WO2001034573A1 - Compounds - Google Patents

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
methyl
sulfanyl
ylsulfanyl
benzimidazol
methylphenyl
Prior art date
Application number
PCT/SE2000/002192
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French (fr)
Inventor
Joseph Abedi
Daniel Carcanague
Thomas Kühler
Youe-Kong Shue
Mark Wuonola
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Astrazeneca Ab
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Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU17464/01A priority Critical patent/AU1746401A/en
Publication of WO2001034573A1 publication Critical patent/WO2001034573A1/en

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    • C07D213/00—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • 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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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/36—Sulfur atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • 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
    • C07D277/70—Sulfur atoms
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    • C07D401/00—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
    • 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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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D471/00—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
    • 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
    • C07D471/04—Ortho-condensed systems
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    • C07D473/00—Heterocyclic compounds containing purine ring systems
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    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—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
    • 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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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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.

Abstract

The invention relates to compounds of formula (I) which have anti-Helicobacter pylori activity.

Description

COMPOUNDS
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. Backeround to the Invention
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. Thus, 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.
In addition, it would be preferable for such analogues to be selective for Helicobacter pylori, since this is desirable to avoid the disruption of the normal gastrointestinal flora, and to reduce the incidence of bacterial resistance development. Summary of the Invention Accordingly, 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. Thus, the compounds of the invention are more stable in acid media. Formula I is as follows:
Figure imgf000003_0001
wherein: X is S; SO2; NH; N(C,-6alkyl); O or CH2;
Y is C,.6alkyl; O(C3-8cycloalkyl); O(Cι-6alkyl); Hal; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal , wherein Hal represents halogen; NRR', wherein R and R' independently represent H or Cι_8alkyl, or NRR' represents an optionally substituted C3.8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR" or COR", R" representing H or Cι-6alkyl; or CH2OH; R1 -(CH2)a-R3; -((CH2)bO)c-R3; -(CH2)d-R3'; -(CH2)aC(=O)R3; -(CH2)dC(=O)R3';
-((CH2)e-O)c'-(CH2)f-R3'; R3 or R3'.
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; R3 is H; Cι-6alkyl; optionally substituted C .8cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C5.ιoaromatic 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; R3' is -Z-M wherein Z represents O, S or NH and M represents H, an optionally substituted mono- or bi- cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S, or an optionally substituted Cs.ioaromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M represents -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9 or -NC(=O)R8; For R4 and R5, either: (i) R4 is H; Cι-8alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; Z -(Ci-8alkyl)aryl, wherein Z represents O or a bond, and the aryl is C6-10, optionally substituted and optionally fused to a C5-10 heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted C6-ιoaryl; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, N and S; (Cι-8alkyl)-R, wherein R represents an optionally substituted mono- or bi-cyclic 5 to 10 membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted -C(=O)O(Cι-8alkyl); optionally substituted -C(=O)O-phenyl; optionally substituted -C(=O)(Cι.8alkyl); optionally substituted -C(=O)-phenyl; or -NC(=O)R6 and
R5 is H; Cι_8alkyl; optionally substituted C3.8cycloalkyl optionally fused to a benzo ring; (Cι-8alkyl)aryl wherein the aryl is C6-ιo and optionally substituted; optionally substituted C6-i0aryl; 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
(ii) the structure -NR4R5 represents a C3.8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6-1o ring structure, -NR4R5 being optionally substituted;
For R6 and R7, either: (i) R6 is H;
Figure imgf000004_0001
optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; optionally substituted (Cι-8alkyl)aryl wherein the aryl is C6-ιo; optionally substituted (Cι-8alkyl)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 or R represents a mono-, bi- or tri-cyclic C3-ι3cycloalkyl; optionally substituted C6-ιoaryl; 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; or -C(=O)O- Ar, wherein Ar represents optionally substituted C6-ι0aryl; and R7 is H; or (ii) the structure -NR6R7 represents a C3-8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S, -NR6R7 being optionally substituted; a represents an integer 1, 2, 3, 4 or 5; each b independently represents an integer 1, 2, 3, 4 or 5; c represents an integer 1, 2, 3, 4 or 5; c' represents an integer 1, 2, 3, 4 or 5; d represents an integer 1, 2, 3, 4 or 5; each e independently represents an integer 1, 2, 3, 4 or 5; f represents an integer 1, 2, 3, 4 or 5; and g represents zero or an integer 1, 2, 3, 4 or 5.
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. Detailed Description of the Invention
The present invention provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000005_0001
wherein: X represents S; SO ; NH; O or CH2. Alternatively, X represents N(Cι_6alkyl), more preferably N-methyl or N(C2. alkyl).
Y represents
Figure imgf000005_0002
(preferably C2-4alkyl, and most preferably methyl); O(C3.8cycloalkyl), preferably O-cyclopropyl, or O-cyclobutyl or O-cyclopentyl; O(Cι_6alkyl), preferably Omethyl or O(C2.4alkyl); Hal, preferably Cl or F; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal , wherein Hal represents halogen (preferably F); NRR', wherein R and R' independently represent H or Cι_8alkyl (preferably methyl or C2-6alkyl or C2-4alkyl) , or NRR' represents an optionally substituted C3.8, preferably C3-6, 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 Ct-6alkyl (preferably methyl, ethyl); or CH2OH. For optional substitution of the heterocyclic ring represented by NRR', at least one (e.g., one, two or three) substituents may be provided independently selected from C1-6alkyl (preferably C2- alkyl, more preferably methyl); phenyl; OCF3; OCHF2; -O(Cι-8alkyl), preferably -O- methyl, -O-ethyl or -O(C3-6alkyl); -C(=O)O(Cι-8alkyl), preferably -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-tert-butyl or -C(=O)O(C3.6alkyl); -C(=O)O-phenyl; -O-phenyl; -C(=O) (C1-8alkyl), preferably -C(=O)-methyl, -C(=O)-ethyl or -C(=O)(C3-6alkyl) ;
-C(=O)OH; -S(C,_8alkyl), preferably -S-methyl, -S-ethyl or -S(C3.6alkyl); OH; halogen (e.g., F, Cl or Br); NRR' where R and R' are independently H or Cι-6alkyl (preferably C2-4alkyl, more preferably methyl, most preferably R=R'=methyl); and nitro.
R1 represents -(CH2)a-R3; -((CH2)bO)c-R3; -(CH2)d-R3'; -((CH2)e-O)c-(CH2)f-R3' (preferably where e=2 and f=2); R3 or R3'. Preferably, R1 represents -(CH2)a-CH3 or -((CH2)bO)c-CH3. More preferably, R1 is selected from -ώσ-Bu; -(CH2CH2O)3CH3; -(CH2CH2)-4-mo holinyl; -(CH2CH2O)5CH3; -(CH2CH2)-l-(2-methyl-5-nitro-imidazolyl); -(CH2CH2)-l-(l,2,4-triazolyl); and -(CH2CH2)-OC(=O)NH-Ph.
R2 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. Preferred examples of 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), indolyl (preferably indol-2-yl). For optional substitution of the heterocycle, at least one (e.g., one, two or three) substituents may be provided independently selected from nitro; carboxylate; -COOH; =O; -S(=O)-(Cι-8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl; -S(=O)-(=O)-(Cι-8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl; halogen (preferably F or Cl); phenyl;
-O(C1-8alkyl), preferably -O-methyl, -O-ethyl or -O(C3.6alkyl); -S(Cι-8alkyl), preferably -S- methyl, -S-ethyl or -S(C3-6alkyl); OH; OCHF2, OCH2F, OCF3; CHF2, CH2F, CF3; -C(=O)NRR', wherein R and R' are independently selected from H and Cι-8alkyl (preferably methyl, ethyl, propyl, isopropyl, or C2-6alkyl), or the structure NRR' represents an optionally substituted C3-8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; and
- R"-NH(CO) R'", wherein R" represents .όalkylene (preferably d or C2) and R"' represents Cι.6alkyl (preferably Ci or C2).
In one preferred embodiment, R2 represents
Figure imgf000006_0001
wherein:
Q is CH or N;
Q' is NH. O or S;
W is CH or N; W is CH or N; and R8 represents Cι-6alkyl (preferably C2- alkyl, and most preferably methyl); O(C -8cycloalkyl), preferably O-cyclopropyl, or O-cyclobutyl or O-cyclopentyl; O(Cι.6alkyl), preferably Omethyl or O(C2.4alkyl); Hal, preferably Cl or F; CHal3, CHHal2, CH2Hal, OCHal3, OCHHah or OCH2Hal, wherein Hal represents halogen (preferably F); NRR', wherein R and R' independently represent H or C[.8alkyl (preferably methyl or C2.6alkyl or C2.4alkyl) , or NRR' represents an optionally substituted C3-8, preferably C3-6, heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR9 or COR9, R9 representing H or Cι.6alkyl (preferably methyl, ethyl); or CH2OH. For optional substitution of the heterocyclic ring represented by NRR', at least one (e.g., one, two or three) substituents may be provided independently selected from Ci.ealkyl (preferably C2-4alkyl, more preferably methyl); phenyl; OCF3; OCHF2; -O(Cι-8alkyl), preferably -O- methyl, -O-ethyl or -O(C3-6alkyl); -C(=O)O(C1.8alkyl), preferably -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-tert-butyl or -C(=O)O(C3.6alkyl); -C(=O)O-phenyl; -O-phenyl; -C(=O) (Cι.8alkyl), preferably -C(=O)-methyl, -C(=O)-ethyl or -C(=O)(C3.6alkyl) ; -C(=O)OH; -S(Cι.8alkyl), preferably -S-methyl, -S-ethyl or -S(C3-6alkyl); OH; halogen (e.g., F, Cl or Br), NRR' where R and R' are independently H or Cι-6alkyl (preferably C2.4alkyl, more preferably methyl, most preferably R=R'=methyl); and nitro.
R3 represents H; Cι-6alkyl; optionally substituted C3.8, preferably C3-6, cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C5.ι0aromatic 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. Preferably, 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)). Preferred examples of the Cι-6alkyl are preferably C2.4alkyl, methyl and butyl (e.g., isobutyl). preferred examples of the heterocyclic ring structure are imidazopyridazine (more preferably 6-imidazo[l,2-b]pyridazine) and imidazolyl (more preferably 1-imidazolyl). For optional substitution of the cycloalkyl, aryl or heterocyclic ring, at least one (e.g., one, two or three) substituents may be provided independently selected from Cι-6alkyl (preferably C2.4alkyl, more preferably methyl) and nitro. R3 represents -Z-M wherein Z represents O, S or NH and M represents H, an optionally substituted mono- or bi- cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S, or an optionally substituted C5.i0aromatic ring structure (e.g., phenyl) optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9 or -NC(=O)R8;
Preferably, the heterocyclic ring structure is selected from imidazopyridazine (more preferably 6-imidazo[l,2-b]pyridazine) and imidazolyl (more preferably 1-imidazolyl). For optional substitution of the aromatic or heterocyclic ring structure, at least one (e.g., one, two or three) substituents may be provided independently selected from Cι-6alkyl (preferably C2- alkyl, more preferably methyl) and nitro.
Most preferably, R3' is selected from -4-morpholinyl; -l-(2-methyl-5-nitro- imidazolyl); -l-(l,2,4-triazolyl); and -OC(=O)NH-Ph. For R4 and R5, either: (i) R4 is H; Cι-8alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; Z2-(Cι.8alkyl)aryl, wherein Z2 represents O or a bond, and the aryl is C6-ι0, optionally substituted and optionally fused to a C5-ι0 heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted C6.ι0aryl; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, N and S; (Cι-8alkyl)-R, wherein R represents an optionally substituted mono- or bi-cyclic 5-, 6-, 1-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted -C(=O)O(Cι-8alkyl); optionally substituted -C(=O)O-phenyl; optionally substituted -C(=O)(Cι_8alkyl); optionally substituted -C(=O)-phenyl; or -NHC(=O)R6; and R5 is H; Cι.8alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; (Cι_8alkyl)aryl wherein the aryl is C6-ιo and optionally substituted; optionally substituted C6-ιoaryl; 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 (ii) the structure -NR4R5 represents a C3.8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6-ι0ring structure, -NR4R5 being optionally substituted. For R4 in option (i), preferably the Ct.8alkyl or the Cι.8alkyl in Z2-(Cι.8alkyl)aryl or the C)-8alkyl in (Cι.8alkyl)-R or the Cι-8alkyl in -C(=O)O(d.8alkyl) or the Cι-8alkyl in -C(=O)(Cι-8alkyl) is selected from C2-6alkyl, methyl, ethyl, propyl (e.g., isopropyl), butyl (e.g., isobutyl or tert-butyl) and pentyl. Preferably, where C6.ι0aryl is mentioned, the aryl is phenyl. Preferably, Z2-(d.8alkyl)aryl represents Z2-(Cι_8alkyl)benzodioxol. Preferably, for R4, 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-pyridyl), quinolyl (e.g., 4-quinolyl), pyrrolidinyl (e.g., 2-pyrrolidinyl), piperazinyl (e.g., 1-piperazinyl), imidazopyridazinyl (e.g., imidazo[l,2-b]pyridazinyl) and tetrazolyl (e.g., tetrazol-2-yl, 1,2,3,4- tetrazol-2-yl). Preferably, for Z2-(Cι_8alkyl)aryl, 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). Preferably, the C3.8cycloalkyl is selected from cyclopropyl C4-6cycloalkyl and cyclopentyl. For optional substitution of the cycloalkyl, aryl, heterocycle or heterocyclic ring structure, at least one (e.g., one, two or three) substituents may be provided independently selected from
Ci-όalkyl (preferably C2-4alkyl, more preferably methyl); phenyl; -O(Cι_8alkyl), preferably -O- methyl, -O-ethyl or -O(C3.6alkyl); -C(=O)O(Cι.8alkyl), preferably -C(=O)O-methyl, -C(=O)O-ethyl or -C(=O)O(C3.6alkyl); -C(=O)O-phenyl; -O-phenyl; -C(=O) (Cι-8alkyl), preferably -C(=O)-methyl, -C(=O)-ethyl or -C(=O)(C3.6alkyl) ; -S(Cι.8alkyl), preferably -S- methyl, -S-ethyl or -S(C3.6alkyl); OH; halogen (e.g., F, Cl or Br), NRR' where R and R' are independently H or Cι.6alkyl (preferably C2. alkyl, more preferably methyl, most preferably R=R'=methyl); and nitro.
For option (ii), the C -8heterocyclic 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). Preferably, the C6-ι0 ring structure is selected from cyclohexyl and a benzo ring. For optional substitution of -NR4R5, at least one(e.g., one, two or three) substituents may be provided independently selected from Cι-6alkyl (preferably C2-4alkyl, more preferably methyl); phenyl; OCF3; OCHF2; -O(Cι.8alkyl), preferably -O-methyl, -O- ethyl or -O(C3.6alkyl); -C(=O)O(Cι.8alkyl), preferably -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-tert-butyl or -C(=O)O(C3.6alkyl); -O-phenyl; -C(=O) (C,.8alkyl), preferably -C(=O)-methyl, -C(=O)-ethyl or -C(=O)(C3.6alkyl) ; -C(=O)OH; -S(C,.8alkyl), preferably -S- methyl, -S-ethyl or -S(C3.6alkyl); OH; halogen (e.g., F, Cl or Br), NRR' where R and R' are independently H or Cι. alkyl (preferably C2.4alkyl, more preferably methyl, most preferably R=R'=methyl); and nitro.
For R6 and R7, either: (i) R6 is H; Cι.ι?alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; optionally substituted (Cι_8alkyl)aryl wherein the aryl is C6-ι0; optionally substituted (Cι.8alkyl)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 or R represents a mono-, bi- or tri-cyclic C3-ι3cycloalkyl; optionally substituted Cό-ioaryl; 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; or -C(=O)- O-Ar, wherein Ar represents optionally substituted C6-ιoaryl; and R7 is H; or
(ii) the structure -NR6R7 represents a C3-8heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6-ι0ring structure, -NR6R7 being optionally substituted.
For R6 in option (ii), preferably Cι_ι2alkyl is selected from Cι.8alkyl, C2.6alkyl, methyl, propyl (e.g., isopropyl), butyl (e.g., isobutyl or tert-butyl), pentyl and adamantyl (e.g., 1- adamantyl). For Cι.8alkyl in (Cι.8alkyl)aryl or (Cι_8alkyl)R, the alkyl is selected from C2.6alkyl, methyl, propyl (e.g., isopropyl), butyl (e.g., isobutyl or tert-butyl) and pentyl. Preferably, where Cό-ioaryl is mentioned, the aryl is phenyl. Preferably, Z2-(Cι-8alkyl)aryl represents Z"-(Cι.8alkyl)benzodioxol. Preferably, where a 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle is mentioned, this is selected from 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-benzofuranyl), pyridyl (e.g., 2-pyridyl or 3- pyridyl), quinolyl (e.g., 4-quinolyl), pyrrolidinyl (e.g., 2-pyrrolidinyl), piperazinyl (e.g., 1- piperazinyl), imidazopyridazinyl (e.g., imidazo[l,2-b]pyridazinyl) and tetrazolyl (e.g., tetrazol-2-yl, l,2,3,4-tetrazol-2-yl). Preferably, the C3.8cycloalkyl is selected from cyclopropyl C -6cycloalkyl and cyclopentyl. For optional substitution of the cycloalkyl, alkylaryl, aryl or heterocycle, at least one (e.g., one, two or three) substituents may be provided independently selected from Cι.6alkyl (preferably C2-4alkyl, more preferably methyl); phenyl; OCF ; OCHF2; -O(C,.8alkyl), preferably -O-methyl, -O-ethyl or -O(C3-6alkyl); -C(=O)O(Cι-8alkyl), preferably -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-tert-butyl or -C(=O)O(C3.6alkyl); -C(=O)O-ρhenyl; -O-phenyl; -C(=O) (Cι-8alkyl), preferably -C(=O)-methyl, -C(=O)-ethyl or -C(=O)(C3-6alkyl) ; -C(=O)OH; -S(C1-8alkyl), preferably -S-methyl, -S-ethyl or -S(C3.6alkyl); OH; halogen (e.g., F, Cl or Br), NRR' where R and R' are independently H or Cι-6alkyl (preferably C2.4alkyl, more preferably methyl, most preferably R=R'=methyl); and nitro.
For option (ii), the C3.8heterocyclic 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). Preferably, the C6-ιoring structure is selected from cyclohexyl and a benzo ring. For optional substitution of -NR6R7, at least one (e.g., one, two or three) substituents may be provided independently selected from C1-6alkyl (preferably C2. alkyl, more preferably methyl); phenyl; OCF3; OCHF2; -O(Cι- alkyl), preferably -O-methyl, -O- ethyl or -O(C3-6alkyl); -C(=O)O(Cι.8alkyl), preferably -C(=O)O-methyl, -C(=O)O-ethyl or -C(=O)O(C3.6alkyl); -O-phenyl; -C(=O) (C1-8alkyl), preferably -C(=O)-methyl, -C(=O)-ethyl or -C(=O)(C3.6alkyl) ; -S(C,.8alkyl), preferably -S-methyl, -S-ethyl or -S(C3-6alkyl); OH; halogen (e.g., F, Cl or Br), NRR' where R and R' are independently H or Cι.6alkyl (preferably C2-4alkyl, more preferably methyl, most preferably R=R'=methyl); and nitro. In formula I, 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). In the present specification, unless otherwise indicated, an alkyl substituent may be linear or branched.
Where optional substitution of aryl is mentioned, the substituent can be selected from Cι.6alkyl (preferably C2. alkyl, and most preferably methyl); O(C3-8cycloalkyl), preferably O- cyclopropyl, or O-cyclobutyl or O-cyclopentyl; O(C|.6alkyl), preferably Omethyl or O(C2-4alkyl); Hal, preferably Cl or F; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen (preferably F); NRR', wherein R and R' independently represent H or Cι.8alkyl (preferably methyl or C2.6alkyl or C2.4alkyl) , or NRR' represents an optionally substituted C3.8, preferably C3-6, 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 Cι-6alkyl (preferably methyl, ethyl); or CH2OH. For optional substitution of the heterocyclic ring represented by NRR', at least one (e.g., one, two or three) substituents may be provided independently selected from Cι.6alkyl (preferably C2-4alkyl, more preferably methyl); phenyl; OCF3; OCHF2; -O(Cι.8alkyl), preferably -O-methyl, -O- ethyl or -O(C3.6alkyl); -C(=O)O(C,.8alkyl), preferably -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-tert-butyl or -C(=O)O(C3.6alkyl); -C(=O)O-phenyl; -O-phenyl; -C(=O) (C] -8alkyl), preferably -C(=O)-methyl, -C(=O)-ethyl or -C(=O)(C3.6alkyl) ; -C(=O)OH; -S(C,.8alkyl), preferably -S-methyl, -S-ethyl or -S(C3-6alkyl); OH; halogen (e.g., F, Cl or Br), NRR' where R and R' are independently H or Ci-δalkyl (preferably C2-4alkyl, more preferably methyl, most preferably R=R'=methyl); and nitro.
In one embodiment, a is 1, 2 or 3; b is 2; c' is 1, 2, 3, 4 or 5; d is 1, 2 or 3; e is 2; f is 1, 2 or 3; and g is 1 or 2.
Another embodiment has the general structure lb
Figure imgf000012_0001
wherein:
X is S, S(=O), S(=O)2 or O.
Y is C,.6alkyl, O(C,.6alkyl), Hal; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal. R1 is -(CH2)a-R3, -((CH2)2O)c-R3, -(CH2)d-R3', -(CH2)aC(=O)R3, -(CH2)dC(=O)R3',
-((CH2)2O)c>-(CH2)f-R3\
R3 is Cι-6alkyl; optionally substituted C3.8cycloalkyl 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.
R3' is -Z-M wherein Z represents O, S or NH and M represents H, an optionally substituted mono- or bi- cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure 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 an optionally substituted Cs.io aromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M represents -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9 or -NC(=O)R8. For R6 and R7, either: (i) R6 is H; Cι_ι alkyl; optionally substituted C3.8cycloalkyl optionally fused to a benzo ring; optionally substituted (Cι.8alkyl)aryl wherein the aryl is C6-ιo; optionally substituted (Cι-8alkyl)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 -ι3cycloalkyl; optionally substituted C6.ι0aryl; 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, 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 -C(=O)-O-Ar, wherein Ar represents optionally substituted C6-ι0aryl; and
R7 is H; or (ii) the structure -NR6R7 represents a C3.8 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; -NR6R7 being optionally substituted.
In one variation of the above embodiments, X is S or O; R1 is -(CH2)2R3, -(CH2)2R3', -CH2C(=O)R3 or -CH2C(=O)R3' ; and R3 is optionally substituted C3-8cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C5.ι0aromatic 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. In another variation of the above embodiments, R1 is selected from -iso- u,
-(CH2CH2O)3CH3, -(CH2CH2)-4-morpholinyl, -(CH2CH2O)5CH3, -(CH2CH2)-l-(2-methyl-5- nitro-imidazolyl), -(CH2CH2)-l-(l,2,4-triazolyl), and -(CH2CH2)-OC(=O)NH-Ph. In still another variation of the above embodiments, R represents
Figure imgf000014_0001
wherein:
Q isCHorN; Q'isNH, OorS;
W isCHorN; W isCHorN; and
R8 is C,.6alkyl; O(C3-8cycloalkyl); O(Cι_6alkyl); Hal; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen; NRR', wherein R and R' independently represent H or Cι_8alkyl, or NRR' represents an optionally substituted C-8heterocyclic 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; COOR9 or COR9, R9 representing H orCι.6alkyl;orCH2OH. Preferred compounds are selected from compounds II, III, IV and V
Figure imgf000014_0002
Figure imgf000015_0001
Specific examples of compounds according to the invention are given below. Mass spectral molecular ion data are reported in units of m/z (mass/charge) in Daltons.
Compound 1
Figure imgf000015_0002
Mass spec' molecular ion: M+H= 331
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-ethanol Compound 2
Figure imgf000015_0003
Mass spec' molecular ion: M+Η=417
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl isopropylcarbamate Compound 3
Figure imgf000016_0001
Mass spec' molecular ion: M+H= 450
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate Compound 4
Figure imgf000016_0002
NMR:
Η NMR (dmso-^6) ppm 2.42 (s, 3Η), 3.26 (t, 7=6.7 Hz, 2H), 4.22 (t, 7=6.7 Hz, 2H), 4.62 (s, 2H), 6.95-7.68 (m, 16H), 9.57 (s, IH, NH), 12.61 (s, 1Η, NH).
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 4- phenoxyphenylcarbamate Compound 5
Figure imgf000017_0001
Mass spec' molecular ion: M+H= 445
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl pentylcarbamate Compound 6
Figure imgf000017_0002
Mass spec' molecular ion: M+Η= 479
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2,5- dimethylphenylcarbamate Compound 7
Figure imgf000017_0003
Mass spec' molecular ion: M+Η= 490 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl (15,2R)-2- phenylcyclopropylcarbamate
Compound 8
Figure imgf000018_0001
Mass spec' molecular ion: M+Η= 456
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyI}sulfanyl)ethyl cyclohexylcarbamate Compound 9
Figure imgf000018_0002
Mass spec' molecular ion: M+Η= 496
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3-(methylsulfanyl)phenylcarbamate
Compound 10
Figure imgf000018_0003
Mass spec' molecular ion: M+H= 478
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenethylcarbamate
Compound 11
Figure imgf000019_0001
Mass spec' molecular ion: M+Η= 484
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2-(2- thienyl)ethylcarbamate Compound 12
Figure imgf000019_0002
Mass spec' molecular ion: M+Η= 388
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl methylcarbamate Compound 13
Figure imgf000019_0003
Mass spec' molecular ion: M+Η= 464 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyI 2- methylphenylcarbamate
Compound 14
Figure imgf000020_0001
Mass spec' molecular ion: M+H= 480
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3- methoxyphenylcarbamate
Compound 15
Figure imgf000020_0002
Mass spec' molecular ion: M+Η= 468
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 4- fluorophenylcarbamate
Compound 16
Figure imgf000020_0003
Mass spec' molecular ion: M+Η= 464 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl benzylcarbamate
Compound 17
Figure imgf000021_0001
Mass spec' molecular ion: M+Η= 508 methyl 3-({ [2-({3-[(lH-benzimidazol-2-ylsuIfanyl)methyl]-2-methylphenyl}sulfanyl)- ethoxy]carbonyl } amino)benzoate
Compound 18
Figure imgf000021_0002
Mass spec' molecular ion: M+Η= 532
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3,4- dichlorobenzylcarbamate
Compound 19
Figure imgf000021_0003
Mass spec' molecular ion: M+H= 486
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl 3,4- difluorophenylcarbamate Compound 20
Figure imgf000022_0001
Mass spec' molecular ion: M+Η= 494
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenyl dicarbonimidoate Compound 21
Figure imgf000022_0002
Mass spec' molecular ion: M+H= 529
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3- bromophenylcarbamate Compound 22
Figure imgf000022_0003
Mass spec' molecular ion: M+H= 478
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3- methylbenzylcarbamate Compound 23
Figure imgf000023_0001
Mass spec' molecular ion: M+Η= 550 ethyl 2-({ [2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethoxy]- carbonyl }amino)-3-phenylpropanoate
Compound 24
Figure imgf000023_0002
Mass spec' molecular ion: M+Η= 469
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3,5-dimethyl-4- isoxazolylcarbamate Compound 25
Figure imgf000024_0001
Mass spec' molecular ion: M+H= 492
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3- acetylphenylcarbamate Compound 26
Figure imgf000024_0002
Mass spec' molecular ion: M+Η= 478
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl benzoylcarbamate Compound 27
Figure imgf000024_0003
Mass spec' molecular ion: M+Η= 499
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl 4-chloro-2- methylphenylcarbamate Compound 28
Figure imgf000025_0001
Mass spec' molecular ion: M+H= 494
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 4- methoxybenzylcarbamate Compound 29
Figure imgf000025_0002
Mass spec' molecular ion: M+Η= 518
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3,4- dichlorophenylcarbamate Compound 30
Figure imgf000025_0003
Mass spec' molecular ion: M+Η= 493
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl
4-(dimethylamino)phenylcarbamate Compound 31
Figure imgf000026_0001
Mass spec' molecular ion: M+H= 518
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2,5- dichlorophenylcarbamate
Compound 32
Figure imgf000026_0002
Mass spec' molecular ion: M+H= 510
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl 3,5- dimethoxyphenylcarbamate Compound 33
Figure imgf000026_0003
Mass spec' molecular ion: M+H= 510
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl 2,4- dimethoxyphenylcarbamate
Compound 34
Figure imgf000027_0001
Mass spec' molecular ion: M+H= 478
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl (1R)-1- phenylethylcarbamate Compound 35
Figure imgf000027_0002
Mass spec' molecular ion: M+Η= 522 ethyl 4-({ [2-({ 3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl }sulfanyl)ethoxy]carbonyl }amino)benzoate Compound 36
Figure imgf000028_0001
Mass spec' molecular ion: M+H= 478
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2- ethylphenylcarbamate Compound 37
Figure imgf000028_0002
Mass spec' molecular ion: M+Η= 496
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 4- fluorobenzoylcarbamate Compound 38
Figure imgf000028_0003
Mass spec' molecular ion: M+Η= 330
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethylamine Compound 39
Figure imgf000029_0001
Mass spec' molecular ion: M+H= 434
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl]benzamide Compound 40
Figure imgf000029_0002
Mass spec' molecular ion: M+Η= 440 N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)ethyl]cyclohexanecarboxamide Compound 41
Figure imgf000029_0003
Mass spec' molecular ion: M+Η= 470
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2-[(45)-
2,5-dioxoimidazolidinyl]acetamide
Compound 42
Figure imgf000030_0001
Mass spec' molecular ion: M+H= 541 tert-butyl 4-({ [2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)ethyl]amino}carbonyl)-l-piperidinecarboxylate
Compound 43
Figure imgf000030_0002
Mass spec' molecular ion: M+Η= 436
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2- pyrazinecarboxamide Compound 44
Figure imgf000030_0003
Mass spec' molecular ion: M+Η= 506
2-(l-adamantyl)-N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)ethyl]acetamide Compound 45
Figure imgf000031_0001
Mass spec' molecular ion: M+H= 550
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2-(l,3- dimethyl-2,6-dioxo-l,2,3,6-tetrahydro-7H-purin-7-yl)acetamide Compound 46
Figure imgf000031_0002
Mass spec' molecular ion: M+Η= 424
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2-furamide Compound 47
Figure imgf000031_0003
Mass spec' molecular ion: M+Η= 469
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-5-nitro-2- furamide Compound 48
Figure imgf000032_0001
Mass spec' molecular ion: M+H= 440
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2- thiophenecarboxamide Compound 49
Figure imgf000032_0002
Mass spec' molecular ion: M+Η= 474
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-l- benzofuran-2-carboxamide Compound 50
Figure imgf000032_0003
Mass spec' molecular ion: M+Η= 466
N-[2-({3-[(lH-benzimidazol-2-yIsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-l-ethyl-3- methyl-lH-pyrazole-5-carboxamide
Compound 51
Figure imgf000033_0001
Mass spec' molecular ion: M+H= 435 N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl }sulfanyl)ethyl]nicotinamide Compound 52
Figure imgf000033_0002
Mass spec' molecular ion: M+Η= 485
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-4- quinolinecarboxamide Compound 53
Figure imgf000033_0003
Mass spec' molecular ion: M+Η= 453
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-3,5- dimethyl-4-isoxazolecarboxamide Compound 54
Figure imgf000034_0001
Mass spec' molecular ion: M+H= 425
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-5- isoxazolecarboxamide Compound 55
Figure imgf000034_0002
Mass spec' molecular ion: M+Η= 344
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)acetamide Compound 56
Figure imgf000034_0003
Mass spec' molecular ion: M+Η= 384
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N- cyclopropylacetamide Compound 57
Figure imgf000035_0001
Mass spec' molecular ion: M+H= 478
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(l,3-benzodioxol- 5-yImethyl)acetamide Compound 58
Figure imgf000035_0002
Mass spec' molecular ion: M+Η= 412
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)-l-(l-piperidinyl)-l- ethanone Compound 59
Figure imgf000035_0003
Mass spec' molecular ion: M+Η= 424 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(2- furylmethyl)acetamide
Compound 60
Figure imgf000036_0001
Mass spec' molecular ion: M+Η= 426
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N- cyclohexylacetamide Compound 61
Figure imgf000036_0002
Mass spec' molecular ion: M+Η= 428
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(tetrahydro-2- furanylmethyl)acetamide Compound 62
Figure imgf000036_0003
Mass spec' molecular ion: M+Η= 412 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N- cyclopentylacetamide
Compound 63
Figure imgf000037_0001
Mass spec' molecular ion: M+Η= 440
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(2- thienylmethyl)acetamide Compound 64
Figure imgf000037_0002
Mass spec' molecular ion: M+Η= 457
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-[2-(4- moφholinyl)ethyl]acetamide
Compound 65
Figure imgf000037_0003
Mass spec' molecular ion: M+Η= 460 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(2,3-dihydro-lH- inden-2-yl)acetamide
Compound 66
Figure imgf000038_0001
Mass spec' molecular ion: M+Η= 434
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-benzylacetamide Compound 67
Figure imgf000038_0002
Mass spec' molecular ion: M+Η= 508 2-({ 3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)-N-(2,5- dimethoxyphenethyl)acetamide Compound 68
Figure imgf000038_0003
ΝMR: Η NMR (dmso-c?6) ppm 2.42 (s, 3H), 2.71 (m, 2H), 3.77 (s, 2H), 4.37 (m, 2H), 4.62 (s, 2H), 7.10-7.16 (m, 7H), 7.56 (m, IH), 7.66 (m, IH), 8.49 (m, IH), 8.75 (m, IH), 12.61 (s, IH, NH).
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-[2-(2- pyridinyl)ethyl]acetamide Compound 69
Figure imgf000039_0001
Mass spec' molecular ion: M+Η= 455
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-[2-(l-methyl-2- pyrrolidinyl)ethyl]acetamide Compound 70
Figure imgf000039_0002
Mass spec' molecular ion: M+Η= 538
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)-N-(3,3- diphenylpropyl)acetamide Compound 71
Figure imgf000040_0001
Mass spec' molecular ion: M+H= 449
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N- phenethylacetamide Compound 72
Figure imgf000040_0002
Mass spec' molecular ion: M+Η= 479
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(4- methoxyphenethyl)acetamide Compound 73
Figure imgf000040_0003
Mass spec' molecular ion: M+Η= 429
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-hexylacetamide Compound 74
Figure imgf000041_0001
Mass spec' molecular ion: M+H= 401
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)-N-isobutylacetamide Compound 75
Figure imgf000041_0002
Mass spec' molecular ion: M+Η= 436
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(4- pyridinylmethyl)acetamide Compound 76
Figure imgf000041_0003
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)acetyl]-2- furohydrazide
Compound 77
Figure imgf000042_0001
Mass spec' molecular ion: M+H= 467
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-octahydro-l(2H)- quinolinyl-l-ethanone Compound 78
Figure imgf000042_0002
Mass spec' molecular ion: M+Η= 450
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)- N-(benzyloxy)acetamide Compound 79
Figure imgf000042_0003
Mass spec' molecular ion: M+Η= 519 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-[4-(2- methoxyphenyl)-l-piperazinyl]-l-ethanone
Compound 80
Figure imgf000043_0001
Mass spec' molecular ion: M+Η= 521
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-[6,7-dimethoxy- 3 ,4-dihydro-2( lH)-isoquinolinyl]- 1 -ethanone Compound 81
Figure imgf000043_0002
Mass spec' molecular ion: M+Η= 477
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(4- butylphenyl)acetamide
Compound 82
Figure imgf000044_0001
Mass spec' molecular ion: M+H= 427
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-(4-methyl-l- piperazinyl)- 1 -ethanone Compound 83
Figure imgf000044_0002
Mass spec' molecular ion: M+Η= 400
2-[(2-methyl-3-{ [2-(4-moφhoIinyl)ethyl]sulfanyl}benzyl)sulfanyl]-lH-benzimidazole Compound 84
Figure imgf000044_0003
Mass spec' molecular ion: M+Η= 413
2-[(2-methyl-3-{ [2-(4-methyl-l-piperazinyl)ethyl]sulfanyl }benzyl)sulfanyl]-lH- benzimidazole Compound 85
Figure imgf000045_0001
Mass spec' molecular ion: M+H= 400
2-({3-[(lH-imidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate Compound 86
Figure imgf000045_0002
Mass spec' molecular ion: M+Η= 478
2-[(2-methyl-3-{ [(5-phenyl-l,3,4-oxadiazol-2-yl)sulfanyl]methyl}phenyl)sulfanyl]ethyl phenylcarbamate Compound 87
Figure imgf000045_0003
Mass spec' molecular ion: M+H= 412
2-({2-methyl-3-[(2-pyrimidinylsulfanyl)methyl]phenyl }sulfanyl)ethyl phenylcarbamate Compound 88
Figure imgf000046_0001
Mass spec' molecular ion: M+H= 478
2-[(2-methyl-3-{[(l-phenyl-lH-l,2,3,4-tetrazol-5-yl)sulfanyl]methyl}phenyl)sulfanyl]ethyl phenylcarbamate Compound 89
Figure imgf000046_0002
Mass spec' molecular ion: M+Η= 552
2-[(3-{ [(4,5-diphenyl-lH-imidazol-2-yl)sulfanyl]methyl}-2-methylphenyl)sulfanyl]ethyl phenylcarbamate Compound 90
Figure imgf000046_0003
Mass spec' molecular ion: M+Η= 451
2-({3-[(3H-imidazo[4,5-c]pyridin-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate Compound 91
Figure imgf000047_0001
Mass spec' molecular ion: M+H= 451
2-({3-[(l,3-benzoxazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate Compound 92
Figure imgf000047_0002
Mass spec' molecular ion: M+H= 411
2-({2-methyl-3-[(2-pyridinylsulfanyl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate Compound 93
Figure imgf000047_0003
Mass spec' molecular ion: M+H= 411
2-({2-methyl-3-[(4-pyridinylsulfanyl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate Compound 94
Figure imgf000048_0001
Mass spec' molecular ion: M+H= 493
2-[(2-methyl-3-{ [(4-phenyl-l,3-thiazol-2-yl)sulfanyl]methyl}phenyl)sulfanyl]ethyl phenylcarbamate Compound 95
Figure imgf000048_0002
Mass spec' molecular ion: M+H= 417
2-({2-methyl-3-[(l,3-thiazol-2-ylsulfanyl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate Compound 96
Figure imgf000048_0003
Mass spec' molecular ion: M+H= 480
2-[(3-{ [(5-methoxy-lH-benzimidazol-2-yl)sulfanyl]methyl }-2-methylphenyl)sulfanyl]ethyl phenylcarbamate Compound 97
Figure imgf000049_0001
Mass spec' molecular ion: M+H= 449
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-N- phenylurea Compound 98
Figure imgf000049_0002
Mass spec' molecular ion: M+Η= 451
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-N-(2- pyrazinyl)urea Compound 99
Figure imgf000049_0003
Mass spec' molecular ion: M+Η= 493
6-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethoxy]-3- nitroimidazo[l,2-b]pyridazine Compound 100
Figure imgf000050_0001
Mass spec' molecular ion: M+H= 522 N-{ [2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl }sulfanyl)ethoxy]carbonyl}phenylalanine Compound 101
Figure imgf000050_0002
Mass spec' molecular ion: M+Η= 383
2-[(2-methyl-3-{ [2-(2H-l,2,3,4-tetrazol-2-yl)ethyl]sulfanyl }benzyl)sulfanyl]-lH- benzimidazole
Compound 102
Figure imgf000050_0003
Mass spec' molecular ion: M+Η= 384
2-[(2-methyl-3-{ [2-(2H-l,2,3,4-tetrazol-2-yl)ethyl]sulfanyl }benzyl)sulfanyl]-3H-imidazo[4,5- c]pyridine Compound 103
Figure imgf000051_0001
NMR:
400 MHz 1H-NMR (CHCI3-α) ppm 1.03 (d, 6H), 2.10 (m, 1H), 2.29 (s, 3H), 3.70 (d,
2H), 4.56 (s, 2H), 6.75 (d, 1H), 6.90 (d, 1H), 7.05 (t, 1H), 7.20 (t, 1H), 7.21 (t, 1H), 7.29 (d, 1H),7.70(d, 1H).
2-[(3-isobutoxy-2-methylbenzyl)sulfanyl]-lH-benzimidazole Compound 104
Figure imgf000051_0002
NMR:
500 MHz 1 H-NMR (CHCI3-d) ppm 2.30 (s, 3H), 2.65 (m, 4H), 2.87 (m, 2H), 3.75 (m,
4H), 4.13 (m, 2H), 4.60 (s, 2H), 6.80 (d, 1H), 6.97 (d, 1H), 7.09 (t, 1H), 7.19-7.30 (m, 2H), 7.33 (d, 1H), 7.74 (d, 1H).
2-({2-methyl-3-[2-(4-moφholinyl)ethoxy]benzyl}sulfanyl)-lH-benzimidazole Compound 105
Figure imgf000052_0001
Mass spec' molecular ion: [M-H]= 324 2-[(3-isobutoxy-2-methylbenzyl)sulfanyl]-lH-indole Compound 106
Figure imgf000052_0002
Mass spec' molecular ion: M+Na= 439
2-[(3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-2-methylbenzyl)sulfanyl]-lH-benzimidazole Compound 107
Figure imgf000052_0003
Mass spec' molecular ion: M+Na = 527
2-{ [2-methyl-3-(3,6,9,12,15-pentaoxahexadec-l-yloxy)benzyl]sulfanyl }-lH-benzimidazole
Compound 108
Figure imgf000053_0001
NMR:
500 MHz 1 H-NMR (CHCI3-C/) ppm 2.43 (s, 3H), 3.02 (t, 2H), 3.35 (s, 3H), 3.52-3.55
(m, 2H), 3.56-3.68 (m, 8H), 4.55 (s, 2H), 7.01 (t, 1 H), 7.12 (d, 1 H), 7.19-7.23 (m, 2H), 7.25 (d, 1 H), 7.50-7.55 (m, 2H).
2-{[3-({2-[2-(2-methoxyethoxy)ethoxy]ethyl}sulfanyl)-2-methylbenzyl]sulfanyl}-lH- benzimidazole Compound 109
Figure imgf000053_0002
Mass spec' molecular ion: M+Na= 543
2- { [2-methyl-3-(3 ,6,9,12,15-pentaoxahexadec- 1 -ylsulfanyl)benzyl]sulfanyl } - 1H- benzimidazole
Compound 110
Figure imgf000053_0003
NMR:
600 MHz H-NMR (CHCI3-αO ppm 1.05 (d, 3H), 1.06 (d, 3H), 2.15 (m, 1H), 2.34 (s,
3H), 3.73 (d, 2H), 4.65 (s, 2H), 6.79 (d, 1H), 7.02 (d, 1H), 7.11 (t, 1H), 7.31 (t, 1H), 7.44 (t, 1H), 7.77 (d, 1H), 7.92 (d, 1H). 2-[(3-isobutoxy-2-methylbenzyl)sulfanyl]-l,3-benzothiazole Compound 111
Figure imgf000054_0001
NMR:
600 MHz 1H-NMR (CHCI3-d) ppm 1.10 (d, 6H), 2.16 (m, 1H), 2.39 (s, 3H), 3.76 (d, 2H), 4.66 (s, 2H), 6.83 (d, 1H), 7.07 (d, 1H), 7.15 (t, 1H), 7.28 (t, 1H), 7.32 (t, 1H), 7.47 (d, 1H),7.68(d, 1H).
2-[(3-isobutoxy-2-methylbenzyl)sulfanyl]- 1 ,3-benzoxazole Compound 112
Figure imgf000054_0002
Mass spec' molecular ion: M+H= 343
2-{[3-(isobutylsulfanyl)-2-methylbenzyl]sulfanyl}-lH-benzimidazole Compound 113
Figure imgf000055_0001
NMR:
300 MHz 1 H-NMR (CH3OH-αf4) ppm 2.26 (s, 3H), 2.43 (s, 3H), 3.29 (t, 2H), 4.40 (t,
2H), 4.49 (s, 2H), 4.89 (broad, >3H, exchangeable with D20), 7.02 (t, 1 H), 7.09-7.19
(m, 3H), 7.29 (d, 1 H), 7.36-7.49 (m, 2H), 7.79 (s, 1 H).
2-[(2-methyl-3-{ [2-(2-methyl-5-nitro-lH-imidazol-l-yl)ethyl]sulfanyl}benzyl)sulfanyl]-lH- benzimidazole
Compound 114
Figure imgf000055_0002
NMR:
300 MHz H-NMR (CHCI3-cJ) ppm 2.37 (s, 3H), 3.28 (t, 2H), 4.30 (t, 2H), 4.43 (s, 2H),
6.86-7.00 (m, 2H), 7.10-7.22 (m, 3H), 7.32-7.72 (broad, 2H), 7.87 (s, 1 H), 7.91 (s, 1 H). 2-[(2-methyl-3-{ [2-(lH-l,2,4-triazol-l-yl)ethyl]sulfanyl }benzyl)sulfanyl]-lH-benzimidazole Compound 115
Figure imgf000056_0001
Mass spec' molecular ion: M+H= 593 ethyl 2-{ [2-methyl-3-(3,6,9,12,15-pentaoxahexadec-l-ylsulfanyl)benzyl]sulfanyl }-lH- benzimidazole-5-carboxylate
Compound 116
Figure imgf000056_0002
Mass spec' molecular ion: M+Na= 599 l-(2-{ [2-methyl-3-(3,6,9,12,15-pentaoxahexadec-l-ylsulfanyl)benzyl]sulfanyl }-lH- benzimidazol-5-yl)-l-propanone Compound 117
Figure imgf000056_0003
Mass spec' molecular ion: M+Na= 558
2- { [2-methyl-3-(3,6,9, 12, 15-pentaoxahexadec- 1 -y lsulfanyl)benzyl]sulf anyl } - 1H- benzimidazol-5-amine Compound 118
Figure imgf000057_0001
Mass spec' molecular ion: M+Na= 573
(2-{ [2-methyl-3-(3,6,9,12,15-pentaoxahexadec-l-ylsulfanyl)benzyl]sulfanyl}-lH- benzimidazol-5-yl)methanol Compound 119
Figure imgf000057_0002
Mass spec' molecular ion: Mass spec' molecular ion: [M-H]- = 329 2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methoxyphenoxy}-l-ethanol Compound 120
Figure imgf000057_0003
Mass spec' molecular ion: M+Η= 450 2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methoxyphenoxy}ethyl phenylcarbamate Compound 121
Figure imgf000058_0001
Mass spec' molecular ion: M+H= 335
2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-chlorophenoxy}-l-ethanol Compound 122
Figure imgf000058_0002
Mass spec' molecular ion: M+Η= 454 2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-chlorophenoxy}ethyl phenylcarbamate The compounds of formula I above may be converted to a pharmaceutically-acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p- toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt.
The compounds of formula I can be prepared by a process comprising any one of steps (a) to (h) as follows:
(a) reducing compound VI
Figure imgf000058_0003
wherein R , 10 represents (CH2)d Or -(CH2)f.,-O-(CH2)e- and R represents H or Cι-6alkyl; or (b) reacting compound VII with R -NCO
Figure imgf000059_0001
wherein Z represents O or NH; or (c) reducing compound VIII
Figure imgf000059_0002
wherein R , 10 represents a bond, (CH2)dθr-(CH2)f-O-(CH )e-; or
(d) reacting compound VII with R6-COOH; or
(e) reacting compound IX with NHR4R5; or
Figure imgf000059_0003
(f) reacting compound X with NHR 4 Rr 5
Figure imgf000059_0004
wherein L1 represents a leaving group and R10 represents (CH2)d Or-(CH2)f -O-(CH2)e-; or
Figure imgf000059_0005
(g) reacting compound XI with R2-SH wherein L2 represents a leaving group; or (h) reducing compound XII
Figure imgf000059_0006
wherein R , 10 represents (CH2) θr -(CH2)f.rO-(CH2)e-. It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, 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 protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and rotective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991).
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. Experimental Scheme 1
Figure imgf000060_0001
Figure imgf000060_0002
3-[(2-Methoxy-2-oxoethyl)suIfanyl]-2-methylbenzoic acid
3-amino-2-methylbenzoic acid, 11.3 g, was dissolved in H2O (100 mL) and cone. HCL
(15 mL) was added at 0 °C NaNO2 (5.5 g) in H2O (40 mL) was added to the above suspension over 30min. The above diazonium salt was kept at 0°C and added slowly (over 40 min) to a solution of methyl thioglycolate, 8.48 g in 50 mL of MeOH at 60 °C. During the addition, the pH of the reaction medium was kept around 5 ~ 6 by adding sat. Na2CO very carefully. After the end of addition, the reaction was heated at 60 to 70 °C for additional 45min. The mixture was cooled to 0 °C and pH was adjusted to ~ 1 with cone. HCL & extracted with EtOAc, dried over Na2SO4, filtered, and the solvent was evaporated to give 17.4 g of crude 3-[(2-methoxy-2-oxoethyl)sulfanyl]-2-methylbenzoic acid. Methyl 2-{[3-(hydroxymethyl)-2-methylphenyl]sulfanyl}acetate
3-[(2-methoxy-2-oxoethyl)sulfanyl]-2-methylbenzoic acid, 15.4 g, was dissolved in 120 mL THF and cooled on an ice bath. Borane-THF solution, 130 mL (IM in THF) was added slowly. The reaction was stirred for 1 hour then quenched with ice water, extracted with EtOAc, dried over Na SO4, purified by flash chromatography (silica gel, CH2Cl2 EtOAc = 20/1) to give 5 grams of methyl 2-{ [3-(hydroxymethyl)-2-methylphenyl]sulfanyl}acetate. 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 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-methylphenyl]sulfanyl} 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 CH2C12 and 300 mL of 5% Na2CO3, the org. layer was collected, dried over Na2SO and evaporated to give 3.1 g methyl 2-({3-[(lH-benzimidazol- 2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)acetate as a light yellow solid. 2-({3-[(lH-Benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-ethanol
Methyl 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl }sulfanyl)acetate, 5.7 g, was dissolved in 100 mL TΗF and cooled on a ice-bath. Lithium aluminum hydride, 0.5 g was added portion-wise under ca 5 min. After 30 min the reaction was quenched with Glauber salt(Na2SO4xl0Η2O). Filtration and evaporation afforded 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)-l-ethanol, 4.1 g. Mass spec; M+H=331.
2-({3-[(l -Benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyI}sulfanyl)ethyl phenylcarbamate
100 g of 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l- ethanol was dissolved in 2 mL DMF, and 35 mg phenyl isocyanate was added, the mixture was stirred for 18 hours at room temp., and concentrated in vacuo. Purification by reverse phase ΗPLC gave 60 mg 2-({3-[(lH-benzimidazol-2-yIsulfanyl)methyl]-2-methylphenyl}- sulfanyl)ethyl phenylcarbamate as a white solid. Mass spec; M+Η=450. Scheme 2
Figure imgf000062_0001
2-({3-[(2-Azidoethyl)suIfanyl]-2-methylbenzyl}sulfanyl)-lH-benzimidazole
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-ethanol, 0.165 g, triphenylphosphine, 0.184 g, and sodium azide, 0.13 g, were combined with stirring in 4 mL DMF on an ice bath, carbon tetrabromide, 0.25 g, was added, and the reaction was allowed to proceed for 18 hours. 20 mL methylene chloride was added, the resulting suspension was filtered, the solids were rinsed with methylene chloride and the filtrate washed with brine, dried over Na2SO , and evaporated. Purification of the residue by flash chromatography (silica gel, EtOAc/Ηexane = 1:5 ) gave 2-({3-[(2-azidoethyl)sulfanyl]-2- methylbenzyl }sulfanyl)-lH-benzimidazole, 0.85 g. Mass spec; M+Η=356
2-({3-[(l_ /-BenzimidazoI-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethylamine
2-({3-[(2-azidoethyl)suIfanyl]-2-methylbenzyl}sulfanyl)-lH-benzimidazole, 0.42 g, was added to a suspension of 0.3 g lithium aluminum hydride in 10 mL TΗF over an ice bath. After 45 minutes, the reaction was quenched with Na2SO .10Η2O until H2 evolution ceased. The mixture was filtered, evaporated, dissolved in ethyl acetate and extracted with IN HCl. The aqueous layer was washed with ethyl acetate and evaporated to give 275 mg of 2-({3- [(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethylamine as a white solid. Mass spec; M+Η=330 N-[2-({3-[(lH-Benzimidazol-2-ylsuIfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2- pyrazinecarboxamide
To a solution of 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)ethylamine (658 mg), 2-pyrazinecarboxylic acid (248 mg), diisopropylethylamine (1 mL) and DMF (8 mL) was added ΗBTU (829 mg). The resulting mixture was stirred overnight. The mixture was transferred to a sep. funnel and diluted with EtOAc (200 mL) and washed with water (2 x 100 mL). The organic layer was washed with Sat. Brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase ΗPLC, C18 column (10-100% MeCN/Η2O) to give N-[2-({3-[(lH- benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2-pyrazinecarboxamide as 600mg white solid. Mass spec; M+Η=436
Scheme 3
Figure imgf000063_0001
2-({3-[(lH-BenzimidazoI-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)acetic acid
Methyl 2-({3-[( lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)acetate, 0.68 g, was dissolved in 14 mL MeOΗ and treated with excess LiOΗ dissolved in 2 mL Η2O for 1 h. The solvents were evaporated and the residue was partitioned between 100 mL 5% Νa2CO3 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. The combined organic layers were dried over MgSO and evaporated to leave 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)acetic acid as a white solid, 0.5 g. 2-({3-[(lH-Benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-(l- piperidinyl)-l-ethanone
100 mg of 2-({3-[(lH-Benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl }sulfanyl)acetic acid was dissolved in 2 mL of DMF, 30 mg piperidine and 120 mg of ΗBTU were added. The mixture was stirred for 18 hours, diluted with ethyl acetate, washed with 5% NaΗCθ3, saturated NaCl, dried over MgSO , and evaporated to give 2-({3- [( lH-benzimidazol-2-y lsulfany l)methy l]-2-methylphenyl } sulfanyl)- 1 -( 1 -piperidinyl)- 1 - ethanone, 110 mg. Mass spec; M+Η=412.
Scheme 4
Figure imgf000064_0001
2-({3-[(2-ChIoroethyl)sulfanyl]-2-methylbenzyl}suIfanyl)-lH-benzimidazole
0.38 g 2-({3-[(lH-Benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l- ethanol was combined with 5 mL CΗ2C12 and cooled to 0 °C. Excess SOCl2 was added. Cold bath removed. Suspension stirred at RT for 2 hours. Concentrated in vacuo, 0.39 g crude 2-({3-[(2-chloroethyl)sulfanyl]-2-methylbenzyl}sulfanyl)-lH-benzimidazole obtained. 2-[(2-methyl-3-{[2-(4-morpholinyl)ethyl]sulfanyl}benzyl)sulfanyl]-lH-benzimidazoIe
2-({3-[(2-Chloroethyl)sulfanyl]-2-methylbenzyl}sulfanyl)-lH-benzimidazole, 0.202 g, 1.3 mL morpholine, 3 mL DMF, and 1 mL DMSO combined and warmed at 80 °C for 1 day. Diluted to 100 mL with ethyl acetate. Washed with water, brine (2X), dried over MgSO , evaporated to give a thick oil. Purified via preparative ΗPLC to give 2-[(2-methyl-3-{ [2-(4- morpholinyl)ethyl]sulfanyl }benzyl)sulfanyl]-lH-benzimidazole as a fine powder, 0.12 g. Mass spec; M+Η=400.
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. Scheme 5
Figure imgf000065_0001
Methyl 2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenoxy}acetate
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 CH2C12 and 300 mL of 5% Na2CO3, the org. layer was collected, dried over Na2SO4 and evaporated to give 3.1 g methyl 2-{3-[(lH-benzimidazol-2- ylsulfanyl)methyl]-2-methylphenoxy}acetate as a light yellow solid. 2-{3-[(lH-Benzimidazol-2-ylsulfanyl)methyl]-2-methyIphenoxy}acetic acid
Methyl 2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenoxy}acetate, 0.68 g, was dissolved in 14 mL MeOΗ and treated with excess LiOΗ dissolved in 2 mL Η2O for 1 h. The solvents were evaporated and the residue was partitioned between 100 mL 5% Na2CO3 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. The combined organic layers were dried over MgSO4 and evaporated to leave 2-{3-[(lH-benzimidazol-2- ylsulfanyl)methyl]-2-methylphenoxy} acetic acid as a white solid, 0.5 g.
2-{3-[(l_ /-BenzimidazoI-2-ylsulfanyl)methyl]-2-methylphenoxy}-l-(4-morpholinyl)-l- ethanone 100 mg of 2- {3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenoxy} acetic acid was dissolved in 2 mL of DMF, 30 mg morpholine and 120 mg of ΗBTU were added. The mixture was stirred for 18 hours, diluted with ethyl acetate, washed with 5% NaΗCθ3, saturated NaCl, dried over MgSO4, and evaporated to give 2-{3-[(lH-benzimidazol-2- ylsulfanyl)methyl]-2-methylphenoxy}-l-(4-moφholinyl)-l-ethanone, 110 mg. 2-({2-Methyl-3-[2-(4-morpholinyl)ethoxy]benzyl}sulfanyl)-lH-benzimidazole
2-{3-[(lH-Benzimidazol-2-ylsulfanyl)methyl]-2-methylphenoxy}-l-(4-moφholinyl)- 1-ethanone, 0.7 g, was dissolve in 20 mL TΗF. 0.2 g lithium aluminum hydride was added, and the mixtue was warmed to 70 °C for 45 minutes. Na2SO -10Η2O was added, the mixture was filtered, concentrated and purified by column chromatography (SiO2 , ethyl acetate) to give 2-({2-methyl-3-[2-(4-moφholinyl)ethoxy]benzyl}sulfanyl)-lH-benzimidazole as a white foam, 0.42 g. Scheme 6
Figure imgf000066_0001
(3-Isobutoxy-2-methylphenyl)methanol
2-Methyl-3-hydroxymethylphenol [prepared by lithium aluminum hydride reduction of 2-methyl-3-hydroxybenzoic acid], 1 g, isobutyl bromide, 1.6 mL, and K2CO3, 3 g, were combined in 10 mL DMF and stirred at 70 °C for 1 day. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and evaporated to give (3-isobutoxy- 2-methylphenyl)methanol as a yellow waxy solid, 1.15 g. l-(3-Isobutoxy-2-methylbenzyl)-lH-benzimidazole
0.5 g (3-isobutoxy-2-methylphenyl)methanol was dissolved in 3 mL CΗ2C12. and 0.7 mL SOCl2 was carefully added. The mixture was stirred for 30 min., then concentrated to give crude l-(chloromethyl)-3-isobutoxy-2-methylbenzene. The crude chloride sample was dissolved in 3 mL DMF, and 0.26 g benzimidazole and 0.6 g K2CO were added. The suspension was stirred at rt overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO , and evaporated to give a residue which was purified by flash chromatography, silica gel, 20-50% ethyl acetate/Hexane. l-(3-isobutoxy-2- methylbenzyl)-lH-benzimidazole was thus obtained as an off-white solid, 0.6g. Mass spec; M+Η=295.
2-[(3-Isobutoxy-2-methylbenzyl)suIfanyl]-l//-benzimidazole
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 CH2C12 and 300 mL of 5% Na2CO3, the org. layer was collected, dried over Na2SO 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.
Compound 111 can be made by a similar scheme by using 2-mercaptobenzoxazole in place of 2-mercaptobenzimidazole. Scheme 7
Figure imgf000067_0001
2-({2-Methyl-3-[(2-pyrimidinylsulfanyl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate
To a solution of 135 mg of 2-{ [3-(chloromethyl)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate in 2 mL DMF was added 65 mg of 2-thiopyrimidine, and 600 mg K2CO3. The suspension was stirred vigorously at RT for 1.5 hrs. The mixture was diluted to 25 mL with ethyl acetate, washed with 15 mL water, 2 X 15mL IN KOΗ, 15mL brine, and dried over MgSO4. Evaporation gave a thick oil. Purification by flash chromatography, silica gel, 10- 30% ethyl acetate/hexane gave 2-({2-methyl-3-[(2- pyrimidinylsulfanyl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate as a waxy solid, 130 mg. Mass spec; M+H=412. Scheme 8
Figure imgf000068_0001
N-[2-({3-[(l_ -Benzimidazol-2-yIsulfanyl)methyl]-2-methylphenyI}sulfanyl)ethyl]-N'- phenylurea
100 mg of the 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)-l-ethanamine was dissolved in 2 mL of DMF and 36 mg of phenyl isocyanate was added. The mixture was stirred at rt overnight. The reaction was evaporated, and the crude compound was purified by reverse phase preparative ΗPLC to give N-[2-({3- [(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-N-phenylurea as a white powder, 85 mg. Mass spec; M+Η=449. Scheme 9
Figure imgf000068_0002
6-[2-({3-[(lH-Benzimidazol-2-yIsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethoxy]-3- nitroimidazo[l,2-6]pyridazine
To a solution of 330 mg of 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)-l -ethanol in 30 mL DMF was added 160 mg sodium hydride (60% dispersion in oil), the suspension was stirred for 30 min, then 199 mg of 6-chloro-3- nitroimidazo[l,2-£]pyridazine (Kobe, J.; Stanovnik, B.; Tisler, Miha. Tetrahedron (1968), 24(1), 239) was added. After stirring the suspension overnight at rt, 5 mL water was added carefully, then the mixture was concentrated under vacuum to leave a brown solid residue. The residue was stirred with acetone and filtered, the filtrate was concentrated and the resulting solids were rinsed with hot ethanol to yield 6-[2-({3-[(lH-benzimidazol-2- ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethoxy]-3-nitroimidazo[l,2-b]pyridazine as a light brown powder, 140 mg. Scheme 10
Figure imgf000069_0001
N-{[2-({3-[(lH-Benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)ethoxy]carbonyl}phenylalanine
25 mg of ethyl 2-({ [2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}- sulfanyl)ethoxy]carbonyl}amino)-3-phenylpropanoate was combined with 0.1 mL IM KOΗ, and 0.5 mL dioxane to give a clear solution. After stirring for lhr at rt the reaction was diluted with water, extracted twice with ethyl acetate, the aq layer was acidified with cone ΗC1 and extracted three times with ethyl acetate. The organic layer was dried over MgSO4 and evaporated to yield a clear oil. Trituration with 1: 1 ether/hexane gave N-{ [2-({3-[(lH- benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethoxy]carbonyl}phenylalanine as a white solid: 20 mg. Mass spec; M+Η=522. Scheme 11
Figure imgf000069_0002
-(2-{[3-({[tert-ButyI(dimethyl)silyl]oxy}methyl)-2-methylphenyl]sulfanyl}ethyl)-2/ - 1 ,2,3,4- tetraazole 2-{ [3-({ [tert-Butyl(dimethyl)silyl]oxy}methyl)-2-methylphenyl]sulfanyl }-l-ethanoI, 1.2 g, triphenylphosphine, 1.6 g, and tetrazole, 0.42 g, were combined in 10 mL THF to give a clear solution. The mixture was cooled to 0 °C, and 0.94 mL diethylazodicarboxylate was added. The reaction was allowed to slowly come to rt while stirring overnight. Evaporation and purification by flash chromatography, silica gel, 9: 1 hexane : ethyl acetate, gave 2-(2- { [3-({ [tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylphenyl]sulfanyl}ethyl)-2H-l,2,3,4- tetraazole as an oil, 770 mg. (2-Methyl-3-{[2-(2H-l,2,3,4-tetraazol-2-yI)ethyI]sulfanyl}phenyl)methanol
2-(2-{ [3-({ [tert-Butyl(dimethyl)silyl]oxy}methyl)-2-methylphenyl]sulfanyl}ethyl)-2H- 1,2,3,4-tetraazole, 770 mg, was dissolved in 20 mL TΗF and treated with 3 mL 75% aq.
TBAF (tetrabutylammonium fluoride). The solution was stirred at rt overnight, concentrated, diluted with ethyl acetate, washed with 10% citric acid, then brine and dried over Na2SO . Evaporation and purification by flash chromatography, silica gel, 1 : 1 hexane : ethyl acetate, gave (2-methyl-3-{ [2-(2H-l,2,3,4-tetraazol-2-yl)ethyl]sulfanyl}phenyl)methanol, 500 mg. 2-(2-{[3-(Chloromethyl)-2-methylphenyl]sulfanyl}ethyl)-2H-l,2,3,4-tetraazole To a solution of 100 mg of (2-methyl-3-{ [2-(2H-l,2,3,4-tetraazol-2- yl)ethyl]sulfanyl}phenyl)methanol in 4 mL methylene chloride at 0 °C was added 1 mL thionyl chloride. The cold bath was removed and the mixture was stirred at rt for 1.5 hrs. Evaporation to dryness gave 2-(2-{ [3-(chloromethyl)-2-methylphenyl]sulfanyl}ethyl)-2H- 1,2,3,4-tetraazole, 105 mg. lH-Benzimidazol-2-yl 2-methyl-3-{[2-(2H-l,2,3,4-tetraazol-2-yl)ethyl]sulfanyl}benzyI sulfide
2-(2-{ [3-(chloromethyl)-2-methylphenyl]sulfanyl}ethyl)-2H- 1,2,3,4-tetraazole, 105 mg, was dissolved in 2 mL DMF, 1 g K2CO3 and 100 mg 2-thiobenzimidazole were added and the suspension was stirred at rt overnight. The mixture was diluted with water, extracted with methylene chloride, washed with brine, dried over MgSO , and evaporated. Purification by flash chromatography, silica gel, 1.5 : 1 ethyl acetate : hexane gave lH-benzimidazol-2-yl 2-methyl-3-{ [2-(2H-l,2,3,4-tetraazol-2-yl)ethyl]sulfanyl}benzyl sulfide as an off-white solid, 70 mg. Mass spec; M+Η=383. Scheme 12
Figure imgf000071_0001
2-Chloro-3-(hydroxymethyl)phenol
2 g 2-chloro-3 -hydroxy benzaldehyde (Ginsburg, D. J.Amer.Chem.Soc. 1951(73), 702) was dissolved in 30 mL THF / 10 mL methanol / 20 mL IN KOH. 1 g NaBH4 was added.
After stirring at RT for 1.5 hrs, the mixture was diluted with water and extracted with ether
(2X). The aqueous layer was acidified with cone HCl, and extracted with ethyl acetate (2X).
The pooled ethyl acetate layer was dried over MgSO and evaporated to give 2-chloro-
3-(hydroxymethyl)phenol as a white solid, 2.02 g. [3-(2-{[te/tf-Butyl(dimethyl)silyl]oxy}ethoxy)-2-chlorophenyl]methanoI
2-Chloro-3-(hydroxymethyl)phenol, 0.317 g, K2CO3, 0.264 g, and (2- bromoethoxy)(tert-butyl)dimethylsilane, 0.429 mL, were combined in 10 mL acetonitrile.
The suspension was refluxed for 18 hrs, and an additional 0.2 mL (2-bromoethoxy)(tert- butyl)dimethylsilane was added. After refluxing the mixture an additional 24 hrs, it was filtered, and evaporated to give a crude residue. Purification by column chromatography (8:2 hexane : ethyl acetate) gave [3-(2-{ [tert-butyl(dimethyl)silyl]oxy}ethoxy)-2- chlorophenyl]methanol as a clear oil, 0.42 g.
{2-[3-(Bromomethyl)-2-chIorophenoxy]ethoxy}(tert-butyl)dimethylsilane
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.
2-{[3-(2-{[terr-Butyl(dimethyl)silyl]oxy}ethoxy)-2-chlorobenzyl]sulfanyI}-lH- benzimidazole 0.5 g {2-[3-(bromomethyl)-2-chlorophenoxy]ethoxy}(tert-butyl)dimethylsilane was combined with 0.2 g benzimidazole and 4 mL 1 M NaOH in 12 mL ethanol. The solution was stirred for 2.5 hrs, and the ethanol was evaporated to yield a slurry. Dilution with ethyl acetate, extraction with water, then sat. NaCl gave a clear solution. The solution was dried over MgSO4, and evaporated to give 2-{ [3-(2-{ [tert-butyl(dimethyl)silyl]oxy}ethoxy)-2- chlorobenzyl]sulfanyl}-lH-benzimidazole as a white foam, 0.53 g.
2-{3-[(lH-Benzimidazol-2-ylsulfanyI)methyI]-2-chlorophenoxy}-l-ethanol
0.53 g 2-{ [3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-chlorobenzyl]sulfanyl}-lH- benzimidazole was dissolved in 10 mL TΗF and 0.52 mL 2.73 M aqueous tetrabutylammonium fluoride was added. The solution was stirred for 2 hrs, diluted with water, and extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried over MgSO and evaporated to yield 2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- chlorophenoxy}-l-ethanol as 0.4 g white foamy oil.
2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-chlorophenoxy}ethyl phenylcarbamate 0.4 g 2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-chlorophenoxy}-l-ethanol was dissolved in 5 mL chloroform and 0.15 mL phenyl isocyante was added. The mixture was stirred at RT for 2 hrs, diluted with chloroform, washed with water, and sat. NaCl. The solution was dried over MgSO and evaporated to yield 2-{3-[(lH-benzimidazol-2- ylsulfanyl)methyl]-2-chlorophenoxy}ethyl phenylcarbamate as 0.52g white solid. Compounds 119 and 120 can be made by a similar route, but using 2-methoxy- 3-(hydroxymethyl)phenol (see Chemistry Letters, 1986,871) in place of 2-chloro- 3-(hydroxymethyl)phenol. Scheme 13
Figure imgf000073_0001
Figure imgf000073_0002
Methyl 2-methyl-3-[2-(2-(2-methoxyethoxy)ethoxy)ethoxy]benzoate
Methyl 2-methyl-3-hydroxybenzoate [Fringuelli, F.; Mancini, V.; Taticchi, A. Tetrahedron, 1969, 25, 4249] ( 0.5 g) was dissolved in 10 mL MeCN, anhydrous K2CO3 ( 1 g) was added followed by 2-[2-(2-methoxyethoxy)ethoxy]ethyl methanesulfonate [prepared by reaction of the corresponding alcohol with methanesulfonyl chloride] (1.09 g). The mixture was allowed to react at reflux over night, cooled, filtered, and taken to dryness. The residue was dissolved in CH2C12 and washed with diluted NaOH (aq) and brine. The organic layer was collected, dried, and evaporated furnishing 0.56g of the title compound which was used without further purification. 2-Methyl-3-[2-(2-(2-methoxyethoxy)ethoxy)ethoxy]benzyl alcohol
A solution of Methyl 2-methyl-3-[2-(2-(2-methoxyethoxy)ethoxy)ethoxy]benzoate
(2.1 mmol) in THF (10 mL) was gently added to a stirred suspension of LiAlH4 (4.5 mmol) in 20 mL THF, then heated to reflux for 2 hours. The reaction was quenched with 0.25 mL water, 0.5 mL 2M NaOH, and 0.25 mL water. The mixture was refluxed for another hour and then filtered to remove the solids. The filtrate was evaporated affording 0.28 g of the title compound. 2-Methyl-3-[2-(2-(2-methoxyethoxy)ethoxy)ethoxy]benzyl chloride
2-Methyl-3-[2-(2-(2-methoxyethoxy)ethoxy)ethoxy]benzyl alcohol (1.1 mmol) was dissolved 5 mL CH2C12 and treated with 0.2 mL SOCl2 for 30 min at ambient temperature.
The solvent and excess reagent were evaporated leaving a quantitative yield of the title compound which was used immediately in the next step.
2-[(3-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}-2-methylbenzyl)suIfanyl]-lH- benzimidazole
2-mercaptobenzimidazole (0.18 g, 1.18 mmol), suspended in 3 mL MeOH, was treated with 2 M NaOH (1.3 mL, 2.6 mmol) and allowed to form a solution. 2-Methyl-3-[2-(2-(2- methoxyethoxy)ethoxy)ethoxy]benzyl chloride (0.33 g, 1.08 mmol) was added and reacted for 18 h at ambient temperature. The solvents were evaporated and the residue partitioned between water and CH2C12 (4 x 25 mL). The organic layers were combined, dried, and evaporated. Reverse phase preparative LC afforded 115 mg (26%) of the title compound.
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.
Scheme 14
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000075_0003
2-Methyl-3-mercapto-benzoic acid
3-Amino-2-methylbenzoic acid, 11.3 g, was dissolved in H2O (100 mL) and cone HCL (15 mL) was added at 0 °C. NaNO2 (5.5g) in H2O (40 mL) was added to the above suspension over 30min. The above diazonium salt was kept at 0 °C and added slowly (over 40 min) to a solution of potassium ethylxanthogenate (14 g) while the pH continually was adjusted to 8 with Na2CO3. The mixture was stirred for 30 minutes, cooled to ambient temperature, and poured onto a mixture of 300 mL concentrated HCl and 700 mL of ice water. The precipitate was collected, taken up in water (300 mL), and treated with NaOH (6 g) at reflux for 20 h. The mixture was poured onto a mixture of 40 mL concentrated HCl in 300 mL ice water and extracted with 3 x 500 mL CH2C12. The combined organic layers were dried and evaporated furnishing 7 g of the title compound as yellow crystals (which slowly oxidized to the corresponding disulfide upon standing) 2-Methyl-3-mercapto-methylbenzoate
2-Methyl-3-mercapto-benzoic acid (14.7 g) was dissolved in 250 mL of MeOH and a few drops of cone H2SO was added. The mixture was heated to reflux for 48 hours and then allowed to cool to ambient temperature before the bulk MeOH was evaporated. The residue was dissolved in Et2θ and washed with 4 x 50 mL H2O and 50 mL brine. The organic layer was collected, dried, and evaporated leaving 14.8 g of the title compound as a viscous yellow oil (which slowly oxidized to the corresponding disulfide upon standing. 2-Methyl-3-mercapto-benzyIalcohol
A solution of 2-Methyl-3-mercapto-methylbenzoate (2.0 g) in THF (5 mL) was added drop wise to a suspension of LiAlH4 (1.32 g) in THF (100 mL) under dry and inert conditions. The mixture was heated to reflux for 2 h and then quenched with 2 mL of water, 4 mL of 2 M NaOH, and another 2 mL of water. After refluxing for another hour, solids were filtered off and washed with THF and methanol. The combined filtrates were evaporated and the residue partitioned between 2M HCl and EtOAc. The organic layer was collected, dried, and evaporated to yield 1.9 g 2-Methyl-3-mercapto-benzylalcohol, contaminated with the corresponding disulfide as an oil. This material could be used in the next step without further purification. 2-Methyl-3-(2-(2-(2-methoxyethoxy)ethoxy)ethylthio)benzyl alcohol
A mixture of 2-Methyl-3-mercapto-benzylalcohol and its disulfide (50 mg, 0.325 mmol monomer) in dioxane/water (4/1) (1 mL) and a small amount of concentrated HCl was reacted with PPh3 (26 mg, 0.1 mmol) for 1 h at ambient temperature in an inert atmosphere. The solvents were removed and the residue taken up in MeCN (1 mL) and reacted with Et3N (290 mL, 2.08 mmol) and 2-[2-(2-methoxyethoxy)ethoxy]ethyl methanesulfonate [prepared by reaction of the corresponding alcohol with methanesulfonyl chloride] (0.30 g, 1.24 mmol) for 3 days at ambient temperature. The solvent was evaporated and the residue partitioned between EtOAc and water. The organic layer was collected, dried, and taken to dryness. The product was purified on silica gel (pentane/Et2O; 6/4 to 0/10) furnishing 50 mg of the title compound as a colorless oil. 2-Methyl-3-[2-(2-(2-methoxyethoxy)ethoxy)ethylthio]benzyl chloride 2-Methyl-3-(2-(2-(2-methoxyethoxy)ethoxy)ethylthio)benzyl alcohol (0.17 mmol) was dissolved in 2 mL CH2C12 and treated with 0.1 mL SOCl2 for 30 min at ambient temperature. The solvent and excess reagent were evaporated leaving a quantitative yield of the title compound which was used immediately in the next step. 2-{[3-({2-[2-(2-Methoxyethoxy)ethoxy]ethyl}sulfanyl)-2-methylbenzyl]sulfanyl}-lH- benzimidazole
2-Mercaptobenzimidazole (0.33 g, 2.16 mmol), suspended in 6 mL MeOH, was treated with 2 M NaOH (2.6 mL) and allowed to form a solution. 2-Methyl-3-[2-(2-(2- methoxyethoxy)ethoxy)ethylthio]benzyl chloride (0.58 g, 1.80 mmol) was added and reacted for 18 h at ambient temperature. The solvents were evaporated and the residue partitioned between water and CH2CI2 (4 x 25 mL). The organic layers were combined, dried, and evaporated. Reverse phase preparative LC afforded 0.47 g of the title compound. 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
Figure imgf000078_0001
ASSAYS
Microdilution assay The microdilution assay tests the anti-H. pylori activity of compounds. In this assay,
MICs (Minimum Inhibitory Concentrations) were determined against four H pylori strains, including ATCC 43504, that exhibit different susceptibilities to known antibiotics. 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 (OD600 of 0.6) and 50 μl of these cultures were inoculated into each well to give a final concentration of 107 cells per mL (OD60o 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 (OD600) with a plate reader (Molecular Devices, Sunnyvale, California). The plates were incubated in a controlled microaerophilic atmosphere (5% O2, 10% CO2 and 85% N2) 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 <10μg/mL are indicative of anύ-Helicobacter pylori activity. Compounds according to the invention were tested in this assay and give MIC values in this range. Selectivity Assays
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 effects on both aerobic ["Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fourth Edition; Approved Standard" NCCLS Document M7-A4 Vol. 17 No. 2, January 1997] and anaerobic ["Methods for Antimicrobial Susceptibility Testing of anaerobic Bacteria -Third Edition; Approved Standard" NCCLS Document Ml 1-A3 Vol. 13 No. 26, December 1993] organisms were measured. Compounds of the invention had no effect in these assays at concentrations of greater than ten times the corresponding MICs determined vs. Helicobacter pylori in the microdilution assay. 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). If desired, 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. 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.
The following illustrate representative pharmaceutical dosage forms containing the compound of the invention, or a pharmaceutically acceptable salt or solvate thereof (hereafter referred to as "compound X"), for therapeutic or prophylactic use in humans, (a)
Figure imgf000080_0001
(d)
Figure imgf000081_0001
Buffers, pharmaceutically acceptable co-solvents (e.g., polyethylene glycol, propylene glycol, glycerol or EtOH) or complexing agents such as hydroxy-propyl β 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. By "therapeutic treatment", we mean the eradication or suppression of a pre-existing Helicobacter pylori infection in the host.
In a further aspect of the invention, there is provided a method of therapeutically treating or preventing Helicobacter pylori infection in a mammal (e.g., a human), the method comprising administering (e.g., orally) to the mammal a compound of formula I or a pharmaceutical formulation as described above. By "therapeutically treating", we mean bringing about the eradication or suppression of a pre-existing Helicobacter pylori infection in the host.

Claims

CLAIMS:
1. A compound of formula I or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000082_0001
wherein:
X is S; SO2; NH; N(C1-6alkyl); O or CH2;
Y is C,.6alkyl; O(C3.8cycloalkyl); O(C1-6alkyl); Hal; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen; NRR', wherein R and R' independently represent H or Cι.8alkyl, or NRR' represents an optionally substituted C3-8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR" or COR", R" representing H or C1-6alkyl; or CH2OH; R' is -(CH2)a-R3; -((CH2)bO)c-R3; -(CH2)d-R3'; -(CH2)aC(=O)R3; -(CH2)dC(=O)R3';
-((CH2)e-O)c'-(CH2)f-R3'; R3 or R3';
R2 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; R3 is H; Cι_6alkyl; optionally substituted C3-8cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C5-10aromatic 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;
RJ is -Z-M wherein Z represents O, S or NH and M represents H, an optionally substituted mono- or bi- cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S, or an optionally substituted Cs.ioaromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M represents -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9 or -NC(=O)R8;
For R6 and R7, either: (i) R6 is H;
Figure imgf000082_0002
optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; optionally substituted (Cι-8alkyl)aryl wherein the aryl is C6_ιo; optionally substituted (Cι-8alkyl)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 or R represents a mono-, bi- or tri-cyclic C3-ι3cycloalkyl; optionally substituted C6-ι0aryl; 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; or -C(=O)- O-Ar, wherein Ar represents optionally substituted C6-ι0aryl; and
R7 is H; or (ii) the structure -NR6R7 represents a C3.8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S, -NR6R7 being optionally substituted; a represents an integer 1, 2, 3, 4 or 5; each b independently represents an integer 1, 2, 3, 4 or 5; c represents an integer 1, 2, 3, 4 or 5; c' represents an integer 1, 2, 3, 4 or 5; d represents an integer 1, 2, 3, 4 or 5; each e independently represents an integer 1, 2, 3, 4 or 5; f represents an integer 1, 2, 3, 4 or 5; and g represents zero or an integer 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt or solvate thereof.
2 2. A compound according to Claim 1, wherein: a is 1, 2 or 3; b is 2; c' is 1, 2, 3. 4 or 5; d is 1, 2 or 3; e is 2; f is 1, 2 or 3; and g is 1 or 2.
3. A compound according to Claim 2, having the general structure lb
Figure imgf000083_0001
wherein:
X is S, S(=O), S(=O)2 or O;
Y is C,.6alkyl, O(C,.6alkyl), Hal; CHal3, CHHal2> CH2Hal, OCHal3, OCHHal2 or OCH2Hal; R1 is -(CH2)a-R3, -((CH2)2O)c-R3, -(CH2)d-R3', -(CH2)aC(=O)R3, -(CH2)dC(=O)R3',
-((CH2)2θ)c-(CH2)f-R3';
R3 is Cι_6alkyl; optionally substituted C3-8cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C5-ι0aromatic 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;
R3' is -Z-M wherein Z represents O, S or NH and M represents H, an optionally substituted mono- or bi- cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure 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 an optionally substituted C5.10 aromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M represents -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9 or -NC(=O)R8; For R6 and R7, either: (i) R6 is H;
Figure imgf000084_0001
optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; optionally substituted (Cι.8alkyl)aryl wherein the aryl is C6-ιo; optionally substituted (Cι-8alkyl)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 C3-ι3cycloalkyl; optionally substituted C6.ι0aryl; 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, 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 -C(=O)-O-Ar, wherein Ar represents optionally substituted C6-ιoaryl; and R7 is H; or (ii) the structure -NR6R7 represents a C3-8 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; -NR6R7 being optionally substituted; or a pharmaceutically acceptable salt or solvate thereof.
4. A compound according to Claim 3, wherein: X is S or O; R1 is -(CH2)2R3, -(CH:)2R3' , -CH2C(=O)R3 or -CH2C(=O)R3' ; and
R3 is optionally substituted C3-8cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O. N and S; optionally substituted C5-ιoaromatic 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.
5. A compound according to either Claim 1, 2 or 3, wherein R1 is selected from -iso-Bu, -(CH2CH2O)3CH3, -(CH2CH2)-4-moφholinyl, -(CH2CH2O)5CH3, -(CH2CH2)-l-(2-methyl-5- nitro-imidazolyl), -(CH2CH2)-l-(l,2,4-triazolyl), and -(CH2CH2)-OC(=O)NH-Ph.
6. A compound according to any one of Claims 1, 2 or 3, wherein R2 represents
Figure imgf000085_0001
wherein:
Q is CH or N; Q' is NH, O or S;
W is CH or N; W' is CH or N; and
R8 is C1-6alkyl; O(C3.8cycloalkyl); O(C,.6alkyl); Hal; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen; NRR', wherein R and R' independently represent H or Cι-8alkyl, or NRR' represents an optionally substituted C -8heterocyclic 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; COOR9 or COR9, R9 representing H or C|.6al yl; or CH2OH.
7. A compound of Claim 1, wherein R1 is -(CH2)a-CH3 or -((CH2)bO)c-CH3.
8. A compound according to Claim 2, wherein R3' is selected from -4-moφholinyl, - l-(2-methyl-5-nitro-imidazolyl), -l-(l,2,4-triazolyl) and -OC(=O)NH-Ph.
9. A compound according to any one of Claims 1 through 8, wherein g is 1.
10. A compound of Claim 1, wherein the compound is selected from:
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methyIphenyl}sulfanyl)-l-ethanol;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl isopropylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 4- phenoxyphenylcarbamate ; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl pentylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2,5- dimethylphenylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl (15,2/?)-2- phenylcyclopropylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl cyclohexylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl
3-(methylsulfanyl)phenylcarbamate; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl pheneth y lcarbamate ;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2-(2- thienyl)ethylcarbamate; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl methylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2- methylphenylcarbamate; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3- methoxypheny lcarbamate ;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 4- fluoropheny lcarbamate ;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl benzylcarbamate; methyl 3-({ [2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl }sulfanyl)ethoxy]carbonyl }amino)benzoate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3,4- dichlorobenzylcarbamate; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3,4- difluorophenylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenyl dicarbonimidoate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3- bromophenylcarbamate;
2-( { 3-[( lH-benzimidazol-2-y lsulfanyl)methyl]-2-methylphenyl } sulfanyl)ethyl 3- methylbenzylcarbamate; ethyl 2-({ [2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)ethoxy]carbonyl}amino)-3-phenylpropanoate; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyI]-2-methylphenyl}sulfanyl)ethyl 3,5-dimethyl-4- isoxazolylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3- acetylphenylcarbamate;
2-({ 3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl benzoylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl 4-chloro-2- methy lpheny lcarbamate ; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 4- methoxybenzylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3,4- dichlorophenylcarbamate; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl
4-(dimethylamino)phenylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2,5- dichlorophenylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 3,5- dimethoxyphenylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2,4- dimethoxyphenylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl (l/?)-l- phenylethylcarbamate; ethyl 4-({ [2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl }sulfanyl)ethoxy]carbonyl }amino)benzoate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 2- ethylphenylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl 4- fluorobenzoylcarbamate;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethylamine;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]benzamide;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)ethyl]cyclohexanecarboxamide; N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2-[(45)-
2,5-dioxoimidazolidinyl]acetamide; tert-butyl 4-({ [2-({ 3-[(lH-benzimi dazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)ethyl]amino}carbonyl)-l-piperidinecarboxylate;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2- pyrazinecarboxamide;
2-(l-adamantyl)-N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl }sulfanyl)ethyl]acetamide; N-[2-({ 3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2-(l,3- dimethyI-2,6-dioxo-l,2,3,6-tetrahydro-7H-purin-7-yl)acetamide;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethyl]-2- furamide; N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-5-nitro-2- furamide;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-2- thiophenecarboxamide;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-l- benzofuran-2-carboxamide;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-l-ethyl-3- methyl-lH-pyrazole-5-carboxamide;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl}sulfanyl)ethyl]nicotinamide; N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-4- quinolinecarboxamide;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-3,5- dimethyl-4-isoxazolecarboxamide;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-5- isoxazolecarboxamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)acetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N- cyclopropylacetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(l,3-benzodioxol- 5-ylmethy)acetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-(l-piperidinyl)-l- ethanone;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(2- f ury Imethy l)acetamide ; 2-({3-[(lH-benzimidaz:ol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N- cyclohexylacetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(tetrahydro-2- furanylmethyl)acetamide; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N- cyclopentylacetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)-N-(2- thienylmethyl)acetamide; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-[2-(4- moφholinyl)ethyl]acetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(2,3-dihydro-lH- inden-2-yl)acetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-benzylacetamide; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(2,5- dimethoxyphenethyl)acetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-[2-(2- pyridinyl)ethyl] acetamide ;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-[2-(l-methyl-2- pyrrolidinyl)ethyl] acetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(3,3- diphenylpropyl)acetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N- phenethylacetamide; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylρhenyl}sulfanyl)-N-(4- methoxyphenethyl)acetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-hexylacetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N- isobutylacetamide; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(4- pyridiny Imethy l)acetamide ;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)acetyl]-2- furohydrazide;
2-({3-[(lH-benzimidazol-2-ylsuIfanyl)methyl]-2-methylphenyl}sulfanyl)-l-octahydro-l(2H)- quinolinyl-1-ethanone;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-
N-(benzyloxy)acetamide; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)-l-[4-(2- methoxyphenyl)-l -piperazinyl]- 1-ethanone;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-[6,7-dimethoxy-
3,4-dihydro-2(lH)-isoquinolinyl]-l-ethanone; 2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-N-(4- butylphenyl)acetamide;
2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)-l-(4-methyl-l- piperaziny 1)- 1 -ethanone;
2-[(2-methyl-3-{ [2-(4-moφholinyl)ethyl]sulfanyl}benzyl)sulfanyl]-lH-benzimidazole; 2-[(2-methyl-3-{ [2-(4-methyl-l-piperazinyl)ethyl]sulfanyl}benzyl)sulfanyl]-lH- benzimidazole;
2-({3-[(lH-imidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate;
2-[(2-methyl-3-{[(5-phenyl-l,3,4-oxadiazol-2-yl)sulfanyl]methyl }phenyl)sulfanyl]ethyl phenylcarbamate; 2-({2-methyl-3-[(2-pyrimidinylsulfanyl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate;
2-[(2-methyl-3-{ [(l-phenyl-lH-l,2,3,4-tetrazol-5-yl)sulfanyl]methyl }phenyl)sulfanyl]ethyl phenylcarbamate;
2-[(3-{ [(4,5-diphenyl-lH-imidazol-2-yl)sulfanyl]methyl}-2-methylphenyl)sulfanyl]ethyl phenylcarbamate; 2-({3-[(3H-imidazo[4,5-c]pyridin-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate;
2-({3-[(l,3-benzoxazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate;
2-({2-methyl-3-[(2-pyridinylsulfanyl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate;
2-({2-methyl-3-[(4-pyridinylsulfanyl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate; 2-[(2-methyl-3-{[(4-phenyl-l,3-thiazol-2-yl)sulfanyI]methyl}phenyl)sulfanyl]ethyl phenylcarbamate;
2-({2-methyl-3-[(l,3-thiazol-2-ylsulfanyl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate;
2-[(3-{ [(5-methoxy-lH-benzimidazol-2-yl)sulfanyl]methyl }-2-methylphenyl)sulfanyl]ethyl phenylcarbamate; N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-N- phenylurea;
N-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfanyl)ethyl]-N-(2- pyrazinyl)urea; 6-[2-({3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl }sulfanyl)ethoxy]-3- nitroimidazo[l,2-b]pyridazine;
2-[(2-methyl-3-{ [2-(2H-l,2,3,4-tetrazol-2-yl)ethyl]sulfanyl }benzyl)sulfanyl]-lH- benzimidazole; 2-[(2-methyl-3-{ [2-(2H-l,2,3,4-tetrazol-2-yl)ethyl]sulfanyl }benzyl)sulfanyl]-3H-imidazo[4,5- c]pyridine;
2-[(3-isobutoxy-2-methylbenzyl)sulfanyl]-lH-benzimidazole;
2-({2-methyl-3-[2-(4-moφholinyl)ethoxy]benzyl}sulfanyl)-lH-benzimidazole;
2-[(3-isobutoxy-2-methylbenzyl)sulfanyl]-lH-indole; 2-[(3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-2-methylbenzyl)sulfanyl]-lH-benzimidazole;
2-{ [2-methyl-3-(3,6,9,12,15-pentaoxahexadec-l-yloxy)benzyl]sulfanyl}-lH-benzimidazole;
2- { [3-( { 2-[2-(2-methoxyethoxy)ethoxy]ethyl } sulfanyl)-2-methylbenzyl]sulfanyl } -1H- benzimidazole;
2- { [2-methyl-3-(3,6,9, 12, 15-pentaoxahexadec- 1 -ylsulfanyl)benzyl]sulfanyl } - 1H- benzimidazole;
2-[(3-isobutoxy-2-methylbenzyl)sulfanyl]-l,3-benzothiazole;
2-[(3-isobutoxy-2-methylbenzyl)sulfanyl]-l,3-benzoxazole;
2-{ [3-(isobutylsulfanyl)-2-methylbenzyl]sulfanyl}-lH-benzimidazole;
2-[(2-methyl-3-{ [2-(2-methyl-5-nitro-lH-imidazol-l-yl)ethyl]sulfanyl }benzyl)sulfanyl]-lH- benzimidazole;
2-[(2-methyl-3-{ [2-(lH-l,2,4-triazol-l-yl)ethyl]sulfanyl}benzyl)sulfanyl]-lH-benzimidazole; ethyl 2- { [2-methy l-3-(3 ,6,9, 12,15-pentaoxahexadec- 1 -ylsulfanyl)benzyl]sulfanyl } - 1H- benzimidazole-5-carboxylate; l-(2-{ [2-methyl-3-(3,6,9,12,15-pentaoxahexadec-l-ylsulfanyl)benzyl]sulfanyl}-lH- benzimidazol-5-yl)-l-propanone;
2- { [2-methyl-3-(3,6,9, 12, 15-pentaoxahexadec- l-ylsulfanyl)benzyl]sulfanyl } - 1H- benzimidazol-5-amine;
(2- { [2-methyl-3-(3 ,6,9,12, 15-pentaoxahexadec- 1 -y lsulfanyl)benzyl]sulfanyl } - 1H- benzimidazol-5-yl)methanol; 2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methoxyphenoxy}-l-ethanol;
2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-methoxyphenoxy}ethyl phenylcarbamate;
2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-chlorophenoxy }-l-ethanol; and 2-{3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2-chlorophenoxy}ethyl phenylcarbamate; N-{ [2-({ 3-[(lH-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl }sulfanyl)ethoxy]carbonyl }phenylalanine; or a pharmaceutically acceptable salt or solvate thereof.
11. A compound according to Claim 1, wherein the compound is selected from compounds II, III, IV and V
Figure imgf000093_0001
wherein,
For R4 and R5, either: (i) R is H; Cι-8alkyl; optionally substituted C3.8cycloalkyl optionally fused to a benzo ring; Z"-(Cι-8alkyl)aryl, wherein Z2 represents O or a bond, and the aryl is C6-ιo, optionally substituted and optionally fused to a C5.10 heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, Ν and S; optionally substituted C6.ι0aryl; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, Ν and S; (Cι_8alkyl)-R, wherein R represents an optionally substituted mono- or bi-cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted -C(=O)O(Cι-8alkyl); optionally substituted -C(=O)O-phenyl; optionally substituted -C(=O)(Cι.8alkyl); optionally substituted -C(=O)-phenyl; or -NHC(=O)R6; and R5 is H; Ci.8alkyl; optionally substituted C .8cycloalkyl optionally fused to a benzo ring; (Cι_8alkyl)aryl wherein the aryl is C6-ι0 and optionally substituted; optionally substituted C6-ιoaryl; 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 (ii) the structure -NR R5 represents a C3.8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6.ιoring structure, -NR4R5 being optionally substituted.
12. A compound according to any one of Claims 1 through 11 for use as a medicament.
13. A pharmaceutical formulation comprising a compound according to any one of Claims 1 through 11 and a pharmaceutically acceptable diluent or carrier.
14. Use of a compound according to any one of Claims 1 through 11, in the manufacture of a medicament, for the therapeutic and/or prophylactic treatment of Helicobacter pylori infection in a mammalian host.
15. A method of therapeutically treating and/or preventing Helicobacter pylori infection in a mammal, comprising administering to the mammal a compound according to any one of Claims 1 to 11.
16. A process for preparing a compound according to Claim 1, wherein the process comprises the steps of: (a) reducing compound VI
Figure imgf000094_0001
wherein R10 represents (CH2)d or -(CH2)f.ι-O-(CH2)e- and R1 ' represents H or Cι.6alkyl; or (b) reacting compound VII with R -NCO
Figure imgf000095_0001
wherein Z represents O or NH; or (c) reducing comound VIII
Figure imgf000095_0002
wherein R , 10' represents a bond, (CH2)dOr-(CH2)f-O-(CH2)e-; or
(d) reacting compound VII with R6-COOH; or
(e) reacting compound IX with NHR4RD; or
Figure imgf000095_0003
(f) reacting compound X with NHR 4 Rr,5
Figure imgf000095_0004
wherein L represents a leaving group and R 10' represents (CH2)d θr-(CH2)f -O-(CH2)e-; or
(g) reacting compound XI with R2-SH
Figure imgf000095_0005
wherein L represents a leaving group; or (h) reducing compound XII
Figure imgf000095_0006
wherein, For R4 and R5, either: (i) R4 is H; Cι.8alkyl; optionally substituted C3.8cycloalkyl optionally fused to a benzo ring; Z2-(Cι_8alkyl)aryl, wherein Z represents O or a bond, and the aryl is C6.ι0, optionally substituted and optionally fused to a C5-ιo heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted C6.ι0aryl; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, N and S; (Cι_8alkyl)-R, wherein R represents an optionally substituted mono- or bi-cyclic 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted -C(=O)O(Cι-salkyl); optionally substituted -C(=O)O-phenyl; optionally substituted -C(=O)(Cι.8alkyl); optionally substituted -C(=O)-phenyl; or -NHC(=O)R5; and
R5 is H; Cι_8alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; (Cι-8alkyl)aryl wherein the aryl is C6-ι0 and optionally substituted; optionally substituted Cό-ioaryl; 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
(ii) the structure -NR4R5 represents a C3-8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6-ιoring structure, -NR R5 being optionally substituted;
R6 is H; Cι.ι2alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; optionally substituted (Cι_8alkyl)aryl wherein the aryl is C6-ιo; optionally substituted (Cι-8alkyl)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 or R represents a mono-, bi- or tri-cyclic C3-ι cycloalkyl; optionally substituted C6.ιoaryl; 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; or -C(=O)- O-Ar, wherein Ar represents optionally substituted C6_ιoaryl; and
R10 is (CH2)dor -(CH2)f.ι-O-(CH2)e-.
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