EP1784182A1 - 2-sulfanyl-benzimidazol-1-yl-acetic acid derivatives as crth2 antagonists - Google Patents

2-sulfanyl-benzimidazol-1-yl-acetic acid derivatives as crth2 antagonists

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Publication number
EP1784182A1
EP1784182A1 EP05778612A EP05778612A EP1784182A1 EP 1784182 A1 EP1784182 A1 EP 1784182A1 EP 05778612 A EP05778612 A EP 05778612A EP 05778612 A EP05778612 A EP 05778612A EP 1784182 A1 EP1784182 A1 EP 1784182A1
Authority
EP
European Patent Office
Prior art keywords
benzoimidazol
acetic acid
propylsulfanyl
amino
ethylsulfanyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05778612A
Other languages
German (de)
French (fr)
Inventor
Heinz Fretz
Kurt Hilpert
Markus Riederer
Matthias Steger
Julien Pothier
Markus Gude
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Priority to EP05778612A priority Critical patent/EP1784182A1/en
Priority claimed from PCT/EP2005/009083 external-priority patent/WO2006021418A1/en
Publication of EP1784182A1 publication Critical patent/EP1784182A1/en
Withdrawn legal-status Critical Current

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Definitions

  • the present invention relates to 2-sulfanyl-benzoimidazol-l-yl-acetic acid derivatives and their use as potent "chemoattractant receptor-homologous molecule expressed on Th2 cells" (hereinafter called CRTH2) antagonists in the treatment of prostaglandin mediated diseases, to pharmaceutical compositions containing these derivatives and to processes for their preparation.
  • CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 cells
  • such derivatives may be used in pharmaceutical compositions for the treatment of both chronic and acute allergic/immune disorders comprising allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases, such as Churg-Strauss syndrome and sinusitis, basophil-related diseases, such as basophilic leukemia and basophilic leukocytosis in humans and other mammals.
  • COPD chronic obstructive pulmonary disease
  • Prostaglandin D2 is a known agonist of the thromboxane A2 (TxA2) receptor, the PGD2 (DP) receptor and the recently identified G-protein-coupled "chemoattractant receptor-homologous molecule expressed on Th2 cells" (CRTH2).
  • cytokines interleukin-4, IL-13, and IL-5
  • IgE immunoglobulin E synthesis
  • mast cell growth and differentiation upregulation of CD23 expression
  • IgE immunoglobulin E synthesis
  • CD23 upregulation of CD23 expression
  • the stimulated release of the array of mediators causes end-organ damage, including constriction and hyperresponsiveness, vascular permeability, edema, mucous secretion, and further inflammation.
  • CRTH2 is preferentially expressed on Th2 cells and is a chemoattractant receptor for PGD2 that mediates PGD2-dependent migration of blood Th2 cells.
  • Chemoattractants are responsible for the recruitment of both Th2 cells and other effector cells of allergic inflammation and may provide the conceptual basis for the development of new therapeutic strategies, especially in allergic conditions.
  • (2-fert.-butoxycarbonyl-l, 2, 3, 4- tetrahydro-pyrido[4,3-b]indol-5-yl)-acetic acid and (2-ethoxycarbonyl-l, 2, 3, 4- tetrahydro-pyrido[4,3-b]indol-5-yl)-acetic acid are disclosed by Kyle F. et al. in two patent specifications i.e. in US 5,817,756 and WO 95/07294, respectively.
  • the present invention relates to the use of 2-sulfanyl-benzoimidazol-l-yl-acetic acids of the general Formula I
  • R 1 , R 2 , R 3 and R 4 each independently represent hydrogen; alkyl; haloalkyl; halogen; nitro; cyano; formyl; methylsulfonyl; or methylcarbonyl; n is 0 or an integer from 1 to 10; r is 0 or the integer I 5 preferably 0;
  • R 5 , R 6 and R 7 each independently represent hydrogen; alkyl; alkenyl; cycloalkyl; aryl; aryloxy; alkylcarbonyl; cycloalkylcarbonyl; alkoxycarbonyl, arylcarbonyl; arylalkylcarbonyl; N-alkyl-N-aryl-carbamoyl; N-alkyl-N-arylalkyl-carbamoyl; N- arylalkyl-N-aryl-carbamoyl; heterocyclyl (especially furanyl, oxazolyl or pyridinyl, all substituted by alkoxycarbonyl and optionally an additional halogen); heterocyclyloxy
  • R 7 together with the carbon atom to which they are attached form cycloalkyl or saturated heterocyclyl;
  • R 8 represents hydrogen or R 9 ;
  • R 9 independently from R 8 represents cycloalkyl; cycloalkylalkyl; aryl; cycloalkylarylalkyl; arylalkyl; (diaryl)-alkyl; alkylcarbonyl; alkenylcarbonyl; cycloalkylcarbonyl; cycloalkylalkylcarbonyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl; arylalkylcarbonyl; arylalkenylcarbonyl; (diaryl)-alkylcarbonyl; cycloalkylarylalkylcarbonyl; heterocyclylcarbonyl, especially furanylcarbonyl or pyridinylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsul
  • R 8 and R 9 together with the nitrogen atom to which they are attached, form a heterocyclyl group;
  • R 11 is hydrogen or methyl, preferably hydrogen; and optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates, meso forms, geometric isomers, and prodrugs of compounds in which a prodrug forming group is present, as well as solvates and pharmaceutically acceptable salts of such compounds, and morphological forms; for the manufacture of medicaments for the control of disorders responding to CRTH2 receptor antagonist treatment.
  • the present invention also relates to the use of a compound of Formula I as defined above, wherein R 1 , R 2 , R 3 and R 4 each independently represent hydrogen, alkyl, haloalkyl, halogen, nitro, cyano or formyl; r is 0; and R 11 is hydrogen.
  • the present invention relates to compounds of Formula I as defined above, with the exception of:
  • a subgroup of novel compounds falling under Formula I are those wherein R 5 represents hydrogen;
  • R 6 represents hydrogen; alkyl; or alkoxycarbonyl; and R 7 represents alkoxycarbonyl; N-alkyl-N-arylalkyl-carbamoyl; N-alkyl-N-aryl- carbamoyl; alkylcarbonyl; N-arylalkyl-N-aryl-carbamoyl; arylalkylcarbonyl; arylcarbonyl; cycloalkylcarbonyl; heterocyclylcarbonyl; heterocyclyloxy; an amino of Formula NR 8 R 9 ; aryl substituted with one or two of alkoxy, alkylcarbonyl, and alkoxycarbonyl and optionally an additional halogen; or heterocyclyl substituted with alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, (diaryl)alkyl carbonyl or heterocyclylcarbonyl and optionally
  • R represents alkyl or alkoxycarbonyl and R represents aryl; or R 6 and R 7 together with the carbon atom to which they are attached form cycloalkyl or saturated heterocyclyl.
  • the present invention especially relates to compounds of Formula I, wherein R 1 , R 2 , R 3 and R 4 each independently represent hydrogen; alkyl; haloalkyl; halogen; nitro; cyano; formyl; methylsulfonyl; or methylcarbonyl; n is 0 or an integer from 1 to 5; r is 0 or the integer 1 ; R 5 , R 6 and R 7 each independently represent hydrogen; alkyl; alkenyl; cycloalkyl, especially cyclohexyl; aryl, wherein aryl is especially phenyl, optionally mono- or di- substituted wherein the substitutents are independently selected from the group consisting of hydroxy-alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, halo, alkylcarbonyl, phenyl, 2,3-dihydro-indole-l-carbonyl, alkylcarbamoyl, morpholine-4-
  • R and R together with the nitrogen atom to which they are attached, form a heterocyclyl group, especially 1, 3 -dioxo-1, 3 -dihydro-isoindol-2-yl, 2,3-dihydro-l- ethyloxycarbonyl-3-oxo-indazol-2-yl, 1-oxo- 1,3 -dihydro-isoindol-2-yl, 2-oxo-2,3- dihydro-benzoimidazol- 1 -yl, 1 -oxo- 1 H-phthalazin-2-yl, 2,4-dioxo- 1 ,4-dihydro-2H- quinazolin-3-yl, or l,l,3-trioxo-l,3-dihydro-l ⁇ 6 -benzo[d]isothiazol-2-yl; and R 11 is hydrogen or methyl; with the exception of the following compounds: (2-octyl
  • aryl groups (preferably phenyl or naphthyl, especially phenyl) present as R 5 -R 8 , especially R 5 -R 9 , alone or in combination, are preferably unsubstituted or mono- or di-substituted with substituents independently selected from lower alkyl; lower alkoxy; halogen; cyano; lower alkoxycarbonyl; lower alkylcarbonyl; aryl, especially phenyl; aryl-lower alkyl; cycloalkyl; and heterocyclyl, such as especially piperidinyl.
  • aryl groups (preferably phenyl, naphthyl, 3-oxo-indan-5-yl, or 8-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl, especially phenyl) present as R 5 -R 9 , alone or in combination, are preferably unsubstituted or mono- or di-substituted with substituents independently selected from lower alkyl; hydroxy-lower alkyl; lower alkoxy; lower alkoxy-lower alkyl; halogen; cyano; lower alkoxycarbonyl; lower alkylcarbonyl; aryl, especially phenyl; aryl-lower alkyl; cycloalkyl; 2,3-dihydro-indole- 1-carbonyl; lower alkylcarbamoyl; morpholine-4-carbonyl; aryl-lower alkylcarbamoyl, especially benzylcarbamoy
  • the substitutents are independently selected from hydroxy-lower alkyl; lower alkoxy; lower alkoxy-lower alkyl; halogen; lower alkoxycarbonyl; lower alkylcarbonyl; phenyl; 2,3-dihydro-indole-l-carbonyl; lower alkylcarbamoyl; morpholine-4-carbonyl; benzylcarbamoyl; N,N-di-lower alkylcarbamoyl; N-lower alkyl-N-benzyl-carbamoyl; hydroxy-lower alkoxy; benzoyl; and piperidinyl.
  • R 5 -R 7 together with the carbon atom, to which they are attached, form saturated heterocyclyl (preferably piperidinyl or pyrrolidinyl)
  • this group may contain one nitrogen atom which is substituted with R 10 , wherein R 10 represents alkylcarbamoyl; alkylcarbonyl; alkoxycarbonyl; alkylsulfonyl; arylalkylcarbamoyl; arylalkylcarbonyl; arylalkoxycarbonyl; arylalkylsulfonyl; arylcarbamoyl; arylcarbonyl; aryloxycarbonyl; arylsulfonyl; cycloalkylcarbamoyl; cycloalkylcarbonyl; cycloalkyloxycarbonyl; cycloalkylsulfonyl; heterocyclylcarbamoyl; heterocyclylcarbamoyl; heterocyclylcar
  • R 5 -R 7 together with the carbon atom, to which they are attached, form saturated heterocyclyl (preferably piperidinyl or pyrrolidinyl), this group may contain one nitrogen atom which is substituted with R 10 , wherein R 10 represents alkylcarbamoyl; alkylcarbonyl; alkoxycarbonyl; alkylsulfonyl; arylalkylcarbamoyl; arylalkylcarbonyl; arylalkoxycarbonyl; arylalkylsulfonyl; arylcarbamoyl; arylcarbonyl; (diaryl)-alkylcarbonyl; aryloxycarbonyl; arylsulfonyl; arylalkenylsulfonyl; cycloalkylcarbamoyl; cycloalkylalkylcarbonyl; cycloalkylcarbonyl; cycloalkylcarbonyl; cycl
  • R 10 represents alkylcarbonyl; alkylsulfonyl; arylalkylcarbonyl, wherein aryl is especially phenyl; arylalkoxycarbonyl, wherein aryl is especially phenyl; arylalkylsulfonyl, wherein aryl is especially phenyl; arylcarbonyl, wherein aryl is especially phenyl substituted by alkoxy or halo or wherein aryl is naphthyl; (diaryl)-alkylcarbonyl, wherein aryl is especially phenyl; arylsulfonyl, wherein aryl is especially phenyl substituted by alkyl or alkoxy or wherein aryl is naphthyl; arylalkenylsulfonyl, wherein aryl is especially phenyl; cycloalkylalkylcarbonyl, wherein cycloalkyl is especially cyclopen
  • substituents R 1 , R 2 , R 3 and R 4 each independently represent hydrogen; methyl; trifluoromethyl; fluoro, chloro, bromo; nitro; cyano; formyl; methylsulfonyl; or methylcarbonyl.
  • substituents R 1 , R 2 , R 3 and R each independently represent hydrogen; methyl; trifluoromethyl; fluoro, chloro, bromo; nitro; cyano; or formyl.
  • R -R are as above or as in Formula I.
  • n in Formula I is 1 or 2; R 5 and R 6 each represent hydrogen; R 7 represents an amino of Formula NR R ;
  • R represents hydrogen or R ;
  • R 9 independently from R 8 represents cycloalkyl; cycloalkylalkyl; aryl; arylalkyl; (diaryl)-alkyl; alkylcarbonyl; cycloalkylcarbonyl; cycloalkylalkylcarbonyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl; arylalkylcarbonyl; arylalkenylcarbonyl; (diaryl)-alkylcarbonyl; heterocyclylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl, wherein aryl groups present as R 8 and/or R 9 , alone or in combination with other groups, preferably represent phenyl or naphthyl, especially phenyl, where
  • n in Formula I is 2 or 3, especially 1 or 2;
  • R 5 and R 6 each represent hydrogen;
  • R 7 represents an amino of Formula NR 8 R 9 ;
  • R 8 represents hydrogen
  • R 9 represents cycloalkyl; aryl; arylalkyl; (diaryl)-alkyl; alkylcarbonyl; cycloalkyl- alkylcarbonyl; cycloalkylcarbonyl; alkenylcarbonyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl; arylalkylcarbonyl; (diaryl)-alkylcarbonyl; heterocyclylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl; or R 8 represents cycloalkyl; arylalkyl; aryl; alkoxycarbonyl; and R 9 represents cycloalkyl; cyclylalkyl-alkyl; aryl; arylalkyl
  • R 8 represents hydrogen; and R 9 represents particularly 3-phenyl-acryloyl; butoxycarbonyl, fert-butoxycarbonyl; ethoxydicarbonyl; propylcarbamoyl; 2,2-dimethyl-propionyl; 3,3-dimethyl-butyryl, 3- octanoyl, pentanoyl; butane- 1-sulfonyl; 4-piperidin-l-yl-phenyl, phenyl; 2,2-diphenyl- ethyl, 3 -benzyl; 2-cyclohexyl-2-phenyl-acetyl, 3,3-diphenyl-propionyl, 3-phenyl- propionyl, diphenylacetyl, phenylacetyl; phenylmethanesulfonyl; phenylcarbamoyl; 4- bromo-benzoyl, 4-methoxy-benzoyl;
  • R 9 represents particularly propylcarbamoyl; pentanoyl; butane-1-sulfonyl; 4-piperidin- l-yl-phenyl, phenyl; benzyl, phenethyl, 2,2-diphenyl-ethyl; benzylcarbamoyl; 2- cyclohexyl-2-phenyl-acetyl, 2-phenylacetyl, 3,3-diphenyl-propionyl, diphenylacetyl, phenylmethanesulfonyl; phenylcarbamoyl; benzenesulfonyl; cyclohexyl, cyclopropyl; or cyclohexylmethyl; or
  • R 8 and R 9 together with the nitrogen atom to which they are attached, represent particularly l-oxo-lH-phthalazin-2-yl; l-oxo-l,3-dihydro-isoindol-2-yl; 2-oxo-2,3- dihydro-benzoimidazol-1-yl; l-ethoxycarbonyl-3-oxo-2,3-dihydro-indazole-2-yl; 2,4- dioxo-l,4-dihydro-2H-quinazolin-3-yl; or l,3-dioxo-l,3-dihydro-isoindol-2-yl; 1,1,3- trioxo-l,3-dihydro-l ⁇ 6 -benzo[d]isothiazol-2-yl.
  • n in Formula I is 0;
  • R 5 and R 6 each represent hydrogen; R 7 represents phenyl; furanyl, oxazolyl, pyridinyl or thiazolyl, all substituted with one or two of alkoxy, alkylcarbonyl, and alkoxycarbonyl and optionally an additional halogen.
  • R 7 represents particularly halogen or alkoxy substituted
  • R 7 represents 3-(methoxycarbonyl)phenyl; 2-bromo-3- (methoxycarbonyl)phenyl, 4-bromo-3-(methoxycarbonyl)phenyl, 5-bromo-3- (methoxycarbonyl)phenyl, 2-bromo-5-(methoxycarbonyl)phenyl, 2-methoxy-5- (methoxycarbonyl)phenyl; 3 -acetyl
  • n in Formula I is 0; R 5 and R 6 each represent hydrogen; and R 7 represents phenyl, optionally mono- or di-substituted wherein the substitutents are independently selected from the group consisting of hydroxy-alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, halo, alkylcarbonyl, phenyl, 2,3-dihydro-indole- 1-carbonyl, alkylcarbamoyl, morpholine-4-carbonyl, benzylcarbamoyl, N 5 N- dialkylcarbamoyl, N-alkyl-N-benzyl-carbamoyl, hydroxyalkoxy and benzoyl; or R 7 represents 3-oxo-indan-5-yl or 8-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl, both substituted by alkoxy.
  • n in Formula I is 1 ; R 5 represents hydrogen;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 5- or 6- membered nitrogen containing saturated heterocyclyl containing one nitrogen ring atom, wherein this nitrogen ring atom contains a substituent R 10 , wherein R 10 is as defined hereinabove; most preferred in this aspect, R 6 and R 7 form a piperidinyl, particularly a piperidin-3-yl ring; and
  • R 10 represents particularly acetyl, butyryl, heptanoyl; 1-phenylacetyl, 3-phenyl- propionyl, diphenylacetyl; naphthalene- 1-carbonyl, 2-methoxy-benzoyl, 3-chloro- benzoyl, 4-bromo-benzoyl; 1-cyclohexanecarbonyl, 3-cyclopentyl-propionyl; or furan- 2-carbonyl, most preferred butyryl.
  • Most preferred novel compounds of the present invention include: ⁇ 2-[3-(butoxycarbonyl-phenetliyl-amino)-propylsulfanyl]-5-nitro-benzoimidazol-l-yl ⁇ - acetic acid; rac [2-(3 - ⁇ (2-cyclohexyl-2-phenyl-acetyl)-[(4-ethyloxycarbonyl)-phenyl] -amino ⁇ - propylsulfanyl)-benzoimidazol-l-yl] -acetic acid; and
  • the present invention also especially relates to a compound selected from:
  • novel compounds of the present invention include:
  • Preferred novel compounds of the present invention include: rac [2-(l-methyl-2-oxo-2-phenyl-ethylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
  • Particulary preferred novel compounds of the present invention include: rac ⁇ 2- [ 1 -(3 ,4-dichloro-benzenesulfonyl)-piperidin-3 -ylmethylsulfanyl]- benzoimidazol-l-yl ⁇ -acetic acid; rac ⁇ 2-[ 1 -(3 -phenyl-acryloyty-piperidin-S-ylmethylsulfanyl] -benzoimidazol- 1 -yl ⁇ - acetic acid;
  • the present invention also relates to precursors of the general Formula II,
  • R 1 -R 7 and n are as in Formula I and R represents an alkyl group, preferably ethyl or tert-butyl, are novel with the exception of:
  • novel precursors also form part of the present invention. They include, e.g. : tert-butyl [2-(2-cyclohexyl-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetic acetate; tert-butyl (2-hexylsulfanyl-benzoimidazol-l -yl)-acetate; tert-butyl (2-pentylsulfanyl-benzoimidazol-l-yl)-acetate; tert-butyl (2-but-3 -enylsulfanyl-benzoimidazol- 1 -yl)-acetate; tert-butyl (2-butylsulfanyl-benzoimidazol- 1 -yl)-acetate; rac tert-butyl [2-(l -phenyl -ethylsulfanyl)-benzoimidazol- 1
  • R 1 -R 4 and R 11 are as defined for Formula I and R represents an alkyl group.
  • Such novel intermdediates include: tert-butyl-(2-mercapto-benzoimidazol- 1 -yl)-acetate; tert-butyl-(2-mercapto-5 -nitro-benzoimidazol- 1 -yl)-acetate; tert-butyl-(2-mercapto-6-nitro-benzoimidazol- 1 -yl)-acetate; tert-butyl (5-formyl-2-mercapto-benzoimidazol- 1 -yl)-acetate; tert-butyl (5,6-difluoro-2-mercapto-benzoimidazol- 1 -yl)-acetate; tert-butyl (2-mercapto-5-methanesulfonyl-benzoimidazol-l-yl)-acetate; tert-butyl (5-acetyl-2-mercapto-benzoimidazol-l -yl
  • any reference to a compound of Formula I is to be understood as referring also to optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates, meso forms, geometric isomers, and prodrugs of compounds in which a prodrug forming group is present, as well as salts (especially pharmaceutically acceptable salts) and solvates (including hydrates) of such compounds, and morphological forms, as appropriate and expedient.
  • alkyl refers to a saturated aliphatic group including a straight or branched hydrocarbon chain containing 1-8, preferably 1-4 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, zso-propyl, ⁇ -butyl, tert-butyl, iso-butyl (or 2- methylpropyl), cyclopropylmethyl, ra-pentyl, zso-pentyl, wo-amyl, ⁇ -amyl, n-hexyl, n- heptyl, ⁇ -octyl and the like.
  • the alkyl group can be optionally substituted with one or more substituents, each independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylendioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminocarbonyl, aryl, arylalkenyl, arylalkoxy, aryloxy, aryloxycarbonyl, arylsulfmyl, arylsulfonyl, arylthio, carboxy, cyano, formyl, halogen, haloalkoxy, heterocyclyl, hydroxy, mercapto, nitro, and the like, appended to any carbon atom of the alkyl moiety.
  • R 9 is arylalkylcarbonyl
  • the alkyl group of this radical can for example be substituted by cyclohexyl,
  • lower alkyl refers to alkyl groups with 1-4 carbon atoms.
  • Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, ⁇ -propyl, wo-propyl, n-butyl, is ⁇ -butyl, t ⁇ r/-butyl and the like.
  • alkenyl refers to a straight or branched hydrocarbon chain containing 2-8, preferably 2-4 carbon atoms with at least one carbon-carbon double bond.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl and the like.
  • alkylenedioxy refers to a -O(CH 2 ) n O- group, wherein n is preferably 1 or 2, and wherein the oxygen atoms are appended to two adjacent carbon atoms of the parent molecular moiety.
  • Representative examples of alkylenedioxy include, but are not limited to, methylenedioxy, ethylenedioxy, and the like.
  • alkynyl refers to a straight or branched hydrocarbon chain containing 2-8 carbon atoms with at least one-carbon- carbon triple bond.
  • Representative examples of alkynyl include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl, 2-pentynyl, and the like.
  • alkoxy refers to an alkyl group appended to the parent molecular moiety through an oxygen bridge.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2- propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
  • alkoxy alkyl refers to an alkoxy group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert- butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.
  • alkoxycarbonyl refers to an alkoxy group appended to the parent molecular moiety through a carbonyl group.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, fert-butoxycarbonyl, and the like.
  • alkoxycarbonylalkyl refers to an alkoxycarbonyl group appended to the parent molecular moiety through an alkyl group.
  • alkoxycarbonylalkyl include, but are not limited to, methoxycarbonylpropyl, ethoxycarbonylbutyl, 2-fert-butoxycarbonylethyl, and the like.
  • alkylcarbonyl or "acyl”, as used herein, alone or in any combination, refers to an alkyl group appended to the parent molecular moiety through a carbonyl group.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1- oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-o ⁇ obutyl, 1-oxopentyl, and the like.
  • alkylcarbonylalkyl refers to an alkylcarbonyl group appended to the parent molecular moiety through an alkyl group.
  • alkylcarbonylalkyl include, but are not limited to, 2- oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, 3-oxopentyl and the like.
  • alkylcarbonyloxy refers to an alkylcarbonyl group appended to the parent molecular moiety through an oxygen bridge.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy and the like.
  • alkylsulfinyl refers to an alkyl group appended to the parent molecular moiety through a sulfinyl group.
  • alkylsulfinyl include, but are not limited to, methylsulfmyl, ethylsulfmyl and the like.
  • alkylsulfinylalkyl refers to an alkylsulfinyl group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulf ⁇ nylmethyl, ethylsulfmylmethyl and the like.
  • alkylsulfonyl refers to an alkyl group appended to the parent molecular moiety through a sulfonyl group.
  • Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.
  • alkylsulfonylalkyl refers to an alkylsulfonyl group appended to the parent molecular moiety through an alkyl group.
  • alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl, ethylsulfonylmethyl and the like.
  • alkylthio (synonym “alkylsulfanyl”), as used herein, alone or in any combination, refers to an alkyl group appended to the parent molecular moiety through an -S- bridge.
  • alkylthio include, but are not limited to, methylthio, ethylthio, fert-butylthio, hexylthio and the like.
  • alkylthioalkyl refers to an alkylthio group appended to the parent molecular moiety through an alkyl group.
  • alkylthioalkyl include, but are not limited to, methylthiomethyl, 2-(ethylthio)ethyl, and the like.
  • aminoalkyl refers to an amino group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of aminoalkyl include, but are not limited to, aminomethyl, 2-(amino)ethyl, and the like.
  • aminocarbonyl or “carbamoyl”, as used herein, alone or in any combination, refers to an amino group appended to the parent molecular moiety through a carbonyl group.
  • aminocarbonylalkyl refers to an aminocarbonyl group appended to the parent molecular moiety through an alkyl group.
  • aryl refers to an carbocyclic group having at least one aromatic ring, e.g. phenyl or biphenyl, or multiple condensed ring systems, in which at least one ring is aromatic, e.g. 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, phenanthryl, fluorenyl, and the like.
  • aromatic e.g. 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, phenanthryl, fluorenyl, and the like.
  • the term preferably relates to phenyl or naphthyl, especially to phenyl.
  • the aryl group may be optionally substituted with one or more functional groups individually and independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, cycloalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfinyl, alkylsulfmylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfmyl, arylsulfmylalkyl
  • arylalkenyl refers to an aryl group appended to the parent molecular moiety through an alkenyl group.
  • the aryl group may be unsubstituted or substituted.
  • Representative examples of arylalkenyl include, but are not limited to, 2-phenylethenyl, 3-phenylpropen-2-yl, 2-naphth-2- ylethenyl, and the like.
  • arylalkoxy refers to an aryl group appended to the parent molecular moiety through an alkoxy group.
  • the aryl group may be unsubstituted or substituted.
  • Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 5-phenylpentyloxy, 3-naphth-2- ylpropoxy, and the like.
  • arylalkyl refers to an aryl group appended to the parent molecular moiety through an alkyl group.
  • the aryl group may be unsubstituted or substituted.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
  • aryloxy refers to an aryl group appended to the parent molecular moiety through an oxygen bridge.
  • the aryl group can be unsubstituted or substituted.
  • Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, A- methylphenoxy, 3,4-dimetho ⁇ yphenoxy, and the like.
  • carbonyl as used herein, alone or in any combination, refers to a -C(O)- group.
  • carboxyalkyl refers to a carboxy group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like.
  • cyano refers to a -C ⁇ N group.
  • cyanoalkyl refers to a cyano group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, 3- cyanopropyl, and the like.
  • cycloalkyl refers to a saturated cyclic hydrocarbon moiety containing 3-15, preferably 3-6, carbon atoms, optionally (less preferred) substituted with one or more groups, each individually and independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfmyl, alkylsulfmylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, ary
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • one of the distal rings may be aromatic, e.g., 1-indanyl, 2-indanyl, tetrahydronaphthyl, bicyclo[4.2.0]octa-l,3,5-trien-7-yl, and the like.
  • formylalkyl refers to a formyl group, appended to the parent molecular moiety through an alkyl group.
  • formylalkyl include, but are not limited to, formylmethyl, 2-formylethyl, and the like.
  • halo or halogen, as used herein, alone or in any combination, refers to fluorine, bromine, chlorine, and iodine.
  • haloalkyl refers to an alkyl group having at least one hydrogen atom replaced with a halogen atom.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
  • haloalkoxy refers to an alkoxy group having at least one hydrogen atom replaced with a halogen atom.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and the like.
  • heterocyclyl refers to a monocyclic, bicyclic or polycyclic ring system containing up to 15 ring atoms, at least one of these, preferably 1 or 2, being a hetero atom independently selected from nitrogen, oxygen or sulfur.
  • the ring system may be saturated, partially unsaturated, unsaturated or aromatic, mono- or bicyclic.
  • heterocyclyl include, but are not limited to, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,
  • heterocyclyl moieties may be optionally substituted with one or more groups, each individually and independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfmyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, arylcarbonyl, arylalkylcarbonyl, (diaryl)alkylcarbonyl, aryloxycarbonyl, aryl
  • the substituents are selected from oxo, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylalkylcarbonyl, arylalkoxycarbonyl, arylalkylsulfonyl, arylcarbonyl, (diaryl)-alkylcarbonyl, arylsulfonyl, arylalkenylsulfonyl, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, and heterocyclylsulfonyl.
  • saturated heterocyclyl is another special case of “heterocyclyl” and refers to saturated rings as defined above for “heterocyclyl”, especially to piperidinyl and pyrrolidinyl.
  • heterocyclylalkenyl refers to a heterocyclyl group appended to the parent molecular moiety through an alkenyl group.
  • Representative examples of heterocyclylalkenyl include, but are not limited to, 2-pyrid- 3-ylethenyl, 3-quinolin-3-ylpropen-2-yl, 5-pyrid-4-ylpenten-4-yl, and the like.
  • heterocyclylalkoxy refers to a heterocyclyl group appended to the parent molecular moiety through an alkoxy group.
  • Representative examples of heterocyclylalkoxy include, but are not limited to, 2-pyrid- 3-ylethoxy, 3-quinolin-3-ylpropoxy, 5-pyrid-4-ylpentyloxy, and the like.
  • heterocyclylalkyl refers to a heterocyclyl group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of heterocyclylalkyl include, but are not limited to, 2-pyrid-3- ylmethyl, 2-pyrimidin-2-ylpropyl, and the like.
  • heterocyclyloxy refers to a heterocyclyl group appended to the parent molecular moiety through an oxy group.
  • Representative examples of heterocyclyloxy include, but are not limited to, pyrid-3- yloxy, quinolin-3-yloxy, and the like, especially (l-ethyloxycarbonyl-indazol-3-yl)- oxy.
  • hydroxy or "hydroxyl” as used herein, alone or in any combination, refers to an -OH group
  • hydroxyalkyl refers to an alkyl group having at least one hydrogen atom replaced with a hydroxy group.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, and the like.
  • nitro refers to a -NO 2 group.
  • oxy refers to an -O- group.
  • compounds of Formula I or pharmaceutically acceptable salts thereof are included that may exist in, and be isolated in, isomeric forms, including cis- or trans isomers or mixtures thereof, and tautomers.
  • Other compounds of this invention may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, and thus may give rise to optically pure enantiomers, mixtures of enantiomers, racemates, enantiomer-pure diastereomers, mixtures of diastereomers, epimers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-, (S)- or (i?,5)-configured, preferably in the (R)- or ( ⁇ -configuration.
  • Such isomers can be obtained by methods within the knowledge of one skilled in the art, e.g. by stereochemical ⁇ controlled synthesis using chiral synthons or chiral reagents, or by means of classical separation techniques, such as chromatographic or crystallization methods, or by other methods known in the art, such as through formation of diastereomeric salts, for example by salt formation with an enantiomerically pure chiral acid, or by means of chromatography, for example by using chromatographic materials modified with chiral ligands.
  • the present invention refers to compounds containing centers of any geometric asymmetry, like, for example, unsymmetrically substituted olefinic double bond, including E or Z geometric isomers and mixtures thereof. Generally, pure isomers of compounds of Formula I are preferred over isomeric mixtures.
  • the compounds of Formula I may be used in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to relatively nontoxic, inorganic or organic acid and base addition salts, which retain the biological effectiveness and properties of the parent compound, and which are not biologically or otherwise undesirable (see, e.g., Berge et al., J. Pharm. Sci. 1977, 66, 1- 19).
  • Certain compounds of the present invention can contain one or more basic functional groups, such as amino, alkylamino, or arylamino, and, thus, be capable of forming pharmaceutically acceptable acid addition salts.
  • These acid addition salts may be prepared by standard procedures in a suitable solvent from the parent compound of Formula I, with an appropriate amount of an inorganic acid, including, but not limited to, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; or of an organic acid, including, but not limited to, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, amino acids, such as glutamic acid or aspartic acid, benzoic acid, cinnamic acid, salicylic acid, mandelic acid, methanesulfonic acid, ethan
  • Certain compounds of the present invention may, on the other hand, contain one or more acidic functional groups and, thus, be capable of forming pharmaceutically acceptable base addition salts.
  • These salts can be prepared by addition of an appropriate amount, usually in stoichiometric ratio, of an alkaline reagent, such as hydroxide, carbonate or alkoxide, containing the appropriate cation, to the free acid in a suitable solvent.
  • an alkaline reagent such as hydroxide, carbonate or alkoxide, containing the appropriate cation
  • Preferred inorganic salts include, but are not limited to, ammonium, sodium, potassium, calcium or magnesium, also zinc salts and the like.
  • Preferred salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, iV-ethylpiperidine, piperidine, polyamine resins, and the like.
  • basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, iV-ethylpiperidine, piperidine, polyamine resins, and the like.
  • Compounds of the present invention containing both acidic and basic groups can also form internal salts (zwitter ions).
  • pharmaceutically unacceptable salts for example perchlorates, picolinates, picrates, or the like.
  • pharmaceutically acceptable salts or free compounds are employed, where applicable in the form of pharmaceutical preparations, and these are therefore preferred.
  • Certain compounds of Formula I may exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the present invention encompasses all such solvated and unsolvated forms.
  • prodrug refers to pharmacologically inactive precursors of a drug that may be converted into its therapeutically active form under physiological conditions in vivo, for example, when they undergo solvolysis, or enzymatic degradation in blood, or in cells (Bundgard H., “Design of Prodrugs", pp. 7-9, 21-24, Elsevier, Amsterdam (1985); Silverman R. B., “The Organic Chemistry of Drug Design and Drug Action", pp. 352-401, Academic Press, San Diego, CA (1992); Higuchi T. et al., "Pro-drug as Novel Delivery Systems", A.C.S. Symposium Series, Vol. 14).
  • prodrug also includes any covalently bonded carriers, which release the active parent compound in vivo when administered to a mammal.
  • Prodrug modifications of a compound often offer advantages of solubility, bioavailability, absorption, tissue compatibility, tissue distribution, or delayed release in the mammalian organism.
  • Prodrugs are variations or derivatives of the compounds of Formula I, which have groups cleavable under metabolic conditions, for example, pharmaceutically acceptable esters, or amides. Such groups can be cleaved enzymatically or non-enzymatically, or hydrolytically to the free hydroxy, carboxy, or amino group of the active parent compound.
  • the prodrug is a reduced form, which is oxidized in vivo to the therapeutic compound, for example, a thiol, which is oxidized to a sulfonate or sulfate, or an alcohol, which is oxidized to a carboxylic acid.
  • pharmaceutically acceptable esters refers to relatively non-toxic, esterified products of the parent compound. These esters can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compounds in its free acid or hydroxyl form with a suitable esterifying agent.
  • Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst.
  • Hydroxyl containing derivatives can be converted into esters via treatment with an esterifying agent such as alkanoyl halides.
  • the term further includes lower hydrocarbon groups capable of being solvated under physiological conditions, for example, alkyl esters, preferred methyl, ethyl, and propyl esters, methoxymethyl esters, methylthiomethyl esters, pivaloyloxymethyl esters and the like (see, e.g., Berge et al., J. Pharm. Sci. 1977, 66, 1-19).
  • the compounds of the present invention have useful, in particular pharmacologically useful, properties. They are able to specifically antagonize the effect of endogenous PGD 2 on the CRTH2 receptor, and may be used for the prevention and/or treatment of chronic and acute allergic immune disorders comprising allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases comprising Churg- Strauss syndrome and sinusitis, basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis in humans and other mammals.
  • a compound or a pharmaceutical composition of the invention may thus be used as a drug (medicine) or therapeutic agent for prevention and/or treatment of both chronic and acute allergic/immune disorders such as those mentioned above, especially allergic asthma, rhinitis, COPD, dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
  • the compounds of Formula I may be used as standard or reference compounds in tests or assays involving the inhibition of the CRTH2 receptor. Such compounds could be made commercially available for use as a reference, quality standard or control, for example in pharmaceutical research when developing new assays or protocols related to CRTH2 activity.
  • compounds of Formula I, or salts, or prodrugs thereof antagonize the PGD 2 activation of the CRTH2 receptor.
  • the biological effect of such compounds may be tested in a variety of in vitro, ex vivo and in vivo assays.
  • the ability of the compounds of Formula I to bind to the CRTH2 receptor may be measured by methods similar to those described in Sawyer N. et al, Br. J. Pharmacol., 2002, 137, 1163-1172 and by the method described below in the experimental part.
  • IC 50 values i. e. the concentrations where half-maximal inhibition of the interaction is found
  • concentrations where half-maximal inhibition of the interaction is found in the range of 0.001 to 10 ⁇ M, preferably values below 1 ⁇ M, in particular values below 0.05 ⁇ M, are found with test compounds of Formula I.
  • Exemplary IC 50 values determined in this test are given below in Table 68.
  • a functional assay with cells expressing the human CRTH2 receptor may be used to detect changes in the levels of intracellular calcium concentration following compound treatment. After addition of the compound the cells are challenged with PGD 2 . In a Fluorescent Imaging Plate Reader (FLIPR , Molecular Devices, Sunnyvale, California) fluorescence emission is recorded during both additions, emission peak values above base level after PGD 2 addition were exported, normalized to low controls (no PGD 2 ) and high controls (no active compound). The relative values of the remaining activity were used to determine IC 50 values by curve fitting the data to a single site to a four-parameter logistic sigmoid dose response curve of the equation (A+((B-A)/(l+((C/x) ⁇ D))).
  • IC 50 values i.e. the concentration of a compound at which the remaining activity is 50%
  • test compounds of Formula I Exemplary IC 5 O values determined in this test are given below in Table 69.
  • a compound of Formula I according to the invention may show therapeutic efficacy against chronic and acute allergic/immune disorders such as allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
  • chronic and acute allergic/immune disorders such as allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
  • COPD chronic obstructive pulmonary disease
  • a compound of Formula I, a pharmaceutically acceptable salt or a prodrug thereof can be administered alone in pure form or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
  • a compound of Formula I can besides or in addition be administered especially for prevention and/or treatment of both chronic and acute allergic or immune disorders in combination with other inflammatory diseases. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are preventive therapies, for example in patients at risk.
  • the invention relates also to pharmaceutical compositions comprising compounds of Formula I, to their use in therapeutic, in a broader aspect of the invention also prophylactic treatment or a method of treatment of the diseases mentioned above, to the compounds for said use and to the preparation of pharmaceutical formulations (medicines).
  • the pharmaceutically acceptable compounds of the present invention may be used, for example, for the preparation of pharmaceutical compositions that comprise an effective amount of the active ingredient together or in admixture with a significant amount of one or more inorganic, organic, solid or liquid, pharmaceutically acceptable carriers.
  • the invention relates also to a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human (or to cells or cell lines derived from a warm-blooded animal, especially a human, for the treatment or, in a broader aspect of the invention, prevention of (i.e. prophylaxis against) a disease that responds to blockade of the interaction of the CRTH2 receptor with PGD 2 , comprising an amount of a compound of Formula I or a pharmaceutically acceptable salt or a prodrug thereof, which is effective for said inhibition, together with at least one pharmaceutically acceptable carrier.
  • compositions according to the invention are those for enteral administration, such as nasal, buccal, rectal, dermal or, especially oral administration, and for parenteral administration, such as intramuscular, intravenous or subcutaneous, intrastemal, intravitreal, injection or infusion, to warm-blooded animals, especially humans.
  • Such compositions comprise an effective dose of the pharmaceutically active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual conditions, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • the invention relates also to a process or a method for the treatment of a pathological condition mentioned hereinabove, especially a disease, which responds to blockade of the interaction of the CRTH2 receptor with PGD 2 , especially allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
  • a pathological condition mentioned hereinabove especially a disease, which responds to blockade of the interaction of the CRTH2 receptor with PGD 2 , especially allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
  • COPD chronic obstructive pulmonary disease
  • dermatitis dermatitis
  • inflammatory bowel disease inflammatory bowel disease
  • rheumatoid arthritis rheumatoid arthritis.
  • the dose to be administered to warm-blooded animals is preferably from approximatively 3 mg to approximatively 3O g, more preferably from approximatively 10 mg to approximatively 1000 mg per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, the weight, and response of the individual patient, the severity of the patient's symptoms, and the like, for example, children usually receive half of the adults dose.
  • compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dosage forms such as coated and uncoated tablets, pills, ampoules, vials, suppositories, dragees, or capsules. Further dosage forms are, for example, ointments, creams, pastes, emulsions, foams, chewable gums, tinctures, lip-sticks, drops, sprays or aerosols, syrups or elixirs, dispersions, transdermal patches or pads, or via an intravitreal device that releases the compound in a sustained capacity, and the like. Examples are capsules containing from about 0.05 g to about 1.0 g active ingredient.
  • compositions of the present invention are prepared in a manner known, per se, for example by means of conventional mixing, granulating, coating, dissolving, lyophilizing or confectioning processes.
  • Solutions of the active ingredient, and also suspensions, and especially isotonic aqueous solutions or suspensions are preferably used, it being possible, for example in the case of lyophilized compositions, that comprise the active ingredient alone or together with a carrier, for example mannitol, for such solutions or suspensions to be produced prior to use.
  • the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilizing processes.
  • the said solutions or suspensions may comprise viscosity- increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
  • Suspensions in oil comprise as the oil component the vegetable, synthetic or semi ⁇ synthetic oils customary for injection purposes.
  • liquid fatty acid esters that contain as the acid component a long-chain fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, ⁇ -carotene or 3,5- ⁇ i-tert- butyl-4-hydroxytoluene.
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is mono- or poly-hydroxy, for example a mono-, di- or trihydroxy, alcohol, for example methanol, ethanol, propanol, butanol, or pentanol or the isomers thereof, but especially glycol and glycerol.
  • fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M2375” (polyoxyethylene glycerol trioleate, Gattefosse, Paris), "Miglyol 812” (triglyceride of saturated fatty acids with chain length of C8 to C 12, HuIs AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
  • injection or infusion compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules or vials and sealing the containers.
  • compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using for example corn, wheat, rice, or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, and/or carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates for example tricalcium phosphate or calcium hydrogen phosphate
  • Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and/or titanium dioxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Capsules are dry-filled capsules made of gelatin and of soft sealed capsules made of gelatine and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable oil excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers and/or antibacterial agents to be added.
  • suitable oil excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers and/or antibacterial agents to be added.
  • Dyes or pigments may be added to the tablets or dragee coatings or the capsule casings, for example for identification purposes or to indicate different dose
  • aqueous solutions of an active ingredient in water- soluble form for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances and stabilizers, are especially suitable.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and be made into a solution before parenteral administration by the addition of solvents.
  • novel compounds of Formula I can be manufactured in accordance with the invention by a) hydrolyzing a precursor of the general Formula II
  • R 1 -R 7 and n are as in Formula I and R represents an alkyl group, preferably ethyl or fert-butyl, with the exception of:
  • L 1 is a leaving group, or c) S-alkylating a mercapto derivative of the general Formula
  • R .1 - ⁇ R>4 are as in Formula I,
  • R > 5 -R and n are as in Formula I and L is a leaving group, and, if desired, converting a compound of Formula I into a pharmaceutically acceptable salt.
  • a synthesis of 2-sulfanyl-benzoimidazol-l-yl-acetic acid of Formula I starts by alkylating a 2-chlorobenzoimidazole of Formula 1 with a compound of Formula L 1 - CH 2 CO 2 R, wherein R represents an alkyl group, preferably ethyl or fert-butyl, and L 1 is a leaving group, in a suitable polar solvent such as JV, N-dimethylformamide, acetone, acetonitrile or the like, in the presence of a base, such as potassium carbonate, cesium carbonate, sodium hydride or the like, to yield an alkyl (2-chloro-benzoimidazol-l-yl)- acetate of Formula 2, as outlined in Scheme 1.
  • Suitable is a leaving group L 1 such as halo, in particular bromo or chloro.
  • a compound of Formula 1 ⁇ -CH 2 CO 2 R is tert-butyl or ethyl bromoacetate.
  • a solution of a chlorobenzoimidazole of Formula 1 in acetone is stirred with e.g. tert-bvdyl bromoacetate in presence of potassium carbonate at reflux, or in DMF at room temperature.
  • Substituted l-fluoro-2-nitro-benzene of Formula 12 is converted to a compound of Formula 13.1 by reacting with an amino acid ester in a suitable solvent such as DMSO, EtOH or the like at elevated temperature from 50°C to 100°C (McFarlane et al, J. Chem. Soc. Perkin Trans. 1 1988, 691-696).
  • a catalyst such as palladium on charcoal in a solvent like tetrahydrofuran leads to a substituted aniline derivative of Formula 13.2, which then is reacted with thiocarbonyle diimidazole to yield Intermediate 3a (Wright, J. L. et al, J. Med. Chem., 2000, 43, 3408-3419; Breslin, H. J. et al, J. Med. Chem. 1995, 38, 771- 793).
  • a reagent of Formula L 2 -(CH 2 ) n -C-R 5 R 6 R 7 is an optionally substituted alkyl halide, particularly an alkyl chloride, or an alkyl bromide, such as commercially available 2-(2-bromo-ethyl)-isoindole-l,3-dione; (2-bromo-ethyl)-carbamic acid tert- butyl ester; (3-bromo-propyl)-carbamic acid tert-butyl ester; (2-bromo-ethyl)- cyclohexane; 1-bromo-hexane; 1-bromo-pentane; 4-bromo-but-l-ene; 1-bromo-butane; bromo-cyclopentane; (l-bromo-ethyl)-benzene; bromo-phenyl-acetic acid methyl ester; 7-bromo-brom
  • a reagent of Formula L 2 -(CH 2 ) n -C-R 5 R 6 R 7 such as benzyl-(3-chloro- propyl)-carbamic acid ester; 5-bromo-pentanoic acid butyl-phenyl-amide; 5- bromo- 1 -(3 ,4-dihydro-2H-quinolin- 1 -yl)-pentan- 1 -one; 5 -bromo-pentanoic acid methyl-phenyl-amide; 1 -(2-bromo-ethoxy)-naphthalene; 2-(2-bromo-ethoxy)- naphthalene; 2-(3-chloro-propyl)-2,3 -dihydro-isoindol- 1 -one; 1 -(3 -chloro-propyl)- 1,3- dihydro-benzoimidazol-2-one; 3-(3-chlor
  • a novel alkyl halide of Formula 1/-(CHa) n -C-R 5 R 6 R 7 such as (3-chloro-propyl)-phenethyl-carbamic acid fert-butyl ester; (3-chloro-propyl)-(4- piperidin-l-yl-phenyl)-carbamic acid tert-butyl ester; 4-[tert-butoxycarbonyl-(3-chloro- propyl)-amino] -benzoic acid ethyl ester; (3-chloro-propyl)-cyclopropyl-carbamic acid tert-butyl ester; (3-chloro-propyl)-phenyl-carbamic acid tert-butyl ester; (3-chloro- propyl)-(2,2-diphenyl-ethyl)-carbamic acid tert-butyl ester; (3-chloro-propyl
  • Preferred alkyl halides of Formula L 2 -(CH 2 ) n -C-R 5 R 6 R 7 are depicted in Formula 5.1 and 5.2.
  • Such compounds can either be prepared and isolated as such, or generated in situ, from a dihaloalkane of Formula Ha ⁇ -(CH 2 VHaI 2 , wherein Hal 1 and Hal 2 represent halo, independently selected from chloro, bromo, or iodo; such as l-chloro-2- iodo-ethane, 1,2-dibromo-ethane, or 1,2-dichloro-ethane; l-chloro-3-iodo-propane, 1,3- dibromo-propane, or 1,3-dichloropropane; l-chloro-4-iodo-butane, 1,4-dibromo- butane, or 1,4-dichloro-butane; with a substituted amine of hereinabove
  • a 2-aryloxyethylbromide is obtained by reacting a hydroxyarene with dibromoethane in aqueous sodium hydroxide (Slyn'ko, N. M.; Tormyshev, V. M. Russ. Journal. Org. Chem. 2000, 36(2), 254-257).
  • a primary amine of Formula H 2 NR wherein R represents alkyl, cycloalkyl, cyclylalkyl, or arylalkyl, reacts with hereinabove defined dihaloalkane of Formula Hal 1 -(CH 2 ) n -Hal 2 forming a secondary amine of Formula 5.3, which then is transformed to its respective amide, sulfonamide, carbamate, urethane of Formula 5.1, wherein R 9 represents alkenylcarbonyl, alkoxycarbonyl, alkylcarbamoyl, alkylcarbonyl, alkylsulfonyl, arylalkenylcarbonyl, arylalkylcarbonyl, arylcarbamoyl, arylcarbonyl, arylalkylsulfonyl, arylsulfonyl, cycloalkylcarbonyl, or cyclylalkylcarbonyl, wherein R represents alkyl,
  • an alkylating reagent of Formula L 2 -(CH 2 ) n -C-R 5 R 6 R 7 can be obtained through transformation of its respective hydroxy analog of Formula R 5 R 6 R 7 C-(CH 2 V OH, by means of known methods.
  • alkylating reagents as depicted in Formula 5.4, 5.5, 5.4bis, are obtained by:
  • halogenation of the methyl group of the benzene and pyridinyl derivatives 6 and 7, respectively with known methods, e.g. preferably by means of N-X succinimide, whereby X represents halogen, such as chloro or bromo, iodo, in a suitable solvent such as tetrachloromethane, chloroform or the like (de Meijere, A. et al., Chem. Ber. 1993, 126, 1635-1641).
  • R' alkyl, alkoxy
  • R' alkyl, alkoxy
  • hydroxyalkoxyacetophenone and alkoxyacetophenone Ibis are obtained by alkylation of hydroxyacetophenone with the corresponding hydroxyalkyl or alkyl halide (Mandoli, A. et al Tetrahedron Asymmetry 2003, 14, 3647-3650).
  • Another preferred alkyl halide of Formula L 2 -(CH 2 ) n -C-R 5 R 6 R 7 also comprises a structure of Formula 5.6, wherein R 7 represents alkoxy, alkyl-arylamino, arylalkyl- arylamino, or 3,4-dihydro-2i7-quinoline.
  • R 7 represents alkoxy, alkyl-arylamino, arylalkyl- arylamino, or 3,4-dihydro-2i7-quinoline.
  • a solution of an Intermediate of Formula 3 in acetone is heated at reflux with an alkylating agent of Formula L 2 -(CH 2 ) n -C-R 5 R 6 R 7 in the presence of a base such as potassium carbonate.
  • a base such as potassium carbonate.
  • L 2 representing chloro, or bromo
  • addition of a catalytic amount of potassium iodide might be beneficial.
  • alkylcarbonyl-3-hydroxymethyl-piperidine examples are alkylcarbonyl-3-hydroxymethyl-piperidine; alkyloxycarbonyl-3-hydroxymethyl- piperidine, such as tert-butyloxycarbonyl-3-hydroxymethyl-piperidme; arylcarbonyl-3- hydroxymethyl-piperidine; alkylsulfonyl-3 -hydroxymethyl-piperidine, arylsulfonyl-3 - hydroxymethyl-piperidine, arylalkyloxycarbonyl-3 -hydroxymethylazetidine, and arylalkylcarbonyl-2-hydroxymethylazetidine.
  • An Intermediate of Formula 3 can also be alkylated to yield a compound of Formula 4.1, with a reagent of Formula L 2 -(CH 2 ) n -C-R 5 R 6 R 7 , wherein either one, e.g. R 7 , of the substituents R 5 , R 6 , or R 7 , is representing a functional group (FG), opted for further transformations.
  • FG functional group
  • Such functional groups include carboxy; halo, such as chloro or bromo; hydroxyl; and amino.
  • a FG group such as amino is introduced in its protected form using a standard protecting group (PG) such as /er/-butoxycarbonyl, benzyloxycarbonyl, or phthaloyl.
  • PG standard protecting group
  • a compound of Formula 4.1 bearing a FG such as carboxy can be transformed to alkoxycarbonyl, N-alkyl-N-arylalkyl-carbamoyl, N-aryl-N-arylalkyl-carbamoyl, N- alkyl-N-aryl-carbamoyl, by means of methods known to a skilled person.
  • a FG such as halo can be transformed to aryloxy, heterocyclyloxy; or an amino of hereinabove defined Formula NR R , by means of known methods.
  • a FG such as hydroxy can be converted to aryloxy, heterocyclyloxy; or an amino of hereinabove defined Formula NR 8 R 9 , by means of known functional group transformations.
  • a FG such as amino (NH 2 ) can be converted stepwise to an amino of hereinabove defined Formula NR 8 R 9 .
  • Preferred modifications of the nitrogen atom include acylation, alkoxycarbonylation, carbamoylation, or sulfonylation, applying standard conditions.
  • R 5 in a compound of Formula 4 represents hydrogen
  • R 6 and R 7 are forming a pyrrolidine, or piperidinyl ring, whereby a protecting group (PG) is appended to the pyrrolidinyl, or piperidinyl nitrogen atom, as depicted in Formula 4.2.
  • a standard protecting group (PG) like e.g. fe/Y-butoxycarbonyl, or benzyloxycarbonyl, is removed by means of standard conditions, yielding a compound of Formula 4.3.
  • the nitrogen atom is being further modified with hereinabove defined substituent R 10 , affording a Precursor of Formula 4.4.
  • Preferred modifications of the nitrogen atom include acylation, alkoxycarbonylation, carbamoylation, or sulfonylation, applying standard conditions.
  • R 5 and R 6 in a compound of Formula 4 represent hydrogen and R 7 is an aromatic ring bearing two substituents R and X as depicted in Formula 4.6, wherein R corresponds to an alkoxy group and X represents a halogen atom such as bromine; or in Formula 4.8 wherein R represents hydroxy and X represents an alkyloxy group.
  • the halogen atom can be replaced by a group R using standard coupling methods known by a person skilled in the art, for example a Suzuki coupling and yielding a compound as depicted in Formula 4.7.
  • R 18 represents an aromatic ring such as a phenyl group.
  • a compound of Formula 4.8 might be obtained in the typical conditions of a Mitsunobu reaction between an Intermediate of Formula 3 or Formula 3a and a suitable hydroxymethylbenzoic acid.
  • a compound of Formula 4.8 is subsequently modified so that the hydroxy group R is replaced by a primary or secondary amine using standard coupling methods such as with HOBt and EDC (N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide) hydrochloride in a DMF / dichloromethane mixture to yield primary or secondary aromatic amides as depicted in Formula 4.9.
  • Examples are compounds wherein R 19 is an indolino-, butylamino-, morpholino-, benzylamino-, diethylamino- or benzylethylamino-group.
  • R 5 and R 6 represent a hydrogen atom and R 7 is an aromatic ring bearing a ketone, as depicted in Formula I-b
  • R 7 is an aromatic ring bearing a ketone
  • the preferred reaction condition is stirring with sodium borohydride in methanol.
  • I-b X alkyloxy
  • R ⁇ i alkyl
  • I-c X alkyloxy
  • R 20 hydroxy, alkoxy
  • a compound of Formula I-a can be further oxidized at the sulphur atom by a method known to a person skilled in the art to yield a sulfoxide as depicted in Formula I-d.
  • Starting 2-chlorobenzoimidazole of Formula 1 can be prepared from the corresponding 2-hydroxybenzimidazole of Formula 8 by means of phosphorous oxychloride, either neat or in a suitable solvent (Naef, R.; Balli, H., HeIv. Chem. Acta 1978, 61, 2958- 2973).
  • 2-Chloro-5-nitrobenzimidazole is obtained following a method described in Jung, F.; Delvare, C; Boucherot, D.; Hamon, A. J. Med. Chem. 1991, 34, 1110-1116.
  • a Precursor of Formula 4 can also be obtained following a preferred alternative synthetic route, e.g. by changing the sequence of reactions.
  • starting IH- benzoimidazole-2-thiol of Formula 9 can be S-alkylated with hereinabove defined reagent of Formula L 2 -(CH 2 ) n -C-R 5 R 6 R 7 under aforementioned conditions to yield 2- alkylsulfanyl-lif-benzoimidazole of Formula 10, which then is iV-alkylated in a second step with tert-butyl or ethyl bromoacetate to a Precursor of Formula 4.
  • Any further functional group manipulations, as discussed hereinabove for Intermediates 4.1, 4.2, 4.3, and 4.4, are preferably accomplished at this stage, prior to ester hydrolysis to the "final compound of Formula I.
  • Starting li7-benzoimidazole-2-thiol of Formula 9 is obtained from 1,2-diaminobenzene of Formula 11, with carbon disulfide, thiocarbonyldiimidazole or potassium xanthogenate in a suitable solvent such as dichloromethane; or an alcohol such as methanol, ethanol, propanol; or water; or a mixture of an alcohol and water; in the presence of a base such as potassium hydroxide, sodium hydroxide, at elevated temperature between 50 and 100°C.
  • a suitable solvent such as dichloromethane
  • an alcohol such as methanol, ethanol, propanol
  • water or a mixture of an alcohol and water
  • a base such as potassium hydroxide, sodium hydroxide
  • Preferred reaction conditions are those described in:
  • KH 2 PO 4 potassium phosphate
  • K 2 CO 3 potassium carbonate
  • 1 liter, ⁇ : micro, m: milli, mol: mole
  • M molar
  • MeOH methanol
  • Me methyl
  • min minute
  • MgSO 4 magnesium sulfate
  • MS mass spectrometry
  • N normality of solution
  • NaHCO 3 sodium hydrogencarbonate
  • Na 2 CO 3 sodium carbonate
  • NaOH sodium hydroxide
  • Na 2 SO 4 sodium sulfate
  • NH 4 Cl ammonium chloride
  • rt room temperature
  • SOCl 2 thionyl chloride
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • fo retention time.
  • LC-I analytical HPLC on an XterraTM MS C 18 column (50 x 2.1 mm, 5 ⁇ m, Waters), with a linear gradient of water containing 0.06% formic acid (A) and acetonitrile containing 0.06% formic acid (B), from 5% to 95% B over 6 min; flow rate 0.25 ml/min, column temperature 30°C, detection at 200- 400 nm.
  • LC-2 analytical HPLC on an XterraTM MS C 18 column (50 x 4.6 mm, 5 ⁇ m, Waters), with a linear gradient of water containing 0.06% formic acid (A) and acetonitrile containing 0.06% formic acid (B), from 5% to 95% B over 2 min; flow rate 0.75 ml/min, column temperature 30°C, detection at 200- 400 nm.
  • LC-3 analytical HPLC on an Zorbax SB-AqTM column (50 x 4.6 mm, 5 ⁇ m, Agilent), with a linear gradient of water containing 0.06% formic acid (A) and acetonitrile containing 0.06% formic acid (B), from 5% to 95% B over 1 min; flow rate 3 ml/min, column temperature 30°C, detection at 200- 400 nm.
  • Intermediate 3-IIa and Intermediate 3-IIb of the following Table 3 are prepared from a (1:1) mixture of f ⁇ rt-butyl (2-chloro-5-nitro-benzoimidazol-l-yl)-acetate (Intermediate 2-IIa) and its 6-nitro regioisomer (Intermediate 2-IIb) analogous to the procedure described for Intermediate 3-1. They are purified and separated by flash- chromatography on silica-gel (AcOEt / heptane, 1 :5).
  • Examples A-02a to A-05a of the following Table 1 are prepared analogous to the procedure described for Example A-OIa, using Precursors A-02b to A-05b in place of A-OIb.
  • Precursors A-02b to A-05b of the following Table 2 are prepared using a procedure analogous to that described for Precursor A-OIb, substituting the appropriate alkyl halide for 2-cyclohexylethyl bromide.
  • Examples B-02a to B-05a of the following Table 4 are prepared analogous to the procedure described for Example B-OIa, using Precursors B-02b to B-05b in place of B-OIb.
  • Example C-OIa [2-(2-Methoxy-benzylsulfanyl)-benzoimidazol- 1 -yl "
  • -acetic acid A solution of tert-butyl [2-(2-methoxy-benzylsulfanyl)-benzoimidazol- 1 -yl]-acetate (Precursor C-OIb, 20 mg, 0.05 mmol) is stirred in TFA / dichloromethane (1:1, 4.0 ml) at rt overnight.
  • Precursors C-02b to C-05b of the following Table 7 are prepared using a procedure analogous to that described for Precursor C-OIb, substituting the appropriate benzyl halide for 2-methoxybenzyl chloride.
  • Examples D-02a to D-07a of the following Table 8 are prepared analogous to the procedure described for Example D-OIa, using Precursors D-02b to D-07b in place of D-OIb.
  • Precursors D-OIb to D-07b of the following Table 9 are prepared using a procedure analogous to that described for Precursor D -02b, substituting the appropriate aryloxyalkylbromide or heterocyclyloxyalkylbromide for (2-bromo-ethoxy)-benzene.
  • Formula t R [min] MS Data
  • Examples E-02a to E-03a of the following Table 10 are prepared analogous to the procedure described for Example E-OIa, using Precursors E-02b and E-03b in place of E-OIb.
  • Precursors E-02b to E-03b of the following Table 11 are prepared using a procedure analogous to that described for Precursor E-OIb, substituting the appropriate alkyl bromide for 6-bromo-hexanoic acid ethyl ester.
  • Examples F-02a to F-05a of the following Table 12 are prepared analogous to the procedure described for Example F-OIa, using Precursors F-02b to F-05b in place of F- 01b.
  • Precursors F-02b to F-05b of the following Table 13 are prepared using a procedure analogous to that described for Precursor F-OIb, substituting the corresponding JV, JV- disubstituted amine for JV-methylaniline.
  • Examples G-02a to G-07a of the following Table 14 are prepared analogous to the procedure described for Example G-OIa, using Precursors G-02b to G-07b in place of G-OIb.
  • Precursors G-02b to G-07b of the following Table 15 are prepared using a procedure analogous to that described for Precursor G-OIb, substituting the appropriate alkylating agent for G-OId.
  • the resulting cloudy solution is allowed to stir for 1 h at rt and is added dropwise under inert atmosphere via a syringe onto a solution of iodochloropropane (268 ⁇ l, 2.5 mmol) in dry DMF (2 ml). The resulting solution is allowed to stir at rt overnight. By addition of water and evaporation under reduced pressure most of the DMF is removed from the crude mixture. The residue is dissolved in AcOEt (25 ml) and the resulting organic phase is washed 3 times with water and once with brine.
  • Alkylating agents G-03d to G-07d of the following Table 16 are prepared using a procedure analogous to that described for alkylating agent G-OId, substituting the appropriate nitrogen containing heterocycle for 3-oxo-2,3-dihydro-indazole-l- carboxylic acid ethyl ester.
  • Examples H-02a to H-I Ia of the following Table 17 are prepared analogous to the procedure described for Example H-OIa, using Precursors H-02b to H-I Ib in place of H-OIb.
  • Precursors H-02b to H-I Ib of the following Table 18 are prepared using a procedure analogous to that described for Precursor H-OIb, substituting the appropriate alkylating agent for 5-bromo-hexanoic acid ethyl ester.
  • Alkylating agents H-02d to H-09d of the following Table 19 are prepared using a procedure analogous to that described for alkylating agent H-08d, substituting the corresponding phenyl or pyridyl derivative analogue for 4-bromo-3-methyl-benzoic acid methyl ester.
  • Example I-01a rac ⁇ 2-( 1 -Butyryl-piperidin-3 -ylmethylsulfanvD-benzoimidazol- 1 -yll -acetic acid rac [2-(Piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid hydrochloride (Precursor I-00a, 10 mg, 0.03 mmol) is suspended in dichloromethane (1 ml) and Et 3 N (12.88 mg, 16.6 ⁇ l, 0.10 mmol) as well as butyryl chloride (3.42 mg, 3.35 ⁇ l, 0.04 mmol) are added subsequently. The resulting mixture is stirred for 30 min at rt.
  • Example I-01a is also synthesized starting from tert-butyl [2-(l-butyryl- piperidin-3 -ylmethylsulfanyl)-benzoimidazol- 1 -yl]-acetate (Precursor 1-01 b) : Precursor I-Olb (802 mg, 1.86 mmol) is dissolved in TFA / dichloromethane (1:1, 10 ml) and stirred overnight at rt. Evaporation of the solvents in vacuo gives an orange oil which is suspended in Et 2 O / heptane (1:1, 2 ml) and sonicated. After filtration, thourough rinsing with Et 2 O and drying, the title compound (670 mg) is obtained in 96% as a white solid.
  • Examples I-02a to I- 13a of the following Table 20 are prepared analogous to the procedures described for Example 1-01 a.
  • Precursor I-00a rac r2-(Piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yll-acetic acid hydrochloride
  • rac tert-butyl [2-(l-tert- butyloxycarbonyl-piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetate Precursor I-00b, 36 mg, 0.08 mmol.
  • the mixture is stirred for 4 h at rt.
  • the precipitated solid is filtered and rinsed with Et 2 O to yield quantitatively the title compound as a slightly yellow solid.
  • Precursor 3-1 1 g, 3.79 mmol
  • l-(3-chloromethyl-piperidin-l-yl)-butan-l-one alkylating agent I-01d, 771 mg, 3.79 mmol
  • K 2 CO 3 (1.05 g, 7.58 mmol) in acetone (10 ml) is refiuxed for 36 h.
  • Example J-OIa ⁇ 2-[3-(tgrt-Butoxycarbonyl-phenethyl-amino)-propylsulfanvn-benzoimidazol-l-vU- acetic acid tert-Buty ⁇ ⁇ 2- [3 -(tert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl] - benzoimidazol-1-yl ⁇ -acetate (Precursor J-OIb, 12.7 mg, 0.025 mmol) is suspended in an aqueous 0.2 M NaOH solution (0.67 ml). After addition of THF (1.3 ml) the resulting solution is allowed to stir overnight at rt.
  • Examples J-02a to J-07a of the following Table 21 are prepared analogous to the procedure described for Example J-OIa, using Precursors J-02b to J-07b in place of J- 01b.
  • Precursors J-02b to J-07b from Table 22 are prepared by a procedure analogous to that described for Precursor J-OIb, using Intermediates J-02c to J-07c in place of J-OIc.
  • Example K-OIa is synthesized analogous to the procedure described for Example J-OIa, using Precursor K-OIb in place of J-OIb.
  • Examples K-02a to K-04a of the following Table 23 are prepared analogous to the procedures described for Example K-OIa, using Precursors K-02b to K-04b in place of K-OIb.
  • Precursor K-OIb fert-Butyl ⁇ 2-r3-(butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l- yl> -acetate is generally prepared analogous to the procedure described for Precursor J-OIb 5 using K-OIc in place of J-OIc.
  • Precursor K-OIb is prepared starting from tert-butyl (2-mercapto- benzoimidazol-l-yl)-acetate (Intermediate 3-1):
  • Precursors K-02b to K-04b in Table 24 are prepared analogous to the procedures described for Precursor K-OIb.
  • Phenethyl-carbamic acid tert-butyl ester (1107 mg, 5.0 mmol) is dissolved in dry DMF (7.75 ml). To this solution, sodium hydride (60 % w/w in oil, 302 mg, 7.55 mmol) is added under vigorous stirring and stirring is continued for 30 min. Then l-chloro-3- iodo-propane (250 mg, 5.0 mmol) is dropped into the solution followed by stirring for 2 h at rt and another hour at 50 0 C.
  • Alkylating agent K-OId O-Chloro-propyD-phenethyl-carbamic acid butyl ester

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Abstract

The invention relates to 2-sulfanyl-benzoimidazol-1-yl-acetic acid derivatives and their use as potent 'chemoattractant receptor-homologous molecule expressed on Th2 cells' antagonists in the treatment of prostaglandin mediated diseases, to pharmaceutical compositions containing these derivatives and to processes for their preparation.

Description

-SULFANYL-BENZIMIDAZOL-l-YL-ACETIC ACID DERIVATIVES AS CRTH2 ANTAGONISTS
The present invention relates to 2-sulfanyl-benzoimidazol-l-yl-acetic acid derivatives and their use as potent "chemoattractant receptor-homologous molecule expressed on Th2 cells" (hereinafter called CRTH2) antagonists in the treatment of prostaglandin mediated diseases, to pharmaceutical compositions containing these derivatives and to processes for their preparation. In particular, such derivatives may be used in pharmaceutical compositions for the treatment of both chronic and acute allergic/immune disorders comprising allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases, such as Churg-Strauss syndrome and sinusitis, basophil-related diseases, such as basophilic leukemia and basophilic leukocytosis in humans and other mammals.
Prostaglandin D2 is a known agonist of the thromboxane A2 (TxA2) receptor, the PGD2 (DP) receptor and the recently identified G-protein-coupled "chemoattractant receptor-homologous molecule expressed on Th2 cells" (CRTH2).
The response to allergen exposure in a previously sensitized host results in a cascade effect involving numerous cell types and release of a number of cytokines, chemokines, and multiple mediators. Among these critical initiators are the cytokines interleukin (IL)-4, IL-13, and IL-5, which play critical roles in Th2 cell differentiation, immunoglobulin (Ig)E synthesis, mast cell growth and differentiation, upregulation of CD23 expression, and the differentiation, recruitment, and activation of eosinophils. The stimulated release of the array of mediators, causes end-organ damage, including constriction and hyperresponsiveness, vascular permeability, edema, mucous secretion, and further inflammation. Because of the number of responses targeted, corticosteroids have proven to be the most effective therapy. Rather than antagonizing these specific responses in a directed way, another approach is to alter the immune response, that is, to change the nature of the immunological response to allergen. CRTH2 is preferentially expressed on Th2 cells and is a chemoattractant receptor for PGD2 that mediates PGD2-dependent migration of blood Th2 cells. Chemoattractants are responsible for the recruitment of both Th2 cells and other effector cells of allergic inflammation and may provide the conceptual basis for the development of new therapeutic strategies, especially in allergic conditions.
So far, few compounds having CRTH2 antagonistic activity have been reported in the patent literature. In GB Patent Specification No. 2388540 Bayer AG claims the use of Ramatroban ((3R)-3 -(4-fluorobenzene-sulfonamido)- 1 ,2,3 ,4-tetrahydrocarbazole-9- propionic acid) for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjuvatitis. Further, (2-fert.-butoxycarbonyl-l, 2, 3, 4- tetrahydro-pyrido[4,3-b]indol-5-yl)-acetic acid and (2-ethoxycarbonyl-l, 2, 3, 4- tetrahydro-pyrido[4,3-b]indol-5-yl)-acetic acid are disclosed by Kyle F. et al. in two patent specifications i.e. in US 5,817,756 and WO 95/07294, respectively.
Furthermore, a certain oral bioavailability of Ramatroban and its ability to inhibit prostaglandin D2-induced eosinophil migration in vitro has been reported in Journal of Pharmacology and Experimental Therapeutics, 305(1), p.347-352 (2003).
The present invention relates to the use of 2-sulfanyl-benzoimidazol-l-yl-acetic acids of the general Formula I
I wherein
R1, R2, R3 and R4 each independently represent hydrogen; alkyl; haloalkyl; halogen; nitro; cyano; formyl; methylsulfonyl; or methylcarbonyl; n is 0 or an integer from 1 to 10; r is 0 or the integer I5 preferably 0;
R5, R6 and R7 each independently represent hydrogen; alkyl; alkenyl; cycloalkyl; aryl; aryloxy; alkylcarbonyl; cycloalkylcarbonyl; alkoxycarbonyl, arylcarbonyl; arylalkylcarbonyl; N-alkyl-N-aryl-carbamoyl; N-alkyl-N-arylalkyl-carbamoyl; N- arylalkyl-N-aryl-carbamoyl; heterocyclyl (especially furanyl, oxazolyl or pyridinyl, all substituted by alkoxycarbonyl and optionally an additional halogen); heterocyclyloxy
(especially l-ethyloxycarbonyl-indazol-3-yl-oxy); heterocyclylcarbonyl (especially
3,4-dihydro-2H-quinolin-l-yl-carbonyl); or an amino of Formula NR8R9; or two of R5-
R7 together with the carbon atom to which they are attached form cycloalkyl or saturated heterocyclyl; R8 represents hydrogen or R9;
R9 independently from R8 represents cycloalkyl; cycloalkylalkyl; aryl; cycloalkylarylalkyl; arylalkyl; (diaryl)-alkyl; alkylcarbonyl; alkenylcarbonyl; cycloalkylcarbonyl; cycloalkylalkylcarbonyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl; arylalkylcarbonyl; arylalkenylcarbonyl; (diaryl)-alkylcarbonyl; cycloalkylarylalkylcarbonyl; heterocyclylcarbonyl, especially furanylcarbonyl or pyridinylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl; or
R8 and R9, together with the nitrogen atom to which they are attached, form a heterocyclyl group; R11 is hydrogen or methyl, preferably hydrogen; and optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates, meso forms, geometric isomers, and prodrugs of compounds in which a prodrug forming group is present, as well as solvates and pharmaceutically acceptable salts of such compounds, and morphological forms; for the manufacture of medicaments for the control of disorders responding to CRTH2 receptor antagonist treatment. The present invention also relates to the use of a compound of Formula I as defined above, wherein R1, R2, R3 and R4 each independently represent hydrogen, alkyl, haloalkyl, halogen, nitro, cyano or formyl; r is 0; and R11 is hydrogen.
The present invention relates to compounds of Formula I as defined above, with the exception of:
(2-octylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-butylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-propylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-ethylsulfanyl-benzoimidazol-l-yl)-acetic acid; (2-methylsulfanyl-benzoimidazol-l -yl)-acetic acid;
(2-isopropylsulfanyl-benzoimidazol-l -yl)-acetic acid;
(2-sec-butylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
2- [(2-methylpropyl)thio]- 1 H-benzimidazole- 1 -acetic acid; (2-allylsulfanyl-benzoimidazol-l-yl)-acetic acid;
(2-cyclohexylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-benzylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-phenethylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
[2-(naphthalen- 1 -ylmethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid; {2- [2-(4-fert-butyl-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; {2-[2-(4-propoxy-phenoxy)-ethylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid;
{2- [2-(4-ethoxy-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
{2-[2-(3,4-dimethyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(3-methylphenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(naphthalen-2-yloxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(4-methoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(4-butoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(4-methylphenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; [2-(2-phenoxy-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid;
{2-[2-(4-ethyl-phenoxy)-ethylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid;
{2-[2-(2-methylphenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(2-isopropyl-4-methyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2- [2-(naphthalen- 1 -yloxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
{2-[2-(2,6-dimethyl-phenoxy)-etb.ylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(4-isopropoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(2-fluoro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(2-methoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; and
{2-[3-methyl-4-(2-morpholin-4-yl-ethylsulfanyl)-pyridin-2-ylmethylsulfanyl]- benzoimidazol-1-yl} -acetic acid (US patent 5,504,082).
A subgroup of novel compounds falling under Formula I are those wherein R5 represents hydrogen;
R6 represents hydrogen; alkyl; or alkoxycarbonyl; and R7 represents alkoxycarbonyl; N-alkyl-N-arylalkyl-carbamoyl; N-alkyl-N-aryl- carbamoyl; alkylcarbonyl; N-arylalkyl-N-aryl-carbamoyl; arylalkylcarbonyl; arylcarbonyl; cycloalkylcarbonyl; heterocyclylcarbonyl; heterocyclyloxy; an amino of Formula NR8R9; aryl substituted with one or two of alkoxy, alkylcarbonyl, and alkoxycarbonyl and optionally an additional halogen; or heterocyclyl substituted with alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, (diaryl)alkyl carbonyl or heterocyclylcarbonyl and optionally an additional halogen; or
R represents alkyl or alkoxycarbonyl and R represents aryl; or R6 and R7 together with the carbon atom to which they are attached form cycloalkyl or saturated heterocyclyl.
The present invention especially relates to compounds of Formula I, wherein R1, R2, R3 and R4 each independently represent hydrogen; alkyl; haloalkyl; halogen; nitro; cyano; formyl; methylsulfonyl; or methylcarbonyl; n is 0 or an integer from 1 to 5; r is 0 or the integer 1 ; R5, R6 and R7 each independently represent hydrogen; alkyl; alkenyl; cycloalkyl, especially cyclohexyl; aryl, wherein aryl is especially phenyl, optionally mono- or di- substituted wherein the substitutents are independently selected from the group consisting of hydroxy-alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, halo, alkylcarbonyl, phenyl, 2,3-dihydro-indole-l-carbonyl, alkylcarbamoyl, morpholine-4-carbonyl, benzylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-benzyl-carbamoyl, hydroxyalkoxy and benzoyl, or wherein aryl is especially 3-oxo-indan-5-yl or 8-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl, both substituted by alkoxy; aryloxy, wherein aryl is especially naphthyl or phenyl, wherein phenyl is optionally substituted by halo; alkoxycarbonyl; arylcarbonyl, wherein aryl is especially phenyl; N-alkyl-N-aryl- carbamoyl, wherein aryl is especially phenyl; N-alkyl-N-arylalkyl-carbamoyl, wherein aryl is especially phenyl; N-arylalkyl-N-aryl-carbamoyl, wherein aryl is especially phenyl; heterocyclyl, especially furanyl, oxazolyl or pyridinyl, all substituted by alkoxycarbonyl and optionally an additional halogen; heterocyclyloxy, especially 1- alkoxycarbonyl-indazol-3-yl-oxy; heterocyclylcarbonyl, especially 3,4-dihydro-2H- quinolin-1-yl-carbonyl; or an amino of Formula NR8R9; or two of R5 -R7 together with the carbon atom to which they are attached form cycloalkyl, especially cyclopentyl, cyclohexyl or bicyclo[4.2.0]octa-l,3,5-trien-7-yl; or or two of R5 -R7 together with the carbon atom to which they are attached form saturated heterocyclyl, especially a 5- or 6-membered nitrogen containing saturated heterocyclyl containing one nitrogen ring atom (preferably piperidin-3-yl or pyrrolidin-3-yl), wherein this nitrogen ring atom contains a substituent R10, wherein R10 is as defined hereinbelow; R8 represents hydrogen or R9; R9 independently from R8 represents cycloalkyl, especially cyclopropyl or cyclohexyl; cycloalkylalkyl, wherein cycloalkyl is especially cyclohexyl; aryl, especially phenyl which is optionally substituted by alkoxycarbonyl or piperidinyl; arylalkyl, wherein aryl is especially phenyl; (diaryl)-alkyl, wherein aryl is especially phenyl; alkylcarbonyl; cycloalkylcarbonyl, wherein cycloalkyl is especially cyclopropyl or cyclohexyl; cycloalkylalkylcarbonyl, wherein cycloalkyl is especially cyclopentyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl, wherein aryl is especially naphthyl or phenyl, wherein phenyl is optionally substituted by alkoxy, halogen or phenyl; arylalkylcarbonyl, wherein aryl is especially phenyl, and wherein the alkyl moiety may optionally be substituted by cyclohexyl; arylalkenylcarbonyl, wherein aryl is especially phenyl; (diaryl)-alkylcarbonyl, wherein aryl is especially phenyl; heterocyclylcarbonyl, wherein heterocyclyl is especially furanyl or pyridinyl; alkylcarbamoyl; arylcarbamoyl, wherein aryl is especially phenyl; arylalkylcarbamoyl, wherein aryl is especially phenyl; alkylsulfonyl; arylsulfonyl, wherein aryl is especially phenyl; arylalkylsulfonyl, wherein aryl is especially phenyl; or
R and R , together with the nitrogen atom to which they are attached, form a heterocyclyl group, especially 1, 3 -dioxo-1, 3 -dihydro-isoindol-2-yl, 2,3-dihydro-l- ethyloxycarbonyl-3-oxo-indazol-2-yl, 1-oxo- 1,3 -dihydro-isoindol-2-yl, 2-oxo-2,3- dihydro-benzoimidazol- 1 -yl, 1 -oxo- 1 H-phthalazin-2-yl, 2,4-dioxo- 1 ,4-dihydro-2H- quinazolin-3-yl, or l,l,3-trioxo-l,3-dihydro-lλ6-benzo[d]isothiazol-2-yl; and R11 is hydrogen or methyl; with the exception of the following compounds: (2-octylsulfanyl-benzoimidazol-l -yl)-acetic acid; (2-butylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-propylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-ethylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-methylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-isopropylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-^ec-butylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-isobutylsulfanyl-benzoimidazol-l-yl)-acetic acid; (2-allylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-cyclohexylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-benzylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-phenethylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
[2-(naphthalen- 1 -ylmethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid;
{2- [2-(4-teτt-butyl-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid; {2-[2-(4-propoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2- [2-(4-ethoxy-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
{ 2- [2-(3 ,4-dimethyl-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
{ 2- [2-(3 -methylphenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
{2- [2-(naphthalen-2-yloxy)-ethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid; {2- [2-(4-methoxy-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
{2- [2-(4-butoxy-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
{2- [2-(4-methylphenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
[2-(2-phenoxy-ethylsulfanyl)-benzoimidazol-l -yl] -acetic acid;
{2-[2-(4-ethyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(2-methylphenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(2-isopropyl-4-methyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(naphthalen-l-yloxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2- [2-(2,6-Dimethyl-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; {2-[2-(4-isopropoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(2-fluoro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(2-methoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; and
{2-[3-methyl-4-(2-morpholin-4-yl-ethylsulfanyl)-pyridin-2-ylmethylsulfanyl]- benzoimidazol-1-yl} -acetic acid.
In the above compounds of Formula I, aryl groups (preferably phenyl or naphthyl, especially phenyl) present as R5 -R8, especially R5-R9, alone or in combination, are preferably unsubstituted or mono- or di-substituted with substituents independently selected from lower alkyl; lower alkoxy; halogen; cyano; lower alkoxycarbonyl; lower alkylcarbonyl; aryl, especially phenyl; aryl-lower alkyl; cycloalkyl; and heterocyclyl, such as especially piperidinyl. In another embodiment, aryl groups (preferably phenyl, naphthyl, 3-oxo-indan-5-yl, or 8-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl, especially phenyl) present as R5-R9, alone or in combination, are preferably unsubstituted or mono- or di-substituted with substituents independently selected from lower alkyl; hydroxy-lower alkyl; lower alkoxy; lower alkoxy-lower alkyl; halogen; cyano; lower alkoxycarbonyl; lower alkylcarbonyl; aryl, especially phenyl; aryl-lower alkyl; cycloalkyl; 2,3-dihydro-indole- 1-carbonyl; lower alkylcarbamoyl; morpholine-4-carbonyl; aryl-lower alkylcarbamoyl, especially benzylcarbamoyl; N,N-di-lower alkylcarbamoyl; N-lower alkyl-N-aryl- lower alkyl-carbamoyl, especially N-lower alkyl-N-benzyl-carbamoyl; hydroxy-lower alkoxy; arylcarbonyl, especially benzoyl; and heterocyclyl, such as especially piperidinyl. Preferably the substitutents are independently selected from hydroxy-lower alkyl; lower alkoxy; lower alkoxy-lower alkyl; halogen; lower alkoxycarbonyl; lower alkylcarbonyl; phenyl; 2,3-dihydro-indole-l-carbonyl; lower alkylcarbamoyl; morpholine-4-carbonyl; benzylcarbamoyl; N,N-di-lower alkylcarbamoyl; N-lower alkyl-N-benzyl-carbamoyl; hydroxy-lower alkoxy; benzoyl; and piperidinyl.
Where two of R5 -R7 together with the carbon atom, to which they are attached, form saturated heterocyclyl (preferably piperidinyl or pyrrolidinyl), this group may contain one nitrogen atom which is substituted with R10, wherein R10 represents alkylcarbamoyl; alkylcarbonyl; alkoxycarbonyl; alkylsulfonyl; arylalkylcarbamoyl; arylalkylcarbonyl; arylalkoxycarbonyl; arylalkylsulfonyl; arylcarbamoyl; arylcarbonyl; aryloxycarbonyl; arylsulfonyl; cycloalkylcarbamoyl; cycloalkylcarbonyl; cycloalkyloxycarbonyl; cycloalkylsulfonyl; heterocyclylcarbamoyl; heterocyclylcarbonyl; heterocyclyloxycarbonyl; or heterocyclylsulfonyl.
In another preferred embodiment of the invention R5 -R7 together with the carbon atom, to which they are attached, form saturated heterocyclyl (preferably piperidinyl or pyrrolidinyl), this group may contain one nitrogen atom which is substituted with R10, wherein R10 represents alkylcarbamoyl; alkylcarbonyl; alkoxycarbonyl; alkylsulfonyl; arylalkylcarbamoyl; arylalkylcarbonyl; arylalkoxycarbonyl; arylalkylsulfonyl; arylcarbamoyl; arylcarbonyl; (diaryl)-alkylcarbonyl; aryloxycarbonyl; arylsulfonyl; arylalkenylsulfonyl; cycloalkylcarbamoyl; cycloalkylalkylcarbonyl; cycloalkylcarbonyl; cycloalkyloxycarbonyl; cycloalkylsulfonyl; heterocyclylcarbamoyl; heterocyclylcarbonyl; heterocyclyloxycarbonyl; or heterocyclylsulfonyl. Preferably R10 represents alkylcarbonyl; alkylsulfonyl; arylalkylcarbonyl, wherein aryl is especially phenyl; arylalkoxycarbonyl, wherein aryl is especially phenyl; arylalkylsulfonyl, wherein aryl is especially phenyl; arylcarbonyl, wherein aryl is especially phenyl substituted by alkoxy or halo or wherein aryl is naphthyl; (diaryl)-alkylcarbonyl, wherein aryl is especially phenyl; arylsulfonyl, wherein aryl is especially phenyl substituted by alkyl or alkoxy or wherein aryl is naphthyl; arylalkenylsulfonyl, wherein aryl is especially phenyl; cycloalkylalkylcarbonyl, wherein cycloalkyl is especially cyclopentyl; cycloalkylcarbonyl, wherein cycloalkyl is especially cyclohexyl; heterocyclylcarbonyl, wherein heterocyclyl is especially furyl; or heterocyclylsulfonyl, wherein heterocyclyl is especially thienyl.
Preferably, in a compound of Formula I substituents R1, R2, R3 and R4 each independently represent hydrogen; methyl; trifluoromethyl; fluoro, chloro, bromo; nitro; cyano; formyl; methylsulfonyl; or methylcarbonyl.
Also preferably, in a compound of Formula I substituents R1, R2, R3 and R each independently represent hydrogen; methyl; trifluoromethyl; fluoro, chloro, bromo; nitro; cyano; or formyl.
In the subgroups (aspects) enumerated below R -R are as above or as in Formula I.
In a preferred aspect, n in Formula I is 1 or 2; R5 and R6 each represent hydrogen; R7 represents an amino of Formula NR R ;
R represents hydrogen or R ; and
R9 independently from R8 represents cycloalkyl; cycloalkylalkyl; aryl; arylalkyl; (diaryl)-alkyl; alkylcarbonyl; cycloalkylcarbonyl; cycloalkylalkylcarbonyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl; arylalkylcarbonyl; arylalkenylcarbonyl; (diaryl)-alkylcarbonyl; heterocyclylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl, wherein aryl groups present as R8 and/or R9, alone or in combination with other groups, preferably represent phenyl or naphthyl, especially phenyl, wherein the phenyl is optionally substituted by alkoxy, alkoxycarbonyl, halogen, phenyl or piperidinyl; or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocyclyl group, wherein said heterocyclyl group preferably represents 1,3-dioxo- 1 ,3 -dihydro-isoindol-2-yl, 2,3-dihydro- 1 -ethyloxycarbonyl-3 -oxo-indazol-2-yl, 1 -oxo- 1 ,3 -dihydro-isoindol-2-yl, 2-oxo-2,3 -dihydro-benzoimidazol- 1 -yl, 1 -oxo- 1 H- phthalazin-2-yl, 2,4-dioxo-l,4-dihydro-2H-quinazolin-3-yl, or l,l,3-trioxo-l,3- dihydro-lλ6-benzo[d]isothiazol-2-yl.
In another preferred embodiment, n in Formula I is 2 or 3, especially 1 or 2; R5 and R6 each represent hydrogen; R7 represents an amino of Formula NR8R9;
R8 represents hydrogen; and
R9 represents cycloalkyl; aryl; arylalkyl; (diaryl)-alkyl; alkylcarbonyl; cycloalkyl- alkylcarbonyl; cycloalkylcarbonyl; alkenylcarbonyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl; arylalkylcarbonyl; (diaryl)-alkylcarbonyl; heterocyclylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl; or R8 represents cycloalkyl; arylalkyl; aryl; alkoxycarbonyl; and R9 represents cycloalkyl; cyclylalkyl-alkyl; aryl; arylalkyl; (diaryl)-alkyl; cycloalkyl- alkylcarbonyl; alkylcarbonyl; arylalkylcarbonyl; (diary l)-alkylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl; or R8 and R9, together with the nitrogen atom to which they are attached, form a phthalazinyl; isoindolyl; benzoimidazolyl; indazolyl; quinazolinyl; or benzoisothiazolyl ring system, such as especially 1, 3 -dioxo- 1,3 -dihydro-isoindol-2-yl, 2,3-dihydro-l- ethyloxycarbonyl-3 -oxo-indazol-2-yl, 1 -oxo- 1,3 -dihydro-isoindol-2-yl, 2-oxo-2,3- dihydro-benzoimidazol- 1 -yl, 1 -oxo- 1 H-phthalazin-2-yl, 2,4-dioxo- 1 ,4-dihydro-2H- quinazolin-3 -yl, or 1 , 1 ,3 -trioxo- 1 ,3 -dihydro- 1 λδ-benzo [d]isothiazol-2-yl.
In a preferred aspect of the invention, R8 represents hydrogen; and R9 represents particularly 3-phenyl-acryloyl; butoxycarbonyl, fert-butoxycarbonyl; ethoxydicarbonyl; propylcarbamoyl; 2,2-dimethyl-propionyl; 3,3-dimethyl-butyryl, 3- octanoyl, pentanoyl; butane- 1-sulfonyl; 4-piperidin-l-yl-phenyl, phenyl; 2,2-diphenyl- ethyl, 3 -benzyl; 2-cyclohexyl-2-phenyl-acetyl, 3,3-diphenyl-propionyl, 3-phenyl- propionyl, diphenylacetyl, phenylacetyl; phenylmethanesulfonyl; phenylcarbamoyl; 4- bromo-benzoyl, 4-methoxy-benzoyl, benzoyl, biphenyl-4-carbonyl, naphthalene- 1- carbonyl, benzenesulfonyl; cyclohexanecarbonyl, cyclopropanecarbonyl, 3- cyclopentyl-propionyl; furan-2-carbonyl, or pyridine-3-carbonyl; or R8 represents particularly butoxycarbonyl, terf-butoxycarbonyl; 4-carboethoxyphenyl, 4-piperidin-l-yl-phenyl, phenyl; benzyl, 2,2-diphenyl-ethyl, phenethyl; cyclopropyl; and
R9 represents particularly propylcarbamoyl; pentanoyl; butane-1-sulfonyl; 4-piperidin- l-yl-phenyl, phenyl; benzyl, phenethyl, 2,2-diphenyl-ethyl; benzylcarbamoyl; 2- cyclohexyl-2-phenyl-acetyl, 2-phenylacetyl, 3,3-diphenyl-propionyl, diphenylacetyl, phenylmethanesulfonyl; phenylcarbamoyl; benzenesulfonyl; cyclohexyl, cyclopropyl; or cyclohexylmethyl; or
R8 and R9, together with the nitrogen atom to which they are attached, represent particularly l-oxo-lH-phthalazin-2-yl; l-oxo-l,3-dihydro-isoindol-2-yl; 2-oxo-2,3- dihydro-benzoimidazol-1-yl; l-ethoxycarbonyl-3-oxo-2,3-dihydro-indazole-2-yl; 2,4- dioxo-l,4-dihydro-2H-quinazolin-3-yl; or l,3-dioxo-l,3-dihydro-isoindol-2-yl; 1,1,3- trioxo-l,3-dihydro-lλ6-benzo[d]isothiazol-2-yl.
In another preferred aspect, n in Formula I is 0;
R5 and R6 each represent hydrogen; R7 represents phenyl; furanyl, oxazolyl, pyridinyl or thiazolyl, all substituted with one or two of alkoxy, alkylcarbonyl, and alkoxycarbonyl and optionally an additional halogen.
In this aspect, R7 represents particularly halogen or alkoxy substituted
(alkoxycarbonyl)phenyl; (alkylcarbonyl)phenyl; (alkoxycarbonyl)furanyl, or (alkoxycarbonyl)pyridinyl; more particularly halogen or alkoxy substituted 3-(alkoxycarbonyl)phenyl; 3- (alkylcarbonyl)phenyl; 5-(alkoxycarbonyl)furan-2-yl, 5-(alkoxycarbonyl)pyridin-3-yl; or 4-(alkoxycarbonyl)pyridin-2-yl; most particularly, R7 represents 3-(methoxycarbonyl)phenyl; 2-bromo-3- (methoxycarbonyl)phenyl, 4-bromo-3-(methoxycarbonyl)phenyl, 5-bromo-3- (methoxycarbonyl)phenyl, 2-bromo-5-(methoxycarbonyl)phenyl, 2-methoxy-5- (methoxycarbonyl)phenyl; 3 -acetyl-phenyl, 5-acetyl-2-methoxy-phenyl; 5- (methoxycarbonyl)pyridine-3-yl, 6-chloro-4-(methoxycarbonyl)pyridine-2-yl; or 5- (ethoxycarbonyl)furan~2-yl; most preferred 5-acetyl-2-methoxy-phenyl.
A preferred embodiment of the invention n in Formula I is 0; R5 and R6 each represent hydrogen; and R7 represents phenyl, optionally mono- or di-substituted wherein the substitutents are independently selected from the group consisting of hydroxy-alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, halo, alkylcarbonyl, phenyl, 2,3-dihydro-indole- 1-carbonyl, alkylcarbamoyl, morpholine-4-carbonyl, benzylcarbamoyl, N5N- dialkylcarbamoyl, N-alkyl-N-benzyl-carbamoyl, hydroxyalkoxy and benzoyl; or R7 represents 3-oxo-indan-5-yl or 8-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl, both substituted by alkoxy.
In a more preferred aspect, n in Formula I is 1 ; R5 represents hydrogen;
R6 and R7 together with the carbon atom to which they are attached form a 5- or 6- membered nitrogen containing saturated heterocyclyl containing one nitrogen ring atom, wherein this nitrogen ring atom contains a substituent R10, wherein R10 is as defined hereinabove; most preferred in this aspect, R6 and R7 form a piperidinyl, particularly a piperidin-3-yl ring; and
R10 represents particularly acetyl, butyryl, heptanoyl; 1-phenylacetyl, 3-phenyl- propionyl, diphenylacetyl; naphthalene- 1-carbonyl, 2-methoxy-benzoyl, 3-chloro- benzoyl, 4-bromo-benzoyl; 1-cyclohexanecarbonyl, 3-cyclopentyl-propionyl; or furan- 2-carbonyl, most preferred butyryl. Most preferred novel compounds of the present invention include: {2-[3-(butoxycarbonyl-phenetliyl-amino)-propylsulfanyl]-5-nitro-benzoimidazol-l-yl}- acetic acid; rac [2-(3 - { (2-cyclohexyl-2-phenyl-acetyl)-[(4-ethyloxycarbonyl)-phenyl] -amino} - propylsulfanyl)-benzoimidazol-l-yl] -acetic acid; and
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid.
The present invention also especially relates to a compound selected from:
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid; rac P-Cl-butyryl-piperidin-S-ylmethylsulfany^-benzoimidazol-l-yy-acetic acid;
{2-[3-(butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[3-(pentanoyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; and pharmaceutically acceptable salts, especially the sodium salt, of these compounds.
Particularly preferred novel compounds of the present invention include:
{ 2- [3 -(butoxycarbonyl-phenethyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid and its sodium salt;
{2-[3-(pentanoyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; (2-{3-[(2,2-diphenyl-ethyl)-pentanoyl-amino]-propylsulfanyl}-benzoimidazol-l-yl)- acetic acid;
[2-(3-methoxycarbonyl-benzylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetic acid; rac {2-[l-(4-bromo-benzoyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; rac [2-(l-butyryl-piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl] -acetic acid;
{2-[(6-methoxy-3-methoxycarbonyl)-benzylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
[5-fluoro-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid and its 6-fluoro regioisomer;
{2-[(6-bromo-3-methoxycarbonyl)-benzylsulfanyl]-benzoimidazol-l-yl}-acetic acid; [2-(3 - {butyloxycarbonyl- [(4-ethyloxycarbonyl)-phenyl] -amino} -propylsulfanyl)- benzoimidazol-1-yl] -acetic acid; [5-cyano-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid and its 6-cyano regioisomer;
[2-(4-ethyloxycarbonyl-butylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetic acid;
[2-(3 - { diphenylacetyl- [(4-ethyloxycarbonyl)-phenyl] -amino } -propylsulfanyl)- benzoimidazol-1-yl] -acetic acid;
[2-(3-{[(4-ethyloxycarbonyl)-phenyl]-pentanoyl-amino}-propylsulfanyl)- benzoimidazol-1-yl] -acetic acid; rac { 2- [ 1 -(furan-2-carbonyl)-piperidin-3 -ylmethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid; { 2- [3 -(benzyl-butoxy carbonyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; rac { 2- [ 1 -(3 -phenyl-propionyl)-piperidin-3 -ylmethylsulfanyl] -benzoimidazol- 1 -yl } - acetic acid;
(2- { 3 -[(4-ethyloxycarbonylphenyl)-(phenylacetyl)-amino] -propylsulfanyl} - benzoimidazol- l-yl)-acetic acid;
{ 2- [3 -(benzyl-pentanoyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
{2-[3-(cyclopropyl-diphenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; and
[2-(3-{diphenylpropionyl-[(4-ethyloxycarbonyl)-phenyl]-amino}-propylsulfanyl)- benzoimidazol-1-yl] -acetic acid.
Preferred novel compounds of the present invention include: rac [2-(l-methyl-2-oxo-2-phenyl-ethylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(3-methoxycarbonyl-benzylsulfanyl)-5-trifluoromethyl-benzoimidazol-l-yl]-acetic acid and its 6-trifluoromethyl regioisomer;
[2-(3,3-diphenyl-propylsulfanyl)-6-nitro-benzoimidazol-l-yl]-acetic acid;
(2-benzylsulfanyl-5-nitro-benzoimidazol-l-yl)-acetic acid and its 6-nitro isomer;
{2-[3-(l -phenethyl-3 -ρropyl-ureido)-propylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid; rac {2-[l-(3-chloro-benzoyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[3-(l ,3-dioxo-l ,3-dihydro-isoindol-2-yl)-propylsulfanyl]-5-nitro-benzoimidazol-l - yl} -acetic acid; {2-[3-(l,l,3-trioxo-l,3-dihydro-lλ6-benzo[d]isothiazol-2-yl)-propylsulfanyl]- benzoimidazol-1-yl} -acetic acid;
(2- {3 - [(2,2-diphenyl-ethyl)-(3 ,3 -diρhenyl-propionyl)-amino]-propylsulfanyl} - benzoimidazol-l-yl)-acetic acid; (2-{3-[cyclopropyl-(3,3-diphenyl-propionyl)-amino]-propylsulfanyl}-benzoimidazol-l- yl)-acetic acid; rac (2-{3-[(2-cyclohexyl-2-phenyl-acetyl)-cyclopropyl-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid;
(2- {3 -[diphenylacetyl-(2,2-diphenyl-ethyl)-amino]-propylsulfanyl} -benzoimidazol- 1 - yl)-acetic acid; rac [2-(l-heptanoyl-piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
{ 2- [3 -(3 ,3 -diphenyl-propionylamino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
(2-{3-[(butane-l-sulfonyl)-phenethyl-amino]-propylsulfanyl}-benzoimidazol-l-yl)- acetic acid; {2-[3-(benzyl-(phenylmethanesulfonyl)-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetic acid;
(2-{3-[(2,2-diphenyl-ethyl)-(phenylacetyl)-amino]-propylsulfanyl}-benzoimidazol-l- yl)-acetic acid;
{2-[3-(benzenesulfonyl-cyclopropyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetic acid;
{2-[3-(plienethyl-(phenylmethanesulfonyl)-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetic acid;
[2-(3,3-diphenyl-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
{2-[3-(phenethyl-(phenylacetyl)amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[3-(diphenylacetyl-phenetb.yl-ainino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
(2- { [(2-chloro-4-methyloxycarbonyl)-pyridin-6-yl] -methyl-sulfanyl} -benzoimidazol- 1 - yl)-acetic acid; rac [2-(bicyclo[4.2.0]octa-l,3,5-trien-7-ylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(3-acetyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid; [5-fluoro-2-(2-phenoxy-ethylsulfanyl)-benzoimidazol-l-yl]-acetic acid and its 6-fluoro regioisomer;
[2-(3-phenylmethanesulfonylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(4-ethyloxycarbonyl-butylsulfanyl)-6-nitro-benzoimidazol-l-yl]-acetic acid; {2-[3 -(1 ,3 -dioxo- 1 ,3 -dihydro-isoindol-2-yl)-propylsulfanyl] -benzoimidazol- 1-yl}- acetic acid;
{2-[3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-propylsulfanyl]-6-nitro-benzoimidazol-l- yl} -acetic acid;
(2- { 3 - [phenylmethanesulfonyl~(4-piperidin- 1 -yl-phenyl)-amino] -propylsulfanyl } - benzoimidazol- 1 -yl)-acetic acid;
[2-(4-ethyloxycarbonyl-butylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid and its
6-fluoro regioisomer;
[2-(3-diphenylacetylamino-propylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetic acid;
{ 2- [3 -(cyclopropyl-(phenylmethanesulfonyl)-amino)-propylsulfanyl] -benzoimidazol- 1 - yl} -acetic acid;
{2- [(5 -bromo-3 -methoxycarbonyl)-benzylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
{ 5 -nitro-2- [2-(4-chloro-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
[2-(3,3-diphenyl-propylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetic acid;
{2-[3-(2,4-dioxo-l,4-dihydro-2/i-quinazolin-3-yl)-propylsulfanyl]-benzoimidazol-l- yl} -acetic acid;
{2-[3-(benzyl-(phenylacetyl)-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
(2-{3-[(2,2-diphenyl-ethyl)-(phenylmethanesulfonyl)-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid; rac [2-(l-acetyl-piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid; (2-{3-[benzyl-(3,3-diphenyl-propionyl)-amino]-propylsulfanyl}-benzoimidazol-l-yl)- acetic acid;
{2-[3-(cyclopropyl-(phenylacetyl)-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; rac [2-( 1 -methyloxycarbonyl- 1 -phenyl-methylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid;
{2-[3-(butoxycarbonyl-cyclohexyl-ammo)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; P-^-diphenylacetylammo-propylsulfanyty-benzoimidazol- 1 -yl]-acetic acid;
{2-[3-(l,3-diphenyl-ureido)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
(2-benzylsulfanyl-6-nitro-benzoimidazol- 1 -yl)-acetic acid; rac [2-(l-diphenylacetyl-piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
{ 2- [3 -(cyclopropyl-ρentanoyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
(2- {3-[benzenesulfonyl-(4-piperidin- 1 -yl-phenyl)-amino]-propylsulfanyl} - benzoimidazol- l-yl)-acetic acid;
{2-[3-(benzyl-diphenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; { 2- [3 -(fer^butoxycarbonyl-phenyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
[2-(3-phenyl-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(3-benzenesulfonylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid; {2- [3 -( 1 -benzyl-3 -propyl-ureido)-propylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
(2-{3-[l-(2,2-diphenyl-ethyl)-3-propyl-ureido]-propylsulfanyl}-benzoimidazol-l-yl)- acetic acid;
[2-(4-ethyloxycarbonyl-butylsulfanyl)-5 -trifluoromethyl-benzoimidazol- 1 -yl] -acetic acid and its 6-trifluoromethyl regioisomer; [5-cyano-2-(4-ethyloxycarbonyl-butylsulfanyl)-benzoimidazol-l-yl]-acetic acid and its
6-cyano regioisomer;
[2-(5-ethyloxycarbonyl-pentylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
(2- { 3 -[(3 ,3 -diphenyl-propionyl)-phenyl-amino] -propylsulfanyl} -benzoimidazol- 1 -yl)- acetic acid; {2- [3 -(butoxycarbonyl-(cyclohexylmethyl)-amino)-propylsulfanyl] -benzoimidazol- 1 - yl} -acetic acid;
(2-{3-[fer/-butoxycarbonyl-(4-piperidin-l-yl-phenyl)-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid;
(2- { 3 - [phenylacetyl-(4-piperidin- 1 -yl-phenyl)-amino]-propylsulfanyl} -benzoimidazol- l-yl)-acetic acid;
{2-[3-(2,3-dihydro-l-ethyloxycarbonyl-3-oxo-indazol-2-yl)-propylsulfanyl]- benzoimidazol- 1 -yl } -acetic acid; rac {2-[l-(3-cyclopentyl-propionyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l- yl} -acetic acid;
(2-{3-[ført-butoxycarbonyl-(2,2-diphenyl-ethyl)-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid; {2-[3-(benzenesulfonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; and
{2- [5-(3 ,4-dihydro-2/f-quinolm- 1 -yl)-5 -oxo-pentylsulfanyl] -benzoimidazol- 1 -yl} - acetic acid.
Further preferred novel compounds of the present invention include:
{2-[3-(phenyl-phenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
(2- { 3 - [(3 ,3 -diphenyl-propionyl)-phenethyl-amino] -propylsulfanyl } -benzoimidazol- 1 - yl)-acetic acid; rac [2-( 1 -cyclohexanecarbonyl-piperidin-3 -ylmethylsulfanyl)-benzoimidazol- 1 -yl] - acetic acid;
{ 2- [3 -(3 -benzyl- 1 -phenyl-ureido)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
{2- [3 -(butane- 1 -sulfonylamino)-propylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid;
{2- [3 -(2-oxo-2,3 -dihydro-benzoimidazol- 1 -yl)-propylsulfanyl] -benzoimidazol- 1 -yl} - acetic acid; {2-[3-(benzyl-ført-butoxycarbonyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2- [3 -(diphenylacetyl-phenyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; rac [2-( 1 -phenylacetyl-piperidin-3 -ylmethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid;
[2-(2-cyclohexyl-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid; [2-(3-phenoxy-propylsulfanyl)-benzoimidazol-l -yl]-acetic acid;
{2-[3 -( 1 -oxo- 1 ,3 -dihydro-isoindol-2-yl)-propylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
[2-(2-methoxy-benzylsulfanyl)-benzoimidazol-l -yl]-acetic acid;
(2- {3 - [(butane- 1 -sulfonyl)-cyclopropyl-amino]-propylsulfanyl} -benzoimidazol- 1 -yl)~ acetic acid;
[5-cyano-2-(2-phenoxy-ethylsulfanyl)-benzoimidazol-l-yl]-acetic acid and its 6-cyano regioisomer; {2-[3-(benzenesulfonyl-benzyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[3-(benzenesulfonyl-phenyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; (2-hexylsulfanyl-benzoimidazol-l-yl)-acetic acid;
{2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-5-methyl-benzoimidazol-l -yl} -acetic acid and its 6-methyl regioisomer; rac (2-{3-[benzyl-(2-cyclohexyl-2-phenyl-acetyl)-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid; {2-[(4-bromo-3-methoxycarbonyl)-benzylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid;
{2-[3-(pentanoyl-phenyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; rac { 2- [ 1 -(2-methoxy~benzoyl)-piperidm-3 -ylmethylsulfanyl] -benzoimidazol- 1 -yl } - acetic acid; rac [2-(l-phenyl-ethylsulfanyl)-benzoimidazol-l-yl]-acetic acid; [2-(4-ethyloxycarbonyl-butylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid;
{2-[3-(3-phenyl-propionylamino)-propylsulfanyl]-benzoimidazol-l -yl} -acetic acid;
{2-[4-(benzyl-phenyl-carbamoyl)-butylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[(2-bromo-3 -methoxycarbonyl)-benzylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
{2-[2-(3-phenyl-ureido)-etb.ylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[3-(3-phenyl-ureido)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[4-(butyl-phenyl-carbamoyl)-butylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[3-(4-bromo-benzoylamino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{ 2- [3 -( 1 -oxo- 1 H-phthalazin-2-yl)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
{2- [3 -(ført-butoxycarbonyl-phenethyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl} - acetic acid;
(2-{3-[pentanoyl-(4-piperidin-l-yl-phenyl)-amino]-propylsulfanyl}-benzoimidazol-l- yl)-acetic acid;
(2-{3-[(3,3-diphenyl-propionyl)-(4-piperidin-l-yl-phenyl)-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid; rac {2-[ 1 -(naphthalene- 1 -carbonyl)-piperidin-3 -ylmethylsulfanyl] -benzoimidazol- 1 - yl} -acetic acid;
[5-nitro-2-(2-phenoxy-ethylsύlfanyl)-benzoimidazol-l-yl]-acetic acid; [2-(3-benzoylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
{2-[3-(2,2-diphenyl-ethylamino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
[2-(3-phenylacetylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(4-phenoxy-butylsulfanyl)-benzoimidazol-l-yl]-acetic acid; {2-[3-(cyclohexanecarbonyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
[2-(3-phenylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
(2- {3 -[(naphthalene- 1 -carbonyl)-amino] -propylsulfanyl} -benzoimidazol- 1 -yl)-acetic acid;
[2-(2-diphenylacetylamino-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid; rac (2-{3-[(2-cyclohexyl-2-phenyl-acetyl)-phenyl-aniino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid;
{2-[3-(l,2-dioxo-2-ethyloxy-ethylamino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-4-methyl-benzoimidazol-l -yl} -acetic acid and its 8-methyl regioisomer;
{2-[3-(tert-butoxycarbonyl-cyclopropyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetic acid;
{2- [(2-methyloxycarbonyl-furan-5 -yl)-methylsulf anyl] -benzoimidazol- 1 -yl } -acetic acid; (2-{3-[diphenylacetyl-(4-piperidin-l-yl-phenyl)-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid;
{2-[4-(methyl-phenyl-carbamoyl)-butylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid;
{2-[4-(benzyl-methyl-carbamoyl)-butylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{ 2- [3 -(4-methoxy-benzoylamino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; {2-[3-(cyclopropanecarbonyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{5-chloro-2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid and its 6-chloro regioisomer;
(2-{3-[(biphenyl-4-carbonyl)-amino]-propylsulfanyl}-benzoimidazol-l-yl)-acetic acid;
{ 2- [3 -(3 -cyclopentyl-propionylamino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
[2-(3-octanoylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid; {2-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[3-(3-phenyl-acryloylamino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[(5-methyloxycarbonyl-pyridin-3-yl)-methylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
[6-iodo-2-(2-phenoxy-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid; rac. {2-[3-(2-cyclohexyl-2-phenyl-acetylamino)-propylsulfanyl]-benzoimidazol-l-yl}- acetic acid;
{2- [3 -(4-piperidin- 1 -yl-phenylamino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; {2-[3-(3 -propyl-ureido)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
[2-(3-fert-butoxycarbonylamino-propylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid;
[2-(2-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid;
(2- { 3 - [(pyridine-3 -carbonyl)-amino] -propylsulfanyl } -benzoimidazol- 1 -yl)-acetic acid;
{2-[3-(3,3-dimethyl-butyrylamino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; (2-{3-[l -(4-piperidin- 1 -yl-phenyl)-3 -propyl-ureido] -propylsulfanyl } -benzoimidazol- 1 - yl)-acetic acid;
(2-cyclopentylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-but-3 -enylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-{3-[(furan-2-carbonyl)-amino]-propylsulfanyl}-benzoimidazol-l-yl)-acetic acid; {2-[3 -(2,2-dimethyl-propionylamino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
[2-(2-tert-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid;
[2-(2-phenylamino-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid;
(2- { 3 - [( 1 -ethyloxycarbonyl-indazol-3 -yl)-oxy] -propylsulfanyl } -benzoimidazol- 1 -yl)- acetic acid; [2-(3-pentanoylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(3-ethyloxycarbonyl-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
{ 2- [3 -( 1 -cyclopropyl-3 -propyl-ureido)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; and [2-(3-benzylamino-propylsulfanyl)-benzoimidazol-l-yl] -acetic acid.
Particulary preferred novel compounds of the present invention include: rac {2- [ 1 -(3 ,4-dichloro-benzenesulfonyl)-piperidin-3 -ylmethylsulfanyl]- benzoimidazol-l-yl}-acetic acid; rac {2-[ 1 -(3 -phenyl-acryloyty-piperidin-S-ylmethylsulfanyl] -benzoimidazol- 1 -yl} - acetic acid;
[2-(l-butyryl-piperidin-3-ylmethylsulfanyl)-5,6-dimethyl-benzoimidazol-l-yl]-acetic acid; [2-(5-methyloxycarbonyl-benzylsulfanyl)-5,6-dichloro-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5,6-dichloro-benzoimidazol- 1 -yl]-acetic acid;
[2-( 1 -butyryl-piperidin-3 -ylmethylsulfanyl)-5 ,6-dichloro-benzoimidazol- 1 -yl]-acetic acid; [2-((R)-I -butyryl-piperidin-3 -ylmethylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5,6-difluoro-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid; rac [2-( 1 -butyryl-piperidin-3 -ylmethylsulfanyl)-5-fluoro-benzoimidazol- 1 -yl] -acetic acid; rac {5-fluoro-2-[l-(furan-2-carbonyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l- yl} -acetic acid; rac {2-[l-(4-bromo-benzoyl)-piperidin-3-ylmethylsulfanyl]-5-fluoro-benzoimidazol-l- yl} -acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-trifluoromethyl-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-methanesulfonyl-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-6-fluoro-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-4-fluoro-benzoimidazol-l-yl]-acetic acid; [5-acetyl-2-(5-acetyl-2-methoxy-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-formyl-benzoimidazol-l-yl]-acetic acid; rac 2- [2-(5 -acetyl-2-methoxy-benzylsulfanyl)-5 -fluoro-benzoimidazol- 1 -yl] -propionic acid;
[2-(5-butylcarbamoyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid;
[2-(5-benzylcarbamoyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]- acetic acid; {2-[5-(2,3-dihydro-indole-l-caxbonyl)-2-niethoxy-benzylsulfanyl]-5-fluoro- benzoimidazol-1-yl} -acetic acid;
[2-(5-diethylcarbamoyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]- acetic acid; [2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-nitro-benzoimidazol- 1 -yl]-acetic acid; rac {2-[l-(4-bromo-benzoyl)-pyrrolidin-3-ylmethylsulfanyl]-5-fluoro-benzoimidazol-l- yl} -acetic acid; rac { 5 -fluoro-2- [ 1 -(furan-2-carbonyl)-pyrrolidin-3 -ylmethylsulfanyl] -benzoimidazol- 1 - yl} -acetic acid; rac { 5-fluoro-2-[ 1 -(2-phenyl-ethenesulfonyl)-pyrrolidin-3 -ylmethylsulfanyl] - benzoimidazol- 1-yl} -acetic acid;
[2-(5-acetyl-2-butoxy-benzylsulfanyl)-5-fluoro-benzoimidazol- 1 -yl]-acetic acid;
{2-[5-acetyl-2-(3-hydroxy-propoxy)-benzylsulfanyl]-5-fluoro-benzoimidazol-l-yl}- acetic acid; [2-(5-benzoyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid;
[5-fluoro-2-(6-methoxy-3-oxo-indan-5-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-ethoxy-benzylsulfanyl)-5-fluoro-benzoimidazol- 1 -yl]-acetic acid;
[2-(5-acetyl-2-propoxy-benzylsulfanyl)-5-fluoro-benzoimidazol- 1 -yl]-acetic acid; and rac [2-(5-acetyl-2-methoxy-phenylmethanesulfmyl)-5-fluoro-benzoimidazol-l -yl]- acetic acid.
Further preferred novel compounds of the present invention include:
[2 -(I -butyryl-piperidin-4-ylmethylsulfanyl)-benzoimidazol-l -yl]-acetic acid; [2-(3-isopropyloxycarbonyl-6-methoxy-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid; rac {2-[l-(propane-2-sulfonyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l-yl}- acetic acid; rac [2-( 1 -methanesulfonyl-ρiperidin-3 -ylmethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid; rac {2-[l-(thiophene-2-sulfonyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l-yl}- acetic acid; rac {2-[l -(butane- 1 -sulfonyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l -yl} - acetic acid; rac P-Cl-phenylmethanesulfonyl-piperidin-S-ylmetliylsulfany^-benzoimidazol-l-yl]- acetic acid; rac {2-[l-(naphthalene-2-sulfonyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l-yl}- acetic acid; rac {2-[l-(toluene-4-sulfonyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l-yl}- acetic acid; rac {2-[l-(4-methoxy-benzenesulfonyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol- 1-yl} -acetic acid;
[2-(5-methyloxycarbonyl-benzylsulfanyl)-5,6-dimethyl-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5,6-dimethyl-benzoimidazol-l-yl]-acetic acid;
[2-(5-methyloxycarbonyl-benzylsulfanyl)-4,6-bis-trifluoromethyl-benzoimidazol-l-yl]- acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-4,6-bis-trifluorometb.yl-benzoimidazol-l-yl]- acetic acid;
[2-(l -butyryl-piperidin-3 -ylmethylsulfanyl)-4,6-bis-trifluoromethyl-benzoimidazol- 1 - yl] -acetic acid; [2-(4-methyloxycarbonyl-oxazol-2-ylmethylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid;
[2-((S)- 1 -butyryl-piperidin-3 -ylmethylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid; rac {2-[5-(l-hydroxy-ethyl)-2-methoxy-benzylsulfanyl]-benzoimidazol-l-yl}-acetic acid; rac { 2-[2-methoxy-5 -( 1 -methoxy-ethyl)-benzylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
[2-(3 -methyloxycarbonyl-ό-phenyl-benzylsulfany^-benzoimidazol- 1 -yl] -acetic acid;
{2-[5-(benzyl-ethyl-carbamoyl)-2-methoxy-benzylsulfanyl]-5-fluoro-benzoimidazol-l- yl} -acetic acid;
{2-[2-methoxy-5-(morpholine-4-carbonyl)-benzylsulfanyl]-5-fluoro-benzoimidazol-l- yl}-acetic acid; rac [2-(l-butyryl-pyrrolidin-3-ylmethylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid; rac [5-fluoro-2-(l -octanoyl-pyrrolidm-S-ylmethylsulfanyO-benzoimidazol-l -yl]-acetic acid; rac { 5 -fluoro-2- [ 1 -(3 -ρhenyl-propionyl)-pyrrolidin-3 -ylmethylsulfanyl] - benzoimidazol-1-yl} -acetic acid; rac [5-fluoro-2-(l-phenylacetyl-pyrrolidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]- acetic acid; rac {2- [ 1 -(butane- 1 -sulfonyl)-pyrrolidin-3 -ylmethylsulfanyl]-5-fluoro-benzoimidazol-
1-yl} -acetic acid; rac { 5 -fluoro-2- [ 1 -(4-methoxy-benzenesulfonyl)-pyrrolidin-3 -ylmethylsulfanyl] - benzoimidazol- 1 -yl} -acetic acid;
[5-fluoro-2-(3-methoxy-8-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylmethylsulfanyl)- benzoimidazol-1-yl] -acetic acid;
(S)-[5-fluoro-2-(l-benzyloxycarbonyl-azetidm-2-ylmethylsulfanyl)-benzoimidazol-l- yl]-acetic acid; and [5-fluoro-2-(l -benzyloxycarbonyl-azetidin-S-ylmethylsulfany^-benzoimidazol-l -yl]- acetic acid
The present invention also relates to precursors of the general Formula II,
II wherein R1 -R7 and n are as in Formula I and R represents an alkyl group, preferably ethyl or tert-butyl, are novel with the exception of:
methyl [2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-benzoimidazol-l-yl]-acetate; methyl [2-(4-chloro-benzylsulfanyl)-benzoimidazol- 1 -yl] -acetate; methyl (2-benzylsulfanyl-benzoimidazol- 1 -yl)-acetate; methyl [2-(5-nitro-pyridin-2-ylsulfanyl)-benzoimidazol- 1 -yl]-acetate; methyl (2-methylsulfanyl-benzoimidazol-l -yl)-acetate; ethyl (2-methylsulfanyl-benzoimidazol- 1 -yl)-acetate; methyl (2-ethylsulfanyl-benzoimidazol- 1 -yl)-acetate; ethyl [2-(l,3,7-trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-ylsulfanyl)- benzoimidazol- 1 -yl]-acetate; ethyl {2-[3-methyl-4-(2-morpholin-4-yl-ethylsulfanyl)-pyridin-2-ylmethylsulfanyl]- benzoimidazol-l-yl}-acetate (US patent 5,504,082) and methyl {2-[3-methyl-4-(2-morpholin-4-yl-ethylsulfanyl)-pyridin-2-ylmethylsulfanyl]- benzoimidazol-1-yl} -acetate (US patent 5,504,082).
These novel precursors also form part of the present invention. They include, e.g. : tert-butyl [2-(2-cyclohexyl-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetic acetate; tert-butyl (2-hexylsulfanyl-benzoimidazol-l -yl)-acetate; tert-butyl (2-pentylsulfanyl-benzoimidazol-l-yl)-acetate; tert-butyl (2-but-3 -enylsulfanyl-benzoimidazol- 1 -yl)-acetate; tert-butyl (2-butylsulfanyl-benzoimidazol- 1 -yl)-acetate; rac tert-butyl [2-(l -phenyl -ethylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl (2-cyclopentylsulfanyl-benzoimidazol-l -yl)-acetate; rac tert-butyl [2-( 1 -methyl oxycarbonyl- 1 -phenyl-methylsulfanyl)-benzoimidazol- 1 -yl] - acetate; rac tert-butyl [2-(bicyclo [4.2.0] octa- 1 ,3 ,5 -trien-7-ylsulfanyl)-benzoimidazol- 1 -yl] - acetate; rac tert-butyl [2-( 1 -methyl -2-oxo-2-phenyl-ethylsulfanyl)-benzoirnidazol- 1 -yl] -acetate; tert-butyl [2-(2-methoxy-benzylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl (2-benzylsulfanyl-benzoimidazol-l -yl)-acetate; tert-butyl (2-phenethylsulfanyl-benzoimidazol- 1 -yl)-acetate; tert-butyl [2-(3 -phenyl -propylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl [2-(3 ,3 -diphenyl-propylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl {2-[2-(4-chloro-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl} -acetate; tert-butyl [2-(2-phenoxy-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl {2-[2-(naphthalen-l-yloxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetate; tert-butyl {2-[2-(naphthalen-2-yloxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetate; tert-butyl [2-(4-phenoxy-butylsulfanyl)-benzoimidazol- 1 -yl]-acetate; tert-butyl (2-{3-[(l-ethyloxycarbonyl-indazol-3-yl)-oxy]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl [2-(4-phenoxy-butylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl [2-(5-ethyloxycarbonyl-pentylsulfanyl)-benzoimidazol-l-yl]-acetate; tert-butyl [2-(3 -ethyloxycarbonyl-propylsulfanyty-benzoimidazol- 1 -yl] -acetate; tert-butyl [2-(4-ethyloxycarbonyl-butylsulfanyl)-benzoimidazol- 1 -yl]-acetate; tert-butyl {2-[4-(benzyl-methyl-carbamoyl)-butylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[5-(3,4-dihydro-2H-quinolin-l-yl)-5-oxo-pentylsulfanyl]-benzoimidazol-
1-yl} -acetate; tert-butyl {2-[4-(benzyl-phenyl-carbamoyl)-butylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[4-(methyl-phenyl-carbamoyl)-butylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[4-(butyl-phenyl-carbamoyl)-butylsulfanyl]-benzoimidazol-l-yl}-acetate; tert-butyl {2-[3-(2,3-dihydro-l-ethyloxycarbonyl-3-oxo-indazol-2-yl)-propylsulfanyl]- benzoimidazol- 1 -yl} -acetate; tert-butyl {2-[3 -( 1 -oxo- 1 ,3 -dihydro-isoindol-2-yl)-propylsulfanyl] -benzoimidazol- 1 - yl} -acetate; tert-butyl {2-[3-(2-oxo-2,3-dihydro-benzoimidazol-l-yl)-propylsulfanyl]- benzoimidazol- 1 -yl} -acetate; tert-butyl {2-[3-(l-oxo-lH-phthalazin-2-yl)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[3-(2,4-dioxo-l,4-dihydro-2H-quinazolin-3-yl)-propylsulfanyl]- benzoimidazol- 1 -yl} -acetate; tert-butyl {2-[3-(l ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl)-propylsulfanyl]-benzoimidazol-
1-yl} -acetate; tert-butyl {2-[3 -(1 , 1 ,3 -trioxo- 1 ,3 -dihydro- 1 λ6-benzo [d]isothiazol-2-yl> propylsulfanyl]-benzoimidazol-l-yl}-acetate; tert-butyl [2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetate; tert-butyl { 2- [(5 -methyloxycarbonyl-pyridin-3 -yl)-methylsulfanyl] -benzoimidazol- 1 - yl} -acetate; tert-butyl (2- { [(2-chloro-4-methyloxycarbonyl)-pyridin-6-yl]-methyl-sulfanyl} - benzoimidazol- 1 -yl)-acetate; tert-butyl { 2- [(2-methyloxycarbonyl-furan- 5 -yl)-methylsulfanyl] -benzoimidazol- 1-yl}- acetate; tert-butyl {2-[(2-bromo-3-methoxycarbonyl)-benzylsulfanyl]-benzoimidazol-l-yl}- aceate; tert-butyl {2-[(4-bromo-3-methoxycarbonyl)-benzylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[(5-bromo-3-methoxycarbonyl)-benzylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[(6-bromo-3-methoxycarbonyl)-benzylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2- [(6-methoxy-3 -methoxycarbonyl)-benzylsulfanyl] -benzoimidazol- 1 -yl } - acetate; tert-butyl [2-(3-acetyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetate; tert-butyl [2-(5-acetyl-2-methoxy-benzylsulfanyl)-benzoimidazol-l-yl]-acetate; rac tert-butyl [2-( 1 -tert-butyloxycarbonyl-piperidin-3 -ylmethylsulfanyl)- benzoimidazol-l-yl]-acetate; rac tert-butyl [2-(l -butyryl-piperidin-3 -ylmethylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl {2-[3-(tert-Butoxycarbonyl-phenethyl-amino)-propylsulfanyl]- benzoimidazol- 1 -yl } -acetate; tert-butyl (2- { 3 -[tert-butoxycarbonyl-(4-piperidin- 1 -yl-phenyl)-amino] - propylsulfanyl}-benzoimidazol-l-yl)-acetate; tert-butyl [2-(3-{[(4-ethyloxycarbonyl)-phenyl]-tert-butyloxycarbonyl-amino}- propylsulfanyl)-benzoimidazol- 1 -yl]-acetate; tert-butyl {2-[3-(benzyl-tert-butoxycarbonyl-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetate; tert-butyl {2-[3-(tert-butoxycarbonyl-cyclopropyl-amino)-propylsulfanyl]- benzoimidazol- 1 -yl}-acetate; tert-butyl {2-[3-(tert-butoxycarbonyl-phenyl-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetate; tert-butyl (2-{3-[tert-butoxycarbonyl-(2,2-diphenyl-ethyl)-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl {2-[3-(butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetate; tert-butyl { 2- [3 -(benzyl-butoxycarbonyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl} - acetate; tert-butyl { 2- [3 -(butoxy carbonyl-cyclohexyl-amino)-propylsulfanyl] -benzoimidazol- 1 - yl}-acetate; tert-butyl {2-[3-(butoxycarbonyl-cyclohexylmethyl-amino)-propylsulfanyl]- benzoimidazol- 1 -yl } -acetate ; tert-butyl { 2- [3 -(pentanoyl-phenyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl } - acetate; tert-butyl {2-[3 -(diphenylacetyl-phenyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl} - acetate; tert-butyl {2-[3-(phenyl-phenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl (2- { 3 - [(3 , 3 -diphenyl-propionyl)-phenyl-arnino] -propylsulfanyl } - benzoimidazol- l-yl)-acetate; tert-butyl {2-[3-(benzenesulfonyl-phenyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; rac tert-butyl (2-{3-[(2-cyclohexyl-2-phenyl-acetyl)-phenyl-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl {2-[3-(l,3-diphenyl-ureido)-propylsulfanyl]-benzoimidazol-l-yl}-acetate; tert-butyl {2- [3 -(3 -benzyl- 1 -phenyl-ureido)-propylsulfanyl] -benzoimidazol- 1 -yl} - acetate; tert-butyl (2-{3-[pentanoyl-(4-piperidin-l-yl-phenyl)-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl (2- {3 -[diphenylacetyl-(4-piperidin- 1 -yl-phenyl)-amino] -propylsulfanyl} - benzoimidazol- 1 -yl)-acetate; tgrt-butyl (2-{3-[ρhenylmethanesulfonyl-(4-piperidin-l-yl-phenyl)-amino]- propylsulfanyl} -benzoimidazol- 1 -yl)-acetate; tert-butyl (2- { 3 - [phenylacetyl-(4-piperidin- 1 -yl-phenyl)-amino] -propylsulfanyl } - benzoimidazol- 1 -yl)~acetate; tert-butyl (2- { 3 -[(3 ,3 -diphenyl~propionyl)-(4~piperidin- 1 -yl-phenyl)-ammo]- propylsulfanyl} -benzoimidazol- 1 -yl)-acetate; tert-butyl (2- { 3 -[ 1 -(4-piperidin- 1 -yl-phenyl)-3 -ρropyl-ureido]-propylsulfanyl} - benzoimidazol- 1 -yl)-acetate; tert-butyl (2- { 3 - [benzenesulfonyl-(4-piperidin- 1 -yl-phenyl)-amino] -propylsulfanyl} - benzoimidazol- 1 -yl)-acetate; tert-butyl [2-(3-{[(4-ethyloxycarbonyl)-phenyl]-pentanoyl-amino}-propylsulfanyl)- benzoimidazol- 1 -yl] -acetate; tert-bλityl [2-(3 - { diphenylacetyl- [(4-ethyloxycarbonyl)-phenyl] -amino } - propylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl (2-{3-[(4-ethyloxycarbonylphenyl)-(phenylacetyl)-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl [2-(3 - { diphenylpropionyl- [(4-ethyloxycarbonyl)-phenyl] -amino } - propylsulfanyl)-benzoimidazol-l-yl]-acetate; rac tert-butyl [2-(3-{(2-cyclohexyl-2-phenyl-acetyl)-[(4-ethyloxycarbonyl)-phenyl]- amino}-propylsulfanyl)-benzoimidazol-l-yl]-acetate; tert-butyl {2-[3-(benzyl-pentanoyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[3-(benzyl-diphenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[3-(benzyl-phenylmethanesulfonyl-amino)-piOpylsulfanyl]- benzoimidazol- 1 -yl} -acetate; tert-butyl {2-[3-(benzyl-phenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl (2- { 3 - [benzyl-(3 ,3 -diphenyl-propionyl)-amino] -propylsulfanyl } - benzoimidazol- l-yl)-acetate; tert-butyl {2-[3 -(I -benzyl-3-propyl-ureido)-propylsulfanyl]-benzoimidazol- 1 -yl} - acetate; tert-butyl {2-[3 -(benzenesulfonyl-benzyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl} - acetate; rac tert-butyl(2- { 3 - [benzyl-(2-cyclohexyl-2-phenyl-acetyl)-amino] -propylsulfanyl} - benzoimidazol- 1 -yl)-acetate; tert-butyl {2- [3 -(cyclopropyl-pentanoyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl } - acetate; tert-butyl (2- { 3 - [(butane- 1 -sulfonyl)-cyclopropyl-amino]-propylsulfanyl} - benzoimidazol- 1 -yl)-acetate; tert-butyl {2-[3-(cyclopropyl-diphenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetate; tert-butyl {2-[3-(cyclopropyl-phenylmethanesulfonyl-amino)-propylsulfanyl]- benzoimidazol- 1 -yl} -acetate; tert-butyl {2-[3-(cyclopropyl-phenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetate; tert-butyl (2-{3-[cyclopropyl-(3,3-diphenyl-propionyl)-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl {2-[3 -( 1 -cyclopropyl-3 -propyl-ureido)-propylsulfanyl] -benzoimidazol- 1 -yl} - acetate; tert-butyl {2-[3-(benzenesulfonyl-cyclopropyl-amino)-propylsulfanyl]-benzoimidazol- 1-yl} -acetate; rac tert-butyl (2- { 3 - [(2-cyclohexyl-2-phenyl-acetyl)-cyclopropyl-amino] - propylsulfanyl } -benzoimidazol- 1 -yl)-acetate; tert-butyl {2-[3-(pentanoyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl (2-{3-[(butane-l-sulfonyl)-phenethyl-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl {2-[3-(diphenylacetyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetate; tert-butyl {2-[3-(phenethyl-phenylmethanesulfonyl-amino)-propylsulfanyl]- benzoimidazol- 1 -yl } -acetate; tert-butyl {2-[3-(phenethyl-phenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; ført-butyl (2-{3-[(3,3-diphenyl-propionyl)-phenethyl-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl {2-[3-(l-phenethyl-3-propyl-ureido)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[3-(benzenesulfonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetate; fer/-butyl(2-{3-[(2,2-diphenyl-ethyl)-pentanoyl-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl (2-{3-[diphenylacetyl-(2,2-diphenyl-ethyl)-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetate; tert-butyl (2-{3-[(2,2-diphenyl-ethyl)-phenylmethanesulfonyl-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl (2-{3-[(2,2-diphenyl-ethyl)-phenylacetyl-amino]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl (2-{3-[(2,2-diphenyl-ethyl)-(3,3-diphenyl-propionyl)-amino]- propylsulfanyl} -benzoimidazol- 1 -yl)-acetate; tert-butyl (2-{3-[l-(2,2-diphenyl-ethyl)-3-propyl-ureido]-propylsulfanyl}- benzoimidazol- 1 -yl)-acetate; tert-butyl [2-(3-{butyloxycarbonyl-[(4-ethyloxycarbonyl)-phenyl]-amino}- propylsulfanyl)-benzoimidazol-l-yl]-acetate; tert-butyl [2-(3-tert-butoxycarbonylamino-propylsulfanyl)-benzoimidazol-l-yl]- acetate; tert-butyl [2-(3 -pentanoylamino-propylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl {2- [3 -(butane- 1 -sulfonylamino)-propylsulfanyl] -benzoimidazol- 1 -yl } - acetate; tert-butyl [2-(3-diphenylacetylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetate; tert-butyl ^-(S-phenylmethanesulfonylammo-propylsulfany^-benzoimidazol- 1 -yl]- acetate; tert-butyl [2-(3-phenylacetylamino-piOpylsulfanyl)-benzoimidazol- 1 -yl]-acetate; fer/-butyl {2-[3 -(3 ,3 -diphenyl-propionylamino)-propylsulfanyl] -benzoimidazol- 1 -yl} - acetate; tert-butyl {2-[3 -(3 -propyl-ureido)-propylsulfanyl] -benzoimidazol- 1 -yl} -acetate; tert-butyl [2-(3 -benzenesulfonylamino-propylsulfany^-benzoimidazol- 1 -yl] -acetate; rac tert-butyl {2-[3-(2-cyclohexyl-2-phenyl-acetylamino)-propylsulfanyl]- benzoimidazol- 1 -yl} -acetate; tert-butyl {2- [3 -(3 -phenyl-ureido)-propylsulfanyl] -benzoimidazol- 1 -yl} -acetate; tert-butyl [2-(3-benzoylamino-propylsulfanyl)-benzoimidazol- 1 -yl]-acetate; tert-butyl {2-[3-(cyclohexanecarbonyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[3-(4-methoxy-benzoylamino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; fert-butyl (2-{3-[(furan-2-carbonyl)-amino]-propylsulfanyl}-benzoimidazol-l-yl)- acetate; tert-butyl {2-[3-(cyclopropanecarbonyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl (2- { 3 - [(naphthalene- 1 -carbonyl)-amino] -propylsulfanyl } -benzoimidazol- 1 - yl)-acetate; tert-butyl {2-[3-(3-cyclopentyl-propionylammo)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[3-(2,2-dimethyl-propionylamino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl {2-[3-(3-phenyl-acryloyIamino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl { 2- [3 -(3 -phenyl -propionylaniino)-propylsulfanyl] -benzoimidazol- 1 -yl } - aceate; tert-butyl {2-[3-(l,2-dioxo-2-ethyloxy-ethylamino)-propylsulfanyl]-benzoimidazol-l- yl} -acetate; tert-butyl (2- { 3 - [(biphenyl-4-carbonyl)-amino] -propylsulfanyl} -benzoimidazol- 1 -yl)- acetate; tert-butyl (2-{3-[(pyridme-3-carbonyl)-amino]-propylsulfanyl}-benzoimidazol-l-yl)- acetate; tert-butyl {2-[3-(3,3-dimethyl-butyrylamino)-propylsulfanyl]-benzoimidazol-l-yl}- acetate; tert-butyl [2-(3 -octanoylamino-propylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl {2-[3-(4-bromo-benzoylamino)-propylsulfanyl]-benzoimidazol-l-yl}-acetate;
[3 -( 1 -tert-butoxy carbonylmethyl- 1 H-benzoimidazol-2-ylsulfanyl)-propyl] -phenethyl- ammonium chloride;
[3-(l-tert-butoxycarbonylmethyl-lH-benzoimidazol-2-ylsulfanyl)-propyl]-(4-piperidin- l-yl-phenyl)-ammonium chloride;
[3 -( 1 -tert-butoxy carbonylmethyl- 1 i7-benzoimidazol-2-ylsulfanyl)-propyl] -(4- ethoxycarbonyl-phenyl)-ammonium chloride; benzyl-[3-(l-ført-butoxycarbonylmethyl-17i-benzoimidazol-2-ylsulfanyl)-propyl]- ammonium chloride; [3 -( 1 -tert-butoxycarbonylmethyl- 1 H-benzoimidazol-2-ylsulfanyl)-propyl] -cyclopropyl- ammonium chloride;
[3-(l-tert-butoxycarbonylmethyl-lH-benzoimidazol-2-ylsulfanyl)-propyl]-phenyl- ammonium chloride;
[3-(l-/er^-butoxycarbonylmethyl-lH-benzoimidazol-2-ylsulfanyl)-propyl]-(2,2- diphenyl-ethyl)-ammonium chloride;
3-(l-tert-butoxycarbonylmethyl-lif-benzoimidazol-2-ylsulfanyl)-propyl-ammonium chloride; te7*t-butyl {2-[2-(l ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl)-ethylsulfanyl]-benzoimidazol- 1 - yl} -acetate; tert-butyl [2-(2-tert-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetate; tert-butyl [2-(2-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetate; ter/-butyl [2-(2-diphenylacetylamino-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetate; tert-butyl {2-[2-(3-phenyl-ureido)-ethylsulfanyl]-benzoimidazol-l-yl}-acetate; tert-butyl [6-iodo-2-(2-phenoxy-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetate; tert-butyl {5-chloro-2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}- acetate and its 6-chloro regioisomer; tert-butyl {2- [2-(4-chloro-phenoxy)-ethylsulfanyl] -4-methyl-benzoimidazol- 1 -yl} - acetate and its 8-methyl regioisomer; tert-butyl (2-benzylsulfanyl-5-nitro-benzoimidazol- 1 -yl)-acetate; tert-butyl [2-(3,3-diphenyl-propylsulfanyl)-5-nitro-benzoimidazol-l -yl]-acetate; tert-butyl {5-nitro-2-[2-(4-chlorophenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetate and its 6-nitro regioisomer; tert-butyl-[5-nitro-2-(2-phenoxy-ethylsulfanyl)-benzoimidazol-l-yl]-acetate; tert-butyl {2-[3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-propylsulfanyl]-5-nitro- benzoimidazol- 1 -yl} -acetate; tert-butyl [2-(4-ethyloxycarbonyl-butylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetate; tert-butyl [2-(3-methoxycarbonyl-benzylsulfanyl)-5-nitro-benzoimidazol- 1 -yl]-acetate; tert-butyl {2-[3-(butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-5-nitro- benzoimidazol- 1 -yl} -acetate; tert-butyl {2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-5-methyl-benzoimidazol-l-yl}- acetate and its 6-methyl regioisomer; tert-butyl [5-cyano-2-(2-phenoxy-ethylsulfanyl)-benzoimidazol-l-yl]-acetate and its 6- cyano regioisomer; tert-butyl [5-cyano-2-(4-ethyloxycarbonyl-butylsulfanyl)-benzoimidazol- 1 -yl]-acetate and its 6-cyano regioisomer; tert-butyl [5-cyano-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetate and its 6-cyano regioisomer; tert-butyl [2-(4-ethyloxycarbonyl-butylsulfanyl)-5-trifluorometb.yl-benzoimidazol- 1 - yl] -acetate and its 6-trifluoromethyl regioisomer; tert-butyl [2-(3-methoxycarbonyl-benzylsulfanyl)-5-trifluoromethyl-benzoimidazol-l- yl] -acetate and its 6-trifluoromethyl regioisomer; tert-butyl (2-benzylsulfanyl-6-nitro-benzoimidazol- 1 -yl)-acetate; tert-butyl [2-(3,3-diphenyl-propylsulfanyl)-6-nitro-benzoimidazol-l-yl]-acetate; tert-butyl [6-nitro-2-(2-phenoxy-ethylsulfanyl)-benzoimidazol-l-yl] -acetate and its 5- nitro regioisomer; tert-butyl [2-(4-ethyloxycarbonyl-butylsulfanyl)-6-nitro-benzoimidazol- 1 -yl] -acetate; tert-butyl {2-[3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-propylsulfanyl]-6-nitro- benzoimidazol- 1 -yl} -acetate; tert-butyl [5-fluoro-2-(2-phenoxy-ethylsulfanyl)-benzoimidazol-l-yl]-acetate and its 6- fluoro regioisomer; tert-butyl [2-(4-ethyloxycarbonyl-butylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetate and its 6-fluoro regioisomer; and tert-butyl [5-fluoro-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetate and its 6-fluoro regioisomer. The present invention also relates to novel intermediates of the general Formula
wherein R1 -R4 and R11 are as defined for Formula I and R represents an alkyl group.
Such novel intermdediates include: tert-butyl-(2-mercapto-benzoimidazol- 1 -yl)-acetate; tert-butyl-(2-mercapto-5 -nitro-benzoimidazol- 1 -yl)-acetate; tert-butyl-(2-mercapto-6-nitro-benzoimidazol- 1 -yl)-acetate; tert-butyl (5-formyl-2-mercapto-benzoimidazol- 1 -yl)-acetate; tert-butyl (5,6-difluoro-2-mercapto-benzoimidazol- 1 -yl)-acetate; tert-butyl (2-mercapto-5-methanesulfonyl-benzoimidazol-l-yl)-acetate; tert-butyl (5-acetyl-2-mercapto-benzoimidazol-l -yl)-acetate; tert-butyl (4-fuoro-2-mercapto-benzoimidazol-l-yl)-acetate; tert-butyl (2-mercapto-5-trifluoromethyl-benzoimidazol-l-yl)-acetate; tert-butyl (5 -fluoro-2-mercapto-benzoimidazol- 1 -yl)-acetate; methyl (6-fluoro-2-mercapto-benzoimidazol-l-yl)-acetate; and rac ethyl 2-(5-fluoro-2-mercapto-benzoimidazol-l -yl)-propionate.
Unless explicitly stated otherwise, the general terms and names used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings:
Any reference to a compound of Formula I is to be understood as referring also to optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates, meso forms, geometric isomers, and prodrugs of compounds in which a prodrug forming group is present, as well as salts (especially pharmaceutically acceptable salts) and solvates (including hydrates) of such compounds, and morphological forms, as appropriate and expedient.
The term "alkyl", as used herein, alone or in any combination, refers to a saturated aliphatic group including a straight or branched hydrocarbon chain containing 1-8, preferably 1-4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, zso-propyl, π-butyl, tert-butyl, iso-butyl (or 2- methylpropyl), cyclopropylmethyl, ra-pentyl, zso-pentyl, wo-amyl, π-amyl, n-hexyl, n- heptyl, π-octyl and the like. Less preferred, the alkyl group can be optionally substituted with one or more substituents, each independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylendioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminocarbonyl, aryl, arylalkenyl, arylalkoxy, aryloxy, aryloxycarbonyl, arylsulfmyl, arylsulfonyl, arylthio, carboxy, cyano, formyl, halogen, haloalkoxy, heterocyclyl, hydroxy, mercapto, nitro, and the like, appended to any carbon atom of the alkyl moiety. In the case R9 is arylalkylcarbonyl, the alkyl group of this radical can for example be substituted by cyclohexyl.
The term "lower alkyl", as used herein, alone or in any combination, refers to alkyl groups with 1-4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, ^-propyl, wo-propyl, n-butyl, isσ-butyl, tør/-butyl and the like.
The term "alkenyl", as used herein, alone or in any combination, refers to a straight or branched hydrocarbon chain containing 2-8, preferably 2-4 carbon atoms with at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl and the like.
The term "alkylenedioxy", as used herein, alone or in any combination, refers to a -O(CH2)nO- group, wherein n is preferably 1 or 2, and wherein the oxygen atoms are appended to two adjacent carbon atoms of the parent molecular moiety. Representative examples of alkylenedioxy include, but are not limited to, methylenedioxy, ethylenedioxy, and the like.
The term "alkynyl", as used herein, alone or in any combination, refers to a straight or branched hydrocarbon chain containing 2-8 carbon atoms with at least one-carbon- carbon triple bond. Representative examples of alkynyl include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl, 2-pentynyl, and the like.
The term "alkoxy", as used herein, alone or in any combination, refers to an alkyl group appended to the parent molecular moiety through an oxygen bridge. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2- propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
The term "alkoxy alkyl", as used herein, alone or in any combination, refers to an alkoxy group appended to the parent molecular moiety through an alkyl group. Representative examples of alkoxyalkyl include, but are not limited to, tert- butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.
The term "alkoxycarbonyl", as used herein, alone or in any combination, refers to an alkoxy group appended to the parent molecular moiety through a carbonyl group. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, fert-butoxycarbonyl, and the like.
The term "alkoxycarbonylalkyl", as used herein, alone or in any combination, refers to an alkoxycarbonyl group appended to the parent molecular moiety through an alkyl group. Representative examples of alkoxycarbonylalkyl include, but are not limited to, methoxycarbonylpropyl, ethoxycarbonylbutyl, 2-fert-butoxycarbonylethyl, and the like.
The term "alkylcarbonyl" or "acyl", as used herein, alone or in any combination, refers to an alkyl group appended to the parent molecular moiety through a carbonyl group. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1- oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oχobutyl, 1-oxopentyl, and the like.
The term "alkylcarbonylalkyl", as used herein, alone or in any combination, refers to an alkylcarbonyl group appended to the parent molecular moiety through an alkyl group. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2- oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, 3-oxopentyl and the like.
The term "alkylcarbonyloxy", as used herein, alone or in any combination, refers to an alkylcarbonyl group appended to the parent molecular moiety through an oxygen bridge. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy and the like.
The term "alkylsulfinyl", as used herein, alone or in any combination, refers to an alkyl group appended to the parent molecular moiety through a sulfinyl group.
Representative examples of alkylsulfinyl include, but are not limited to, methylsulfmyl, ethylsulfmyl and the like.
The term "alkylsulfinylalkyl", as used herein, alone or in any combination, refers to an alkylsulfinyl group appended to the parent molecular moiety through an alkyl group. Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfϊnylmethyl, ethylsulfmylmethyl and the like.
The term "alkylsulfonyl", as used herein, alone or in any combination, refers to an alkyl group appended to the parent molecular moiety through a sulfonyl group. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.
The term "alkylsulfonylalkyl", as used herein, alone or in any combination, refers to an alkylsulfonyl group appended to the parent molecular moiety through an alkyl group. Representative examples of alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl, ethylsulfonylmethyl and the like. The term "alkylthio" (synonym "alkylsulfanyl"), as used herein, alone or in any combination, refers to an alkyl group appended to the parent molecular moiety through an -S- bridge. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, fert-butylthio, hexylthio and the like.
The term "alkylthioalkyl" (synonym "alkylsulfanylalkyl"), as used herein, alone or in any combination, refers to an alkylthio group appended to the parent molecular moiety through an alkyl group. Representative examples of alkylthioalkyl include, but are not limited to, methylthiomethyl, 2-(ethylthio)ethyl, and the like.
The term "aminoalkyl", as used herein, alone or in any combination, refers to an amino group appended to the parent molecular moiety through an alkyl group. Representative examples of aminoalkyl include, but are not limited to, aminomethyl, 2-(amino)ethyl, and the like.
The term "aminocarbonyl" or "carbamoyl", as used herein, alone or in any combination, refers to an amino group appended to the parent molecular moiety through a carbonyl group.
The term "aminocarbonylalkyl", as used herein, alone or in any combination, refers to an aminocarbonyl group appended to the parent molecular moiety through an alkyl group.
The term "aryl", as used herein, alone or in any combination, refers to an carbocyclic group having at least one aromatic ring, e.g. phenyl or biphenyl, or multiple condensed ring systems, in which at least one ring is aromatic, e.g. 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, phenanthryl, fluorenyl, and the like. The term preferably relates to phenyl or naphthyl, especially to phenyl. The aryl group may be optionally substituted with one or more functional groups individually and independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, cycloalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfinyl, alkylsulfmylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfmyl, arylsulfmylalkyl, arylsulfonyl, arylsulfonylalkyl, arylthio, arylthioalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, heterocyclyl (preferably piperidinyl), hydroxy, hydroxyalkyl, mercapto, nitro, and the like.
The term "arylalkenyl", as used herein, alone or in any combination, refers to an aryl group appended to the parent molecular moiety through an alkenyl group. The aryl group may be unsubstituted or substituted. Representative examples of arylalkenyl include, but are not limited to, 2-phenylethenyl, 3-phenylpropen-2-yl, 2-naphth-2- ylethenyl, and the like.
The term "arylalkoxy", as used herein, alone or in any combination, refers to an aryl group appended to the parent molecular moiety through an alkoxy group. The aryl group may be unsubstituted or substituted. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 5-phenylpentyloxy, 3-naphth-2- ylpropoxy, and the like.
The term "arylalkyl", as used herein, alone or in any combination, refers to an aryl group appended to the parent molecular moiety through an alkyl group. The aryl group may be unsubstituted or substituted. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
The term "aryloxy", as used herein, alone or in any combination, refers to an aryl group appended to the parent molecular moiety through an oxygen bridge. The aryl group can be unsubstituted or substituted. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, A- methylphenoxy, 3,4-dimethoχyphenoxy, and the like. The term "carbonyl", as used herein, alone or in any combination, refers to a -C(O)- group.
The term "carboxy", as used herein, alone or in any combination, refers to a -CO2H group.
The term "carboxyalkyl", as used herein, alone or in any combination, refers to a carboxy group appended to the parent molecular moiety through an alkyl group. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like.
The term "cyano", as used herein, alone or in any combination, refers to a -C≡N group.
The term "cyanoalkyl", as used herein, alone or in any combination, refers to a cyano group appended to the parent molecular moiety through an alkyl group. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, 3- cyanopropyl, and the like.
The term "cycloalkyl", as used herein, alone or in any combination, refers to a saturated cyclic hydrocarbon moiety containing 3-15, preferably 3-6, carbon atoms, optionally (less preferred) substituted with one or more groups, each individually and independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfmyl, alkylsulfmylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfmyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, arylthio, arylthioalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, mercapto, nitro, and the like. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. In polycyclic cycloalkyl groups one of the distal rings may be aromatic, e.g., 1-indanyl, 2-indanyl, tetrahydronaphthyl, bicyclo[4.2.0]octa-l,3,5-trien-7-yl, and the like.
The term "formyl", as used herein, alone or in any combination, refers to a -C(O)H group.
The term "formylalkyl", as used herein, alone or in any combination, refers to a formyl group, appended to the parent molecular moiety through an alkyl group. Representative examples of formylalkyl include, but are not limited to, formylmethyl, 2-formylethyl, and the like.
The term "halo" or "halogen", as used herein, alone or in any combination, refers to fluorine, bromine, chlorine, and iodine.
The term "haloalkyl", as used herein, alone or in any combination, refers to an alkyl group having at least one hydrogen atom replaced with a halogen atom. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
The term "haloalkoxy", as used herein, alone or in any combination, refers to an alkoxy group having at least one hydrogen atom replaced with a halogen atom. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and the like.
The term "heterocyclyl", as used herein, alone or in any combination, refers to a monocyclic, bicyclic or polycyclic ring system containing up to 15 ring atoms, at least one of these, preferably 1 or 2, being a hetero atom independently selected from nitrogen, oxygen or sulfur. The ring system may be saturated, partially unsaturated, unsaturated or aromatic, mono- or bicyclic. Representative examples of heterocyclyl include, but are not limited to, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, benzimidazolyl, phthalazinyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, indolyl, indolinyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, quinolinyl, quinazolinyl and the like. Defined heterocyclyl moieties may be optionally substituted with one or more groups, each individually and independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfmyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, arylcarbonyl, arylalkylcarbonyl, (diaryl)alkylcarbonyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfinyl, arylsulfϊnylalkyl, arylsulfonyl, arylsulfonylalkyl, arylthio, arylthioalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl., formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, and the like. Preferably the substituents are selected from oxo, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylalkylcarbonyl, arylalkoxycarbonyl, arylalkylsulfonyl, arylcarbonyl, (diaryl)-alkylcarbonyl, arylsulfonyl, arylalkenylsulfonyl, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, and heterocyclylsulfonyl.
The term "saturated heterocyclyl" is another special case of "heterocyclyl" and refers to saturated rings as defined above for "heterocyclyl", especially to piperidinyl and pyrrolidinyl.
The term "heterocyclylalkenyl", as used herein, alone or in any combination, refers to a heterocyclyl group appended to the parent molecular moiety through an alkenyl group. Representative examples of heterocyclylalkenyl include, but are not limited to, 2-pyrid- 3-ylethenyl, 3-quinolin-3-ylpropen-2-yl, 5-pyrid-4-ylpenten-4-yl, and the like. The term "heterocyclylalkoxy", as used herein, alone or in any combination, refers to a heterocyclyl group appended to the parent molecular moiety through an alkoxy group. Representative examples of heterocyclylalkoxy include, but are not limited to, 2-pyrid- 3-ylethoxy, 3-quinolin-3-ylpropoxy, 5-pyrid-4-ylpentyloxy, and the like.
The term "heterocyclylalkyl", as used herein, alone or in any combination, refers to a heterocyclyl group appended to the parent molecular moiety through an alkyl group. Representative examples of heterocyclylalkyl include, but are not limited to, 2-pyrid-3- ylmethyl, 2-pyrimidin-2-ylpropyl, and the like.
The term "heterocyclyloxy", as used herein, alone or in any combination, refers to a heterocyclyl group appended to the parent molecular moiety through an oxy group. Representative examples of heterocyclyloxy include, but are not limited to, pyrid-3- yloxy, quinolin-3-yloxy, and the like, especially (l-ethyloxycarbonyl-indazol-3-yl)- oxy.
The term "hydroxy" or "hydroxyl" as used herein, alone or in any combination, refers to an -OH group
The term "hydroxyalkyl", as used herein, alone or in any combination, refers to an alkyl group having at least one hydrogen atom replaced with a hydroxy group. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, and the like.
The term "nitro", as used herein, alone or in any combination, refers to a -NO2 group.
The term "oxo", as used herein, alone or in any combination, refers to an =0 group.
The term "oxy", as used herein, alone or in any combination, refers to an -O- group. The terms "mercapto" and "thiol", as used herein, alone or in any combination, refer to a -SH group.
The terms "thio" (synonym "sulfanyl"), "sulfmyl" and "sulfonyl", as used herein, alone or in any combination, refer to a -S(O)n group with n= 0, 1 and 2, respectively.
Within the scope of the present invention, unless indicated otherwise, compounds of Formula I or pharmaceutically acceptable salts thereof are included that may exist in, and be isolated in, isomeric forms, including cis- or trans isomers or mixtures thereof, and tautomers. Other compounds of this invention may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, and thus may give rise to optically pure enantiomers, mixtures of enantiomers, racemates, enantiomer-pure diastereomers, mixtures of diastereomers, epimers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-, (S)- or (i?,5)-configured, preferably in the (R)- or (^-configuration. Such isomers can be obtained by methods within the knowledge of one skilled in the art, e.g. by stereochemical^ controlled synthesis using chiral synthons or chiral reagents, or by means of classical separation techniques, such as chromatographic or crystallization methods, or by other methods known in the art, such as through formation of diastereomeric salts, for example by salt formation with an enantiomerically pure chiral acid, or by means of chromatography, for example by using chromatographic materials modified with chiral ligands. Furthermore, the present invention refers to compounds containing centers of any geometric asymmetry, like, for example, unsymmetrically substituted olefinic double bond, including E or Z geometric isomers and mixtures thereof. Generally, pure isomers of compounds of Formula I are preferred over isomeric mixtures.
In the present invention, the compounds of Formula I may be used in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to relatively nontoxic, inorganic or organic acid and base addition salts, which retain the biological effectiveness and properties of the parent compound, and which are not biologically or otherwise undesirable (see, e.g., Berge et al., J. Pharm. Sci. 1977, 66, 1- 19).
Certain compounds of the present invention can contain one or more basic functional groups, such as amino, alkylamino, or arylamino, and, thus, be capable of forming pharmaceutically acceptable acid addition salts. These acid addition salts may be prepared by standard procedures in a suitable solvent from the parent compound of Formula I, with an appropriate amount of an inorganic acid, including, but not limited to, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; or of an organic acid, including, but not limited to, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, amino acids, such as glutamic acid or aspartic acid, benzoic acid, cinnamic acid, salicylic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,/>-toluenesulfonic acid, or other acidic organic compounds.
Certain compounds of the present invention may, on the other hand, contain one or more acidic functional groups and, thus, be capable of forming pharmaceutically acceptable base addition salts. These salts can be prepared by addition of an appropriate amount, usually in stoichiometric ratio, of an alkaline reagent, such as hydroxide, carbonate or alkoxide, containing the appropriate cation, to the free acid in a suitable solvent. Preferred inorganic salts include, but are not limited to, ammonium, sodium, potassium, calcium or magnesium, also zinc salts and the like. Preferred salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, iV-ethylpiperidine, piperidine, polyamine resins, and the like.
Compounds of the present invention containing both acidic and basic groups can also form internal salts (zwitter ions). For isolation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, for example perchlorates, picolinates, picrates, or the like. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed, where applicable in the form of pharmaceutical preparations, and these are therefore preferred.
Certain compounds of Formula I, including their salts, may exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present. The present invention encompasses all such solvated and unsolvated forms.
The present invention also relates to prodrug derivatives of the parent compounds of Formula I. The term "prodrug" refers to pharmacologically inactive precursors of a drug that may be converted into its therapeutically active form under physiological conditions in vivo, for example, when they undergo solvolysis, or enzymatic degradation in blood, or in cells (Bundgard H., "Design of Prodrugs", pp. 7-9, 21-24, Elsevier, Amsterdam (1985); Silverman R. B., "The Organic Chemistry of Drug Design and Drug Action", pp. 352-401, Academic Press, San Diego, CA (1992); Higuchi T. et al., "Pro-drug as Novel Delivery Systems", A.C.S. Symposium Series, Vol. 14). The term "prodrug" also includes any covalently bonded carriers, which release the active parent compound in vivo when administered to a mammal. Prodrug modifications of a compound often offer advantages of solubility, bioavailability, absorption, tissue compatibility, tissue distribution, or delayed release in the mammalian organism. Prodrugs are variations or derivatives of the compounds of Formula I, which have groups cleavable under metabolic conditions, for example, pharmaceutically acceptable esters, or amides. Such groups can be cleaved enzymatically or non-enzymatically, or hydrolytically to the free hydroxy, carboxy, or amino group of the active parent compound. In another embodiment, the prodrug is a reduced form, which is oxidized in vivo to the therapeutic compound, for example, a thiol, which is oxidized to a sulfonate or sulfate, or an alcohol, which is oxidized to a carboxylic acid. Further included within the scope of the present invention are pharmaceutically acceptable esters of the compounds of Formula I. The term "pharmaceutically acceptable esters" refers to relatively non-toxic, esterified products of the parent compound. These esters can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compounds in its free acid or hydroxyl form with a suitable esterifying agent. Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst. Hydroxyl containing derivatives can be converted into esters via treatment with an esterifying agent such as alkanoyl halides. The term further includes lower hydrocarbon groups capable of being solvated under physiological conditions, for example, alkyl esters, preferred methyl, ethyl, and propyl esters, methoxymethyl esters, methylthiomethyl esters, pivaloyloxymethyl esters and the like (see, e.g., Berge et al., J. Pharm. Sci. 1977, 66, 1-19).
The compounds of the present invention have useful, in particular pharmacologically useful, properties. They are able to specifically antagonize the effect of endogenous PGD2 on the CRTH2 receptor, and may be used for the prevention and/or treatment of chronic and acute allergic immune disorders comprising allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases comprising Churg- Strauss syndrome and sinusitis, basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis in humans and other mammals.
A compound or a pharmaceutical composition of the invention may thus be used as a drug (medicine) or therapeutic agent for prevention and/or treatment of both chronic and acute allergic/immune disorders such as those mentioned above, especially allergic asthma, rhinitis, COPD, dermatitis, inflammatory bowel disease, and rheumatoid arthritis. In another aspect, the compounds of Formula I may be used as standard or reference compounds in tests or assays involving the inhibition of the CRTH2 receptor. Such compounds could be made commercially available for use as a reference, quality standard or control, for example in pharmaceutical research when developing new assays or protocols related to CRTH2 activity.
As mentioned earlier, compounds of Formula I, or salts, or prodrugs thereof, antagonize the PGD2 activation of the CRTH2 receptor. The biological effect of such compounds may be tested in a variety of in vitro, ex vivo and in vivo assays.
The ability of the compounds of Formula I to bind to the CRTH2 receptor may be measured by methods similar to those described in Sawyer N. et al, Br. J. Pharmacol., 2002, 137, 1163-1172 and by the method described below in the experimental part.
With this type of assay, IC50 values (i. e. the concentrations where half-maximal inhibition of the interaction is found) in the range of 0.001 to 10 μM, preferably values below 1 μM, in particular values below 0.05 μM, are found with test compounds of Formula I. Exemplary IC50 values determined in this test are given below in Table 68.
A functional assay with cells expressing the human CRTH2 receptor may be used to detect changes in the levels of intracellular calcium concentration following compound treatment. After addition of the compound the cells are challenged with PGD2. In a Fluorescent Imaging Plate Reader (FLIPR , Molecular Devices, Sunnyvale, California) fluorescence emission is recorded during both additions, emission peak values above base level after PGD2 addition were exported, normalized to low controls (no PGD2) and high controls (no active compound). The relative values of the remaining activity were used to determine IC50 values by curve fitting the data to a single site to a four-parameter logistic sigmoid dose response curve of the equation (A+((B-A)/(l+((C/x)ΛD)))). The ability of the compounds to inhibit PGD2 induced change of intracellular calcium levels via CRTH2 activation may be measured by methods known of one skilled in the art or by the method described below in the experimental part. With this assay, IC50 values (i.e. the concentration of a compound at which the remaining activity is 50%) in the range of 0.001 and 10 μM, preferably below 0.5 μM, are obtained with test compounds of Formula I. Exemplary IC5O values determined in this test are given below in Table 69.
The results of these assays clearly demonstrate, that the present invention provides functional antagonists of the PGD2 receptor.
On the basis of |the biological studies discussed hereinabove, a compound of Formula I according to the invention may show therapeutic efficacy against chronic and acute allergic/immune disorders such as allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
A compound of Formula I, a pharmaceutically acceptable salt or a prodrug thereof, can be administered alone in pure form or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents. A compound of Formula I can besides or in addition be administered especially for prevention and/or treatment of both chronic and acute allergic or immune disorders in combination with other inflammatory diseases. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are preventive therapies, for example in patients at risk.
The invention relates also to pharmaceutical compositions comprising compounds of Formula I, to their use in therapeutic, in a broader aspect of the invention also prophylactic treatment or a method of treatment of the diseases mentioned above, to the compounds for said use and to the preparation of pharmaceutical formulations (medicines). The pharmaceutically acceptable compounds of the present invention may be used, for example, for the preparation of pharmaceutical compositions that comprise an effective amount of the active ingredient together or in admixture with a significant amount of one or more inorganic, organic, solid or liquid, pharmaceutically acceptable carriers.
The invention relates also to a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human (or to cells or cell lines derived from a warm-blooded animal, especially a human, for the treatment or, in a broader aspect of the invention, prevention of (i.e. prophylaxis against) a disease that responds to blockade of the interaction of the CRTH2 receptor with PGD2, comprising an amount of a compound of Formula I or a pharmaceutically acceptable salt or a prodrug thereof, which is effective for said inhibition, together with at least one pharmaceutically acceptable carrier.
The pharmaceutical compositions according to the invention are those for enteral administration, such as nasal, buccal, rectal, dermal or, especially oral administration, and for parenteral administration, such as intramuscular, intravenous or subcutaneous, intrastemal, intravitreal, injection or infusion, to warm-blooded animals, especially humans. Such compositions comprise an effective dose of the pharmaceutically active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual conditions, individual pharmacokinetic data, the disease to be treated and the mode of administration.
The invention relates also to a process or a method for the treatment of a pathological condition mentioned hereinabove, especially a disease, which responds to blockade of the interaction of the CRTH2 receptor with PGD2, especially allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, and rheumatoid arthritis. The compounds of Formula I or salts or prodrugs thereof can be administered as such or especially in the form of pharmaceutical compositions. The dose to be administered to warm-blooded animals, for example humans of approximatively 70 kg body weight, is preferably from approximatively 3 mg to approximatively 3O g, more preferably from approximatively 10 mg to approximatively 1000 mg per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, the weight, and response of the individual patient, the severity of the patient's symptoms, and the like, for example, children usually receive half of the adults dose.
The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dosage forms such as coated and uncoated tablets, pills, ampoules, vials, suppositories, dragees, or capsules. Further dosage forms are, for example, ointments, creams, pastes, emulsions, foams, chewable gums, tinctures, lip-sticks, drops, sprays or aerosols, syrups or elixirs, dispersions, transdermal patches or pads, or via an intravitreal device that releases the compound in a sustained capacity, and the like. Examples are capsules containing from about 0.05 g to about 1.0 g active ingredient.
The pharmaceutical compositions of the present invention are prepared in a manner known, per se, for example by means of conventional mixing, granulating, coating, dissolving, lyophilizing or confectioning processes.
Solutions of the active ingredient, and also suspensions, and especially isotonic aqueous solutions or suspensions, are preferably used, it being possible, for example in the case of lyophilized compositions, that comprise the active ingredient alone or together with a carrier, for example mannitol, for such solutions or suspensions to be produced prior to use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilizing processes. The said solutions or suspensions may comprise viscosity- increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
Suspensions in oil comprise as the oil component the vegetable, synthetic or semi¬ synthetic oils customary for injection purposes. There may be mentioned as such especially liquid fatty acid esters that contain as the acid component a long-chain fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, β-carotene or 3,5-άi-tert- butyl-4-hydroxytoluene. The alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is mono- or poly-hydroxy, for example a mono-, di- or trihydroxy, alcohol, for example methanol, ethanol, propanol, butanol, or pentanol or the isomers thereof, but especially glycol and glycerol. The following examples of fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M2375" (polyoxyethylene glycerol trioleate, Gattefosse, Paris), "Miglyol 812" (triglyceride of saturated fatty acids with chain length of C8 to C 12, HuIs AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
The injection or infusion compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules or vials and sealing the containers.
Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts.
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using for example corn, wheat, rice, or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, and/or carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and/or titanium dioxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Capsules are dry-filled capsules made of gelatin and of soft sealed capsules made of gelatine and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with stabilizers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable oil excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers and/or antibacterial agents to be added. Dyes or pigments may be added to the tablets or dragee coatings or the capsule casings, for example for identification purposes or to indicate different doses of active ingredient.
For parenteral administration, aqueous solutions of an active ingredient in water- soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances and stabilizers, are especially suitable. The active ingredient, optionally together with excipients, can also be in the form of a lyophilizate and be made into a solution before parenteral administration by the addition of solvents.
The novel compounds of Formula I can be manufactured in accordance with the invention by a) hydrolyzing a precursor of the general Formula II
wherein R1 -R7 and n are as in Formula I and R represents an alkyl group, preferably ethyl or fert-butyl, with the exception of:
methyl [2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-benzoimidazol-l-yl]-acetate; methyl [2-(4-chloro-benzylsulfanyl)-benzoimidazol-l -yl]-acetate; methyl (2-benzylsulfanyl-benzoimidazol- 1 -yl)-acetate; methyl [2-(5-nitro-pyridin-2-ylsulfanyl)-benzoimidazol-l-yl]-acetate; methyl (2-methylsulfanyl-benzoimidazol-l -yl)-acetate; ethyl (2-methylsulfanyl-benzoimidazol- 1 -yl)-acetate; methyl (2-ethylsulfanyl-benzoimidazol-l-yl)-acetate; ethyl [2-(l,3,7-trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-ylsulfanyl)- benzoimidazol- 1 -yl]-acetate; ethyl {2-[3-methyl-4-(2-moipholin-4-yl-ethylsulfanyl)-pyridin-2- ylmethylsulfanyl]-benzoimidazol-l-yl}-acetate; and methyl {2- [3 -methyl-4-(2-morpholin-4-yl-ethylsulfanyl)-pyridin-2- ylmethylsulfanyl]-benzoimidazol- 1 -yl} -acetate; or b) alkylating a benzoimidazole derivative of the general Formula
wherein R .1 - rR>7 and n are as in Formula I,
with a compound of the general Formula
iλCKfeCOOH
wherein L1 is a leaving group, or c) S-alkylating a mercapto derivative of the general Formula
wherein R .1 - τR>4 are as in Formula I,
with an alkylating agent of the general Formula
wherein R > 5 -R and n are as in Formula I and L is a leaving group, and, if desired, converting a compound of Formula I into a pharmaceutically acceptable salt.
Compounds of the invention may be manufactured by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by Larock R. C. in "Comprehensive organic transformations: a guide to functional group preparations", VCH publishers, 1999.
In the reactions described hereinafter, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for example see Greene T. W. and Wuts P. G. M. in "Protective groups in organic synthesis" Wiley-Interscience, 1999.
Generally, a synthesis of 2-sulfanyl-benzoimidazol-l-yl-acetic acid of Formula I starts by alkylating a 2-chlorobenzoimidazole of Formula 1 with a compound of Formula L1- CH2CO2R, wherein R represents an alkyl group, preferably ethyl or fert-butyl, and L1 is a leaving group, in a suitable polar solvent such as JV, N-dimethylformamide, acetone, acetonitrile or the like, in the presence of a base, such as potassium carbonate, cesium carbonate, sodium hydride or the like, to yield an alkyl (2-chloro-benzoimidazol-l-yl)- acetate of Formula 2, as outlined in Scheme 1.
Scheme 1
The dotted lines in Formula 2 indicate that the double bond is in either of the two possible positions; the -CH2COOR residue is connected to either of the two nitrogen atoms; this is of significance for producing regioisomers, i.e. when R1 and R4, or R2 and R3, are substituents different from each other (cf. below Formulas 2a and 2b).
Suitable is a leaving group L1 such as halo, in particular bromo or chloro. Preferably, a compound of Formula 1^-CH2CO2R is tert-butyl or ethyl bromoacetate.
Under preferred conditions a solution of a chlorobenzoimidazole of Formula 1 in acetone is stirred with e.g. tert-bvdyl bromoacetate in presence of potassium carbonate at reflux, or in DMF at room temperature.
It is noteworthy, that under such alkylating conditions an unsymmetrically substituted 2-chlorobenzoimidazole of Formula 1, wherein R1 and R4, or R2 and R3 are different from each other, delivers a mixture of the respective C(4) and C(7), or C(5) and C(6) substituted alkyl (2-chloro-benzoimidazol-l-yl)-acetate regioisomers of Formula 2a and 2b.
Applying a procedure described by Migawa, M. T. et al., J. Med. Chem. 1998, 41, 1242- 1251 , an alkyl (2-chloro-benzoimidazol- 1 -yl)-acetate of Formula 2 is treated with thiourea in a solvent such as methanol or ethanol at reflux, to give an Intermediate of Formula 3.
A novel method to regioselectively produce an intermediate of Formula 3a has been developed:
Substituted l-fluoro-2-nitro-benzene of Formula 12 is converted to a compound of Formula 13.1 by reacting with an amino acid ester in a suitable solvent such as DMSO, EtOH or the like at elevated temperature from 50°C to 100°C (McFarlane et al, J. Chem. Soc. Perkin Trans. 1 1988, 691-696). Subsequent hydrogenolysis with hydrogen in the presence of a catalyst such as palladium on charcoal in a solvent like tetrahydrofuran leads to a substituted aniline derivative of Formula 13.2, which then is reacted with thiocarbonyle diimidazole to yield Intermediate 3a (Wright, J. L. et al, J. Med. Chem., 2000, 43, 3408-3419; Breslin, H. J. et al, J. Med. Chem. 1995, 38, 771- 793).
Generally, when a reaction or synthesis involves an Intermediate of Formula 3 and when obtaining the product as only one single regioisomer is wished, then an Intemediate of Formula 3 a can be used in place of an Intermediate of Formula 3.
Subsequent S-alkylation of an Intermediate of Formula 3 occurs with a suitable alkylating agent of Formula L2-(CH2)n-C-R5R6R7; wherein R5, R6, and R7 and n are defined as hereinabove, and L2 is a leaving group such as halo, in particular chloro, bromo, or iodo; alkylsulfonate, or arylsulfonate, such as methylsulfonate, or p-toluenesulfonate; in a solvent such as ΛζN-dimethylformamide, acetone, acetonitrile or the like, in the presence of a base such as triethylamine, ΛζJV-diisopropylethylamine, sodium hydroxide, potassium carbonate; affording a Precursor of Formula 4.
Typically, a reagent of Formula L2-(CH2)n-C-R5R6R7 is an optionally substituted alkyl halide, particularly an alkyl chloride, or an alkyl bromide, such as commercially available 2-(2-bromo-ethyl)-isoindole-l,3-dione; (2-bromo-ethyl)-carbamic acid tert- butyl ester; (3-bromo-propyl)-carbamic acid tert-butyl ester; (2-bromo-ethyl)- cyclohexane; 1-bromo-hexane; 1-bromo-pentane; 4-bromo-but-l-ene; 1-bromo-butane; bromo-cyclopentane; (l-bromo-ethyl)-benzene; bromo-phenyl-acetic acid methyl ester; 7-bromo-bicyclo[4.2.0]octa-l(6),2,4-triene; 2-bromo-l-phenyl-propan-l-one; 6-bromo- hexanoic acid ethyl ester; 4-bromo-butyric acid ethyl ester; 5-bromo-pentanoic acid ethyl ester; bromomethyl-benzene; l-chloromethyl-2-methoxy-benzene; (2-bromo- ethyl)-benzene; (3-bromo-propyl)-benzene; 3,3-diphenyl-propyl bromide; l-(2-bromo- ethoxy)-4-chloro-benzene; (2-bromo-ethoxy)-benzene; (4-bromo-butoxy)-benzene; (5- bromo-pentyloxy)-benzene; 2-(3 -bromo-propyl)-isoindole- 1 ,3 -dione; 3 -bromomethyl- benzoic acid methyl ester; 5-chloromethyl-furan-2-carboxylic acid ethyl ester; l-(3- chloromethyl-4-ethoxy-phenyl)-ethanone; or 1 -(3-cmoromethyl-4-methoxy-phenyl)~ ethanone.
More preferred is a reagent of Formula L2-(CH2)n-C-R5R6R7, such as benzyl-(3-chloro- propyl)-carbamic acid ester; 5-bromo-pentanoic acid butyl-phenyl-amide; 5- bromo- 1 -(3 ,4-dihydro-2H-quinolin- 1 -yl)-pentan- 1 -one; 5 -bromo-pentanoic acid methyl-phenyl-amide; 1 -(2-bromo-ethoxy)-naphthalene; 2-(2-bromo-ethoxy)- naphthalene; 2-(3-chloro-propyl)-2,3 -dihydro-isoindol- 1 -one; 1 -(3 -chloro-propyl)- 1,3- dihydro-benzoimidazol-2-one; 3-(3-chloro-propyl)-lH-quinazoline-254-dione; 2-(3- chloro-propyl)- 1 , 1 -dioxo- 1 ,2-diliydro- 1 λ6-benzo [d]isothiazol-3 -one; 2-bromo-5- bromomethyl-benzoic acid methyl ester; 4-bromo-3-bromomethyl-benzoic acid methyl ester; 3-bromomethyl-4-methoxy-benzoic acid methyl ester; l-(3-chloromethyl~4- propoxy-phenyl)-ethanone; 1 -(3-chloromethyl-4-butoxy-phenyl)-ethanone; (3- chloromethyl-4-methoxy-phenyl)-phenyl-methanone; 2-chloromethyl-oxazole-4- carboxylic acid methyl ester; or l-(3-bromomethyl-phenyl)-ethanone.
Particularly preferred is a novel alkyl halide of Formula 1/-(CHa)n-C-R5R6R7, such as (3-chloro-propyl)-phenethyl-carbamic acid fert-butyl ester; (3-chloro-propyl)-(4- piperidin-l-yl-phenyl)-carbamic acid tert-butyl ester; 4-[tert-butoxycarbonyl-(3-chloro- propyl)-amino] -benzoic acid ethyl ester; (3-chloro-propyl)-cyclopropyl-carbamic acid tert-butyl ester; (3-chloro-propyl)-phenyl-carbamic acid tert-butyl ester; (3-chloro- propyl)-(2,2-diphenyl-ethyl)-carbamic acid tert-butyl ester; (3-chloro-propyl)- phenethyl-carbamic acid butyl ester; benzyl-(3-chloro-propyl)-carbamic acid butyl ester; (3-chloro-propyl)-cyclohexyl-carbamic acid butyl ester; (3-chloro-propyl)- cyclohexylmethyl-carbamic acid butyl ester; 4-[(3-chloro-propyl)-(2-cyclohexyl-2- phenyl-acetyl)-amino] -benzoic acid ethyl ester; pentanoic acid (3-chloro-propyl)- phenethyl-amide; 4-[butoxycarbonyl-(3-chloro-propyl)-amino]-benzoic acid ethyl ester; 5-bromo-pentanoic acid benzyl-phenyl-amide; 5-bromo-pentanoic acid benzyl- methyl-amide; 3-(3-chloro-propoxy)-indazole-l-carboxylic acid ethyl ester; 2-(3- chloro-propyl)-3-oxo-2,3-dihydro-indazole-l-carboxylic acid ethyl ester; 2-(3-chloro- propyl)-2H-phthalazin-l-one; 5-bromomethyl-nicotinic acid methyl ester; 2- bromomethyl-6-chloro-isonicotinic acid methyl ester; 2-bromo-3 -bromomethyl-benzoic acid methyl ester; 3-bromo-5-bromomethyl-benzoic acid methyl ester; 3-methoxy-5~ chloromethyl -benzoic acid isopropyl ester; l-[3-chloromethyl-4-(3-hydroxy-propoxy)- phenylj-ethanone; 7-chloromethyl-6-methoxy-3,4-dihydro-2H-naphthalen-l-one; and 1 -(3 -chloromethyl -piperi din- 1 -yl)-butan- 1 -one. Preferred alkyl halides of Formula L2-(CH2)n-C-R5R6R7 are depicted in Formula 5.1 and 5.2. Such compounds can either be prepared and isolated as such, or generated in situ, from a dihaloalkane of Formula Ha^-(CH2VHaI2, wherein Hal1 and Hal2 represent halo, independently selected from chloro, bromo, or iodo; such as l-chloro-2- iodo-ethane, 1,2-dibromo-ethane, or 1,2-dichloro-ethane; l-chloro-3-iodo-propane, 1,3- dibromo-propane, or 1,3-dichloropropane; l-chloro-4-iodo-butane, 1,4-dibromo- butane, or 1,4-dichloro-butane; with a substituted amine of hereinabove defined Formula HNR8R9, whereby R8 and R9 both are not hydrogen, such as alkylcarbonyl- aryl-amine, alkoxycarbonyl-arylalkyl-amine, alkoxycarbonyl-arylamine, alkoxycarbonyl-cyclylalkyl-amine, alkoxycarbonyl-cycloalkyl-amine, arylalkylcarbonyl-aryl-amine, alkylsulfonyl-alkylamine, arylalkylsulfonyl-alkylamine, arylsulfonyl-alkylamine, alkylsulfonyl-cycloalkylamine, arylalkylsulfonyl- cycloalkylamine, arylsulfonyl-cycloalkylamine, alkylsulfonyl-arylalkylamine, arylalkylsulfonyl-arylalkylamine, arylsulfonyl-arylalkylamine, alkylsulfonyl- arylamine, arylalkylsulfonyl-arylamine, arylsulfonyl-arylamine, 1,3-dihydro- benzoimidazol-2-one, 2,3 -dihydro-isoindol- 1 -one, 1 , 1 -dioxo- 1 ,2-dihydro- 1 λ6- benzo [d]isothiazol-3 -one, isoindole- 1 ,3-dione, 3 -oxo-2,3 -dihydro-indazole- 1 - carboxylic acid ethyl ester, l//-quinazoline-2,4-dione, 2/f-phthalazin-l-one; or with a hydroxy-arene of Formula HOR7 , wherein R7 represents a substituted phenyl, naphthyl or heterocyclyl such as indazol-3-yl-l -carboxylic acid ethyl ester; in a polar solvent such as iV,N-dimethylformamide, tetrahydrofuran or acetonitrile; in the presence of a base such as sodium hydride, potassium ter/-butylate.
A 2-aryloxyethylbromide is obtained by reacting a hydroxyarene with dibromoethane in aqueous sodium hydroxide (Slyn'ko, N. M.; Tormyshev, V. M. Russ. Journal. Org. Chem. 2000, 36(2), 254-257).
5.1 5.2 5.3 Alternatively, a primary amine of Formula H2NR , wherein R represents alkyl, cycloalkyl, cyclylalkyl, or arylalkyl, reacts with hereinabove defined dihaloalkane of Formula Hal1-(CH2)n-Hal2 forming a secondary amine of Formula 5.3, which then is transformed to its respective amide, sulfonamide, carbamate, urethane of Formula 5.1, wherein R9 represents alkenylcarbonyl, alkoxycarbonyl, alkylcarbamoyl, alkylcarbonyl, alkylsulfonyl, arylalkenylcarbonyl, arylalkylcarbonyl, arylcarbamoyl, arylcarbonyl, arylalkylsulfonyl, arylsulfonyl, cycloalkylcarbonyl, or cyclylalkylcarbonyl (Briner, K. et. al.. Bioorg. Med. Chem. 2002, 10, 3649-3661).
Furthermore, an alkylating reagent of Formula L2-(CH2)n-C-R5R6R7 can be obtained through transformation of its respective hydroxy analog of Formula R5R6R7C-(CH2V OH, by means of known methods.
Especially preferred alkylating reagents, as depicted in Formula 5.4, 5.5, 5.4bis, are obtained by:
a) halogenation of the methyl group of the benzene and pyridinyl derivatives 6 and 7, respectively, with known methods, e.g. preferably by means of N-X succinimide, whereby X represents halogen, such as chloro or bromo, iodo, in a suitable solvent such as tetrachloromethane, chloroform or the like (de Meijere, A. et al., Chem. Ber. 1993, 126, 1635-1641).
5.4
L2: Hal (Cl, Br, I) X: Cl, Br, alkoxy
X: Cl, Br, alkoxy, hydroxyalkoxy R': alkyl, alkoxy
R': alkyl, alkoxy
L2: Hal (Cl, Br, I) X: Cl, Br
X: Cl, Br R': alkyl, alkoxy
R': alkyl, alkoxy
b) direct chloromethylation of the benzene derivatives 7 bis or of the bicyclic aromatic compounds lter with known methods, e.g. preferably by means of methoxyacetyl chloride and aluminium trichloride or a suitable Lewis acid in an polar solvent such as nitromethane, carbon disulfide or the like (McKillop, A.; Madjdabadi, F., A.; Long. D. A. Tetrahedron Lett., 1983, 24, 1933-1936).
X: alkoxy, hydroxyalkyloxy R': alkyl, aryl, alkoxy
5Λbis lter
X: alkoxy, hydroxyalkyloxy X: alkoxy, hydroxyalkyloxy n = 0, 1 n = 0, 1
In a preferred embodiment, hydroxyalkoxyacetophenone and alkoxyacetophenone Ibis are obtained by alkylation of hydroxyacetophenone with the corresponding hydroxyalkyl or alkyl halide (Mandoli, A. et al Tetrahedron Asymmetry 2003, 14, 3647-3650).
Another preferred alkyl halide of Formula L2-(CH2)n-C-R5R6R7 also comprises a structure of Formula 5.6, wherein R7 represents alkoxy, alkyl-arylamino, arylalkyl- arylamino, or 3,4-dihydro-2i7-quinoline. Such compounds are obtained by applying methods known to a skilled person.
5.6
Under preferred reaction conditions, a solution of an Intermediate of Formula 3 in acetone is heated at reflux with an alkylating agent of Formula L2-(CH2)n-C-R5R6R7 in the presence of a base such as potassium carbonate. In case of L2 representing chloro, or bromo, addition of a catalytic amount of potassium iodide might be beneficial.
Other preferred reaction conditions are those described in:
- Yeh, C-M. and Sun, C-M. Tetrahedron Lett. 1999, 40, 7247-7250, using alkylbromide in dichloromethane with triethylamine;
- Kϋhler, T. C. et al., J. Med. Chem. 2002, 45, 4282-4299, using benzylchloride in aqueous sodium hydroxide;
- Matthews, C. et al., J. Chem. Soc, Dalton Trans., 1996, 1531-1538, using alkylhalides in tetrahydrofuran with ΛζiV-diisopropyl-ethylamine;
- Terashima, K. et al., Chem. Pharm. Bull 1995, 43, 1985-1991, using alkylbromides with potassium carbonate in ΛζiV-dimethylformamide; - Ram, S. et al., J. Heterocyclic Chem., 1985, 22, 1269-1274, using alkylbromides with potassium carbonate in ethanol or tetrahydrofuran.
In case L2 in Formula L2-(CH2)n-C-R5R6R7 represents hydroxy, an alternative method can be applied for the alkylation of an Intermediate of Formula 3, following typical Mitsunobu reaction conditions: a compound of Formula 3 reacts with an optionally substituted hydroxyalkyl of Formula R5R6R7C-(CH2)n-OH in the presence of a trialkyl-, or triaryl-phosphane, and a dehydrating agent, such as a dialkyl azodicarboxylate, particularly di-tert-butyl azodicarboxylate, in a suitable solvent, such as toluene, or tetrahydrofurane.
Particularly preferred are hydroxyalkyl of Formula R5R6R7C-(CH2VOH, whereby R5 represents hydrogen, R6 and R7 together with the carbon atom to which they are attached form a 4-, 5- or 6-membered heterocyclic ring, containing one nitrogen atom, such as azetidinyl, pyrrolidinyl, or piperidinyl, respectively. Examples are alkylcarbonyl-3-hydroxymethyl-piperidine; alkyloxycarbonyl-3-hydroxymethyl- piperidine, such as tert-butyloxycarbonyl-3-hydroxymethyl-piperidme; arylcarbonyl-3- hydroxymethyl-piperidine; alkylsulfonyl-3 -hydroxymethyl-piperidine, arylsulfonyl-3 - hydroxymethyl-piperidine, arylalkyloxycarbonyl-3 -hydroxymethylazetidine, and arylalkylcarbonyl-2-hydroxymethylazetidine.
An Intermediate of Formula 3 can also be alkylated to yield a compound of Formula 4.1, with a reagent of Formula L2-(CH2)n-C-R5R6R7, wherein either one, e.g. R7, of the substituents R5, R6, or R7, is representing a functional group (FG), opted for further transformations. Such functional groups include carboxy; halo, such as chloro or bromo; hydroxyl; and amino. Preferably, a FG group such as amino is introduced in its protected form using a standard protecting group (PG) such as /er/-butoxycarbonyl, benzyloxycarbonyl, or phthaloyl. Prior to further modifications, PG might be removed by means of standard methods.
4.1 FG = -COOH, Cl, Br, I, OH, NH2 PG = protecting group A compound of Formula 4.1 bearing a FG such as carboxy can be transformed to alkoxycarbonyl, N-alkyl-N-arylalkyl-carbamoyl, N-aryl-N-arylalkyl-carbamoyl, N- alkyl-N-aryl-carbamoyl, by means of methods known to a skilled person.
A FG such as halo can be transformed to aryloxy, heterocyclyloxy; or an amino of hereinabove defined Formula NR R , by means of known methods.
A FG such as hydroxy can be converted to aryloxy, heterocyclyloxy; or an amino of hereinabove defined Formula NR8R9, by means of known functional group transformations.
A FG such as amino (NH2) can be converted stepwise to an amino of hereinabove defined Formula NR8R9. Preferred modifications of the nitrogen atom include acylation, alkoxycarbonylation, carbamoylation, or sulfonylation, applying standard conditions.
In a preferred embodiment, R5 in a compound of Formula 4 represents hydrogen, and R6 and R7 are forming a pyrrolidine, or piperidinyl ring, whereby a protecting group (PG) is appended to the pyrrolidinyl, or piperidinyl nitrogen atom, as depicted in Formula 4.2. A standard protecting group (PG), like e.g. fe/Y-butoxycarbonyl, or benzyloxycarbonyl, is removed by means of standard conditions, yielding a compound of Formula 4.3. Subsequently, the nitrogen atom is being further modified with hereinabove defined substituent R10, affording a Precursor of Formula 4.4. Preferred modifications of the nitrogen atom include acylation, alkoxycarbonylation, carbamoylation, or sulfonylation, applying standard conditions.
4.2 R" = PG m= 0,l
4.3 R" = H
4.4 R" = R10 Under the conditions used to remove the protecting group (PG) in a compound of Formula 4.2, the acetic ester group might be hydrolysed, leading to a compound of Formula 4.5. In that case, applying a method described for the conversion of a compound of Formula 4.3 to a compound of Formula 4.4 furnishes directly an example of Formula I-e.
In a preferred embodiment, R5 and R6 in a compound of Formula 4 represent hydrogen and R7 is an aromatic ring bearing two substituents R and X as depicted in Formula 4.6, wherein R corresponds to an alkoxy group and X represents a halogen atom such as bromine; or in Formula 4.8 wherein R represents hydroxy and X represents an alkyloxy group.
4.6 R1" = alkoxy, X = halogeπe (Br, Cl, I) 4.7 R'" = alkoxy, X = R18
4.8 R " = hydroxy, X = alkoxy 4.9 R"' = R19, X = alkoxy
In the case of a compound of Formula 4.6, the halogen atom can be replaced by a group R using standard coupling methods known by a person skilled in the art, for example a Suzuki coupling and yielding a compound as depicted in Formula 4.7. Examples are compounds were R18 represents an aromatic ring such as a phenyl group.
A compound of Formula 4.8, might be obtained in the typical conditions of a Mitsunobu reaction between an Intermediate of Formula 3 or Formula 3a and a suitable hydroxymethylbenzoic acid. A compound of Formula 4.8 is subsequently modified so that the hydroxy group R is replaced by a primary or secondary amine using standard coupling methods such as with HOBt and EDC (N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide) hydrochloride in a DMF / dichloromethane mixture to yield primary or secondary aromatic amides as depicted in Formula 4.9. Examples are compounds wherein R19 is an indolino-, butylamino-, morpholino-, benzylamino-, diethylamino- or benzylethylamino-group.
Hydrolysis of the ester group R in a Precursor of Formula 4 can be carried out using routine procedures, as outlined in Scheme 2, for example by means of aqueous lithium hydroxide, or sodium hydroxide in an organic solvent such as tetrahydrofuran, dioxane, methanol, or with trifluoroacetic acid in dichloromethane to give a compound of Formula I-a.
I-a
Scheme 2
In a particular case, an example wherein both R5 and R6 represent a hydrogen atom and R7 is an aromatic ring bearing a ketone, as depicted in Formula I-b, can be further modified by a reduction reaction by means of known methods to yield the compound of Formula I-c wherein R represents hydroxy or alkyloxy . The preferred reaction condition is stirring with sodium borohydride in methanol.
I-b X = alkyloxy, Rπi =alkyl I-c X = alkyloxy, R20 = hydroxy, alkoxy
In a preferred embodiment, a compound of Formula I-a can be further oxidized at the sulphur atom by a method known to a person skilled in the art to yield a sulfoxide as depicted in Formula I-d.
I-d
Starting 2-chlorobenzoimidazole of Formula 1 can be prepared from the corresponding 2-hydroxybenzimidazole of Formula 8 by means of phosphorous oxychloride, either neat or in a suitable solvent (Naef, R.; Balli, H., HeIv. Chem. Acta 1978, 61, 2958- 2973).
2-Chloro-5-nitrobenzimidazole is obtained following a method described in Jung, F.; Delvare, C; Boucherot, D.; Hamon, A. J. Med. Chem. 1991, 34, 1110-1116.
A Precursor of Formula 4 can also be obtained following a preferred alternative synthetic route, e.g. by changing the sequence of reactions. In a first step, starting IH- benzoimidazole-2-thiol of Formula 9 can be S-alkylated with hereinabove defined reagent of Formula L2-(CH2)n-C-R5R6R7 under aforementioned conditions to yield 2- alkylsulfanyl-lif-benzoimidazole of Formula 10, which then is iV-alkylated in a second step with tert-butyl or ethyl bromoacetate to a Precursor of Formula 4. Any further functional group manipulations, as discussed hereinabove for Intermediates 4.1, 4.2, 4.3, and 4.4, are preferably accomplished at this stage, prior to ester hydrolysis to the "final compound of Formula I.
Starting li7-benzoimidazole-2-thiol of Formula 9 is obtained from 1,2-diaminobenzene of Formula 11, with carbon disulfide, thiocarbonyldiimidazole or potassium xanthogenate in a suitable solvent such as dichloromethane; or an alcohol such as methanol, ethanol, propanol; or water; or a mixture of an alcohol and water; in the presence of a base such as potassium hydroxide, sodium hydroxide, at elevated temperature between 50 and 100°C.
Preferred reaction conditions are those described in:
- Ikeda, K.; Hata, S.-L; Tanaka, Y.; Yamamomto, T. OPPI Briefs, 2000, 32, 401- 405, using carbondisulfide and potassium hydroxide in a mixture of ethanol and water;
- Kϋhler, T. C; Fryklund, J.; Bergman, N.-A.; Weilitz, J.; Lee, A.; Larson, H.; J. Med. Chem, 1995, 38, 4906-4916, using potassium ethylxanthogenate in a mixture of ethanol and water;
- Ram, S.; Wise, D. S.; Townsend, L. B. J. Heterocyclic Chem., 1985, 22, 1269- 1274, using potassium ethylxanthogenate and sodium hydroxide in water;
- Wright, J. L.; Gregory, T. F.; Kesten, S. R; Boxer, P. A.; Serpa, K. A.; Meltzer, L.T.; Wise, L. D.; Espitia, S. A.; Konkoy, C. S.; Whittermore, E. R.; Woodward, R. M.; J. Med. Chem., 2000, 43, 3408-3419 using thiocarbonyldiimidazole in tetrahydrofuran.
Examples
Temperatures are indicated in degrees Celsius (0C). Unless otherwise indicated, the reactions are performed at rt.
In mixtures, relations of parts of solvent or eluent or reagent mixtures in liquid form are given as volume relations (v/v), unless indicated otherwise.
Abbreviations and acronyms used:
AcOEt: ethyl acetate, AcOH: acetic acid, AIBN: 2,2'-azobisisobutyronitrile, CDCl3: deuterochloroform, CCl4: tetrachlorocarbon, DCE: 1,2-dichloroethane, DBU: 1,8- Diazabicyclo[5.4.0]undec-7-ene, DIPEA: AζJV-diisopropylethylamine, DMF: N,N- dimethylformamide, DMSO-d6: deuterated dimethyl sulfoxide, DVB: divinyl benzene, eq.: equivalent, ESI: electon spray inonization, Et3N: triethylamine, Et2O: diethylether, EtOH: ethanol, g: gram, h: hour, HCl: hydrochloric acid, HOBt: 1- hydroxybenzotriazole, HPLC: high-performance liquid chromatography, k: kilo,
KH2PO4: potassium phosphate, K2CO3: potassium carbonate, 1: liter, μ: micro, m: milli, mol: mole, M: molar, MeOH: methanol, Me: methyl, min: minute, MgSO4: magnesium sulfate, MS: mass spectrometry, N: normality of solution, NaHCO3: sodium hydrogencarbonate, Na2CO3: sodium carbonate, NaOH: sodium hydroxide, Na2SO4: sodium sulfate, NH4Cl: ammonium chloride, rt: room temperature, SOCl2: thionyl chloride, TFA: trifluoroacetic acid, THF: tetrahydrofuran, fo: retention time.
Instruments and methods:
-HPLC/MS analyses were performed on a Waters 2795 Alliance HPLC instrument, equipped with a Photodiode Array Detector Waters 996 and a Micromass ZQ™ Waters mass spectrometer (electron spray ionization). -Analytical HPLC conditions:
LC-I : analytical HPLC on an Xterra™ MS C18 column (50 x 2.1 mm, 5μm, Waters), with a linear gradient of water containing 0.06% formic acid (A) and acetonitrile containing 0.06% formic acid (B), from 5% to 95% B over 6 min; flow rate 0.25 ml/min, column temperature 30°C, detection at 200- 400 nm.
LC-2: analytical HPLC on an Xterra™ MS C18 column (50 x 4.6 mm, 5μm, Waters), with a linear gradient of water containing 0.06% formic acid (A) and acetonitrile containing 0.06% formic acid (B), from 5% to 95% B over 2 min; flow rate 0.75 ml/min, column temperature 30°C, detection at 200- 400 nm.
LC-3: analytical HPLC on an Zorbax SB-Aq™ column (50 x 4.6 mm, 5μm, Agilent), with a linear gradient of water containing 0.06% formic acid (A) and acetonitrile containing 0.06% formic acid (B), from 5% to 95% B over 1 min; flow rate 3 ml/min, column temperature 30°C, detection at 200- 400 nm.
-Preparative HPLC conditions:
Separations and purifications of compounds on a preparative scale are performed on Waters HPLC system, equipped with a Waters 600 controller, a Waters Preparative Xterra™ Prep MS C18 column (19 x 50 mm, 5μm, a Waters 2767 sample manager, a Waters 996 Photodiode Array Detector, and a Micromass ZQTM Waters mass spectrometer (electron spray ionization), with a gradient of water containing 0.825% formic acid (A) and acetonitrile containing 0.825% formic acid (B) from 5% to 95% B over 13 min; flow rate 20 ml / min, column temperature 30°C, detection at 200-400 nm.
-1H NMR spectra were recorded on a Varian Mercury 300VX FT-NMR spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) downfield by reference to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for dimetylsulfoxide <5(H) 2.49 ppm, for chloroform c5(H) 7.24 ppm. Syntheses of Intermediates of Formula 3:
Intermediate 3-1 tert-Butyl-f 2-mercapto-benzoimidazol- 1 -yl) acetate According to the procedure described in: Migawa, M. T.; Girardet, J.-L.; Walker II, J. A.; Koszalka, G. W.; Chamberlain, S. D.; Drach, J. C; Townsend, L. B., J. Med. Chem. 1998, 41, 1242-1251, a solution of tert-bntyl (2-chloro-benzoimidazol-l-yl)- acetate (Intermediate 2-1, 7 g, 26.3 mmol) and thiourea (7.98 g, 105 mmol) in methanol (100 ml) is refluxed for 2 h. The mixture is cooled down and most of the methanol is removed in vacuo. After addition of saturated aqueous NH4Cl solution (150 ml), the resulting aqueous phase is extracted three times with Et2O. The combined organic phases are washed with brine and dried over Na2SO4. The solvent is evaporated in vacuo and the residue dried under high vacuum, yielding the title compound (6.46 g) in 93% as a white powder: tR = 6.14 min (LC-I), ESI-MS (neg.): m/z 263.31 [M-H]+; 1H- NMR (CDCl3): δ (ppm) 1.50 (s, 9H, fflu), 4.94 (s, 2H, CH2CO2), 6.99-7.05 (m, 1 Harom), 7.16-7.24 (m, 1 HarOm), 10.69 (bs, IH5 SH).
Intermediate 3-IIa and Intermediate 3-IIb of the following Table 3 are prepared from a (1:1) mixture of ført-butyl (2-chloro-5-nitro-benzoimidazol-l-yl)-acetate (Intermediate 2-IIa) and its 6-nitro regioisomer (Intermediate 2-IIb) analogous to the procedure described for Intermediate 3-1. They are purified and separated by flash- chromatography on silica-gel (AcOEt / heptane, 1 :5).
te/f-Butyl (2-
, .. mercapto-5-nitro- C13H15N3O4S 2.16 , ,„„ ,„
J"πa benzoimidazol-1-yl)- 309.34 (LC-2) n/a ύUϋ-άZ acetate terf-Butyl (2-
- ... mercapto-6-nitro- C13H15N3O4S 2.16 , ,nfi ,o
J""D benzoimidazoi-1-yl)- 309.34 (LC-2) n/a dUB"" acetate
Table 3 Syntheses of Intermediates of Formula 2:
Intermediate 2-1 tert-Butyl (2-chloro-benzoimidazol- 1 -vD-acetate In a round bottomed flask are added K2CO3 (9.34 g, 67.7 mmol), 2- chlorobenzimidazole (5.16 g, 33.8 mmol) and tert-butyl bromoacetate (6.6 g, 5 ml, 33.8 mmol) in acetone (100 ml). The resulting suspension is refluxed for 1 h. The crude mixture is filtered through a filter paper and water (100 ml) is added. The resulting aqueous phase is extracted three times with Et2O. The combined organic phases are washed with brine and dried over MgSO4 .The solvent is evaporated under reduced pressure yielding the title compound (7.98 g) in 88% as a white powder: fa = 2.20 min (LC-2), ESI-MS (pos.): m/z 267.2 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.48 (s, 9H, tBύ), 4.92 (s, 2H, CH2CO2), 7.24-7.40 (m, 3Harom), 7.76-7.80 (m, lHarom).
Intermediate 2-IIa and 2-IIb tert-Butyl (2-chloro-5-nitro-benzoimidazol-l-yl)-acetate and its 6-nitro regioisomer are prepared according to the same procedure (yield 93%): fa = 6.68 min (LC-I), ESI- MS (pos.): m/z 312.08 [M+H]+, 310.28 [M-H]+; 1H-NMR(CDCl3): δ (ppm) 1.50 (s, 9H, tBu), 1.52 (s, 9H, tBu), 5.04 and 5.06 (s, 2H, CH2CO2), 7.38 (d, 1 Harom), 7.86 (d, 1 Harom), 8.32-8.40 (m, 3 Harom), 8.96 (m, 1 Harom).
Example A-OIa
[2-f2-Cyclohexyl-ethylsulfanyl)-benzoimidazol- 1 -yli-acetic acid
A solution of tert-butyl [2-(2-cyclohexyl-ethylsulfanyl)-benzoimidazol-l-yl] -acetate (Precursor A-OIb, 42 mg, 0.13 mmol) in TFA / dichloromethane (1:1, 0.5 ml) is stirred at rt for 4 h. The solvents are removed in vacuo. The crude residue is sonicated in Et2O / heptane (1:1, 1 ml) until a solid precipitates. It is rinsed with heptane and purified by flash chromatography on silica gel (AcOEt / heptane, 1 :1 containing 1% of AcOH), yielding the title compound (12 mg) in 30% as a white solid: fa = 6.44 min (LC-I), ESI-MS (pos.): m/z 319.12 [M+H]+, ESI-MS (neg.): m/z 317.37 [M-H]+; 1H-NMR (CDCl3): S (ppm) 0.82-0.94 (m, 2H), 1.09-1.23 (m, 3H), 1.37 (m, IH), 1.54 (q, 2H, SCH2CH2), 1.68 (m, 5H), 3.34 (t, 2H, SCH2), 4.88 (s, 2H, CH2CO2), 7.22 (s, 3 Harom),
7.65 (m, 1 Harom).
Examples A-02a to A-05a of the following Table 1 are prepared analogous to the procedure described for Example A-OIa, using Precursors A-02b to A-05b in place of A-OIb.
Formula tR [min] MS Data MS Data
Example Name MoI weight (Meth.) m/z [M+H]+ m/z [M-H]
(2-Hexylsulfanyl- πςH?0N?θ?ς B n?
A-02a benzoimidazol-1-yl)-acetic °" 9 "m > n r i \ 293-27 29135 acid zyz.wx ^- ιj
(2-Pentylsulfanyl- Π /H-II RMOΠOQ ς w
A-03a benzoimidazol-1-yl)-acetic C14_H 7 1 R 8N2O2S 5^ 279.08 277.31 acid
(2-But-3-enylsulfanyl- C13H14N2O2S 4 69
A-04a benzoimidazol-1-yl)-acetic ϋ13 9™4 ,.™v 263.1 261.28 acid
(2-Butylsulfanyl- mHifiN?n?q Λ Q
A-05a benzoimidazol-1-yl)-acetic U I J" '°!:.β & ** 265.28 263.23
OΛ,:J ZO4.O4CS (LO- 1 ; acid
Table 1
Precursor A-OIb fe/Y-Butyl [2-(2-cvclohexyl-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetate
To a suspension of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-
I, 53 mg, 0.2 mmol) and K2CO3 (41.4 mg, 0.4 mmol) in acetone (0.8 ml) is added 2- cyclohexylethyl bromide (28.8 mg, 22.6 μl). The reaction mixture is kept stirring at reflux for 5 h then filtered on a short plug of silica gel. The solvents are evaporated and the crude is purified by preparative HPLC yielding the title compound in 60% as a colourless oil: tR = 7.39 min (LC-I), ESI-MS (pos.): m/z 321.36 [M+H]+; 1H NMR
(CDCl3): £(ppm) 0.80-0.91 (m, 2H), 1.04-1.23 (m, 3H), 1.35 (s, 9H, ffiu), 1.35 (m,
IH), 1.54-1.72 (m, 6H), 1.83 (br. s, IH), 3.32 (t, 2H, SCH2), 4.65 (s, 2H, CH2CO2),
7.07-7.17 (m, 3 Harom), 7.61 (m, 1 Harom). Precursors A-02b to A-05b of the following Table 2 are prepared using a procedure analogous to that described for Precursor A-OIb, substituting the appropriate alkyl halide for 2-cyclohexylethyl bromide.
Formula MS Data tR [min]
Precursor Name m/z MoI weight (Meth.) [M+H]+
terf-Butyl (2-hexylsulfanyl- C19H28N2O2S 7.99
A-02b 349.41 benzoimidazol-1-yl)-acetate 348.51 (LC-1)
ferf-Butyl (2-pentylsulfanyl- C18H26N2O2S 7.63
A-03b 335.35 benzoimidazol-1-yl)-acetate 334.48 (LC-1)
tert-Butyl (2-but-3- ri7H2?N2θ?ς 7 ΠΛ A-04b enylsulfanyl-benzoimidazol-1- ^t Λ ,, ZZ, 319.33 yl)-acetate d1 B-44 (Lυ'υ
terf-Butyl (2-butylsulfanyl- C17H24N2O2S 7.39
A-05b 321.36 benzoimidazol-1 -yl)-acetate 320.46 (LC-1)
Table 2
Example B-OIa rac [2-(l-Phenyl-ethylsulfanyl)-benzoimidazol-l-yi] -acetic acid
A solution of rac tert-butyl [2-(l-phenyl-ethylsulfanyl)-benzoimidazol-l-yl]-acetate
(Precursor B-OIb, 46.5 mg, 0.13 mmol) is dissolved in TFA / dichloromethane (1:1, 4.0 ml) and stirred at rt for 3 h. The volatiles are removed in vacuo and the residue is dried under high vacuum, affording the title compound (26.7 mg) as a yellow oil in 67% yield: tR = 5.50 min (LC-I), MS (pos.): m/z 313.03 [M+H]+, MS (neg.): m/z 311.16
[M-H]+; 1H NMR (DMSOd6): £(ppm) 1.72 (d, 2H, CHCH3), 4.76 (s, 2H, CH2CO2),
5.03 (m, 2H, SCH2), 7.10 (m, 2 Harom), 7.23-7.32(m, 3 Harom), 7.36 (m, 3 Harom), 7.54
(m, 1 Haroni). Examples B-02a to B-05a of the following Table 4 are prepared analogous to the procedure described for Example B-OIa, using Precursors B-02b to B-05b in place of B-OIb.
Formula tR [min] MS Data MS Data
Example Name MoI weight (Meth.) m/z [M+H]+ m/z [M-H]+
(2-Cyclopentylsulfanyl- C14H 16N2O2S 4 7
B-02a benzoιmιdazol-1-yl)-acetιc „„ ^cg n/a 275.19
(LC-1) acid rac [2-(1-
Methyloxycarbonyl-1 -
C18H16N2O4S 5.79
B-03a phenyl-methylsulfanyl)- 356.99 355.13 356.401 (LC-1) benzoimidazol-1 -yl]-acetic acid rac [2-(Bicyclo[4.2.0]octa- 1 ,3,5-trien-7-ylsulfanyl)- C17H14N2O2S 5.65
B-04a 312.34 309.14 benzoimidazoi-1-yl]-acetic 310.376 (LC-1) acid rac [2-(1-Methyl-2-oxo-2- phenyl-ethylsulfanyl)- C18H16N2O3S 5.7
B-05a n/a 339.15 benzoimidazol-1-yl]-acetic 340.402 (LC-1) acid
Table 4
Precursor B-OIb ført-Butyl [2-( 1 -phenyl-ethylsulfanyP-benzoimidazol- 1 -yl] -acetate A mixture of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-1, 50 mg, 0.19 mmol), 1-bromomethyl-benzene (38.5 mg, 28.5 μl, 0.2 mmol) and K2CO3 (52 mg, 0.38 mmol) in acetone (3 ml) is stirred at reflux overnight. The suspension is cooled to rt and filtered through Celite. Evaporation of the solvent in vacuo and drying under high vacuum yields quantitatively the title compound as a slightly yellow oil. This material is used in the next step without further purification, fø = 7.45 min (LC-I), MS (pos.): m/z 369.21 [M+H]+; 1H-NMR (DMSO-d6): £(ρpm) 1.36 (s, 9H, tBu), 1.73 (d, 3H, Me), 4.94 (m, 2H, CH2CO2), 5.09 (q, IH, SCHMePH), 7.16-7.20 (m, 2 Harom), 7.26-7.36 (m, 3 Umom), 7.44-7.50 (m, 3 HarOm), 7.61 (m, 1 Harom). Precursors B-02b to B-05b of the following Table 5 are prepared using a procedure analogous to that described for Precursor B-OIb, substituting the appropriate alkyl halide for 1-bromomethyl-benzene.
MS Data
Formula tR [min] MS Data
Precursor Name m/z MoI weight (Meth.) m/z [M-H]" [M+H]+
tert-Butyl (2- C18H24N2O2S 7.24 B-02b cyclopentylsulfanyl- n/a 332.46 (LC-1) 333.18 benzoimidazol-1 -yl)-acetate
rac tert-Butyl [2-(1-
7.25
B-03b methyloxycarbonyl-1 -phenyl- C22H24N2O4S methylsulfanyl)- 412.5 (LC-1) 413.16 411.19 benzoimidazol-1 -yl]-acetate
terf-Butyl [2- lo[4.2.0]octa-1 ,3,5- C21 H22N2O2S 7.51
B-04b (bicyc
367.14 n/a trien-7-ylsulfanyl)- 366.48 (LC-1) benzoimidazol-1 -yl]-acetate terf-Butyl [2-(1-methyl-2-oxo- rwμ, ,M,mς
7.39
B-05b 2-phenyl-ethylsulfanyl)- 396 5 (LC-1) 397.13 395.23 benzoimidazol-1 -yl]-acetate
Table 5
Example C-OIa [2-(2-Methoxy-benzylsulfanyl)-benzoimidazol- 1 -yl"|-acetic acid A solution of tert-butyl [2-(2-methoxy-benzylsulfanyl)-benzoimidazol- 1 -yl]-acetate (Precursor C-OIb, 20 mg, 0.05 mmol) is stirred in TFA / dichloromethane (1:1, 4.0 ml) at rt overnight. The volatiles are removed in vacuo and and the residue is dried under high vacuum, yielding the title compound (16.0 mg) in 94 % as a white solid: t& = 5.27 min (LC-I)5 MS (pos.): m/z 329.22 [M+H]+, MS (neg.): m/z 327.20 [M-H]+; 1H-NMR (DMSOd6): £(ppm) 3.82 (s, 3H, OCH3), 4.51 (s, 2H, SCH2), 4.92 (s, 2H, CH2CO2), 6.89 (t, 1 Harom), 7.04 (d, 1 Harom), 7.18 (m, 2 Harom), 7.30 (t, 1 Harom), 7.40 (d, 1 Harom), 7.50 (m, 1 Harom), 7.61 (m, 1 Harora). Examples C-02ato C-05a of the following Table 6 are prepared analogous to the procedure described for Example C-OIa, using Precursors C-02b to C-05b in place of C-OIb.
Formula tR [min] MS Data MS Data
Example Name MoI weight (Meth.) m/z [M+H]+ m/z [M-H]+
(2-Benzylsulfanyl- C16H14N2O2S 5.37
C-02a benzoimidazol-1 -yl)-acetic w ' "όg^aβ ™ (LC-I ) 299'21 297.22 acid ' \ ' )
(2-Phenethylsulfønyl- H16N2O2S ^
C-03a benzoιmιdazol-1-yl)-acetιc „.„ ,QO n n A \ 313.09 311.22 acid
[2-(3-Phenyl-
C-04a propylsulfanyl)- C18H18N2O2S 5.9
327.06 325.26 benzoimidazol-1 -yl]-acetic 326.419 (LC-1) acid
[2-(3,3-Diphenyl- propylsulfanyl)- C24H22N2O2S 6.7
C-05a 403.2 401.26 benzoimidazol-1 -yl]-acetic 402.517 (LC-1) acid
Table 6
Precursor C-OIb ferf-Butyl [2-(2-methoxy-benzylsulfanyl)-benzoimidazol- 1 -yl"|-acetate A suspension Of K2CO3 (31.4 mg, 0.23 mmol) in acetone (3 ml) containing tert-hvXyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-1, 30 mg, 0.11 mmol) and 2- methoxybenzyl chloride (17.8 mg, 15.8 μl, 0.11 mmol) is stirred at rt overnight. Filtration over Celite and evaporation of the solvent in vacuo affords the pure title compound (27 mg) in 62% yield as a yellow oil: ^R = 7.47 min (LC-I), MS (pos.): m/z 385.20 [M+H]+; 1HNMR (DMSO-d6): £(ppm) 1.37 (s, 9H5 fflu), 3.90 (s, 3H, OCH3), 4.53 (s, 2H, SCH2), 4.92 (s, 2H, CH2CO2), 6.87 (t, 1 Harom), 7.03 (d, 1 H810n,), 7.21 (m, 2 Harom), 7.28 (t, 1 Harom), 7.40 (d, 1 Harom), 7.50 (m, 1 Harom), 7.64 (m, 1 Harom).
Precursors C-02b to C-05b of the following Table 7 are prepared using a procedure analogous to that described for Precursor C-OIb, substituting the appropriate benzyl halide for 2-methoxybenzyl chloride. Formula fR [min] MS Data
Precursor Name MoI weight (Meth.) m/z [M+H]+ tert-Butyl (2-benzylsulfanyl- C20H22N2O2S 7.27 C-02b benzoimidazol-1-yl)-acetate 354.47 355.36 (LC-1) terf-Butyl (2-
C21 H24N2O2S C-03b 7.46 phenethylsulfanyl- 369.35 368.5 (LC-1) benzoimidazol-1 -yl)-acetate tert-Butyl [2-(3-phenyl-
C22H26N2O2S 2.62
C-04b propylsulfanyl)- 383.31 382.52 (LC-2) benzoimidazol-1 -yl]-acetate tert-Butyl [2-(3,3-diphenyl-
C28H30N2O2S 8.17 C-05b propylsulfaπyl)- 459.42
458.62 (LC-1) benzoimidazol-1 -yl]-acetate
Table 7
Example D-OIa
{2-[2-(4-ChloiO-phenoxyVethylsulfanyl]-benzoimidazol-l-γl>-acetic acid A solution tert-butyl {2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}- acetate (Precursor D-OIb, 33 mg, 0.79 mmol) is stirred in TFA / dichloromethane (1:1, 0.8 ml) at rt for 3 h. The volatiles are removed in vacuo and the residue is purified by fiash-chromatography on silica gel (AcOEt / heptane, 1:1; then pure AcOEt), yielding the title compound (27 mg) in 95% as a white solid: tR = 5.73 min (LC-I), MS (pos.): m/z 362.8 [M+H]+, MS (neg.): m/z 360.8 [M-H]+; 1H-NMR (CDCl3): £(ρpm) 3.88 (m, 2H, SCH2), 4.22 (t, 2H, OCH2), 4.88 (s, 2H, CH2CO2), 6.54 (d, 2H, H arom), 7.12 (d, 2 Harom), 7.32-7.46 (m, 3 Harom), 7.82 (m, 1 Harom).
Examples D-02a to D-07a of the following Table 8 are prepared analogous to the procedure described for Example D-OIa, using Precursors D-02b to D-07b in place of D-OIb.
Example Formula tR [min] MS Data MS Data
Name MoI weight (Meth.) m/z [M+H]+ m/z [M-H]
[2-(2-Phenoxy- ethylsulfanyl)- C17H16N2O3S 5.68
D-02a 329.23 327.24 benzoimidazol-1-yl]-acetic 328.392 (LC-1) acid {2-[2-(Naphthalen-1-
D-03a yloxy)-ethylsulfanyl]- C21 H18N2O3S 6.39 benzoimidazol-1-yl}-acetic 378.451 (LC-1) 379.26 377.34 acid
{2-[2-(Naphthalen-2-
D-04a yloxy)-ethylsulfanyl]- C21 H18N2O3S 6.43
379.26 377.28 benzoimidazol-1-yl}-acetic 378.451 (LC-1) acid
[2-(3-Phenoxy- propylsulfanyl)- C18H18N2O3S 5.81
D-05a 343.27 341.22 benzoimidazol-1-y)]-acetic 342.418 (LC-1) acid
(2-{3-[(1 -Ethyloxycarbonyl- indazol-3-yl)-oxy]- C22H22N4O5S 2.44
D-06a propylsulfanyl}- 454 5Q6 ,, c 2) 453.26 455.11 benzoimidazol-1-yl)-acetic 404'0Ub I^ ^ acid
[2-(4-Phenoxy- butylsulfanyl)- C19H20N2O3S 6.02
D-07a 357.19 355.21 benzoimidazol-1-yl]-acetic 356.445 (LC-1) acid
Table 8
Precursor D-02b tert-Butyl [2-(2-phenoxy-ethylsulfanyl)-benzoimidazol- 1 -γl] -acetate
A mixture of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-1, 53 mg, 0.2 mmol), l-(2-bromo-ethoxy)-benzene (48.3 mg, 0.22 mmol) and K2CO3 (41.4 mg, 0.3 mmol) in acetone (0.8 ml) is refluxed for 3 h. The suspension is cooled to rt and filtered through a short pad of silica-gel. The volatiles are removed in vacuo and the residue is dried under high vacuum affording the title compound as a colourless oil.
This material was used in the next step without further purification: fo = 2.55 min (LC-
2), MS (pos.): m/z 385.2 [M+H]+; 1H NMR (CDCl3): £(ppm) 1.48 (s, 9H, fBu), 3.96
(m, 2H, SCH2), 4.48 (t, 2H, OCH2), 4.90 (s, 2H, CH2CO2), 6.90 (d, 2 Harom), 7.24-7.38
(m, 5 Harom), 7.86 (m, 1 Harom).
Precursors D-OIb to D-07b of the following Table 9 are prepared using a procedure analogous to that described for Precursor D -02b, substituting the appropriate aryloxyalkylbromide or heterocyclyloxyalkylbromide for (2-bromo-ethoxy)-benzene. Formula tR [min] MS Data
Precursor Name MoI weight (Meth.) m/z [M+Hf terf-Butyl {2-[2-(4-chloro-
C21H24N2O3S 7.25
D-OIb phenoxy)-ethylsulfanyl]- 384.49 (LC-1) 418.66 benzoimidazol-1-yl}-acetate ferf-Butyl {2-[2-(naphthalen-1-
D-03b C25H26N2O3S 7.99 yloxy)-ethylsulfanyl]- 435.34
434.558 (LC-1) benzoimidazol-1 -yl}-acetate terf-Butyl {2-[2-(naphthalen-2-
C25H26N2O3S 7.94
D-04b yloxy)-ethylsulfanyl]- 435.34
434.56 (LC-1) benzoimidazol-1 -yl}-acetate terf-Butyl [2-(4-phenoxy-
C23H28N2O3S 2.63
D-05b butylsulfanyl)-benzoimidazol-
412.55 413.35
(LC-2)
1-yl]-acetate terf-Butyl (2-{3-[(1-
D-06b ethyloxycarbonyl-indazol-3- C26H30N4O5S 2.94 yl)-oxy]-propylsulfanyl}- 510.61 511.24
(LC-2) benzoimidazol-1-yl)-'acetate terf-Butyl [2-(4-phenoxy-
C23H28N2O3S 7.68
D-07b butylsulfanyl)-benzoimidazol- 413.37
412.55 (LC-1)
1-yl]-acetate
Table 9
Preparation of 3-(3-chloro-propoxy)-indazole-l-carboxylic acid ethyl ester (alkylating agent D-06-d) is described in the paragraph relating the preparation of 2-(3-chloro- propyl)-3-oxo-2,3-dihydro-indazole-l-carboxylic acid ethyl ester (alkylating agent G- 01 d).
Example E-OIa p-fS-Emyloxycarbonyl-pentylsulfanylVbenzoimidazol-l-yl'j-acetic acid
A solution of tert-bntyl [2-(5-ethyloxycarbonyl-pentylsulfanyl)-benzoimidazol-l-yl]- acetate (Precursor E-OIb, 44 mg, 0.11 mmol) in TFA / dichloromethane (1:1, 2 ml) is stirred at rt for 3 h. The solvents are removed under a stream of air. The solid residue is suspended in Et2O (2 ml) and sonicated. Filtration, rinsing with Et2O and drying under high vacuum yields the title compound (32 mg) as a white solid in 85% yield: fø= 5.33 min (LC-I), ESI-MS (pos.): m/z 351.07 [M+H]+, ESI-MS (neg.): m/z 349.22 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 1.25 (t, 3H CH3), 1.44 (s, 9H5 11Bu), 1.32-1.44 (m, 2H), 1.52-1.70 (m, 4H), 2.24 (t, 2H, CH2C=O), 3.24 (t, 2H, SCH2), 4.10 (q, 2H, OCH2), 4.15 (br. s, IH, CO2H), 4.86 (s, 2H, CH2CO2), 7.24 (s, 3 Harom), 7.63 (m, 1 Harom). Examples E-02a to E-03a of the following Table 10 are prepared analogous to the procedure described for Example E-OIa, using Precursors E-02b and E-03b in place of E-OIb.
P _mn,- Nl Formula tR [min] MS Data IWS Data txampie Name Mo| weight (Meth.) m/z [M+H]+ m/z [M-H]+
[2-(3-Ethyloxycarbonyl-
E 02a propylsulfanyl)- C15H18N2O4S 4.87 t υ^a benzoimidazoi-1-yl]-acetic 322.384 (LC-1) *""" άZ i Z* acid
[2-(4-Ethyloxycarbonyl-
P: n,α butylsulfanyl)- C16H20N2O4S 5.09 ,, . _ ,
**** benzoimidazol-1-yl]-acetic 336.411 (LC-1) ύύ t Λ* ύόύ άΛ acid
Table 10
Precursor E-OIb fert-Butyl [2-(5-ethyloxycarbonyl-pentylsulfanyl)-benzoimidazol- 1 -yl]-acetate
A mixture of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-1, 52 mg, 0.2 mmol), 6-bromo-hexanoic acid ethyl ester (49 mg, 39 μl, 0.22 mmol) and K2CO3 (55 mg, 0.4 mmol) is refluxed in acetone (2 ml) for 5 h and stirred at rt overnight. Evaporation of the solvent in vacuo affords a residue that is purified by flash-chromatography on silica-gel (AcOEt / heptane, 25 :75), yielding the title compound (55 mg) in 68% as a colourless oil: fø = 7.24 min (LC-I), ESI-MS (pos.): m/z 407.23 [M+H]+, ESI-MS (neg.) 405.22 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 1.25 (t, 3H CH3), 1.44 (s, 9H, tBu), 1.48 (m, 2H), 1.66 (quint., 2H), 1.79 (quint., 2H), 2.30 (t, 2H, CH2C=O), 3.38 (t, 2H, SCH2), 4.10 (q, 2H, OCH2), 4.73 (s, 2H, CH2CO2), 7.17- 7.25 (m, 3 Harom), 7.69 (m, 1 Harom).
Precursors E-02b to E-03b of the following Table 11 are prepared using a procedure analogous to that described for Precursor E-OIb, substituting the appropriate alkyl bromide for 6-bromo-hexanoic acid ethyl ester. Formula MS Data
Precursor Name fe [min] MoI weight m/z (Meth.) [M+H]+ tort-Butyl [2-(3- ethyloxycarbonyl- C19H26N2O4S 2.34
E-02b propylsulfanyl)- 378.49 379.36 (LC-2) benzoimidazol-1 -yl]-acetate
terf-Butyl [2-(4- ethyloxycarbonyl- C20H28N2O4S 7.04
E-03b 393.35 butylsulfanyl)-benzoimidazol- 392.51 (LC-1) 1-yl]-acetate
Table 11
Example F-OIa
{2-r4-(Methyl-phenyl-carbamoyl)-butylsulfanyll-benzoimidazol- 1 -yl} -acetic acid te7't-Butyl {2-[4-(methyl-phenyl-carbamoyl)-butylsulfanyl]-benzoimidazol-l-yl}- acetate (Precursor F-OIb, 25.6 mg, 0.06 mmol) is dissolved in TFA / dicbloromethane (1 :1, 3 ml) and stirred for 3 h at rt. Evaporation of the solvent in vacuo and drying under high vacuum yields the title compound (19.4 mg) in 87% as a yellow oil: fø = 5.20 min (LC-I), ESI-MS (pos.): m/z 398.20 [M+H]+, ESI-MS (neg.): m/z 396.19 [M- H]+; 1H-NMR (DMSOd6): δ (ppm) 1.56 (m, 4H, CH2CH2), 2.05 (m, 2H, CH2C=O), 3.14 (s, 3H, NMe), 3.22 (m, 2H, SCH2), 5.00 (s, 2H5 CH2CO2), 7.18-7.32 (m, 5 Harom), 7.38 (m, 2 Harom), 7.53 (m, 2 Harom).
Examples F-02a to F-05a of the following Table 12 are prepared analogous to the procedure described for Example F-OIa, using Precursors F-02b to F-05b in place of F- 01b.
Formula tR [min] MS Data MS Data
Example Name MoI weight (Meth.) m/z [M+H]+ m/z [M-H]+
{2-[5-(3,4-Dihydro-2H- quinolin-1-yl)-5-oxo-
C23H25N3O3S 5.58 F-02a pentylsulfanyl]- 424.22 422.23 423.536 (LC-1) benzoimidazol-1 -yl}-acetic acid {2-[4-(Benzyl-phenyl- P n,_ carbamoyl)-butylsulfanyl]- C27H27N3O3S 6.17 ._ benzoimidazol-1-yl}-acetic 473.595 (LC-1) 4^" " 4/z^a acid
{2-[4-(benzyl-methyl-
P 04. carbamoyl)-butylsulfanyl]- C22H25N3O3S 5.31 r a benzoimidazol-1-yl}-acetic 411.525 (LC-1) 4 I^Z 4m ι° acid;
{2-[4-(Butyl-phenyl-
P f,,-. carbamoyl)-butylsulfanyl]- C24H29N3O3S 6.13 ΔAn . . 9R benzoimidazol-1-yl}-acetic 439.578 (LC-1) 44U> I / 4<j0^° acid
Table 12
Precursor F-OIb tert-Butyl |2-[4-(methyl-phenyl-carbamoyl)-butylsulfanyll-benzoimidazol-l-yl}- acetate
To a suspension of 5-bromovaleryl chloride (24.8 mg, 16.6 μl, 0.12 mmol) and K2CO3 (31.2 mg, 0.23 mmol) in acetonitrile (3 ml) is added N-methylaniline (14.5 mg, 14.7 μl, 0.14 mmol). After 1 h of stirring, tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intel-mediate 3-1, 30 mg, 0.11 mmol) is added and the resulting mixture is refluxed overnight. The crude suspension is filtered over a fritted funnel and the solvent evaporated in vacuo. The crude yellow oil is purified by fiash-chromatography on silica gel (AcOEt / heptane, 2:1 containing 3% Of Et3N), yielding the title compound (38.4 mg) in 75% as a yellowish oil: fo = 6.84 min (LC-I), ESI-MS (pos.): m/z 455.46 [M+H]+, ESI-MS (neg.): m/z 452.19 [M-H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.38 (s, 9H, ffiu). 1.56 (m, 4H, CH2CH2), 2.03 (m, 2H, CH2C=O), 3.17 (m, 2H, SCH2), 3.31 (s, 3H, NMe)5 4.92 (s, 2H, CH2CO2), 7.12-7.16 (m, 2 Harom), 7.26-7.30 (m, 3 Harom), 7.36- 7.46 (m, 3 Harom), 7.51 (m, 1 Harom).
Precursors F-02b to F-05b of the following Table 13 are prepared using a procedure analogous to that described for Precursor F-OIb, substituting the corresponding JV, JV- disubstituted amine for JV-methylaniline.
y-' r tert-Butyl {2-[5-(3,4-dihydro-
2H-quinoIin-1-yl)-5-oxo- C27H33N3O3S
F-02b 7.23 pentylsulfanyl]-benzoimidazol- 479.63 (LC-1) 481.31 n/a 1-yl}-acetate
tert-Butyl {2-[4-(benzyl- phenyl-carbamoyl)- C31 H35N3O3S 7.62
F-03b butylsulfanyl]-benzoimidazol- 529.69 531.43 n/a (LC-1)
1-yl}-acetate
tert-Butyl {2-[4-(benzyl- yl-carbamoyl)- C26H33N3O3S 6.91
F-04b meth
468.08 466.34 butylsulfanyl]-benzoimidazol- 467.62 (LC-1)
1-yl}-acetate tert-Butyl {2-[4-(butyl-phenyl-
C28H37N3O3S 7.7
F-05b carbamoyl)-butylsulfanyl]- 497.44 n/a 495.68 (LC-1) benzoimidazol-1 -yl}-acetate
Table 13
Example G-OIa
(2-[3-(2,3-Dihvdro-l-ethyloxycarbonyl-3-oxo-indazol-2-yl)-propylsulfanyl1- benzoimidazol-1-yll -acetic acid tert-Butyl {2-[3-(2,3-dihydro-l-ethyloxycarbonyl-3-oxo-indazol-2-yl)-propylsulfanyl]- benzoimidazol-1-yl} -acetate (Precursor G-OIb, 63.8 mg, 0.1 mmol) is stirred in TFA / dichloromethane (1:1, 2 ml) at rt overnight. The solvents are removed in vacuo. The crude is taken up in chloroform (1 ml) and filtered over cotton wool. The solvent is removed in vacuuo and the residue is dried under high vacuum. This yields the title compound (6 mg) in 11 % as a colourless oil: fø = 2.24 min (LC-2), ESI-MS (pos.): m/z 455.11 [M+H]+, ESI-MS (neg.): m/z 453.22 [M-H]+; 1H-NMR (DMSOd6): δ (ppm) 1.31 (t, 3H5 CH3), 2.03 (quint., 2H, CH2CH2N), 3.18 (m ,2H, SCH2), 4.23 (t, 2H, CH2N), 4.36 (q., 2H, OCH2), 4.94 (s, 2H, CH2CO2), 7.10-7.15 (m, 2 Harom), 7.39 (t, 1 Harom), 7.46 (m, 2 Harom), 7.70-7.78 (m, 2 Harom), 7.87 (d, 1 Harom)
Examples G-02a to G-07a of the following Table 14 are prepared analogous to the procedure described for Example G-OIa, using Precursors G-02b to G-07b in place of G-OIb.
Formula tR [min] MS Data MS Data
Example Name MoI weight (Meth.) m/z [M+H]+ m/z [M-H]+ {2-[3-(1-Oxo-1 ,3-dihydro-
G-02a pro7y?s°ϋlfønjli- ^^g038 (LC-2) 382-43 380-29 benzoimidazol-1 -yl}-acetic acid
{2-[3-(2-Oxo-2,3-dihydro- benzoimidazol-1-yl)- <-Mqu18N,4O3S 2 00
G-03a propylsulfanyl]- 332 443 (LC-2) 383-19 381 "21 benzoimidazol-1 -yl}-acetic acid
{2-[3-(1-Oxo-1W- phthalazin-2-yl)- r9nni RN4mς ? n
G-04a propylsulfanyl]- Ic 2) 395"1 393-19 benzoimidazol-1 -yl}-acetic acid
{2-[3-(2,4-Dioxo-1 ,4- dihydro-2/-/-quinazolin-3- PonU1 QM4nAo 1 qq
G-OSa yl)-propylsulfanyl]- ∞0™ ^1404S 1 99 41 1 /| 5 4og/| 8 benzoimidazol-1 -yl}-acetic 4 1 u-4Doi ^LO z^ acid
{2-[3-(1 ,3-Dioxo-1 ,3- dihydro-isoindol-2-yl)- C20HI 7N3O4S 5 36
G-06a propylsulfanyl]- ,0/?« S( 396-15 394.23 benzoimidazol-1 -yl}-acetic 395'438 (L0'1 ) acid
{2-[3-(1 ,1,3-Trioxo-1 ,3- dihydro-1λ-
G 07 benzo[d]isothiazol-2-yl)- C19H17N3O5S2 2.21 _
^078 propylsulfanyl]- 431.492 (LC-2) 4^ υb 4<iU" 14 benzoimidazol-1 -yl}-acetic acid
Table 14
Precursor G-OIb tert-Butyl {2-|"3-(2,3-dihvdro-l-ethyloxycarbonyl-3-oxo-indazol-2-yl)-propylsulfanyl1- benzoimidazol- 1 -yl) -acetate
A mixture of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-1, 66 mg, 0.25 mmol), 2-(3-chloro-propyl)-3-oxo-2,3-dihydro-indazole-l-carboxylic acid ethyl ester (alkylating agent G-OId, 70 mg, 0.25 mmol), a few crystals of potassium iodide and K2CO3 (69 mg, 0.5 mmol) in acetone (1 ml) is refluxed overnight.
Evaporation of the solvent under a stream of air affords a residue that is purified by flash-chromatography on silica-gel (AcOEt / heptane, 3:2), yielding the title compound as a colourless oil: tκ = 2.75 min (LC-2), ESI-MS (pos.): m/z 511.15 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.37 (s, 9H5 tBu), 1.37 (t, 3H, CH3), 2.14 (quint., 2H, CH2CH2N), 3.28 (m , 2H, SCH2), 4.30-4.40 (m, 4H), 4.69 (s, 2H, CH2CO2), 7.10 (m, 3 Harom), 7.26 (t, 1 Harotn), 7.55 (m, 2 Harom), 7.81 (t, 2 Rmom).
Precursors G-02b to G-07b of the following Table 15 are prepared using a procedure analogous to that described for Precursor G-OIb, substituting the appropriate alkylating agent for G-OId.
Formula fR [min] MS °ata MS Data
Precursor Name MoI weight (Meth.) JnJ1Jm+ m/z [M"H]+ fe/f-Butyl {2-[3-(1-oxo-1 ,3- dihydro-isoindol-2-yl)- C24H27N3O3S 2.19
G-02b 438.29 n/a propylsulfanyl]- 437.55 (LC-2) benzoimidazol-1 -yl}-acetate fe/f-Butyl {2-[3-(2-oxo-2,3-
G-03b dihydro-benzoimidazol-1 -yl)- C23H26N4O3S 2.67
439.24 437.27 propylsulfanyl]- 438.54 (LC-2) benzoimidazol-1 -yl}-acetate terf-Butyl {2-[3-(1 -oxo-1 H- phthalazin-2-yl)- C24H26N4O3S 2.67
G-04b 451.22 n/a propylsulfanyl]- 450.55 (LC-2) benzoimidazol-1 -yl}-acetate tert-Butyl {2-[3-(2,4-dioxo-1 ,4- dihydro-2/-/-quinazolin-3-yl)- C24H26N4O4S 2.21
G-05b 467.28 465.24 propylsulfanyl]- 466.55 (LC-2) benzoimidazol-1 -yl}-acetate te/t-Butyl {2-[3-(1 ,3-dioxo-1 ,3- dihydro-isoindol-2-yl)- C24H25N3O4S 6.99
G-06b 452.40 n/a propylsulfanyl]- 451.55 (LC-1) benzoimidazol-1 -yl}-acetate ferf-Butyl {2-[3-(1 ,1 ,3-trioxo-
1 ,3-dihydro-1λ6-
G-07b C23H25N3O5S2 2.73 benzo[d]isothiazol-2-yl)- 488.17 n/a 487.59 (LC-2) propylsulfanyl]- benzoimidazol-1 -yl}-acetate
Table 15
Alkylating agent G-OId
2-(3-Chloro-propyl)-3-oxo-2,3-dihydro-indazole-l-carboxylic acid ethyl ester To a solution of 3-oxo-2,3-dihydro-indazole-l-carboxylic acid ethyl ester (410 mg, 2 mmol) dissolved in dry DMF (10 ml) is added sodium hydride (60% w/w in oil, 120 mg, 3 mmol). The resulting cloudy solution is allowed to stir for 1 h at rt and is added dropwise under inert atmosphere via a syringe onto a solution of iodochloropropane (268 μl, 2.5 mmol) in dry DMF (2 ml). The resulting solution is allowed to stir at rt overnight. By addition of water and evaporation under reduced pressure most of the DMF is removed from the crude mixture. The residue is dissolved in AcOEt (25 ml) and the resulting organic phase is washed 3 times with water and once with brine. The crude product is purified by chromatography on silica gel (AcOEt / heptane, 2:3), yielding the title compound (78 mg) in 15 % as a colourless oil: fa = 2.17 min (LC-2), ESI-MS (pos.): m/z 283.05 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.38 (t, 3H, CH3), 2.08 (quint., 2H5 CH2CH2N), 3.42 (t, 2H5 CH2Cl), 4.25 (t, 2H, NCH2), 4.39 (q, 2H, OCH2CH3), 7.22 (t, 1 Harom), 7.53 (t, 1 Harom), 7.79 (t, 2 Harom), and 3-(3-chloro- propoxy)-indazole-l-carboxylic acid ethyl ester (125 mg) in 24% as a colourless oil: tR = 2.49 min (LC-2), ESI-MS (pos.): m/z 283.05 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.44 (t, 3H, CH3), 2.26 (quint., 2H, CH2CH2N), 3.71 (t, 2H, CH2Cl), 4.49 (q, 2H, OCH2CH3), 4.59 (t, 2H, OCH2CH2), 7.20 (t, 1 Harom), 7.46 (t, 1 Harom), 7.59 (d, 1 Harom), 8.02 (d, 1 Harom)- 3-(3-Chloro-propoxy)-indazole-l-carboxylic acid ethyl ester is used as alkylating agent D-06d in the preparation of Precursor D-06b.
Alkylating agents G-03d to G-07d of the following Table 16 are prepared using a procedure analogous to that described for alkylating agent G-OId, substituting the appropriate nitrogen containing heterocycle for 3-oxo-2,3-dihydro-indazole-l- carboxylic acid ethyl ester.
Alkylating N Formula tR [min] MSJ?_ata MS Data agent Name MoI weight (Meth.) ™JJJ »+ m/z [M-H]+
1-(3-Chloro-propy!)- ri nH1 i πN?n 1 87
G-03d 1 ,3-dihydro- VVn Si , Λ L 211.11 209.1 benzoimidazol-2-one 2m66 (LC"2)
G 04d 2-(3-Ch!oro-propyl)- C11H11CIN2O 2.02
G"04d 2H-phthalazin-1-one 222.67 (LC-2) 223" 1 1 n/a
3-(3-Chloro-propyl)- r1 1 H1 1 r|Monn 1 9
G-05d 1H-quinazoline-2,4- ^"V^ „ A o^ 239-06 237.05 dione 238'67 (LC'2) 2-(3-Chloro-propyl)-
1 ,1-dioxo-1 ,2-dihydro- ΛinpmπMmc o -n; 1λ - 259 71 (LC-2) 260 01 ^a benzo[d]isothiazol-3- ' ^ one
Table 16
Example H-OIa |~2-(3 -Methoxycarbonyl-benzylsulfanvD-benzoimidazol- 1 -yll -acetic acid
A solution of fer/-butyl [2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]- acetate (Precursor H-OIb, 31 mg, 0.075 mmol) in TFA / dichloromethane (1:1, 2 ml) is stirred at rt for 4 h. The solvents are removed under a stream of air. The solid residue is suspended in Et2O (2 ml) and sonicated. Filtration, rinsing with Et2O and drying under high vacuum, yields the title compound (19.6 mg) in 73% as a white solid: fø = 5.52 min (LC-I), ESI-MS (pos.): m/z 357.25 [M+H]+, ESI-MS (neg.): m/z 355.29 [M-H]+; 1H-NMR (DMSO-d6): δ (ppm) 3.83 (s, 3H, OMe), 4.65 (s, 2H, SCH2), 4.92 (s, IH, CH2CO2), 7.15-7.21 (m, 2 HaT001), 7.42-7.48 (m, 2 Harom), 7.57 (m, 1 Harom), 7.72 (d, 1
Harom), 7.81 (d, 1 Harom), 8.05 (S, 1 Harom).
Examples H-02a to H-I Ia of the following Table 17 are prepared analogous to the procedure described for Example H-OIa, using Precursors H-02b to H-I Ib in place of H-OIb.
{2-[(5-Methyloxycarbonyl- pyridin-3-yl)- ri7Hi ^t\no4S i βa
H-02a methylsulfanyl]- T™ „ V 1 358.16 356.18 benzoimidazol-1-yl}- 357'389 (LC'2) acetic acid
(2-{[(2-Chloro-4- methyloxycarbonyl)- ri 7H14Nlo04r|S 5 81
H-03a pyridin-6-yl]-methyl- C1™1 Q, R 3£4CIS .?* „ 392-05 390.13 sulfanylj-benzoimidazol- ^ ;
1-yl)-acetic acid {2~[(2-Methyloxycarbonyl- furan-5-yl)-
C17H16N2O5S 5.45
H-04a methylsulfanyl]- 360.389 (LC-1) 361.08 359.09 benzoimidazol-1-yl}- acetic acid
{2-[(2-Bromo-3- methoxycarbonyl)-
H-05a C18H15N2O4BrS 2.04 benzylsulfanyl]- 437.02 435.1 435.297 (LC-2) benzoimidazol-1 -yl}- acetic acid
{2-[(4-Bromo-3- methoxycarbonyl)-
H-06a C18H15N2O4BrS 2.06 benzylsuifanyl]- 436.95 435.297 (LC-2) 435.1 benzoimidazol-1 -yl}- acetic acid
{2-[(5-Bromo-3- methoxycarbonyl)-
C18H15N2O4BrS 2.18
H-07a benzylsulfanyl]- 437.02 435.1 435.297 (LC-2) benzoimidazol-1 -yl}- acetic acid
{2-[(6-Bromo-3- methoxycarbonyl)-
H-OSa C18H15N2O4BrS 6.02 benzylsulfanyl]- 437.05 435.03 435.297 (LC-1) benzoimidazol-1-yl}- acetic acid
{2-[(6-Methoxy~3- methoxycarbonyl)-
C19H18N2O5S 1.80
H-09a benzylsulfanyl]- 387.2 385.16 386.427 (LC-2) benzoimidazol-1 -yl}- acetic acid
[2-(3-Acetyl- benzylsulfanyl)- C18H16N2O3S 6.48
H-10a 341.16 339.14 benzoimidazol-1 -yl]-acetic 340.402 (LC-1) acid
[2-(5-Acetyl-2-methoxy- benzyisulfanyl)- C19H18N2O4S 5.03
H-11a 371.06 369.11 benzoimidazol-1 -yl]-acetic 370.428 (LC-1) acid
Table 17
Precursor H-OIb ferf-Butyl F2-C3 -methoxycarbonyl-benzylsulfanyD-benzoimidazol- 1 -yl]-acetate
A mixture of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-1, 264 mg, 1 mmol), 3-bromomethyl-benzoic acid methyl ester (252 mg, 1.1 mmol) and
K2CO3 (276 mg, 2 mmol) in acetone (4 ml) is allowed to stir at rt for 2.5 h. The suspension is cooled down to rt and filtered on a funnel filled with cotton wool.
Evaporation of the solvent in vacuo affords a residue that is purified by flash- chromatography on silica-gel (AcOEt / heptane, 1:3), yielding the title compound (310 mg) in 75% as a colourless syrup: fe = 7.19 min (LC-I), ESI-MS (pos.): m/z 413.3 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.42 (s, 9H, /Bu), 3.92 (s, 3H, OMe), 4.65 (s, 2H), 4.69 (s, IH), 7.19-7.26 (m, 3 Harom), 7.36 (t, 1 Harom), 7.59 (d, 1 H3101n), 7.73 (m, 1
Harom), 7.92 (d, 1 Harom), 8.06 (S, 1 Harom).
Precursors H-02b to H-I Ib of the following Table 18 are prepared using a procedure analogous to that described for Precursor H-OIb, substituting the appropriate alkylating agent for 5-bromo-hexanoic acid ethyl ester.
Formula fR [min]
Precursor Name MS °ata MS Data MoI weight (Meth.)
[M+H]+ m/z IM-Hl+ terf-Butyl {2-[(5- methyloxycarbonyl-pyridin-3- C21 H23N3O4S 2.21
H-02b 414.21 n/a yl)-methyisulfanyl]- 413.49 (LC-2) benzoimidazol-1 -yl}-acetate tert-Butyl (2-{[(2-chloro-4- methyloxycarbonyl)-pyridin- C21H22CIN3O4S 2.78
H-03b 448.16 n/a 6-yl]-methyl-sulfanyl}- 447.94 (LC-2) benzoimidazol-1 -yl)-acetate te/f-Butyl {2-[(2- methyloxycarbonyl-furan-5- C21 H24N2O5S 2.41
H-04b 417.21 n/a yl)-methylsulfanyl]- 416.49 (LC-2) benzoimidazol-1 -yl}-acetate terf-Butyl {2-[(2-bromo-3- methoxycarbonyl)- C22H23BrN2O4S 2.58
H-05b 493.08 n/a benzylsulfanyl]- 491.4 (LC-2) benzoimidazol-1-yl}-aceate tert-Butyl {2-[(4-bromo-3- methoxycarbonyl)- C22H23BrN2O4S 2.58
H-06b 493.08 n/a benzylsulfanyl]- 491.4 (LC-2) benzoimidazol-1 -yl}-acetate tert-Butyl {2-[(5-bromo-3- methoxycarbonyl)- C22H23BrN2O4S 2.70
H-07b 493.08 n/a benzylsulfanyl]- 491.4 (LC-2) benzoimidazol-1 -yl}-acetate tert-Butyl {2-[(6-bromo-3-
H-OSb methoxycarbonyl)- C22H23BrN2O4S 2.69
492.77 n/a benzylsulfanyl]- 491.4 (LC-2) benzoimidazol-1 -yl}-acetate tert-Butyl {2-[(6-methoxy-3- methoxycarbonyl)- C23H26N2O5S 2.82
H-09b 443.26 n/a benzylsulfanyl]- 442.53 (LC-2) benzoimidazol-1 -yl}-acetate terf-Butyl [2-(3-acetyl- C22H24N2O3S 8.31 H-IOb benzylsulfanyl)- 396.5 (LC-1) 397.22 395.22 benzoimidazol-1-yl]-acetate ferf-Butyl [2-(5-acetyl-2- C25H26N2O4S 6.86 H-11b methoxy-benzylsulfanyl)- 426.53 (LC-1) 427.00 425.14 benzoimidazol-1 -yl]-acetate
Table 18
Alkylating agent H-08d 4-Bromo-3-bromomethyl-benzoic acid methyl ester
As described in: PuIs, C; Stolle, A.; de Meijere, A., Chem. Ber. 1992, 1635-1641, and Lew, A.; Chamberlin, A. R., Bioorg. Med. Chem. Lett., 1999, 9, 3267-3272. A solution of 4-bromo-3-methyl-benzoic acid methyl ester (1 g, 4.37 mmol) and N- bromosuccinimide (855 mg, 4.8 mmol) in CCl4 (5 ml) is refluxed for 2 h. AIBN (20 mg, 0.12 mmol, 3%) is added and the mixture is refluxed for 2 h. This process is repeated twice and the reaction mixture is refluxed overnight. The solvent is evaporated and the yellow residue purified by chromatography on silica-gel (AcOEt / heptane, 1:9), yielding a (2:1) mixture of the title compound and 4-bromo-3,3-dibromomethyl- benzoic acid methyl ester as a colourless solid, which is used without further purification in the next step: tκ = 2.31 min (LC-2), ESI-MS (pos.): m/z 308.99 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 3.92 (s, 3H, OCH3), 4.60 (s, CH2Br)5 7.65 (d, 1 Harom), 7.79 (m, 1 Harom), 8.10 (d, 1 Harom).
Alkylating agents H-02d to H-09d of the following Table 19 are prepared using a procedure analogous to that described for alkylating agent H-08d, substituting the corresponding phenyl or pyridyl derivative analogue for 4-bromo-3-methyl-benzoic acid methyl ester.
Alkylating Formula tR [min] MS ?ata agent Name MoI weight (Meth.) ™jjL
5-Bromomethyl- ral ,RRrN]n;, Λ 7R
H-02d nicotinic acid methyl w.™w n ' n, 232.15 ester 230-06 (LC"2) 2-Bromomethyl-6- rou7Rrp|Mn? 9 91 H-03d chloro-isonicotinic 264 50 (LC-2} 266'08 acid methyl ester ' \ - 1
2-Bromo-3- C9H8Br2O2 2.31
H-05d bromomethyl-benzoic ^nj 07 (LC-2) 308.99 acid methyl ester
2-Bromo-5-
C9H8Br2O2 2.31
H-06d bromomethyl-benzoic 307.98 (LC-2) 308.99 acid methyl ester
U Tι " 2.45 H-Λ07dl „ brom 3o"mBerithTyl-;b5enzoi ■c C93HQ87B gr2gO2 (LC-2) 308.99 acid methyl ester
3-Bromomethyl-4- rinH1 1 R-m
2.62 H-09d methoxy-benzoic acid ," ' ,7. 259.07 (LC-2) methyl ester zoy' ι υ
Table 19
Example I-01a rac \2-( 1 -Butyryl-piperidin-3 -ylmethylsulfanvD-benzoimidazol- 1 -yll -acetic acid rac [2-(Piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid hydrochloride (Precursor I-00a, 10 mg, 0.03 mmol) is suspended in dichloromethane (1 ml) and Et3N (12.88 mg, 16.6 μl, 0.10 mmol) as well as butyryl chloride (3.42 mg, 3.35 μl, 0.04 mmol) are added subsequently. The resulting mixture is stirred for 30 min at rt. Water (1 ml) is then added and the crude acid is extracted twice with dichloromethane. The combined organic phases are washed with brine and dried over Na2SO4. Evaporation of the solvent in vacuo affords 6 mg of a brown oil. It is suspended in Et2O (1 ml) and sonicated until a solid forms. This solid is rinsed with ether and dried under vacuum, yielding the title compound (5.9 mg) in 55% as a beige solid: fo = 1.68 min (LC-2), ESI-MS (pos.): m/z 376.25 [M+H]+ 5 ESI-MS (neg.): m/z 374.21 [M-H]+; 1H-NMR (DMSO-d6, 100°C): δ (ppm) 0.86 (t, 3H9 CH2CH3), 1.27-1.44 (m, 2H), 1.54 (td, 2H, CH2CH3), 1.68 (m, IH), 1.79-1.95 (m, 2H), 2.25 (t, 2H, CH2C=O), 2.81 (bm, 2H, SCH2), 3.32 (d, 2H, CHCH2N), 3.65 (bm, 2H, CH2CH2N), 4.97 (s, 2H, CH2CO2), 7.18 (m, 2 Harom), 7.44 (m, lHarom), 7.54 (m, 1 Harom). Alternatively, Example I-01a is also synthesized starting from tert-butyl [2-(l-butyryl- piperidin-3 -ylmethylsulfanyl)-benzoimidazol- 1 -yl]-acetate (Precursor 1-01 b) : Precursor I-Olb (802 mg, 1.86 mmol) is dissolved in TFA / dichloromethane (1:1, 10 ml) and stirred overnight at rt. Evaporation of the solvents in vacuo gives an orange oil which is suspended in Et2O / heptane (1:1, 2 ml) and sonicated. After filtration, thourough rinsing with Et2O and drying, the title compound (670 mg) is obtained in 96% as a white solid.
Examples I-02a to I- 13a of the following Table 20 are prepared analogous to the procedures described for Example 1-01 a.
rac {2-[1-(2-Methoxy- benzoy!)-piperidin-3- C23H25N3O4S 1 80 l-02a ylmethylsulfanyl]- ^4 =<?* n r i\ 440-2 438-29 benzoimidazol-1 -yl}-acetic 4^-*"0 iLU-z) acid rac [2-(1-Phenylacetyl- piperidin-3- μ „ n l-03a ylmethylsulfanyl)- ^ Si n r O\ 424-21 422-3 benzoimidazol-1-yl]-acetic 4^'0* [L^> acid rac [2-(1-
Cyclohexanecarbonyl- l-04a piperidin-3- C22H29N3O3S 1.96 41 , 3 ι υ4a ylmethylsulfanyl)- 415.556 (LC-2) 4 lb^° ^ 14-"34 benzoimidazol-1 -yl]-acetic acid rac {2-[1-(3-Cyclopentyl- propionyl)-piperidin-3- l-05a ylmethylsulfanyl]- 430-26 428-35 benzoimidazol-1 -yl}-acetic acid rac [2-(1-Diphenylacetyl- piperidin-3- POQW9QN^D^^ O I R l-06a ylmethylsulfanyl)- TQQ ^-? n r n 50α28 498-3 benzoimidazol-1 -yl]-acetic 499-633 C-0"2) acid rac [2-(1-Acetyl-piperidin-
3-ylmethylsulfanyl)- C17H21N3O3S 1.51 ^ 1
1 a benzoimidazol-1 -yl]-acetic 347.438 (LC-2) άWι l0 ^b-zo acid rac [2-(1-Heptanoyl- piperioin-o- ΠOOVA^Λ MKTIQ O Λ l-08a ylmethylsulfanyl)- 418.29 416.31 benzoimidazol-1-yl]-acetic acid rac {2-[1-(3-Chloro- benzoyi)-piperidin-3- poo l-09a ylmethylsulfanyl]- 444-15 442-24 benzoimidazol-1-yl}-acetic acid rac {2-[1-(3~Phenyl- propionyl)-piperidin-3- ro4Ho7Nmoe 1 q7
MOa ylmethylsulfanyl]- 407 «0 n r ^ 438-23 436-31 benzoimidazol-1-yl}-acetic ^1 -00* K^-^) acid rac {2-[1-(Furan-2- carbonyl)-piperidin-3- r20H21 N3θ4ς 1 7R l-11a ylmethylsulfanyl]- C2 ,Q 2 T S ,, r ^ 4O0-2 398.22 benzoimidazol~1-yl}-acetic lLL*"^ acid rac {2-[1-(Naphthalene-1- carbonyl)-piperidin-3- r?fiH?ςNo0oo 1 qR l-12a ylmethylsulfanyl]- ^ CRQ MV ^ 460-2 458-29 benzoimidazol-1-yl}-acetic ^ov.ow ^υ-/) acid rac {2-[1-(4-Bromo- benzoyl)-piperidin-3- ro9H??N|oπoRrς 1 qq
M3a ylmethylsulfanyl]- C22 40« Λς r n l 490-08 n/a benzoimidazol-1-yl}-acetic 4bB-4Uδ l1-^"^) acid
Table 20
Precursor I-00a rac r2-(Piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yll-acetic acid hydrochloride To a 2M HCl solution in Et2O (2 ml) is added rac tert-butyl [2-(l-tert- butyloxycarbonyl-piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetate (Precursor I-00b, 36 mg, 0.08 mmol). The mixture is stirred for 4 h at rt. The precipitated solid is filtered and rinsed with Et2O to yield quantitatively the title compound as a slightly yellow solid.
Precursor I-00b rac tert-Butyl \2-( 1 -fert-butyloxycarbonyl-piperidm-3 - ylmethylsulfanyl)- benzoimidazol- 1 -yll -acetate tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-1, 792 mg, 3 mmol), S-hydroxymethyl-piperidine-l-carboxylic acid tert-butyl ester (838 mg, 3.9 mmol) and triphenylphosphane (1021 mg, 3.9 mmol) are dissolved and stirred under inert atmosphere at O0C in dry THF (20 ml). Di-tert-butyl-azodicarboxylate (690 mg, 3 mmol) is added under the same reaction conditions to the solution. The initially deep yellow colour disappears after 10 min. The reaction mixture is slowly allowed to warm up to rt overnight. Evaporation of the solvent in vacuo and purification upon two chromatographies on silica gel (AcOEt / heptane, 1 :4), provides the title compound (552 mg) in 38% as a colourless syrup: tR = 7.66 min (LC-I), ESI-MS (pos.): m/z 462.32 [M+H]+; 1H-NMR (DMSOd6 at 100°C): δ (ppm) 1.36 (s, 9H, tBu), 1.40 (m, 2H), 1.42 (s, 9H, tBu), 1.58 (m, IH), 1.75 (m, IH), 1.85 (m, IH), 2.85 (m, 2H, SCH2), 3.24 (m, 2H, NCH2), 3.67 (m, IH, NCH2), 3.86 (m, IH, NCH2), 4.96 (m, 2H, CH2CO2), 7.14 (m, 2 Harom), 7.46 (m, 1 Harom), 7.53 (m, 1 Harom).
Precursor 1-0 Ib rac fert-Buτyl [2-( 1 -butyryl-piperidin-3 -ylmethylsulfanylVbenzoimidazol- 1 -yll -acetate A suspension of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Precursor 3-1, 1 g, 3.79 mmol), l-(3-chloromethyl-piperidin-l-yl)-butan-l-one (alkylating agent I-01d, 771 mg, 3.79 mmol) and K2CO3 (1.05 g, 7.58 mmol) in acetone (10 ml) is refiuxed for 36 h. The crude mixture is filtered over a fritted-funnel and the solvent evaporated in vacuo. The resulting brown gum is purificated by column chromatography on silica-gel (AcOEt / heptane, 3:7 to 1 :1), yielding the title compound (802 mg) in 49% as a colourless oil: tR = 2.19 min (LC-I), ESI-MS (pos.): m/z 432.24 [M+H]+.
Alkylating agent 1-0 Id
1 -(3 -Chloromethyl-piperidin- 1 -vD-butan- 1 -one
A solution of l-(3-hydroxymethyl-piperidin-l-yl)-butan-l-one (Starting material I-Ole, 1.33 g, 7.20 mmol) in dry chloroform (10 ml) is cooled down to 00C with an ice-water bath. A solution Of SOCl2 (1.43 g, 876 μl, 12 mmol) in dry chloroform (10 ml) is added dropwise. The mixture is allowed to stir at reflux for 30 min. The solution is cooled down to rt, SOCl2 (0.48 g, 0.3 ml, 4.1 mmol) is added dropwise and the resulting solution is allowed to stir at reflux for another 30 min. Evaporation of the solvents under reduced pressure gives a brown liquid which is purified by column chromatography on silica-gel (AcOEt / heptane, 35:65), yielding the title compound (1.15 g) in 78% as a colourless liquid: 1H-NMR (CDCl3): The product is a (1:1) mixture of rotamers: δ (ppm) 0.95 (t, 3H, CH3), 1.33-1.54 (m, 2H), 1.58-1.95 (m, 3H), 1.68 (quint., IH, CH2CH2CH3), 2.32 (dd, 2H, CH2C=O), 2.60 (t, 0.5H), 2.83 (t, 0.5H), 2.99 (m, 2H), 3.36-3.55 (m, 2H), 3.77 (d, 0.5 H), 3.93 (d, 0.5 H), 4.30 (d, 0.5 H), 4.54 (d, 0.5 H).
Starting material I-Ole 1 -(3 -Hvdroxymethyl-piperidin- 1 -vD-butan- 1 -one
To a solution of piperidin-3-yl-methanol (2.3 g, 20 mmol) in water (30 ml) is slowly added NaOH (1.2 g, 30 mmol). After total dissolution butyryl chloride (2.15 g, 2.11 ml, 20.2 mmol) is slowly added dropwise. The resulting mixture is allowed to stir overnight at rt. The water phase is extracted three times with dichloromethane. The combined organic phases are washed with brine and dried over Na2SO4. The solvents are evaporated in vacuo yielding the title compound (2.48 g) in 66% as a colourless oil which solidifies on standing: tκ = 1.52 min (LC-2), ESI-MS (pos.): m/z 208.00 [M+Na]+; 1H-NMR (CDCl3): The product is a (1:1) mixture of rotamers: δ (ppm) 0.92 (t, 3H, CH3), 1.21 (m, 0.5 H), 1.33-1.52 (m, 2H), 1.57-1.84 (m, 5H), 2.26-2.32 (m, 2H, CH2C=O), 2.74 (dt, 0.5H), 2.87 (dd, 0.5H), 3.10 (dd, IH), 3.26 (ddd, IH), 3.39-3.45 (m, 1.5 H), 3.51-3.59 (m, IH), 3.91 (dd, 1 H), 4.29 (dt, 0.5 H).
Example J-OIa {2-[3-(tgrt-Butoxycarbonyl-phenethyl-amino)-propylsulfanvn-benzoimidazol-l-vU- acetic acid tert-Buty\ {2- [3 -(tert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl] - benzoimidazol-1-yl} -acetate (Precursor J-OIb, 12.7 mg, 0.025 mmol) is suspended in an aqueous 0.2 M NaOH solution (0.67 ml). After addition of THF (1.3 ml) the resulting solution is allowed to stir overnight at rt. It is then treated with IM aqueous HCl (3.35 ml), water (2 ml) and dichloromethane (3 ml). The phases are separated and the dichloromethane is removed under reduced pressure. Drying under high vacuum yields the pure title compound: fo = 2.12 min (LC-2), ESI-MS (neg.): m/z 470.47 [M- H]+; 1H-NMR (DMSOd6): δ 1.31 (s, 9H, ffiu), 1.88 (quint., 2H, SCH2CH2), 2.73 (m, 2H, CH2Ph), 3.24 (t, 2H), 3.28-3.36 (m, 4H), 4.94 (s, 2H, CH2CO2), 7.13 (m, 5 HarOm), 7.23 (t, 2 Harom), 7.42-7.50(m, 2 Harom).
Examples J-02a to J-07a of the following Table 21 are prepared analogous to the procedure described for Example J-OIa, using Precursors J-02b to J-07b in place of J- 01b.
I- m .α ,.. „ Formula fR [min] MS Data MS Data txampie Name MoI weight (Meth.) m/z [M+H]+ m/z [M-H]+
(2-{3-[ferf-Butoxycarbonyl- (4-piperidin-1-yl-phenyl)- roβHoβN4n4e - 7R
J-02a amino]-propylsulfanyl}- " ? ~WA A l 525.53 523.62 benzoimidazol-1-yl)-acetic 0Z4-ba4 VLU-ZJ acid
{2-[3-(Benzyl-fert- butoxycarbonyl-amino)- C24H29N3O4S 2 24
J-04a propylsulfanyl]- «„77 n r n 456 46 454-55 benzoimidazol-1-yl}-acetic *υo-°" ^"^ acid {2-[3-(terf-Butoxycarbonyl- cyclopropyl-amino)- r20H27N?O49 ? n<5
J-05a propylsulfanyl]- 2Tn/^ π r 1 406.38 404.47 benzoimidazol-1-yl}-acetic ^0-0 " ^-*> acid
{2-[3-(te/f-Butoxycarbonyl- phenyl-amino)- c?w?7MinΔ^ 0 1R
J-OSa propylsulfanyl]- AT, JI04S Λ ,V 442.38 440.47 benzoimidazol-1-yl}-acetic ^ 1 -00 VLW-^; acid
(2-{3-[tert-Butoxycarbonyl-
(2,2-diphenyl-ethyl)- C31 H35Noo4S 9 <si
J-07a amino]-propylsulfanyl}- ^ y09 n r ^ 546.56 544.65 benzoimidazol-1-yl)-acetic D40 /u^ ^O-ZJ acid Table 21
Precursor J-OIb tert-Butyl {2-[3-(fert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl]- benzoimidazol- 1 -yl| -acetate 2-[3-(ført-Butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazole
(Precursor J-OIc, 239 mg, 0.58 mmol), ter^-butyl bromoacetate (136 mg, 103 μl, 0.70 mmol) and cesium carbonate (227 mg, 0.70 mmol) are dissolved in dry DMF (6 ml) and allowed to stir for 1 h at rt. N-(2-Mercaptoethyl)aminomethyl polystyrene (1.4 mmol/g, 0.5 g, 0.36 mmol) is added and the crude mixture is stirred at rt for 1 h. After filtration and removal of the solvent in vacuo, the crude product is diluted in dichloromethane, washed with a 10% aqueous citric acid solution and with a saturated aqueous NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent evaporated in vacuo, yielding the title compound: tR = 2.79 min (LC-2), ESI-MS (neg.): m/z 526.61 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 1.46 (s, 18H, 2 x fflu), 2.00 (m, 2H, SCH2CH2), 2.85 (m, 2H, CH2Ph), 3.26-3.85 (m, 6H), 4.77 (s, 2H, CH2CO2), 7.44-7.59 (m, 8 Harom), 7.94 (m, 1 Harom).
Precursors J-02b to J-07b from Table 22 are prepared by a procedure analogous to that described for Precursor J-OIb, using Intermediates J-02c to J-07c in place of J-OIc.
Formula tR [min] MS ™<*
Precursor Name MoI weight (Meth.) «JJJjj+ ferf-Butyl (2-{3-[ferf- butoxycarbonyl-(4-piperidin-1 -
C32H44N4O4S 2.40
J-02b yl-phenyl)-amino]- 581.67 580.79 (LC-2) propylsulfanyl}- benzoimidazol-1 -yl)-acetate ferf-Butyl [2-(3-{[(4- ethyloxycarbonyl)-phenyl]-ferf-
C30H39N3O6S 2.75
J-03b butyloxycarbonyl-amino}- 569.72 (LC-2) 570.65 propylsulfanyl)- benzoimidazol-1 -yl]-acetate ferf-Butyl {2-[3~(benzyl-tert- butoxycarbonyl-amino)- C28H37N3O4S 2.73
J-04b 512.59 propylsulfanyl]-benzoimidazol- 511.69 (LC-2)
1-yl}-acetate ferf-Butyl {2-[3-(ferf- butoxycarbonyl-cyciopropyl- C24H35N3O4S 2.62
J-05b 462.51 amino)-propylsulfanyl]- 461.63 (LC-2) benzoimidazol-1 -yl}-acetate ferf-Butyl {2-[3-(ferf- butoxycarbonyl-phenyl- C27H35N3O4S 2.68
J-06b 498.57 amino)-propylsulfanyl]- 497.66 (LC-2) benzoimidazol-1 -yl}-acetate ferf-Butyl (2-{3-[ferf- butoxycarbonyl-(2,2-diphenyl- C35H43N3O4S 2.89
J-07b 602.70 ethyl)-amino]-propylsulfanyl}- 601.81 (LC-2) benzoimidazol-1 -yl)-acetate Table 22
Example K-OIa (2-r3-(Butoxycarbonyl-phenethyl-aminoVpropylsulfanyl]-benzoimidazol-l-vU-acetic acid
A solution of fer/-butyl {2~[3-(butoxycarbonyl-phenethyl-amino)-propylsulfanyi]- benzoimidazol-1-yl} -acetate (Precursor K-OIb, 200 mg, 0.38 rnmol) is dissolved in TFA / dichloromethane (1:1, 3 ml). The resulting solution is allowed to stir at rt overnight. The solvent is evaporated under reduced pressure and the crude product is triturated in Et2O (2 ml) until a solid forms. It is filtered, washed thoroughly with Et2O and dried under high vacuum, yielding quantitatively the title compound (179 mg) as a white powder: fe = 6.82 min (LC-I), ESI-MS (neg.): m/z 470.19 [M-H]+, ESI-MS (neg.): m/z 468.32 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 0.82 (t, 3H, CH2CH3), 1.29 (m, 2H, CH2CH3), 1.48 (quint., 2H, OCH2CH2), 1.71 (m, 2H, SCH2CH2), 2.67 (bs, 2H, PhCH2), 3.12 (m, 4H), 3.26 (bs, 2H, PhCH2CH2N), 3.94 (bs, 2H, OCH2), 4.77 (s, 2H, CH2CO2), 7.05 (s, 2 Harom), 7.08-7.18 (m ,6 Harora), 7.53 (m, 1 HarOm).
Alternatively, Example K-OIa is synthesized analogous to the procedure described for Example J-OIa, using Precursor K-OIb in place of J-OIb.
Examples K-02a to K-04a of the following Table 23 are prepared analogous to the procedures described for Example K-OIa, using Precursors K-02b to K-04b in place of K-OIb.
P I Mαmo Formula tR [min] MS Data MS Data example roame MQ| wejght {Meth.) m/z p+Hf m/z [M-H]+
{2-[3-(Benzyl- butoxycarbonyl-amino)- C24u29N3O4S 2 28
K-02a propylsulfanyl]- «« Ϊ77 n r o\ 456-52 45461 benzoimidazol-1-yl}-acetic 400 D" ^"^ acid {2-[3-(Butoxycarbonyl- cyclohexyi-amino)- C23H33N3O4S 2 39
K-03a propylsulfanyl]- ΪΛQR M Γ ^ 448.49 446.58 benzoimidazol-1-yl}-acetic 44Λ59b V-^1) acid
{2-[3-(Butoxycarbonyl- (cyclohexylmethyl)-amino)-C2 H3 _ 5Q
K-04a propylsulfanyl]- ^7^ n r n 462-57 460-60 benzoimidazol-1-yl}-acetic 4b1 bZb ^-z> acid
Table 23
Precursor K-OIb fert-Butyl {2-r3-(butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l- yl> -acetate is generally prepared analogous to the procedure described for Precursor J-OIb5 using K-OIc in place of J-OIc.
Alternatively, Precursor K-OIb is prepared starting from tert-butyl (2-mercapto- benzoimidazol-l-yl)-acetate (Intermediate 3-1):
To a suspension of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3- I, 290 mg, 1.1 mmol) and K2CO3 (304 mg, 2.2 mmol, 2 eq.) in acetone (4 ml) are added (3-chloro-propyl)-phenethyl-carbamic acid butyl ester (alkylating agent K-OId, 387 mg, 1.3 mmol) and a few crystals of potassium iodide. The resulting mixture is allowed to stir at reflux overnight. It is cooled down and filtered on a fritted funnel. Evaporation of the solvent in vacuo affords a crude oil that is purified by chromatography on silica gel (AcOEt / heptane, 15:85), yielding the title compound (210 mg) in 36% as a white solid: tR = 8.25 min (LC-I), ESI-MS (pos.): m/z 526.28 [M+H]+, ESI-MS (neg.): m/z 524.14 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 0.95 (t, 3H, CH2CH3), 1.42 (m, 2H, CH2CH3), 1.46 (s, 9H, /Bu), 1.62 (quint., 2H, OCH2CH2), 2.01 (m, 2H5 SCH2CH2), 2.85 (bs, 2H5 PhCH2), 3.34 (m, 2H)5 3.45 (m, 2H, SCH2CH2CH2N)5 4.08 (bs, 2H5 OCH2), 4.74 (s, 2H5 CH2CO2), 7.14-7.30 (m, 8 Harom),
7.64 (ms 1 Harom). Precursors K-02b to K-04b in Table 24 are prepared analogous to the procedures described for Precursor K-OIb.
MS Data
Formula tR [min]
Precursor Name MoI weight (Meth.) m/z [M+H]+ tert-Butyl {2-[3-(benzyl- butoxycarbonyl-amino)- C28H37N3O4S 2.74
K-02b 512.59 propylsulfanyl]-benzoimidazol- 511.68 (LC-2)
1-yl}-acetate tert-Butyl {2-[3- (butoxycarbonyl-cyclohexyl- C27H41 N3O4S 2.86
K-03b 504.56 amino)-propylsulfanyl]- 503.71 (LC-2) benzoimidazol-1-yl}-acetate tert-Butyl {2-[3-
(butoxycarbonyl-
C28H43N3O4S 2.96
K-04b cyclohexylmethyl-amino)-
(LC-2) propylsulfanyl]-benzoimidazol- 517.73 518.58
1-yl}-acetate
Table 24
Intermediate J-OIc
2-[3-(tgrt-Butoxycarbonyl-phenethyl-amino)-propylsulfanyll-benzoimidazole Phenethyl-carbamic acid tert-butyl ester (1107 mg, 5.0 mmol) is dissolved in dry DMF (7.75 ml). To this solution, sodium hydride (60 % w/w in oil, 302 mg, 7.55 mmol) is added under vigorous stirring and stirring is continued for 30 min. Then l-chloro-3- iodo-propane (250 mg, 5.0 mmol) is dropped into the solution followed by stirring for 2 h at rt and another hour at 50 0C. After switching off the heating and addition of sodium lH-benzoimidazole-2-thiolate (1722 mg, 10 mmol) the mixture is allowed to stir overnight at rt. All the DMF is evaporated in vacuo and the remaining crude is dissolved in DCE. This organic phase is washed twice with water, dried over Na2SO4 and evaporated to give the crude product which is purified by flash chromatography on silica gel (AcOEt / heptane, 1 :9 to 1:1), yielding the title compound (289 mg) in 14% as a colourless oil: tR = 2.24 min (LC-2), ESI-MS (pos.): m/z 412.43 [M+H]+, MS (neg.): m/z 410.46 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 1.48 (s, 9H, ffiu), 1.89 (br. s, 2H, SCH2CH2), 2.83 (t, 2H, PhCH2CH2N), 3.09 (br. s, 2H), 3.26 (br. s, IH), 3.42 (t, 2H, PhCH2CH2N), 3.47 (br. s, 2H)5 7.13-7.30 (m ,7 Harom), 7.52 (m, 2H). Intermediates J-02c to J-07c and K-OIc to K-04c of the following Table 25 are prepared using a procedure analogous to that described for Intermediate J-OIc, substituting the appropriate carbamate or amide for phenethyl-carbamic acid tert-butyl ester.
MS Data
Formula tR [min] MS Data
Intermediate Name m/z MoI weight (Meth.) m/z [M-H]+ [M+H]+
2-{3-[ferf-
Butoxycarbonyl-(4- pipeιϊdin-1-yl- C26H34N4O2S 1.84
J-02c 467.48 465.50 phenyl)-amino]- 466.648 (L.C-2) propylsulfanyl}- benzoimidazole
2-(3-{[(4- Ethyloxycarbonyl)- phenyl]-ferf-
C24H29N3O4S 2.20
J-03c butyloxycarbonyl- 456.46 454.48 455.577 (LC-2) amino}- propylsulfanyl)- benzoimidazole
2-[3-(Benzyl-ferf- butoxycarbonyl-
C22H27N3O2S 2.18
J-04c amino)- 398.38 396.46 397.541 (LC-2) propylsulfanyl]- benzoimidazole
2-[3-(terf-
Butoxycarbonyl-
C18H25N3O2S 1.96
J-05c cyclopropyl-amino)- 348.42 346.38 347.482 (LC-2) propylsulfanyl]- benzoimidazole
2-[3-(fert- Butoxycarbonyl-
C21H25N3O2S 2.13
J-06c phenyl-amino)- 384.40 382.41 383.514 (LC-2) propylsulfanyl]- benzoimidazole
2-{3-[fert- Butoxycarbonyl-(2,2- diphenyl-ethyl)- C29H33N3O2S 2.44
J-07c 488.44 486.53 amino]- 487.666 (LC-2) propylsulfanyl}- benzoimidazole
2-[3-
(Butoxycarbonyl-
C23H29N3O2S 2.23
K-01C phenethyl-amino)- 412.37 410.52 411.56 (LC-2) propylsulfanyl]- benzoimidazole 2-[3-(Benzyl-
K-O2C bUl0Sryl' C22S™5f2S Λ" 398.43 396.44 propyisulfanyl]- v ' benzoimidazole
2-[3-
(Butoxycarbonyl- C2I H31 N3O2S 2 26
K-03c cyclohexyl-amino)- 309 55 ,fc 2) 390 39 388-48 propyisulfanyl]- " \ ~ > benzoimidazole
2-{3-
[Butoxycarbonyl-
K 04c (cyclohexylmethyl)- C22H33N3O2S 2.41
*"υ4C amino]- 403.58 (LC-2) 4U4"4' 4U2 bb propylsulfanyl}- benzoimidazole
Table 25
Alkylating agent K-OId O-Chloro-propyD-phenethyl-carbamic acid butyl ester
To a solution of phenethyl-carbamic acid butyl ester (3.9 g, 17.64 mmol) in dry DMF (20 ml) cooled to 00C with an ice-water bath is added sodium hydride (60% w/w in oil, 705 mg, 17.64 mmol). After addition is complete the resulting slurry is allowed to stir at rt for 30 min. It is then cooled down to O0C again and iodochloropropane (9.0 g, 4.73 ml, 44.1 mmol) is added over 5 min. The slurry is allowed to stir at rt overnight. Water is added until pH=7 and the water phase is extracted twice with AcOEt. The combined organic phases are washed with water / brine (1:1) and dried over MgSO4. The solvent is evaporated in vacuo to afford 5 g of a yellow oil containing some DMF. It is purified by flash chromatography on silica-gel (AcOEt / heptane, 1 :1), yielding the title compound (1.45 g) in 30% as a colourless oil: tR = 7.77 min (LC-I), ESI-MS (pos.): m/z 298.18 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 0.96 (t, 3H, CH3), 1.40 (m, 2H, CH2CH2), 1.64 (m, 2H, CH2CH2), 1.99 (m, 2H, CH2CH2N), 2.87 (m, 2H, CH2Ph), 3.32 (m, 2H, CH2N), 3.46-3.53 (m, 4H), 7.16-7.22 (m, 3 HarOm), 7.24-7.32 (m, 3 Harom).
Example Q-OIa
{2-[3-(Pentanoyl-phenethyl-amino)-propylsulfanyll-benzoimidazol-l-yll-acetic A solution of tert-bvdyl {2-[3-(pentanoyl-ρhenethyl-amino)-propylsulfanyl]- benzoimidazol-l-yl}-acetate (Precursor Q-OIb, 5.5 mg, 0.01 mmol) in TFA / dichloromethane (1:1, 1.5 ml) is stirred for 3 h at rt. Toluene (2 ml) is added in the reaction mixture and the solvents are evaporated in vacuo yielding the title compound: tκ = 2.17 min (LC-2), ESI-MS (pos.): m/z 454.55 [M+H]+, ESI-MS (neg.): m/z 452.57 [M-H]+; 1H-NMR (DMSOd6 at 10O0C): δ (ppm) 0.80 (t, 3H, CH2CH3), 1.19 (m, 2H, CH2CH3), 1.31-1.46 (m, 2H, CH2CH2CH3), 1.93 (m, 2H, CH2CH2N), 2.09 (m, IH, COCHa), 2.27 (m, IH, COCHb), 2.71-2.81 (m, 2H, CH2Ph), 3.24-3.34 (m, 2H), 3.37- 3.51 (m, 4H), 5.01 (m, 2H, CH2CO2), 7.15-7.28 (m ,7 Harom), 7.53 (m, 2 Harom).
All the Examples of the following Table 26 are prepared analogous to the procedure described for Example Q-OIa, using the appropriate Precursor in place of Q-OIb.
Formula tR [min] MS Data MS Data
Example Name MoI weight (Meth.) JJJJji* m/z [M-H]+
{2-[3-(Pentanoyl-phenyl- amino)-propylsuifanyl]- C23H27N3O3S 2.15
L-OIa 426.45 424.54 benzoimidazol-1-yl}-acetic 425.551 (LC-2) acid
{2-[3-(Diphenylacetyl-phenyl- amino)-propylsulfanyl]- C32H29N3O3S 2.40
L-02a 536.49 535.64 benzoimidazol-1 -yl}-acetic 535.666 (LC-2) acid
{2-[3-(Phenyl-phenylacetyl- amino)-propylsulfanyl]- C26H25N3O3S 2.13
L-03a 460.41 458.56 benzoimidazol-1 -yl}-acetic 459.569 (LC-2) acid
(2-{3-[(3,3-diphenyl- propionyl)-phenyl-amino]-
C33H31N3O3S 2.39
L-04a propylsulfanyl}- 550.57 548.66 549.693 (LC-2) benzoimidazol-1 -yl)-acetic acid;
{2-[3-(Benzenesulfonyl- phenyl-amino)-propylsulfanyl]- C24H23N3O4S2 2.12
L-05a 482.45 480.48 benzoimidazol-1 -yl}-acetic 481.596 (LC-2) acid rac (2-{3-[(2-Cyclohexyl-2- phenyl-acetyl)-phenyl-amino]- C32H35N3O3S 2.65
L-06a propylsulfanyl}- 542.54 540.7 541.714 (LC-2) benzoimidazol-1 -yl)-acetic acid
{2-[3-(1 ,3-Diphenyl-ureido)- propylsulfanyl]- C25H24N4O3S 2.04
L-07a 461.43 459.58 benzoimidazol-1 -yl}-acetic 460.557 (LC-2) acid {2-[3-(3-Benzyl-1 -phenyl- ureido)-propylsulfanyl]- C26H26N4O3S 2.02
L-08a 475.51 473.53 benzoimidazol-1 -yl}-acetic 474.583 (LC-2) acid
(2-{3-[Pentanoyl-(4-piperidin- 1-yl-phenyl)-amino]-
C28H36N4O3S 1.99
M-OIa propylsulfanyl}- 509.53 507.62 508.685 (LC-2) benzoimidazol-1 -yl)-acetic acid
(2-{3-[Diphenylacetyl-(4- piperidin-1 -yl-phenyl)-amino]-
C37H38N4O3S 2.41
M-02a propylsulfanyl}- 619.66 617.74 618.8 (LC-2) benzoimidazol-1-yl)-acetic acid
(2-{3-[Phenylmethanesulfonyl-
(4-piperϊdin~1-yl-phenyl)-
C30H34N4O4S2 1.99
M-03a amino]-propylsulfanyl}- 579.57 577.66 578.756 (LC-2) benzoimidazol-1 -yl)-acetic acid
(2-{3-[Phenylacetyl-(4- piperidin-1 -yl-phenyl)-amino]-
C31 H34N4O3S 2.03
M-04a propylsulfanyi}- 543.56 n/a 542.702 (LC-2) benzoimidazol-1 -yl)-acetic acid
(2-{3-[(3,3-Diphenyl- propionyl)-(4-piperidin-1 -yl- phenyl)-amino]- C38H40N4O3S 2.41
M-05a 633.68 631.76 propylsulfanyl}- 632.827 (LC-2) benzoimidazol-1-yl)-acetic acid
(2-{3-t1-(4-Piperidin-1-yl- phenyl)-3-propyl-ureido]~
C27H35N5O3S 1.68
M-06a propylsulfanyl}- 510.55 508.64 509.673 (LC-2) benzoimidazol-1 -yl)-acetic acid
(2-{3-[Benzenesulfonyl-(4- piperidin-1-yl-phenyl)-amino]- C29H32N4O4S2 2.01
M-07a propylsulfanyl}- 5β4 72g ., c ,. 565.55 563.57 benzoimidazol-1-yl)-acetic ∞^- ^» ^υ z.) acid
[2-(3-{[(4-Ethyloxycarbonyl)- phenyl]-pentanoyl-amino}-
C26H31 N3O5S 2.21 N-01a propylsulfanyl)- 498.51 496.6 497.614 (LC-2) benzoimidazol-1 -yl]-acetic acid
[2-(3-{Diphenylacetyl-[(4- ethyloxycarbonyl)-phenyl]-
C35H33N3O5S 2.47
N-02a amino}-propylsulfanyl)- 608.63 606.72 607.729 (LC-2) benzoimidazol-1 -yl]-acetic acid (2-{3-[(4-
Ethyloxycarbonylphenyl)- (phenylacetyl)-amino]- C29H29N3O5S 2.22
N-03a 532.48 530.56 propylsulfanyl}- 531.631 (LC-2) benzoimidazol-1 -yl)-acetic acid
[2-(3-{Diphenylpropionyl-[(4- ethyloxycarbonyl)-phenyl]-
C36H35N3O5S 2.45
N-04a amino}-propylsulfanyl)- 621.756 (LC-2) 622.65 620.67 benzoimidazol-1 -yl]-acetic acid rac [2-(3-{(2-Cyciohexyl-2- phenyl-acetyl)-[(4- ethyloxycarbonyl)-phenyl]- C35H39N3O5S 2.71
N-05a amino}-propylsulfanyl)- 613.777 (LC-2) 614.62 612.71 benzoimidazol-1 -yl]-acetic acid
{2-[3-(Benzyl-pentanoyl- amino)-propylsuifanyl]- C24H29N3O3S 2.10
O-01a 440.47 438.55 benzoimidazol-1-yl}-acetic 439.578 (LC-2) acid
{2-[3-(Benzyl-diphenylacetyl- amino)-propylsulfanyl]- C33H31 N3O3S 2.38
O-02a 550.51 548.66 benzoimidazol-1 -yl}-acetic 549.693 (LC-2) acid
{2-[3-(Benzyl-
(phenylmethanesulfonyl)-
O-03a C26H27N3O4S2 2.20 amino)-propylsuifanyi]- 509.649 (LC-2) 510.43 508.58 benzoimidazol-1 -yl}-acetic acid
{2-[3-(Benzyl-(phenylacetyl)- amino)-propylsulfanyl]- C27H27N3O3S 2.11
O-04a 474.49 472.58 benzoimidazol-1-yl}-acetic 473.595 (LC-2) acid
(2-{3-[Benzyl-(3,3-diphenyl- propionylj-amino]-
C34H33N3O3S 2.37
O-05a propylsulfanyl}- 564.59 562.62 563.72 (LC-2) benzoimidazol-1 -yl)-acetic acid
{2-[3-( 1 -Benzy l-3-propyl- ureido)-propylsulfanyl]- C23H28N4O3S 1.93
O-06a benzoimidazol-1 -yl}-acetic 440.566 (LC-2) 441.48 439.57 acid
{2-[3-(Benzenesulfonyl- benzyl-amino)-propylsulfanyi]- C25H25N3O4S2 2.20
O-07a benzoimidazol-1-yl}-acetic 495.622 (LC-2) 496.41 494.5 acid rac (2-{3-[Benzyl-(2- cyclohexyl-2-phenyl-acetyl)-
C33H37N3O3S 2.58
O-08a amino]-propylsulfanyl}- 555.741 (LC-2) 556.56 554.72 benzoimidazol-1-yl)-acetic acid
{2-[3-(Cyclopropyl-pentanoyl- amino)-propylsulfanyl]- C20H27N3O3S 1.93
P-OIa 390.46 388.48 benzoimidazol-1-yl}-acetic 389.518 (LC-2) acid
(2-{3-[(Butane-1-sulfonyl)- cyclopropyl-amino]-
C19H27N3O4S2 1.96
P-02a propylsulfanyl}- 426.39 424.47 425.572 (LC-2) benzoimidazol-1-yl)-acetic acid
{2-[3-(Cyclopropyl- diphenylacetyl-amino)-
C29H29N3O3S 2.25
P-03a propylsulfanyl]- 500.49 498.57 499.633 (LC-2) benzoimidazol-1 -yl}-acetic acid
{2-[3-(Cyclopropyl-
(phenylmethanesulfonyl)-
C22H25N3O4S2 1.99
P-04a amino)-propylsulfanyl]- 460.41 458.5 459.589 (LC-2) benzoimidazol-1 -yl}-acetic acid
{2-[3-(Cyclopropyl- (phenylacetyl)-amino)-
C23H25N3O3S 1.94
P-05a propylsulfanyl]- 424.41 422.5 423.536 (LC-2) benzoimidazol-1 -yl}-acetic acid
(2-{3-[Cyclopropyl-(3,3- diphenyl-propionyl)-amino]-
C30H31 N3O3S 2.23
P-06a propylsulfanyl}- 513.66 (LC-2) 514.51 512.66 benzoimidazol-1 -yl)-acetic acid
{2-[3-(1-Cyclopropyl-3-propyl- ureido)-propylsulfanyl]- C19H26N4O3S 1.71
P-07a 391.41 389.5 benzoimidazol-1-yl}-acetic 390.506 (LC-2) acid
{2-[3-(Benzenesulfonyl- cyclopropyl-amino)-
C21H23N3O4S2 2.06
P-08a propylsulfanyl]- 446.45 444.48 445.563 (LC-2) benzoimidazol-1 -yl}-acetic acid rac (2-{3-[(2-Cyclohexyl-2- phenyl-acetyl)-cyclopropyl- C29H35N3O3S 2.48
P-09a amino]-propylsulfanyl}- 505.681 (LC-2) 506.60 504.63 benzoimidazol-1 -yl)-acetic acid (2-{3-[(Butane-1 -sulfonyl)- phenethyl-amino]-
C24H31N3O4S2 2.25 Q-02a propylsulfanyl}- 490.55 488.51 489.659 (LC-2) benzoimidazol-1 -yl)-acetic acid
{2-[3-(Diphenylacetyl- phenethyl-amino)-
C34H33N3O3S 2.42 Q-03a propylsulfanyl]- 564.66 562.62 563.72 (LC-2) benzoimidazol-1 -yl}-acetic acid
{2-[3-(phenethyl-
(phenylmethanesulfonyl)-
C27H29N3O4S2 2.26
Q-04a amino)-propylsulfanyl]- 523.676 (LC-2) 524.57 522.53 benzoimidazol-1 -yl}-acetic acid;
{2-[3~(Phenethyl- (phenylacetyl)amino)-
C28H29N3O3S 2.17 Q-05a propylsulfanyl]- 488.57 486.53 487.622 (LC-2) benzoimidazol-1 -yl}-acetic acid
(2-{3-[(3,3-Diphenyl- propionyl)-phenethyl-amino]-
C35H35N3O3S 2.42 Q-06a propylsulfanyl}- 578.68 576.64 577.747 (LC-2) benzoimidazol-1 -yl)-acetic acid
{2-[3-(1 -Phenethyl-3-propyl- ureido)-propylsulfanyl]- C24H30N4O3S 2.00
Q-07a 455.57 453.53 b6nzoimidazol-1 -yl}-acetic 454.593 (LC-2) acid
{2-[3-(Benzenesulfonyl- phenethyl-amino)-
C26H27N3O4S2 2.27 Q-08a propylsuifanyl]- 510.55 508.52 509.649 (LC-2) benzoimidazol-1 -yl}-acetic acid
(2-{3-[(2,2-Diphenyl-ethyl)- pentanoyl-amino]-
C31H35N3O3S 2.37 R-OIa propylsulfanyl}- 530.69 528.65 529.703 (LC-2) benzoimidazol-1 -yl)-acetic acid
(2-{3-[Diphenyiacetyl-(2,2- diphenyl-ethyl)-amino]-
C40H37N3O3S 2.59 R-02a propylsulfanyl}- 640.75 638.71 639.818 (LC-2) benzoimidazol-1 -yl)-acetic acid
(2-{3-[(2,2-Diphenyl-ethyl)-
(phenylmethanesulfonyl)-
C33H33N3O4S2 2.43
R-03a amino]-propylsulfanyl}- 600.66 598.62 599.774 (LC-2) benzoimidazol-1 -yl)-acetic acid (2-{3-[(2,2-Diphenyl-ethyl)- (phenylacetyl)-amino]-
C34H33N3O3S 2.38
R-04a propylsulfanyl}- 563.72 564.66 562.62 (LC-2) benzoimidazol-1 -yl)-acetic acid
(2-{3-[(2,2-Diphenyl-ethyl)-
(3, 3-diphenyl-propionyl)-
C41H39N3O3S
R-05a 2.58 amino]-propylsulfanyl}- 653.845 654.83 652.73 (LC-2) benzoimidazol-1 -yl)-acetic acid
(2-{3-[1 -(2,2-Diphenyl-ethyl)-
3-propyl-ureido]-
C30H34N4O3S 2.22
R-06a propylsulfanyl}- 531.65 529.61 530.691 (LC-2) benzoimidazol-1 -yl)-acetic acid
[2-(3-Pentanoylamino- propylsulfanyl)- C17H23N3O3S 1.62
T-02a 350.45 348.42 benzoimidazol-1 -yl]-acetic 349.454 (LC-2) acid
{2-[3-(Butane-1- sulfonylamino)-
C16H23N3O4S2 1.73
T-03a propylsulfanylj- 386.44 384.4 385.508 (LC-2) benzoimidazol-1 -yl}-acetic acid
[2-(3-Diphenylacetylamino- propylsulfanyl)- C26H25N3O3S 2.05
T-04a 460.53 458.56 benzoimidazol-1 -yi]-acetic 459.569 (LC-2) acid
[2-(3- Phenylmethanesulfonylamino- C19H21 N3O4S2 1 J8
T-05a propylsulfanyl)- 419 525 420.46 418.42
(LC-2) benzoimidazol-1 -yl]-acetic acid
[2-(3-Phenylacetylamino- propylsulfanyl)- C20H21N3O3S 1.67
T-06a 384.47 382.43 benzoimidazol-1 -yl]-acetic 383.471 (LC-2) acid
{2-[3-(3,3-Diphenyl- propionylamino)-
C27H27N3O3S 2.02
T-07a propylsulfanyl]- 473.595 (LC-2) 474.55 472.58 benzoimidazol-1-yl}-acetic acid
{2-[3-(3-Propyl-ureido)- propylsulfanyl]- C16H22N4O3S 1.47
T-08a 351.47 349.43 benzoimidazol-1 -yl}-acetic 350.442 (LC-2) acid
[2-(3-Benzenesulfonylamino- propylsuifanyl)- C18H19N3O4S2 1.76
T-09a 406.44 404.41 benzoimidazol-1 -yl]-acetic 405.498 (LC-2) acid rac {2-[3-(2-Cyclohexyl-2- phenyl-acetylamino)-
C26H31N3O3S 2.23
T-IOa propylsulfanyl]- 465.616 (LC-2) 466.65 464.55 benzoimidazol-1-yl}-acetic acid
{2-[3-(3-Phenyl-ureido)- propylsulfanyl]- C19H20N4O3S 1.67
T-11a 385.49 383.38 benzoimidazol-1 -yl}-acetic 384.459 (LC-2) acid
[2-(3-Benzoylamino- propylsulfanyl)- C19H19N3O3S 2.27
T-12a 370.28 368.36 benzoimidazol-1 -yl]-acetic 369.444 (LC-2) acid
{2-[3-(Cyc)ohexanecarbonyl- amino)-propylsulfanyl]- C19H25N3O3S 1.75
T-13a 376.38 374.39 benzoimidazol-1-yl}-acetic 375.492 (LC-2) acid
{2-[3-(4-Methoxy- benzoylamino)-
C20H21N3O4S 1.68
T-14a propylsulfanyl]- 400.31 399.47 399.47 (LC-2) benzoimidazol-1 -yl}-acetic acid
(2-{3-[(Furan-2-carbonyl)- amino]-propyisulfanyl}- C17H17N3O4S 1.51
T-15a 360.27 358.29 benzoimidazol-1 -yl)-acetic 359.405 (LC-2) acid
{2-[3-(Cyclopropanecarbonyl- amino)-propylsu)fanyl]- C16H19N3O3S 1.42
T-16a 334.29 332.37 benzoimidazol-1-yl}-acetic 333.411 (LC-2) acid
(2-{3-[(Naphthalene-1- carbonyl)-amino]-
C23H21 N3O3S 1.88
T-17a propylsulfanyl}- 420.33 418.40 419.504 (LC-2) benzoimidazol-1 -yl)-acetic acid
{2-[3-(3-Cyclopentyl- propioπylamino)-
C20H27N3O3S 2.08
T-18a propylsulfanyl]- 390.36 n/a 389.518 (LC-2) benzoimidazol-1-yl}-acetic acid
{2-[3-(2,2-Dimethyl- propionylamino)-
C17H23N3O3S 1.61
T-19a propylsulfanyl]- 350.33 348.41 349.454 (LC-2) benzoimidazol-1 -yl}-acetic acid
{2-[3-(3-Phenyl- acryloylamino)-
C21H21 N3O3S 1.80
T-20a propylsulfanylj- 396.27 394.41 395.482 (LC-2) benzoimidazol-1 -yl}-acetic acid {2-[3-(3-Phenyl- propionylamino)- C21H23N3O3S 1 74
T-21a propylsulfanyl]- ?Q7 ?QR n r o\ 398-32 396-39 benzoimidazol-1-yl}-acetic M*»O (^-Z) acid
{2-[3-(1 ,2-Dioxo-2-ethyloxy-
T 9,_ ethylamino ))--pprrooppylsulfanyi]- C16H19N3O5S 1.50 - . r"ZZa benzoimid aazzooll--11-ylJ-acetic 365.409 (LC-2) 366 24 364"32 acid
(2-{3-[(Biphenyl-4-carbonyl)- T 23 amino]-propylsulfanyl}- C25H23N3O3S 2.09 a benzoimidazol-1-yl)-acetic 445.542 (LC-2) ^°-άZ 444-40 acid
(2-{3-[(Pyridine-3-carbonyl)-
T 94_ amino]-p 'rrooppyyllss ulfanyl}- C18H18N4O3S 1.34 Λ ... Q „
1 a benzoimida azzooll--11-yl)-acetic 370.432 (LC-2) "" ^ 1 ^9-"3" acid
{2-[3-(3,3-Dimethyl- yryiamino)-propylsulfanyl]- C18H25N3O3S 1.70
T-25a but benzoimidazol-1 -yl}-acetic 363.481 (LC-2) 364.38 362.39 acid
[2-(3-Octanoylamino- propylsulfanyl)- C20H29N3O3S 2.03
T-26a benzoimidazol-1 -yl]-acetic 391.534 (LC-2) 392.42 390.43 acid
{2-[3-(4-Bromo- benzoylamino)-
T-27a C19H18BrN3O3S 1.90 propylsulfanylj- 448.34 (LC-2) 450.23 448.31 benzoimidazol-1 -yl}-acetic acid
Table 26
Precursor Q-OIb fert-Butyl {2-r3-(pentanoyl-phenethyl-amino)-propylsulfanyll-benzoimidazol-l-vU- acetate
[3 -( 1 -ferf-Butoxycarbonylmethyl- l#-benzoimidazol-2-ylsulfanyl)-propyl] -phenethyl- ammonium chloride (Precursor U-OIb, 11.6 mg, 0.025 mmol) and Et3N (12.2 mg, 17.2 μl, 0.1 mmol) are dissolved in 1,2-dichloroethane (0.2 ml). To this solution is added valerylchloride (9 mg, 8.95 μl, 0.075 mmol) and the stirring is continued for 2 h. Then 1,2-dichloroethane (0.4 ml) and tris-(2-aminoethyl) amine polystyrene (3.4 mmol/g, 22 mg, 0.075 mmol) are added. After 30 min of shaking the resin is filtered off. Then niethylisocyanate polystyrene (2.5 mmol/g, 30 mg, 0.075 mmol) is added as well as 1,2-dichloroethane (0.5 ml) and the resulting suspension is stirred for 2 h. It is filtered and the organic filtrate is washed with an aqueous KH2PO4 solution (pH = 4) and water. Finally the organic phase is dried over Na2SO4 and evaporated to dryness yielding the title compound: tR = 2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+; 1H-NMR (DMSO-d6 at 100°C): δ (ppm) 0.80 (t, 3H, CH2CH3), 1.19 (m, 2H, CH2CH3), 1.37 (m, 2H, CH2CH2CH3), 1.40 (s, 9H, /Bu), 1.91 (m, 2H, CH2CH2N), 2.08 (m, IH, COCHa), 2.24 (m, IH, COCHb), 2.71-2.83 (m, 2H, CH2Ph), 3.30 (m, 2H), 3.32-3.43 (m, 4H), 4.98 (m, 2H, CH2CO2), 7.12-7.26 (m, 7 Harom), 7.50 (m, 2 Harom).
Alternatively, Precursor Q-OIb is synthesized analogous to the procedure described for Precursor K-OIb, using alkylating agent Q-OId in place of K-OId.
All the Precursors of the following Table 27 are prepared analogous to the procedures described for Precursor Q-O Ib.
MS Data
Formula tR [min]
Precursor Name m/z
MoI weight (Meth.) [M+H]+ terf-Butyl {2-[3-(pentanoyl-
C27H35N3O3S 2.63
L-OIb phenyl-amino)-propylsulfanyl]- 482.45
481.66 (LC-2) benzoimidazol-1-yl}-acetate terf-Butyl {2-[3-
(diphenylacetyl-phenyl- C36H37N3O3S 2.79
L-02b 592.57 amino)-propylsulfanyl]- 591.77 (LC-2) benzoimidazol-1 -yl}-acetate terf-Butyl {2-[3-(phenyl- phenylacetyl-amino)- C30H33N3O3S 2.59
L-03b 516.48 propylsulfanyl]-benzoimidazol- 515.67 (LC-2)
1-yl}-acetate terf-Butyl (2-{3-[(3,3-diphenyl- propionyl)-phenyl-amino]- C37H39N3O3S 2.78
L-04b 506.59 propylsulfanyl}-benzoimidazol- 605.80 (LC-2)
1-yl)-acetate terf-Butyl {2-[3-
(benzenesulfonyl-phenyl- C28H31 N3O4S2 2.57
L-05b amino)-propylsulfanyl]- 537.70 (LC-2) 538.40 benzoimidazol-1 -yl}-acetate rac terf-Butyl (2-{3-[(2- cyclohexyl-2-phenyl-acetyl)- C36H43N3O3S 3.02
L-06b 598.62 phenyl-amino]-propylsulfanyl}- 597.82 (LC-2) benzoimidazol-1 -y|)~acetate tert-Butyl {2-[3-(1 ,3-diphenyl-
C29H32N4O3S 2.51
L-07b ureido)-propylsulfanyl]- 516.66 (LC-2) 517.44 benzoimidazol-1 -yl}-acetate tert-Butyl {2-[3-(3-benzyl-1- C30H34N4O3S
L-08b 2.48 phenyl-ureido)-propylsulfanyl]- 530.69 531.46 (LC-2) benzoimidazol-1-yl}-acetate ferf-Butyl (2-{3-[pentanoyl-(4- piperidin-1 -yl-phenyl)-amino]- C32H44N4O3S
M-OIb 2.66
565.61 propylsulfanyl}-benzoimidazol- 564.79 (LC-2)
1-yl)-acetate tert-Butyl (2-{3- [diphenylacetyl-(4-piperidin-1 -
C41 H46N4O3S 2.90
M-02b yl-phenyl)-amino]- 675.67 674.91 (LC-2) propylsulfanyl}-benzoimidazol-
1-yl)-acetate tert-Butyl (2-{3-
[phenylmethanesulfonyl-(4- C34U42M40482
M-03b 2.54 piperidin-1-yl-phenyl)-amino]- 634 g6 635.59 (LC-2) propylsulfanyl}-benzoimidazol- 1-yl)-acetate fe/f-Butyl (2-{3-[phenylacetyl-
(4-piperidin-1 -yl-phenyl)- C35H42N4O3S
M-04b 2.64
599.64 amino]-propylsulfanyl}- 598.81 (LC-2) benzoimidazol-1 -yl)-acetate tert-Butyl (2-{3-[(3,3-diphenyl- propionyi)-(4-piperidin-1 -yl-
C42H48N4O3S 2.90
M-05b phenyl)-amino]~ 688.93 (LC-2) 689.70 propylsulfanylj-benzoimidazol-
1-yl)-acetate terf-Butyl (2-{3-[1-(4-piperidin-
M-06b 1 -yl-phenyl)-3-propy!-ureido]- C31 H43N5O3S 2.30
566.63 propylsulfanyl}-benzoimidazol- 565.78 (LC-2)
1-yl)-acetate tert-Butyl (2-{3- [benzenesulfonyl-(4-piperidin-
C33H40N4O4S2 2.60
M-07b 1-yl-phenyl)-amino]- 621.57 620.84 (LC-2) propylsulfanyl}-benzoimidazol-
1-yl)-acetate terf-Butyl [2-(3-{[(4- ethyloxycarbonyl)-phenyl]-
C30H39N3O5S 2.67
N-OIb pentanoyl-amino}- 554.52 553.72 (LC-2) propylsulfanyl)-benzoimidazol-
1-yl]-acetate tert-Butyl [2-(3-
{diphenylacetyl-[(4-
C39H41 N3O5S 2.83
N-02b ethyloxycarbonyl)-phenyl]- 663.84 664.65 (LC-2) amino}~propylsu!fanyl)- benzoimidazol-1 -yl]-acetate terf-Butyl (2-{3-[(4- ethyloxycarbonylphenyl)-
N-03b C33H37N3O5S 2.64
(phenylacetyl)-amino]- 588.56 587.74 (LC-2) propylsulfanyl}-benzoimidazol-
1-yl)-acetate terf-Butyl [2-(3- {diphenylpropionyl-[(4-
N-04b C40H43N3O5S 2.83 ethyloxycarbonyl)-phenyl]- 678.67 677.86 (LC-2) aminoj-propylsulfanyl)- benzoimidazol-1 -yl]-acetate rac terf-Butyl [2-(3-{(2- cyclohexyl-2-phenyl-acetyl)-
N-05b C39H47N3O5S 3.07
[(4-ethyloxycarbonyl)-phenyl]- 670.70 669.88 (LC-2) amino}-propylsulfanyl)- benzoimidazol-1 -yl]-acetate terf-Butyl {2-[3-(benzyl- pentanoyl-amino)- C28H37N3O3S 2.59
O-01b 496.47 propylsulfanylj-benzoimidazol- 495.69 (LC-2)
1-yl}-acetate fert-Butyl {2-[3-(benzyl- diphenylacetyl-amino)- C37H39N3O3S 2.78
O-02b propylsulfanylj-benzoimidazol- 605.80 (LC-2) 606.59
1-yl}-acetate fert-Butyl {2-[3-(benzyl- phenylmethanesulfonyl- C30H35N3O4S2 2.61
O-03b 566.51 amino)-propylsulfanyl]- 565.76 (LC-2) benzoimidazol-1 -yl}-acetate fert-Butyl {2-[3-(benzyl- phenylacetyl-amino)- C31H35N3O3S 2.57
O-04b 530.50 propylsulfanyl]-benzoimidazol- 529.70 (LC-2)
1-yl}-acetate fert-Butyl (2-{3-[benzyl-(3,3- diphenyl-propionyl)-amino]- C38H41 N3O3S 2.76
O-05b 620.61 propylsulfanylj-benzoimidazol- 619.83 (LC-2)
1-yl)-acetate fert-Butyl {2-[3-(1-benzyl-3-
C27H36N4O3S 2.42
O-06b propyl-ureido)-propylsulfanyl]- 497.49 496.67 (LC-2) benzoimidazol-1 -yl}-acetate fert-Butyl {2-[3-
(benzenesulfonyl-benzyl- C29H33N3O4S2 2.63
O-07b 552.49 amino)-propylsulfanyl]- 551.73 (LC-2) benzoimidazol-1 -yl}-acetate rac ferf-Butyl(2-{3-[benzyl-(2- cyclohexyl-2-phenyl-acetyl)- C37H45N3O3S 2.96
O-08b 612.64 amino]-propylsulfanyl}- 611.85 (LC-2) benzoimidazol-1 -yl)-acetate fert-Butyl {2-[3-(cyclopropyl- pentanoyl-amino)- C24H35N3O3S 2.48
P-OIb 440.34 propylsulfanyl]-benzoimidazol- 445.63 (LC-2)
1-yl}-acetate terf-Butyl (2-{3~[(butane-1- sulfonyl)-cyclopropyl-amino]- C23H35N3O4S2 2.48
P-02b 482.45 propylsulfanyl}-benzoimidazol- 481.68 (LC-2)
1-yl)-acetate fert-Butyl {2-[3-(cyclopropyl- diphenylacetyl-amino)- C33H37N3O3S 2.68
P-03b 556.56 propylsulfanyO-benzoimidazol- 555.74 (LC-2)
1-yl}-acetate ferf-Butyl {2-[3-(cyclopropyl- phenylmethanesulfonyl- C26H33N3O4S2 2.50
P-04b amino)-propylsulfanyl]- 515.70 (LC-2) 516.42 benzoimidazol-1 -yl}-acetate fert-Butyl {2-[3-(cyclopropyl- phenylacetyl-amino)- C27H33N3O3S 2.45
P-05b propylsulfanyl]-benzoimidazol- 479.64 (LC-2) 480.41 1-y|}-acetate ferf-Butyl (2-{3-[cyclopropyl-
(3,3-diphenyl-propionyl)- C34H39N3O3S 2.67
P-06b 570.58 amino]-propylsulfanyl}- 569.77 (LC-2) benzoimidazol-1 -yl)-acetate ferf-Butyl {2-[3-(1-cyclopropyl-
3-propyl-ureido)- C23H34N4O3S 2.30
P-07b 447.47 propylsulfanyl]-benzoimidazol- 446.61 (LC-2) 1-yl}-acetate fert-Butyl {2-[3- (benzenesulfonyi-cyclopropyl- C25H31 N3O4S2 2.50
P-08b 502.40 amino)-propylsulfanyi]- 501.67 (LC-2) benzoimidazol-1 -yl}-acetate rac tert-Butyl (2-{3-[(2- cyclohexyl-2-phenyl-acetyl)-
C33H43N3O3S 2.90
P-09b cyclopropyl-amino]- 562.62 561.79 (LC-2) propylsulfanylj-benzoimidazol-
1-yl)-acetate ferf-Butyl (2-{3-[(butane-1- sulfonyl)-phenethyl-amino]- C28H39N3O4S2 2.68
Q-02b 546.49 propylsulfanyl}-benzoimidazol- 545.77 (LC-2) 1-yl)-acetate tert-Butyl {2-[3-
Q-03b (diphenylacetyl-phenethyl- C38H41 N3O3S 2.79
620.61 amino)-propylsulfanyl]- 619.83 (LC-2) benzoimidazol-1 -yl}-acetate fert-Butyl {2-[3-(phenethyl-
Q-04b phenylmethanesulfonyl- C31 H37N3O4S2 2.66
580.53 amino)-propylsulfanyl]- 579.78 (LC-2) benzoimidazol-1 -yl}-acetate fert-Butyl {2-[3-(phenethyl-
Q-05b phenylacetyl-amino)- C32H37N3O3S 2.62
544.52 propylsulfanyl]-benzoimidazol- 543.73 (LC-2)
1-yl}-acetate fert-Butyl (2-{3-[(3,3-diphenyl- propionyl)-phenethyl-amino]- C39H43N3O3S 2.80
Q-06b 634.63 propylsulfanyl}-benzoimidazol- 633.85 (LC-2) 1-yl)-acetate fert-Butyl {2-[3-(1-phenethyl-3- r?RmfiN4m.
2.48
Q-07b propyl-ureido)-propylsulfanyl]- CZS™°N4 Q ϋόb 511.51 (LC-2) benzoimidazol-1 -yl}-acetate fert-Butyl {2-[3- (benzenesulfonyl-phenethyl- C30H35N3O4S2 2.68
Q-08b 566.51 amino)-propylsulfanyl]- 565.76 (LC-2) benzoimidazol-1 -yl}-acetate terf-Butyl (2-{3-[(2,2-diphenyl- ethyl)-pentanoyl-amino]- C35H43N3O3S
R-01b 2.78
586.58 propylsulfanyl}-benzoimiclazol- 585.81 (LC-2) 1-yl)-acetate tert-Butyl (2-{3-
R-02b [diphenylacetyl-(2,2-diphenyl- C44H45N3O3S 2.90 ethyl)-amino]-propylsulfanyl}- 695.93 696.71 (LC-2) benzoimidazol-1-yl)-acetate tert-Butyl (2-{3-[(2,2-diphenyl-
R-03b ethyl)-phenylmethanesulfonyl- C37H41N3O4S2 2.78
656.62 amino]-propy)sulfanyl}- 655.88 (LC-2) benzoimidazol-1 -yl)-acetate terf-Butyl (2-{3-[(2,2-diphenyl-
R-04b ethyl)-phenylacetyl-amino]- C38H41 N3O3S 2.75 620.61 propylsulfanyij-benzoimidazol- 619.83 (LC-2)
1-yl)-acetate tert-Butyl (2-{3-[(2,2-diphenyl- ethyl)-(3,3-diphenyl- C45H47N3O3S 2.90
R-05b propionyl)-aminoj- 710.73 709.95 (LC-2) propylsulfanylj-benzoimidazol-
1-yl)-aceate terf-Butyl (2-{3-[1-(2,2- diphenyl-ethyl)-3-propyl- C34H42N4O3S 2.62
R-06b 587.60 ureido]-propylsulfanyl}- 586.80 (LC-2) benzoimidazol-1-yl)-acetate terf-Butyl [2-(3-
C21 H31 N3O3S
T-02b pentanoylamino- 2.23 propylsulfanyl)-benzoimidazol- 405.56 406.44 (LC-2)
1-yl]-acetate terf-Butyl {2-[3-(butane-1-
C20H31 N3O4S2
T-03b 2.32 sulfonylamino)-propylsulfanyl]- 442.38 441.61 (LC-2) benzoimidazol-1 -yl}-acetate tert-Butyl [2-(3-
T-04b diphenylacetylamino- C30H33N3O3S 2.50 propylsulfanyl)-benzoimidazol- 515.67 516.48 (LC-2)
1-yl]-acetate tert-Butyl [2-(3- phenylmethanesulfonylamino- C23H29N3O4S2 2.35
T-05b 476.40 propylsulfanyl)-benzoimidazol- 475.63 (LC-2) 1-yl]-acetate terf-Butyl [2-(3-
T-06b phenylacetylamino- C24H29N3O3S 2.24
440.40 propylsulfanyl)-benzoimidazol- 439.57 (LC-2)
1-yl]-acetate terf-Butyl {2-[3-(3,3-diphenyl-
T-07b propionylamino)- C31H35N3O3S 2.47
530.50 propylsulfanyl]-benzoimidazol- 529.70 (LC-2)
1-yl}-acetate tert-Butyl {2-[3-(3-propyl-
C20H30N4O3S 2.08
T-08b ureido)-propylsulfanyl]- 407.40 406.55 (LC-2) benzoimidazol-1 -yl}-acetate terf-Butyl [2-(3- τ nQh benzenesulfonylamino- C22H27N3O4S2 2.33 ,„„ _ft propylsulfanyl)-benzoimidazol- 461.60 (LC-2) 4bλ<iB
1-yl]-acetate rac tert-Butyl {2-[3-(2-
-r mh cyclohexyl-2-phenyl- C30H39N3O3S 2.67 ς ,„ acetylamino)-propylsuifanyl]- 521.72 (LC-2) 0^'00 benzoimidazol-1 -yl}-acetate tβrtΥϊl {2-[3f:fhe "yl" C23H28N4O3S 2.23 T-11b ureιdo)-propylsulfanyl]- 440 56 (LC-2} 441-42 benzoimidazol-1 -yl}-acetate " \ - )
Table 27
Alkylating agent N-05d rac 4-[(3-Chloro-propyl)-(2-cvclohexyl-2-phenyl-acetylVamino1-benzoic acid ethyl ester
To a solution of 4-(2-cyclohexyl-2-phenyl-acetylamino)-benzoic acid ethyl ester (Starting material N-05e, 1 g, 2.74 mmol) and 1,3-iodochloropropane (559 mg, 294 μl, 2.74 mmol, 1 eq.) in dry DMF (10 ml) is added sodium hydride (60% w/w in oil, 72 mg, 3 mmol). After addition is complete, the resulting slurry is allowed to stir for 1 h. Then the same quantity of 1,3-iodochloropropane and of sodium hydride are added again and the resulting slurry is heated up to 50°C overnight. After cooling to rt, water is added until pH=7 and the water phase is extracted twice with AcOEt. The organic phase is washed with water / brine (1:1). The organic phase is dried over MgSO4 and the solvent evaporated to afford a yellow oil containing some DMF. It is purified by flash chromatography on silica-gel (AcOEt / heptane / AcOH, 1 :9:0.5), yielding the title compound (365 mg) in 30% as a colourless oil: fa = 8.74 min (LC-I), ESI-MS (pos.): m/z 442.20 [M+H]+.
Starting material N-05e rac 4-(2-Cvclohexyl-2-phenyl-acetylamino)-benzoic acid ethyl ester To a flask containing thionyl chloride (1.52 g, 929 μl, 12.8 mmol) and 1 drop of DMF is added cyclohexylphenylacetic acid (1.87 g, 8.54 mmol). The resulting solution is stirred for 1 h. The thionyl chloride is evaporated under reduced pressure and the resulting crude acid chloride is diluted in dichloromethane (15 ml). To this solution is added dropwise a solution of 4-amino-benzoic acid ethyl ester (1.41 g, 8.54 mmol) and triethylamine (1.49 ml, 1.08 g, 10.67 mmol) in dichloromethane (15 ml). The resulting mixture is stirred for 30 min at rt. It is diluted with dichloromethane and the resulting organic phase is washed with a 10% aqueous citric acid solution, with a saturated aqueous Na2CO3 solution and with water. It is dried over Na2SO4 and the solvent is evaporated in vacuo. The crude residue is purified on silica gel (AcOEt / heptane, 1 :4), yielding the title compound (3.04 g) in 97% as a white solid: /R = 8.00 min (LC-I), ESI-MS (pos.): m/z 366.18 [M+H]+, ESI-MS (neg.): m/z 364.25 [M-H]+.
Alkylating agent Q-OId Pentanoic acid (3-chloiO-propylVphenethyl-amide
To a solution of valeryl chloride (342 mg, 338 μl, 2.83 mmol) in dichloromethane (6 ml) and cooled to O0C is added a solution of (3-chloro-propyl)-phenethyl-amine (Starting material Q-OIe, 560 mg, 2.83 mmol). The colourless solution turns yellow and after 2 min, a solid crystallizes out. Upon dropwise addition OfEt3N (315 mg, 409 μl, 2.83 mmol) the solution turns colourless again and the solid dissolves instantaneously. The mixture is allowed to stir for 4 h at which time yet again a solid had crystallized out. Saturated aqueous NH4Cl solution is added and the organic phase is washed once with some saturated aqueous NaHCO3 solution and dried over Na2SO4. The solvent is removed in vacuo and the residue is dried under high vacuum, yielding the title compound as an orange oil: tR = 2.48 min (LC-2), ESI-MS (pos.): m/z 282.07 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 0.86-0.97 (m, 3H, CH3), 1.23-1.44 (m, 4H, CH2CH3), 1.55 (quint., IH, CH2CH2CH3), 1.65 (quint., IH, CH2CH2CH3), 1.95 (quint., 2H, CH2CH2N), 2.03-2.19 (m, 2H, CH2C=O), 2.90 (t, 2H, CH2Ph), 3.35-3.59 (m, 6H),
7.15-7.34 (m, 2 Harom).
Starting material Q-OIe
(3-Chloro-propylVphenethyl-arnine
This compound is synthesized according to the procedure described in Brinner, K. M.;
Kim, J. M.; Habashita, H.; Gluzman, I. Y.; Goldberg, D. E.; Ellman, J. A., Bioorg. Med. Chem. 2002, 10, 3649, 3661.
A mixture of phenethylamine (7.1 g, 7.38 ml, 58.5 mmol) and bromochloropropane
(3.07 g, 1.93 ml, 19.5 mmol) in acetonitrile (15 ml) is stirred for 16 h. In the course of the reaction a white crystalline solid forms. Saturated aqueous NaHCO3 solution is added to adjust the pH to 9-10. The free amine is extracted three times with AcOEt. The combined organic phases are dried over Na2SO4. Evaporation of the solvent in vacuo yields a yellow oil. It is purified by chromatography on silica-gel (dichloromethane / MeOH, 95:5), yielding the title compound (1.02 g) in 26% as a slightly yellow oil which crystallizes on standing: 1H-NMR (CDCl3): δ (ppm) 1.91 (quint, 2H, CH2CH2N), 2.75 (m, 4H), 2.81-2.89 (m, 2H)5 3.59 (t, 2H, CH2Cl), 7.20 (m, 3 Harom), 7.24-7.32 (m, 2 Harom).
Example S-OIa
[2-(3-{Butyloxycarbonyl-[(4-ethyloxycarbonylVphenyl]-amino}-propylsulfanyl)- benzoimidazol-1-yl] -acetic acid tert-Butyl [2-(3 - {butyloxycarbonyl- [(4-ethyloxycarbonyl)-phenyl]-amino } - propylsulfanyl)-benzoimidazol-l-yl]-acetate (Precursor S-OIb, 233 mg, 0.41 mmol) is dissolved in TFA / dichloromethane (1:1, 5 ml). The solution is allowed to stir at rt overnight. Evaporation of the solvents in vacuo and drying under high vacuum yields the title compound (206 mg) in 97% as an off-white solid: tR = 6.71 min (LC-I), ESI- MS (pos.): m/z 514.23 [M+H]+, ESI-MS (neg.): m/z 512.31 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 0.86 (t, 3H5 CH2CH3), 1.25 (m, 2H, CH2CH3), 1.39 (t, 3H, OCH2CH3), 1.50 (quint., 2H, OCH2CH2), 1.89 (br. t, 2H, SCH2CH2), 3.38 (br. t, 2H, SCH2), 3.81 (m, 2H, CH2N), 4.04 (t, 2H, OCH2CH2), 4.39 (q, 2H, OCH2CH3)4.88 (s, 2H, CH2CO2), 7.20 (d, 2 Harom), 7.40 (m, 2Harom), 7.59 (br. s, IH, ac. H), 7.71 (d, 2
Harom)j 8.14 (d, 2 Haroni).
Precursor S-OIb fert-Butyl [2-(3 - {butyloxycarbonyl- r(4-ethyloxycarbonyiy phenyl] -amino! - propylsulfanvD-benzoimidazol- 1 -yl] -acetate
To a suspension of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3- I, 264 mg, 1 mmol) and K2CO3 (276 mg, 2 mmol, 2 eq.) in acetone (3 ml) are added 4- [butoxycarbonyl-(3-chloro-propyl)-amino]-benzoic acid ethyl ester (341 mg, 1 mmol) and a few crystals of sodium iodide. The resulting mixture is allowed to stir at reflux for 36 h. It is then cooled down and filtered on a fritted funnel to remove all solid impurities. Evaporation of the solvent in vacuo affords a crude oil that is purified by chromatography on silica gel (AcOEt / heptane, 1:4) yielding the title compound (280 mg) in 49% as a white solid: tκ = 8.07 min (LC-I), ESI-MS (pos.): m/z 570.31 [M+Hf ; 1H-NMR (CDCl3): δ (ppm) 0.88 (t, 3H, CH2CH3), 1.25-1.32 (m, 2H5 CH2CH3), 1.34 (t, 3H, OCH2CH3), 1.40 (s, 9H, tBu), 1.50 (m, 2H, OCH2CH2), 2.05 (quint., 2H, SCH2CH2), 3.38 (br. t, 2H, SCH2), 3.87 (m, 2H, CH2N), 4.06 (t, 2H5 OCH2CH2), 4.35 (q, 2H, OCH2CH3), 4.66 (s, 2H5 CH2CO2), 7.14-7.24 (m, 3 Harom), 7.28 (d, 2 Harom)5 7.68 (m, 2 KUn), 8.00 (d, 2 Harom).
Alkylating agent S-OId 4-[Butoxycarbonyl-(3-chloro-propyiyamino"]-benzoic acid ethyl ester is prepared analogous to the procedure described for alkylating agent K-OId, substituting the appropriate carbamate for phenethyl-carbamic acid fert-butyl ester. It is obtained as a colourless oil: tR - 2.60 min (LC-2), MS (pos.): m/z 342.17 [M+H]+.
Example T-OIa
[2-(3-fert-ButoxYcarbonylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid is prepared analogous to the procedure described for Example J-OIa, using Precursor T- 01b in place of J-OIb: tR = 1.78 min (LC-2), ESI-MS (pos.): m/z 366.31 [M+H]+, ESI- MS (neg.): m/z 364.40 [M-H]+.
Precursor T-OIb ferf -Butyl [2-(3 -fer^-butoxycarbonylamino-propylsulfanyD-benzoimidazol- 1 -yl] -acetate A solution of fert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-I5 502 mg, 1.9 mmol) and DBU (289 mg, 284 μl, 1.9 mmol) in THF (1 ml) is added onto a solution of (3-bromo-propyl)-carbamic acid tert-bntyl ester (407 mg, 1.71 mmol) in THF (1 ml). The resulting solution is stirred at rt for 2 h. It becomes slowly turbid and the undesired solid is filtered on a fritted funnel. The solution is diluted with THF (2 ml) and DIPEA (491 mg, 650 μl, 3.8 mmol) is added. The mixture is poured onto a suspension of 2-chlorotrityl chloride resin (200-400 mesh), 1% DVB (1.0 - 1.6 mmol / g, 475 mg, 0.76 mmol) in THF (1 ml) and allowed to stir for 3 h. The resin is filtered and rinsed with THF. The solvent is removed in vacuo and the residue diluted with dichloromethane (5 ml). This organic phase is washed with an aqueous citric acid solution (pH=4) and with water. The solvent is evaporated under reduced pressure. The same purification process is repeated using dichloromethane instead of THF as the solvent. The obtained organic phase is washed with a saturated aqueous KH2PO4 solution and water. Evaporation of the solvent in vacuo affords a residue that is purified by flash chromatography on silica-gel (AcOEt / heptane, 1 :2), yielding the title compound (587 mg) in 73% as a colourless oil: fo = 2.41 min (LC-2), ESI-MS (pos.): m/z 422.50 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.37 (s, 9H, tBu), 1.39 (s, 9H, tBu), 1.74 (quint. 2H, CH2CH2N), 3.20 (dd, 2H), 3.38 (t, 2H), 4.67 (s, 2H, CH2CO2), 5.82 (br. s, IH, NH), 7.10-7.29 (m, 3Harom), 7.65 (m, mwom).
Precursor T- 12b ferf-Butyl [2-(3-benzoylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetate To a suspension of 3-(l-^rt-butoxycarbonylmethyl-l/f-benzoimidazol-2-ylsulfanyl)- propyl-ammonium chloride (Precursor U-08b, 6 mg, 0.02 mmol) in dichloromethane (0.4 ml) are added subsequently DIPEA (lOmg, 15 μl, 0.085 mmol) and benzoyl chloride (3.9 mg, 3.24 μl, 0.03 mmol) and the resulting solution is allowed to stir for 1 h at rt. Tris-(2-aminoethyl) amine polystyrene (3.4 mmol/g, 33mg, 0.11 mmol) is added and the mixture is allowed to stir for another 3 h at rt. The solvent is evaporated and the residue dried under high vacuum, yielding the title compound as a colourless oil: fø = 2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+.
Precursors T-13b to T-27b of the following Table 28 are prepared using a procedure analogous to that described for Precursor T- 12b, substituting the appropriate acyl chloride for benzoyl chloride.
MS Data MS Data
Formula MoI tR [min]
Ex. Name m/z m/z [M- weight (Meth.) [M+Hf H]-
{2-[3-(Cyclohexanecarbonyl- amino)-propylsιιlfanyl]- C23H33N3O3S 2.34
T-13b 432.29 n/a benzoimidazol-1-yl}-acetic 431.59 (LC-2) acid tert-butyl ester
{2-[3-(4-Methoxy- benzoylamino)-
C24H29N3O4S na
T-14b propylsulfanyl]-benzoimidazol- n/a n/a 455.57 (LC-2)
1-yl}-acetic acid tert-butyl ester (2-{3-[(Furan-2-carbonyl)-
T-15b amino]-propylsulfanyl}- C21H25N3O4S 2.15
416.41 benzoimidazol-1 -yl)-acetic 415.51 (LC-2) n/a acid tert-butyl ester
{2-[3-(Cyclopropanecarbonyl-
T-16b amino)-propylsulfanyl]- C20H27N3O3S 2.10 benzoimidazol-1 -yl}-acetic 390.43 388.47 389.51 (LC-2) acid tert-butyl ester
(2-{3-t(Naphthalene-1- carbonyl)-amino]-
T-17b C27H29N3O3S 2.41 propylsulfanylj-benzoimidazol- 476.48 474.62 475.61 (LC-2)
1-yl)-acetic acid tert-butyl ester
{2-[3-(3-Cyclopentyl- propionylamino)-
T-18b C24H35N3O3S 2.45 propylsulfanyl]-benzoimidazol- 446.44 444.58 445.63 (LC-2)
1-yl}-acetic acid tert-butyl ester
{2-[3-(2,2-Dimethyl- propionylamino)-
C21 H31 N3O3S 2.26
T-19b propylsulfanylj-benzoimidazol- 406.47 n/a 405.56 (LC-2)
1-yl}-acetic acid tert-butyl ester
{2-[3-(3-Phenyl- acryloylamino)-propylsulfanyl]- C25H29N3O3S 2.33
T-20b 452.48 450.49 benzoimidazol-1 -yl}-acetic 451.59 (LC-2) acid tert-butyl ester
{2-[3-(3-Phenyl- propionylamino)-
C25H31N3O3S 2.29
T-21b propylsulfanyl]-benzoimidazol- 454.47 452.60 453.60 (LC-2)
1-yl}-acetic acid tert-butyl ester
N-[3-(1-tert-
Butoxycarbonylmethyl-1 H-
C20H27N3O5S 2.39
T-22b benzoimidazol-2-ylsulfanyl)- 422.45 420.52 421.52 (LC-2) propyl]-oxalamic acid ethyl ester
(2-{3-[(Biphenyl-4-carbonyl)-
T-23b amino]-propylsulfanyl}- C29H31 N3O3S 2.55
502.47 500.48 benzoimidazol-1-yl)-acetic 501.65 (LC-2) acid tert-butyl ester
(2-{3-t(Pyridine-3-carbonyl)- amino]-propylsulfanyl}- C22H26N4O3S 1.97
T-24b 427.39 425.53 benzoimidazol-1 -yl)-acetic 426.54 (LC-2) acid tert-butyl ester
{2-[3-(3,3-Dimethyl-
T-25b butyrylamino)-propylsulfanyl]- C22H33N3O3S 2.30
420.46 n/a benzoimidazol-1 -yl}-acetic 419.59 (LC-2) acid tert-butyl ester
[2-(3-Octanoylamino-
T-26b propylsulfanyl)-benzoimidazol- C24H37N3O3S 2.54
448.50 446.57
1-yl]-acetic acid tert-butyl 447.64 (LC-2) ester 506.38 504.46
Table 28
Example U-OIa
[2-(3-Phenethγlainmo-propylsulfanyl)-benzoimidazol-l-yll-acetic acid tert-Butyl {2-[3-(tert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl]- benzoimidazol-1-yl} -acetate (Precursor J-OIb, 5.5 mg, 0.015 mmol) is dissolved in TFA / dichloromethane (1:1, 1.5 ml) and stirred at rt for 1.5 h. The solvents are evaporated under reduced pressure and the residue is dried under high vacuum, yielding the pure title compound: tR = 1.51 min (LC-2), ESI-MS (pos.): m/z 370.39 [M+H]+; ESI-MS (neg.): m/z 368.42 [M-H]+.
Examples U-02a to U-07a of the following Table 29 are prepared analogous to the procedure described for Example U-OIa, using Precursors J-02b to J-07b in place of J- 01b.
Formula tR [min] MS Data MS Data
Example Name MoI weight (Meth.) m/z [M+H]+ m/2 [M-H]+
[2-(3-Benzylamino- propylsulfanyl)- C19H21 N3O2S 1.45
U-04a 356.38 354.47 benzoimidazol-1-yl]-acetic 355.461 (LC-2) acid
[2-(3-Phenylamino- propylsulfanyl)- C18H19N3O2S 1.65
U-06a 342.30 340.39 benzoimidazol-1-y!]-acetic 341.434 (LC-2) acid
{2-[3-(2,2-Diphenyl- ethylamino)-
C26H27N3O2S 1.73
U-07a propylsulfanyl]- 446.39 n/a 445.585 (LC-2) benzoimidazol-1 -yl}-acetic acid
Table 29 Precursor U-OIb r3-(l-fert-Butoχvcarbonylmethyl-l//-benzoimida2ol-2-ylsulfanyl)-proρyl]-phenethyl- ammonium chloride tert-Butyl {2-[3-(tert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl]- benzoimidazol-1-yl} -acetate (Precursor J-OIb, 199 mg, 0.38 mmol) is dissolved in a IM HCl solution in ethyl acetate (1.89 ml). The resulting solution is stirred at rt for 1 h. The solvent is evaporated and the crude solid is dissolved in dichloromethane, the resulting organic phase is washed with a saturated aqueous NaHCO3 solution and with water. Evaporation of the solvent in vacuo and chromatography of the residue on silica- gel (dichloromethane / MeOH, 92:8) yields the title compound (107 mg) in 61% as a white solid: /R = 2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+.
Precursors U-02b to U-08b of the following Table 30 are prepared analogous to the procedure described for Precursor U-OIb, using Precursors J-02b to J-08b in place of J- 01b.
MS Data
Formula tR [min]
Precursor Name m/z MoI weight (Meth.) [M+H]+
[3-(1 -tert-
Butoxycarbonylmethyl-1 H-
C27H37CIN4O2S 1.82
U-02b benzoimidazol-2-ylsulfanyl)- 481.43 517.12 (LC-2) propyl]-(4-piperidin-1 -yl- phenyl)-ammonium chloride
[3-(1 -tert-
Butoxycarbonylmethyl-1 H-
C25H32CIN3O4S 2.55
U-03b benzoimidazol-2-ylsulfanyl)- 470.41 506.05 (LC-2) propyl]-(4-ethoxycarbonyl- phenyl)-ammonium chloride
Benzyl-[3-(1-ferf- butoxycarbonylmethyl-1 H- C23H30CIN3O2S 1.81
U-04b 411.55 benzoimidazol-2-ylsulfanyl)- 448.02 (LC-2) propylj-ammonium chloride
[3-(1 -tert-
Butoxycarbonylmethyl-1 H- _ , qH28r]NoO2 c
U-05b benzoimidazol-2-ylsulfanyl)- C19H28QN3O2S 1.70
362.36 (LC-2) propyl]-cyclopropyl- ammonium chloride [3-(1-ferf-
Butoxycarbonylmethyl-1 H-
U-OGb C22H28CIN3O2S benzoimidazol-2-ylsulfanyl)- 2.39
398.4 433.99 propyl]-phenyl-ammonium (LC-2) chloride
[3-(1-tert-
Butoxycarbonylmethyl-IH- C30H36c|N3O2S 1 g7
U-07b benzoιmιdazol-2-ylsulfanyl)- -.„„ ΛA ,, r ,< 502.46 propyl]-(2,2-diphenyl-ethyl)- Oόϋ- l4 ^LU~^ ammonium chloride
3-(1-ferf-
U-OSb Butoxycarbonylmethyl-IH- C16H24CIN3O2S 1.60
322.37 benzoimidazol-2-ylsulfanyl)- 357.90 (LC-2) propyl-ammonium chloride
Table 30
Example V-OIa
{2-[2-(l ,3-Dioxo-l ,3-dihvdro-isoindol-2-yl)-ethylsulfanyl]-benzoimidazol-l -yl) -acetic acid is prepared analogous to the procedure described for Example G-OIa, using Precursor
V-OIb in place of G-OIb: tR = 5.21 min (LC-I), ESI-MS (pos.): m/z 382.15 [M+H]+,
ESI-MS (neg.): m/z 380.20 [M-H]+.
Example V-02a
[2-(2-fert-Butoxycarbonylamino-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid tert-Butyl [2-(2-ført-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetate (Precursor V-02b, 28.5 mg, 0.07 mmol) is suspended in 0.2 M aqueous NaOH (2.1 ml), THF (3.95 ml) is then added and the initially turbid suspension becomes a clear solution. After 7 h, IM aqueous HCl solution (420 μl) is added. The solution is diluted with water (10 ml) and extracted with dichloromethane (15 ml). The organic phase is dried over MgSO4 filtered over a fritted funnel and the solvents are evaporated in vacuo. Drying of the residue under high vacuum yields the title compound (19 mg) in 77% as a colourless solid: tR - 1.74 min (LC-2), ESI-MS (pos.): m/z 352.17 [M+H]+, ESI-MS (neg.): m/z 350.20 [M-H]+.
Examples V-03a to V-05a of the following Table 31 are prepared analogous to the procedure described for Example V-02a, using Precursors V-03b to V-05b in place of V-02b. Formula tR [min] MS Data MS Data
Example Name MoI weight (Meth.) m/z [M+Hf m/z [M-H]+
[2-(2-
Butoxycarbonylamino- C16H21 N3O4S 174
V-03a ethylsulfanyl)- 351.42 352.2 350.2
(LC-2) benzoimidazol-1 -yl]-acetic acid
[2-(2-Diphenylacetylamino-
V-04a ethylsulfanyl)- C25H23N3O3S 2.00
446.26 benzoimidazol-1-yl]-acetic 445.53 (LC-2) 444.29 acid
{2-[2-(3-Phenyl-ureido)- ethylsulfanyl]- C18H18N4O3S 1.58
V-05a 371.22 369.12 benzoimidazol-1-yl}-acetic 370.43 (LC-2) acid
Table 31
Precursor V-OIb tert-Butyl {2-f2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethylsulfanyll-benzoimidazol-l- yl) -acetate is prepared using a procedure analogous to that described for Precursor G-OIb, substituting 2-(2-bromo-ethyl)-isoindole-l,3-dione for G-OId: tR = 6.84 min (LC-I),
ESI-MS (pos.): m/z 438.35 [M+H]+.
Precursor V-02b fert-Butyl P-^-tert-butoxycarbonylamino-ethylsulfanylVbenzoimidazol- 1 -yl]-acetate To a solution of tert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-1, 1.31 g, 4.97 mmol) in diy THF (2.6 ml) cooled to 0°C is added a solution of DBU (756.6 mg, 742.5 μl, 0.47 mmol) in dry THF (1 ml). This yields a paste that is diluted with dry THF (2.5 ml). A solution of (2-bromo-ethyl)-carbamic acid tert-butyl ester (1.17 g, 5.22 mmol) in dry THF (2.6 ml) is then added and the resulting mixture is allowed to stir for 2 h. The solvent is removed under reduced pressure and saturated aqueous KH2PO4 solution (50 ml) is added. The product is extracted with AcOEt (150 ml), the organic phase is washed once with water and once with brine and dried over Na2SO4. The solvent is removed in vacuo and the crude mixture is purified by flash chromatography on silica-gel (AcOEt / heptane, 1:12), yielding the title compound (1.41 g) in 69% as a colourless oil: tR = 2.35 min (LC-2), ESI-MS (pos.): m/z 408.27 [M+H]+.
Precursor V-03b fert-Butyl r2-(2-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol- 1 -yll-acetate tert-butyl [2-(2-førf-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol- 1 -yl]-acetate (Precursor V-02b) is dissolved in 3M HCl in AcOEt and stirred for 1 h at rt. Evaporation of the solvent in vacuo yields 2-(l-tert-butoxycarbonylmethyl-li7- benzoimidazol-2-ylsulfanyl)-ethyl-ammonium chloride as a colourless solid. To a solution of rc-butylchloroformate (14.9 mg, 14 μl, 0.11 mmol) in dry THF (0.5 ml) cooled to O0C is added a solution of HOBt (17.3 mg, 0.11 mmol) and DIPEA (18 mg, 23.8 μl, 0.14 mmol) in dry THF (0.5 ml). The resulting mixture is stirred for 10 min. It is then added dropwise at 0°C onto a solution of 2-(l-tert-butoxycarbonylmethyl-l/J- benzoimidazol-2-ylsulfanyl)-ethyl-ammonium chloride (30 mg, 0.09 mmol) and DIPEA (11.2 mg, 14.9 μl, 0.09 mmol) in dry THF (0.7 ml). The resulting mixture is stirred for 1 h at rt. Then tris-(2-aminoethyl) amine polystyrene (3.4 mmol/g, 25.6 mg) is added and the resulting slurry is allowed to stir for 2 h at rt and then filtered. The solvent is removed in vacuo and the residue is diluted with dichloromethane (5 ml). This organic phase is washed once with a saturated aqueous NaHCO3 solution and a saturated aqueous KH2PO4 solution. Evaporation of the solvent in vacuo yields the title compound (17.1 mg) in 48% as a colourless oil: fo = 2.35 min (LC-2), ESI-MS (pos.): m/z 408.29 [M+H]+.
Precursors V-04b and V-05b of the following Table 32 are prepared using a procedure analogous to that described for Precursor V-03b, substituting the appropriate acid chloride or isocyanate for Tϊ-butylchloroformate. In the case of the isocyanate, no HOBt is used.
ferf-Butyl [2-(2-
\ι c\Λh diphenylacetylamino- C29H31 N3O3S 2.46 ,„, „ κnn v"υ4D ethylsulfanyl)-benzoimidazol- 501.64 (LC-2) bUΛ>" bυυ-d
1 -yl]-acetate terf-Butyl {2-[2-(3-phenyl- C22H26N4O3S 2 17
V-05b ureido)-ethylsulfanyl]- ΪJ « n r ^ 427.28 425.3 benzoimidazol-1-yl}-acetate 4Zb-0ύ (L^>
Table 32
Intermediate 4-1 fert-Butyl r2-(2-bromo-ethylsulfanylVbenzoimidazol- 1 -yli-acetate
To a solution of fert-butyl (2-mercapto-benzoimidazol-l-yl)-acetate (Intermediate 3-1, 0.5 g, 1.9 mmol) in THF (1 ml) is added DBU (304 mg, 300 μl, 2 mmol) and the resulting mixture is allowed to stir 2 min at rt. This solution is added slowly dropwise onto dibromoethane (7.5 ml, 88 mmol). The resulting solution is allowed to stir at rt for I h. After addition of dichloromethane (20 ml) the organic phase is washed with aqueous citric acid solution (pH=4), with water and with brine. Evaporation of the solvents in vacuo yields the title compound as a colourless oil: fa = 1.43 min (LC-2), ESI-MS (pos.): m/z 373.23 [M+H]+.
Example W-OIa
[2-(2-Phenylamino-ethylsulfanyl)-benzoimidazol- 1 -yl~|-acetic acid To tert-butyl [2-(2-bromo-ethylsulfanyl)-benzoimidazol-l-yl]-acetate (Intermediate 4- I, 25 mg, 0.065 mmol) in EtOH (0.7 ml) is added aniline (31.3 mg, 0.34 mmol). The resulting mixture is heated up to 7O0C for 1 h. After cooling the solvent is evaporated in vacuo and the crude ester is dissolved in TFA / dichloromethane (3 :2, 2 ml) and stirred at rt for 2 h. Evaporation of the solvents in vacuo affords a crude product that is purified by chromatography on silica-gel (dichlromethane / MeOH, 100:7.5), yielding the pure title compound: fa - 2.11 min (LC-2), ESI-MS (pos.): m/z 328.33 [M+H]+, ESI-MS (neg.): m/z 326.34 [M-H]+.
Example (5/6>Me-D-01a
{2-[2-(4-Chloro-phenoxy)-ethylsulfanyl]-5-methyl-benzoimidazol-l-vU-acetic acid and its 6-methyl regioisomer
A solution of fert-butyl-{2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-5-methyl- benzoimidazol-l-yl}-acetate and its 6-methyl regioisomer (Precursor (5/6)-Me-D-01b, 80.5 mg, 0.15 mmol) in TFA / dichloromethane (1:1, 0.5 ml) is stirred overnight at rt. The solvents are evaporated in vacuo. The product solidifies by addition of AcOEt / heptane (1:1, 1 ml) and sonication. It is filtered and rinsed with the same solvent twice then dried under high vacuum. The title compound and its 6-methyl regioisomer (42 mg) are obtained as a (3:2) mixture in 74% total yield as a white solid: fø = 6.32 min (LC-I), ESI-MS (pos.): m/z 377.18 [M+H]+, ESI-MS (neg.): m/z 375.24 [M-H]+; 1H- NMR (DMSOd6): δ (ppm) 2.41 (s, 3H, Me), 3.67 (t, 2H, SCH2), 4.30 (t, 2H5 CH2O)5 4.96 and 4.97 (s, 2H5 CH2CO2), 6.97-7.01 (m, 3 Harom), 7.27-7.36 (m, 3 Harom), 7.44 (d,
1 Harom) •
Example (5/6)-CN-H-01 a
|"5-Cvano-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid and its 6-cyano regioisomer
A solution tert-bntyl [(5-cyano-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol- l-yl]-acetate and its 6-cyano regioisomer (Precursor (5/6)-CN-H-01b, 20 mg, 0.045 mmol) in TFA / dichloromethane (1:1, 1 ml) is stirred at rt overnight. The solvents are evaporated in vacuo. The residue is precipitated in AcOEt / heptane (1:1, containing 1% of AcOH), filtered and dried under high vacuum. The title compound and its 6- cyano regioisomer are obtained (5 mg) as a (1 :1) mixture in 28% total yield as a white solid: tR = 5.97 min (LC-I), ESI-MS (pos.): m/z 382.13 [M+H]+, ESI-MS (neg.): m/z 380.14 [M-H]+; 1H-NMR (DMSO-d6): δ (ppm) 3.82 (s, 3H, Me)5 4.72 and 4.73 (s, 2H, SCH2), 5.03 and 5.04 (s, 2H, CH2CO2), 7.44 (t, 1 Harom), 7.58 (dt, 1 Harom), 7.69-7.76 (m, 2Harom), 7.83 (d, 1 Harom), 8.08 and 8.17 (s, 1 Harom), 8.08 (m, 1 Harom).
Example (5/6)-F-E-03a [2-(4-Ethyloxycarbonyl-butylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid and its 6-fluoro regioisomer
A solution of tert-butyl [2-(4-ethyloxycarbonyl-butylsulfanyl)-5-fluoro-benzoimidazol- l-yl]-acetate and its 6-fluoro regioisomer (Precursor (5/6)-F-E-03b, 24 mg, 0.075 mmol) in TFA /dichloromethane (1 :1, 2 ml) is stirred overnight at rt. The solvents are evaporated in vacuo and the crude mixture is taken up in Et2O (1 ml) and sonicated. The solid is filtered, rinsed twice with Et2O and dried under high vacuum. The title compound and its 6-fluoro regioisomer are obtained (8 mg) as a (1:1) mixture in 30% total yield as a white solid: tR = 1.96 min (LC-2), ESI-MS (pos.): m/z 355.04 [M+H]+, ESI-MS (neg.): m/z 353.13 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 1.19 (t, 3H, CH3), 1.72 (m, 4H), 2.36 (t, 2H, CH2CO), 3.32 (t, 2H, SCH2), 4.06 (q, 2H, CH2O), 5.00 and 5.02(s, IH, CH2CO2), 7.01 (dt, 1 Harom), 7.39 and 7.47 (dd, 1 Harom), 7.52 (m, 1 Harom).
Examples 6-I-D-02a to (5/6)-F-H-01a of the following Table 33 are prepared using a procedure analogous to one of those described for Examples (5/6)-Me-D-01a, (5/6)- CN-H-OIa, or (5/6)-F-E-03a, using Precursors 6-I-D-02b to (5/6)-F-H-01b in place of (5/6)-Me-D-01b, (5/6)-CN-H-01b, or (5/6)-F-E-03b, respectively.
MS Data
Formula *R [min] MS Data
Example Name m/z MoI weight (Meth.) m/z [M-H]+ [M+H]+
[6-lodo-2-(2-phenoxy- ethylsulfanyl)- C17H15IN2O3S 6.75
6-l-D-02a 455.18 453.29 benzoimidazol-1 -yl]- 454.283 (LC-1) acetic acid
{5-Chloro-2-[2-(4-chloro- phenoxy)-ethylsulfanyl]~ C17H14CI2N2O3S 6.98
(5/6)-CI-D-01a benzoimidazol-1-yl}- 397.13 395.18
397.281 (LC-1) acetic acid and its 6- chloro regioisomer
{2-[2-(4-Chloro- phenoxy)-ethylsulfanyl]: C18H17CIN2O3S 6.49
(4/7)-Me-D-01a 4-methyl-benzoimidazol- 377.19 375.24
376.863 (LC-1) 1-yl}-acetic acid and its 7-methyl regioisomer
[5-Cyano-2-(2-phenoxy- ethylsulfanyl)- C18H15N3O3S 6.18
(5/6)-CN-D-02a benzoιmιdazol-1-yl]- 354.14 352.14
353.401 (LC-1) acetic acid and its 6- cyano regioisomer
[5-Cyano-2-(4- ethyloxycarbonyl- butylsulfanyl)- C16H17N3O4S 5.77
(5/6)-CN-E-03a 362.16 360.18 benzoimidazol-1-yl]- 347.394 (LC-1) acetic acid and its 6- cyano regioisomer
[2-(4-Ethyloxycarbonyl- butylsulfanyl)-5- trifluoromethyl-
C17H19F3N2O4S 6.46
(5/6)-CF3-E-03a benzoimidazol-1 -yl]- 405.27 403.36 404.408 (LC-1) acetic acid and its 6- trifluoromethyl regioisomer [2-(3-Methoxycarbonyl- benzylsulfanyl)-5- trifluoromethyl- R RR
(5/6)-CF3-H-01a benzoimidazol-1-yl]- n r Λ \ 425.16 423.08 acetic acid and its 6- ^"^ (LO"η ' trifluoromethyl regioisomer
[5-Fluoro-2-(2-phenoxy- ethylsulfanyl)- ri7Hi <SN?Ω3FS 2 1
(5/6)-F-D-02a benzoimidazol-1-yl]- ^f , IV n r 0\ 345.1 347.08 acetic acid and its 6- MDldB ' [L^> fluoro regioisomer
[5-Fluoro-2-(3- methoxycarbonyi-
^v p u ni, benzylsulfanyl)- C18H15N2O4FS 2.02 „ . ,
(5/6)-F-H-01a benzoimidazol-1-yl]- 374.391 (LC-2) 373"13 375"1 acetic acid and its 6- fluoro regioisomer
Table 33
Precursor (5/6)-Me-D-01b ført-Butyl-{2-r2-(4-cb.loro-phenoxy)-etriylsulfaiiyl]-5-methyl-benzoimidazol-l-yl}- acetate and its 6-methyl regioisomer
A suspension of 2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-5-methyl-benzoimidazole (Intermediate 5-Me-D-Olc, 106 mg, 0.3 mmol), tert-bvAy\ bromoacetate (59 mg, 44.3 μl, 0.3 mmol) and K2CO3 (83 mg, 0.6 mmol) in DMF (2 ml) is stirred at rt for 3 h. After addition of water, the aqueous phase is extracted twice with AcOEt. The combined organic phases are washed with water / brine (1:1) and dried over Na2SO4. Evaporation of the solvent in vacuo and drying of the residue under high vacuum affords the title compound and its 6-methyl regioisomer (131 mg) as a (3:2) mixture in a quantitative total yield as a colourless oil. It is used without purification in the next step: fe = 2.73 min (LC-2), ESI-MS (pos.): m/z 433.29 [M+H]+.
Precursor (5/6)-CN-H-01b ferf-Butyl [5-cvano-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol- 1 -yl"j- acetate and its 6-cyano regioisomer A suspension of 5-cyano-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazole
(Intermediate 5-CN-H-Olc, 25 mg, 0.075 mmol), fert-butyl bromoacetate (12 mg, 9 μl, 0.06 mmol) and K2CO3 (30 mg, 0.155 mmol) in acetone (0.3 ml) is stirred at reflux for 2 h. The crude suspension is cooled down and filtered on a short pad of silica gel using AcOEt as eluent. The solvent is evaporated in vacuo and the residue dried under high vacuum. The title compound and its 6-cyano regioisomer are obtained as a (1:1) mixture as a brownish oil which is used without purification in the next step: fa = 2.47 min (LC-2). ESI-MS (pos.): m/z 438.14.29 [M+H]+.
Precursor (5/6)-F-E-03b tert-Butyl |"2-(4-ethyloxycarbonyl-butylsulfanvD-5-fluoro-benzoimidazol-l-yl1-acetate and its 6-fluoro regioisomer
A suspension of 2-(4-ethyloxycarbonyl-butylsulfanyl)-5-fluoro-benzoimidazole (Intermediate 5-F-E-03c, 44 mg, 0.15 mmol), tert-butyl bromoacetate (31 mg5 24 μl, 0.155 mmol) and K2CO3 (41 mg, 0.3 mmol) in acetone (0.5 ml) is stirred at reflux for 3 h. The crude suspension is cooled down and filtered on a short pad of silica gel using AcOEt as eluent. The solvent is removed under vacuum and the residue purified by flash chromatography on silica-gel (AcOEt / heptane, 3:7). The title compound and its 6-fluoro regioisomer are obtained as a (1 :1) mixture as a colourless solid: fø = 7.25 min (LC-I), ESI-MS (pos.): m/z 411.26 [M+H]+, ESI-MS (neg.): m/z 408.93 [M-H]+; 1H- NMR (CDCl3): δ (ppm) 1.25 (t, 3H, CH3), 1.42 and 1.44 (s, 9H, Φu), 1.79 (m, 4H), 2.34 (t, 2H, CH2CO), 3.36 (dd, 2H, SCH2), 4.12 (q, 2H, CH2O), 4.70 and 4.72 (s, IH, CH2CO2), 6.86 and 7.01 (dd, 1 HarOm), 6.94 (t, 1 Harom), 7.39 and 7.56(dd, lHarom).
Precursors 5-Cl-D-Olb to 5-F-H-Olb of the following Table 34 as well as Precursor D- 01b are prepared using a procedure analogous to one of those described for Precursors (5/6)-Me-D-01b, (5/6)-CN-H-01b or (5/6)-F-E-03b, using Intermediates 5-Cl-D-Olc to 5-F-H-Olb and D-OIc in place of 5-Me-D-Olc, 5-CN-H-Olc or 5-F-E-03c.
MS Data
Formula tR [min]
Precursor Name m/z MoI weight (Meth.) [M+H]+
tert-Butyl {5-chloro-2-[2-(4- chloro-phenoxy)- r?iH2?ri?N?mς ? 81 (5/6)-CI-D-01b ethylsulfanyl]-benzoimidazol- ^1 τto oo ,, r ^ 453.18
1-yl}-acetate and its 6-chloro ^-Jo ^-z; regioisomer ferf-Butyl {2-[2-(4-chloro- phenoxy)-ethylsulfanyl]-4- r9?mcr|N?mς 9 R
(4/7)-Me-D-01b methyl-benzoimidazol-1-yl}- f?, nl « Λ 433-23 acetate and its 7-methyl ^-yD (LU~^ regioisomer
C22H23N3O3S 2.58 λ Λ ri Λ Λ 409.5 (LC-2) 410"14 ferf-Butyl [5-cyano-2-(4- ethyloxycarbonyl- C21H27N3O4S 2 45
(5/6)-CN-E-03b butylsulfanyl)-benzoimidazol- /Λ% ,7- - 418.23
1-yl]-acetate and its 6-cyano ' l /; regioisomer ferf-Butyl [2-(4- ethyloxycarbonyl- butylsulfanyl)-5- r9iH97F^M9π_iς O R^
(5/6)-CF3-E-03b trifluoromethyl- C21 HJ^3^2O4S .^ 461.40 benzoimidazol-1-yl]-acetate ' ^ " ' and its 6-trifluoromethyl regioisomer ferf-Butyl [2-(3- methoxycarbonyl- benzylsulfanyl)-5- C2^H2^F3N?O4S 7 aς (5/6)-CF3-H-01b trifluoromethyl- C23H23F3N2O4S 7.85 4g1 24 benzoimidazol-1-yl]-acetate 4 l ; its 6-trifluoromethyl regioisomer ferf-Butyl [2-(2-phenoxy-
,,,fi, - n (Wh ethylsulfanyl)-5-fluoro- C21 H23N2O3FS 2.6 .„„ 9n l&/6)-i-LMWD benzojmjdazoi.-i.yij.acetate 402.49 (LC-2) 4U<3 /iU and its 6-fluoro regioisomer ferf-Butyl [5-fluoro-2-(3- methoxycarbonyl- C22H23N2O4FS 2 49
(5/6)-F-H~01b benzylsulfanyl)- /on ςn π ni 43116 benzoimidazol-1-yl]-acetate ^^u.ou ^LO--C; its 6-fluoro regioisomer
Table 34
Intermediate D-OIc 2- 1~2-( 4-Chloro-phenoxyy ethylsulfanyl] -benzoimidazole
According to a procedure described by Matthews, C. J.; Clegg, W.; Elsegood, M. R. J.; Leese, T. A.; Thorp, D.; Thornton, P.; Lockart, J. C, J. Chem. Soc. Dalton Trans., 1996, 1531-1538. A solution of 2-sulfanylbenzimidazole (159 mg, 1.06 mmol) and DIPEA (150 mg, 200 μl, 1.16 mmol) in dry THF (3 ml) is refluxed for half an hour. After cooling to rt, l-(2- bromo-ethoxy)-4-chloro-benzene (250 mg, 1.06 mmol) is added. After a further 4 h of reflux, the solvents are removed in vacuo and the residue purified by flash chromatography on silica gel (AcOEt / heptane, 1 :9 to 3 :7), yielding the title compound (285 mg) in 88% as a white solid: tκ = 5.40 min (LC-I), ESI-MS (neg.): m/z 303.0 [M- H]+; 1H-NMR (CDCl3): δ 3.76 (t, 2H, SCH2), 4.31 (t, 2H, OCH2), 6.76 (d, 2 Harom), 7.18 (d, 2 Harom), 7.22-7.32 (m, 3 Harom), 7.57 (m, 1 Haroffl).
Intermediate 5 -Me-D-01 c
2-[2-(4-Chloro-phenoxy')-ethylsulfanyl1-5-methyl-benzoimidazole A suspension of 5 -methyl- l/i-benzoimidazole-2-thiol (492 mg, 3 mmol), l-(2-bromo- ethoxy)-4-chloro-benzene (777 mg, 3.3 mmol) and K2CO3 (828 mg, 6 mmol) in acetone (10 ml) is refluxed for 3 h. It is cooled down and filtered on filter paper. The solvent is removed in vacuo and the crude purified by flash chromatography on silica-gel (AcOEt / heptane, 3:7), yielding the title compound (530 mg) in 55% as an off-white solid: fo = 2.02 min (LC-2), ESI-MS (pos.): m/z 319.21 [M+H]+, ESI-MS (neg.): m/z 317.23 [M- H]+; 1H-NMR (CDCl3): δ (ppm) 2.36 (s, 3H, Me), 3.59 (t, 2H, SCH2), 4.23 (t, 2H, CH2O), 6.75 (d, 2Harom), 6.97 (d, 1 Harom), 7.13 (d, 2 Harom), 7.18 (s, 1 Harom), 7.34 (d, lHarom).
Intermediate 5 -CN-H-O Ic
5-Cvano-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazole
A suspension of 5-cyano-lH-benzoimidazole-2-thiol (35 mg, 0.2 mmol), 3- bromomethyl-benzoic acid methyl ester (46 mg, 0.2 mmol) and K2CO3 (55 mg, 0.4 mmol) in acetone (0.6 ml) and 3 drops of DMF is refluxed for 2 h. It is cooled down and filtered over a short plug of silica gel and rinsed with AcOEt. The solvent is removed under a stream of air. The crude residue is purified by flash chromatography on silica-gel (AcOEt / heptane, 1 :2), yielding the title compound (38 mg) in 59% as a yellowish gum: tR = 6.14 min (LC-I), ESI-MS (pos.): m/z 324.14 [M+H]+, ESI-MS (neg.): m/z 322.22 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 3.92 (s, 3H, Me), 4.67 (s, 2H, SCH2), 5.29 (S, IH, NH), 7.36-7.56 (m, 4Harora), 7.65 (d, lHarom), 7.94 (d, lHarom), 8.10
(S, lrlarom) Intermediate 5-F-E-03c
2-(4-Ethyloxycarbonyl-butylsulfanyl)-5-fluoro-berizoimidazole A suspension of 5-fluoro-li7-benzoimidazole-2-thiol (168 mg, 1 mmol), 5-bromo- pentanoic acid ethyl ester (188 mg, 0.9 mmol, 145 μl) and K2CO3 (276 mg, 2 mmol) in acetone (2 ml) is refluxed for 3 h. It is cooled down and filtered over a short plug of silica gel and rinsed with AcOEt. The solvent is removed in vacuo. The crude is purified by flash chromatography on silica-gel (AcOEt / heptane, 1 :2), yielding the title compound (190 mg) in 64% as a brown oil: tR = 1.87 min (LC-2), ESI-MS (pos.): m/z 297.28 [M+H]+, ESI-MS (neg.): m/z 295.30 [M-H]+; 1H-NMR (CDCl3): δ (ppm) 1.25 (t, 3H, CH3), 1.79 (br. t, 4H), 2.36 (br. t, 2H, CH2CO), 3.28 (br. t, 2H, SCH2), 4.14 (q, 2H, CH2O), 6.93 (dt, lHarom), 7.20 (dd, lHarom), 7.41 (dd, lHarom).
Intermediates 5 -Cl-D-O Ic to 5 -F-H-O Ic of the following Table 35 are prepared using a procedure analogous to one of those described for Intermediates 5-Me-D-Olc, 5-CN-H- 01c or 5-F-E-03c, using the appropriate 5-substituted benzimidazole-2-thiol in place of 5-methyl-lH-benzoimidazole-2-thiol, 5-cyano-lH-benzoimidazole-2-thiol or 5-fluoro- 1 //-benzoimidazole-2-thiol .
Formula tR [min] MS *?ata MS Data
Intermediate Name MoI weight (Wleth.) ™* + m/z [M-H]+
5-Chloro-2-[2-(4- chloro-phenoxy)- C15H12CI2N2OS 7.23
5-CI-D-Oic 353,12 355.15 ethylsulfanyl]- 339.24 (LC-1) benzoimidazole
2-[2-(4-Chloro- phenoxy)-
C16H15CIN2OS 6.18
4-Me-D-Oic ethylsulfanyl]-4- 317.13 319.19 318.82 (LC-1) methyl- benzoimidazole
5-Cyano-2-(2- phenoxy- C16H13N3OS 6.37
5-CN-D-02C 296.02 294.21 ethylsulfanyl)- 295.36 (LC-1) benzoimidazole
5-Cyano-2-(4- ethyloxycarbonyl- C15H17N3O2S 5.96
5-CN-E-03C 304.17 302.22 butylsulfanyl)- 303.38 (LC-1) benzoimidazole 5-CF3-E-03C T truiSfluoromethy-tl- C15Hl 3I4 6 6F|dr7 2S , (LLC°- 11,) «™ *" benzoimidazole
2-(3-
Methoxycarbonyl- n7H1,F3N™, 4 14
5-CF3-H-01C benzyisulfanyl)-5- U ftj b Λ11 300.19 298.17 trifluoromethyl- 366-36 (LC>1 ) benzoimidazole
5-Fluoro-2-(2-
5 F D 02c phenoxy- C15H13N2OFS 2.11
5-F-D-02C ethylsulfanyl)- 288.345 (LC-2) 289'19 287'22 benzoimidazole
5-Fluoro-2-(3-
- F u ni r methoxycarbonyl- C16H13N2O2FS 6.05 ~Λ 7 Λ Λ o 1 ς 9R 5-F-H-Oic benzylsulfanyl)- 316.355 (LC-1) 317"1 1 315'26 benzoimidazole
Table 35
Example 5-NO2-C-02a (2-Benzylsulfanyl-5-nitro-benzoimidazol-l -vD-acetic acid fe7*t-Butyl (2-benzylsulfanyl-5-nitro-benzoimidazol-l-yl)-acetate (Precursor 5-NO2-C- 02b, 20 mg, 0.05 mmol) is dissolved in TFA / dichloromethane (1:1, 0.5 ml) and stirred for 2 h at rt. The solvents are evaporated under a stream of air and Et2O (1 ml) is added to the crude mixture. The solid obtained is filtered, rinsed twice with Et2O and dried under high vacuum yielding the title compound (10.4 mg) in 60% as a slightly yellow solid: tκ = 6.30 min (LC-I), ESI-MS (pos.): m/z 344.23 [M+H]+, ESI-MS (neg.): m/z 342.34 [M-H]+; 1H-NMR (DMSO-d6): δ (ppm) 4.66 (s, 2H, SCH2), 5.07 (s, 2H, CH2CO2), 7.23-7.33 (m, 3 Harom), 7.46 (dd, 2 Harom), 7.74 (d, 1 Harom), 8.13 (dd, 1
Harom), 8.44 (d, 1 Harom).
Examples 5-NO2-D-01a to 6-NO2-G-06a of the following Table 36 are prepared analogous to the procedure described for Example 5-NO2-C-02a, using Precursors 5- NO2-D-01b to 6-NO2-G-06b in place of 5-NO2-C-02b.
r {5-Nitro-2-[2-(4-chloro)-
5 NO2-D-01a Phenoxy-ethylsulfanyl]- C17H14CIN3O5S 6.84 5-NO2-D 01a benzoimidazol-1-yl}- 407.833 (LC-1) 4ϋ8-12 406'21 acetic acid
5-N itro-2-(2-phen oxy- ethylsulfanyl)- C17H15N3O5S 6 46
(5/6)-NO2-D-02a benzoimidazol-1-yl]-acetic υ 37' ° 38g 00 °£° 374.25 372.36 acid and its 6-Nitro " [ ' ' regioisomer
(2-Benzylsulfanyl-5-nitro- PH RU ^MOΠAQ R I
5-NO2-C-02a benzoimidazol-1-yl)- 343 362 (LC-D 344 23 342'34 acetic acid ' *■
[2-(3,3-Diphenyl-
5-NO2-C-05a Propylsulfanyl)-5-nitro- C24H21 N3O4S 7^24 benzoιmιdazol-1-yl]-acetic 447.514 (LC-1) acid
[2-(4-Ethyloxycarbonyl- butylsulfanyl)-5-nitro- C16H19N3O6S 6.11
5-NO2-E-03a 382.3 380.34 benzoimidazol-1-yl]-acetic 381.408 (LC-1) acid
{2-[3-(1,3-Dioxo-1 ,3- dihydro-isoindol-2-yl)-
C20H16N4O6S 6.14
5-NO2-G-06a propylsulfanyl]-5-nitro- 441.29 439.33 440.435 (LC-1) benzoimidazol-1-yl}- acetic acid
[2-(3-Methoxycarbonyl- benzylsulfanyl)-5-nitro- C18H15N3O6S 6.24
5-NO2-H-01a 402.24 400.28 benzoimidazol-1-yl]-acetic 401.398 (LC-1) acid
{2-[3-(Butoxycarbonyl- phenethyl-amino)-
C25H30N4O6S 7.37
5-NO2-K-01a propylsulfanyl]-5-nitro- 513.3 515.2 514.601 (LC-1) benzoimidazol-1-yl}- acetic acid
[2-(3-
Diphenylacetylamino-
C26H24N4O5S 2.24
5-NO2-T-04a propylsulfanyl)-5-nitro- 505.58 503.54 504.56 (C) benzoimidazol-1 -yl]-acetic acid
(2-Benzylsulfanyl-6-nitro- ri Rμ«Wqn4ς R ?7
6-NO2-C-02a benzoimidazol-1-yl)- TΛ o«o /i r \ 344 3 342-34 acetic acid Md.&t ^LO- I ) [2-(3,3-Diphenyl-
R Mn, r n. propylsulfanyl)-6-nitro- C24H21 N3O4S 7.26
448.36 446.4 b-iMu^o-u&a benzoimidazol-1-yl]-acetic 447.514 (LC-1) acid
[2-(4-Ethyloxycarbonyl-
R κιrv> F M butylsulfanyl)-6-nitro- C16H19N3O6S 6.07 b-Nυz-c-uoa benzojm iύaz0\^. y|]-acetic 381.408 (LC-1) 382.3 380.34 acid
{2-[3-(1,3-Dioxo-1,3- dihydro-isoindol-2-yl)-
C20H16N4O6S 6.11
6-NO2-G-06a propylsulfanyl]-6-nitro- 439.4 440.435 (LC-1) 441.29 benzoimidazol-1 -yl}- acetic acid
Table 36
Precursor 5-NO2-C-02b fert-Butyl (2-benzylsulfanyl-5-mtro-benzoimidazol-l -yl)
A suspension of tert-butyl-(2-mercapto-5-nitro-benzoimidazol-l-yl)-acetate
(Intermediate 3-IIa, 31 mg, 0.1 mmol), benzyle bromide (18.8 mg, 13 μl, 0.11 mmol) and K2CO3 (28 mg, 0.2 mmol) in acetone (1 ml) is refluxed for 2h 30min. The crude mixture is filtered on a short pad of silica-gel and rinsed with acetone. Evaporation of the solvent in vacuo and drying under high vacuum yields the title compound as a yellow oil which is used in the next step without further purification: t& = 7.69 min
(LC-I), ESI-MS (pos.): m/z 400.28 [M+H]+; 1H-NMR (CDCl3): δ (ppm) (CDCl3): 1.33
(s, 9H, /Bu), 4.60 (s, 2H), 4.65 (s, 2H), 7.13 (d, 2 Harom), 7.17-7.26 (m, 3 Harom), 7.34
(m, 2 Harom), 8.12 (dd, 1 Harom), 8.55 (d, 1 Harom).
Precursors 5-NO2-C-05b to 6-NO2-G-06b of the following Table 37 are prepared analogous to the procedure described for Precursor 5-NO2-C-02b, using the appropriate alkyl or aryl halogenide for benzyl bromide and the appropriate Intermediate 3-IIa or Intermediate 3-IIb, or a (1:1) mixture of both, respectively.
MS Data
Formula
Precursor tR [min] MS Data
Name m/z MoI weight (Meth.) m/z [M-H]+ [M+H]+ ferf-Butyl (2-Benzylsulfanyl-5- C20H21 N3O4S
5-NO2-C-02b nitro-benzoimidazol-1-yl)- 399 45 400.28 n/a acetate
ferf-Butyl [2-(3,3-diphenyl- r,ou9QWon4ς R ΔT>
5-NO2-C-05b propylsulfanyl)-5-nitro- 503 51 (LC-I) 504-43 502A7 benzoimidazol-1-yl]-acetate
fert-Butyl {5-nitro-2-[2-(4-
5-NO2-D-01b chloro)-phenoxy- C21 H22CIN3O5S 8.03 o INUZ u υ1 D ethylsulfanyl]-benzoimidazol- 463.93 (LC-1) 4b4-14 4b^'
1-yl}-acetate
ferf-Butyl [5-nitro-2-(2-
(5/6)-NO2-D-02b Phenoxy-ethylsulfanyl)- C21H23N3O5S 7.76 ., Q ion*) INUZ u UZD benz0imjdaz0|.1_y|].acetate 429.49 (LC-2) 4dU ci1 4^a^4 and its 6-nitro regioisomer
fe/t-Butyl [2-(4-
5-NO2-E-03b ethyloxycarbonyl- C20H27N3O6S 7.45
5-NU/ t ϋJD butylsulfanyl)-5-nitro- 437.51 (LC-1) 4άii όb Λόb ™ benzoimidazol-1 -yl]-acetate
terf-Butyl {2-[3-(1 ,3-dioxo-1,3- c MΠO n ncu dihydro-isoindol-2-vl)- C24H24N4O6S 7.38 .„ QC .nc .
5-NO2-G-06b prOpylsulfanyl]-5-nitro- 496.54 (LC-1) 497 36 495'4 benzoimidazol-1 -yl}-acetate
fert-Butyl [2-(3-
, wn, u nih methoxycarbonyl- C22H23N3O6S 2.54 . „„ 4ςR ςo
5-NO2-H-01b benzylsulfanyl)-5-nitro- 457.5 (LC-2) 458-38 456 58 benzoimidazol-1 -yl]-acetate
fert-Butyl {2-[3- π Nn, κ ni h (butoxycarbonyl-phenethyl- C29H38N4O6S 8.43 71 .„ ___ a-iMUZ-^-uiD amino).prOpy|SU|fanyl]_5.nitro_ 570 7 (L^1) ^^^υ ∞»-4 benzoimidazol-1 -yl}-acetate
fert-Butyl (2-benzylsulfanyl-6- r90H91 N3n4o 7 67 6-NO2-C-02b nitro-benzoimidazol-1-yl)- 399 45 (LC 1) 400 35 n/a
fert-Butyl [2-(3,3-diphenyl- cτmwMOA^ 8 44
6-NO2-C-05b propylsulfanyl)-6-nitro- =«? «"? n r \\ 504-33 502-54 benzoimidazol-1 -yl]-acetate 0Uό-° ' 1LO" ' ; terf-Butyl [6-nitro;2-(2- C21 H23N3O5S 7J6
6-NO2-D-02b phenoxy-ethylsulfanyl)-
429.49 430.31 428.24
(LC-1) benzoimidazol-1-yl]-acetate
fert-Butyl [2-(4- ethyloxycarbonyl- C20H27N3O6S 7.43
6-NO2-E-03b butylsulfanyl)-6-nitro- 437.51 (LC-1) 438.35 436.39 benzoimidazol-1 -yi]-acetate
ferf-Butyl {2-[3-(1 ,3-dioxo-1 ,3- dihydro-isoindol-2-yl)- C24H24N4O6S 7.38
6-NO2-G-06b 497.36 propylsulfanyl]-6-nitro- 496.54 (LC-1) 495.4 benzoimidazol-1 -yl}-acetate
Table 37
Examples H- 12a to H- 14a of the following Table 38 are prepared analogous to the procedure described for Example H-OIa, using Precursors H- 12b to H- 14b in place of H-OIb.
MS Data MS Data
Formula fR [min]
Example Name m/z m/z [M- MoI weight (Meth.) [M+H]+ H]+
[2-(3-lsopropyloxycarbonyl-
6-methoxy-benzylsulfanyl)- C21H22N2O5S 0.86
H-12a 415.23 n/a benzoimidazol-1 -yl]-acetic 414.47 (LC-3) acid
[2-(3-Methyloxycarbonyl-6- phenyl-benzylsulfanyl)- C24H20N2O4S 1.05
H-13a 432.92 431.04 benzoimidazol-1 -yl]-acetic 432.49 (LC-3) acid
[2-(4-Methyloxycarbonyl- oxazol-2-ylmethylsulfanyl)- C15H13N3O5S 1.70
H-14a 347.88 346 benzoimidazol-1 -yl]-acetic 347.35 (LC-2) acid
Table 38
Precursors H- 12b and H- 14b of the following Table 39 are prepared using a procedure analogous to that described for Precursor H-OIb, using Alkylating agents H-12d and H- 14d in place of 5-bromo-hexanoic acid ethyl ester. tert-Butyl [2-(3- u 19h isopropyloxycarbonyl-6- C25H30N2O5S 2.70 .71 qQ methoxy-benzylsulfanyl)- 470.58 (LC-2) 4/ Lay benzoimidazol-1-yl]-acetate tert-Butyl [2-(4- μ ΛΛh methyloxycarbonyl-oxazol- C19H21N3O5S 2.24 ._„ Q 2-ylmethylsulfanyl)- 403.45 (LC-2) 4υύ-az benzoimidazol-1-yl]-acetate
Table 39
Alkylating agent H- 12d
3-Chloromethyl-4-methoxy-benzoic acid isopropyl ester
As described in: McKillop, A.; Madjdabadi, F., A.; Long. D. A. Tetrahedron Lett.,
1983, 24, 1933-1936.
To a solution of 4-methoxybenzoic acid isopropyl ester (370 mg, 1.89 mmol) in dry nitromethane (10 ml) is added AlCl3 (301 mg, 2.26 mmol, 1.2 eq.) and methoxyacetylchloride (181 μl, 215 mg, 1.98 mmol, 1.05 eq.) and the mixture is stirred overnight at rt. Water (10 ml) is added and the aqueous phase is extracted twice with dichloromethane. The organic phase is dried over Na2SO4 and the solvent removed in vacuo. The yellowish residue is purified by chromatography on silica-gel (AcOEt / heptane, 1 :4), yielding the title compound (87 mg) in 29%: tR = 2.47 min (LC-2), ESI- MS (pos.): m/z 242.95 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.33 (d, 6H, CH(CH3)2), 3.91 (s, 3H, OCH3), 4.61 (s, CH2Cl), 5.19 (sept., IH, CH(CH3)2), 6.87 (d, 1 Harom), 7.98
(m, 2 Harom).
Alkylating agent H14-d is prepared accordingly to the described 4 steps procedure: Hermitage, S. A.; Cardwell, K. S.; Chapman, T.; Cooke, J. W. B.; Newton, R. Org. Proc. Res. Development, 2001, 5, 37-44.
Precursor H- 13b tert-Butyl [2-(3-methyloxycarbonyl-6-plienyl-ben2ylsulfaιiylVbenzoimidazol-l-yl]- acetate
To tert-butyl {2-[(6-bromo-3-methoxycarbonyl)-benzylsulfanyl]-benzoimidazol-l-yl}- acetate (Precursor H-08b, 49.1 mg, 0.1 mmol) in 1,2-dimethoxyethane (1.5 ml) are added phenylboronic acid (12.2 mg, 0.1 mmol, 1 eq.), bis(triphenylphosphine)palladium dichloride (0.7 mg, 1 μmol, 1 % mol) and some saturated Na2CO3 solution in water (0.3 ml). The resulting biphasic mixture is allowed to stir 25 h at 80°C then 2 h at reflux. Then another load of catalyst is added and the reaction is refluxed overnight. The mixture is allowed to cool down to rt and the solvents are removed in vacuo. The yellowish residue is purified twice by chromatography on silica-gel (AcOEt / heptane, 1:4), yielding the title compound (9 mg) in 19% as a colourless oil: tR = 1.22 min (LC-3), ESI-MS (pos.): m/z 488.98 [M+H]+.
Examples H- 15a and H- 16a rac (2-[2-Methoxy-5-d-methoxy-ethyl)-benzylsulfanyl1-benzoimidazol-l-vU-acetic acid and rac {2-[5-(l-Hvdroxy-ethyl)-2-methoxy-benzylsulfanyl]-benzoimidazol-l-yl)- acetic acid To a solution of [2-(5-acetyl-2-methoxy-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid (Example H-IIa, 75 mg, 0.2 mmol) in dry methanol (1 ml) is added sodium borohydride (36 mg, 0.92 mmol, 0.46 eq.) and the mixture is stirred at rt for a few minutes. Some 1 N aqueous HCl solution (5 ml) is added and the mixture is extracted three times with AcOEt. The combined organic phase is washed with brine and dried over MgSO4. The solvents are removed under a stream of air to afford a yellowish solid residue which is purified by preparative HPLC yielding: rac {2-[2-methoxy-5-(l- methoxy-ethyl)-benzylsulfanyl]-benzoimidazol-l-yl}-acetic acid (4.6 mg) in 6% as a white solid : tκ = 1.70 min (LC-2), ESI-MS (pos.): m/z 385.16 [M+H]+ and rac {2-[5- (l-hydroxy-ethyl)-2-methoxy-benzylsulfanyl]-benzoimidazol-l-yl}-acetic acid (2.9 . mg) in 4% as a white solid: tκ = 1.73 min (LC-2), ESI-MS (pos.): m/z 372.24 [M+H]+.
Examples (R)-I-OIa and (S)-I-OIa of the following Table 40 are prepared over two steps analogous to the procedures described for Example I-01a, using Precursors (R)-I- 00b and (S)-I-OOb in place of I-00b. They both were purified by preparative thin-layer chromatography on silica-gel: Eluent (Chloroform/ MeOH/ AcOH, 90:10:1).
MS Data
Formula *R [min]
Example Name MoI weight m/z (Meth.) [M+H]+
[2-((R)-1 -Butyryl-piperidin-3- ylmethylsulfanyl)- C19H25N3O3S 0.72
(R)-I-OIa 376.33 benzoimidazol-1-yl]-acetic 375.493 (LC-3) acid
[2-((S)-1 -Butyryl-piperidin-3- ylmethylsuifanyi)- C19H25N3O3S 0.72
(S)-I-OIa 376.33 benzoimidazol-1 -yl]-acetic 375.494 (LC-3) acid
Table 40
Examples (R)-I-OOb and (S)-I-OOb of the following Table 41 are prepared analogous to the procedures described for Example I-01b, using (R)-3-hydroxymethyl-piperidine-l- carboxylic acid tert-butyl ester or (S)-3-hydroxymethyl-piperidine-l-carboxylic acid ter/-butyl ester instead of rac 3 -hydroxymethyl-piperidine- 1 -carboxylic acid tert-butyl ester.
MS Data
Formula tR [min]
Precursor Name m/z MoI weight (Meth.) [M+H]+ te/f-Butyl [2-((R)-1 -tert- butyloxycarbonyl-piperidin- C24H35N3O4S 1.02
(R)-I-OOb 462.36
3-ylmethylsulfanyl)- 461.63 (LC-3) benzoimidazol-1 -yl]-acetate terf-Butyl [2-((S)-1-terf- butyloxycarbonyl-piperidin- C24H35N3O4S 1.02
(S)-I-OOb 462.36
3-ylmethylsulfanyl)- 461.64 (LC-3) benzoimidazol-1 -yl]-acetate
Table 41
Example I- 14a rac {2-[ 1 -(3 -Phenyl-acryloγD-ρiperidin-3 -ylmethylsulfanyl] -benzoimidazol- 1 -vU - acetic acid rac tert-Butyl {2-[l -(2-phenyl-ethenesulfonyl)-piperidin-3-ylmethylsulfanyl]- benzoimidazol-1-yl} -acetate (Precursor I-14b, 6 mg, 0.011 mmol) in TFA / dichloromethane (1 :1, 1 ml) is allowed to stir overnight at rt. The solvents are removed under a stream of air and the resulting product is dried under high vacuum. This yields the title compound (5.6 mg) in 100% as a colourless oil which crystallizes on standing: tR = 1.06 min (LC-3), ESI-MS (pos.): m/z 471.88 [M+H]+.
Examples I-15a to 1-23 a of the following Table 42 are prepared analogous to the procedures described for Example I- 14a, using Precursors I- 15b to I-23b in place of I- 14b.
MS Data
Formula fR [min]
Example Name m/z
MoI weight (Meth.) [MH-H]+ rac {2-[1-(3,4-Dichloro- benzenesulfonyl)-piperidin-
1-15a C21 H21CI2N3O4S2 1.16
3-ylmethylsulfanyl]- 513.84 514.45 (LC-3) benzoimidazol-1 -yl}-acetic acid rac [2-(1- Phenylmethanesulfonyl- piperidin-3- C22H25N3O4S2 1.01
1-16a 459.91 ylmethylsulfanyl)- 459.58 (LC-3) benzoimidazol-1 -yl]-acetic acid rac {2-[1-(Toluene-4- sulfonyl)-piperidin-3-
C22H25N3O4S2 1.06 l-17a ylmethylsulfanyl]- 459.91 459.58 (LC-3) benzoimidazol-1 -yl}-acetic acid rac {2-[1-(Naphthalene-2- sulfonyl)-piperidin-3-
C25H25N3O4S2 1.12
1-18a ylmethylsulfanyl]- 495.91 495.61 (LC-3) benzoimidazol-1 -yl}-acetic acid rac {2-[1-(Butane-1- sulfonyl)-piperidin-3-
C19H27N3O4S2 0.98
1-19a ylmethylsulfanyl]- 425.92 425.57 (LC-3) benzoimidazol-1 -yl}-acetic acid rac {2-[1-(4-Methoxy- benzenesulfonyl)-piperidin- l-20a C22H25N3O5S2 1.02
3-ylmethylsulfanyl]- 475.9 475.58 (LC-3) benzoimidazol-1 -yl}-acetic acid rac {2-[1-(Propane-2-
1-21 a sulfonyl)-piperidin-3- C18H25N3O4S2 0.89
411.87 ylmethylsulfanyl]- 411.54 (LC-3) benzoimidazol-1 -yl}-acetic acid
rac {2-[1-(Thiophene-2- sulfonyl)-pipeπdin-3- C19H21N3O4S3 1.00 λRΛ Λ . l-22a ylmethylsulfanyl]- 451 58 /LC-3) 451 -81 benzoimidazol-1-yl}-acetic " \ ' i acid rac [2-(1-Methanesulfonyl-
.-23a ylmXSa'n'yl)- ∞™*™*™2 °£° 383.91 benzoimida2ol-1-yl]-acetic ' ^ ' acid
Table 42
Precursor I- 14b rac ført-Butyl {2-[l -(2-phenyl-ethenesulfonyl)-piperidin-3-ylmethylsulfanyl1- benzoimidazol- 1 -yl| -acetate
To a solution of DIPEA (63.9 μl, 48.3 mg, 0.37 mmol, 4.5 eq.) and 2-phenyl- ethenesulfonyl chloride (25.2 mg, 0.125 mmol, 1.5 eq.) in 1,2-dichloroethane (0.5 ml) was added 3 -( 1 -ført-butoxycarbonylmethyl- 1 H-benzoimidazol-2-ylsulfanylmethyl)- piperidinium chloride (Intermediate I-OOb-bis, 30 mg, 0.083 mmol) in 1,2- dichloroethane (1 ml). The reaction mixture is stirred at rt overnight. The solvents are evaporated under reduced pressure and the crude is purified by preparative HPLC yielding the title compound in 18% as a colourless oil: tR = 1.20 min (LC-3), ESI-MS (pos.): m/z 528.35 [M+H]+.
Precursors I- 15b to I-23b of the following Table 43 are prepared using a procedure analogous to that described for Precursor I- 14b, substituting the appropriate sulfonyl chloride for 2-phenyl-ethenesulfonyl chloride
c^-™,,^ * rmini MS Data MS Data
Precursor Name M Mo ,I we ■ig ϊh*t Ϊ (MΛeth..J) [M m+/Hz]+ m/ Hz] [+M-
rac terf-Butyl {2-[1-(3,4- dichloro-benzenesulfonyl)- r?EH?qπ?Nnθ4S2 n/a l-15b piperidin-3- C25H29CI2N3O4S2 n/a n/g n/g
570.55 (LC-3) ylmethylsulfanyl]- benzoimidazol-1 -yl}-acetate rac ferf-Butyl [2-(1- phenylmethanesulfonyl-
M 6b C26H33N3O4S2 1.18 piperidin-3- 515.69 (LC-3) 516.3 n/a ylmethylsulfanyl)- benzoimidazol-1 -yl]-acetate rac fe/t-Butyl {2-[1-(toluene- 4-sulfonyl)-piperidin-3- C26H33N3O4S2 1.21 l-17b ylmethylsulfanyl]- 515.69 (LC-3) 516.3 n/a benzoimidazol-1 -yl}-acetate rac tert-Butyl {2-[1- (naphthalene-2-sulfonyl)-
C29H33N3O4S2 1.24
1-18b piperidin-3- 552.39 55Oy 551.72 (LC-3) ylmethylsulfanyl]- benzoimidazol-1 -yl}-acetate rac tert-Butyl {2-[1-(butane- 1 -sulfonyl)-piperidin-3- C23H35N3O4S2 1.17
M9b 482.3 ylmethylsulfanyl]- 481.67 (LC-3) n/a benzoimidazol-1 -yl}-acetate rac te/f-Butyl {2-[1-(4- methoxy-benzenesulfonyl)- l-20b C26H33N3O5S2 1.19 piperidin-3- n/a n/a 531.69 (LC-3) ylmethylsulfanyl]- benzoimidazol-1 -yl}-acetate rac terf-Butyl {2-[1-
(9ropane-2-sulfonyl)-
C22H33N3O4S2 1.13
1-21 b piperidin-3- 468.31 n/a 467.65 (LC-3) ylmethylsulfanyl]- benzoimidazol-1 -yl}-acetate rac fert-Butyl {2-[1- (thiophene-2-sulfonyl)- l-22b C23H29N3O4S3 piperidin-3- 1.17 508.27 n/a 507.69 (LC-3) ylmethylsulfanyl]- benzoimidazol-1 -yl}-acetate rac ferf-Butyl [2-(1- methanesulfonyl-piperidin- C20H29N3O4S2 1.08 l-23b 440.26
3-ylmethylsulfanyl)- 439.59 (LC-3) n/a benzoimidazol-1 -yl]-acetate
Table 43
Intermediate I-00b-bis
3 -( 1 -fert-Butoxycarbonylmethyl- 1 H-benzoimidazol-2-ylsulfanylmethyl)-piperidinium chloride rac tert-Butyl [2-(l-ført-butyloxycarbonyl-piperidin-3-ylmethylsulfanyl)- benzoimidazol-1-yl] -acetate (Intermediate I-00b, 409 mg, 0.89 mmol) is dissolved in
AcOEt / Et2O (1:1, 4 ml), and 2.2 ml of a 2M HCl solution in Et2O are added. After 45 min the solvent is removed in vacuo and the crude solid formed is dried under high vacuum, yielding the title compound (360 mg) in 100% as a white solid: tR = 0.74 min (LC-3), ESI-MS (pos.): m/z 362.31 [M+H]+.
Example I-24a of the following Table 44 is prepared analogous to the procedures described for Example I-01a, using Precursors I-24b in place of I-01b. It is purified by flash-chromatography on silica-gel using (AcOEt/ Acetone/ Water/ Acetic acid) (16:2:1:1) as the eluent.
MS Data MS Data
Formula tR [min]
Example Name m/z m/z [M- MoI weight (Meth.) [M+H]+ H]+
[2-(1 -Butyryl-piperidin-4- l-24a ylmethylsulfanyl)- C19H25N3O3S 2.00 benzoimidazol-1 -yl]-acetic 375.49 376.25 374.21 (LC-2) acid
Table 44
Precursor I-24b of the following Table 45 is prepared analogous to the procedures described for Example I-00b, using 4-hydroxymethyl-piperidine-l-carboxylic acid tert- butyl ester in place of S-hydroxymethyl-piperidine-l-carboxylic acid tert-butyl ester
MS Data
Formula tR [min]
Precursor Name m/z MoI weight (Meth.) [M+H]+ rac fe/f-Butyl [2-(1-fe/t- l-24b butyloxycarbonyl-piperidin- C24H35N3O4S 8.95
462.26
4-ylmethylsulfanyl)- 461.62 (LC-1) benzoimidazol-1 -yl]-acetate
Table 45
Example 5-NO2-H-1 Ia of the following Table 46 is prepared analogous to the procedure described for Example 5-NO2-C-02a, using Precursor 5-NO2-H-1 Ib in place of 5-NO2-C-02b. Formula MS Data fR [min] MS Data
Example Name MoI weight (Meth.) m/z m/z [M- [M+Hf H]+
[2-(5-Acetyl-2-methoxy~ lfanyl)-5-nitro- C19H17N3O6S 1.02
5-NO2-H-11a benzylsu
416.06 414.12 benzoimidazol-1 -yl]-acetic 415.42 (LC-3) acid
Table 46
Precursor 5-NO2-H-1 Ib of the following Table 47 is prepared analogous to the procedure described for Precursor 5-NO2-C-02b, using l-(3-chloromethyl-4-methoxy- phenyl)-ethanone in place of benzyl bromide.
MS Data MS Data
Formula tR [min]
Precursor Name MoI weight (Meth.) [M- te/f-Butyl [2-(5-acetyl-2- methoxy-benzylsulfanyl)-5- C23H25N3O6S 1.17
5-NO2-H-11b nitro-benzoimidazol-1-yl]- 471.53 (LC-3) 472.10 470.16 acetate
Table 47
Examples 4,6-CF32-H-01a to 5,6-02-1-0 Ia of the following Table 48 are prepared using a procedure analogous to one of those described for Examples (5/6)-Me-D-01a, (5/6)-CN-H-01a, or (5/6)-F-E-03a, using Precursors 4,6-CF32-H-01b to 5,6-C12-I-01b in place of (5/6)-Me-D-01b, (5/6)-CN-H-01b, or (5/6)-F-E-03b, respectively.
MS Data
Formula fR [min]
Example Name m/z MoI weight (Meth.) [M+H]+
[2-(5-Methyloxycarbonyl-
4,6-CF32-H- benzylsulfanyl)-4,6-bis- C20H14F6N2O4S 2.60 01a trifluorometnyl- 4g2 3g 492.91 (LC-2) benzoimidazol-1-yl]-acetic acid
[2-(5-Acety)-2-methoxy-
4.6-CF32-H- benzylsulfanyl)-4,6-bis- C21H16F6N2O4S 2.55
506.95 11a trifluoromethyl- 506.42 (LC-2) benzoimidazol-1 -yl]-acetic acid
[2-(1 -Butyryl-piperidin-3-
4.6-CF32-I- ylmethylsulfanyl)-46-bis- C21 H23F6N3O3S 1.19 _, . _ . 01a . tπfluoromethy - „ LC 512.04 benzoιmιdazol-1-yl]-acetιc v ' acid
[2-(5-Methyloxycarbonyl- 5,6-Me2-H- benzylsulfanyl)-5,6- C20H20N2O4S 0.98
01a dimethyl-benzoimidazol-1- 384.45 (LC-3) Jcμf-yo yl]-acetic acid
[2-(5-Acetyl-2-methoxy- 5,6-Me2-H- benzylsu!fanyl)-5,6- C21H22N2O4S 0.96
11a dimethyl-benzoimidazol-1- 398.48 (LC-3) ύaa-κ4 yl]-acetic acid
[2-(1-Butyryl-piperidin-3-
5 6 Me2 I O1a ylmethylsulfanyl)-5,6- C21 H29N3O3S 0.90 o,b-Nie-i i υia djmethyi.benzojmidazoi.^ 403.54 (|_C-3) 4U4" u yl]-acetic acid
[2-(5-Methyloxycarbonyl-
K R no n nd o benzylsulfanyl)-5,6- C18H14CI2N2O4S 1.14 A0R n9 a.b-ui^-M-uia dich|oro_benzojmidaZo|.i- 425.29 (LC-3) 4^U/ yl]-acetic acid
[2-(5-Acetyl-2-methoxy-
, R ri, u 11 a benzylsulfanyl)-5,6- C19H16CI2N2O4S 0.97 &,b-uιz-M-na djchioro.benzojmjdazoi.-i. 439^31 (LC-3) 4^' ' yl]-acetic acid
[2-(1-Butyryl-piperidin-3- ς fi ri2 i nia ylmethylsulfanyl)-5,6- C19H23CI2N3O3S 1.09 ϋ,b-uι_j-ι-ιπa djch|oro.benzoimidazo|.i_ 444.38 (LC-3) 44ύ'ay yl]-acetic acid
Table 48
Precursors 4,6-CF32-H-01b to 5,6-C12-H-l lb of the following Table 49 are prepared using a procedure analogous to one of those described for Precursors (5/6)-Me-D-01b, (5/6)-CN-H-01b or (5/6)-F-E-03b, using Intermediates 4,6-CF32-H-01b to 5,6-C12-H- 11b in place of 5-Me-D-Olc, 5-CN-H-Olc or 5-F-E-03c.
Formula fR [min] MS °ata Precursor Name MoI weight (Meth.) "^ + tert-Butyl [2-(5-
4,6-CF32-H- . mett?yl?f XyC?°^. C24H22F6N2O4S 1.33
01. benzylsulfanyl)-4,6-bιs- c 548.95
01 b trifluoromethyl- MB-°U {L^ ά> benzoimidazol-1 -yl]-acetate tert-Butyl [2-(5-Acetyl-2- 4,6-CF32-H- methoxy-benzylsulfanyl)- C25H24F6N2O4S 1.32
11b 4,6-bis-trifluoromethyl- 562.52 (LC-3) ∞*-&* benzoimidazol-1 -yl]-acetate toff-Butyl [2-(l-butyryl-
4,6-CF32-l- . ^ ^^'"if^ β u- C25H31F6N3O3S 1.33 cco no ni h ylmethylsulfanyl)-4,6-bιs- _„ _Q ,. r _ 568.06 uq D trifluoromethyl- bb Λb9 (Lυ"d) benzoimidazol-1 -yl]-acetate tert-Butyl [2-(5-
5,6-Me2-H- Methyloxycarbonyl- C24H28N2O4S 1.21 ΛΔΛ M 1 b benzylsulfanyl)-5,6- 441.01 ϋ1 D dimethyl-benzoimidazol-1- 44υ t3b (Lυ ό) yl]-acetate tert-Butyl [2-(5-acetyl-2-
5,6-Me2-H- methoxy-benzylsulfanyl)- C25H30N2O4S 1.17 . _ Q 11b 5,6-dimethyl- 454.58 (LC-3) 4S4-yy benzoimidazol-1 -yl]-acetate tert-Butyl [2-(1-butyryl- piperidin-3-
5,6-Wle2-l-01b ylmethylsulfanyl)-5,6- 460 05 dimethyl-benzoimidazol-1- yl]-acetate tert-Butyl [2-(5- methyloxycarbonyl- COIWICΌWOA^ 1 97 5,6-CI2-H-01b benzylsulfanyl)-5,6- C22H22CI2N2O4S 1 27 48Q g8 dichloro-benzoimidazol-1- W Uό* (L^'ύ) yl]-acetate tert-Butyl [2-(5-acetyl-2-
, fi π. „ ,,. methoxy-benzylsulfanyl)- C23H24CI2N2O4S 1.26 .^ 87 S| 5,6-dichloro-benzoimidazol- 495.42 (LC-3)
1-yl]-acetate rac tert-Butyl [2-(1-butyryl-
5,6-CI2-l-01b ylmethylsulfanyl)-5,6- C23H3.1 nn^«3°3S ,,V2I 499.92 dichloro-benzoimidazol-1- buυ-4δ (Lϋ"d) yl]-acetate
Table 49
Intermediates 4,6-CF32-H-01c to 5,6-C12-I-01c of the following Table 50 are prepared using a procedure analogous to one of those described for Intermediates 5 -Me-D-O Ic, 5-CN-H-Olc or 5-F-E-03c, using the appropriate 5-substituted benzimidazole-2-thiol in place of 5-methyl-li7-benzoimidazole-2-thiol, 5-cyano-l/J-benzoimidazole-2-thiol or 5-fluoro- 1 /f-benzoimidazole-2-thiol, respectively. MS Data MS Data
Formula tR [min]
Intermediate Name MoI weight (Meth.) m/z m/z [M- [M+H]+ H]+
4,6-bis-Trifluoromethyl-2-(3- 4,6-CF32-H- methyloxycarbonyl- C18H12F6N2O2S 1.22
434.85 433.26 01c benzylsulfanyl)- 434.36 (LC-3) benzoimidazole
4,6-bis-Trifluoromethyl-2-(3-
4,6-CF32-H- acetyl-6- C19H14F6N2O2S 1.21
448.83 447.17 11c methoxybenzylsulfanyl)- 448.38 (LC-3) benzoimidazole rac 4,6-Bis-trifluoromethyl-
4,6-CF32-l- 2-(1 -butanoyl-piperidin-3- C19H21F6N3OS 1.19
453.89 453.26 01c ylmethylsulfanyl)- 453.44 (LC-3) benzoimidazole
5,6-Dimethyl-2-(3-
5,6-Me2-H- methyloxycarbonyl- C18H18N2O2S 0.93
326.91 325.11 01c benzylsulfanyl)- 326.41 (LC-3) benzoimidazole
5,6-Dimethyl-2-(3-acetyl-6-
5,6-Me2-H- C19H20N2O2S 0.88 methoxybenzylsulfanyl)- 340.95 339.22 11c 340.44 (LC-3) benzoimidazole rac 5,6-Dimethyl-2-(1- butanoyl-piperidin-3- C19H27N3OS 0.85
5,6-Me2-l-01c 346 344.27 ylmethylsulfanyl)- 345.50 (LC-3) benzoimidazole
5,6-dichloro-2-(3- methyloxycarbonyl- C16H12CI2N2O2S 0.93
5,6-CI2-H-01c 326.91 325.11 benzylsulfanyl)- 367.25 (LC-3) benzoimidazole
5,6-dichioro-2-(3-acetyl-6-
C17H14CI2N2O2S 1.14 5,6-CI2-H-11 c methoxybenzylsulfanyl)- 380.87 n/a 381.28 (LC-3) benzoimidazole rac 5,6-Dichloro-2-(1- butanoyl-piperidin-3- C17H21C12N3OS 1.1
5,6-CI2-l-01c 385.92 n/a ylmethylsulfanyl)- 386.34 (LC-3) benzoimidazole
Table 50
Example 5-HCO-H-l Ia
[2-(5-Acetyl-2-methoxy-benzylsulfanyl)-5-formyl-benzoimidazol-l-yl]-acetic acid A solution of fert-butyl [2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-formyl- benzoimidazol-l-yl]-acetate (Precursor 5-HCO-H-l Ib5 16 mg, 0.035 mmol) in TFA / dichloromethane (1:1, 4 ml) is allowed to stir overnight at rt. The solvents are removed under a stream of air and the resulting products are dried under high vacuum. This yields the title compound (14 mg) in 100% as a yellow solid: fø = 0.94 min (LC-3), ESI-MS (pos.): m/z 398.86 [MH-H]+, ESI-MS (neg.): m/z 397.06 [M-H]+; 1H-NMR (DMSOd6): δ (ppm) 2.46 (s, 3H, COCH3), 3.88 (s, 3H, OCH3), 4.59 (s, 2H, SCH2), 4.96 (s, 2H, CH2CO2), 7.11 (d, 1 Harora), 7.65 (d, 1 Harom), 7.74 (d, 1 Harom), 7.90 (dd, 1 Harom), 8.06 (d, 1 8.12 (d, 1 Harom), 10.01 (s, IH, CHO).
Examples 5,6-F2-H-l Ia to 5-F-H-l Ia of the following Table 51 are prepared analogous to the procedure described for Example 5-HCO-H-l Ia, using Precursors 5,6-F2-H-l Ib to 5-F-H-l Ib in place of 5-HCO-H-l Ib.
MS Data MS Data
Formula tR [min]
Example Name m/z m/z [M- MoI weight (Meth.) [M+H]+ H]+
[2-(5-Acetyl-2-methoxy-
. . ,., „ 11 benzylsulfanyl)-5,6-difluoro- C19H16F2N2O4S 1.01
406.96 405.09 3>0 """ benzoimidazol-1-yl]-acetic 406.40 (LC-2) acid
[2-(5-Acetyl-2-methoxy- benzylsulfany))-5-
5-MeSO2-H- C20H20N2O6S2 0.91 methanesulfonyl- 448.83 447.03 11a 448.51 (LC-3) benzoimidazol-1 -yl]-acetic acid
[5-Acetyl-2-(5-acetyl-2-
5-MeCO-H- methoxy-benzylsulfanyl)- C21 H20N2O5S 0.94
412.84 411.04 11a benzoimidazol-1 -yl]-acetic 412.46 (LC-3) acid
[2-(5-Acetyl-2-methoxy- benzylsulfanyl)-4-fluorc~ C19H17FN2O4S 0.99
4-F-H-11a 388.83 387.03 benzoimidazol-1 -yl]-acetic 388.41 (LC-3) acid
[2-(5-Acetyl-2-methoxy- benzylsulfanyl)-5-
C20H17F3N2O4S 1.07
5-CF3-H-11a trifluoromethyl- 438.86 437.06 438.42 (LC-3) benzoimidazol-1 -yl]-acetic acid
[2-(5-Acetyl-2-methoxy- benzylsulfanyl)-5-fluoro- C19H17FN2O4S 0.96
5-F-H-11a 388.94 387.08 benzoimidazol-1 -yl]-acetic 388.41 (LC-3) acid
Table 51 Example 6-F-H-l Ia
F2-(5 - Acetyl-2-methoχv-benzylsulfanylV6-fluoro-benzoimidazol- 1 -yl] -acetic acid To a solution of methyl [2-(5-acetyl-2-methoxy-benzylsulfanyl)-6-fluoro- benzoimidazol-l-yl]~acetate (Precursor 6-F-H-l Ib5 11.3 mg, 0.029 mmol) in dry THF (0.3 ml) is added some 1 N aqueous lithium hydroxide solution (0.140 ml, 5 eq.). The resulting biphasic solution is allowed to stir 1 h at rt. The solvents are removed in vacuo, water is added as well as IN HCl in water so as to set the pH of the aqueous solution to pH=l. The resulting acidic aqueous phase is extracted three times with AcOEt. The organic phase is dried over Na2SO4 and the solvent removed in vacuo and the product was dried under high vacuum. This yields the title compound (6 mg) in
55% as a greyish solid: tR = 0.95 min (LC-3), ESI-MS (pos.): m/z 388.89 [M+H]+, ESI- MS (neg.): m/z 387.10 [M-H]+; 1H-NMR (DMSO-d6): δ (ppm) 2.40 (s, 3H, COCH3), 3.87 (s, 3H, OCH3), 4.49 (s, 2H, SCH2), 4.82 (s, 2H, CH2CO2), 7.01 (t, 1 Harom), 7.09 (d, 1 Harom), 7.42 (d, 1 Harom), 7.53 (dd, 1 Harom), 7.86 (d, 1 Harom), 7.98 (s, 1 Harom).
Example 5-F-H-l Ia (1'-Me) of the following Table 52 is prepared analogous to the procedure described for Example 6-F-H-l Ia, using Precursor 5-F-H-l Ib (1'-Me) in place of 6-F-H-l Ib.
rac 2-[2-(5-Acetyl-2-
5-F-H-11a (1'- methoxy-benzylsulfanyl)-5- C20H19FN2O4S 1.00 ,n9 R7 ,m f17 Me) fluoro-benzoimidazoi-1-yl]- 402.44 (LC-3) 4UZ'0 / ^u ι u / propionic acid
Table 52
Precursors 5-HCO-Hl lb to 5-F-H-l Ib (1'-Me) of the following Table 53 are prepared using a procedure analogous to that described for Precursor H-OIb, substituting l-(3- chloromethyl-4-methoxy-phenyl)-ethanone for 5-bromo-hexanoic acid ethyl ester and using Intermediates 3 -III to 3-IXbis for Intermediate 3-1. cnrm..ι^ + Trnin-i WS Data WIS Data
Precursor Name .J*™* « ™ n* mfcpt
IWl+MJ MJ ferf-Butyl [2-(5-acetyl-2-
,, Hrn u Λ Λ h methoxy-benzylsulfanyl)-5- C24H26N2O5S 1.13 ,,- , Q_ .
5-HCO-H-11b formyl.b y enzoit;idazoi.i.y|]. 454.54 (LC-3) 45492 n/a acetate ferf-Butyl [2-(5-acetyl-2-
* fi P9 n nh methoxy-benzylsulfanyl)- C23H24F2N2O4S 1.06 , a.b-i-z-H-nD 5,6-difluoro-benzoimidazol- 462.51 (LC-3) 4bό-όZ n/a
1-yl]-acetate ferf-Butyl [2-(5-acetyl-2- 5-MeSO2-H- methoxy-benzylsulfanyl)-5- C24H28N2O6S2 1.08
11b methanesulfonyi- 504.62 (LC-3) ϋU4-ai &υd^& benzoimidazol-1 -yl]-acetate ferf-Butyl [5-acetyl-2-(5-
5-MeCO-H- acetyl-2-methoxy- C25H28N2O5S 1.13 ΛRo Qo ,
11a benzylsulfanyl)- 468.57 (LC-3) 4bo yo n/a benzoimidazol-1 -yl]-acetate ferf-Butyl [2-(5-acetyl-2-
4 F H 11H methoxy-benzylsulfanyl)-4- C23H25FN2O4S 1.16 . ,
4-r-H- ι i D f|uoro-benzoimidazol-1-yl]- 444.52 (LC-3) 444'0y n/a acetate ferf-Butyl [2-(5-acetyl-2- c z-co u ^K methoxy-benzylsulfanyl)-5- C24H25F3N2O4S 1.21 ,n, n, ,
5-CF3-H-11b trffiuoromethyl- 494.53 (LC-3) 494-94 n/a benzoimidazol-1 -yl]-acetate ferf-Butyl [2-(5-acetyl-2- π c u .H I, methoxy-benzylsulfanyl)-5- C23H25FN2O4S 1.16 , ,,,- πo /
5-F-H-11b fluoro.benjjoimidazoi.ij.y,]. 444.52 (LC-3) 445-03 n/a acetate
Methyl [2-(5-acetyl-2-
R P U 11 K methoxy-benzylsulfanyl)-6- C20H19FN2O4S 1.06 ,n0 R7 , b-i-M-no fiuoro.beπzoimidazoi^.yi]. 402.44 (LC-3) 4U^a' n/a acetate
Ethyl 2-[2-(5-acetyl-2-
5-F-H-Ha (I1- methoxy-benzylsulfanyl)-5- C22H23FN2O4S 1.12 ,. Q7 ,
Me) fluoro-benzoimidazol-1-yl]- 430.49 (LC-3) propionate
Table 53
Intermediate 3 -VIII ført-Butyl (2-mercapto-5 -trifluoromethyl-benzoimidazol- 1 -vD-acetate
In a test tube equipped with a septum, tert-butyl (2-nitro-4-trifluoromethyl- phenylamino)-acetate (Starting material 5-VIII, 80 mg, 0.25 mmol) is dissolved in dry THF (0.5 ml). Argon is allowed to bubble through this solution for 10 min. Then dry palladium on carbon (10% w/w, 26 mg, 10% mol) is added and the flask is set under H2 atmosphere. The resulting mixture is shaken vigorously at rt overnight. If necessary, another 8% mol of palladium on charcoal 10% w/w is added and the resulting suspension is stirred for another hour under H2 atmosphere. The crude mixture is then filtered over celite to remove any solid particle. The celite is rinsed once with dry THF. To the resulting light yellow solution is added, under argon, 1,1'- thiocarbonyldiimidazole (89 mg, 0.5 mmol, 2 eq.). The resulting orange solution is allowed to stir at rt for 5 h. Water is then added. The yellow solid formed is filtered over a fritted funnel, rinsed thoroughly with water and dried under high vacuum. This yields the title compound (60 mg) in 73% as a yellow solid: fo = 1.10 min (LC-3), ESI- MS (pos.): m/z 332.99 [M+H]+, 331.13 [M-H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.41 (s, 9H5 ffiu), 5.06 (s, 2H, NHCH2CO2), 7.44 (s, IH, Harora), 7.57 (s, 2H, Harom), 13.25 (br. s, IH, SH).
Intermediates 3 -III to 3-IXbis of the following Table 54 are prepared using a procedure analogous to that described for Intermediate 3 -VIII, using Starting materials 5 -III to 5- IXbis in place of Starting material 5-VIII.
In some cases the product was purified by flash-chromatography on silica-gel using a suitable (AcOEt / heptane) mixture [(3:7), (4:6) or (5:5)] as the eluent.
i-wr«,.iα * rmir.i WS Data MS Data ,πtermediate Name „*£* J£jJ
tert-Butyl (5-formyl-2- C14H16N2O3S 1
3-Ilf mercapto-benzoimidazol-1- ,«, « n fl ~ π/a 291.15 yl)-acetate z^ όb [L^~ά)
tert-Butyl (5,6-difluoro-2- r1oH14F?κ,o0?q - O1
3-IV mercapto-benzoimidazol-1- «„„ ,,, n n L n/a 299.17 yl)-acetate 300-32 (LC"3)
tert-Butyl (2-mercapto-5- C14H18N2O4S2 0 97
3-V methanesulfonyl- 342 43 (LC-3) 34Z82 34116 benzoimidazol-1-yl)-acetate '
tert-Butyl (5-acetyl-2- r1 w1 oM,mς 1
3-VI mercapto-benzoimidazol-1- ,«£ ,£ ι\ r n\ n/a 305-12 yl)-acetate 306-38 (LC"3) •* vπ tert-Butyl (4-fuoro-2- C13H15FN2O2S 1.03 , oo, _
3-vll mercapto-benzoιmιdazol-1- 282 33 (LC-3) 281.13 yl)-acetate
ferf-Butyl (5-fluoro-2- C13H15FN2O2S 1.05 . 0_, „
3-IX mercapto-benzoimιdazol-1- OQO M ,, ^ - n/a 281.13 yl)-acetate v y
Methyl (6-fluoro-2- noHqFN?02S 0 9
3-X mercapto-benzoimidazol-1- 240 25 (LC-3) 240'89 239-17 yl)-acetate ' ( ' )
rac Ethyl 2-(5-fluoro-2- riou-i <5FN9n:?ς n QQ
3-IXbis mercapto-benzoimidazol-1- 268 31 (LC 3Ϊ 268>" 267 09 yl)-propionate ' \ ~ )
Table 54
Starting material 5 -VIII fert-Butyl (2-nitro-4-trifluoiOmethyl-phenylamino)-acetate
A mixture of 4-fluoro-3-nitrobenzotrifluoride (209 mg, 1 mmol), glycine tert-butyl ester hydrochloride (201 mg, 1.2 mmol) and NaHCO3 (128 mg, 2 mmol) in dry DMSO (1 ml) is stirred overnight at 50 or 650C. In case the reaction is not complete a further heating at 85°C to 1000C for 3 h is necessary. The reaction is then cooled to rt and water is added. The yellow to orange solid formed is filtered over a fritted funnel, rinsed thoroughly with water and dried under high vacuum. This yields the title compound (254 mg) in 79% as a yellow solid: tR = 1.08 min (LC-3), ESI-MS (pos.): m/z 403.2 [M+2AcCN]+, m/z 321.56 [M+H]+, 1H-NMR (DMSO-d6): δ (ppm) 1.44 (s, 9H, *Bu). 4.23 (d, 2H, NHCH2CO2), 7.08 (d, IH, Harom), 7.80 (dd, IH, Harom), 8.34 (br. s, IH, Harom), 8.65 (t, I H5 NH).
Starting materials 5-III to 5-IXbis of the following Table 55 are prepared using a procedure analogous to that described for Starting material 5 -V, substituting the appropriate o-nitrofluorobenzene for 4-fluoro-3-nitrobenzotrifluoride and the appropriate amino-acid ester hydrochloride for glycine tert-bvAyl ester hydrochloride. In some cases the product is purified by recrystallization out of a heptane / toluene (1:1) mixture or by flash-chromatography on silica gel using a heptane / AcOEt (4:1) mixture as eluent. Starting Formula tR [min] MS Data MS Data material Name MoI weight (Meth.) m/z m/z [M-
[MtH]+ HΓ
fert-Butyl (4-formyl-2-nitro- C13H16N2O5 1.09
5-III n/a 279.33 phenylamino)-acetate 280.28 (LC-3)
- .w tert-Butyl (4,5-difluoro-2- C12H14F2N2O4 1.09 , 007 14 nitro-phenylamino)-acetate 288.25 (LC-3) n/a ∞t- w
π 5-uV me Hth,a fneerfs'uB|lffoynly Il4-O2-n •ι♦tro- C13H18N2O6S (L 1C.0.43) n/a 329.19 phenylamιno)-acetate '
tert-Butyl (4-acetyl-2-nitro- C14H18N2O5 1.1
5-VI 294.89 n/a phenylamino)-acetate 294.30 (LC-3)
_ .... tert-Butyl (3-fluoro-2-nitro- C12H15FN2O4 1.01 , ,
°"v" phenylamino)-acetate 270.26 (LC-3) π/a n/a
.y tert-Butyl (4-fluoro-2-nitro- C12H15FN2O4 1.03 71 „ . . phenylamino)-acetate 270.26 (LC-3) ^ '
Methyl (5-fluoro-2-nitro- C9H9FN2O4 1.94
5-X 228.8 227.2 phenylamino)-acetate 228.18 (LC-2)
rac Ethyl 2-(4-Fluoro-2-
C11H13FN2O4 1.14 5-IXbis nitro-phenylamino)- 271.03 n/a 256.23 (LC-3) propionate
Table 55
Example 5-F-H-17a
{2-r5-(2,3-Dihydro-indole-l-carbonyl)-2-methoxy-benzylsulfanyl]-5-fluoro- benzoimidazol-1-vU -acetic acid tert-Butyl {2-[5-(2,3-dihydro-indole-l-carbonyl)-2-methoxy-benzylsulfanyl]-5-fluoro- benzoimidazol-1-yl} -acetate (Precursor 5-F-H-17b, 26 mg, 0.047 mmol) in a TFA / dichloromethane mixture (1:1, 0.5 ml) is allowed to stir at rt for 4 h. The solvents are removed under a stream of air. The product is precipitated in Et2O, filtered, rinsed with Et2O and dried under high vacuum. This yields the title compound (22 mg) in 99% as a light pink solid: tR = 1.04 min (LC-3), ESI-MS (pos.): m/z 492.11 [M+H]+, ESI-MS (neg.): m/z 490.18 [M-H]+; 1H-NMR (DMSO-d6): δ (ppm) 2.88 (t, 2H5 NCH2CH2Ar)5 3.85 (t, 2H, NCH2CH2Ar), 3.89 (s, 3H5 OCH3), 4.54 (s, 2H5 SCH2), 4.95 (s, 2H5 CH2CO2), 6.97 (t, 1 Harom), 7.02-7.09 (m, 4 Harom)5 7.11 (d5 1 Harom)5 7.21 (d, 1 H3T01n), 7.38-7.57 (m, 3 Harom).
Examples 5-F-H-18ato 5-F-H-29a of the following Table 56 are prepared analogous to the procedure described for Example 5-F-H-17a, using Precursors 5-F-H-18b to 5-F-H- 29b in place of 5-F-H-17b. In some cases purification must be carried out by preparative HPLC.
Formula .R [min] MS Data MS Data
Example Name m/z m/z [M- MoI weight (Meth.) [M+H]+ H]+
[2-(5-Butylcarbamoyl-2- methoxy-benzylsulfanyl)-5- C22H24FN3O4S 1.00
5-F-H-18a 446.12 444.18 fluoro-benzoimidazol-1-yl]- 445.51 (LC-3) acetic acid
{2-[2-Methoxy-5-
(morpho)ine-4-carbonyl)-
C22H22FN3O5S 0.88
5-F-H-19a benzylsulfanyl]~5-fluorc- 460.18 458.17 459.49 (LC-3) benzoimidazol-1 -yl}-acetic acid
[2-(5-Benzylcarbamoyl-2- methoxy-benzylsulfanyl)-5- C25H22FN3O4S 1.01
5-F-H-20a 480.13 478.19 fluoro-benzoimidazol-1 -yl]- 479.52 (LC-3) acetic acid
[2-(5-Diethylcarbamoyl-2- methoxy-benzylsulfanyl)-5- C22H24FN3O4S 0.96
5-F-H21a fluoro-benzoimidazol-1-yl]- 445.51 (LC-3) 446.19 444.18 acetic acid
{2-[5-(Benzyl-ethyl- carbamoyl)-2-methoxy-
C27H26FN3O4S 1.04
5-F-H22a benzylsulfanyl]-5-fluoro- 508.19 506.25 507.58 (LC-3) benzoimidazol-1-yl}-acetic acid
[2-(5-Acetyl-2-ethoxy- benzylsulfanyl)-5-fluoro- C20H19FN2O4S 1.01
5-F-H23a 403.04 401.1 benzoimidazol-1 -yl]-acetic 402.44 (LC-3) acid
{2-[5-Acetyl-2-(3-hydroxy- propoxy)-benzylsulfanyl]-5- C21 H21 FN2O5S 1.48
5-F-H-24a 433.3 431.16 fluoro-benzoimidazol-1 -yl}- 432.47 (LC-3) acetic acid [2-(5-Acetyl-2-propoxy-
* F n o*a benzylsulfanyl)-5-fluoro- C21H21FN2O4S 1.05 5-F-H-25a benzoimidazol-1-yl]-acetic 416.47 (LC-3) 417" 1 415"16 acid
[2-(5-Acetyl-2-butoxy- ς F H9Ra benzylsulfanyl)-5-fluoro- C22H23FN2O4S 1.09 5-F-H26a benzoimidazol-1-yl]-acetic 430.49 (LC-3) 43106 429/l 5 acid
[2-(5~Benzoyl-2-methoxy-
5-F-H27a benzylsulfanyl)-5-fluoro- C24H19FN2O4S 1.07 O h H^a benzoimidazol-1 -yl]-acetic 450.48 (LC-3) 4i3i "U4 44B"ab acid
[5-Fluoro-2-(6-methoxy-3-
5-F-H28a ylmethJϊsuTanyl)- ^n^2043 n°r 9l 401.04 399.1 benzoimidazol-1 -yl]-acetic ™'^ *L ; acid [5-Fluoro-2-(3-methoxy-8- oxo-5, 6,7, 8-tetrahydro-
5-F-H29a naphthalen-2- C21H19FN2O4S 1.00 δ h M/aa ylmethylsulfanyl)- 414.45 (LC-3) 41 b'Uv3 41 ci-υy benzoimidazol-1 -yl]-acetic acid
Table 56
5-F-H-17b tert-Butyl {2-[5-(2,3-dihydro-indole-l-carbonyl)-2-methoxy-benzylsulfanyl]-5-fluoro- benzoimidazol- 1 -yl) -acetate
To a [2-(3-hydroxycarbonyl-benzylsulfanyl)-5-fluoro- benzoimidazol-1-yl] -acetate (Precursor 5-F-H-OOb, 44.6 mg, 0.1 mmol) in dry DMF (0.8 ml) are added successively Et3N (21.1 μl, 15.2 mg, 0.15 mmol, 1.5 eq.), HOBt (23.0 mg, 0.15 mmol, 1.5 eq.), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (28.8 mg, 0.15 mmol, 1.5 eq.) and indoline (16.8 μl, 17.9 mg, 0.15 mmol, 1.5 eq.). The reaction mixture is stirred at rt overnight. The solvents are evaporated under reduced pressure, dichloromethane (4 ml) is added and the resulting organic phase is washed once with 2 ml of a IM NaHCO3 solution in water and once with 2 ml of a IM solution of sodium hydrogen sulfate in water. The acidic aqueous phase was extracted once with dichloromethane (2 ml). The combined organic phase is washed with brine. The solvent is removed under a stream of air and the resulting crude product is dried under high vacuum overnight yielding the title compound (40 mg) in 83% as a light brown oil: tR = 1.20 min (LC-3), ESI-MS (pos.): m/z 548.23 [M+H]+, 1H-NMR (CDCl3): δ (ppm) 1.400 (s, 9H, tBu), 2.95 (t, 2H, NCH2CH2Ar), 3.91 (s, 3H, OCH3), 3.95 (t, 2H, NCH2CH2Ar), 4.65 (s, 2H, SCH2), 4.72 (s, 2H, CH2CO2), 6.91- 7.19 (m, 7 Harom), 7.45 (m, 1 Harom), 7.52 (m, 1 Harom), 7.64 (m, 1 Harom).
Precursors 5-F-H-18b to 5-F-H22b of the following Table 57 are prepared using a procedure analogous to that described for Precursor 5-F-H-17b, substituting the appropriate sulfonyl chloride for 2-phenyl-ethenesulfonyl chloride.
MS Data MS Data
Formula tR [min]
Precursor Name m/z m/z [M- MoI weight (Meth.) [M+H]+ H]+ ferf-Butyl [2-(5- butylcarbamoyl-2-methoxy- C26H32FN3O4S 1.16
5-F-H-18b benzylsulfanyl)-5-fluoro- 501.61 502.23 500.23
(LC-3) benzoimidazol-1 -yl]-acetate terf-Butyl {5-fluoro-2-[2- methoxy-5~(morpholine-4- C26H30FN3O5S 1.09
5-F-H-19b 514.56 carbonyl)-benzylsu!fanyl]- 515.60 516.29
(LC-3) benzoimidazol-1 -yl}-acetate ferf-Butyl [2-(5- benzylcarbamoyl-2-methoxy- C29H30FN3O4S 1.17
5-F-H-20b 536.24 534.23 benzylsulfanyl)-5-fluoro- 535.63 (LC-3) benzoimidazol-1 -yl]-acetate ferf-Butyl [2-(5- diethylcarbamoyl-2-methoxy- C26H32FN3O4S 1.14
5-F-H21b 502.3 n/a benzylsulfanyl)-5-fluoro- 501.61 (LC-3) benzoimidazol-1 -yl]-acetate ferf-Butyl {2-[5-(benzyl-ethyl- carbamoyl)-2-methoxy~ C31H34FN3O4S 1.21
5-F-H22b 564.30 n/a benzylsulfanyl]-5-fluoro- 563.68 (LC-3) benzoimidazol-1 -yl}-acetate
Table 57
Precursor 5-F-H-OOb ferf-Butyl |"2-(3-hvdroxycarbonyl-benzylsulfanyl)-5-fluoro-benzoimidazol-l-vn-acetate To a solution of 3-hydroxymethyl-4-methoxy-benzoic acid (Starting material H-OOe, 910 mg, 5 mmol) in dry THF (50 ml) cooled to 0°C under inert atmosphere are added successively triphenylphosphine (1782 mg, 6 mmol, 1.2 eq.) and di-tert-buty\- azodicarboxylate (1381 mg, 6 mmol, 1.2 eq). The initially deep yellow colour disappears after 10 min. Then tert-butyl (5-fluoro-2-mercapto-benzoimidazol-l-yl)- acetate (Intermediate 3-HI9 1270 mg, 0.9 mmol, 0.9 eq.) is added. The reaction mixture is allowed to warm up to rt and stirred at this temperature for 1 h. Evaporation of the solvent in vacuo and purification by fiash-chromatography on silica gel (AcOEt / heptane/ AcOH, 10:90:1), provides the title compound (680 mg) in 30% as beige solid: fR = 1.08 min (LC-3), ESI-MS (pos.): m/z 447.09 [M+H]+, ESI-MS (neg.): m/z 426.18 [M-H]+.
Starting material H-OOe
3 -Hvdroxymethyl-4-methoxy-benzoic acid Onto a warm solution of Ca(OCl)2 (7.14 g, 49.95 mmol, 3.3 eq.) in water (25 ml) is added a warm solution Of K2CO3 (5.14 g, 37.35 mmol, 2.49 eq.) and KOH (1.46 g, 26.1 mmol, 1.74 eq.) in water (25 ml) . After 30 min of vigourous stirring, the undesired solid formed is filtered and rinsed with little water. The solution obtained is poured onto a suspension of l-(3-chloromethyl-4-methoxy-phenyl)-ethanone (2.98 g, 15 mmol) in 1 ,4-dioxane (10 ml). The resulting suspension is stirred 2 h at rt and 2 h at 70°C.Under cooling of the suspension in an ice bath, are subsequently added solid NaHSO3 (100 mg), then 96% sulfuric acid until pH = 3. The aqueous phase thus obtained is extracted four times with AcOEt. The combined organic phase is washed with brine and dried over Na2SO4. Evaporation of the solvent in vacuo yields the title compound (1.8 g) in 66% as a white solid, fR = 0.72 min (LC-3), ESI-MS (pos.): m/z 182.99 [M+Hf.
Precursors 5-F-H-23b to 5-F-H-29b of the following Table 58 are prepared using a procedure analogous to that described for Precursor H-OIb, using Alkylating agents H- 23 d to H-29d in place of 5-bromo-hexanoic acid ethyl ester.
MS Data
Formula tR [min]
Precursor Name MoI weight (Meth.) m/z [M+Hf ferf-Butyl [2-(5-acetyl-2- ethoxy-benzylsulfanyl)-5~ C24H27FN2O4S 1.18
5-F-H23b 459.14 fluoro-benzoimidazol-1 -yl]- 458.55 (LC-3) acetate tert-Butyl {2-[5-acetyl-2-(3- hydroxy-propoxy)- C25H29FN2O5S 1.08
5-F-H-24b benzylsulfanyl]-5-fluoro- 488.57 (LC-3) 489.07 benzoimidazol-1 -yl}-acetate tert-Butyl [2-(5-acetyl-2- propoxy-benzylsulfanyl)-5- C25H29FN2O4S 1.22
5-F-H-25b 473.20 fluoro-benzoimidazol-1 -yl]- 472.57 (LC-3) acetate tert-Butyl [2-(5-acetyl-2- butoxy-benzylsulfanyl)-5- C26H31 FN2O4S 1.24
5-F-H26b 487.13 fluoro-benzoimidazol-1 -yl]- 486.60 (LC-3) acetate tert-Butyl [2-(5-benzoyl-2- methoxy-benzylsulfanyl)-5- C28H27FN2O4S 1.22
5-F-H27b 507.22 fluoro-benzoimidazol-1 -yl]- 506.59 (LC-3) acetate tert-Butyl [5-fluoro-2-(6-
5-F-H28b methoxy-3-oxo-indan-5- C24H25FN2O4S 1.16 457.14 ylmethylsulfanyl)- 456.53 (LC-3) benzoimidazol-1 -yl]-acetate tert-Butyl [5-fluoro-2-(3- methoxy-8-oxo-5, 6,7,8-
5-F-H29b C25H27FN2O4S 1.17 tetrahydro-naphthalen-2- 470.56 (LC-3) 471.20 ylmethylsulfanyl)- benzoimidazol-1 -yl]-acetate
Table 58
Alkylating agents H-23d to H-29d of the following Table 59 are prepared using a procedure analogous to that described for Alkylating agent H-12d, substituting the corresponding reagent or H-24g for 4-methoxybenzoic acid isopropyl ester.
Alkylating Formula
Name agent MoI weight (Mβth.) „£* .
H-23d 1-(3-Chloromethyl-4-ethoxy- C11 H13CIO2 1.07
213.09 phenyl)-ethanone 212.67 (LC-3)
1-[3-Chloromethyl-4-(3-
C12H15CIO3 0.92 H-24d hydroxy-propoxy)-phenyl]- 243.05 242.70 (LC-3) ethanone
1-(3-Chloromethyl-4- C12H15CIO2 1.11
H-25d propoxy-phenyl)-ethanone 226.70 (LC-3) 227.13 „ ,. . 1-(3-Chloromethyl-4-butoxy- C13H17CIO2 1.15 oα phenyl)-ethanone 240.73 (LC-3) ^4 ' ' "
H __ . (S-ChloromethyW-methoxy- C15H13CIO2 1.01 „„ . , . phenyl)-phenyl-methanone 260.72 (LC-3) π - π
6-Chloromethyl-5-methoxy- C11H11CIO2 0.99
H-28d indan-1-one 210.66 (LC-3) 211.08
7-Chloromethyl-6-methoxy-
C12H13CIO2 1.04 H-29d 3,4-dihydro-2H-naphthalen- 225.06 224.68 (LC-3) 1-one
Table 59
Starting material H-24g 1 - [4-(3 -Hydroxy-propoxyVphenyl] -ethanone is prepared according to the procedure described in: Mandoli, A.; Calamante, M.; Feringa, B. L.; Salvadori, P. Tetrahedron Asymmetry 2003, 14, 3647-3650.
Examples 5-F-I-01a to 5-F-I-35a of the following Table 60 are prepared analogous to the second procedure described for the synthesis of Example I-01a, using Precursors 5- F-I-OIb to 5-F-I-35b in place of 5-F-H-17b. The products which did not crystallize were pure enough to be used as such in the next step.
MS Data MS Data
Formula t* [min]
Example Name m/z m/z [M- MoI weight (Meth.) [M+H]+ H]+ rac [2-(1-Butyryl-piperidin- 5-F-I-OIa 3-y'methyIsulfanyl)-5-fluoro- C19H24FN3O3S 0.92
394.02 392.22 benzoimidazol-1-yl]-acetic 393.48 (LC-3) acid rac {5-Fluoro-2-[1-(furan-2-
5-F-l-11a 417.89 416.16
(LC-3) benzoimidazol-1-yl}~acetic " acid rac {2-[1-(4-Bromo- benzoyl)-piperidin-3- C22H21 BrFN3O3S 1.01 5-F-l-13a ylmethylsulfanyl]-5-fluoro- 507.89 506.09 506.39 (LC-3) benzoimidazoi-1-yl}-acetic acid
(S)-[5-Fluoro-2-(1- benzyloxycarbonyl-azetidin- C21H20FN3O4S 1.02 5-F-l-34a 2-ylmethylsulfanyl)- 430.12 428.18 429.46 (LC-3) benzoimidazol-1 -yl]-acetic acid
[5-Fluoro-2-(1- benzyloxycarbonyl-azetidin-
C21H20FN3O4S 1.01 5-F-l-35a 3-ylmethylsulfanyl)- 429.98 428.11 429.46 (LC-3) benzoimidazol- 1 -yl]-acetic acid
Table 60
Precursor 5-F-I-Olb rac ferf-Butyl [2-(l-butyryl-piperidm-3-ylmethylsulfanyl)-5-fluoro-benzoimidazol-l- yl] -acetate
To a solution of l-(3-hydroxymethyl-piperidin-l-yl)-butan-l-one (Starting material I- 01e, 278 mg, 1.5 mmol, 1.5 eq.) in dry THF (10 ml) cooled to 00C under inert atmosphere are added successively triphenylphosphine (458 mg, 1.75 mmol, 1.75 eq.) and di-fert-butyl-azodicarboxylate (402 mg, 1.75 mmol, 1.75 eq). The initially deep yellow colour disappears after 10 min. Then te7"t-butyl (5-fluoro-2-mercapto- benzoimidazol-l-yl)-acetate (Intermediate 3 -III, 280 mg, 1 mmol) is added. The reaction mixture is slowly allowed to warm up to rt overnight. Evaporation of the solvent in vacuuo and purification by flash-chromatography on silica gel (AcOEt / heptane, 2:3), provides the title compound (217 mg) in 95% as a slightly yellow resin: tR = 1.14 min (LC-3), ESI-MS (pos.): m/z 450.08 [M+H]+.
Precursors 5-F-I-l Ib to 5 -1-35b of the following Table 61 are prepared using a procedure analogous to that described for Precursor 5-F-I-Olb, using Starting material I- 11 e to 1-35 e in place of Starting material 1-01 e.
M Formula tR [min] MS D. ata
Precursor Name MoI weight (NMh.) [M"£]+ rac tert-Butyl {5-fluoro-2-[1- (furan-2-carbonyl)-piperidin- C24H28FN3O4S
5-F-I-11 b 1.19
3-ylmethylsulfanyl]- 473.56 474.03 (LC-3) benzoimidazol-1 -yl}-acetate rac te/f-Butyl {2-[1-(4- bromo-benzoyl)-piperidin-3- C26H29BrFN3O3S
5-F-l-13b 1.18 ylmethylsulfanyl]-5-fluoro- 562.49 (LC-3) 563.98 benzoimidazol-1 -yl}-acetate
(S)-fert-Butyl [5-Fluoro-2-(1- benzyloxycarbonyl-azetidin- C25H28FN3O4S
5-F-l-34b 1.19
2-ylmethylsulfanyl)- 485.57 (LC-3) 485.98 benzoimidazol-1-yl]-acetate terf-Butyl [5-fluoro-2-(1-
5-F-l-35b benzyloxycarbonyl-azetidin- C25H28FN3O4S 1.16
3-ylmethylsulfanyl)- 485.57 (LC-3) 486.02 benzoimidazol-1-yl]-acetate
Table 61
Starting materials 1-1 Ie and I-13e of the following Table 62 are prepared using a procedure analogous to that described for Starting material I-Ole, substituting the corresponding acid chloride to butyryl chloride.
Starting Formula fe [min] ^1?* material vam MoI weight (Meth.) πjj+m*
ruran-_i-yl-(o- PI U-H ^MΠ^ n R9 l-11e hydroxymethyl-piperidin-1- όnα ™ /i r l 210-15 yl)-methanone 209-24 (LC"3)
(4-Bromo-phenyl)-(3- π ^H-)fiRrNΩ? n 77 l-13e hydroxymethyl-piperidin-1- oaa Tά n r τ\ 298 ' 1 yl)-methanone 298" 18 (LC'3)
Table 62
Starting material 1-34e
(S)-2-HvdiOxymethyl-azetidine-l-carboxylic acid benzyl ester
To a solution of (S)-Azetidine-l,2-dicarboxylic acid 1 -benzyl ester (Starting material I-
34f, 94 mg, 0.4 mmol) in 0.3 ml dry THF cooled to 0°C is added dropwise 450 μl of a IM solution of borane in THF. The resulting solution is allowed to stir for 1 h at 0°C and warm up to rt overnight. AcOH (1 ml) and water (1 ml) are then added as well as some saturated NaHCO3 solution in water until pH=9 and no more gas evolution occurs. The resulting aqueous phase is extracted three times with AcOEt. The combined organic phase is washed once with some saturated NaHCO3 solution in water and once with water. The solvents are evaporated in vacuo and the crude oil dried under high vacuum overnight, yielding the title compound (79 mg) in 89% as a colourless oil: tR = 0.84 min (LC-3), ESI-MS (pos.): m/z 222.08 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 2.00 (m, IH, CH2CH2N), 2.22 (m, IH, CH2CH2N), 3.78-4.01 (m, 5H, CH2N and CH2OH), 4.52 (s, 2 H, OCH2Ph), 7.35 (s, 5 H, Harom.).
Starting material 1-35 e of the following Table 63 is prepared using a procedure analogous to that described for Starting material I-34e, substituting Starting material I- 35f for l-34f.
MS Data
Starting Formula tR [min]
Name m/z material WIoI weight (Meth.) [M+H]+
3-Hyd roxymethyl-azetid ine-
C12H15NO3 0.87 l-35e 1-carboxylic acid benzyl 222.22 221.26 (LC-3) ester
Table 63
Starting material I-34f (S)-Azetidine-l,2-dicarboxylic acid 1 -benzyl ester To a solution of L-azetidine-2-carboxylic acid (101.1 mg, 1 mmol) in 2N aqueous NaOH (0.675 ml) is added benzylchloroformiate (169 μl, 204.7 mg, 1.2 eq.) and the resulting mixture is stirred at rt for 2 h. The aqueous phase is washed once with Et2O. The aqueous solution is set to pH=2 with a concentrated aqueous HCI solution and then saturated with solid Na2SO4. It is extracted three times with AcOEt. The combined organic phase is dried over Na2SO^ The solvents are evaporated under a stream of air and the crude oil dried under high vacuum overnight, yielding the title compound (126 mg) in 53% as a colourless oil: tR = 0.76 min (LC-3), ESI-MS (pos.): m/z 277.16 [M+Na]+; 1H-NMR (CDCl3): δ (ppm) 2.53 (bs, 2H, CH2CH2N), 4.01 (t, 2H, CH2N), 4.82 (t, 1 H, CHCO2H), 5.15 (s, 2H, OCH2Ph)5 7.35 (s, 5 H, Harom.).
Starting material 1-35f of the following Table 64 is prepared using a procedure analogous to that described for Starting material I-34f, substituting 3-azetidine carboxylic acid for L-azetidine-2-carboxylic acid.
MmKM. Name J*^ WJJJJ jT
. ,_, Azetidine-1 ,3-dicarboxylic C12H13NO4 0.75 _„_ . .
1^0 acid monobenzyl ester 235.25 (LC-3) ύ°' 4
Table 64
Example 5-F-I-29a rac [5-Fluoro-2-(l-phenylacetyl-pyrrolidin-3-ylmethylsulfanyl)-benzoimidazol-l-yll- acetic acid rac [2-(Pyrrolidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl] -acetic acid (Precursor 5 -F- I-36a, 17.3 mg, 0.05 mmol) is suspended in dichloromethane (1 ml) and Et3N (10.2 mg, 14.3 μl, 0.1 mmol, 2 eq.) as well as phenylacetyl chloride (9.28 mg, 8.00 μl, 0.06 mmol, 1.2 eq.) are added subsequently. The resulting mixture is stirred for 1 h at rt. Some IN aqueous NaOH solution (1 ml) was added and the mixture is allowed to stir at rt for 1 h. Then dichloromethane (1 ml) and water (1 ml) are added and the aqueous solution is washed twice with dichloromethane to remove non-acidic impurities. The combined organic phase is washed with brine. Both aqueous phases (basic + brine) are then made acidic with 1 ml AcOH and the crude acid is extracted twice with dichloromethane (2 ml). The combined organic phases are washed with brine and dried over Na2SO4. Evaporation of the solvent in vacuo and drying under high vacuum, yields the title compound (15 mg) in 68% as a white solid: tR = 0.94 min (LC-2), ESI- MS (pos.): m/z 428.11 [M+H]+, ESI-MS (neg.): m/z 426.18 [M-H]+. Examples 5-F-I-25ato 5-F-I-33a of the following Table 65 are prepared analogous to the procedures described for 5-F-I-29a, substituting the corresponding acid chloride or sulfonyl chloride for phenylacetyl chloride.
MS Data MS Data
Example Formula fR [min]
Name m/z m/z [M- MoI weight (Meth.) [M+Hf H]+ rac {2-[1-(4-Bromo- benzoyl)-pyrrolidin-3-
C21H19BrFN3O3S 0.99
5-F-l-25a ylmethylsulfanyl]-5-fluoro- 493.92 491.98 492.36 (LC-3) benzoimidazol-1 -yl}-acetic acid rac {5-Fluoro-2-[1-(furan-2- carbonyl)-pyrrolidin-3-
C19H18FN3O4S 0.90
5-F-l-26a ylmethylsulfanyl]- 404.08 402.14 403.43 (LC-3) benzoimidazol-1 -yl}-acetic acid rac [2-(1 -Butyryl-pyrrolidin-
3-ylmethylsulfanyl)-5~fluoro- C18H22FN3O3S 0.89
5-F-l-27a 380.12 378.11 benzoimidazol-1 -yl]-acetic 379.45 (LC-3) acid rac {5-Fluorc~2-[1-(3- phenyl-propionyl)-pyrrolidin-
5-F-l-28a C23H24FN3O3S 0.99
3-ylmethylsulfanyl]- 441.52 (LC-3) 442.11 440.17 benzoimidazol-1 -yl}-acetic acid rac [5-Fluoro-2-(1-octanoyl- pyrrolidin-3-
C22H30FN3O3S 1.08
5-F-l-30a ylmethylsulfanyl)- 436.15 434.21 435.56 (LC-3) benzoimidazol-1 -yl]-acetic acid rac {5-Fluorc~2-[1-(2- phenyl-ethenesulfonyl)-
5-F-l-31a pyrrolidin-3- C22H22FN3O4S2 1.04 476.04 474.1 ylmethylsulfanyl]- 475.56 (LC-3) benzoimidazol-1 -yl}-acetic acid rac {2-[1-(Butane-1- sulfonyl)-pyrrolidin-3-
5-F-l-32a ylmethylsulfanyl]-5-fluoro- C18H24FN3O4S2 0.99
430.05 428.18 benzoimidazol-1 -yl}-acetic 429.53 (LC-3) acid rac {5-Fluoro-2-[1-(4- methoxy-benzenesulfonyl)- pyrrolidin-3- C21H22FN3O5S2 1.01
5-F-l-33a 480.06 478.12 ylmethylsulfanyl]- 479.54 (LC-3) benzoimidazol-1 -yl}-acetic acid
Table 65 Precursor 5-F-I-36a of the following Table 66 is prepared using a procedure analogous to that described for Precursor I-00a, substituting the corresponding Precursor 5-F-I- 25b for Precursor I-00b.
MS Data
Formula tR [min]
Example Name m/z MoI weight (Meth.) [M+H]+
[5-Fluoro-2-(pyrrolidin-3- ylmethylsulfanyl)- C14H16FN3O2S 0.62
5-F-l-36a 310.12 benzoimidazol-1 -yl]-acetic 309.36 (LC-3) acid
Table 66
Precursor 5-F-I-25b of the following Table 67 is prepared using a procedure analogous to that described for Precursor I-00b, substituting the corresponding Intermediate 3 -III for Intermediate 3-1 and 3-hydroxymethyl-pyrrolidin-l-carboxylic acid tert-buty\ ester for S-hydroxymethyl-piperidine-l-carboxylic acid tert-butyl ester.
Precursor Name M *£*£ 1 r
rac te/t-Butyl [2-(1-ferf-
- P 1 91-. butyloxycabonyl-pyrrolidin- C23H32FN3O4S 1.18 ARR OR D 3-ylmethylsulfanyl)-5-fluoro- 465.58 (LC-3) 4Dt>^° benzoimidazol-1-yl]-acetate
Table 67
Example Oxy-F-H-l la rac r2-(5-Acetyl-2-methoxy-phenylmethanesulfinyl)-5-fluoro-benzoimidazol-l-yl]- acetic acid
To a suspension of [2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-fiuoro-benzoimidazol-l- yl]-acetic acid (Example 5-F-H-l Ia, 194 mg, 0.5 mmol) in dichloromethane (3 ml) cooled to 0°C is added m-chloroperbenzoic acid (103 mg, 0.6 mmol, 1.2 eq.) and the mixture is stirred at rt for 3 h. The solid is filtered over a fritted funnel and rinsed thoroughly with dichloromethane. The white solid obtained is dried under high vacuum yielding the title compound (120 mg) in 59% as a white solid: tR = 0.89 min (LC-3), ESI-MS (pos.): m/z 404.91 [M+H]+; 1H-NMR (DMSO-d6): δ (ppm) 2.39 (s, 3H5 C=OCH3), 3.65 (s, 3H, OCH3), 4.66 (dd, 2H, S=OCH2), 5.20 (d, 2 H, CHCO2H), 7.11 (d, IH, Harom.), 7.29 (dt, 1 H, Harom.), 7.59 (dd, 1 H, Harom.), 7.75 (m, 1 H, Harom.), 7.98 (dd, l H, Harom,).
Biological assays:
Preparation of CRTH2 membranes and radioligand binding assay:
Preparation of the membranes and radioligand binding assays are performed according to known procedures, e.g. Sawyer N. et al. (Br. J. Pharmacol., 2002, 137, 1163-1172). A clonal HEK 293 cell line, expressing high level of recombinant hCRTH2 receptor, is selected for the preparation of membranes. Cells are detached from culture plates in 5 ml buffer A per plate (5 mM Tris, 1 mM MgCl2x6 H2O, 0.1 mM PMSF, 0.1 mM phenanthroline) using a police rubber and transferred into centrifugation tubes and frozen at -80°C. After thawing, the cells are centrifuged at 500 g for 5 min and then resuspended in buffer A. Cells are then fragmented by homogenization with a Polytron homogenizer for 30 s. The membrane fragments are centrifuged at 3000 g for 40 min and resuspended in membranes in buffer B (50 mM Tris, 25 mM MgCl2, 250 mM saccharose, pH 7.4) and aliquots are stored frozen.
Binding assay is performed in a total volume of 250 μl. In each well, 75 μl buffer C [50 mM Tris, 100 mM NaCl, 1 mM EDTA, 0.1% BSA (protease free), 0.01 % NaN3, pH 7.4] is mixed with 50 μl (3H)-PGD2 [at 2.5 nM (220.000 dpm per well) from Amersham, TRK734], 100 μl CRTH2 membranes to give 80 μg per well and 25 μl of test compound in buffer C containing 1% DMSO. For unspecific binding, PGD2 is added to the reaction mixture at 1 μM final concentration. This binding assay mix is incubated at rt for 90 min and then filtered through a GF/C filter plate. The filter is washed three times with ice cold binding buffer. Then, 40 μl per well Microscint-40 (Packard) are added and the bound radioactivity is quantified by means of Topcount (Packard).
Test for antagonist binding to the CRTH2 receptor: Compounds of Formula I display IC50 values of less than 10 μM, as exemplified in the following Table 68.
Table 68 Intracellular calcium mobilization assay (FLIPR):
Cells (HEK-293), stably expressing the hCRTH2 receptor under the control of the cytomegalovirus promotor from a single insertion of the expression vector pcDNA5 (Invitrogen), are grown to confluency in DMEM (low glucose, Gibco) medium supplemented with 10% fetal calf serum (both Bioconcept, Switzerland) under standard mammalian cell culture conditions (37°C in a humidified atmosphere of 5% CO2). Cells are detached from culture dishes using a dissociation buffer (0.02% EDTA in PBS, Gibco) for 1 min, and collected by centrifugation at 200 g at rt for 5 min in assay buffer [equal parts of Hank's BSS (HBSS, Bioconcept) and DMEM (low glucose, without phenol red, Gibco)]. After incubation for 45 min (370C and 5% CO2) in the presence of 1 μM Fluo-4 and 0.04% Pluronic F- 127 (both Molecular Probes), 20 mM HEPES (Gibco) in assay buffer, the cells are washed with and resuspended in assay buffer, then seeded onto 384-well FLIPR assay plates (Greiner) at 50,000 cells in 66 μl per well, and sedimented by centrifugation.
Stock solutions of test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in assay buffer to concentrations required for inhibition dose response curves. Prostaglandin D2 (Biomol, Plymouth Meeting, PA) is used as an agonist.
A FLIPR384 instrument (Molecular Devices) is operated according to the manufacturer's standard instructions, adding 4 μl of test compound dissolved at 10 mM in DMSO and diluted prior to the experiment in assay buffer to obtain the desired final concentration. An assay buffer containing 10 μl of 80 nM prostaglandin D2 (Biomol, Plymouth Meeting, PA), supplemented with 0.8% bovine serum albumin (fatty acid content <0.02%, Sigma), is then added to obtain a final concentration of 10 nM and
0.1%, respectively. Changes in fluorescence are monitored before and after the addition of test compounds at λex=488 nm and λem=540 nm. Emission peak values above base level after prostaglandin D2 addition are exported after base line subtraction. Values are normalized to high-level control (no test compound added) after subtraction of base line value (no prostaglandin D2 added). The program XLlfit 3.0 (IDBS) is used to fit the data to a single site dose response curve of the equation (A+((B-A)/(l+((C/x)AD)))) and to calculate the IC5O values.
Antagonist analysis:
Compounds of Formula I antagonize prostaglandin D2 mediated hCRTH2 receptor activity with an IC50 of less than 10 μM as exemplified in the following Table 69.
Table 69
Formulations:
The compounds of the invention can be formulated as the active ingredient according to methods known per se to give e.g. pharmaceutical preparations of the following composition:
L 500 me tablets Active ingredient 500 mg Powdered lactose 149 mg Polyvinylpyrrolidone 15 mg Dioctyl sodium sulfosuccinate l mg Sodium carboxymethyl starch 30 mg Magnesium stearate 5 mg Total 700 mg
2. 50 me tablets Active ingredient 50 mg Powdered lactose 50 mg Microcrystalline cellulose 82 mg Sodium carboxymethyl starch 15 mg Total 200 mg 3. 100 nig capsules
Active ingredient 100.0 mg
Powdered lactose 104.7 mg
Corn starch 70.0 mg
Hydroxypropylmethyl cellulose 10.0 mg
Dioctyl sodium sulfosuccinate 0.3 mg
Talc 12.0 mg
Magnesium stearate 3.0 mg
Total 300.0 mg
4. 500 mg suppositories
Active ingredient 500 mg
Suppository mass ad 2000 mg
5. 100 mε soft gelatine capsules
Active ingredient 100 mg
Medium chain triglyceride 300 mg
Total 400 mg

Claims

1. Use of a compound selected from the group consisting of 2-sulfanyl-benzoimidazol- 1-yl-acetic acids of the general Formula I
I wherein
R1, R2, R3 and R4 each independently represent hydrogen; alkyl; haloalkyl; halogen; nitro; cyano; formyl; methylsulfonyl; or methyl carbonyl; n is 0 or an integer from 1 to 10; r is 0 or the integer 1 ;
R5, R and R7 each independently represent hydrogen; alkyl; alkenyl; cycloalkyl; aryl; aryloxy; alkylcarbonyl; cycloalkylcarbonyl; alkoxycarbonyl, arylcarbonyl; arylalkylcarbonyl; N-alkyl-N-aryl-carbamoyl; N-alkyl-N-arylalkyl-carbamoyl; N- arylalkyl-N-aryl-carbamoyl; heterocyclyl; heterocyclyloxy; heterocyclylcarbonyl; or an amino of Formula NR8R9; or two of R5 -R7 together with the carbon atom to which they are attached form cycloalkyl or saturated heterocyclyl;
R8 represents hydrogen or R9; R9 independently from R8 represents cycloalkyl; cycloalkylalkyl; aryl; cycloalkylarylalkyl; arylalkyl; (diaryl)-alkyl; alkylcarbonyl; alkenylcarbonyl; cycloalkylcarbonyl; cycloalkylalkylcarbonyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl; arylalkylcarbonyl; arylalkenylcarbonyl; (diaryl)-alkylcarbonyl; cycloalkylarylalkylcarbonyl; heterocyclylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl; or
R8 and R9, together with the nitrogen atom to which they are attached, form a heterocyclyl group; R11 is hydrogen or methyl; and optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates, meso forms, geometric isomers, and prodrugs of compounds in which a prodrug forming group is present, as well as solvates and pharmaceutically acceptable salts of such compounds, and morphological forms; for the manufacture of medicaments for the control of disorders responding to CRTH2 receptor antagonist treatment.
2. The use of a compound of Formula I according to claim 1, wherein R1, R2, R3 and R4 each independently represent hydrogen, alkyl, haloalkyl, halogen, nitro, cyano or formyl; r is 0; and R11 is hydrogen.
3. Compounds as defined in Claim 1 or 2 for use as therapeutically active substances, with the exception of {2-[3-methyl-4-(2-morpholin-4-yl-ethylsulfanyl)- pyridin-2-ylmethylsulfanyl]-benzoimidazol-l-yl}-acetic acid.
4. A medicament containing one or more compounds according to Claim 3 and a pharmaceutically acceptable carrier.
5. Compounds as defined in Claim 1 or 2, with the exception of:
(2-octylsulfanyl-benzoimidazol-l -yl)-acetic acid; (2-butylsulfanyl-benzoimidazol-l-yl)-acetic acid;
(2-propylsulfanyl-benzoimidazol-l -yl)-acetic acid;
(2-ethylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-methylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-isopropylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-^ec-butylsulfanyl-benzoimidazol-l-yl)-acetic acid;
(2-isobutylsulfanyl-benzoimidazol-l -yl)-acetic acid; (2-allylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; ^-cyclohexylsulfanyl-benzoimidazol-l -yl)-acetic acid; (2-benzylsulfanyl-benzoimidazol-l-yl)-acetic acid;
(2-phenethylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
^-(naphthalen-l-ylmethylsulfany^-benzoimidazol-l-ylj-acetic acid;
{2-[2-(4-tert-butyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(4-propoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(4-ethoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(3,4-dimethyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(3-methylphenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(naphthalen-2-yloxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2- [2-(4-methoxy-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid; {2-[2-(4-butoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2- [2-(4-methylphenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
[2-(2-phenoxy-ethylsulfanyl)-benzoimidazol-l -yl] -acetic acid;
{2-[2-(4-ethyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(2-methylphenoxy)-ethylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid; {2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid;
{2-[2-(2-isopropyl-4-methyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}- acetic acid;
{2-[2-(naphthalen-l-yloxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{ 2-[2-(2,6-Dimethyl-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
{2-[2-(4-isopropoxy-phenoxy)-ethylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid; {2-[2-(2-fluoro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(2-methoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; and
{2-[3-metliyl-4-(2-niorpholin-4-yl-ethylsulfanyl)-pyridin-2-ylmethylsulfanyl]- benzoimidazol-1-yl} -acetic acid.
6. Compounds according to Claim 5, wherein
R5 represents hydrogen; R6 represents hydrogen; alkyl; or alkoxycarbonyl; and
R7 represents alkoxycarbonyl; N-alkyl-N-arylalkyl-carbamoyl; N-alkyl-N-aryl- carbamoyl; alkylcarbonyl; N-arylalkyl-N-aryl-carbamoyl; arylalkylcarbonyl; arylcarbonyl; cycloalkylcarbonyl; heterocyclylcarbonyl; heterocyclyloxy; an amino of Formula NR8R9; aryl substituted with one or two of alkoxy, alkylcarbonyl, and alkoxycarbonyl and optionally an additional halogen; or heterocyclyl substituted with alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, (diaryl)alkyl carbonyl or heterocyclylcarbonyl and optionally an additional halogen; or
R6 represents alkyl or alkoxycarbonyl and R7 represents aryl; or
R6 and R7 together with the carbon atom to which they are attached form cycloalkyl or saturated heterocyclyl.
7. Compounds according to Claim 1, wherein R1, R2, R3 and R4 each independently represent hydrogen; alkyl; haloalkyl; halogen; nitro; cyano; formyl; methylsulfonyl; or methylcarbonyl; n is 0 or an integer from 1 to 5; r is 0 or the integer 1 ; R5, R6 and R7 each independently represent hydrogen; alkyl; alkenyl; cycloalkyl; aryl; aryloxy; alkoxycarbonyl, arylcarbonyl; N-alkyl-N-aryl-carbamoyl; N-alkyl-N- arylalkyl-carbamoyl; N-arylalkyl-N-aryl-carbamoyl; heterocyclyl; heterocyclyloxy; heterocyclylcarbonyl; or an amino of Formula NR8R9; or two of R5 -R7 together with the carbon atom to which they are attached form cycloalkyl or saturated heterocyclyl; R8 represents hydrogen or R9; R9 independently from R8 represents cycloalkyl; cycloalkylalkyl; aryl; arylalkyl; (diaryl)-alkyl; alkylcarbonyl; cycloalkylcarbonyl; cycloalkylalkylcarbonyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl; arylalkylcarbonyl; arylalkenylcarbonyl; (diaryl)-alkylcarbonyl; heterocyclylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl; or R and R , together with the nitrogen atom to which they are attached, form a heterocyclyl group; and R11 is hydrogen or methyl; with the exception of the following compounds: (2-octylsulfanyl-benzoimidazol-l-yl)-acetic acid;
(2-butylsulfanyl-benzoimidazol-l -yl)-acetic acid;
(2-propylsulfanyl-benzoimidazol-l -yl)-acetic acid;
(2-ethylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-methylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-isopropylsulfanyl-benzoimidazol-l-yl)-acetic acid;
(2-sec-butylsulfanyl-benzoimidazol-l -yl)-acetic acid;
(2-isobutylsulfanyl-benzoimidazol-l -yl)-acetic acid;
(2-allylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
(2-cyclohexylsulfanyl-benzoimidazol- 1 -yl)-acetic acid; (2-benzylsulfanyl-benzoimidazol-l-yl)-acetic acid;
(2-phenethylsulfanyl-benzoimidazol- 1 -yl)-acetic acid;
[2-(naphthalen-l-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
{2-[2-(4-ført-butyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(4-propoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(4-ethoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl} -acetic acid;
{2-[2-(3,4-dimethyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2- [2-(3 -methylphenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
{2-[2-(naphthalen-2-yloxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[2-(4-methoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(4-butoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l -yl}-acetic acid;
{2-[2-(4-methylphenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
[2-(2-phenoxy-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid; {2-[2-(4-ethyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(2-methylphenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2- [2-(4-chloro-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid; {2-[2-(2-isopropyl-4-methyl-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}- acetic acid;
{2-[2-(naphthalen- 1 -yloxy)-ethylsulfanyl]-benzoimidazol- 1 -yl} -acetic acid; { 2- [2-(2, 6-Dimethyl-phenoxy)-ethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; {2-[2-(4-isopropoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(2-fluoro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid; {2-[2-(2-methoxy-phenoxy)-ethylsulfanyl]-benzoimidazol-l -yl}-acetic acid; and
{2- [3 -methyl-4-(2-morpholin-4-yl-etb.ylsulfanyl)-pyridin-2-ylmethylsulfanyl] - benzoimidazol- 1-yl} -acetic acid.
8. Compounds according to Claim 5 or 7, wherein aryl groups present as R5 -R9, alone or in combination, are unsubstituted or mono- or di-substituted with substituents independently selected from lower alkyl; hydroxy-lower alkyl; lower alkoxy; lower alkoxy-lower alkyl; halogen; cyano; lower alkoxycarbonyl; lower alkylcarbonyl; aryl; aryl-lower alkyl; cycloalkyl; 2,3-dihydro-indole-l-carbonyl; lower alkylcarbamoyl; morpholine-4-carbonyl; aryl-lower alkylcarbamoyl; N,N-di-lower alkylcarbamoyl; N- lower alkyl-N-aryl-lower alkyl-carbamoyl; hydroxy-lower alkoxy; arylcarbonyl; and heterocyclyl.
9. Compounds according to any one of Claims 5-8, wherein R6 and R7 together with the carbon atom, to which they are attached, form a saturated heterocyclyl ring containing one nitrogen atom which is substituted with R10, wherein R10 represents alkylcarbamoyl; alkylcarbonyl; alkoxycarbonyl; alkylsulfonyl; arylalkylcarbamoyl; arylalkylcarbonyl; arylalkoxycarbonyl; arylalkylsulfonyl; arylcarbamoyl; arylcarbonyl;
(diaryl)-alkylcarbonyl; aryloxycarbonyl; arylsulfonyl; arylalkenylsulfonyl; cycloalkylcarbamoyl; cycloalkylalkylcarbonyl; cycloalkyl carbonyl; cycloalkyloxycarbonyl; cycloalkylsulfonyl; heterocyclylcarbamoyl; heterocyclylcarbonyl; heterocyclyloxycarbonyl; or heterocyclylsulfonyl.
10. Compounds according to any one of Claims 5-9, wherein R1, R2, R3 and R4 each independently represent hydrogen; methyl; trifluoromethyl; fluoro, chloro, bromo; nitro; cyano; or formyl.
11. Compounds according to any one of Claims 5-10, wherein n is 1 or 2; R5 and R6 each represent hydrogen; R7 represents an amino of Formula NR8R9;
R8 represents hydrogen; and R9 represents cycloalkyl; aryl; arylalkyl; (diaryl)-alkyl; alkylcarbonyl; cycloalkyl- alkylcarbonyl; cycloalkylcarbonyl; alkenylcarbonyl; alkoxycarbonyl; alkoxydicarbonyl; arylcarbonyl; arylalkylcarbonyl; (diaryl)-alkylcarbonyl; heterocyclylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl; or
R8 represents cycloalkyl; arylalkyl; aryl; alkoxycarbonyl; and
R9 represents cycloalkyl; cyclylalkyl-alkyl; aryl; arylalkyl; (diaryl)-alkyl; cycloalkyl- alkylcarbonyl; alkylcarbonyl; arylalkylcarbonyl; (diaryl)-alkylcarbonyl; alkylcarbamoyl; arylcarbamoyl; arylalkylcarbamoyl; alkylsulfonyl; arylsulfonyl; arylalkylsulfonyl; or
R8 and R9, together with the nitrogen atom to which they are attached, form a phthalazinyl; isoindolyl; benzoimidazolyl; indazolyl; quinazolinyl; or benzoisothiazolyl ring system.
12. Compounds according to Claim 11, wherein R8 represents hydrogen; and R9 represents 3-phenyl-acryloyl; butoxycarbonyl, tez't-butoxycarbonyl; ethoxydicarbonyl; propylcarbamoyl; 2,2-dimethyl-propionyl; 3,3-dimethyl-butyryl, 3- octanoyl, pentanoyl; butane- 1-sulfonyl; 4-piperidin-l-yl-phenyl, phenyl; 2,2-diphenyl- ethyl, 3 -benzyl; 2-cyclohexyl-2-phenyl-acetyl, 3,3-diphenyl-propionyl, 3-phenyl- propionyl, diphenylacetyl, phenylacetyl; phenylmethanesulfonyl; phenylcarbamoyl; 4- bromo-benzoyl, 4-methoxy-benzoyl, benzoyl, biphenyl-4-carbonyl, naphthalene- 1- carbonyl, benzenesulfonyl; cyclohexanecarbonyl, cyclopropanecarbonyl, 3- cyclopentyl-propionyl; furan-2-carbonyl, or pyridine-3 -carbonyl; or R8 represents butoxycarbonyl, tøt-butoxycarbonyl; 4-carboethoxyphenyl, 4-piperidin- 1-yl-phenyl, phenyl; benzyl, 2,2-diphenyl-ethyl, phenethyl; cyclopropyl; and R9 represents propylcarbamoyl; pentanoyl; butane- 1-sulfonyl; 4-piperidin-l-yl-phenyl, phenyl; benzyl, phenethyl, 2,2-diphenyl-ethyl; benzylcarbamoyl; 2-cyclohexyl-2- phenyl-acetyl, 2-phenylacetyl, 3,3-diphenyl-propionyl, diphenylacetyl, phenylmethanesulfonyl; phenylcarbamoyl; benzenesulfonyl; cyclohexyl, cyclopropyl; or cyclohexylmethyl; or R8 and R9, together with the nitrogen atom to which they are attached, represent 1-oxo- lH-phthalazin-2-yl; 1 -oxo-1 ,3-dihydro-isoindol-2-yl; 2-oxo-2,3-dihydro- benzoimidazol- 1 -yl; 1 -ethoxycarbonyl-3 -oxo-2,3 -dihydro-indazole-2-yl; 2,4-dioxo- 1 ,A- dihydro-2H"-quinazolin-3-yl; or l,3-dioxo-l,3-dihydro-isoindol-2-yl; l,l,3-trioxo-l,3- dihydro- 1 λ6-benzo[d]isothiazol-2-yl.
13. Compounds according to any one of Claims 5-10, wherein n is 0; R5 and R each represent hydrogen; and R7 represents phenyl; furanyl, oxazolyl, pyridinyl or thiazolyl, all substituted with one or two of alkoxy, alkylcarbonyl, and alkoxycarbonyl and optionally an additional halogen.
14. Compounds according to any one of Claims 5-10, wherein n is 0; R5 and R6 each represent hydrogen; and R7 represents phenyl, optionally mono- or di-substituted wherein the substitutents are independently selected from the group consisting of hydroxy-alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, halo, alkylcarbonyl, phenyl, 2,3- dihydro-indole-1 -carbonyl, alkylcarbamoyl, morpholine-4-carbonyl, benzylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-benzyl-carbamoyl, hydroxyalkoxy and benzoyl; or R7 represents 3-oxo-indan-5-yl or 8-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl, both substituted by alkoxy.
15. Compounds according to any one of Claims 5-10, wherein n is i;
R5 represents hydrogen; and R6 and R7 together with the carbon atom to which they are attached form a 5- or 6-membered saturated heterocyclyl containing one nitrogen ring atom, wherein this nitrogen ring atom contains a substituent R10, wherein R10 is as defined in Claim 9.
16. Compounds according to Claim 5 selected from the group consisting of:
{ 2- [3 -(butoxycarbonyl-phenethyl-amino)-propylsulfanyl] -5 -nitro-benzoimidazol- 1 -yl} - acetic acid; rac [2-(3 - { (2-cyclohexyl-2-phenyl-acetyl)-[(4-ethyloxycarbonyl)-phenyl] -amino } - propylsulfanyl)-benzoimidazol-l -yl]-acetic acid; (2- { 3 -[(2,2-diphenyl-ethyl)-pentanoyl-amino] -propylsulfanyl} -benzoimidazol- 1 -yl)- acetic acid;
[2-(3-methoxycarbonyl-benzylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetic acid; rac {2-[ 1 -(4-bromo-benzoyl)-piperidin-3 -ylmethylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid; {2-[(6-methoxy-3-methoxycarbonyl)-benzylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
[5-fluoro-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid and its 6-fluoro regioisomer;
{2- [(6-bromo-3 -methoxycarbonyl)-benzylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
[2-(3 - {butyloxycarbonyl- [(4-ethyloxycarbonyl)-phenyl]-amino } -propylsulfanyl)- benzoimidazol- 1-yl] -acetic acid;
[5-cyano-2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid and its 6-cyano regioisomer;
[2-(4-ethyloxycarbonyl-butylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetic acid;
[2-(3-{diphenylacetyl-[(4-ethyloxycarbonyl)-phenyl]-amino}-propylsulfanyl)- benzoimidazol- 1-yl] -acetic acid;
[2-(3-{[(4-ethyloxycarbonyl)-phenyl]-pentanoyl-amino}-propylsulfanyl)- benzoimidazol- 1 -yl]-acetic acid; rac { 2 - [ 1 -(furan-2 -carbonyl)-piperidin-3 -ylmethylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; {2-[3-(benzyl-butoxycarbonyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; rac {2-[ 1 -(3 -phenyl-propionyl)-piperidin-3 -ylmethylsulfanyl] -benzoimidazol- 1 -yl} - acetic acid; (2- { 3 - [(4-ethyloxycarbonylphenyl)-(phenylacetyl)-amino] -propylsulfanyl } - benzoimidazol-l-yl)-acetic acid;
{2-[3-(benzyl-pentanoyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{ 2- [3 -(cyclopropyl-diplienylacetyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
[2-(3 - {diphenylpropionyl- [(4-ethyloxycarbonyl)-phenyl] -amino } -propylsulfanyl)- benzoimidazol-1-yl] -acetic acid; rac [2-(l -methyl-2-oxo-2-phenyl-ethylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid;
[2-(3-methoxycarbonyl-benzylsulfanyl)-5-trifluoromethyl-beiizoimidazol-l-yl]-acetic acid and its 6-trifluoromethyl regioisomer;
[2-(3 ,3 -diphenyl-propylsulfanyl)-6-nitro-benzoimidazol- 1 -yl] -acetic acid;
(2-benzylsulfanyl-5-nitro-benzoimidazol-l-yl)-acetic acid and its 6-nitro isomer;
{2-[3-(l -phenethyl-3-propyl-ureido)-propylsulfanyl]-benzoimidazol-l -yl}-acetic acid; rac {2-[l-(3-chloro-benzoyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-propylsulfanyl]-5-nitro-benzoimidazol-l- yl} -acetic acid;
{2-[3-(l , 1 ,3-trioxo-l ,3-dihydro-l λ6-benzo[d]isothiazol-2-yl)-propylsulfanyl]- benzoimidazol-1-yl} -acetic acid; (2- { 3 - [(2,2-diphenyl-ethyl)-(3 ,3 -diphenyl-propionyl)-amino] -propylsulfanyl} - benzoimidazol- l-yl)-acetic acid;
(2- { 3 - [cyclopropyl-(3 ,3 -diphenyl-propionyl)-amino] -propylsulfanyl} -benzoimidazol- 1 - yl)-acetic acid; rac (2-{3-[(2-cyclohexyl-2-phenyl-acetyl)-cyclopropyl-amino]-propylsulfanyl}- benzoimidazol- l-yl)-acetic acid;
(2-{3-[diphenylacetyl-(2,2-diphenyl-ethyl)-amino]-propylsulfanyl}-benzoimidazol-l- yl)-acetic acid; rac [2-(l-heptanoyl-piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
{2- [3 -(3,3 -diphenyl-propionylamino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid; (2- { 3 - [(butane- 1 -sulfonyl)-phenethyl-amino] -propylsulfanyl } -benzoimidazol- 1 -yl)- acetic acid; { 2- [3 -(benzyl-(phenylmethanesulfonyl)-amino)-propylsulfanyl] -benzoimidazol- 1 -yl} - acetic acid;
(2-{3-[(252-diphenyl-ethyl)-(phenylacetyl)-ammo]-propylsulfanyl}-benzoimidazol-l- yl)-acetic acid; {2-[3-(benzenesulfonyl-cyclopropyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}- acetic acid;
{2-[3-(phenethyl-(phenylmethanesulfonyl)-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetic acid;
[2-(3,3-diphenyl-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid; {2-[3-(phenethyl-(phenylacetyl)amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2- [3 -(diphenylacetyl-phenethyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl } -acetic acid;
(2-{[(2-chloro-4-methyloxycarbonyl)-pyridin-6-yl]-methyl-sulfanyl}-benzoimidazol-l- yl)-acetic acid; rac [2-(bicyclo[4.2.0]octa-l,3,5-trien-7-ylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(3-acetyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[5-fluoro-2-(2-phenoxy-ethylsulfanyl)-benzoimidazol-l-yl]-acetic acid and its 6-fluoro regioisomer; [2-(3-phenylmethanesulfonylamino-piOpylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(4-ethyloxycarbonyl-butylsulfanyl)-6-nitiO-benzoimidazol- 1 -yl]-acetic acid;
{2-[3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-propylsulfanyl]-benzoimidazol-l-yl}- acetic acid;
{2-[3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-propylsulfanyl]-6-nitro-benzoimidazol-l- yl}-acetic acid;
(2-{3-[phenylmethanesulfonyl-(4-piperidin-l-yl-phenyl)-amino]-propylsulfanyl}- benzoimidazol-1-yl) -acetic acid;
[2-(4-ethyloxycarbonyl-butylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid and its
6-fluoro regioisomer; [2-(3-diphenylacetylamino-propylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetic acid;
{2-[3-(cyclopropyl-(phenylmethanesulfonyl)-amino)-propylsulfanyl]-benzoimidazol-l- yl}-acetic acid; {2-[(5-bromo-3-methoxycarbonyl)-benzylsulfanyl]-beiizoimidazol-l-yl}-acetic acid;
{5-nitro-2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
[2-(3,3-diphenyl-propylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetic acid;
{2-[3-(2}4-dioxo-l,4-dihydro-2H-quinazolin-3-yl)-proρylsulfanyl]-benzoimidazol-l- yl} -acetic acid;
{2-[3-(ben.zyl-(phenylacetyl)-ammo)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
(2-{3-[(2,2-diphenyl-ethyl)-(phenylmethanesulfonyl)-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid; rac [2-(l-acetyl-piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid; (2- {3-[benzyl-(3 ,3 -diphenyl-propionyl)-amino]-propylsulfanyl} -benzoimidazol- 1 -yl)- acetic acid;
{2-[3-(cyclopropyl-(phenylacetyl)-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; rac [2 -(I -methyloxycarbonyl- 1 -phenyl-methylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid;
{2-[3 -(butoxycarbonyl-cyclohexyl-amino)-propylsulfanyl] -benzoimidazol- 1 -yl} -acetic acid;
[2-(3-diphenylacetylamino-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
{2-[3-(l ,3-diphenyl-ureido)-propylsulfanyl]-benzoimidazol-l -yl} -acetic acid; (2-benzylsulfanyl-6-nitro-benzoimidazol-l-yl)-acetic acid; rac [2-( 1 -diphenylacetyl-piperidin-3 -ylmethylsulfanyl)-benzoimidazol- 1 -yl]-acetic acid;
{2-[3-(cyclopropyl-pentanoyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
(2-{3-[benzenesulfonyl-(4-piρeridin-l-yl-phenyl)-amino]-proρylsulfanyl}- benzoimidazol- l-yl)-acetic acid;
{2-[3-(benzyl-diphenylacetyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
{2-[3-(tert-butoxycarbonyl-phenyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid;
[2-(3-phenyl-propylsulfanyl)-benzoimidazol-l-yl]-acetic acid; [2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(3 -benzenesulfonylamino-propylsulfanyty-benzoimidazol- 1 -yl] -acetic acid;
{2-[3-(l-benzyl-3-propyl-ureido)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; (2-{3-[l-(2,2-diphenyl-ethyl)-3-propyl-ureido]-propylsulfanyl}-benzoimidazol-l-yl)- acetic acid;
[2-(4-ethyloxycarbonyl-butylsulfanyl)-5-trifluoromethyl-benzoimidazol-l-yl]-acetic acid and its 6-trifluoromethyl regioisomer; [5 -cyano-2-(4-ethyloxycarbonyl-butylsulfanyl)-benzoimidazol- 1 -yl] -acetic acid and its
6-cyano regioisomer;
[2-(5-ethyloxycarbonyl-pentylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
(2-{3-[(3,3-diphenyl-propionyl)-phenyl-amino]-propylsulfanyl}-benzoimidazol-l-yl)- acetic acid; {2-[3-(butoxycarbonyl-(cyclohexylmethyl)-amino)-propylsulfanyl]-benzoimidazol-l- yl} -acetic acid;
(2- { 3 - |/ert-butoxycarbonyl-(4-piperidm- 1 -yl-phenyl)-amino] -propylsulfanyl } - benzoimidazol-l-yl)-acetic acid;
(2-{3-[ph.enylacetyl-(4-piperidin-l-yl-ph.enyl)-aminoj-propylsulfanyl}-benzoimidazol- l-yl)-acetic acid;
{2-[3-(2,3-dihydro-l-ethyloxycarbonyl-3-oxo-indazol-2-yl)-propylsulfanyl]- benzoimidazol-1-yl} -acetic acid; rac {2-[l-(3-cyclopentyl-propionyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l- yl} -acetic acid; (2-{3-[tert-butoxycarbonyl-(2,2-diphenyl-ethyl)-amino]-propylsulfanyl}- benzoimidazol-l-yl)-acetic acid;
{2-[3-(benzenesulfonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-l-yl}-acetic acid; and
{ 2- [5 -(3 ,4-dihydro-2H-quinolin- 1 -yl)-5 -oxo-pentylsulfanyl] -benzoimidazol- 1 -yl } - acetic acid.
17. Compounds according to Claim 1 selected from the group consisting of: rac {2-[l-(3,4-dichloro-benzenesulfonyl)-piperidin-3-ylmethylsulfanyl]- benzoimidazol-1-yl} -acetic acid; rac {2- [ 1 -(3 -phenyl-acryloyl)-piperidin-3 -ylmethylsulfanyl] -benzoimidazol- 1 -yl } - acetic acid; [2-( 1 -butyryl-piperidin-3 -ylmethylsulfanyl)-5,6-dimethyl-benzoimidazol- 1 -yl] -acetic acid;
[2-(5-methyloxycarbonyl-benzylsulfanyl)-5,6-dichloro-benzoimidazol-l-yl]-acetic acid; [2-(5-acetyl-2-methoxy-benzylsulfanyl)-5,6-dichloro-benzoimidazol-l -yl]-acetic acid;
[2-(l-butyryl-piperidin-3-ylmethylsulfanyl)-5,6-dich.loro-benzoimidazol-l-yl]-acetic acid;
[2-((R)-l-butyryl-piperidin-3-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5,6-difluoro-benzoimidazol- 1 -yl]-acetic acid; [2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid; rac [2-(l -butyryl-piperidin-3-ylmethylsulfanyl)-5-fluoro-benzoimidazol-l -yl]-acetic acid; rac {5-fluoro-2-[l-(furan-2-carbonyl)-piperidin-3-ylmethylsulfanyl]-benzoimidazol-l- yl} -acetic acid; rac {2-[l-(4-bromo-benzoyl)-piperidin-3-ylmethylsulfanyl]-5-fluoro-benzoimidazol-l- yl}-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-trifluoromethyl-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-methanesulfonyl-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-6-fluoro-benzoimidazol- 1 -yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-4-fluoro-benzoimidazol-l-yl]-acetic acid;
[5-acetyl-2-(5-acetyl-2-methoxy-benzylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-formyl-benzoimidazol-l-yl]-acetic acid; rac 2- [2-(5 -acetyl-2-methoxy-benzylsulfanyl)-5 -fluoro-benzoimidazol- 1 -yl] -propionic acid;
[2-(5-butylcarbamoyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid;
[2-(5-benzylcarbamoyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]- acetic acid;
{2-[5-(2,3-dihydro-indole-l-carbonyl)-2-methoxy-benzylsulfanyl]-5-fluoro- benzoimidazol-1-yl) -acetic acid; [2-(5-diethylcarbamoyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]- acetic acid;
[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-nitro-benzoimidazol-l-yl]-acetic acid; rac {2-[l-(4-bromo-benzoyl)-pyrrolidm-3-ylniethylsulfanyl]-5-fluoro-benzoimidazol-l- yl} -acetic acid; rac { 5-fluoro-2- [ 1 -(furan-2-carbonyl)-pyrrolidin-3 -ylmethylsulfanyl]-benzoimidazol- 1 - yl} -acetic acid; rac {5-fluoro-2-[l-(2-phenyl-ethenesulfonyl)-pyrrolidin-3-ylmethylsulfanyl]- benzoimidazol-1-yl} -acetic acid; [2-(5-acetyl-2-butoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid;
{ 2- [5 -acetyl-2-(3 -hydroxy-propoxy)-benzylsulfanyl] -5 -fluoro-benzoimidazol- 1 -yl } - acetic acid;
[2-(5-benzoyl-2-methoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid;
[5-fluoro-2-(6-methoxy-3-oxo-indan-5-ylmethylsulfanyl)-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-ethoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l-yl]-acetic acid;
[2-(5-acetyl-2-propoxy-benzylsulfanyl)-5-fluoro-benzoimidazol-l -yl]-acetic acid; and rac [2-(5-acetyl-2-methoxy-phenylmethanesulfmyl)-5-fluoro-benzoimidazol-l-yl]- acetic acid.
18. Compounds of the general Formula II
wherein R*-R7 and n are as in Formula I and R represents an alkyl group, with the exception of:
methyl [2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-benzoimidazol-l-yl]-acetate; methyl [2-(4-chloro-benzylsulfanyl)-benzoimidazol-l-yl]-acetate; methyl (2-benzylsulfanyl-benzoimidazol- 1 -yl)-acetate; methyl [2-(5-nitro-pyridin-2-ylsulfanyl)-benzoimidazol-l-yl]-acetate; methyl (2-methylsulfanyl-benzoimidazol- 1 -yl)-acetate; ethyl (2-methylsulfanyl-benzoimidazol- 1 -yl)-acetate; methyl (2-ethylsulfanyl-benzoimidazol- 1 -yl)-acetate; ethyl [2-(l,3,7-trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-ylsulfanyl)- benzoimidazol-l-yl]-acetate;
ethyl {2-[3-methyl-4-(2-morpholin-4-yl-ethylsulfanyl)-pyridin-2- ylmethylsulfanyl]-benzoimidazol- 1 -yl} -acetate; and methyl {2-[3-methyl-4-(2-morpholin-4-yl-ethylsulfanyi)-pyridin-2- ylmethylsulfanylj-benzoimidazol- 1 -yl} -acetate.
19. Compounds of the general Formula
wherein R^-R7 and n are as in Formula I.
20. Compounds of the general Formula wherein R1 -R4 and R11 are as defined for Formula I and R represents an alkyl group.
21. Compounds as defined in Claim 5 for use as therapeutically active substances.
22. A medicament containing one or more compounds according to Claim 5 and a pharmaceutically acceptable carrier.
23. The use of compounds according to Claim 5 for the manufacture of medicaments for the control of disorders responding to CRTH2 receptor antagonist treatment.
EP05778612A 2004-08-26 2005-08-23 2-sulfanyl-benzimidazol-1-yl-acetic acid derivatives as crth2 antagonists Withdrawn EP1784182A1 (en)

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EP05778612A EP1784182A1 (en) 2004-08-26 2005-08-23 2-sulfanyl-benzimidazol-1-yl-acetic acid derivatives as crth2 antagonists
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