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  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
  • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
  • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems

Definitions

• the present invention relates to compounds of the formula I,
• the compounds of the formula 1 are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardio- vascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor Vila (FVlla), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor Vila is present or for the cure or prevention of which an inhibition of factor Xa and/or factor Vila is intended.
• the invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
• Normal haemeostasis is the result of a complex balance between the processes of clot initiation, formation and clot dissolution.
• Many significant disease states are related to abnormal haemeostasis. For example, local thrombus formation due to rupture of athereoslerotic plaque a major cause of acute myocardial infarction and unstable angina. Treatment of an occlusive coronary thrombus by either thrombolytic therapy or percutaneous angioplasty may be accompanied by acute thrombolytic reclosure of the affected vessel.
• factor Xa-specific blood clotting inhibitors that are effective but do not cause unwanted side effects have been described, for example, in WO-A-95/29189.
• further low molecular weight factor Xa specific blood clotting inhibitors which are effective and have the above advantages as well.
• the present invention satisfies the above needs by providing novel compounds of the formula I, which exhibit better factor Xa and/or factor Vila inhibitory activity and are favorable agents with high bioavailability.
• R° is 1) a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is mono-, di- or trisubstituted independently of one another by R8,
• a monocyclic or bicyclic 4- to 15-membered heterocyclyl containing one, two, three or four heteroatoms chosen from nitrogen, sulfur or oxygen, wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8, and which is additionally substituted by a monocyclic or bicyclic 4- to 15-membered heterocyclyl, containing one, two, three or four heteroatoms chosen from nitrogen, sulfur or oxygen, wherein heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8, R8 is 1) halogen,
• aryl is mono-, di- or trisubstituted independently of one another by halogen or -0-(C-
• R8 is at least one halogen, -C(0)-NH2 or -0-(C-]-Cs)-alkyl residue, if R° is a monocyclic or bicyclic 6- to 14-membered aryl, provided that R8 is not a — O-(C- ⁇ -Cs)-alkyl residue, if R° and V are a monocyclic or bicyclic 6- to 14-membered aryl, the substructure
• Q is a direct bond, -(C 0 -C 2 )-alkylene-C(0)-NR 10 -, -NR 0 -C(O)-NR 10 -, -NR 10 -C(O)-,
• n and m are independently of one another identical or different and are the integers zero, 1, 2, 3, 4, 5 or 6, wherein the alkylene residues which are formed by -(CH2)nr or "(CH2)n _ are unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, - H2 or -OH; or -(C3-C5)-cycloalkylen, wherein cycloalkylen is unsubstituted or mono-, di- or trisubstitutedute
• R 1 is a hydrogen atom, -(C- ⁇ -C ⁇ -alkyl, wherein alkyl is unsubstituted or substituted one to three times by R13; -(C ⁇ -C3)-alkylene-C(0)-NH-R°, -(Gi-C ⁇ -alkylene-C ⁇ -O-R 10 , a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is mono-, di- or trisubstituted independently of one another by R8, wherein R8 is as defined above; a monocyclic or bicyclic 4- to 15-membered heterocyclyl, containing one, two, three or four heteroatoms chosen from nitrogen, sulfur or oxygen; -(G ⁇ -C3)-perfluoroalkylene,
• het is a 3- to 7- membered cyclic residue, containing up to 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen, wherein said cyclic residue is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, R 4> and R 5 ' are independent of one another are identical or different and are hydrogen atom or -(O
• R2 is a direct bond
• R1-N-R 2 -V can f orm a 4. to 8-membered cyclic group, containing 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen, wherein said cyclic group is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• V is 1) a 6- to14-membered aryl, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, or 2) a heterocyclyl out of the group acridinyl, 8-aza-bicyclo[3.2.1]oct-3-yl, azaindole ( 1 H-pyrrolopyridine), azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, c
• n and m are independently of one another identical or different and are the integers zero, 1 , 2, 3, 4, 5 or 6, M is 1) a hydrogen atom,
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• R14 7) -(C3-C 8 )-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, or 8) a 3- to 7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen, wherein said cyclic residue is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, wherein R14 is defined above,
• R3 is 1) hydrogen atom
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, 4) -(0
• Me is methyl, or if two -OR19 residues are attached to adjacent atoms they can form together with the atoms which they are attached to a 5- or 6- membered ring, which is unsubstituted or substituted one, two, three or four times by R13,
• R11 and R12 are independently of one another identical or different and are
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, 3) -(C 0 -C 6 )-alkyl-(C 3 -C 8 )-cycloalkyl,
• alkyl and heterocyclyl independently from one another are unsubstituted or mono-, di- or trisubstituted by R13, or R11 and R12 together with the nitrogen atom to which they are bonded can form a 4- to 8- membered monocyclic heterocyclic ring which in addition to the nitrogen atom can contain one or two identical or different ring heteroatoms chosen from oxygen, sulfur and nitrogen; wherein said heterocyclic ring is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• R 10 and R 20 are independently of one another hydrogen, -(C-j-CgJ-alkyl, -(C ⁇ -C4)-alkyl-OH, -(Co-C4)-alkyl-0-(C-
• R15 and R16 are independently of one another hydrogen, -(Ci-CgJ-alkyl, or together with the carbon atom to which they are bonded they can form a 3- to 6 membered carbocyclic ring which is unsubstituted or substituted one to three times by R 10
• R17 is-(Oj-Cg)-al yl, -(Cq-C ⁇ -alkyl-OH, -(C-
• R° is " 1) a monocyclic or bicyclic 6- to 14-membered aryl out of the group phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, wherein aryl is mono-, di- or trisubstituted independently of one another by R8,
• heterocyclyl out of the group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl,. benzothiazolyl, benzothiophenyl, cinnolinyl, chromanyl, indazolyl, indolyl, isochromanyl, isoindolyl, isoquinolinyl, phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyridyl, pyridoimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, quinazolinyl, quinolyl, quinoxalinyl or 1,4,5,6-tetrahydro-pyridazinyl, wherein said heterocyclyl is ⁇ ns ' ubstituted or mono-, di- or trisubstitute
• heterocyclyl wherein heterocyclyl is selected out of the group acridinyl, azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH- carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrochinolinyl, 4,5- dihydrooxa-zolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 6H-1,5,2- di
• aryl is as defined above and wherein aryl is mono-, di- or trisubstituted independently of one another by halogen or -0-(Ci-C 8 )-alkyl, 9) -(G ⁇ -C 8 )-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, NH 2 , -OH or a methoxy residue, or
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, NH 2 , -OH or a methoxy residue,
• R8 is at least one halogen, -C(0)-NH or -0-(C- ] -C 8 )-alkyl residue, if R° is a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is as defined above, provided that R8 is not a -0-(C- ⁇ -C 8 )-al yl residue, if R° and V are a monocyclic or bicyclic 6- to 14-membered aryl, substructure D is a residue selected out of the group azetidine, azetine, azocane, azocane- 2-one, cydobutyl, cyclooctane cyclooctene, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,4- diazepane,
• R "1 is a hydrogen atom, -(G
• het is a residue selected out of the group azepine, azetidine, aziridine, azirine, 1,4-diazapane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazole, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, ketopiperazine, morpholine, 1,4- oxazepane, 1,2-oxa-thiepane, 1,2-oxathiolane, 1,2-oxazine, 1,3-ox
• R 2 is a direct bond
• R1 -N-R 2 -V can form a 4- to 8-membered cyclic group selected out of the group azepine, azetidine, dioxazole, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, ketopiperazine, morpholine, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazol ne, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidi none, pyrroline, tetrahydropyridine, tetrazine, te
• V is 1) a monocyclic or bicyclic 6- to 14-membered aryl out of the group phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, wherein aryl is mono-, di- or trisubstituted independently of one another by R14,
• G is a direct bond, -(CH 2 ) m -NR 10 -S0 2 -NR 'I O -(CH 2 ) n -, -(CH 2 ) m -CH(OH)-(CH 2 ) n -,
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• R13, 24 di- or trisubstituted independently of one another by R13, 24) wherein het is unsubstitqted or mono-, di- or trisubstituted independently of one another by R13, 5) -(Co-C3)-alkylene-0-CH 2 -(C C3)-perfluoroalkylene-CH 2 -0-(Co-C3)-aIkyl, 26) -SO w -N(R 1 )-R 13 , wherein w is 1 or 2,
• a nd wherein Me is methyl, or if two -0R19 residues are attached to adjacent atoms they can form together with the atoms which they are attached to a 1,3-dioxole ring or a 2,3-dihydro-[1,4]dioxine ring, which is substituted one, two, three or four times by R13,
• R11 and R12 are independently of one another identical or different and are
• alkyl and heterocyclyl are as defined above and are independently from one another unsubstituted or rnono- , di- or trisubstituted by R13, or R11 and R12 together with the nitrogen atom to which they are bonded form a heterocyclic ring out of the group azepine, azetidine, dioxazole, dioxazine, 1,4-diazepane, 1,2- diazepine, 1 ,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2- isoxazoline, ketopiperazine, morpholine, [1,4]oxa
• -S-R 10 -SO r R 10 , wherein r is 1 or 2, -S(0) v -N(R 10 )-R 20 , wherein v is 1 or 2, -C(0)-R 10 , -(G
• Me is methyl
• R 10 and R 20 are independently of one another hydrogen, -(G
• R15 and R16 are independently of one another hydrogen, -(Ci-CgJ-alkyl, cyclopropyl, cydobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or substituted one to three times by R 10 , and R17 is -(C-
• the present invention also relates to the compounds of the formula I, wherein
• R° is 1) a monocyclic or bicyclic 6- to 14-membered aryl out of the group phenyl, naphthyl, biphenyl, anthryl or fluorenyl, wherein aryl is mono-, di- or trisubstituted independently of one another by R8,
• heterocyclyl out of the group benzimidazolyl, 1 ,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, chromanyl, indazolyl, indolyl, isochromanyl, isoindolyl, isoquinolinyl, phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyridyl, pyridoimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, quinazolinyl, quinolyl, quinoxalinyl or 1,4,5,6-tetrahydro-pyridazinyl, wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one
• aryl is as defined above and is mono-, di- or trisubstituted independently of one another by halogen or — O-(C-]-C )-alkyl,
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, NH 2 , -OH or a methoxy residue, or
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, NH , -OH or a methoxy residue, 11. -S0 2 CH 3 or
• R8 is at least one halogen, -C(0)-NH 2 or -0-(O ⁇ -C 8 )-alkyl residue, if R0 is a aryl or a heterocyclyl, which are as defined above, provided that R8 is not a -0-(O
• Q is a direct bond, -(C 0 -C )-alkylene-C(0)-NR 10 -, -NR 10 -C(O)-NR 10 -, -NR1°-C(0)-, -S0 2 -, methylene or -(C ⁇ -C3)-alkylene-C(0)-0-(C ⁇ -C 2 )-alkylene ,
• R 1 is a hydrogen atom, -(C ⁇ -C4)-alkyl, wherein alkyl is unsubstituted or substituted one to three times by R13; -(C ⁇ -C3)-alkylene-C(0)-NH-R°, -(O ⁇ -C3)-alkylene-C(0)-0-R15, -(O ⁇ -C3)-perfluoroalkylene, -(G ⁇ -C3)-alkylene-S(0)-(C ⁇ -C4)-alkyl,
• het is a residue selected out of the group azepine, azetidine, aziridine, azirine, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazole, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, ketopiperazine, morpholine, 1,2- oxa-thiepane, 1,2-oxathiolane, 1,4-oxazepane, 1,2-oxazine, 1,3-o
• R 2 is a direct bond
• 1,2,4-triazole wherein said cyclic group is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• V is 1) a het residue out of the group 8-aza-bicydo[3,2.1]oct-3-yl, azaindole ( 1 H- pyrrolopyridine), azepine, azetidine, aziridine, azirine, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazole, dioxazine, dioxole, 1,3- dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothi
• G is a direct bond, -(CH 2 ) m -NR 10 -S0 2 -NR 10 -(CH 2 ) n -, -(CH 2 ) m -CH(OH)-(CH 2 ) n -,
• n and m are independently of one another identical or different and are the integers zero, 1 , 2, 3, 4, 5 or 6, M is 1) a hydrogen atom,
• heterocyclyl wherein heterocyclyl is a residue out of the group which can be derived from azepane, azepine, .1,4-diazepane, 1,2-diazepine, 1,3-diazepine,
• 1,4-diazepine imidazole, isothiazole, isoxazole, isoxazolidine, 2-isoxazoline, ketomorpholine, ketopiperazine, morpholine, oxazole, [1,4]-oxazepane, piperazine, piperazinone, piperidine, piperidinone, pyrazine, pyridazine, pyridazinone, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydro-pyridazinyl, tetrazine, tetrazole, thiadiazole, thiazole, thiomorpholine, 1 ⁇ 6-thiomorpholinyl, thiophene, 1,2,3-triazine, 1,2,4- triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, or c) phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, dd)) -CF 3 , or e) CHF 2 , ) -CN,
• het is as defined above and is. unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• R13, R11 and R12 are independently of one another identical or different and are 1) hydrogen atom, 2) -(0 ] -C5)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, 3) -(Cr j -C6)-alkyl-(C6-Ci4)-aryl, wherein aryl is as defined above and wherein alkyl and aryl are independently from one another unsubstituted or mono-, di- or trisubstituted by R13, 4) -O-R 17 or
• alkyl and heterocyclyl is as defined above and independently from one another are unsubstituted or mono-, di- or trisubstituted by R13, or R11 and R12 together with the nitrogen atom to which they are bonded can form a ring selected out of the group azepine, azetidine, 1,4-diazepane, dioxazole, dioxazine, 1 ,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, ketopiperazine, morpholine, [1 ,4]oxazepane, ox
• R 10 and R 20 are independently of one another hydrogen, -(0
• R15 and R16 are independently of one another hydrogen, -(C-i-CgJ-alkyl, or together form a ring out of the group cyclopropyl, cydobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or substituted one to three times by R 1 0, and R17 is -(C-)-C 6 )-alkyl, -(C-j-C 6 )-alkyl-OH, -(C C 6 )-alkyl-0-(O ⁇ -C6)-alkyl, -(C
• the present invention also relates to the compounds of the formula I, wherein RO is 1) phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8,
• heterocyclyl out of the group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, chromanyl, indazolyl, indolyl, isochromanyl, isoindolyl, isoquinolinyl, phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyridyl, pyridoimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, quinazolinyl, quinolyl, quinoxalinyl or 1,4,5,6- tetrahydro-pyridazinyl, wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another
• a heterocyclyl out of the group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl, wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8, and in addition is substituted by a residue selected out of the group pyridyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 2-
• R8 is 1. F, CI, Br orJ, 2. -C(0)-NH 2 , 3. -(O ⁇ -C4)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, -OH or a methoxy residue, or
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen or a methoxy residue, provided that R8 is at least one halogen, -C(0)-NH 2 or — O-(C-]-C )-alkyl residue, if RO is a aryl or a heterocyclyl, which are as defined above, provided that R8 is not a — O-(C- -C 8 )-alkyl residue, if R° and V are phenyl, substructure Dis a residue selected out of the group phenyl, pyridyl, pyridyl-N-oxide, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, isothiazolyl, thiadiazol
• Q is a direct bond, -C(O)-; -S0 2 - , methylene, -(Cn-C 2 )-alkylene-C(0)-NR 1 °- or
• R is hydrogen atom, -(G
• R 2 is a direct bond
• R 1 -N-R 2 -V can form a 4- to 7- membered cyclic group out of the group azetidine, azetidinone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,4- diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, ketopiperazine, 1,4- oxazepane, oxazole, isoxazole, isoxazolidine, 2-isoxazoline, morpholine, thiazole, isothiazole, thiadiazole or thiomorpholine,
• R 18 and R 21 are independently from each other hydrogen atom, -(0]-C3)-perfluoroalkyl or-(C ⁇ -C4)-alkyl,
• V is 1. a cyclic residue out of the group containing compounds which are derived from 8-aza-bicyclo[3.2.1]oct-3-yl, azaindole ( 1 H-pyrrolopyridine), aziridine, azirine, .
• G is a direct bond, -(CH 2 ) m -, or -(CH 2 ) m -NRl°-, m is the integers zero, 1 , 2, 3 or 4,
• M is 1. a hydrogen atom
• heterocyclyl wherein heterocyclyl is a residue out of the group which can be derived from azepane, azepine, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4- diazepine, imidazole, isothiazole, isoxazole, isoxazolidine, 2-isoxazoline, ketomorpholine, ketopiperazine, morpholine, oxazole, [1,4]-oxazepane, piperazine, piperazinone, piperidine, piperidinone, pyrazine, pyridazine, pyridazinone, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydro- pyridazinyl, tetrazine, tetrazole, thiadiazole
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, 4) -(0
• Me is methyl, if two -OR19 residues are attached to adjacent atoms they can form together with the atoms which they are attached to a 1,3-dioxole ring or a 2,3-dihydro-[1,4]dioxine ring, which is substituted one, two, three or four times by R13,
• R 1 1 and R1 2 together with the nitrogen atom to which they are bonded can form a ring selected out of the group azepine, azetidine, 1 ,4-diazepane, dioxazole, dioxazine, 1,2- diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2- isoxazoline, ketopiperazine, morpholine, [1,4]-oxazepane, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline,
• R 20 -C(0)-R 10 , -(C-]-C 8 )-alkyl, -(C- ⁇ -C 8 )-alkoxy, phenyl, phenyloxy-, -0-CF 3 ,
• R 1 ⁇ and R 2 ⁇ are independently of one another hydrogen, -(C-i-CgJ-alkyl, -(Crj-C4)-alkyl-OH,
• R15 and R16 are independently of one another hydrogen, -(C-i-CgJ-alkyl, or together form a ring out of the group cyclopropyl, cydobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or substituted one to three times by R1°, and
• R17 is -(C C 6 )-alkyl, -(C C 6 )-alkyl-OH, -(C ⁇
• the present invention also relates to the compounds of the formula I, wherein RO is 1. phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8,
• heterocyclyl selected out of the group indolyl, isoindolyl, benzofuranyl, benzothiophenyl, 1,3-benzodioxolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, chromanyl, isochromanyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyridoimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyridyl, purinyl and pteridinyl, wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8, 3.
• heterocyclyl out of the group pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, furyl, 2-furyl, 3-furyl; thienyl, 2-thienyl, 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl, wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8, and in addition is substituted by a residue selected out of the group pyridyl, 2-pyridyl,
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, -OH or a methoxy residue, or
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen or a methoxy residue, provided that R8 is at least one halogen, -C(0)-NH 2 or -0-(CrCs)-alkyl residue, if RO is a aryl or a heterocyclyl, which are as defined above, provided that R8 is not a — O-(C -C )-alkyl residue, if R° and V are phenyl, substructure Dis a residue selected out of the group phenyl, pyridyl, pyridyl-N-oxide, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, isothiazolyl, thiadiazolyl, pyrimi
• R 1 is hydrogen atom or -(C ⁇ -C 2 )-alkyl
• R 2 is a direct bond
• R1-N-R 2 -V can form a 4- to 7-membered cyclic group out of the group piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4-triazine, 1,3,5- triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, ketopiperazine, oxazole, isoxazole, isoxazolidine, 2-isoxazoline, morpholine, thiazole, isothiazole, thiadiazole or thiomorpholine, wherein said cyclic group is unsubstit
• R14, R14 is fluorine, chlorine, -(C-
• V is 1. a cyclic residue out of the group containing compounds, which are derived from 8-aza-bicyclo[3.2.1]oct-3-yl, azaindolyl (1 H-pyrrolopyridyl), azetidine, azepine, aziridine, azirine, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diazirine, 1,3- dioxolane, dioxazole, furan, imidazole, isoquinoline, isothiazole, isothiazolidine, isothiazoline, isoxazole, 2-isoxazoline, isoxazolidine, ketopiperazine, morpholine, 1,2- oxazine, 1,3-oxazine, 1,4-o
• phenyl wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• G is a direct bond, -(CH 2 ) m -, or -(CH 2 ) m -NR 10 -, m is the integers zero, 1, 2, 3 or 4, is 1. a hydrogen atom, 2. heterocyclyl, wherein heterocyclyl is a residue out of the group which can be derived from 1,4-diazepane, ketomorpholine, thiophene, pyridazone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, pyridonyl, imidazole, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4- triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1 ,4-diazepine,
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, or 4.
• (C 3 -C 6 )-cycloalkyl
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• Me is methyl
• R11 and R12 are independently of one another identical or different and are
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• alkyl and heterocyclyl independently from one another are unsubstituted or mono-, di- or trisubstituted by R13 and wherein heterocyclyl js selected out of the group azetidine, cyclopropyl, cydobutyl, 4,5-dihydro-oxazole, imidazolidine, morpholine, (1 ,4)-oxazepane, oxazolidine, piperidine, piperazine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine, or R11 and R12 together with the nitrogen atom to which they are bonded form a heterocyclic ring, which is selected out of the group azetidine, cyclopropyl, cydobutyl, 4,5-dihydro-oxazole, imid
• R 10 and R 20 are independently of one another hydrogen, -(G
• R 15 and Rl ⁇ are independently of one another hydrogen, -(G ⁇ -C4)-alkyl, or together form a ring out of the group cyclopropyl, cydobutyl, cyclopentyl or cyclohexyl, wherein each , ring is unsubstituted or substituted one to three times by R 1 ⁇ and
• R17 is -(C C 6 )-alkyl, -(C-j-C 6 )-alkyl-OH, -(C 1 -C 6 )-alkyl-O-(C 1 -C 8 )-alkyl-(C 3 -C 8 )-cycloalkyi
• the present invention also relates to the compounds of the formula I, wherein RO is 1. phenyl, wherein phenyl is unsubstituted or mono- or disubstituted independently of one another by R8, 2. ' pyridyl or 1H-indazolyl, wherein pyridyl and 1H-indazolyl are unsubstituted or mono- or disubstituted independently of one another by R8, or
• a heterocyclyl out of the group thienyl, thiadiazolyl, isoxazolyl and thiazolyl wherein said heterocyclyl is substituted by a residue selected out of the group thienyl, 2-thienyl and 3-thienyl, wherein said residue is unsubstituted or mono- or disubstituted independently of one another by R8, R8 is F, CI, Br, -0-CH 3 or -C(0)-NH 2 , provided that R8 is not a -0-(G
• Q is a direct bond, -C(O)-; -SO2-, -C(0)-0-methylene, -CH2-C(0)-NH- or methylene,
• R1 is hydrogen atom
• R 2 is a direct bond
• V is 1. a residue out of the group containing compounds which is derived from 8-aza-bicyclo[3.2.1]oct-3-yl, azaindolyl (1H-pyrrolopyridyl), azetidine, 1,4- diazepane, isoxazole, isoquinoline, piperazine, piperidine, pyrazine, pyridazine, pyrimidine, pyrrolidine, quinazoline, quinoline or tetrahydropyrane, wherein said cyclic residue is unsubstituted or mono- or disubstituted independently of one another by R14, or 2. phenyl, wherein phenyl is unsubstituted or mono- or disubstituted independently of one another by R14,
• G is a direct bond, -(CH 2 ) m -, -C(O)- or -(CH2) m - Rl°-, m is the integers zero, 1 or 2
• M is a hydrogen atom, (C2-C4)-alkyl, azepanyl, cyclopropyl, cydobutyl, cyclopentyl, cyclohexyl, imidazolyl, ketomorpholinyl, morpholinyl, [1,4]Oxazepanyl, piperazinyl, piperidinyl, piperidonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolidinyl, 1 ⁇ 6- thiomorpholinyl, 1,4,5,6-tetrahydro-pyridazinyl, or tetrahydropyranyl, wherein the residues are unsubstit
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• R11 and R12 are independently of one another identical or different and are 1) hydrogen atom, 2) , -(G
• R 10 and R 20 are independently of one another hydrogen, -(C-i -C )-a l_kyl or -(C-1-C3)- perfluoroalkyl,
• R 15 and R 16 are independently of one another hydrogen, -(0]-C4)-alkyl, or together form a ring out of the group cyclopropyl, cydobutyl, cyclopentyl or cyclohexyl, wherein each ring is unsubstituted or substituted one to three times by R 10 , and R17 is -(C -C 6 )-alkyl, -(C- ⁇ -C 6 )-alkyl-OH, -(C- ⁇ -C 6 )-alkyl-0-(C- ⁇ -C8)-alkyl-(C3-C8)-cycloalkyl,
• R-IO in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically tolerable salts. • 7)
• the present invention also relates to the compounds of the formula I, wherein RO is 1. phenyl, wherein phenyl is unsubstituted or mono- or disubstituted independently of one another by R8, 2. pyridyl or 1H-indazolyl, wherein pyridyl and 1H-indazolyl are unsubstituted or mono- or disubstituted independently of one another by R8, or 3.
• heterocyclyl out of the group thiadiazolyl, isoxazolyl and thiazolyl, wherein said heterocyclyl is substituted by a residue selected out of the group thienyl, 2-thienyl and 3-thienyl, wherein said residue is unsubstituted or mono- or disubstituted independently of one another by R8,
• Q is -CH2-C(0)-NH- or methylene
• R 1 is hydrogen atom
• R 2 is a direct bond
• V is piperidinyl or phenyl, wherein phenyl is unsubstituted or mono- or disubstituted independently of one another by R14, .
• G is a direct bond or -C(O)-
• M is a hydrogen atom, isopropyl, cyclopropyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrimidyl, pyrrolidinyl or 1 ⁇ 6-thiomorpholinyl, wherein the residues are unsubstituted or mono- or disubstituted independently of one another by R14 R3 is
• R11 and R12 are independently of one another identical or different and are
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, or 3) -(C ⁇ -C 6 )-alkyl-(C 3 -C 6 )-cycloalkyl or
• R11 and R12 together with the nitrogen atom to which they are bonded can form a ring, which is selected out of the group azetidine, morpholine, (1,4)-oxazepane or piperidine, wherein said ring is unsubstituted or mono-, di- or trisubstituted by R13,
• R 10 is hydrogen atom or -(Ci-C ⁇ -alkyl
• RlS and Rl ⁇ are independently of one another hydrogen atom or -(C-
• R17 is -(G
• the present invention also relates to the compounds of the formula I, which are 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1 H-benzoimidazole-2-carboxylic acid (1- isopropyl-piperidin-4-yl)-amide, 1-[(4-Chloro-phenylcarbamoyl)-methyl]-1H-benzoimidazole-2-carboxylic acid (1-isopropyl- piperidin-4-yl)-amide,
• alkyl is to be understood in the broadest sense to mean hydrocarbon residues which can be linear, e.g. straight-chain, or branched and which can be acyclic or cyclic residues or comprise any combination of acyclic and cyclic subunits.
• alkyl as used hereirTexpressly includes saturated groups as well as unsaturated groups which latter groups contain one or more, for example one, two or three, double bonds and/or triple bonds, provided that the double bonds are not located within a cyclic alkyl group in such a manner that an aromatic system results.
• Alkyl residues can also be unsaturated when they are substituted. Examples of -(C 3 -C 8 )-cycIoa I ky I cyclic alkyl residues are cycloalkyl residues containing 3, 4, 5, 6,
• ring carbon atoms like cyclopropyl, cydobutyl, cyclopentyl, cyclohexyl, cyloheptyl or cyclooctyl, which can also be substituted and/or unsaturated.
• Unsaturated cyclic alkyl groups and unsaturated cycloalkyl groups like, for example, cyclopentenyl or cyclohexenyl can be bonded via any carbon atom.
• a monocyclic or bicyclic 6- to 14-membered aryl or "-(C6-C-
• -(Cg-C- ⁇ -aryl radicals are phenyl, naphthyl, for example 1-naphthyl and 2- naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl.
• Biphenylyl radicals, naphthyl radicals and, in particular, phenyl radicals are preferred aryl radicals.
• mono- or bicyclic 4- to 15-membered heterocyclyl or "-(C4-Ci5)-heterocyclyl” refer to heterocycles in which one or more of the 4 to 15 ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur.
• Examples are acridinyl, 8-aza-bicyclo[3.2.1]oct-3-yl, azaindole ( 1H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrochinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl
• heterocyclyls such as benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, 2-furyl, 3-furyl; imidazolyl, indolyl, indazolyl, isochromanyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridoimidazolyl, " pyridopyridinyl, pyridopyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrrolyl; 2-
• heterocycles refer to structures of heterocycles which can be derived from compounds such as azepine, azetidine, aziridine, azirine, 1,4 diazepane, 1,2-diazepine, 1,3-diazepine, 1,4- diazepine, diaziridine, diazirine, dioxazole, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, ketomorpholine, ketopiperazine, morpholine, 1,2-oxa-thiepane, 1,2-oxathiolane
• R1-N-R 2 -V can form a 4- to 8-membered cyclic group " or "R 11 and R 12 together with the nitrogen atom to which they are bonded can form a 4- to 8-membered monocyclic heterocyclic ring which in addition to the nitrogen atom can contain one or two identical or different ring heteroatoms chosen from oxygen, sulfur and nitrogen” refer to structures of heterocycles which can be derived from compounds such as azepane, azepine, azetidine, dioxazole, dioxazine, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 2,3 dihydroindole, imidazole, imidazoline, imidazolidine, indole, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isox
• R15 and Rl ⁇ together with the carbon atom to which they are bonded can form a 3- to 6 membered carbocyclic ring
• structures which can be derived from compounds such as cyclopropyl, cydobutyl, cyclopentyl or cyclohexyl.
• the "substructure D" is a 4-to 8 membered saturated, partially unsaturated or aromatic cyclic group containing zero, 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen” refer to structures, which can be derived from compounds such as azepane, azetidine, azetine, azocane, azocane-2-one, cydobutyl, cyclooctane, cyclooctene, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,2- diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, [1,4]diazocane, [1,2]diazocan-3-one, [1 ,3]diazocan-2-one, dioxazole, dioxazine, dioxole, 1,3-dioxolene
• substrate D is a 5 to 6 membered saturated, partially unsaturated or aromatic cyclic group containing zero, 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen
• structures which can be derived from compounds such as cyclopentyl, cyclohexyl, dioxazole, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, ketomorpholine, ketopiperazine, morpholine, 1,2-oxathiolan, 1,2-oxazine, 1,3- oxazine, 1,4-oxazine, oxazole, piperazine, piperidine, phenyl, pyran, pyr
• R 1 and R 3 together with the atoms to which they are bonded can form a 6- to 8- membered cyclic group, containing up to 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen
• the 4-15 membered mono- or polycydic group could only be derived from the respective unsaturated ring system.
• the names here only serve to describe the ring system with respect to ring size and the number of the heteroatoms and their relative positions.
• the 4-15 membered mono- or polycydic group can be saturated or partially unsaturated or aromatic, and can thus be derived not only from the before-listed heterocycles themselves but also from all their partially or completely hydrogenated analogues and also from their more highly unsaturated analogues if applicable.
• -(C ⁇ -C3)-perfluoroalkyl is a partial or totally fluorinated alkyl-residue, which can be derived from residues such as -CF , -CHF 2 , -CH 2 F, -CHF-CF3, -CHF-CHF 2 , -CHF-CH 2 F, -CH 2 -
• -(O ⁇ -C3)-perfluoroalkylene is a partial or totally fluorinated alkylene-residue, which can be derived from residues such as -CF 2 -, -CHF-, -CHF-CHF 2 -, -CHF-CHF-, -CH 2 -CF 2 -, -CH 2 -CHF-, -CF 2 -CF 2 -, -CF 2 -CHF-, -CH 2 -CHF-CF 2 -, -CH 2 -CHF-CHF-, -CH 2 -CH 2 -CF 2 -, -CH 2 -CH 2 -CHF, -CH -CF 2 -CF 2 -, -CH 2 -CF 2 -CHF-, -CHF-CHF-CF 2 -, -CHF-CHF-CF 2 -, -CHF-CHF-CHF-, -CHF-CHF-CF 2 -
• Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine or bromine.
• Optically active carbon atoms present in the compounds of the formula I can independently of each other have R configuration or S configuration.
• the compounds of the formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and/or diastereomers, for example in the form of racemates.
• the present invention relates to pure enantiomers and mixtures of enantiomers as well as to pure diastereomers and mixtures of diastereomers.
• the invention comprises mixtures of two or of more than two stereoisomers of the formula I, and it comprises all ratios of the stereoisomers in the mixtures.
• the compounds of the formula I can be present as E isomers or Z isomers (or cis isomers or trans isomers) the invention relates both to pure E isomers and pure Z isomers and to E/Z mixtures in all ratios.
• the invention also comprises all tautomeric forms of the compounds of the formula I.
• Diastereomers including E/Z isomers, can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary methods, for example by chromatography on chiral phases or by resolution, for example by crystallization of diastereomeric salts obtained with optically active acids or bases. Stereochemically uniform compounds of the formula I can also be obtained by employing stereochemically uniform starting materials or by using stereoselective reactions.
• Physiologically tolerable salts of the compounds of formula I are nontoxic salts that are physiologically acceptable, in particular pharmaceutically utilizable salts.
• Such salts of compounds of the formula I containing acidic groups, for example a carboxyl group COOH are for example alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts and calcium salts, and i ⁇ so salts with physiologically tolerable quaternary ammonium ions such as tetramethylammonium or tetraethylammonium, and acid addition salts with ammonia and physiologically tolerable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine.
• Basic groups contained in the compounds of the formula I form acid addition salts, for example with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
• inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid
• organic carboxylic acids and sulfonic acids such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methane
• Salts of compounds of the formula I can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the formula I with an inorganic or organic acid or base in a solvent or dispersant, or from other salts by cation exchange or anion exchange.
• the present invention also includes all salts of the compounds of the formula I which, because of low.physiologically tolerability, are not directly suitable for use in pharmaceuticals but are suitable, for example, as intermediates for carrying out further chemical modifications of the compounds of the formula I or as starting materials for the preparation of physiologically tolerable salts.
• the present invention furthermore includes all solvates of compounds of the formula I, for example hydrates or adducts with alcohols.
• the invention also includes derivatives and modifications of the compounds of the formula I, for example prodrugs, protected forms and other physiologically tolerable derivatives, as well as active metabolites of the compounds of the formula I.
• the invention relates in particular to prodrugs and protected forms of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions.
• Suitable prodrugs for the compounds of the formula I i. e. chemically modified derivatives of the compounds of the formula I having properties which are improved in a desired manner, for example with respect to solubility, bioavailability or duration of action, are known to those skilled in the art.
• prodrugs for the compounds of the formula I are especially acyl prodrugs and carbamate prodrugs of acylatable nitrogen-containing groups such as amino groups and the guanidino group and also ester prodrugs and amide prodrugs of carboxylic acid groups which may be present in compounds of the formula I.
• acyl prodrugs and carbamate prodrugs one or more, for example one or two, hydrogen atoms on nitrogen atoms in such groups are replaced with an acyl group or a carbamate, preferably a - (G]-C6)-alkyloxycarbonyl group.
• Suitable acyl groups and carbamate groups for acyl prodrugs and carbamate prodrugs are, for example, the groups RP 1 -C0- and RP 2 0-C0-, in which RP 1 is hydrogen, (G-G 8 )-alkyl, (G-C ⁇ J-cycloal yl, (C 3 -C 8 )-cydoalkyl-(C ⁇ -G)-alkyl-, (C 6 -G 4 )-aryl, Het-, (C 5 - G )-aryl-(G-G)-alkyl- or Het-(G-G)-alkyl- and in which RP 2 has the meanings indicated for RP 1 with the exception of hydrogen.
• Especially preferred compounds of the formula I are those wherein two or more residues are defined as indicated before for preferred compounds of the formula I, or residues can have one or some of the specific denotations of the residues given in their general definitions or in the definitions of preferred compounds before. All possible combinations of definitions given for preferred definitions and of specific denotations of residues explicitly are a subject of the present invention.
• the compounds of the formula I can be prepared by utilising procedures and techniques, which per se are well known and appreciated by one of ordinary skill in the art. Starting materials or building blocks for use in the general synthetic procedures that can be applied in the preparation of the compounds of formula I are readily available to one of ordinary skill in the art. In many cases they are commercially available or have been described in the literature. Otherwise they can be prepared from readily available precursor compounds analogously to procedures described in the literature, or by procedures or analogously to procedures described in this application.
• compounds of the formula I can be prepared, for example in the course of a convergent synthesis, by linking two or more fragments which can be derived retrosy nth etica I ly from the formula I. More specifically, suitably substituted starting benzoimidazole derivatives are employed as building blocks in the preparation of the compounds of formula I. If not commercially available, such benzoimidazole derivatives can be prepared according to the well-known standard procedures for the formation of the benzoimidazole ring system.
• a benzoimidazole carrying a hydrogen atom in the 2-position can also be obtained by saponification and subsequent decarboxylation of benzoimidazole carrying an ester group in the respective position.
• Carboxylic acid groups and acetic acid groups in the 2- position, the 4-position, 5-position, 6-position and the 7-position can be converted into their homologues by usual reactions for chain elongation of carboxylic acids.
• Halogen atoms can be introduced,. for example according to procedures described in the literature like the following.
• N-fluoro-2,4,6-trimethylpyridinium triflate is the reagent of choice (T. Umemoto, S. Fukami, G. Tomizawa, K.
• Halogens or hydroxy groups - via the triflate or nonaflate - or primary amines - via its diazonium salt - or after interconversion to the corresponding stannane, or boronic acid - present in the benzoimidazole structure can be converted into a variety of other functional groups like for example -CN, -CF 3 , -C2F5, ethers, acids, amides, amines, alkyl- or aryl- groups mediated by means of transition metals, namely palladium or nickel catalysts or copper salts and reagents for example referred to below (F. Diederich, P.
• nitro groups can be reduced to amino group with various reducing agents, such as sulfides, dithionites, complex hydrides or by catalytic hydrogenation.
• a reduction of a nitro group may also be carried out at a later stage of the synthesis of a compound of the formula I, and a reduction of a nitro group to an amino group may also occur simultaneously with a reaction performed on another functional group, for example when reacting a group like a cyano group with hydrogen sulfide or when hydrogenating a group.
• amino groups can then be modified according to standard procedures for alkylation, for example by reaction with (substituted) alkyl halogenides or by reductive amination of carbonyl compounds, according to standard procedures for acylation, for example by reaction with activated carboxylic acid derivatives such as acid chlorides, anhydrides, activated esters or others or by reaction with carboxylic acids in the presence of an activating agent, or according to standard procedures for sulfonylation, for example by reaction with sulfonyl chlorides.
• Ester groups present in the benzoimidazole nucleus can be hydrolyzed to the corresponding carboxylic acids, which after activation can then be reacted with amines or alcohols under standard conditions. Furthermore these ester or acid groups can be reduced to the corresponding alcohols by many standard procedures.
• Ether groups present at the benzoimidazole nucleus for example benzyloxy groups or other easily cleavable ether groups, can be cleaved to give hydroxy groups which then can be reacted with a variety of agents, for example etherification agents or activating agents allowing replacement of the hydroxy group by. other groups. Sulfur-containing groups can be reacted analogously.
• the structural elements present in the residues in the 1-position of the benzoimidazole ring in the compounds of the formula I and in the COR 8 ' group present in the 2-position of the benzoimidazole ring can be introduced into the starting benzoimidazole derivative obtainable as outlined above by consecutive reaction steps using parallel synthesis methodologies like those outlined below using procedures which per se are well known to one skilled in the art.
• the residues R 8' that can be introduced in formula 2 for example, by condensing a corresponding carboxylic acid of the formula 2 with a compound of the formula HR 8' , i. e. with an amine of the formula HN(R 1' )R 2 '-V-G-M to give a compound of the formula 3.
• the compound of the formula 3 thus obtained can already contain the desired final groups, i. e. the groups R 8' and R 62 can be the groups -N(R 1 )-R 2 -V-G-M and R°-Q- as defined in the formula I, or. optionally in the compound of the formula 3 thus obtained subsequently the residue or the residues R 8 and the residue R 62 are converted into the residues -N(R )-R 2 -V-G-M and R°-Q- , respectively, to give the desired compound of the formula I.
• the groups R 8' and R 62 can be the groups -N(R 1 )-R 2 -V-G-M and R°-Q- as defined in the formula I, or. optionally in the compound of the formula 3 thus obtained subsequently the residue or the residues R 8 and the residue R 62 are converted into the residues -N(R )-R 2 -V-G-M and R°-Q- , respectively, to give the desired compound of the formula
• residues R 8 ' and the residues R 1 ' and R 2 '-V-G-M contained therein can have the denotations of R 1 and R 2 -V-G-M, respectively, given above or in addition in the residues R and R 2 '— V-G-M functional groups can also be present in the form of groups that can subsequently be transformed into the final groups R 1 and R /-G-M, i.e. functional groups can be present in the form of precursor groups or of derivatives, for example in protected form.
• cyano groups examples include carboxylic acid derivatives or by reduction into aminomethyl groups, or the nitro groups may be transformed by reduction like catalytic hydrogenation into amino groups.
• Protective groups can also have the meaning of a solid phase, and cleavage from the solid phase stands for the removal of the protective group. The use of such techniques is known to those skilled in the art (Burgess K (Ed.) Solid Phase Organic Synthesis, New York, Wiley, 2000).
• a phenolic hydroxy group can be attached to a trityl-polystyrene resin, which serves as a protecting group, and the molecule is cleaved from this resin by treatment with TFA at a later stage of the synthesis.
• the residue R 62 in the compounds of the formulae 2 and 3 can denote the group -Q-R 0 as defined above which finally is to be present in the desired target molecule of the formula I, or it can denote a group which can subsequently be transformed into the group -Q-R 0 , for example a precursor group or a derivative of the group -Q-R 0 in which functional groups are present in protected form, or R 62 can denote a hydrogen atom or a protective group for the nitrogen atom of the benzoimidazole ring.
• residues R 30 have the corresponding definitions of R 3 in formula I as defined above, however, for the synthesis of the compounds of the formula I these residues, too, can in principle be present at the stage of the condensation of a compound of the formula 2 with a compound of the formula HR 8 ' giving a compound of the formula 3 in the form of precursor groups or in protected form.
• the residues R 63 in the compounds of the formula 2 which can be identical or different, can be, for example, hydroxy or (d- ⁇ j-alkoxy, i. e., the groups COR 63 present in the compounds of the formula 2 can be, for example, the free carboxylic acids or esters thereof like alkyl esters as can be the groups COR 8 ' in the compounds of the formula I.
• the groups COR 53 can also be any other activated derivative of a carboxylic acid which allows amide formation, ester formation or thioester formation with a compound of the formula HR 8 '.
• the group COR 63 can be, for example, an acid chloride, an activated ester like a substituted phenyl ester, an azolide like an imidazolide, an azide or a mixed anhydride, for example a mixed anhydride with a carbonic acid ester or with a sulfonic acid, which derivatives can all be prepared from the carboxylic acid by standard procedures and can be reacted with an amine, an alcohol or a mercaptan of the formula HR 8 ' under standard conditions.
• a carboxylic acid group COOH representing COR 63 in a compound of the formula 2 can be obtained, for example, from an ester group introduced into the benzoimidazole system during a benzoimidazole synthesis by standard hydrolysis procedures.
• Compounds of the formula I in which a group COR 8 ' is an ester group can also be prepared from compounds of the formula 2 in which COR 63 is a carboxylic acid group by common esterification reactions like, for example, reacting the acid with an alcohol under acid catalysis, or alkylation of a salt of the carboxylic acid with an electrophile like an alkyl halogenide, or by transesterification from another ester.
• Compounds of the formula I in which a group COR 8 ' is an amide group can be prepared from amines and compounds of the formula 2 in which COR 63 is a carboxylic acid group or an ester thereof by common amination reactions.
• the compounds of the formula 2 in which COR 63 is a carboxylic acid group can be condensed under standard conditions with compounds of the formula HR 8 ' which are amines by means of common coupling reagents used in peptide synthesis.
• Such coupling reagents are, for example, carbodiimides like dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, carbonyldiazoles like carbonyldiimidazole (CDI) and similar reagents, propylphosphonic anhydride, 0-((cyano-(ethoxycarbonyl)-methylene)amino)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TOTU), diethylphosphoryl cyanide (DEPC) or bis-(2-oxo- 3-oxazo ⁇ dinyl)-phosphoryl chloride (BOP-Cl) and many others.
• DEC diethylphosphoryl cyanide
• BOP-Cl bis-(2-oxo- 3-oxazo ⁇ dinyl)-phosphoryl chloride
• residue -Q-R 0 present in a benzoimidazole of the formula I or the residue R 63 present in a benzoimidazole.of the formula 2, or a residue in which functional groups within the residue - Q-R°or R 63 are present in protected form or in the form of a precursor group, have not already been introduced during a preceding step, for example during a synthesis of the benzoimidazole nucleus, these residues can, for example, be introduced into the 1-position of the benzoimidazole system by conventional literature procedures well known to one skilled in the art for N-alkylation, reductive amination, N-arylation, N-acylation or N-sulfonylation of ring nitrogen atoms of heterocycles.
• N-Alkylation of a ring nitrogen atom can, for example, be performed under standard conditions, preferably in the presence of a base like K 2 C0 3 , Cs 2 C0 3 , NaH or KO l Bu, using an alkylating compound of the formula LG-Q-R°or of the formula R 62 -LG, wherein the atom in the group Q or in the group R 62 bonded to the group LG in this case is an aliphatic carbon atom of an alkyl moiety and LG is a leaving group, for example halogen like chlorine, bromine or iodine, or a sulfonyloxy group like tosyloxy, mesyloxy or trifluormethylsulfonyloxy.
• LG may, for example, also be a hydroxy group which, in order to achieve the alkylation reaction, is activated by a conventional activating agent.
• a conventional activating agent for the preparation of compounds in which A is a direct linkage and an aromatic group is directly bonded to the 1-position of the benzoimidazole system, conventional arylation procedures can be used.
• aryl fluorides like alkyl fluorobenzoates or 4-fluorophenyl methyl sulfones can be employed as arylating agents.
• Such processes are described, for example, by M. Yamada et al. J. Med. Chem. 1996, 39, 596; J. Ohmori et al. J. Med. Chem. 1996, 39, 3971.
• aryl iodides, aryl bromides or aryl triflates can serve as arylating agents at the 1-position of the heterocyclic nitrogen in a copper salt or palladium mediated reaction according for example to P. Cozzi et al. Farmaco 1987, 42, 205; P. Unangst, D. Connor, R. Stabler, R. Weikert, J. Heterocyd. Chem. 1987, 24, 811; G. Tokmakov, I. Grandberg, Tetrahedron 1995, 51, 2091; D. Old, M. Harris, S. Buchwald, Org. Lett. 2000, 2, 1403, G. Mann, J. Hartwig, M.
• the invention also relates to a process for preparing a compound of the formula IV.
• Another object of the present invention is to find a process for the amination of the compounds of the formula V in high yields and purity.
• the invention therefore relates to a process for producing the compound of formula IV,
• x is the integer zero or 1
• R24 are identical or different and are independent from each other a) a hydrogen atom, b) -(G
• 15-membered heterocyclyl containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8, and which is additionally substituted by a monocyclic or bicyclic 4- to 15- membered heterocyclyl, containing one, two, three or four heteroatoms chosen from nitrogen, sulphur or oxygen, wherein heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R8, h) -(O ⁇ -C3)-perfluoroalkylene, i) -( .
• R13 c) -(C C 3 )-alkylene-C(0)-NH-R ⁇ , d) -(Ci-C 3 )-alkylene-C(0)-0-R 10 , e) -(Crj-C4)-alkyl-aryl, wherein aryl is a monocyclic or bicyclic 6- to 14-membered aryl and is mono-, di- or trisubstituted independently of one another by R8, f) -(Crj-GjJ-alkyl-heteroaryl, wherein heteroaryl is a monocyclic or bicyclic 4- to 15- membered heterocyclyl, containing one, two, thre or four heteroatoms chosen from nitrogen, sulphur or oxygen and is mono-, di- or trisubstituted independently of one another by R8, g) -(Cn-C4)-alkyl-heterocyclyl, wherein heterocyclyl is a monocyclic or bicyclic
• R23 is a) a hydrogen atom, b) -(C ⁇ -C4)-alkyl, wherein alkyl is unsubstituted or substituted one to three times by
• substructure in formula IV is a 4-to 8 membered saturated, partially unsaturated or aromatic cyclic group containing zero, 1 , 2, 3 or 4 heteroatoms chosen from nitrogen, sulphur or oxygen and is unsubstituted or substituted 1, 2, 3, 4, 5 or 6 times by R3, wherein R3 is as defined in formula I,
• R23 is as defined in formula IV and substructure in formula V is as defined in formula IV, with a primary amine or a secondary amine in the presence of water, at least one base and at least one water-miscible organic solvent.
• Another object of the present invention is a process for the preparation of a compound of formula IV, wherein the primary amine is a) NH 2 -R21, wherein R21 is as defined in formula IV, b) NH 2 -R 2 -V-G-M, wherein R 2 , V, G and M are as defined in formula IV, c) NH 2 -N(R21)-R22, wherein R21 and R22 are as defined in formula IV or
• Another object of the present invention is a process for the preparation of a compound of formula IV, wherein the secondary amine is
• R 2 , R21, R24, V, G and M are as defined in formula IV.
• water-miscible organic solvent is taken to mean, for example, organic solvents such as: Tetrahydrofuran, acetonitrile, dimethylsulfoxide, dioxane, 1,2-dimethoxyethane, N,N- dimethylformamide, N-methylpyrrolidone, acetone or sulfolane.
• base is taken to mean alkali metal carbonates, for example sodium bicarbonate or potassium bicarbonate, in solid form or in the form of solutions of differing concentrations. Basically all inorganic salts, particularly bicarbonates, which have a basicity comparable to sodium bicarbonate, can be used for the above described process. Also, the term “base” is taken to mean tertiary amines, such as triethylamine or diisopropylethylamine.
• primary amine is taken to mean an amine, which is substituted by one residue at the nitrogen atom.
• secondary amine is taken to mean an amine, which is substituted by two residues at the nitrogen atom.
• a primary amine or a secondary amine are used per 1 mol of the compound of the formula V.
• the amount of water-miscible organic solvent used is generally from 5 g to 300 g per 1 g of the compound of the formula V, preferably from 10 g to 200 g.
• the reaction time is generally between a few minutes and 24 hours, preferably 1 to 5 hours, depending on the composition of the mixture and the temperature range selected.
• the reaction temperature is from 5 °C to 120 °C, preferably from 10 °C to 35°C, in particular 25 °C.
• the reaction temperature is from 50 °C to 120 °C, preferably from 70 °C to 100 °C, in particular 90 °C
• the residual content of starting substrate of the compound of the formula V was reduced to a content, which is below 0.5 % in the isolated compound of formula IV.
• amines with a very low reactivity for example amines which even do not react with the corresponding benzoimidazole-2-carboxyIic acid chlorides, such as (4-amino-3-fluoro- phenyl)-pyrrolidin-1-yl-methanone (example 165) or 2-amino-3-nitro-benzoic acid methyl ester (example 167), react in a smooth way (under very mild conditions) allowing the construction of special imidazole-2-carboxylic acid anilides, which are difficult to synthesize by other existing methods.
• benzoimidazole-2-carboxyIic acid chlorides such as (4-amino-3-fluoro- phenyl)-pyrrolidin-1-yl-methanone (example 165) or 2-amino-3-nitro-benzoic acid methyl ester (example 167)
• Preferred methods include, but are not limited to those described in the examples.
• the compounds of the present invention are serine protease inhibitors, which inhibit the activity of the blood coagulation enzyme factors Xa and/or factor Vila. In particular, they are highly active inhibitors of factor Xa. They are specific serine protease inhibitors inasmuch as they do not substantially inhibit the activity of other proteases whose inhibition is not desired.
• the activity of the compounds of the formula I can be determined, for example, in the assays described below or in other assays known to those skilled in the art.
• a preferred embodiment of the invention comprises compounds which have a Ki ⁇ 1 mM for factor Xa inhibition as determined in the assay described below, with or without concomitant factor Vila inhibition, and which preferably do not substantially inhibit the activity of other proteases involved in coagulation and fibrinolysis whose inhibition is not . desired (using the same concentration of the inhibitor).
• the compounds of the invention inhibit factor Xa catalytic activity either directly, within the prothrombinase complex or as a soluble subunit, or indirectly, by inhibiting the assembly of factor Xa into the prothrombinase complex.
• the compounds of the formula I and their physiologically tolerable salts and their prodrugs are generally suitable for the therapy and prophylaxis of conditions in which the activity of factor Xa and/or factor Vila plays a role or has an undesired extent, or which can favorably be influenced by inhibiting factor Xa and/or factor Vila or decreasing their activities, or for the prevention, alleviation or cure of which an inhibition of factor Xa and/or factor Vila or a decrease in their activity is desired by the physician.
• the compounds of the formula I and their physiologically tolerable salts and their prodrugs are generally suitable for reducing blood clotting, or for the therapy and prophylaxis of conditions in which the activity of the blood coagulation system plays a role or has an undesired extent, or which can favorably be influenced by reducing blood clotting, or for the prevention, alleviation or cure of which a decreased activity of the blood coagulation system is desired by the physician.
• a specific subject of the present invention thus are the reduction or inhibition of unwanted blood clotting, in particular in an individual, by administering an effective amount of a compound I or a physiologically tolerable salt or a prodrug thereof, as well as pharmaceutical preparations therefor.
• the present invention also relates to the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for use as pharmaceuticals (or medicaments), to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for the production of pharmaceuticals for inhibition of factor Xa and/or factor Vila or for influencing blood coagulation, inflammatory response or fibrinolysis or for the therapy or prophylaxis of the diseases mentioned above or below, for example for the production of pharmaceuticals for the therapy and prophylaxis of cardiovascular disorders, thromboembolic diseases or restenoses.
• the invention also relates to the use of the compounds of the formula 1 and/or their physiologically tolerable salts and/or their prodrugs for the inhibition of factor Xa and/or factor Vila or for influencing blood coagulation or fibrinolysis or for the therapy or prophylaxis of the diseases mentioned above or below, for example for use in the therapy and prophylaxis of cardiovascular disorders, thromboembolic diseases or restenoses, and to methods of treatment aiming at such purposes including methods for said therapies and prophylaxis.
• the present invention also relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an effective amount of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs in addition to a customary pharmaceutically acceptable carrier, i. e. one or more pharmaceutically acceptable carrier substances or excipients and/or auxiliary substances or additives.
• the invention also relates to the treatment of disease states such as abnormal thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication or bypass grafting of the coronary or peripheral arteries, vessel luminal narrowing, restenosis post coronary or venous angioplasty, maintenance of vascular access patency in long-term hemodialysis patients, pathologic thrombus formation occurring in the veins of the lower extremities following abdominal, knee or hip surgery, pathologic thrombus formation occurring in the veins of the lower extremities following abdominal, knee and hip surgery, a risk of pulmonary thromboembolism, or disseminated systemic intravascular coagulatopathy occurring in vascular systems during septic shock, certain viral infections or cancer.
• disease states such as abnormal thrombus formation, acute myocardial infarction, unstable angina, thro
• the compounds of the present invention can also be used to reduce an inflammatory response.
• specific disorders for the treatment or prophylaxis of which the compounds of the formula I can be used are coronary heart disease, myocardial infarction, angina pectoris, vascular restenosis, for example restenosis following angioplasty like PTCA, adult respiratory distress syndrome, multi-organ failure and disseminated intravascular clotting disorder.
• Examples of related complications associated with surgery are thromboses like deep vein and proximal vein thrombosis, which can occur following surgery.
• the compounds of the formula I and their physiologically tolerable salts and their prodrugs can be administered to animals, preferably to mammals, and in particular to humans as pharmaceuticals for therapy or prophylaxis. They can be administered on their own, or in . mixtures with one another or in the form of pharmaceutical preparations, which permit enteral or parenteral administration.
• the pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures.
• Administration can also be carried out rectally for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
• compositions according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically acceptable inert inorganic and/or organic carriers being used in addition to the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs.
• pharmaceutically acceptable inert inorganic and/or organic carriers being used in addition to the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs.
• pharmaceutically acceptable inert inorganic and/or organic carriers being used in addition to the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs.
• Carriers for soft gelatine capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc.
• Suitable carriers for the production of solutions for example injection solutions, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc.
• Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.
• the pharmaceutical preparations normally contain about 0.5 % to 90 % by weight of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs.
• the amount of the active ingredient of the formula I and/or its physiologically tolerable salts and/or its prodrugs in the pharmaceutical preparations normally is from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg.
• the pharmaceutical preparations can contain additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.
• the pharmaceutical preparations can also contain two or more compounds of the formula I, and/or their physiologically tolerable salts and/or their prodrugs.
• a pharmaceutical preparation contains two or more compounds of the formula I
• the selection of the individual compounds can aim at a specific overall pharmacological profile of the pharmaceutical preparation. For example, a highly potent compound with a shorter duration of action may be combined with a long-acting compound of lower potency.
• the flexibility permitted with respect to the choice of substituents in the compounds of the formula I allows a great deal of control over the biological and physico- chemical properties of the compounds and thus allows the selection of such desired compounds.
• the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.
• the dose can vary within wide limits and, as is customary and is known to the physician, is to be suited to the individual conditions in each individual case. It depends, for example, on the specific compound employed, on the nature and severity of the disease to be treated, on the mode and the schedule of administration, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out.
• An appropriate dosage can be established using clinical approaches well known in the medical art.
• the daily dose for achieving the desired results in an adult weighing about 75 kg is from 0.01 mg/kg to 100 mg/kg, preferably from 0.1 mg/kg to 50 mg/kg, in particular from 0.1 mg/kg to 10 mg/kg, (in each case in mg per kg of body weight).
• the daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. As usual, depending on individual behaviour it may be necessary to deviate upwards or downwards from the daily dose indicated.
• a compound of the formula I can also advantageously be used as an anticoagulant outside an individual.
• an effective amount of a compound of the invention can be contacted with a freshly drawn blood sample to prevent coagulation of the blood sample.
• a compound of the formula I or its salts can be used for diagnostic purposes, for example in in vitro diagnoses, and as an auxiliary in biochemical investigations.
• a compound of the formula I can be used in an assay to identify the presence of factor Xa and/or factor Vila or to isolate factor Xa and/or factor Vila in a substantially purified form.
• a compound of the invention can be labelled with, for example, a radioisotope, and the labelled compound bound to factor Xa and/or factor Vila is then detected using a routine method useful for detecting the particular label.
• a compound of the formula I or a salt thereof can be used as a probe to detect the location or amount of factor Xa and/or factor Vila activity in vivo, in vitro or ex vivo.
• the compounds of the formula I can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by introduction of substituents or modification of functional groups.
• an acid such as trifluoroacetic acid or acetic acid was used, for example when trifluoroacetic acid was employed to remove a tBu group or when a compound was purified by chromatography using an eluent which contained such an acid, in some cases, depending on the work-up procedure, for example the details of a freeze-drying process, the compound was obtained partially or completely in the form of a salt of the acid used, for example in the form of the acetic acid salt or trifluoroacetic acid salt or hydrochloric acid salt.
• Example 5 a) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H-benzoimidazole-5-carboxylic acid methyl ester b) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)- 3H-benzoimidazole-5-carboxylic acid methyl ester (i) Methyl-2-trichloromethyl-1 H-benzoimidazole-5-carboxylate
• Example 8 a) 1-[2-(5-Chloro-thiophen-2-yl)-thiazol-5-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester b) 3-[2-(5-Chloro-thiophen-2-yl)-thiazol-5-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H- benzoimidazole-5-carboxylic acid methyl ester To a solution of 80.0 mg (0.23 mmol) 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-5-carboxylic acid methyl ester in 5 ml DMF 9.3 mg sodium hydride (60% supension in mineral oil) were added.
• Example 11 a) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester b) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)- 3H-benzoimidazole-4-carboxylic acid methyl ester (i) Methyl-2,3-diamino-benzoate
• Methyl-2-trichloromethyl-1H-benzoimidazole-4-carboxylate was prepared similarly to methyl- 2-trichloromethyl-1 H-benzoimidazole-5-carboxylate as described in example 5 i) starting from
• Both isomers were obtained by an analogous procedure as described for example 5 iii) starting from 150.0 mg (0.44 mmol) 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid methyl ester and 145.6 mg (1.2 equiv.) 3-bromomethyl-5-(5- chloro-thiophen-2-yl)-isoxazole. In this case the ratio of both isomers was 3:1. As described in example 5 iii) the isomers were separated by NP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol, methanol and diethyl amine as solvent. Again structural assignment of both isomers was achieved by NOE ; spectroscopy.
• Example 12 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H-benzoimidazole-4-carboxylic acid
• Example 14 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2- carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (i) 3H-lmidazo[4,5-b]pyridine-2-carboxylic acid methyl ester
• Example 15 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester 100.8 mg (0.29 mmol) 2-(lsopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 6 ml DMF.
• Example 16 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H-benzoimidazole-4-carboxylic acid
• Example 17 a) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H-benzoimidazole-5-carboxylic acid methyl ester b) 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H- benzoimidazole-5-carboxylic acid methyl ester
• Example 18 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H-benzoimidazole-5-carboxylic acid
• Example 21 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H-benzoimidazole-4-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester was prepared by adopting the procedure described for example 20 starting from 50 mg (0.08 mmol) 1-[5-(5- chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-
• Example 22 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-benzoimidazole-2,4- dicarboxylic acid 4-[(2-hydroxy-ethyl)-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] 30 mg (0.057 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin- 4- ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid were dissolved in 3 ml DMF.
• Example 23 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(3-hydroxy-azetidine-1- carbonyl)- 1 H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(3-hydroxy-azetidine-1-carbonyl)- 1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 50 mg (0.08 mmol) 1-[5-(5-chloro-thiophen-2- yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1 H-benzoimidazo
• Example 24 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-benzoimidazole-2,4- dicarboxylic acid 4-[(2-hydroxy-ethyl)-methyl-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1 H-benzoimidazole-2,4-dicarboxylic acid 4- [(2-hydroxy-ethyl)-methyl-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 40 mg (0.067 mmol) 1-[5-(5-chloro-thiophen- 2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl
• Example 25 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-benzoimidazole-2,5- dicarboxylic acid 5-[(2-hydroxy-ethyl)-methyl-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] 1 -[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1 H-benzoimidazole-2,5-dicarboxylic acid 5- [(2-hydroxy-ethyl)-methyl-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.08 mmol) 1-[5-(5-chloro-thiophen-2- yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbam
• Example 26 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(3-hydroxy-azetidine-1- carbonyl)- 1 H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(3-hydroxy-azetidine-1-carbonyl)- 1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 50 mg (0.08 mmol) 1-[5-(5-chloro-thiophen-2- yl)-isoxazol-3-ylmethyl]-5-(3-hydroxy-azetidine-1-carbonyl)- 1H- benzoimidazole-2-carboxylic
• Example 27 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid 1-ethoxycarbonyloxy-ethyl ester 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H- benzoimidazole-5-carboxylic acid 1-ethoxycarbonyloxy-ethyl ester was prepared by adopting the procedure described for example 20 starting from 50 mg (0.08 mmol) 1-[5-(5-chloro- thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamo
• Example 28 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoy!)-1H-benzoimidazole-5-carboxylic acid 1-cydohexyloxycarbonyloxy-ethyl ester 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H- benzoimidazole-5-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester was prepared by.
• Example 29 a) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(2-hydroxy-ethanesulfonyl)- 1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide b) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-6-(2-hydroxy-ethanesulfonyl)-1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide 5 (i) 2-(2-Trichloromethyl-1 H-benzoimidazole-5-sulfonyl)-ethanol 500 mg (2.31 mmol) 3,4-diamino-benzene-sulfonylethan-2-ol were dissolved in 10 ml concentrated acetic acid.
• Example 30 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2,4-dicarboxylic acid 4- [(2-hydroxy-ethyl)-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2,4-dicarboxylic acid 4- [(2- hydroxy-ethyl)-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 40 mg (0.08 mmol) 1-[(5-chloro-pyridin-2-ylcarbamoyl)- methyl]- 2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-4-carboxylic
• Example 31 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2,4-dicarboxylic acid 4- [(2-hydroxy-ethyl)-methyl-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide]
• Example 33 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid 1-ethoxycarbonyloxy-ethyl ester 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid 1-ethoxycarbonyloxy-ethyl ester was prepared by a procedure according to example 20 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1 H-benzoimidazole-4-carbo
• Example 34 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid 1-cydohexyloxycarbonyloxy-ethyl ester 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester was prepared by a procedure according to example 20 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benz
• Example 36 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-[4-(3-oxo-morpholin-4-yl)- phenylcarbamoyl]- 1H-benzoimidazole-4-carboxylic acid methyl ester (i) 2-[4-(3-Oxo-morpholin-4-yl)-phenylcarbamoyl]-1 H-benzoimidazole-4-carboxylic acid methyl ester
• Example 38 1-(3-Methoxy-benzyl)-1H-benzoimidazole-2-carboxylic acid [4-(4-oxo-4H-pyridin-1- yl)- phenyl]-amide
• the title compound was prepared analogously to example 37 with the difference that 1- Bromomethyl-3-methoxy-benzene was used instead of 3-BromomethyI-5-(5-chloro-thiophen-2- yl)-isoxazole in the alkylation step.
• MS (ES + ): m/e 451.
• Example 39 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2-carboxylic acid [4-(4- oxo-4H-pyridin-1-yl)-phenyl]-amide
• Example 41 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1 H-benzoimidazole-2-carboxylic acid [4-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-phenyl]-amide
• Example 42 1 -[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1 H-benzoimidazole-2-carboxylic acid [4-(2-oxo-oxazolidin-3-yl)-phenyl]-amide
• Example 46 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-benzoimidazole-2-carboxylic acid [4-(1,1-dioxo-1 ⁇ 6-thiomorpholin-4-yl)-phenyl]-amide (i) [4-(1,1-Dioxo-1 ⁇ 6-thiomorpholin-4-yl)-phenyl]-carbamic acid tert-butyl ester A solution of 408 mg (4-Amino-phenyl)-carbamic acid tert-butyl ester and 254 mg Ethenesulfonyl-ethene in 4 ml EtOH were heated for 30 min at 140°C under microwave irradiation (100 W, CEM DiscoverTM apparatus).
• Example 48 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1 H-benzoimidazole-2-carboxylic acid [4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide
• Example 50 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1 H-benzoimidazole-2-carboxylic acid [4-(2-oxo-piperazin-i-yl)-phenyl]-amide (i) 1-(4-Amino-phenyl)-piperazin-2-one
• Example 51 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2-carboxylic acid [4-(2- oxo-piperazin-1-yl)-phenyl]-amide
• Example 52 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2-methoxy-ethoxy)-1H- benzoimidazole-2- carboxylic acid [4-(3-oxo-morpholin-4-yl)-phenyl]-amide (i) 2-(2-Methoxy-ethoxy)-6-nitro-phenylamine
• Example 53 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-meth ⁇ l]-2-[4-(3-oxo-morpholin-4-yl)- phenylcarbamoyl]- 1H-benzoimidazole-4-carboxylic acid
• Example 54 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-(3-hydroxy-azetidine-1-carbonyl)- ' 1 H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-(3-hydroxy-azetidine-1-carbonyl)-1H- • benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid and 8.1 mg (0
• Example 55 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-6-(3-hydroxy-azetidine-1-carbonyl)- 1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide
• 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-6-(3-hydroxy-azetidine-1-carbonyl)-1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 3-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid and 8.1 mg (0.
• Example 56 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2,5-dicarboxylic acid 5- [(2-hydroxy-ethyl)-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1 H-benzoimidazole-2,5-dicarboxylic acid 5- [(2- hydroxy-ethyl)-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2-ylcarbamoyl)- methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid
• Example 58 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1 H-benzoimidazole-2,5-dicarboxylic acid 5- [(2-hydroxy-ethyl)-methyl-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2,5-dicarboxylic acid 5- [(2- hydroxy-ethyl)-methyl-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]-1 H-benzoimidazole-2,5-dicarboxylic acid 5- [(2- hydroxy-ethyl)-methyl-amide]
• Example 59 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-3H-benzoimidazole-2,5-dicarboxylic acid 5- [(2-hydroxy-ethyl)-methyl-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-3H-benzoimidazole-2,5-dicarboxylic acid 5- [(2- hydroxy-ethyl)-methyl-amide] 2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 3-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-
• Example 60 1-[(5-Chloro-pyridin-2-ylcarbamoyI)-methyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H- benzoimidazole-5-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1 H- benzoimidazole-5-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester was prepared by a procedure according to example 20 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1 H-benzoimi
• Example 61 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-3H- benzoimidazole-5-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H- benzoimidazole-5-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester was prepared by a procedure according to example 20 starting from 50 mg (0.10 mmol) 3-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benz
• Example 62 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H- benzoimidazole-5-carboxylic acid 1-ethoxycarbonyloxy-ethyl ester 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-5-carboxylic acid 1-ethoxycarbonyloxy-ethyl ester was prepared by a procedure according to example 20 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carbox
• Example 63 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-3H- benzoimidazole-5-carboxylic acid 1-ethoxycarbonyloxy-ethyl ester 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H- benzoimidazole-5-carboxylic acid 1-ethoxycarbonyloxy-ethyl ester was prepared by a procedure according to example 20 starting from 50 mg (0.10 mmol) 3-[(5-chloro-pyridin-2- ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carbox
• Example 64 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid 2-hydroxy-ethyl ester
• Example 65 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid 2-hydroxy-ethyl ester
• Example 66 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H-benzoimidazole-4-carboxylic acid carboxymethyl ester
• Example 68 a) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-(2-hydroxy-ethanesulfonyl)-1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide b) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-6-(2-hydroxy-ethanesulfonyl)-1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide
• Example 69 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H- benzoimidazole-4-carboxylic acid cyclopropylmethyl ester 325.1 mg (0.57 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H- benzoimidazole-4-carboxylic acid were dissolved in 20 ml CH2CI2.
• Example 70 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid 2-methoxy-ethyl ester 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyI)-1H- benzoimidazole-4-carboxylic acid 2-methoxy-ethyl ester was prepared by a procedure according to example 69 starting from 112 mg (0.22 mmol) 1-[(5-Chloro-pyridin-2- ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid and 177
• Example 72 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2-methoxy-ethoxymethyl)-1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide 81.6 mg (0.065 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-hydroxymethyl-1H- benzoimidazole-2- carboxylic acid (1-isopropyl-piperidin-4-yl)-amide were dissolved in 5 ml abs. DMF. At 0 °C 21.9 mg (0.195 mmol) potassium tert.butylate were added.
• Example 74 1 -[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-([1 ,4]oxazepane-4-carbonyl)-1 H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide
• Example 75 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2,6-dimethyl-piperidine-1- carbonyl)-1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide
• 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2,6-dimethyl-piperidine-1-carbonyl)-1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 100 mg (0.20 mmol) 1-[(5-Chloro-pyridin-2- ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid and 50.0
• Example 76 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(4,4-difluoro-piperidine-1- carbonyl)-1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide
• 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(4,4-difluoro-piperidine-1-carbonyl)-1 H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 870 mg (1.70 mmol) 1-[(5-Chloro-pyridin-2- ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-4-carbox
• Example 77 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-([1,4]oxazepane-4-carbonyl)-1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide
• 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-([1,4]oxazepane-4-carbonyl)-1H- benzoimidazole- 2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 147.8 mg (0.296 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]- 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-5-carboxylic acid
• Example 78 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid 2-hydroxy-ethyl ester 1-[5-(5-ChIoro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H- benzoimidazole-5-carboxylic acid 2-hydroxy-ethyl ester was prepared by a procedure according to example 65 starting from 100 mg (0.17 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3- ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H-benzoimid
• Example 79 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid carboxymethyl ester
• 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H- benzoimidazole-5-carboxylic acid carboxymethyl ester was prepared by a procedure according to example 66 starting from 100 mg (0.17 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3- ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-5-carbox
• Example 80 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(3-methoxy-azetidine-1- carbonyl)- 1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide 1-[5-(5-Chloro-thiophen-2 ' -yl)-isoxazol 3-ylmethyl]-4-(3-methoxy-azetidine-1 -carbonyl)- 1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 205 mg (0.34 mmol) 1-[5-(5-chloro-thiophen- 2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4 ylcarbamoyl)-1
• Example 81 a) 2-(1-lsopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H- benzoimidazole-4- carboxylic acid b) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-3-(3-methoxy-benzyl)-3H-benzoimidazole-4- carboxylic acid 1.45 g (4.21 mmol) 2-(1-lsopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 45 ml DMF.
• That mixture of isomers was dissolved in 100 ml MeOH. 12.8 ml (12.8 mmol) of a 1 M aqueous LiOH-solution were added and the resulting suspension was stirred for 3 h at 60°C. The mixture was acidified by the addition of a 1 M HCl-solution and concentrated under reduced pressure.
• Example 82 a) 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole- 4-carboxylic acid b) 3-[2-(4.-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole- 4- carboxylic acid 1.45 g (4.21 mmol) 2-(1-lsopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 45 ml DMF.
• That mixture of isomers was dissolved in 100 ml MeOH. 16.2 ml (16.2 mmol) of a 1 M aqueous LiOH-solution were added and the resulting suspension was stirred for 3 h at 60°C. The mixture was acidified by the addition of a 1 M HCl-solution and concentrated under reduced pressure.
• Example 83 4-(3-Hydroxy-azetidine-1-carbonyl)-1-(3-methoxy-benzyl)-1 H-benzoimidazole-2- carboxylic acid (1-isopropyl-piperidin-4-yl)-amide
• Example 84 1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-hydroxy-azetidine-1-carbonyl)-1H- benzoimidazole-2- carboxylic acid (1-isopropyl-piperidin-4-yl)-amide
• Example 85 1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-methoxy-azetidine-1-carbonyl)-1H- benzoimidazole-2- carboxylic acid (1-isopropyl-piperidin-4-yl)-amide 1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-methoxy-azetidine-1-carbonyl)-1 H-benzoimidazole-2- carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 50 mg (0.097 mmol) 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl- piperidin-4-ylcarbam
• Example 86 a) 2-(1-lsopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H- benzoimidazole-5- carboxylic acid methyl ester b) 2-(1-lsopropyl-piperidin-4-ylcarbamoyl)-3-(3-methoxy-benzyl)-3H-benzoimidazole-5- carboxylic acid methyl ester 2-(1-lsopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-5- carboxylic acid methyl ester and 2-(1-lsopropyl-piperidin-4-ylcarbamoyl)-3-(3-methoxy-benzyl)-3H- benzoimidazole-5- carboxylic acid methyl ester were prepared by a procedure according to example 5 iii) starting
• Example 87 a) 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole- 5-carboxylic acid methyl ester b) 3-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole- 5- carboxylic acid methyl ester 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1 H-benzoimidazole- 5- carboxylic acid methyl ester and 3-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-3H-benzo
• Example 88 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidi.n-4-ylcarbamoyl)-1H- benzoimidazole- 5-carboxylic acid
• Example 89 a) 1-(5-Chloro-benzo[b]thiophen-2-ylmethyl)-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1 H- benzoimidazole-4-carboxylic acid b) 3-(5-Chloro-benzo[b]thiophen-2-ylmethyl)-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H- benzoimidazole-4-carboxylic acid
• Example 90 1-(5-Chloro-1H-indazol-3-ylmethyl)-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H- benzoimidazole-4-carboxylic acid
• 1-(5-Chloro-1H-indazol-3-ylmethyl)-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1 H- benzoimidazole-4-carboxylic acid was prepared by a procedure according to example 81 starting from 200 mg (0.58 mmol) 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole- 4-carboxylic acid methyl ester and 116.8 mg (0.58 mmol) 5-chloro-3-chloromethyl-1H- indazole.
• Example 91 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(4-hydroxy-piperidine-1- carbonyl)- 1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(4-hydroxy-piperidine-1 -carbonyl)- 1H- benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 670 mg (1.10 mmol) 1-[5-(5-chloro-thiophen- 2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimi
• Example 93 a) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4- ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester b) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4- ylcarbamoyl)- 3H-benzoimidazole-5-carboxylic acid methyl ester (i) (1-Cyclopropyl-piperidin-4-yl)-carbamic acid tert-butyl ester To a solution of 14.0 g (0.0699 mol) piperidin-4-yl-carbamic acid tert-butyl ester in 500 ml abs.
• Example 94 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4- ylcarbamoyl)-1 H-benzoimidazole-5-carboxylic acid 7.84 g (14.52 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cydopropyl- piperidin-4- ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester were dissolved in 400 ml MeOH.

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