Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
  • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof

Definitions

• the present invention relates to new carbocyclic and heterocyclic amidines, their preparation and their use as thrombin inhibitors.
• Thrombin belongs to the group of serine proteases and plays a central role as a terminal enzyme in the blood coagulation cascade. Both the intrinsic and the extrinsic coagulation cascade lead to the formation of thrombin from prothrombin over several amplification stages. The thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates blood coagulation and platelet aggregation, which in turn increases the formation of thrombin by binding platelet factor 3 and coagulation factor XIII and a whole series of highly active mediators.
• thromboin formation and action are central events in the development of both white, arterial and red, venous thrombi and therefore potentially effective targets for pharmaceuticals.
• thrombin inhibitors are able, independently of cofactors, to completely inhibit the effects of free thrombin as well as that bound to platelets. They can prevent thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis in the acute phase and serve as anticoagulants in the extracorporeal circulation (cardiopulmonary machine, hemodialysis). They can also be used for general thrombosis prophylaxis
• Thrombin inhibitor described (C. Mattson et al., Folia Haematol, 109, 43 to 51, 1983).
• the invention relates to compounds of the formula I
• R 1 H, C 1-4 alkyl
• R 2 H, C 1-4 alkyl, phenyl, phenyl C 1-4 alkylene, R 18 O-CH 2 -,
• R 19 OOC-C 1-6 -alkylene-CO-, HO 3 SC 1-3 -alkylene-CO-, C 1-7 -alkyl
• R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1 -4 -alkylene- and R 19 -NH-CO-C 1-4 -alkylene-, where R 20 and R 21 together can also be a - (CH 2 ) 3-6 group), or R 19 -O-
• R 4 H, C 1-12 alkyl, aryl C 1-4 alkylene or
• R 5 H, C 1-4 alkyl or benzyl
• R 6 C 3-8 -cycloalkyl-, where the aliphatic rings can be provided with up to 4 C 1-4 -alkyl and / or CH 3 O groups and one or more methylene group (s) by -O-, -S- or NC 1-4 -alkyl- can be replaced,
• Phenyl- which can be substituted by up to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-,
• R 25 R 26 CH-, where R 25 is C 1-6 alkyl- and R 26 is H- or C 1-6 alkyl-,
• Adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl, which on one or both rings can be monosubstituted, dicyclohexylmethyl-, phenyl-C (CH 3 ) 2 -, phenyl-CH (CH 2 -CH 2 -OR 19 ) -, C 1-4 -alkyl-C ⁇ C-, aryl- C ⁇ C-, (CH 3 ) 3 Si-, R 19 -S-CH 2 -,
• R 22 OC (R 23 R 24 ) -, where R 22 is H, C 1-4 alkyl, phenyl,
• HO-C 1-3 alkylene, phenyl or benzyl and R 24 H Are C 1-4 alkyl, HO-C 1-3 alkylene, phenyl or benzyl,
• R 7 H-, C 1-12 -alkyl-, C 1-20 -alkyl-CO-, R 19 OOC-C 1-4 -alkylene-, R 19 OOC-C 1-4 -alkylene-CO-, R 19 NH-CO-C 1-4 alkylene,
• R 20 R 21 N-CO-, HO 3 SC 1-4 -alkylene-, HO 3 SC 1-4 -alkylene-CO-, 5- (1H) -tetrazolyl-CH 2 -, (R 19 O) 2 OP -CH 2 - or the acyl residue of a natural or unnatural bile acid
• R 8 phenyl, which is represented by 1 to 3 identical or different residues of the group F-, Cl-, C 1-3 -alkyl-, C 1-3 -alkyl -O-, HO or CF 3 - can be substituted,
• C 3-8 cycloalkyl where the aliphatic rings can be provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) by -O-, -S- or -NC 1-4 -alkyl - can be replaced,
• R 25 R 26 CH- where R 25 is C 1-6 alkyl, C 5-8 cycloalkyl or phenyl, which is substituted by 1 to 3 F, Cl, C 1-3 alkyl, C 1-3 -Alkyl-O-, HO- or CF 3 - may be substituted, and R 26 is H- or has one of the meanings given for R 25 , R 22 O-CH 2 -, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl,
• C 1-4 alkyl-C C-, aryl-C ⁇ C-, (CH 3 ) 3 Si or dibenzosuberyl-, which can be monosubstituted on one or both aromatic rings,
• R 9 H, C 1-4 alkyl, aryl or C 5-6 cycloalkyl, (R 9 can
• R 10 , R 11 and R 12 and p, q, r and Y have the following meanings: p: 0 or 1 q: 1 or 2 r: 1, 2, 3, 4 or 5 Y: a methylene group,
• -CH 2 -S-, -CH 2 -SO-, -CH 2 -O-, -CH CH- or a propylene group, in which the resulting cycle in the 3- and / or 4-position on the carbon is a C 1 -4 can carry alkyl group or in which a -CH 2 group can be replaced by -O-, -S- or -SO-,
• R 10 H, C 1-4 alkyl or phenyl
• R 11 H, C 1-4 alkyl, C 3-8 cycloalkyl, phenyl or benzyl,
• R 12 H, C 1-6 alkyl, C 3-8 cycloalkyl, phenyl or benzyl,
• R 13 , R 14 and R 15 which may be the same or different:
• R 30 is H-, C 1-6 -alkyl-, C 3-6 -cycloalkyl-, benzyl- or phenyl-, or
• R 17 H, F, Cl, C 1-4 alkyl, phenyl -C 1-2 alkylene, phenyl, R 31 OOC, R 31 -NH-, R 31 -O- or R 31 OOC-CH 2 -O-,
• R 29 H- or C 1-4 -alkyl-, C 1-4 -alkoxy-, C 1-4 -alkoxy-CO,
• R 2 H, C 1-4 alkyl, phenyl and phenyl -C 1-4 alkylene, R 18 O-CH 2 -, R 18 -CO-, R 18 -O-CH 2 -CO -, R 18 O-CO-CO-, R 18 -NH-CO-CO-, wherein R 18 is H- or C 1-4 -alkyl-, CF 3 -CO- or C 2 F 5 -CO- ,
• substituents have the following meanings: m: 0 or 1, n: 2 or 3, R 3 : H, C 1-12 alkyl, aryl C 1-4 alkylene, R 19 OOC-C 1-6 alkylene
• R 20 R 21 N-CO- (R 20 and R 21 are identical or different and denote H-, C 1-6 -alkyl-, aryl-, aryl-C 1-4 -alkylene-,
• R 19 OOC-C 1-4 alkylene, R 19 -NH-CO-C 1-4 alkylene or R 20 and
• R 21 together represent a - (CH 2 ) 3 - 6 group
• R 4 H, C 1-12 alkyl or aryl -C 1-4 alkylene,
• R 5 H or C 1-4 alkyl
• R 6 C 3 _ 8 -cycloalkyl-, where the aliphatic rings can be provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) by -O-, may be replaced by adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which are monosubstituted on one or both aromatic rings can, diphenylmethyl, which can be monosubstituted on one or both rings, dicyclohexylmethyl-, phenyl-C (CH 3 ) 2 -, C 1-4 -alkyl -C ⁇ C-, R 22 OC (R 23 R 24 ) -, wherein R 22 H- or
• C 1-4 alkyl- and R 23 and R 24 represent H-, C 1-4 -alkyl-, HO-C 1-3 -alkylene- or phenyl-,
• Phenyl which can be substituted by up to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-, R 25 R 26 CH-, wherein R 25 represents C 1-6 alkyl- and R 26 represents H- or C 1-6 alkyl-,
• R 7 H-, C 1-12 -alkyl-, C 1-20 -alkyl-CO-, R 19 OOC-C 1-4 -alkylene-, R 19 OOC-C 1-4 -alkylene-CO-, R 20 R 21 N-CO-, HO 3 SC 1-4 -alkylene-, or the acyl residue of a natural or unnatural bile acid,
• Phenyl which can be substituted by up to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-,
• R 25 R 26 CH-, wherein R 25 is 1- 6 alkyl is C, and R 26 H or C 1-6 alkyl,
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 can, according to the formula IIc, be a substituent on all ring positions except the 1- and 2-position), the structures IIa to IIc are preferably in the D configuration.
• R 11 H or C 3-6 cycloalkyl
• R 12 H, C 1-6 alkyl or C 5-6 cycloalkyl, R 13 , R 14 and R 15 , which are the same or different:
• Structures IIIa to Illf are preferably in the L configuration.
• Particularly preferred among the compounds la are those in which the substituents R and A and B have the following meanings:
• R 3 H, C 1-6 alkyl, benzyl, R 19 OOC-C 1-6 alkylene (R 19 signified tet H, C 1-4 alkyl, benzyl), HO 3 SC 1 - 3 -alkylene-, or R 20 R 21 N-CO- (R 20 and R 21 are identical or different and mean H-, C 1 - 6 -alkyl-, or benzyl- or R 20 and R 21 together represent a - (CH 2 ) 4-5 group),
• R 5 H or CH 3 -
• R 6 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which one Methylene group can be replaced by -O-, phenyl-, which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl-, dicyclohexylmethyl-, isopropyl-, tert.
• R 7 H, C 1-6 alkyl-CO- or R 19 OOC-C 1-4 alkylene,
• R 8 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl - Which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert.
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 can, according to formula IIc, be a substituent on all ring positions except the 1- and 2-position).
• the structures Ila to IIc are preferably in the D configuration.
• R 13 H-, HO-, CH 3 O-, EtO-, (CH 3 ) 2 CH-O-, Cl-, Br- or I-
• R 14 H-, HO-, CH 3 O- or Cl-
• R 15 H, HO, CH 3 O or Cl,
• Structure IIIa is preferably in the L configuration.
• R 2 H, C 1-4 alkyl, phenyl, phenyl -C 1-4 alkylene, R 18 O-CH 2 -, R 18 -CO-, R 18 -O-CH 2 -CO -, R 18 O-CO-CO-, R 18 -NH-CO-CO-, where R 18 is H- and C 1-4 -alkyl-, CF 3 -CO- and C 2 F 5 -CO- ,
• R 3 H-, C 1-12 -alkyl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1-6 -alkylene (R 19 preferably denotes H-, C 1-4 -alkyl-, Benzyl-), HO 3 SC 1-3 -alkylene-, C 1-7 -alkyl-OOC-, benzyl-OOC-, or R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1-4 -alkylene-, R 19 -NH-CO-C 1-4 -alkylene- or R 20 and R 2: together represent a - (CH 2 ) 3-6 group), R 4 : H, C 1-12 alkyl or aryl-C 1-4 alkylene,
• R 5 H or C 1-4 alkyl
• R 6 C 3-8 cycloalkyl, where the aliphatic rings can be provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) replaced by -O- may be adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which may be monosubstituted on one or both aromatic rings , Diphenylmethyl, which can be monosubstituted on one or both rings, dicyclohexylmethyl-, phenyl -C (CH 3 ) 2 -, C 1-4 -alkyl -C ⁇ C-, R 22 OC (R 23 R 24 ) -, wherein R 22 H- or
• C 1-4 alkyl- and R 23 and R 24 represent H-, C 1-4 -alkyl-, HO-C 1-3 -alkylene- or phenyl-,
• Phenyl- which can be substituted by up to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-,
• R 25 R 26 CH-, where R 25 is C 1-6 alkyl- and R 26 is H- or C 1-6 alkyl-,
• R 7 H-, C 1-12 -alkyl-, C 1-20 -alkyl-CO-, R 19 OOC-C 1-4 -alkylene-, R 19 OOC-C 1-4 -alkylene-CO-, R 20 R 21 N-CO-, HO 3 SC 1-4 -alkylene-, or the acyl residue of a natural or unnatural bile acid,
• R 8 C 3-8 cycloalkyl, where the aliphatic rings can be provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) replaced by -O- can be (can), adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl, which can be monosubstituted on one or both rings , Dicyclohexylmethyl-, phenyl -C (CH 3 ) 2 -, C 1-4 -alkyl -C ⁇ C-, R 22 OC (R 23 R 24 ) -, where R 22 is H- or C 1-4 -alkyl- and R 23 and R 24 represent H-, C 1-4 -alkyl-, HO-C 1-3 -
• R 25 R 26 CH-, where R 25 is C 1-6 alkyl- and R 26 is H- or C 1-6 alkyl-,
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 can, according to formula IIc, be a substituent on all ring positions except the 1- and 2-position),
• the structures Ila to IIc are preferably in the D configuration.
• Y is a methylene group, an ethylene group, in which the resulting cycle in the 4-position can carry a hydroxy or C 1-4 alkoxy group
• -CH CH-, -CH 2 - S-, -CH 2 -O- or a propylene group, in which the resulting cycles in the 3- and / or 4-position on the carbon can carry a C 1-4 alkyl group or in which a -CH 2 group can be replaced by -O - can be replaced
• R 11 H- or C 3-6 -cycloalkyl-,
• R 12 H, C 1-6 alkyl or C 5-6 cycloalkyl
• R 16 H-, F-, Cl-, C 1-4 -alkyl-, R 31 OOC-, wherein R 31 is H- or
• C 1-4 alkyl- means R 31 -O-
• R 17 H, F, Cl, C 1-4 alkyl, R 31 OOC or R 31 O, where R 31 is H or C 1-4 alkyl,
• the structures IIIa to IIIf are preferably in the L configuration.
• Particularly preferred compounds Ib are those in which the substituents R, fragments A and B and X have the following meanings: R 2 : H,
• R 3 H, C 1-6 alkyl, benzyl, R 19 OOC-C 1-6 alkylene (R 19 means H, C 1-4 alkyl, benzyl), HO 3 SC 1-3 -alkylene-, or R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl- or benzyl- or R 20 and R 21 together mean one - (CH 2 ) 4-5 group,
• R 5 H or CH 3 -
• R 6 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl -, which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neo-pentyl , tert-butoxymethyl, phenoxymethyl, adamantyl, norbonyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl - or
• R 7 H-, C 1-6 -alkyl-CO- or R 19 OOC-C 1-4 -alkylene-
• R 8 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl -, which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neo-pentyl , tert-butoxymethyl, phenoxymethyl, adamantyl, norbonyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl - or (CH 3 ) 3 Si,
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 can, according to formula IIc, be a substituent on all ring positions except the 1- and 2-position).
• the structures Ila to IIc are preferably in the D-config; ration before.
• -CH CH-, -CH 2 -S-, -CH 2 -O- or a propylene group
• the structure purple is preferably in the L configuration
• R 2 H, C 1-4 alkyl, phenyl and phenyl C 1-4 alkylene, R 18 O-CH 2 -, R 18 -CO-, R 18 -O-CH 2 -CO -, R 18 O-CO-CO-, R 18 -NH-CO-CO-, in which R 18 is H- and C 1-4 -alkyl, CF 3 -CO- or C 2 F 5 -CO-,
• n 2 or 3
• R 3 H-, C 1-12 -alkyl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1-6 -alkylene (R 19 preferably denotes H-, C 1-4 -alkyl-, Benzyl-), HO 3 SC 1-3 -alkylene-, C 1-7 -alkyl-OOC-, benzyl-OOC-, or R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1-4 -alkylene-, R 19 -NH-CO-C 1-4 -alkylene- or R 20 and R 21 together represent a - (CH 2 ) 3-6 group),
• R 4 H, C 1-12 alkyl or aryl -C 1-4 alkylene,
• R 5 H or C 1-4 alkyl
• R 6 C 3-8 cycloalkyl, where the aliphatic rings can be provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) replaced by -O- can be adamantyl, norbornyl, 1-decalinyl, 1-T-tralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl-, dibenzosuberyl-, which may be monosubstituted on one or both aromatic rings, diphenylmethyl, which may be monosubstituted on one or both rings, dicyclohexylmethyl-, phenyl-C (CH 3 ) 2 -, C 1-4 -alkyl -C ⁇ C-, R 22 OC (R 23 R 24 ) -, wherein R 22 is H- or
• C 1-4 alkyl- and R 23 and R 24 represent H-, C 1-4 -alkyl-, HO-C 1-3 -alkylene- or phenyl-,
• Phenyl- which by up to 3 identical or different radicals of the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or
• R 25 R 26 CH-, where R 25 is C 1-6 alkyl- and R 26 is H- or C 1-6 alkyl-,
• R 7 H-, C 1-12 -alkyl-, C 1-20 -alkyl -CO-, R 19 OOC-C 1-4 -alkylene-,
• R 19 OOC-C 1-4 -alkylene-CO-, R 20 R 21 N-CO-, HO 3 SC 1-4 -alkylene-CO-, or the acyl residue of a natural or unnatural bile acid,
• R 8 C 3-8 cycloalkyl, where the aliphatic rings can be provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) by -O-, -S- or NC 1-4 alkyl can be replaced,
• R 22 OC (R 23 R 24 ) -, wherein R 22 is H- or C x . 4 -Alkyl- and R 23 and R 24 represent H-, C 1-4 -alkyl-, HO-C 1 .3 -alkylene- or phenyl-, phenyl-, which by up to 3 identical or different radicals of Group C 1-4 alkyl-, CF 3 -, C 1-4 alkoxy-, F- or
• R 25 R 26 CH-, where R 25 is C 1-6 alkyl- and R 26 is H- or C 1-6 alkyl-,
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 may
• Structures IIa to IIc are preferably in the D configuration.
• R 11 H or C 3-6 cycloalkyl
• R 12 H, C 1-6 alkyl and C 5-6 cycloalkyl
• R 16 H-, F-, Cl-, C 1-4 -alkyl-, R 31 -OOC-, wherein R 31 is H- or
• C 1-4 alkyl- means R 31 -O-
• Rl 7 H-, F-, Cl-, C 1-4 -alkyl-, R 31 -OOC-, R 31 -O-, where R 31 is H- or C 1-4 -alkyl-.
• the structures purple to Illf are preferably in the L configuration.
• n 2 or 3
• R 3 H, C 1-6 alkyl, benzyl, R 19 OOC-C 1-6 alkylene (R 19 means H, C 1-4 alkyl, benzyl), HO 3 SC 1-3 -alkylene-, or R 20 R 21 N-CO- (R 20 and R 21 are identical or different and mean H-, C 1 -6- alkyl- or benzyl- or R 20 and R 21 together mean one - (CH 2 ) 4-5 group),
• R 5 H or CH 3 -
• R 6 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl -, which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neo-pentyl , tert-butoxymethyl, phenoxymethyl, adamantyl, norbonyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl - or (CH 3 ) 3 Si,
• R 7 H-, C 1-6 -alkyl-, or R 19 OOC-C 1-4 -alkylene-,
• R 8 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl - Which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert.
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 can, according to formula IIc, be a substituent on all ring positions except the 1- and 2-position).
• Structures IIa to IIc are preferably in the D configuration.
• Y a methylene group, an ethylene group
• -CH CH-, -CH 2 -S-, -CH 2 -O- or a propylene group
• R 16 H-, R 17 H-.
• Structure IIla is preferably in the L configuration.
• R 2 H, C 1-4 alkyl, phenyl and phenyl C 1-4 alkylene,
• R 18 O-CH 2 -, R 18 -CO-, R 18 -O-CH 2 -CO-, R 18 O-CO-CO-, R 18 -NH- CO-CO-, where R 18 is H- and C 1-4 alkyl-, CF 3 -CO- and C 2 F 5 -CO-,
• n 2 or 3
• R 3 H-, C 1-12 -alkyl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1-6 -alkylene (R 19 preferably denotes H-, C 1-4 -alkyl-, Benzyl-), HO 3 SC 1-3 -alkylene-, C 1-7 -alkyl-OOC-, benzyl -OOC-, or R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1-4 -alkylene-, R 19 -NH-CO-C 1-4 -alkylene- or R 20 and R 21 together represent a - (CH 2 ) 3-6 group),
• R 4 H, C 1-12 alkyl or aryl C 1-4 alkylene,
• R 5 H or C 1-4 alkyl
• C 1-4 alkyl- and R 23 and R 24 represent H-, C 1-4 -alkyl-, HO-C 1-3 -alkylene- or phenyl-,
• Phenyl- which can be substituted by up to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-,
• R 25 R 26 CH- where R 25 is C 1-6 alkyl- and R 26 is H- or C 1-6 alkyl-, R 7 : H-, C 1-12 -alkyl-, C 1-20 alkyl-CO-, R 19 OOC-C 1-4 -alkylene-,
• R 19 OOC-C 1-4 -alkylene-CO-, R 20 R 21 N-CO-, HO 3 SC 1-4 -alkylene-CO-, or the acyl residue of a natural or unnatural bile acid
• R 8 C 3- 8 -cycloalkyl-, where the aliphatic rings can be provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) can be replaced by -O-, Adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl, which on one or both rings can be monosubstituted, dicyclohexylmethyl-, phenyl -C (CH 3 ) 2 -, C 1-4 -alkyl -C ⁇ C-, R 22
• C 1-4 alkyl- and R 23 and R 24 represent H-, C 1-4 -alkyl-, HO-C 1-3 -alkylene- or phenyl-,
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 may
• the structures Ila to IIc are preferably in the D configuration. q: 1 or 2 r: 3 or 4
• Y is a methylene group
• -CH CH-, -CH 2 -S-, -CH 2 -O- or a propylene group, in which the resulting cycles in the 3- and / or 4-position on the carbon can carry a C 1-4 alkyl group or wherein a -CH 2 group can be replaced by -O-.
• R 11 H or C 3-6 cycloalkyl
• R 12 H, C 1-6 alkyl or C 5-6 cycloalkyl
• R 16 H, F, Cl, C 1-4 alkyl, R 31 -OOC-, wherein R 31 H- or
• R 17 H-, F-, Cl-, C 1-4 -alkyl-, R 31 -OOC- or R 31 -O-, where R 16 and R 17 do not simultaneously mean H- and not simultaneously F- and R 31 denotes H- or C 1-4 -alkyl.
• Structures IIIa to IIIf are preferably in the L configuration.
• n 2 or 3
• R 3 H, C 1-6 alkyl, benzyl, R 19 OOC-C 1-6 alkylene (R 19 means H, C 1-4 alkyl, benzyl), HO 3 SC 1 -3 -alkylene-, or R 20 R 21 N-CO- (R 20 and R 21 are identical or different and mean H-, C 1-6 -alkyl- or benzyl- or R 20 and R 21 together mean a - (CH 2) 4 - 5 group),
• R 5 H or CH 3 -
• R 6 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl - Which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert.
• R 7 H-, C 1-6 -alkyl-CO- or R 19 OOC-C 1-4 -alkylene-,
• R 8 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl - Which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert.
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 can, according to formula IIc, be a substituent on all ring positions except the 1- and 2-position).
• Structures IIa to IIc are preferably in the D configuration.
• Y a methylene group, an ethylene group
• -CH CH-, -CH 2 -S-, -CH 2 -O- or a propylene group
• R 16 H, Cl, C 1-4 alkyl or CH 3 O,
• R 17 H-, Cl-, C 1-4 -alkyl- or CH 3 O-, where R 16 and R 17 are not simultaneously H-,
• Structure IIIa is preferably in the L configuration.
• R 2 H, C 1-4 alkyl, phenyl, phenyl C 1-4 alkylene,
• R 18 O-CH 2 -, R 18 -CO-, R 18 -O-CH 2 -CO-, R 18 O-CO-CO-, R 18 -NH-CO-CO-, wherein R 18 is H or C 1-4 -alkyl-, CF 3 -CO- or C 2 F 5 -CO-,
• R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1 -4 -alkylene- and R 19 -NH-CO-C 1-4 -alkylene-, or R 20 and R 21 together mean a - (CH 2 ) 3-6 group),
• R 4 H, C 1-12 alkyl or aryl C 1-4 alkylene
• R 5 is H or C 1-4 alkyl
• R 6 C 5-8 cycloalkyl, the aliphatic rings having up to 4 C 1-4 alkyl and / or CH 3 O groups and / or one or more CH 2 groups through -O- is (are) replaced,
• Phenyl which is substituted by 2 to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-,
• R 7 H-, C 1-12 -alkyl-, C 1-20 -alkyl-CO-, R 19 OOC-C 1-4 -alkylene-,
• R 19 OOC-C 1-4 -alkylene-CO-, R 20 R 21 N-CO-, HO 3 SC 1-4 -alkylene-CO-, or the acyl residue of a natural or unnatural bile acid,
• R 8 C 5-8 cycloalkyl, the aliphatic rings having up to 4 C 1-4 alkyl and / or CH 3 O groups and / or one or more CH 2 group (s) -O- is (are) replaced,
• Phenyl which is substituted by 2 to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F or Cl-,
• Structures IIa to IIc are preferably in the D configuration.
• R 11 H or C 3-6 cycloalkyl
• R 12 H, C 1-6 alkyl or C 5-6 cycloalkyl.
• the structures purple to Illf are preferably in the L configuration. Those listed under a) are particularly preferred
• R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, or benzyl-, or R 20 and R 21 together mean a - (CH 2 ) 4 -5 group),
• R 5 H or CH 3 -, R 6 C 5-8 cycloalkyl, the aliphatic rings having up to 4 C 1-4 alkyl and / or CH 3 O groups and / or a CH 2 group being replaced by -O- Phenyl which is substituted by 2 to 3 identical or different radicals from the group CH 3 -, CF 3 -, CH 3 O-, F- or Cl-,
• R 7 H-, C 1-6 -alkyl-CO- or R 19 OOC-C 1-4 -alkylene-,
• R 8 C 5-8 cycloalkyl, where the aliphatic rings are provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and / or a CH 2 group is replaced by -O- ,
• Phenyl which is substituted by 2 to 3 identical or different radicals from the group CH 3 -, CF 3 -, CH 3 O-, F- or Cl-,
• R 9 C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 may
• the structures Ila to IIc are preferably in the D configuration.
• Y a methylene group, an ethylene group
• -CH CH-, -CH 2 -S-, -CH 2 -O- or a propylene group
• Structure IIIa is preferably in the L configuration or in the compound le the substituents R, the fragments A and B and X have the following meanings: b)
• R 2 H, C 1-4 alkyl, phenyl, phenyl C 1-4 alkylene, R 18 O-CH 2 -,
• R 3 H-, C 1-12 -alkyl, aryl-C 1-4 -alkylene-, R 19 OOC-C 1- 6 -alkylene- (R 19 preferably denotes H-, C 1-4 -alkyl-, benzyl-), HO 3 SC 1-3 -alkylene-, C 1-7 -alkyl-OOC-, benzyl-OOC-, or R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1 -4 -alkylene-, R 19 -NH-CO-C 1-4 -alkylene- or R 20 and R 21 together mean a - (CH 2 ) 3-6 group),
• R 4 H, C 1-12 alkyl or aryl C 1-4 alkylene,
• R 5 H or C 1-4 alkyl
• R 6 C 3-8 cycloalkyl, which can be substituted by up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, adamantyl, norbornyl -, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, phenyl-C (CH 3 ) 2 -, C 1-4 -alkyl-C ⁇ C - or R 22 OC (R 23 R 24 ) -, in which R 22 is H- or C 1-4 -alkyl- and R 23 and R 24 are H-, C 1-4 -alkyl-, HO-C 1- 3 -alkylene- or phenyl-, Phenyl, which is characterized by up to 3 identical or different
• R 25 R 26 CH- wherein R 25 represents C 1-6 alkyl, C 5-8 cycloalkyl or phenyl, which by 1 to 3 F, Cl, C 1-3 alkyl, C 1-3 -Alkyl-O-, HO- or CF 3 - may be substituted, and R 26 is H- or has one of the meanings given for R 25 ,
• R 7 H-, C 1-12 -alkyl-, C 1-20 -alkyl -CO-, R 19 OOC-C 1-4 -alkylene-,
• R 19 OOC-C 1-4 -alkylene-CO-, R 20 R 21 N-CO-, HO 3 SC 1-4 -alkylene-CO-, or the acyl residue of a natural or unnatural bile acid,
• R 8 c 3-8 -cycloalkyl-, where the aliphatic rings can be provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) by -O-, can be replaced,
• R 25 R 26 CH- in which R 25 is C 1-6 alkyl, C 6-8 cycloalkyl or phenyl, which is substituted by 1 to 3 identical or different radicals of group 3 F-, Cl-, C 1- 3 -alkyl-,
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 -Cycloalkyl- (R 9 can
• the structures Ila to IIc are preferably in the D configuration.
• R 11 H or C 3-6 cycloalkyl
• R 12 C 1-6 alkyl or C 5-6 cycloalkyl
• Y: -CH CH-, -CH 2 -S-, -CH 2 -O- or a propylene group, in which the resulting cycles in the 3- and / or 4-position on the carbon bear a C 1-4 alkyl group or in which a CH 2 group can be replaced by -O-,
• R 3 H, C 1-6 alkyl, benzyl, R 19 OOC-C 1- 6 alkylene (R 19 means H, C 1-4 alkyl, benzyl), HO 3 SC 1 - 3 -alkylene-, or R 20 R 21 N-CO- (R 20 and R 21 are identical or different and mean H-, C 1-6 -alkyl- or benzyl- or R 20 and R 21 together mean a - (CH 2) 4 - 5 group),
• R 5 or CH 3 -
• R 6 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl -, Which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neo-pentyl , tert-butoxymethyl, phenoxymethyl, adamantyl, norbonyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH 3 ) 3 Si,
• R 7 H, C 1-6 alkyl-CO- or R 19 OOC-C 1-4 alkylene
• R 8 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl -, Which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neo-pentyl , tert-butoxymethyl, phenoxymethyl, adamantyl, norbonyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH 3 ) 3 Si,
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 can, according to formula IIc, be a substituent on all ring positions except the 1- and 2-position),
• the structures Ila to IIc are preferably in the D configuration.
• the structure purple is preferably in the L configuration.
• R 2 H, C 1-4 alkyl, phenyl, phenyl C 1-4 alkylene,
• R 18 O-CH 2 -, R 18 -CO-, R 18 -O-CO-, R 18 -O-CH 2 -CO-, R 18 O-CO-CO-, R 18 -NH-CO-CO -, where R 18 is H, C 1-4 alkyl,
• R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1 20 and R 21 together denote -4 alkylene or R 19 -NH-CO-C 1-4 alkylene- or R a - (CH 2) 4 - 5 group),
• R 4 H, C 1-12 alkyl or aryl C 1-4 alkylene,
• R 5 is H or C 1-4 alkyl
• R 6 C 5-8 -cycloalkyl-, the aliphatic rings being provided with up to 4 C 1-4 -alkyl and / or CH 3 O groups and / or one or more -CH 2 group (s) is replaced by -O-,
• Phenyl- which is substituted by 2 to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-,
• R 7 H-, C 1-12 -alkyl-, C 1-20 -alkyl-CO-, R 19 OOC-C 1-4 -alkylene-,
• R 19 OOC-C 1-4 -alkylene-CO-, R 20 R 21 N-CO-, HO 3 SC 1-4 -alkylene-CO-, and the acyl residue of a natural or unnatural bile acid,
• R 8 C 5-8 -cycloalkyl-, the aliphatic rings being provided with up to 4 C 1-4 -alkyl and / or CH 3 O groups and / or one or more -CH 2 group (s) is replaced by -O-,
• Phenyl which is substituted by 2 to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-,
• R 9 C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 may
• corresponding to the formula IIc can be a substituent at all ring positions except the 1 and 2 positions).
• the structures Ila to IIc are preferably in the D configuration.
• Y is a methylene group, an ethylene group, in which the resulting cycle in the 4-position can carry a hydroxy or C 1-4 alkoxy group,
• -CH CH-, -CH 2 -S-, -CH 2 -O- or a propylene group, in which the resulting cycles in the 3- and / or 4-position on the carbon can carry a C 1-4 alkyl group or in which a -CH 2 group can be replaced by -O-,
• R 11 H or C 3-6 cycloalkyl
• R 12 H, C 1-6 alkyl or C 5-6 cycloalkyl
• R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, or benzyl-, or R 20 and R 21 together mean a - (CH 2 ) 4 - 5 group),
• R 6 C 5-8 cycloalkyl, the aliphatic rings having up to 4 C 1-4 alkyl and / or CH 3 O groups and / or a CH 2 group being replaced by -O- , Phenyl, which is substituted by 2 to 3 identical or different radicals from the group CH 3 -, CF 3 -, CH 3 O-, F- or Cl-,
• R 7 H-, C 1-6 -alkyl-CO- or R 19 OOC-C 1-4 -alkylene-,
• R 8 C 5-8 cycloalkyl, where the aliphatic rings are provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and / or a CH 2 group is replaced by -O- ,
• Phenyl which is substituted by 2 to 3 identical or different radicals from the group CH 3 -, CF 3 -, CH 3 O-, F- or Cl-,
• R 9 C 1-4 -alkyl-, phenyl- or C 5-6 -cycloalkyl- (R 9 can, according to the formula IIc, be a substituent on all ring positions except the 1-and 2-position),
• Structures IIa to IIc are preferably in the D configuration.
• Y a methylene group, an ethylene group
• Structure IIIa is preferably in the L configuration, or in the compound the substituents R and the fragments A and B have the following meanings: b)
• R 2 H, C 1-4 alkyl, phenyl, phenyl -C 1-4 alkylene, R 18 O-CH 2 -,
• R 3 H-, C 1-12 -alkyl-, aryl-C 1-4 -alkylene-, R 19 OOC-C 1-6 -alkylene (R 19 preferably denotes H-, C 1-4 -alkyl-, Benzyl-), HO 3 SC 1-3 -alkylene-, C 1-7 -alkyl-OOC-, benzyl-OOC-, or R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-, aryl-C 1-4 -alkylene-, Ri 9 OOC-C 1-4 -alkylene-, R 19 -NH-CO-C 1-4 -alkylene- or R 20 and R 21 together represent a - (CH 2 ) 4-5 group),
• R 4 H, C 1-12 alkyl or aryl C 1-4 alkylene,
• R 5 H or C 1-4 alkyl
• R 6 C 3-8 cycloalkyl, the aliphatic rings being provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) can be replaced by -O-, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl -, Dibenzosuberyl-, which can be monosubstituted on one or both aromatic rings, diphenylmethyl, which can be monosubstituted on one or both rings, dicyclohexylmethyl-, phenyl-C (CH 3 ) 2 -, C 1-4 -alkyl-C ⁇ C-, R 22 OC (R 23 R 24 ) -, wherein R 22 is H- or
• C 1-4 alkyl- and R 23 and R 24 represent H-, C 1-4 -alkyl-, HO-C 1-3 -alkylene- or phenyl-,
• Phenyl which can be substituted by up to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-,
• R 25 R 26 CH- where R 25 is C 1-6 alkyl- and R 26 is H- or C 1-6 alkyl-, R 7 : H-, C 1-12 -alkyl-, C 1-20 alkyl-CO-, R 19 OOC-C 1-4 -alkylene-,
• R 19 OOC-C 1-4 -alkylene-CO-, R 20 R 21 N-CO-, HO 3 SC 1-4 -alkylene-CO-, or the acyl residue of a natural or unnatural bile acid
• R 8 C 3- 8 -cycloalkyl-, where the aliphatic rings can be provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and one or more methylene group (s) can be replaced by -O- , Adamantyl, norbornyl,
• C 1-4 alkyl- and R 23 and R 24 represent H-, C 1-4 -alkyl-, HO-C 1-3 -alkylene- or phenyl-,
• Phenyl which can be substituted by up to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-, R 25 R 26 CH-, wherein R 25 represents C 1-6 alkyl- and R 26 represents H- or C 1-6 alkyl-,
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 can, according to the formula IIc, be a substituent on all ring positions except the 1- and 2-position),
• the structures Ila to IIc are preferably in the D configuration.
• Y -CH CH-, -CH 2 -S-, -CH 2 -O- or a propylene group, in which the resulting cycles in the 3- and / or 4-position on the carbon can carry a C 1-4 alkyl group or in which a -CH 2 group can be replaced by -O-,
• R 11 H or C 3-6 cycloalkyl
• R 12 H, C 1-6 alkyl or C 5-6 cycloalkyl
• Structures IIIa to IIIf are preferably in the L configuration. Those listed under b) are particularly preferred
• R 3 H, C 1-6 alkyl, benzyl, R 19 OOC-C 1-6 alkylene (R 19 means H, C 1-4 alkyl, benzyl), HO 3 SC 1 -3-alkylene-, or R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl- or benzyl- or R 20 and R 21 together mean one - (CH 2 ) 4-5 group),
• R 5 H or CH 3 -
• R 6 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl - Which can be substituted by 1 to 3 identical or different radicals from the group F-, Cl-, CH 3 - or CH 3 O-, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert.
• R 7 H-, C 1-6 -alkyl-CO- or R 19 OOC-C 1-4 -alkylene-,
• R 8 C 5-8 cycloalkyl, where the aliphatic rings can be substituted with up to 4 C 1-4 alkyl and / or CH 3 O groups and in which a methylene group can be replaced by -O-, phenyl -, which by 1 to 3 same or various radicals of the group F-, Cl-, CH 3 - or CH 3 O- can be substituted, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neo-pentyl, tert-butoxymethyl, phenoxymethyl , Adamantyl, norbonyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH 3 ) 3 Si,
• R 9 H, C 1-4 alkyl, phenyl or C 5-6 cycloalkyl (R 9 can, according to the formula IIc, be a substituent on all ring positions except the 1 and 2 positions),
• the structures Ila to IIc are preferably in the D configuration.
• Y: -CH CH-, -CH 2 -S-, -CH 2 -O- or a propylene group.
• Structure IIIa is preferably in the L configuration.
• R 2 H, C 1-4 alkyl, phenyl, phenyl C 1-4 alkylene,
• R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-aryl-C 1-2 -alkylene-, or R 20 R 21 together mean a - (CH 2 ) 4-5 group),
• R 4 H, C 1-12 alkyl or aryl C 1-2 alkylene,
• R 6 H, C 1-12 alkyl
• Y -CH 2 -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -
• the amino acid containing Y is preferably L-configured. Those listed under a) are particularly preferred
• R 20 R 21 N-CO- (R 20 and R 21 are identical or different and denote H, C 1-6 alkyl, or benzyl, or R 20 R 21 together denote one - (CH 2 ) 4 - 5 group),
• R 6 H, C 1-4 alkyl
• Y -CH 2 -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -
• the amino acid containing Y is preferably L-configured. or in the compound Ig, the substituents R and Y have the following meanings: b)
• R 2 H, C 1-4 alkyl, phenyl, phenyl C 1-4 alkylene,
• R 18 O-CH 2 -, R 18 -CO-, R 18 -O-CH 2 -CO-, R 18 -NH-CO-CO-, where R 18 is H- or C 1-4 -alkyl- , CF 3 -CO- or C 2 F 5 -CO-, R 3 : H, C 1-12 alkyl, aryl C 1-2 alkylene,
• R 20 R 21 N-CO- (R 20 and R 21 are the same or different and mean H-, C 1-6 -alkyl-, aryl-, aryl-C 1-2 -alkylene-, or R 20 and R 21 together represent a - (CH 2 ) 4-5 group),
• R 4 H, C 1-12 alkyl or aryl-C 1-2 alkylene
• R 6 H, C 1-12 alkyl
• the amino acid containing Y is preferably L-configured.
• the compounds Ig listed under b) are particularly preferred, in which the substituents R and the function of Y have the following meanings:
• R 20 and R 21 are identical or different and mean H-,
• R 4 H, C 1-12 alkyl or aryl C 1-2 alkylene,
• R 6 H, C 1-4 alkyl
• the amino acid containing Y is preferably L-configured.
• R 2 H, C 1-4 alkyl, phenyl, phenyl C 1-4 alkylene,
• R 18 O-CH 2 -, R 18 -CO-, R 18 -O-CH 2 -CO-, R 18 -NH-CO-CO-, where R 18 is H or C 1-4 -alkyl-, CF 3 -CO- or C 2 F 5 -CO-,
• R 3 H, C 1-12 alkyl, aryl-C 12 alkylene,
• R 20 R 21 N-CO- (R 20 and R 21 are identical or different and denote H, C 1-6 alkyl, aryl, aryl C 1-2 alkylene, or R 20 and R 21 together represent a - (CH 2 ) 4-5 group),
• R 4 H, C 1-12 alkyl or aryl C 1-2 alkylene,
• R 5 C 1-4 alkyl
• R 6 H, C 1-12 alkyl.
• R 11 H or C 3-6 cycloalkyl
• R 12 H, C 1-6 alkyl or C 5-6 cycloalkyl
• Structures IIIa to IIIf are preferably in the L configuration.
• R 20 and R 21 are identical or different and mean H-, C 1 -6 alkyl, or benzyl, or R 20 and R 21 together represent a - (CH 2) 4 - 5 group),
• R 5 CH 3 -
• R 6 H, C 1-4 alkyl.
• Structure IIIa is preferably in the L configuration.
• substituents R, the fragment B and m have the following meanings: m: 0, 1 R 2 : H-, C 1-4 -alkyl-, phenyl-, phenyl-C 1-4 -alkylene-,
• R 18 O-CH 2 -, R 18 -CO-, R 18 -O-CH 2 -CO-, R 18 -NH-CO-CO-, where R 18 is H- or C 1-4 -alkyl- , CF 3 -CO- or C 2 F 5 -CO-,
• R 5 H or C 1-4 alkyl
• R 7 H-, C 1-12 -alkyl-, C 1-20 -alkyl -CO-,
• R 20 , R 21 are identical or different and mean H, C 1-6 alkyl or benzyl or R 20 and R 21 together mean a - (CH 2 ) 4-5 group) ,
• R 8 C 3-8 cycloalkyl, where the aliphatic rings are provided with up to 4 C 1-4 alkyl and / or CH 3 O groups and / or one or more methylene group (s) by -O- is (are) replaced,
• Phenyl which is substituted by 2 to 3 identical or different radicals from the group C 1-4 -alkyl-, CF 3 -, C 1-4 -alkoxy-, F- or Cl-,
• R 11 H or C 3-6 cycloalkyl
• R 12 H, C 1-6 alkyl, C 5-6 cycloalkyl.
• Structures IIIa to IIIf are preferably in the L configuration.
• R 5 H or CH 3 -
• R 7 H, C 1-6 alkyl-CO-
• R 19 OOC -C 1-4 alkylene
• (R 19 H, C 1 -4 alkyl
• R 8 C 5-8 -cycloalkyl-, where the aliphatic rings are substituted with up to 4 CH 3 and / or CH 3 O groups and / or a methylene group is replaced by -O-,
• Phenyl which is substituted by 2 to 3 identical or different radicals from the group CH 3 -, CF 3 -, CH 3 O-, F- or Cl-, adamantyl, norbonyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, diphenylmethyl, dicyclohexylmethyl, Me 3 Si or tert-butoxymethyl,
• Y a methylene group, an ethylene group
• the structure purple is preferably in the L configuration.
• Aryl means carbo- and heterocyclic aromatics, which can be mono- or bicyclic.
• the invention further relates to the compounds of the formulas
• the Cbz and Boc groups are particularly suitable as protective groups for the protected form.
• the new intermediates are used to manufacture the
• D has the meaning given above is new and valuable as a component of serine protease inhibitors and in particular of thrombin inhibitors.
• the compounds of the formula I can be present as such or in the form of their salts with physiologically tolerated acids.
• acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, hydroxy succinic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid
• the new compounds can continue to be used for the therapy and prophylaxis of thrombin-dependent thromboembolic events such as deep vein thrombosis, pulmonary embolism, myocardial or cerebral infarction and unstable angina, and for the therapy of disseminated intravascular coagulation (DIC). They are also suitable for combination therapy with thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other plasminogen activators to shorten the reperfusion time and extend the reocclusion time.
• thrombin-dependent thromboembolic events such as deep vein thrombosis, pulmonary embolism, myocardial or cerebral infarction and unstable angina
• DIC disseminated intravascular coagulation
• thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other
• the compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally, rectally) in the customary manner. It can also be applied with vapors or sprays through the nasopharynx.
• the dosage depends on the age, condition and weight of the patient and on the type of application.
• the daily dose of active ingredient per person is between approximately 10 and 2000 mg when administered orally and between approximately 1 and 200 mg when administered parenterally. This dose can be given in 2 to 4 single doses or once a day as a depot form.
• the new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, dragées, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
• the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al .: Pharmaceuticals Technology, Thieme-Verlag, Stuttgart, 1978).
• the administration forms thus obtained normally contain the active ingredient in an amount of 0.1 to 99 percent by weight.
• the compounds of the formula I can be derived from the N-terminally protected ⁇ -amino acids or ⁇ -hydroxycarboxylic acids A-OH, the ⁇ -amino acid B-OH and the building block H 2 NC (R 1 R 2 ) -E according to Scheme 1 and 2 represent.
• classic methods of protecting group and coupling chemistry are used.
• the residues R 3 and R 4 or R 7 can optionally after coupling the building blocks A-OH, B-OH and H 2 NC (R 1 R 2 ) -E to ABNC (R-LR 2 ) -E after cleavage the protective group of A or are part of A-OH from the beginning.
• W is one of the usual N-terminal protective groups (preferably Boc or Cbz) and W 'is methyl, ethyl, tert. Is butyl or benzyl.
• Boc protective groups are removed by means of dioxane / HCl or TFA / DCM, Cbz protective groups hydrogenolytically or with HF.
• the saponification of ester functions takes place with LiOH in an alcoholic solvent or in dioxane / water.
• t-Butyl esters are cleaved with TFA.
• N-terminal alkyl radicals are introduced by means of reductive alkylation or direct N-alkylation.
• Alkanoyl residues (see R 7 ) are introduced after standard coupling reactions or esterification reactions.
• the amidino function can be produced from a nitrile function using several methods: One method is the classic Pinner synthesis (R. Boder,
• the starting compounds can be prepared using the following methods:
• Boc- (4-Me) cyclohexylglycine were via the corresponding 2-For ethyl methyl acrylate (U. Schöllkopf and R. Meyer,
• the hydrochloride formed was reacted with an NaHCO 3 solution of 3.4 g of trimethylsilylalanine ethyl ester and, under customary conditions, converted into the Boc-protected compound almost quantitatively with di-tert-butyl dicarbonate.
• the ethyl ester was hydrolyzed with dilute sodium hydroxide solution in methanol, the salt formed was protonated with dilute hydrochloric acid and the product was extracted with ethyl acetate / ether 1: 1. 4.0 g of Boc-trimethylsilylalanine were obtained.
• Boc-N-cyclopropylglycine was prepared from N-cyclopropylglycine ethyl ester, bromoacetic acid ethyl ester and cyclopropylamine (analogously to JW Skiles et al., J. Med. Chem. 1992, 35, 641), then converted into the Boc-protected form under standard conditions, then with MeOH / 2N NaOH hydrolyzed and finally acidified with 1N HCl.
• Boc-suberylglycine was synthesized analogously to the literature (O.P. Goel et al. Tetrahedron Lett. 1993, 34, 953).
• Adamantylglycine can also be used according to Y.N. Belokon et al. Zhu. Org. Khi, 1985, 21, 1327.
• Boc- (3-Ph) -Pro-OH was analogous to a procedure by J.Y.L. Chung et al. (J.Y.L. Chung et al. J.Org.Chem. 1990, 55, 270).
• Boc-1-tetralinylglycine was prepared starting from 1,2-dihydronaphthalene. 1,2 dihydronaphthalene was first mixed with HBr
• Boc-cycloleucine was prepared according to Jorgensen (E.C. Jorgensen J. Med. Chem. 1971, 14, 904).
• Boc-1- (D, L) Tic-OH was according to a regulation by R. T. Shuman et al. (R.T. Shuman et al. J. Med. Chem. 1993, 36, 314).
• Boc- (D, L) -Dpa-OH (1mmol) was hydrogenated in 12 ml MeOH together with catalytic amounts of 5% Rh / Al 2 O3 at 5 bar. After filtration and removal of the solvent in vacuo, the product was obtained in quantitative yield.
• Boc- (D, L) - (3,4,5- (MeO) 3 ) Phe-OH was prepared by alkylation of ethyl benzophenone imine with trimethoxybenzyl chloride, subsequent introduction of Boc protective groups and ester saponification.
• 4-Bromomethyl-tetrahydropyran which was prepared by reacting 4-hydroxymethyl-tetrahydropyran (see DE 92 42 33 430) with PBr 3 and diethyl acetamidomalonate, previously deprotonated with NaH in DMF, was added to acetamido- (tetrahydropyran-4-yl ) -methyl-malonic acid diethyl ester and then hydrolyzed the esters and the acetyl group with simultaneous decarbonylation with 6N HCl and glacial acetic acid at 100 ° C. to (tetrahydropyran-4-yl) -alanine hydrochloride.
• the amino group was protected with a Boc group by methods known from the literature.
• the crude product was taken up in ethyl acetate, extracted with 0.5 N NaOH, the water phase acidified with 1N HCl and the product extracted with DCM. After drying over Na 2 SO 4 , the solvent was completely stripped off. Clean N-tert-butyloxycarbonyl- (D, L) - (tetrahydropyran-4-yl) alanine was obtained.
• reaction mixture was poured into 300 ml of water and extracted several times with ether. After drying with Na 2 SO 4 and removal of the solvent in vacuo, 6.8 g of yellowish crystals remained which were used in the subsequent reaction without further purification.
• the alcohol obtained was converted into the amine as described above and isolated as the hydrochloride.
• the solvent was largely removed in vacuo, the residue was mixed with 50 ml of water and extracted with ethyl acetate. After washing with water, NaHCO 3 solution and drying over Na 2 SO 4 , the ethyl acetate was distilled off, the remaining oily residue was dissolved in methanol and adjusted to pH 2 with p-toluenesulfonic acid. This solution remained at RT for 6 h. The methanol was then distilled off, the residue taken up in ethyl acetate, washed with water, 5% citric acid and NaHCO 3 solution.
• the thioamide was dissolved in 40 ml acetone and left to stand for 6 hours at RT after adding 4 ml methyl iodide. After the solvent had been stripped off, the amorphous residue was stirred with dry ether and then dried.
• the S-methylthioimidic acid methyl ester hydroiodide was dissolved in 50 ml of ethanol, mixed with 15 ml of 10% ammonium acetate solution and heated to 60 ° C. for 3 h. For isolation, the solvent was stripped off, the residue was dissolved in 100 ml of CH 2 Cl 2 , the insoluble constituents were filtered off and the CH 2 Cl 2 was then distilled off.
• stage a The methyl ester (stage a) was dissolved in 50 ml of THF, a solution of 5 g of LiOH in 50 ml of water was added and the mixture was stirred at RT overnight. After distilling off the THF, the aqueous phase was acidified with KHSO 4 solution and several times with Extracted ethyl acetate. The combined ethyl acetate phases were washed with brine, dried over Na 2 SO 4 and then evaporated to dryness. 4.1 g (78% of theory) of white crystals were isolated; FAB-MS (M + H + ): 326.
• the compound was obtained by reacting O-tetrahydropyranyl-3-cyclohexyl- (D) -lactic acid (WO 93/18060) with
• Example 6c N- (6-cyano-3-picolyl) prolinamide (Example 6c) analogously to Example 3a and subsequent amidine formation analogously to Ib.
• the organic phase was separated and washed with aqueous K 2 CO 3 solution, 0.5 N hydrochloric acid and 5% NaHCO 3 solution. After drying with Na 2 SO 4 , the solvent was distilled off, the oily residue (42 g) was dissolved in 400 ml of ethanol, 120 ml of 1N NaOH were added and the mixture was stirred at RT for 2 h. After the alcohol had been distilled off, the aqueous phase was diluted with water and repeated several times with methyl tert. -butyl ether extracted. The aqueous phase was washed with KHSO 4 solution. acidified and extracted 3 times with CH 2 CI 2 .
• step c (6.6 mmol) of the above compound (step c) was added. After a short time, the hydroxyamidine compound separated out, after stirring for 30 min, was filtered off with suction and washed with a little cold water and ethanol. The ethanol-moist residue was dissolved in 40 ml of ethanol and 8 ml of glacial acetic acid, with 250 mg
• Boc- (D) -cyclohexylglycine was coupled with methyl azetidine-2-carboxylic acid hydrochloride, saponified with LiOH to give free dipeptide acid and coupled again with 6-cyano-3-picolylamine hydrochloride.
• the dihydrochloride was obtained as a white powder; FAB-MS ( M + H + ): 373.
• BOC- (D, L) -chea-OH (preparation see above) was coupled with H-Pro-OCH 3 -HCl to the dipeptide Boc- (D, L) -chea-Pro-OCH 3 , the ester group hydrolyzed, coupled with 6-cyano-3-picolylamine dihydrochloride to the Boc- (D, L) -chea-Pro-NH-3- (6-CN) -pico and the cyano function converted to the amidine via the hydroxyamidine stage.
• the Boc protective group was cleaved off using HCl.
• Boc- (D, L) - (1-tetralinyl) Gly-OH (preparation see above) with H-Pro-OCH 3 -HCl to the dipeptide Boc- (D, L) - (1-tetralinyl) Gly-Pro-OCH 3 coupled, the ester group hydrolyzed with 6-cyano-3-picolylamine dihydrochloride to form Boc- (D, L) - (1-tetralinyl) Gly-Pro-NH-3- (6-CN) - pico coupled and the cyano function is converted into the amidine via the hydroxyamidine stage.
• Boc- (D, L) - (3,4,5-trimethoxy) Phe-Pro-OMe shown, the ester group hydrolyzed with 6-cyano-3-picolylamine dihydrochloride to Boc- (D, L) - (3, 4,5- (OCH 3 ) 3 ) Phe-Pro-NH-3- (6-CN) -pico coupled and the cyano function converted to the amidine via the hydroxyamidine stage.
• the Boc protective group was cleaved off using HCl.
• H- (D, L) - (3,4,5-trimethoxy) Phe-Pro-NH-3- (6-am) -pico-dihydrochloride was obtained as a white amorphous powder.
• Boc- (D, L) - (3-phenyl) -Pro-OH (the trans-amino acid described in the literature J. Org. Chem. 1990, 5JL, 270 - was used) and 1.45 g (5, 1 mmol) H-Pro (6-carboxamido) -3-picolylamide hydrochloride 1.01 g Boc- (D, L) - (3-phenyl) Pro-Pro (6-amidino) -3-picolylamide hydroacetate with a purity of 98% (HPLC); FAB-MS (M + H + ): 521.
• Boc-Pyr-OH (23.4 mmol) were suspended together with 5.25 g 6-carboxyamido-3-picolylamine dihydrochloride and 32.1 ml diisopropylethylamine (187 mmol) in 50 ml CH 2 Cl 2 and 23.5 ml of propanephosphonic anhydride (50% solution in ethyl acetate) are added dropwise at 0-5 ° C. while stirring. The mixture was then stirred at RT overnight. The solution was diluted to 150 ml with CH 2 Cl 2 , successively with
• Example 23 (a) Analogously to Example 23 (a), 12.5 g of Boc- (N-cyclopropyl) Gly-OH (58 mmol) were added to 13.3 g (58 mmol) of 6-carboxamido-3-pi-colylamine dihydrochloride to give 11.3 g H- (N-cyclopropyl) gly- (6-carboxamido) -3-picolylamide hydrochloride;
• Boc- (D) -cyclohexylglycyl-proline (4-amidino) -1-naphthyl-methylamide acetate Boc- (D) -cyclohexlyglycyl-proline, produced by reacting Boc- (D) -cyclohexylglycine with proline methyl ester and subsequent saponification , was coupled with 1-aminomethyl-4-cyanonaphthalene hydrochloride according to general instructions 2 and then the cyano group was converted into the amidine function according to general instructions 1. The acetate was isolated in the form of white crystals. Mp 144-147 ° C; FAB-MS (M + H + ): 526.
• the Boc group was cleaved from the above compound using isopropanolic hydrochloric acid and gave the dihydrochloride in the form of white crystals. Mp 228-232 ° -c;
• the hydroxyamidine was obtained by reacting the nitrile with hydroxylamine hydrochloride as in Example 26 (b).
• Boc- (D, L) - (2-norbornyl) Gly-Pro (2-MeO-4-am) -benzylamide was cleaved off in DCM / hydrochloride gas, the corresponding amidine dihydrochloride resulting after removal of the solvent; FAB-MS (M + H + ): 428.
• amidine dihydrochloride was obtained after cleavage of the Boc protective group in DCM with hydrochloride gas; FAB / MS (M + H + ): 464.
• Example 48 The compound was prepared analogously to Example 48 or 23 (b). To this was added 1.5 g (4.1 mmol) of Boc- (D) -Chg-Pic-OH, which was obtained by condensing Boc- (D) -Chg-OH with H-Pic-OMe hydrochloride and subsequent alkaline saponification of the Ester was prepared with 0.8 g (4.1 mmol) of (2-MeO-4-CN) benzylamine hydrochloride
• Example 47 was prepared analogously to Examples 48 and 23 (b). To this was added 1.5 g (4.2 mmol) of Boc- (D) -Chg- (N-cyclopropyl) -Gly-OH, which by condensation of Boc- (D) -Chg-OH with H- (N-cyclopropyl ) -Gly-OMe hydrochloride and subsequent alkaline saponification of the ester with 0.83 g (4.2 mmol)
• Boc- (D) -Chg-Pro (2-I-4-CN) -benzylamide condensed. 3.0 g of this compound were further converted via the step of the hydroxyamidine with subsequent hydrogenation to 0.9 g of Boc- (D) -Chg-pro- (2-I-4-am) -benzylamide hydroacetate. After the Boc protective group had been split off, 0.3 g of H- (D) -Chg-pro- (2-1-4-am) -benzylamide dihydrochloride was obtained; FAB-MS (M + H + ): 512.
• (D) -cyclohexylglycyl-prolin- (3-methoxy-4-amidino) -benzylamide a) Boc- (D) -Chg-Pro (3-MeO-4-CN) -benzylamide: from 2.7 g ( 7.6 mmol) of Boc- (D) -Chg-Pro-OH and 1.5 g (7.6 mmol) of (3-MeO-4-CN) -benzylamine hydrochloride were obtained analogously to Example 48 (b) 3, 0 g of product (a).
• Example 51 were hydrogenated with Pd / C / hydrogen, analogously to Example 44.
• 1.35 g of Boc- (D) -Chg-Pro (2-OH-4-CN) -benzylamide were obtained, which was mixed with an equimolar amount of K 2 CO 3 in 30 ml of DMF and 0.41 ml (2.80 mmol) tert-butyl bromoacetate was stirred in 3d at RT.
• the product was extracted by adding 100 ml of water and 100 ml of ethyl acetate / ether 1: 1 into the organic phase, dried over Na 2 SO 4 and the solvent was stripped off.
• Example 39 after splitting off the Boc protective group, analogously to Example 56 with tert-butyl bromoacetate to 1.4 g of tBuOOC-CH 2 - (D, L) -Cog-Pro (2-MeO- 4-CN) -benzylamide implemented.
• This substance was analogously to Example 23 (b) via the step of the hydroxyamidine with subsequent hydrogenation to 1.0 g of tBuOOC- CH 2 - (D, L) -Cog-Pro (2-MeO-4-am) -benzylamide hydroacetate implemented; FAB-MS (M + H + ): 558.
• Example 64 The substance was analogous to Example 23 (b), further via the step of the hydroxyamidine with subsequent hydrogenation and cleavage of the tert. -Butyl ester to 1.8 g of crude HOOC-CH 2 - (D) -Cha-Pic- (2-MeO-4-am) -benzylamide dihydrochloride. Part of the substance was purified by means of MPLC; FAB-MS (M + H + ): 502 Example 64
• Example 23 were further analogous to Example 23 (b) via the step of the hydroxyamidine with subsequent hydrogenation to 1.0 g of the corresponding amidine hydroacetate (purity: 99% - HPLC) and after cleavage of the tert-butyl ester to 0. 6 g of HOOC-CH 2 - (D) -Chg-pro- (2-Cl-4-am) -benzylamide dihydrochloride;

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