセラ インコーポレイテッド 眼の疾患及び障害治療用のアミン誘導体化合物
US8716529B2 (en) 2007-11-01 2014-05-06 Acucela Inc. Amine derivative compounds for treating ophthalmic diseases and disorders
US9056849B2 (en) 2007-11-01 2015-06-16 Acucela Inc. Amine derivative compounds for treating ophthalmic diseases and disorders
US9452153B2 (en) 2007-11-01 2016-09-27 Acucela Inc. Amine derivative compounds for treating ophthalmic diseases and disorders
CN110156752A (zh) * 2019-05-28 2019-08-23 沈阳药科大学 2-[(吡啶-2-基甲基)硫基]-1h-苯并咪唑类化合物及应用
CN110156752B (zh) * 2019-05-28 2021-03-19 沈阳药科大学 2-[(吡啶-2-基甲基)硫基]-1h-苯并咪唑类化合物及应用
US11970489B1 (en) 2023-10-23 2024-04-30 King Faisal University 4-[(substituted 1H-benzimidazol-2-ylsulfanyl)methyl]-6-substituted-2H-chromen-2-ones as larvicidal agents

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