US20090163480A1 - Modified amino acids, pharmaceuticals containing these compounds and method for their production - Google Patents

Modified amino acids, pharmaceuticals containing these compounds and method for their production Download PDF

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US20090163480A1
US20090163480A1 US12/336,858 US33685808A US2009163480A1 US 20090163480 A1 US20090163480 A1 US 20090163480A1 US 33685808 A US33685808 A US 33685808A US 2009163480 A1 US2009163480 A1 US 2009163480A1
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dihydro
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phenyl
groups
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Klaus Rudolf
Wolfgang Eberlein
Wolfhard Engel
Helmut Pieper
Henri Doods
Gerhard Hallermayer
Michael Entzeroth
Wolfgang Wienen
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Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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Priority claimed from US09/254,281 external-priority patent/US6344449B1/en
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Priority to US12/336,858 priority Critical patent/US20090163480A1/en
Publication of US20090163480A1 publication Critical patent/US20090163480A1/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/9406—Neurotransmitters

Definitions

  • the present invention relates to modified amino acids of general formula
  • R denotes an unbranched C 1-7 -alkyl group which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl and alkylamino groups in the ⁇ -position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C 3-8 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piper)carbon
  • X denotes an oxygen atom or 2 hydrogen atoms
  • Z denotes a methylene group or the group —NR 1 , wherein
  • R 11 denotes a hydrogen atom, a C 1-3 -alkyl group, an alkoxycarbonyl group having a total of 2 to 4 carbon atoms or a phenylmethyl group,
  • n denotes the number 1 or 2 or, if m is 1, n may also be 0,
  • n denotes the number 0 or 1
  • R 2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
  • A denotes a bond or the divalent group of formula
  • R 3 denotes a hydrogen atom
  • a C 1-7 -alkyl group which may be substituted in the ⁇ -position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino, 4-alkyl-1-piperazinyl or 4-( ⁇ -hydroxyalkyl)-1-piperazinyl group,
  • R 4 denotes a hydrogen atom or a C 1-3 -alkyl group optionally substituted by a phenyl or pyridinyl group or
  • R 3 and R 4 together with the enclosed nitrogen atom denote a group of general formula
  • alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 7 carbon atoms, unless otherwise specified,
  • aroyl group used above denotes, for example, the benzoyl or naphthoyl group.
  • protecting groups mentioned in the foregoing definitions and hereinafter are the protecting groups which are commonly known from peptide chemistry, particularly
  • alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety
  • the present invention relates to racemates, where the compounds of general formula I have only one chiral element. However, the application also covers the individual diastereomeric pairs of antipodes or mixtures thereof which occur when there is more than one chiral element in the compounds of general formula (I).
  • the preferred isomers are those which are spatially constructed analogously to the (R)-configured partial structure of formula V with regard to the partial structure of formula VI
  • the compounds of general formula I have valuable pharmacological properties based on their selective CGRP-antagonistic properties.
  • the invention further relates to medicaments containing these compounds, their use and the preparation thereof.
  • R 2 , R 3 , R 4 , R 11 , X, Z and m and n are as hereinbefore defined and
  • R denotes an unbranched C 1-6 -alkylamino group optionally substituted at the nitrogen atom by a C 1-6 -alkyl group or by a phenylmethyl group, which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ⁇ -position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C 3-8 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)
  • alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise stated,
  • R 2 , R 3 , R 4 , R 11 , X, Z and m and n are defined as for the first subgroup hereinbefore,
  • R denotes an unbranched C 1-7 -alkyl group which may be substituted in the ⁇ -position
  • phenyl, naphthyl- and biphenylyl- groups mentioned hereinbefore for the substitution of the alkyl groups in the ⁇ -position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C 3-8 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidiny
  • A denotes a single bond
  • alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms unless otherwise stated,
  • R denotes an unbranched C 1-5 -alkyl group which may be substituted in the ⁇ -position
  • X denotes the oxygen atom or 2 hydrogen atoms
  • Z denotes the methylene group or the group —NR 1 — wherein
  • R 11 denotes a hydrogen atom, a C 1-3 -alkyl group or an alkoxycarbonyl group having 2 to 4 carbon atoms altogether,
  • n denotes the number 1 or 2 or, if m is 1, n may also be 0,
  • n denotes the number 0 or 1
  • R 2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
  • A denotes a bond or the divalent group of formula
  • R 3 denotes a hydrogen atom
  • a C 1-4 -alkyl group which may be substituted in the ⁇ -position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-azepin-1-yl, [bis-(2-hydroxyethyl)]amino, 4-methyl-1-piperazinyl- or 4-( ⁇ -hydroxyalkyl)-1-piperazinyl group,
  • R 4 denotes a hydrogen atom or a methyl or ethyl group optionally substituted by a phenyl or pyridinyl group
  • alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise specified,
  • aroyl group used above denotes, for example, the benzoyl or naphthoyl group
  • R 2 , R 3 , R 4 , R 11 , X, Z and m and n are defined as given hereinbefore defined for the preferred compounds of general formula I,
  • R denotes an unbranched C 1-4 -alkylamino group optionally substituted at the nitrogen atom by a C 1-3 -alkyl group or by a phenylmethyl group, which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ⁇ -position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C 5-7 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)
  • alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise stated,
  • R 2 , R 3 , R 4 , R 11 , X, Z and m and n are defined as for the first preferred subgroup hereinbefore,
  • R denotes an unbranched C 1-5 -alkyl group which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkyl groups in the ⁇ -position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C 5-7 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)
  • A denotes a single bond
  • alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms unless otherwise stated,
  • R denotes an unbranched C 1-3 -alkyl group which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkyl and alkylamino groups in the ⁇ -position as well as optionally partially hydrogenated mono- and bicyclic heteroaromatic rings may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups, whilst the substituents may be the same or different,
  • X denotes an oxygen atom or 2 hydrogen atoms
  • Z denotes a methylene group or the group —NR 1 — wherein
  • R 11 denotes the hydrogen atom or a methyl or methoxycarbonyl group
  • n denotes the number 1 or 2 or, if m is the number 1, n may also denote 0,
  • n denotes the number 0 or 1
  • R 2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, pyridinyl or quinolinyl group,
  • A denotes a bond or the divalent group of formula
  • R 3 denotes a hydrogen atom
  • a C 1-4 -alkyl group optionally substituted in the ⁇ -position by a cyclohexyl, phenyl, pyridinyl, hydroxy, amino, methylamino, dimethylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-(1-piperidinyl)-1-piperidinyl group,
  • R 4 denotes the hydrogen atom or a C 1-2 -alkyl group optionally substituted by a phenyl or pyridinyl group
  • alkyl and alkoxy groups and the alkyl groups present within the other groups named may contain 1 to 3 carbon atoms, unless otherwise stated, and
  • R 2 , R 3 , R 4 , R 11 , X, Z and m and n are defined as for the particularly preferred compounds of general formula I hereinbefore and
  • R denotes an unbranched C 1-4 -alkylamino group optionally substituted at the nitrogen atom by a methyl or ethyl group, which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkylamino groups in the ⁇ -position, as well as optionally any partially hydrogenated mono- and bicyclic heteroaromatic rings may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups, whilst the substituents may be identical or different,
  • alkyl and alkoxy groups and the alkoxy groups present within the other named radicals may contain 1 to 3 carbon atoms unless otherwise stated,
  • R 2 , R 3 , R 4 , R 11 , X, Z and m and n are as hereinbefore defined for the first-mentioned particularly preferred subgroup
  • R denotes an unbranched C 1-3 -alkyl group which may be substituted in the ⁇ -position
  • any partially hydrogenated mono- and bicyclic heteroaromatic rings may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups wherein the substituents may be identical or different,
  • alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 3 carbon atoms unless otherwise specified,
  • R denotes an unbranched C 1-3 -alkyl group which may be substituted in the ⁇ -position
  • X denotes an oxygen atom or 2 hydrogen atoms
  • Z denotes a methylene group or the group —NR 1 , wherein
  • R 11 denotes a hydrogen atom, a methoxycarbonyl, ethoxycarbonyl or methyl group
  • n denotes the number 1 and m denotes the number 0 or
  • n denotes the number 0 and m denotes the number 1,
  • R 2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 2-thienyl, 3-thienyl, thiazolyl or alkylthiazolyl group having 1 to 3 carbon atoms in the alkyl moiety, a pyridinyl or quinolinyl group,
  • A denotes a bond or the divalent group of formula
  • R 3 denotes a hydrogen atom
  • a C 1-4 -alkyl group optionally substituted in the ⁇ -position by an amino, methylamino, dimethylamino- or 4-(1-piperidinyl)-1-piperidinyl group,
  • R 4 denotes a hydrogen atom or a methyl or ethyl group
  • alkyl groups and the alkyl groups present within the other named groups may contain 1 to 3 carbon atoms, unless otherwise specified,
  • R 2 , R 3 , R 4 , R 11 , X, Z and m and n are as hereinbefore defined for the most particularly preferred compounds of general formula I and
  • R denotes an unbranched C 1-4 -alkylamino group optionally substituted at the nitrogen atom by a methyl or ethyl group, which may be substituted in the ⁇ -position
  • R 2 , R 3 , R 4 , R 11 , X, Z and m and n are as defined hereinbefore for the first-mentioned particularly preferred subgroup
  • R denotes an unbranched C 1-3 -alkyl group which may be substituted in the ⁇ -position
  • the compounds of general formula I are prepared by methods which are known in principle, particularly using processes derived from peptide chemistry (cf. for example Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2).
  • the amino protecting groups used may be those described in Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/1, of which urethane protecting groups such as the fluorenylmethoxycarbonyl, phenylmethoxycarbonyl or tert.-butyloxycarbonyl group are preferred.
  • Any functional groups present in the groups R 2 and/or A of the compounds of general formula I or in the precursors thereof are additionally protected by suitable protecting groups in order to prevent side reactions (cf. for example: G. B.
  • side-chain-protected amino acids of this kind include, in particular, Arg(NO 2 ), Arg(Mtr), Arg(di-z), Arg(Pmc), Lys(Boc), Lys(Z), Orn(Boc), Orn(Z), Lys(Cl-Z) which are commercially obtainable, possibly in the form of derivatives. Particular care should be taken to ensure that so-called orthogonal combinations of protecting groups are used to protect the ⁇ -amino and the side chain amino group, e.g.:
  • amino acids or derivatives thereof which carry precursor functions and in particular are substituted by nitro or cyano in the side chain such as 5-o-cyanonorvalin may also be used.
  • protecting groups which are particularly suitable for the (aminoiminomethyl)- group are the p-toluenesulphonyl, mesitylene sulphonyl- (Mts), methoxytrimethylphenylsulphonyl- (Mtr), 2,2,5,7,8-pentamethylchroman-6-sulphonyl- (Pmc), pentachlorophenoxycarbonyl- and nitro-protecting groups.
  • carbodiimides such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)N,N—N′,N′-tetramethyluronium-hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodiimide
  • DI diisopropylcarbodiimide
  • ethyl-(3-dimethylaminopropyl)-carbodiimide O-(1H-benzotriazol-1-yl)N,N—N′,N′-tetramethylur
  • the couplings are normally carried out with equimolar amounts of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30 and +30° C., preferably between ⁇ 20 and +20° C. If necessary, N-ethyl-diisopropylamine (DIEA) is preferred as an additional auxiliary base (Hünig base).
  • solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30 and +30° C., preferably between ⁇ 20 and +20° C.
  • DIEA N-ethyl-diisoprop
  • the mixed anhydride is obtained from the optionally N 2 -protected ⁇ -amino acid which is to be coupled, and the mono-isobutylcarbonate, using isobutylchlorocarbonate in the presence of base such as 4-methylmorpholine or 4-ethylmorpholine.
  • base such as 4-methylmorpholine or 4-ethylmorpholine.
  • Any protecting groups present in the side chains of ⁇ -amino acid partial structures are finally cleaved, after the formation of the N- and C-terminally substituted amino acid derivative, with suitable reagents which are also known from the literature in principle, specifically arylsulphonyl and hetarylsulphonyl protecting groups, preferably by acidolysis, i.e. by the action of strong acids, preferably trifluoroacetic acid, nitro- and arylmethoxycarbonyl protecting groups are preferably cleaved by hydrogenolysis, e.g. using hydrogen in the presence of palladium black and with glacial acetic acid as solvent. If the substrate contains functions which are sensitive to hydrogenolysis, e.g.
  • halogen atoms such as chlorine, bromine or iodine, a phenylmethanol or hetarylmethanol function or some other benzyl heteroatom bond, particularly a benzyl-oxygen bond
  • the nitro group may also be cleaved non-hydrogenolytically, e.g. with zinc/2N trifluoroacetic acid (cf. also A. Turan, A. Patthy and S. Bajusz, Acta Chim. Acad. Sci. Hung, Tom. 85 (3), 327-332 [1975]; C.A.
  • Any precursor functions which may be present in the side chain of the ⁇ -amino acid may also subsequently be converted by hydrogenolysis into the desired amino functions; nitroalkyl groups yield aminoalkyl groups under conditions which will be familiar to the chemist, whilst the cyano group is converted into the aminomethyl group.
  • nitrile functions may also be reduced with complex hydrides which are selective in relation to other critical functions contained in the molecule, particularly amide groups (cf. also: J. Seyden-Penne, “Reductions by the Alumino- and Borohydrides in Organic Synthesis”, VCH Publishers Inc., 1991, p. 132ff.), e.g.
  • R denotes an unbranched C 1-7 -alkyl group which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl groups in the ⁇ -position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C 3-8 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbon
  • R 5 , R 6 , R 7 , R N , Y 1 , o and p are as hereinbefore defined
  • Y 2 denotes a CH— group
  • Z denotes an NR 1 — group, wherein R 1 is as hereinbefore defined:
  • R 2 , R 3 , R 4 , R 11 , A, X, m and n are as hereinbefore defined, and
  • Z denotes an NR 1 — group, wherein R 1 is as hereinbefore defined, and, if necessary, subsequently cleaving any protecting groups or modifying precursor functions in accordance with the methods described hereinbefore.
  • the coupling is carried out using the methods known from peptide chemistry described above, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
  • R is defined as in a) and Nu denotes a leaving group, for example a halogen atom such as the chlorine, bromine- or iodine atom, an alkylsulphonyloxy group having 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms or by methyl- or nitro groups, wherein the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl- optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4
  • R 2 , R 3 , R 4 , R 11 , A, X, m and n are as hereinbefore defined and
  • Z denotes an NR 1 — group, whilst R 1 is as hereinbefore defined,
  • the reaction is carried out under Schotten-Baumann or Einhorn-conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between ⁇ 50° C. and +120° C., preferably between ⁇ 10° C. and +30° C., optionally in the presence of solvents.
  • auxiliary bases which may be used are preferably alkali-metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetate, e.g.
  • sodium- or potassium acetate as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-Diazabicyclo[2,2,2]octane or 1,8-diazabicyclo-[5,4,0]undec-7-ene, whilst the solvents which may be used include, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or -acetates are used as auxiliary bases, water may also be added to the reaction mixture as a cosolvent.
  • R denotes an unbranched C 1-6 -alkylamino group optionally substituted at the nitrogen atom by a C 1-6 -alkyl group or by a phenylmethyl group, which may be substituted in the ⁇ -position
  • R 5 , R 6 , R 7 , R N , Y 1 , o and p are as hereinbefore defined
  • Y 2 denotes the N-atom
  • Z denotes the NR 1 — group, wherein R 1 is as hereinbefore defined:
  • X 1 is a nucleofugic group, preferably the 1H-imidazol-1-yl, 1H-1,2,4-triazol-1-yl, trichloromethoxy- or 2,5-dioxopyrrolidin-1-yloxy group,
  • R 2 , R 3 , R 4 , R 11 , A, X, m and n are as hereinbefore defined and Z denotes an NR 1 — group, wherein R 1 is as hereinbefore defined,
  • the theoretically two-step reactions are generally carried out as one-pot processes, preferably by reacting one of the two components X or VIII with equimolar amounts of the carbonic acid derivative of general formula XI in a suitable solvent at fairly low temperature, in the first step, and then adding at least equimolar amounts of the other component VIII or X and finishing the reaction at elevated temperature.
  • the reactions with bis-(trichloromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-carbonat) of a tertiary base, e.g.
  • solvent which should be anhydrous
  • examples of solvent include tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile, if bis-(trichloromethyl)-carbonate is used as the carbonyl component, anhydrous chlorohydrocarbons such as dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred.
  • the reaction temperatures are between ⁇ 30 and +25° C. for the first step of the reaction, preferably between ⁇ 5 and +10° C., and between +15° C. and the boiling temperature of the solvent used, preferably between +20° C.
  • R denotes an unbranched C 1-6 -alkylamino group optionally additionally substituted at the nitrogen atom by a C 1-6 -alkyl group or by a phenylmethyl group, which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ⁇ -position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C 3-8 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-pyrrol
  • Z denotes the group NR 1 and
  • X 2 denotes a phenoxy group, if X 3 is the (1H)-1,2,3,4-tetrazol-1-yl group, the 4-nitrophenoxy group, if X 3 is the 4-nitrophenoxy group, and the chlorine atom if X 3 is the 2,4,5-trichlorophenoxy group, and with compounds of general formula VIII′,
  • R 2 , R 3 , R 4 , R 11 , X, A, m and n are as hereinbefore defined and
  • R 1 denotes a hydrogen atom or, provided that R is an unbranched alkylamino group unsubstituted at the nitrogen and optionally substituted in the ⁇ -position, R 1 may also denote an alkyl or phenylalkyl group, and
  • the reactions are in two steps, in principle, with intermediate formation of urethanes, which can be isolated. However, the reactions may also be carried out as one-pot reactions.
  • one of the two components X′ or VIII′ is reacted with equimolar amounts of the carbonic acid derivative of general formula XI′ in a suitable solvent at low temperature, then at least equimolar amounts of the other component VIII′ or X′ are added and the reaction is completed at elevated temperature.
  • the reactions are preferably carried out in anhydrous solvents, e.g.
  • reaction temperatures are between ⁇ 15 and +40° C., preferably between ⁇ 10 and +25° C. for the first step, between +20° C. and the boiling temperature of the solvent used, preferably between +20° C. and 100° C. for the second reaction step (cf. also: R. W. Adamiak and J.
  • R denotes an unbranched C 1-6 -alkylamino group optionally substituted at the nitrogen atom by a C 1-6 -alkyl group or by a phenylmethyl group, which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl groups in the ⁇ -position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C 3-8 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbony
  • R 5 , R 6 , R 7 , R N , Y 1 , o and p are as hereinbefore defined and Y 2 denotes an N-atom:
  • R 2 , R 3 , R 4 , R 11 , A, X, m and n are as hereinbefore defined,
  • R is as hereinbefore defined and, if necessary, subsequently cleaving protecting groups or modifying precursor functions using the processes described above.
  • the reaction is carried out at temperatures between 0° C. and 150° C., preferably between 20° C. and 100° C., optionally in the presence of anhydrous solvents, e.g. tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone or mixtures thereof.
  • anhydrous solvents e.g. tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone or mixtures thereof.
  • R denotes an unbranched C 1-6 -alkylamino group unsubstituted at the nitrogen atom, which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ⁇ -position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C 3-8 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)
  • Z denotes the NR 1 — group wherein R 1 is as hereinbefore defined:
  • R 2 , R 3 , R 4 , R 11 , A, X, m and n are as hereinbefore defined and
  • Z denotes an NR 1 — group, wherein R 1 is as hereinbefore defined,
  • the reaction is carried out at temperatures between 0 and 150° C., preferably at temperatures between 20 and 100° C., and optionally in the presence of anhydrous solvents, e.g. tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone.
  • anhydrous solvents e.g. tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone.
  • R 2 ′ has the meanings given for R 2 hereinbefore or denotes a group R 2 substituted by the above-mentioned protecting groups
  • A′ has the meanings given for A hereinbefore or, if A denotes the divalent group of an amino acid, it optionally bears in the side chain a precursor group for the group R 9 , e.g. a cyanopropyl group,
  • the coupling is carried out using the methods known from peptide chemistry and described hereinbefore, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
  • the starting compound XIV used is enantiomerically pure, partial racemisation of the C-terminal amino acid must be expected during the coupling step and possibly quantitative racemisation must be expected if triethylamine is used as the auxiliary base and dimethylformamide, dimethylacetamide or N-methyl-pyrrolidone is used as solvent.
  • R, Z, R 11 , m and n are as hereinbefore defined and R 2 ′ has the meanings given for R 2 hereinbefore or denotes a group R 2 substituted by the above-mentioned protecting groups,
  • A′ has the meanings given for A hereinbefore or, if A denotes the divalent group of an amino acid, A′ optionally bears in the side chain a precursor group for the group R 9 , e.g. a cyanopropyl group, and
  • R 3 and R 4 are as hereinbefore defined
  • the coupling is carried out using the methods known from peptide chemistry and described above, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
  • R denotes an unbranched C 1-6 -alkylamino group optionally substituted at the nitrogen atom by a C 1-6 -alkyl group or by a phenylmethyl group, which may be substituted in the ⁇ -position
  • phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ⁇ -position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C 3-8 -cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-pyrrol
  • X denotes two hydrogen atoms
  • A denotes a single bond
  • m denotes the value 1
  • n denotes the value 0:
  • the coupling is carried out using the methods known from peptide chemistry and described above, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
  • R 3 ′ and R 4 ′ have the meanings given for R 3 and R 4 hereinbefore with the exception of hydrogen atoms
  • R is as hereinbefore defined and R 2 is as hereinbefore defined, but with the proviso that any acid functions present such as hydroxy groups are appropriately protected by suitable protecting groups.
  • the reaction is preferably carried out in a slightly acidic medium, using alcohols, e.g. methanol or ethanol, or lower aliphatic carboxylic acids, such as glacial acetic acid, as solvents and at temperatures between room temperature and the boiling point of the solvent in question.
  • alcohols e.g. methanol or ethanol
  • lower aliphatic carboxylic acids such as glacial acetic acid
  • an inorganic acid salt such as the hydrochloride of a secondary amine of general formula XVa is heated with paraformaldehyde and a ketone of general formula XIX in glacial acetic acid to temperatures between 50° C. and 80° C.
  • Nu 2 is a leaving group, e.g. an alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl group each having 1 to 10 carbon atoms in alkyl moiety, e.g. a methoxy, ethoxy, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, methylsulphonyl or ethylsulphonyl group, the chlorine atom, the SO 2 H, SO 3 H— or OPOCl 2 — group, or the group of general formula XXII,
  • R 15 and R 16 which may be identical or different, denote hydrogen atoms or C 1-3 -alkyl groups.
  • auxiliary bases especially alkali metal carbonates such as sodium- or potassium carbonate, or tertiary amines, preferably N-ethyl-diisopropylamine or triethylamine.
  • amino acids of general formula I modified according to the invention contain at least one chiral centre. If the group A is also chiral, the compounds may occur in the form of two diastereomeric pairs of antipodes.
  • the invention includes the individual isomers as well as the mixtures thereof.
  • the diastereomers are separated on the basis of their different physicochemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
  • Racemates covered by general formula I may be separated, for example, by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated by means of the diastereomeric optically active salts which are formed on reacting with an optically active acid, e.g.
  • (+)- or ( ⁇ )-tartaric acid (+)- or ( ⁇ )-diacetyl tartaric acid, (+)- or ( ⁇ )-monomethyl-tartrate or (+)-camphor sulphonic acid or an optically active base such as (R)-(+)-1-phenylethylamine, (S)-( ⁇ )-1-phenylethylamine or (S)-brucine.
  • the racemate of a compound of general formula I is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the crystalline, diastereomeric, optically active salts obtained are separated on the basis of their different solubilities.
  • This reaction may be carried out in solvents of any kind provided that they are sufficiently different in terms of the solubility of the salts.
  • methanol, ethanol or mixtures thereof are used, e.g. in a ratio by volume of 50:50.
  • each of the optically active salts is dissolved in water, neutralised with a base such as sodium carbonate or potassium carbonate, sodium hydroxide solution or potassium hydroxide solution, and in this way the corresponding free compound is obtained in the (+)- or ( ⁇ )-form.
  • a base such as sodium carbonate or potassium carbonate, sodium hydroxide solution or potassium hydroxide solution
  • Isocyanates of general formula XII can easily be obtained from ⁇ -amino acid derivatives of general formula VIII′ wherein R 1 denotes a hydrogen atom and the other groups are as hereinbefore defined, or from the hydrochlorides thereof by reacting with phosgene, diphosgene or triphosgene in the presence of pyridine (see also: J. S. Nowick, N. A. Powell, T. M. Nguyen and G. Noronha, J. Org. Chem. 57, 7364-7366 [1992]).
  • Carboxylic acids of general formulae XIV and XVI may be obtained from the corresponding carboxylic acid esters by saponification, preferably in the presence of lithium hydroxide.
  • the carboxylic acids of general formula XVIII are obtained by saponifying corresponding carboxylic acid esters which are in turn prepared from suitable secondary amines, 4-aryl-4-oxobutanoic acid esters and formaldehyde by Mannich reaction.
  • the compounds of general formula I may be converted into their physiologically acceptable salts with inorganic or organic acids, particularly for pharmaceutical applications.
  • suitable acids for this purpose include hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I thus obtained contain an acid function, for example a carboxy group, they may if desired be converted into the addition salts thereof with inorganic or organic bases, more particularly for pharmaceutical use, into the physiologically acceptable addition salts thereof.
  • Bases which may be considered include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of general formula I and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP-receptor binding studies.
  • the compounds exhibit CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
  • SK-N-MC-cells are cultivated in Dulbecco's modified Eagle Medium. The medium of confluent cultures is removed. The cells are washed twice with PBS-buffer (Gibco 041-04190 M), detached by the addition of PBS-buffer mixed with 0.02% EDTA and isolated by centrifuging. After resuspension in 20 ml of Balanced Salts Solution [BSS (in mM): NaCl 120, KCl 5.4, NaHCO 3 16.2, MgSO 4 0.8, NaHPO 4 1.0, CaCl 2 1.8, D-Glucose 5.5, HEPES 30, pH7.40] the cells are centrifuged twice at 100 ⁇ g and resuspended in BSS.
  • BSS Balanced Salts Solution
  • the cells are homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000 ⁇ g. The supernatant is discarded and the pellet is recentrifuged and resuspended (1 ml/1000000 cells) in Tris-buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40), enriched with 1% bovine serum albumin and 0.1% bacitracin. The homogenate is frozen at ⁇ 80° C. The membrane preparations are stable for more than 6 weeks under these conditions.
  • the homogenate is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230 ⁇ l of the homogenate are incubated at ambient temperature for 180 minutes with 50 pM of 125 I-Iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 ⁇ l. Incubation is ended by rapid filtration using GF/B-glass fibre filters treated with polyethyleneimine (0.1%) by means of a cell harvester. The protein-bound radioactivity is measured using a gammacounter. The non-specific binding is defined as the radioactivity bound after the presence of 1 ⁇ M of human CGRP-alpha during incubation.
  • assay buffer 50 mM Tris, 150 mM NaCl, 5
  • concentration binding curves are analysed using a computer-aided non-linear curve adaptation.
  • the compounds of general formula I show IC 50 values ⁇ 10000 nM in the test described.
  • SK-N-MC-cells (1 million cells) are washed twice with 250 ⁇ l of incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP (10 ⁇ l) as agonist in increasing concentrations (10 ⁇ 11 to 10 ⁇ 6 M) or additionally of substance in 3 to 4 different concentrations, incubation is continued for a further 15 minutes.
  • incubation buffer Horte, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4
  • Intracellular cAMP is then extracted by the addition of 20 ⁇ l of 1M HCl and centrifugation (2000 ⁇ g, 4° C. for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at ⁇ 20° C.
  • the cAMP contents of the samples are determined by radioimmunoassay (Amersham) and the pA 2 -values of antagonistically acting substances are determined graphically.
  • the compounds of general formula I display CGRP-antagonistic properties in a dosage range between 10 ⁇ 11 and 10 ⁇ 5 M in the in vitro test model described.
  • the compounds of general formula I and the salts thereof with physiologically acceptable acids or bases are thus suitable for acute and prophylactic treatment of headache, particularly migraine and cluster headaches.
  • the compounds of general formula I also have a beneficial effect on the following diseases: non-insulin-dependent diabetes mellitis (NIDDM), cardiovascular diseases, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g. inflammatory joint diseases (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases which involve excessive vasodilation and resultant reductions in circulation, e.g. shock and sepsis, as well as morphine tolerance.
  • NIDDM non-insulin-dependent diabetes mellitis
  • cardiovascular diseases skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g. inflammatory joint diseases (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases which involve excessive vasodilation and resultant reductions in circulation, e.g. shock and seps
  • the dosage needed to achieve such effects is appropriately 0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, by intravenous or subcutaneous route, and 0.01 to 10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight, when administered orally, nasally or by inhalation, in each case 1 to 3 times a day.
  • the compounds of general formula I prepared according to the invention may be formulated, optionally in combination with other active substances, such as antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin-antagonists, anti-convulsants, histamine-H1-receptor antagonists, antimuscarinics, ⁇ -blockers, ⁇ -agonists and ⁇ -antagonists, ergot alkaloids, mild analgesics, non-steroidal antiphlogistics, corticosteroids, calcium-antagonists, 5-HT 1D -agonists or other antimigraine agents, together with one or more inert conventional carriers and/or diluents, e.g.
  • active substances such as antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin-antagonists, anti-convulsants, histamine-H1-receptor antagonists, antimuscarinics, ⁇ -blockers, ⁇ -agonists and ⁇ -ant
  • corn starch lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metering aerosol or suppositories.
  • additional active substances which may be considered for the above-mentioned combinations include, for example, meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidon, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenyloin, valproate, amitryptilin, lidocaine, diltiazem or sumatriptan and other 5-HT 1D -agonists such as naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan.
  • the dosage for these active substances is appropriately 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dosage, i.e. 20 to 100 mg
  • the invention further relates to the use of the compounds of general formula I as valuable auxiliary agents for the production and purification (by affinity chromatography) of anti-bodies and, after suitable radiolabelling, e.g. by direct labelling with 125 I or 131 I or by tritiation of suitable precursors for example by replacing halogen atoms with tritium, in RIA- and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.
  • the mixture was stirred for 5 hours at room temperature, then 19.5 g (0.296 mol) of sodium cyanate, 18 ml of glacial acetic acid and 10 ml of water were added and stirring was continued for 12 hours at room temperature.
  • the mixture was stirred into 1 l of ice water, the dichloromethane phase was separated off, washed twice with 200 ml of water, 5% aqueous sodium hydrogen carbonate solution, 20% aqueous citric acid solution and once more with water, dried over magnesium sulphate and evaporated down in vacuo. The residue was taken up in methanol.
  • R f 0.5 (dichloromethane/methanol/conc. ammonia 90/10/0.1 v/v/v)
  • the yellowish oil was used in the following stage without further purification
  • the yellowish oil was used in the following stage without further purification
  • the yellowish oil was used in the following stage without further purification
  • the crystalline salt was suction filtered, washed with methanol and diethylether, then taken up in water and made alkaline with saturated aqueous potassium carbonate solution. The mixture obtained was extracted thoroughly with ethyl acetate, the combined ethyl acetate extracts were dried over sodium sulphate and evaporated down. 58.2 g (70.6% of theory) of a brownish-yellow oil were obtained, which was further processed without any more purification.
  • N 2 -(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamide was obtained from N 2 -(1,1-dimethylethoxycarbonyl)-D,L-phenylalanine and 4-amino-1-(phenylmethyl)piperidine in a yield of 85% of theory.
  • the aqueous phase remaining was acidified with hydrochloric acid, whilst being externally cooled, extracted thoroughly with diethylether and then made alkaline with 50% potassium hydroxide solution.
  • the mixture was extracted thoroughly with dichloromethane, the combined dichloromethane extracts were dried over magnesium sulphate and evaporated down in vacuo.
  • the colourless, highly viscous, slowly crystallising oil remaining was further processed without any more purification.
  • the aqueous phase was extracted twice more with a mixture of ethyl acetate/methanol (10/1, v/v) and the combined organic phases were washed once with saturated sodium hydrogen carbonate solution.
  • the organic phase was, after drying over sodium sulphate, evaporated down in vacuo and the residue was taken up in 750 ml of ethyl acetate and washed four times with 100 ml of water, six times with 100 ml of 1% potassium hydrogen sulphate solution, once with 100 ml of water, twice with 100 ml of 31 aqueous ammonia solution and twice with 100 ml of water.
  • the organic phase was evaporated down after drying over sodium sulphate. 120 g (87% of theory) of the desired product were obtained as an oil, which was used without further purification for the subsequent reactions.
  • the catalyst was filtered off, the filtrate evaporated down in vacuo, the residue was taken up in isopropanol/methanol and adjusted to pH 7-8 by the addition of a concentrated aqueous ammonia solution. The solution was filtered and evaporated to dryness. 87 g (97% of theory) of an oil were obtained.
  • the combined aqueous phases were extracted once with tetrahydrofuran and the combined tetrahydrofuran phases were washed once with saturated aqueous saline solution. After drying the organic phase with sodium sulphate it was evaporated down in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was filtered after drying again and evaporated down in vacuo. 52.5 g of the intermediate compound were obtained as a viscous oil, which was then mixed with 300 ml of methylene chloride and 8.0 ml of trifluoroacetic acid and stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo, the residue formed was triturated with ether. 45.8 g (72% of theory) of the desired product were obtained as a white amorphous solid.
  • the reaction mixture was evaporated down in vacuo and the residue divided between ethyl acetate/methanol (10/1 v/v) and saturated aqueous sodium hydrogen carbonate solution.
  • the organic phase was washed once with saturated aqueous sodium hydrogen carbonate solution and after drying evaporated down in vacuo.
  • 0.5 g (40% of theory) of a colourless amorphous solid was obtained.

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Abstract

The present invention relates to modified amino acids of general formula
Figure US20090163480A1-20090625-C00001
wherein
A, Z, X, n, m, R, R2, R3, R4 and R11 are defined as in claims 1 to 5, their tautomers, their diastereomers, their enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for preparing them as well as their use for the production and purification of antibodies and as labelled compounds in RIA- and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.

Description

  • The present invention relates to modified amino acids of general formula
  • Figure US20090163480A1-20090625-C00002
  • their tautomers, their diastereomers, their enantiomers, their mixtures and salts thereof, particularly physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for preparing them.
  • In the above general formula I
  • R denotes an unbranched C1-7-alkyl group which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
      • by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, wherein the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups and the substituents may be identical or different,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one, two or three nitrogen atoms,
        • whilst a 1,4-butadienylene group may be attached both to the above-mentioned 5-membered heteroaromatic monocyclic rings and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo-[4,5-b]pyridin-3-yl- group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
      • by a 6-membered heteroaromatic ring linked via a carbon atom, containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl and alkylamino groups in the ω-position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group, or the group of formula
  • Figure US20090163480A1-20090625-C00003
  • wherein
      • p denotes the number 1 or 2,
      • o denotes the number 2 or 3 or, if Y1 and Y2 are not simultaneously nitrogen atoms, o may also denote 1.
      • Y1 denotes the nitrogen atom if R5 is a free pair of electrons, or the carbon atom,
      • Y2 is the nitrogen atom or the group >CH—,
      • R5 is a free pair of electrons if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 denotes a hydrogen atom, a C1-3-alkyl group, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl, aminocarbonylamino, phenylmethyl or phenyl group,
      • R6 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom, R6 together with R5 may denote an additional bond,
      • R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together constitute an additional bond, R7 together with RN may also denote a 1,4-butadienylene group,
      • RN denotes a hydrogen atom or a C1-6-alkyl group which may be mono- or disubstituted in the ω-position
        • by a C5-7-cycloalkyl group, by a 1-naphthyl, 2-naphthyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl, alkylaminocarbonyl, acetylamino, cyano, aminocarbonylamino or alkylaminocarbonylamino group or by phenyl, pyridinyl or diazinyl groups, whilst these substituents may be identical or different,
      • a C5-7-cycloalkyl group, a phenyl, pyridinyl, cyano, amino, benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino, N-(aminocarbonylaminocarbonyl)-N-phenylamino, N-(pyridinyl)-N-(aminocarbonyl)amino, N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino, 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl or diazinylamino group,
      • a saturated, mono- or di-unsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza- or S,S-dioxido-thiadiaza-heterocycle.
        • wherein the above-mentioned heterocycles may be linked via a carbon or nitrogen atom and
        • may contain one or two carbonyl groups adjacent to a nitrogen atom,
        • may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl, aroyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
        • may be substituted at one or two carbon atoms by a branched or unbranched alkyl group or by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, wherein the substituents may be the same or different,
        • and wherein a C3-6-alkylene group may additionally be attached to the above-mentioned heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring,
      • or if Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 may also denote the 1,4-butadienylene group,
      • or, if Y1 is a carbon atom, RN together with R5, including Y1, also denotes a carbonyl group or a saturated or monounsaturated 5- or 6-membered 1,3-diaza-heterocycle which may optionally contain one or two carbonyl groups in the ring and, if it is unsaturated, may be benzofused at the double bond and may be substituted at one of the nitrogen atoms by a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
      • whilst the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl- or 1-methylimidazolyl groups contained in the residues mentioned under R5, R7 and RN, as well as benzo, thieno, pyrido- and diazino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluormethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino, benzoylaminocarbonylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group
      • and unless otherwise specified the alkyl groups contained in the above-mentioned radicals may contain 1 to 5 carbon atoms,
  • X denotes an oxygen atom or 2 hydrogen atoms,
  • Z denotes a methylene group or the group —NR1, wherein
      • R1 denotes a hydrogen atom or an alkyl or phenylalkyl group,
  • R11 denotes a hydrogen atom, a C1-3-alkyl group, an alkoxycarbonyl group having a total of 2 to 4 carbon atoms or a phenylmethyl group,
  • n denotes the number 1 or 2 or, if m is 1, n may also be 0,
  • m denotes the number 0 or 1,
  • R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
      • whilst the above-mentioned aromatic and heteroaromatic groups in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched alkyl groups, C3-8-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, and the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group,
  • A denotes a bond or the divalent group of formula
  • Figure US20090163480A1-20090625-C00004
  • (which is linked to the NR3R4 group via the —CX group)
  • wherein
      • R8 and R9 together denote an n-propylene group or
      • R8 denotes a hydrogen atom or an alkyl- or phenylalkyl group and
      • R9 denotes a hydrogen atom or a branched or unbranched C1-5-alkyl group which, if it is unbranched, may be substituted in the ω-position by a hydroxy, mercapto, amino, alkylamino, dialkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, hexahydro-1-azepinyl, methylthio, hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-naphthyl, 2-naphthyl- or pyridinyl group, whilst the above-mentioned heterocycles, phenyl and naphthyl groups may in turn be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, trifluoromethoxy, methylsulphonyloxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different, and wherein the hydroxy, mercapto, amino, guanidino, indolyl and imidazolyl groups contained in the groups mentioned for R9 may be substituted with the protecting groups commonly used in peptide chemistry, preferably with the acetyl, benzyloxycarbonyl or tert.butyloxycarbonyl group,
  • R3 denotes a hydrogen atom,
  • a C1-7-alkyl group which may be substituted in the ω-position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino, 4-alkyl-1-piperazinyl or 4-(ω-hydroxyalkyl)-1-piperazinyl group,
  • a phenyl or pyridinyl group,
      • wherein the above-mentioned heterocyclic groups and phenyl groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, methylsulphonyloxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and the substituents may be identical or different,
  • R4 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a phenyl or pyridinyl group or
  • R3 and R4 together with the enclosed nitrogen atom denote a group of general formula
  • Figure US20090163480A1-20090625-C00005
  • wherein
      • Y3 denotes a carbon atom or, if R12 denotes a free pair of electrons, Y3 may also be the nitrogen atom,
      • r denotes the number 0, 1 or 2,
      • q denotes the number 0, 1 or 2,
      • R10 denotes a hydrogen atom or an amino, alkylamino, dialkylamino, alkyl, cycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino, cycloalkylaminocarbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or carboxy group,
      • a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl- or phenylcarbonyl- group which may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(dialkylamino)alkyl, ω-(dialkylamino)hydroxyalkyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different,
      • a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or 3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, which may be substituted by a phenyl group or fused at the double bond to a benzene, pyridine or diazine ring,
      • a 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl group,
      • a 4- to 10-membered azacycloalkyl group, a 5- to 10-membered oxaza, thiaza- or diazacycloalkyl group or a 6- to 10-membered azabicycloalkyl group,
        • wherein the above-mentioned mono- and bicyclic heterocycles may be bound via a nitrogen or carbon atom and
        • may be substituted by a C1-7-alkyl group, by an alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulphonyl, cycloalkyl- or cycloalkylalkyl group, by a cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group optionally substituted in the ring,
          • whilst the alicyclic parts contained in these substituents may comprise 3 to 10 ring members and the heteroalicyclic parts may comprise 4 to 10 ring members and
          • the above-mentioned phenyl and pyridinyl groups may in turn be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different, or
      • R10 together with R12 and Y3 denotes a 4- to 7-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(alkyl)- group,
        • whilst a hydrogen atom bound to a nitrogen atom within the group R10 may be replaced by a protecting group,
      • R12 denotes a hydrogen atom,
      • a C1-4-alkyl group, wherein an unbranched alkyl group may be substituted in the ω-position by a phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl- or hexahydro-1H-1-azepinyl group,
      • an alkoxycarbonyl, cyano or aminocarbonyl group or a free pair of electrons, if Y3 denotes a nitrogen atom, and
      • R13 and R14 in each case denote a hydrogen atom or,
      • if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom or
      • if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes a partially hydrogenated or aromatic 5- to 7-membered mono- or bicyclic carbocycle or heterocycle,
  • whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 7 carbon atoms, unless otherwise specified,
  • all the above-mentioned cycloalkyl groups and the cycloalkyl groups present within the other groups named may contain 5 to 10 carbon atoms, unless otherwise specified, and
  • the term “aroyl group” used above denotes, for example, the benzoyl or naphthoyl group.
  • The protecting groups mentioned in the foregoing definitions and hereinafter are the protecting groups which are commonly known from peptide chemistry, particularly
  • a phenylalkoxycarbonyl group having 1 to 3 carbon atoms in the alkoxy moiety, optionally substituted in the phenyl nucleus by a halogen atom, by a nitro or phenyl group or by one or two methoxy groups,
      • for example the benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl, 4-nitro-benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-Biphenylyl-α,α-dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-α,α-dimethyl-benzyloxycarbonyl group,
  • an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety,
      • for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl or tert.butyloxycarbonyl group,
  • the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or 9-fluorenylmethoxycarbonyl group or
  • the formyl, acetyl or trifluoroacetyl group.
  • The present invention relates to racemates, where the compounds of general formula I have only one chiral element. However, the application also covers the individual diastereomeric pairs of antipodes or mixtures thereof which occur when there is more than one chiral element in the compounds of general formula (I).
  • Particularly preferred are compounds of general formula I wherein Z denotes NR1 and m assumes the value 0 and which are in the D- or (R)-configuration with regard to the partial amino acid structure of the formula
  • Figure US20090163480A1-20090625-C00006
  • and which are in the L- or (S)-configuration with regard to the partial amino acid structure of formula
  • Figure US20090163480A1-20090625-C00007
  • which may be present in the group A. As for the other compounds covered by general formula I, the preferred isomers are those which are spatially constructed analogously to the (R)-configured partial structure of formula V with regard to the partial structure of formula VI
  • Figure US20090163480A1-20090625-C00008
  • The compounds of general formula I have valuable pharmacological properties based on their selective CGRP-antagonistic properties. The invention further relates to medicaments containing these compounds, their use and the preparation thereof.
  • A subgroup of compounds of general formula I which deserves special mention comprises those wherein
  • A, R2, R3, R4, R11, X, Z and m and n are as hereinbefore defined and
  • R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl- group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
      • by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
  • whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise stated,
  • their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.
  • Another subgroup of compounds of general formula I deserving special mention comprises those wherein
  • R2, R3, R4, R11, X, Z and m and n are defined as for the first subgroup hereinbefore,
  • R denotes an unbranched C1-7-alkyl group which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl- group,
      • by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl- or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl- group, whilst the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight-chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups, and the substituents may be identical or different,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or in addition to a nitrogen atom contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one, two or three nitrogen atoms,
        • whilst a 1,4-butadienylene group may be attached both to the above-mentioned 5-membered and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl- and biphenylyl- groups mentioned hereinbefore for the substitution of the alkyl groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group, and
  • A denotes a single bond,
  • whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms unless otherwise stated,
  • their tautomers, their diastereomers, their enantiomers and the salts thereof.
  • Preferred compounds of the above general formula I are those wherein
  • R denotes an unbranched C1-5-alkyl group which may be substituted in the ω-position
      • by a C4-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
      • by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-positions by lower straight-chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups, and the substituents may be identical or different,
      • by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a 6-membered heteroaromatic ring linked via a carbon atom and containing one or two nitrogen atoms,
        • whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • or an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a C1-3-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
      • by a C4-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxo-imidazo[4,5-b]pyridin-3-yl group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1 or 2 nitrogen atoms, whilst a 1,4-butadienylene group may be attached to both the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl and alkylamino groups in the ω-position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C5-7-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
  • or the group of formula
  • Figure US20090163480A1-20090625-C00009
  • wherein
      • p denotes the number 1 or 2,
      • o denotes the number 2 or, if Y1 and Y2 are not simultaneously nitrogen atoms, o may also denote 1.
      • Y1 denotes the nitrogen atom if R5 is a free pair of electrons, or the carbon atom,
      • Y2 is the nitrogen atom or the group >CH—,
      • R5 is a free pair of electrons if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 denotes a hydrogen atom, a C1-3-alkyl group, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl, aminocarbonylamino, phenylmethyl or phenyl group,
      • R6 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom, R6 together with R5 may denote an additional bond,
      • R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together constitute an additional bond, R7 together with RN may also denote a 1,4-butadienylene group,
      • RN denotes the hydrogen atom or a C1-3-alkyl group, which may be monosubstituted in the ω-position
        • by a C5-7-cycloalkyl group or by a 1-naphthyl, 2-naphthyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl, alkylaminocarbonyl, acetylamino, cyano, aminocarbonylamino or alkylaminocarbonylamino group, or may be mono- or disubstituted by phenyl, pyridinyl or diazinyl groups, whilst these substituents may be identical or different,
      • a cyclohexyl, phenyl, pyridinyl, cyano, amino, benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [N-phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino, N-(aminocarbonylaminocarbonyl)-N-phenylamino, N-(pyridinyl)-N-(aminocarbonyl)amino, N-(pyridinyl)-N-(alkylamino-carbonyl)amino, phenylamino, pyridinylamino, diazinylamino or 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl group,
      • a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza- or S,S-dioxidothiadiaza heterocycle,
        • whilst the above-mentioned heterocycles may be linked via a carbon or nitrogen atom and
        • may contain one or two carbonyl groups adjacent to a nitrogen atom,
        • may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl, aroyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
        • may be substituted at one or two carbon atoms by a branched or unbranched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, whilst the substituents may be identical or different,
        • and wherein a C3-4-alkylene group may additionally be attached to the above-mentioned heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring,
      • or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 may also denote the 1,4-butadienylene group or,
      • if Y1 denotes a carbon atom, RN together with R5, with the inclusion of Y1, may also denote a carbonyl group or a saturated or monounsaturated 5- or 6-membered 1,3-diaza-heterocycle which may contain one or two carbonyl groups in the ring adjacent to a nitrogen atom and, if it is unsaturated, may also be benzo-fused at the double bond and substituted at one of the nitrogen atoms by a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
      • whilst the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups contained in the residues mentioned under R5, R7 and RN, as well as benzo-, thieno-, pyrido- and diazino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C4-7-cycloalkyl groups, nitro, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)-carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluormethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the alkyl groups contained in the above-mentioned groups may contain 1 to 3 carbon atoms unless otherwise specified,
  • X denotes the oxygen atom or 2 hydrogen atoms,
  • Z denotes the methylene group or the group —NR1— wherein
      • R1 denotes a hydrogen atom or a C1-3-alkyl group,
  • R11 denotes a hydrogen atom, a C1-3-alkyl group or an alkoxycarbonyl group having 2 to 4 carbon atoms altogether,
  • n denotes the number 1 or 2 or, if m is 1, n may also be 0,
  • m denotes the number 0 or 1,
  • R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
      • whilst the above-mentioned aromatic and heteroaromatic groups in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, or by branched or unbranched alkyl groups, C4-7-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, and the substituents may be identical or different,
  • A denotes a bond or the divalent group of formula
  • Figure US20090163480A1-20090625-C00010
  • (linked to the R3R4N— group of general formula (I) via the carbonyl group)
  • wherein
      • R8 and R9 together denote an n-propylene group or
      • R8 denotes a hydrogen atom or a C1-3-alkyl group and
      • R9 denotes a hydrogen atom or a branched or unbranched C1-4-alkyl group which, if it is unbranched, may be substituted in the ω-position
        • by a hydroxy, mercapto, amino, alkylamino, dialkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, hexahydro-1-azepinyl, methylthio, hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-naphthyl, 2-naphthyl- or pyridinyl group, whilst the above-mentioned heterocycles and phenyl groups may in turn be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, trifluoromethoxy, methylsulphonyloxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and any hydroxy, mercapto, amino, guanidino, indolyl and imidazolyl groups contained in the groups mentioned for R9 may be substituted by a protecting group,
  • R3 denotes a hydrogen atom,
  • a C1-4-alkyl group which may be substituted in the ω-position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-azepin-1-yl, [bis-(2-hydroxyethyl)]amino, 4-methyl-1-piperazinyl- or 4-(ω-hydroxyalkyl)-1-piperazinyl group,
  • a phenyl or pyridinyl group,
      • wherein the above-mentioned heterocyclic radicals and phenyl groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, methylsulphonyloxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and the substituents may be identical or different,
  • R4 denotes a hydrogen atom or a methyl or ethyl group optionally substituted by a phenyl or pyridinyl group
  • or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula
  • Figure US20090163480A1-20090625-C00011
  • wherein
      • Y3 denotes a carbon atom or, if R12 denotes a free pair of electrons, Y3 may also be the nitrogen atom,
      • r denotes the number 0, 1 or 2,
      • q denotes the number 0, 1 or 2,
      • R10 denotes a hydrogen atom or an amino, alkylamino, dialkylamino, alkyl, cycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino, cycloalkylaminocarbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or carboxy group,
      • a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group which may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(dialkylamino)alkyl, ω-(dialkylamino)hydroxyalkyl, (ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl-oder trifluoromethylsulphonyl groups, whilst the substituents may be identical or different,
      • a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or 3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, which may be substituted by a phenyl group or fused at the double bond to a benzene, pyridine or diazine ring,
      • a 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl group,
      • a 4- to 10-membered azacycloalkyl group, a 5- to 10-membered oxaza, thiaza or diazacycloalkyl group or a 6- to 10-membered azabicycloalkyl group,
        • wherein the above-mentioned mono- and bicyclic heterocycles may be bound via a nitrogen or carbon atom and
        • may be substituted by a C1-7-alkyl group, by an alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulphonyl, cycloalkyl or cycloalkylalkyl group, by a cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group optionally alkyl substituted in the ring,
          • whilst the alicyclic parts contained in these substituents may comprise 3 to 10 ring members and the heteroalicyclic parts may comprise 4 to 10 ring members and
          • the above-mentioned phenyl and pyridinyl groups may in turn be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different, or
      • R10 together with R12 and Y3 denotes a 4- to 7-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(alkyl)- group,
        • whilst a hydrogen atom bound to a nitrogen atom within the group R10 may be replaced by a protecting group,
      • R12 denotes a hydrogen atom, a C1-2-alkyl group which may be substituted in the ω-position by a phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl or hexahydro-1H-azepin-1-yl- group,
      • an alkoxycarbonyl, cyano- or aminocarbonyl group or a free pair of electrons, if Y3 denotes a nitrogen atom, and
      • R13 and R14 in each case denote a hydrogen atom or,
      • if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom or
      • if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes a partially hydrogenated or aromatic 5- to 7-membered mono- or bicyclic carbocycle or heterocycle,
  • whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise specified,
  • all the above-mentioned cycloalkyl groups and the cycloalkyl groups present within the other groups named may contain 5 to 7 carbon atoms, unless otherwise specified, and
  • the term “aroyl group” used above denotes, for example, the benzoyl or naphthoyl group;
  • their tautomers, their diastereomers, their enantiomers and their salts.
  • One subgroup of preferred compounds of general formula I deserving special mention comprises those wherein
  • A, R2, R3, R4, R11, X, Z and m and n are defined as given hereinbefore defined for the preferred compounds of general formula I,
  • R denotes an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a C1-3-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
      • by a C4-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxo-imidazo[4,5-b]pyridin-3-yl group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, and containing a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1 or 2 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C5-7-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
  • whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise stated,
  • their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.
  • Another subgroup of compounds of general formula I deserving special mention comprises those wherein
  • R2, R3, R4, R11, X, Z and m and n are defined as for the first preferred subgroup hereinbefore,
  • R denotes an unbranched C1-5-alkyl group which may be substituted in the ω-position
      • by a C4-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
      • by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight-chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups, and the substituents may be identical or different,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or in addition to a nitrogen atom contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one or two nitrogen atoms,
        • whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkyl groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C5-7-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group, and
  • A denotes a single bond,
  • whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms unless otherwise stated,
  • their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.
  • Preferred compounds of the above general formula I are those wherein
  • R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
      • by a C5-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
      • by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may be substituted in the carbon skeleton by a phenyl, pyridinyl or diazinyl group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, wherein a nitrogen of an imino group may be substituted by an alkyl group,
      • or may be substituted by a pyridinyl group,
        • whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and to the pyridinyl group, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • or an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a methyl or ethyl group, which may be substituted in the ω-position
      • by a C5-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2(1H)-oxoquinolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a pyridinyl group,
        • whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and to the pyridinyl group, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkyl and alkylamino groups in the ω-position as well as optionally partially hydrogenated mono- and bicyclic heteroaromatic rings may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups, whilst the substituents may be the same or different,
  • or the group of formula
  • Figure US20090163480A1-20090625-C00012
  • wherein
      • p denotes the number 1 or 2,
      • o denotes the number 2 or, if Y1 and Y2 are not simultaneously nitrogen atoms, it may also denote the number 1,
      • Y3 denotes the nitrogen atom if R5 denotes a free pair of electrons, or the carbon atom,
      • Y2 denotes the nitrogen atom or the group >CH—,
      • R5 denotes a free pair of electrons if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 denotes a hydrogen atom, a C1-3-alkyl group, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl or aminocarbonylamino group or a phenylmethyl or phenyl group optionally substituted at the aromatic moiety by a fluorine, chlorine or bromine atom or by a methyl, methoxy, ethoxy, trifluoromethyl, hydroxy, amino or acetylamino group,
      • R6 denotes the hydrogen atom or, if Y1 is not a nitrogen atom, R6 together with R5 may also denote an additional bond,
      • R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, R7 together with RN may also denote the 1,4-butadienylene group,
      • RN denotes the hydrogen atom or a C1-3-alkyl group, which may be monosubstituted in the ω-position
        • by a C5-7-cycloalkyl group or by a 1-naphthyl, 2-naphthyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl, methylaminocarbonyl, acetylamino, cyano, aminocarbonylamino or alkylaminocarbonylamino group, or may be mono- or disubstituted by phenyl, pyridinyl or diazinyl groups, whilst these substituents may be identical or different,
      • a cyclohexyl, phenyl, pyridinyl, cyano, amino, benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [N-phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino, N-(aminocarbonylaminocarbonyl)-N-phenylamino, N-(pyridinyl)-N-(aminocarbonyl)amino, N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino, diazinylamino or 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl group,
      • a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S,S-dioxidothiadiaza heterocycle,
        • whilst the above-mentioned heterocycles may be linked via a carbon or nitrogen atom and
        • may contain one or two carbonyl groups adjacent to a nitrogen atom,
        • may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
        • may be substituted at one or two carbon atoms by a methyl, phenyl, phenylmethyl, naphthyl, biphenylyl, thienyl, pyridinyl or diazinyl group, wherein the substituents may be identical or different,
          • and wherein a C3-4-alkylene group may additionally be attached to the above-mentioned heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the above-mentioned heterocycles may be fused to a thiophene, benzene, pyridine, quinoline or diazine ring,
      • or, if Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 may also denote a 1,4-butadienylene group or,
      • if Y1 denotes a carbon atom, RN together with R5 with the inclusion of Y1 may also denote a carbonyl group or a saturated or monounsaturated 5- or 6-membered 1,3-diaza-heterocycle which may contain one or two carbonyl groups in the ring adjacent to a nitrogen atom and, if it is unsaturated, may also be benzo-fused at the double bond and may be substituted at one of the nitrogen atoms by a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
        • whilst the phenyl, pyridinyl or diazinyl groups contained in the groups mentioned under RN and the thieno-, benzo-, pyrido- or diazino-condensed heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by methyl groups, nitro, methoxy, ethoxy, methylsulphonylamino, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)-carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, methylaminocarbonylamino, acetyl, cyano or trifluoromethoxy groups, whilst the substituents may be identical or different,
        • and the alkyl groups contained in the above-mentioned radicals may contain 1 to 3 carbon atoms, unless otherwise specified,
  • X denotes an oxygen atom or 2 hydrogen atoms,
  • Z denotes a methylene group or the group —NR1— wherein
      • R1 is a hydrogen atom or a methyl group,
  • R11 denotes the hydrogen atom or a methyl or methoxycarbonyl group,
  • n denotes the number 1 or 2 or, if m is the number 1, n may also denote 0,
  • m denotes the number 0 or 1,
  • R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, pyridinyl or quinolinyl group,
      • wherein the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by branched or unbranched C1-5-alkyl groups, allyl, vinyl, methoxy, ethoxy, propoxy, 1-methylethoxy, dimethylaminoethoxy, trifluoromethyl, hydroxy, nitro, amino, acetylamino, propionylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetyl, cyano, methylsulphonyloxy or trifluoromethoxy groups, by tetrazolyl, phenyl pyridinyl, thiazolyl or furyl groups and the substituents may be identical or different, or
  • A denotes a bond or the divalent group of formula
  • Figure US20090163480A1-20090625-C00013
  • (linked to the NR3R4— group of general formula (I) via the carbonyl group)
  • wherein
      • R8 and R9 together denote an n-propylene group or
      • R8 denotes the hydrogen atom or the methyl group and
      • R9 denotes a hydrogen atom or an unbranched C1-4-alkyl group which may be substituted in the ω-position
        • by a hydroxy, amino, methylamino, dimethylamino, hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl or pyridinyl group, wherein the phenyl and pyridinyl group may in turn be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl or cyano group and wherein any hydroxy, amino and guanidino groups contained in the groups given for R9 may be substituted by a protecting group, e.g. the phenylmethoxycarbonyl or tert.butyloxycarbonyl group,
  • R3 denotes a hydrogen atom,
  • a C1-4-alkyl group optionally substituted in the ω-position by a cyclohexyl, phenyl, pyridinyl, hydroxy, amino, methylamino, dimethylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-(1-piperidinyl)-1-piperidinyl group,
  • a phenyl or pyridinyl group,
      • whilst the above-mentioned phenyl and pyridinyl groups may additionally be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl or cyano group,
  • R4 denotes the hydrogen atom or a C1-2-alkyl group optionally substituted by a phenyl or pyridinyl group
  • or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula
  • Figure US20090163480A1-20090625-C00014
  • wherein
      • Y3 denotes a carbon atom or, if R12 denotes a free pair of electrons, Y3 may also be a nitrogen atom,
      • r denotes the number 0, 1 or 2,
      • q denotes the number 0, 1 or 2,
        • with the proviso that the sum of the numbers given for r and q is 0, 1, 2 or 3,
      • R10 denotes a hydrogen atom, an alkyl, cycloalkyl, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonylamino, alkoxycarbonyl, alkoxycarbonylmethyl, carboxymethyl or carboxy group,
      • a phenyl, pyridinyl, diazinyl, pyridinylcarbonyl or phenylcarbonyl group which may be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by methyl, ethyl, propyl, methoxy, hydroxy, ω-(dialkylamino)-alkyl, ω-(dialkylamino)hydroxyalkyl or alkanoyl groups, whilst the substituents may be identical or different,
      • a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or 3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, which may be substituted by a phenyl group or may be fused at the double bond to a benzene, pyridine or diazine ring,
      • a 5- to 7-membered azacycloalkyl group, a 4- to 7-membered oxaza- or diazacycloalkyl group or a 7- to 9-membered azabicycloalkyl group,
        • wherein the above-mentioned mono- and bicyclic heterocycles are bound via a nitrogen or a carbon atom and
        • may be substituted by a C1-7-alkyl group, or by an alkanoyl, dialkylamino, phenylcarbonyl, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety, alkylsulphonyl, cycloalkyl or cycloalkylalkyl group or by an azacycloalkylcarbonyl or diazacycloalkylcarbonyl group optionally alkyl-substituted in the ring,
          • whilst the alicyclic groups contained in these substituents may comprise 3 to 7 ring members and the heteroalicyclic groups may comprise 4 to 7 ring members and
          • the above-mentioned phenylcarbonyl group may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino or acetylamino group, or
      • R10 together with R12 and Y3 denotes a 4- to 6-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(CH3)— group,
        • whilst a hydrogen atom bound to a nitrogen atom within the group R10 may be replaced by a protecting group, e.g. the phenylmethoxycarbonyl or tert.butyloxycarbonyl group,
      • R12 denotes a hydrogen atom, a C1-2-alkyl group which may be substituted in the ω-position by a phenyl, pyridinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-methyl-1-piperazinyl group,
      • a methoxycarbonyl or ethoxycarbonyl, cyano or aminocarbonyl group or a free pair of electrons, if Y3 denotes a nitrogen atom, and
      • R13 and R14 each denote a hydrogen atom or,
      • if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom, or
      • if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes a partially hydrogenated or aromatic 5- or 6-membered mono- or bicyclic carbocycle or heterocycle, containing one or two nitrogen atoms,
  • whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups named may contain 1 to 3 carbon atoms, unless otherwise stated, and
  • all the above-mentioned cycloalkyl groups and the cycloalkyl groups present within the other groups named may contain 5 to 7 carbon atoms, unless otherwise specified,
  • their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.
  • One subgroup of particularly preferred compounds of general formula I deserving special mention comprises those wherein
  • A, R2, R3, R4, R11, X, Z and m and n are defined as for the particularly preferred compounds of general formula I hereinbefore and
  • R denotes an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a methyl or ethyl group, which may be substituted in the ω-position
      • by a C5-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2(1H)-oxoquinolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a pyridinyl group,
        • whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and also to the pyridinyl group, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkylamino groups in the ω-position, as well as optionally any partially hydrogenated mono- and bicyclic heteroaromatic rings, may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups, whilst the substituents may be identical or different,
  • whilst all the above-mentioned alkyl and alkoxy groups and the alkoxy groups present within the other named radicals may contain 1 to 3 carbon atoms unless otherwise stated,
  • their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.
  • Another subgroup of particularly preferred compounds of general formula I which deserves special mention comprises those compounds wherein
  • R2, R3, R4, R11, X, Z and m and n are as hereinbefore defined for the first-mentioned particularly preferred subgroup,
  • R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
      • by a C5-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
      • by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may be substituted in the carbon skeleton by a phenyl, pyridinyl or diazinyl group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, wherein a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a pyridinyl group,
        • whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and also to the pyridinyl group via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkyl groups in the ω-position as well as optionally any partially hydrogenated mono- and bicyclic heteroaromatic rings may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups wherein the substituents may be identical or different,
  • and A denotes a single bond,
  • whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 3 carbon atoms unless otherwise specified,
  • their tautomers, their diastereomers, their enantiomers and their salts.
  • More particularly preferred compounds of the above general formula I are those wherein
  • R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
      • by a C5-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group, whilst the above-mentioned aromatic groups may additionally be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, amino or acetylamino group,
      • by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl or isoquinolinyl group,
  • or an unbranched C1-4-alkylamino group which is optionally additionally substituted at the nitrogen atom by a methyl or ethyl group and which may be substituted in the ω-position
      • by a C5-7-cycloalkyl group,
      • by a phenyl group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms, or by methyl, nitro, methoxy, trifluoromethyl, hydroxy, amino or acetylamino groups, whilst the substituents may be identical or different,
      • by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl or isoquinolinyl group,
  • or the group of formula
  • Figure US20090163480A1-20090625-C00015
  • wherein
      • p denotes the number 1 or 2,
      • o denotes the number 2 or, if Y1 and Y2 are not simultaneously nitrogen atoms, it may also denote the number 1,
      • Y1 denotes the nitrogen atom if R5 denotes a free pair of electrons, or the carbon atom,
      • Y2 denotes the nitrogen atom or the group >CH—,
      • R5 denotes a free pair of electrons, if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 may denote the hydrogen atom, a C1-2-alkyl group or the cyano or phenyl group,
      • R6 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom, R6 together with R5 may also denote an additional bond,
      • R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, R7 together with RN may also denote the 1,4-butadienylene group,
      • RN denotes the hydrogen atom or a C1-3-alkyl group, which may be substituted in the ω-position
        • by one or two phenyl or pyridinyl groups, wherein the substituents may be identical or different,
        • or by a hydroxy or methoxy group,
      • a phenyl group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl groups, nitro, methoxy, ethoxy, trifluoromethyl, hydroxy or cyano groups, whilst the substituents may be identical or different, or a phenyl group substituted by a methylenedioxy group,
      • a 2-pyridinyl or 4-pyridinyl group,
      • an amino, benzoylamino, aminocarbonyl, methylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonylamino, methylaminocarbonylamino, N-(aminocarbonyl)-N-methylamino, N-(methylaminocarbonyl)-N-methylamino, N-(aminocarbonyl)-N-(4-fluorophenyl)amino, N-(methyl-aminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [N-phenyl(methylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-methylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino group or a phenylamino group optionally substituted in the phenyl ring by an aminocarbonylamino or methylsulphonylamino group,
      • a 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, a 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl, 1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl, 1H-indol-3-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl, 1,3(2H)-dioxo-1H-isoindol-2-yl, 1H-benzimidazol-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 2(3H)-oxobenzoxazol-3-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-d]pyrimidin-3-yl, 2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[2,3-d]pyrimidin-3-yl, 2(1H)-oxoquinolin-3-yl, 3,4-dihydro-2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinazolin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 2,4(1H,3H)-dioxothieno[3,4-d]-pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl, 1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl, 2,5-dioxo-4-phenylmidazolidin-1-yl, 2,5-dioxo-4-(phenylmethyl)-imidazolidin-1-yl, 3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl, 1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl, 1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl, 1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 4-phenyl-2(1H)-oxopyrimidin-1-yl, 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2-[1H]-oxopyrido[4,3-d]pyrimidin-3-yl or 2,3-dihydro-4(1H)-oxoquinazolin-3-yl group,
        • wherein the above-mentioned mono- and bicyclic heterocycles may be substituted at one of the nitrogen atoms by a methoxycarbonylmethyl group and/or
        • the above-mentioned mono- and bicyclic heterocycles may be mono-, di- or trisubstituted in the carbon skeleton and/or at the phenyl groups contained in these groups by fluorine, chlorine or bromine atoms, or by methyl, trifluoromethyl, methoxy, hydroxy, amino, nitro, phenyl, phenylmethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (1-piperidinyl)carbonyl or (4-methyl-1-piperazinyl)carbonyl groups wherein the substituents may be identical or different and multiple substitution with the last three substituents is ruled out,
      • or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 also denotes the 1,4-butadienylene group,
      • or, provided that Y1 denotes a carbon atom, RN together with R5 with the inclusion of Y1 may also denote a carbonyl group or saturated or monounsaturated five- or six-membered 1,3-diaza-heterocycle,
        • which may contain a carbonyl group in the ring, adjacent to a nitrogen atom,
        • may be substituted by a phenyl group at one of the nitrogen atoms
        • and, if it is unsaturated, may also be benzo-condensed at the double bond,
  • X denotes an oxygen atom or 2 hydrogen atoms,
  • Z denotes a methylene group or the group —NR1, wherein
      • R1 denotes a hydrogen atom or a methyl group,
  • R11 denotes a hydrogen atom, a methoxycarbonyl, ethoxycarbonyl or methyl group,
  • n denotes the number 1 and m denotes the number 0 or
  • n denotes the number 0 and m denotes the number 1,
  • R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 2-thienyl, 3-thienyl, thiazolyl or alkylthiazolyl group having 1 to 3 carbon atoms in the alkyl moiety, a pyridinyl or quinolinyl group,
      • wherein the above-mentioned phenyl and naphthyl groups may be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched C1-5-alkyl groups, by C1-3-alkoxy groups, by vinyl, allyl, trifluoromethyl, methylsulphonyloxy, 2-(dimethylamino)ethoxy, hydroxy, cyano, nitro or amino groups, by tetrazolyl, phenyl, pyridinyl, thiazolyl or furyl groups and the substituents may be identical or different, and multiple substitution with the last five substituents is ruled out,
  • A denotes a bond or the divalent group of formula
  • Figure US20090163480A1-20090625-C00016
  • (linked to the group —NR3R4 of formula (I) via the carbonyl group)
  • wherein
      • R8 and R9 together denote an n-propylene group or
      • R8 denotes the hydrogen atom or the methyl group and
      • R9 denotes the hydrogen atom or an unbranched C1-4-alkyl group,
      • which may be substituted in the ω-position by an amino, methylamino, dimethylamino, aminoiminomethylamino or aminocarbonylamino group, whilst in the above-mentioned substituents a hydrogen atom bound to a nitrogen atom may be replaced by a protecting group, e.g. the phenylmethoxycarbonyl or tert.butyloxycarbonyl group,
  • R3 denotes a hydrogen atom or
  • a C1-4-alkyl group optionally substituted in the ω-position by an amino, methylamino, dimethylamino- or 4-(1-piperidinyl)-1-piperidinyl group,
  • R4 denotes a hydrogen atom or a methyl or ethyl group
  • or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula
  • Figure US20090163480A1-20090625-C00017
  • wherein
      • Y3 denotes the carbon atom or, if R12 denotes a free pair of electrons, Y3 may also denote a nitrogen atom,
      • r denotes the number 1,
      • q denotes the number 1,
      • R10 denotes the hydrogen atom, an alkyl, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonylamino, alkoxycarbonyl, alkoxycarbonylmethyl, carboxymethyl or carboxy group or a cycloalkyl group having 4 to 7 carbon atoms in the ring,
      • a benzoyl, pyridinylcarbonyl, phenyl, pyridinyl or diazinyl group, each of which may be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom, or by an acetyl, methyl, ethyl or methoxy group, or by a dimethylaminoalkyl group having 1 to 4 carbon atoms in the alkyl moiety optionally hydroxysubstituted in the alkyl moiety,
      • a 1,3-dihydro-2-oxo-2H-imidazolyl group bound via a nitrogen atom, which may be fused to a benzene or pyridine ring at the double bond,
      • a 1-pyrrolidinyl, 1-piperidinyl, 4-(dimethylamino)-1-piperidinyl, 4-piperidinyl or 4-morpholinyl group, wherein the nitrogen atom of the 4-piperidinyl group may be substituted by an alkanoyl- or alkyl group each having 1 to 7 carbon atoms or by a benzoyl, methylsulphonyl, 3-carboxy-propionyl, cyclopropylmethyl, alkoxycarbonylmethyl or carboxymethyl group or by a protecting group, e.g. the phenylmethoxycarbonyl or tert.butyloxycarbonyl group, or it may represent a hexahydro-1H-1-azepinyl, 8-methyl-8-azabicyclo[3,2,1]oct-3-yl, 4-alkyl-1-piperazinyl, hexahydro-4-alkyl-1H-1,4-diazepin-1-yl, 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group,
      • or
      • R10 together with R12 and Y3 denotes a 5-membered cycloaliphatic ring in which a methylene group may be replaced
      • by an —NH— or —N(CH3)— group,
      • R12 denotes a hydrogen atom, a C1-2-alkyl group which may be substituted in the ω-position by a 1-pyrrolidinyl, 1-piperidinyl or 4-methyl-1-piperazinyl group,
      • a methoxycarbonyl or ethoxycarbonyl or a cyano group,
      • a free pair of electrons if Y3 denotes a nitrogen atom, and
      • R13 and R14 each denote a hydrogen atom or,
      • provided that Y3 is a carbon atom, R12 together with R14 may also denote an additional carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom or,
      • provided that Y3 is a carbon atom, R12 together with R14 may also denote an additional carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes an indole group fused on via the 5-membered ring,
  • whilst all the above-mentioned alkyl groups and the alkyl groups present within the other named groups may contain 1 to 3 carbon atoms, unless otherwise specified,
  • their tautomers, their diastereomers, their enantiomers and their salts.
  • A subgroup of most particularly preferred compounds of general formula I deserving special mention comprises those wherein
  • A, R2, R3, R4, R11, X, Z and m and n are as hereinbefore defined for the most particularly preferred compounds of general formula I and
  • R denotes an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a methyl or ethyl group, which may be substituted in the ω-position
      • by a C5-7-cycloalkyl group,
      • by a phenyl group, which may be mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl, nitro, methoxy, trifluoromethyl, hydroxy, amino or acetylamino groups, wherein the substituents may be identical or different, or
      • by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl or isoquinolinyl group,
  • their tautomers, their diastereomers, their enantiomers, mixtures thereof and salts thereof.
  • Another subgroup of most particularly preferred compounds of general formula I deserving special mention comprises those wherein
  • R2, R3, R4, R11, X, Z and m and n are as defined hereinbefore for the first-mentioned particularly preferred subgroup,
  • R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
      • by a C5-7-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group, whilst the above-mentioned aromatic groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, amino or acetylamino group,
      • or by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl- or isoquinolinyl group,
  • and A denotes a single bond,
  • their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.
  • The following are mentioned as examples of most particularly preferred compounds:
    • (1) 1-[N2-[N-[[[2-(2-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (2) 1-[N2-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (3) 1-[N2-[N-[[[2-(2,5-Dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (4) 1-[N2-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-arginyl]-4-(4-pyridinyl)-piperazine
    • (5) 1-[N2-[N-[[[2-(2,3-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (6) 1-[N2-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (7) 1-[N2-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(4-piperidinyl)-piperazine
    • (8) 1-[N2-[N-[[[2-(3,4-dihydroxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine
    • (9) 1-[N2-[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (10) 1-[N2-[N-[4-(3-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (11) 1-[N2-[N-[[(2-Phenylethyl)amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (12) 1-[N2-[N-[[[2-(4-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (13) 1-[N2-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3-(1-naphthyl)-D-alanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (14) 1-[N2-[N-[[[2-(3-Hydroxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (15) 1-[N2-[N-[3-(3-Methoxyphenyl)-1-oxopropyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (16) 1-[N2-[N-[[[2-(3-Methoxyphenyl)ethyl]methylamino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (17) 1-[N2-[N-(4-Phenyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (18) 1-[N2-[N-[4-(2-Methylphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (19) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (20) 1-[N2-[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dichloro-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine
    • (21) 1-[N2-[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidin
    • (22) 1-[N2-[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (23) 1-[N2-[N-(4-Phenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (24) 1-[N2-[N-[4-(4-Fluorophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (25) 1-[N2-[N-[4,4-Diphenyl-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (26) 1-[N2-[N-[4-Cyclohexyl-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (27) 1-[N2-[N-[4-(4-Acetylaminophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (28) 1-[N2-[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dichloro-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine
    • (29) 1-[N2-[N-[4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl]-carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine
    • (30) 1-[N2-[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (31) 1-[N2-[N-[4-(3,4-Methylenedioxyphenyl)-1-piperazinyl]-carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (32) 1-[N2-[N-(4-Methyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (33) 1-[N2-[N-[4-(2-Hydroxyethyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (34) 1-[N2-[N-[4-(4-Pyridinyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (35) 1-[N2-[N-[4-(2-Pyridinyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (36) 1-[N2-[N-[4-(Diphenylmethyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (37) 1-[N2-[N-[4-(Phenylmethyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (38) 1-[N2-[N-[4-(4-Nitrophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (39) 1-[N2-[N-[4-(Ethoxycarbonyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (40) 1-[N2-[N-[[[3-(2-Methoxyphenyl)propyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (41) 1-[N2-[N-[[[2-(3-Bromophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (42) 1-[N2-[N-[[[2-(3-Nitrophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (43) 1-[N2-[N-[[[2-(3-Acetylaminophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (44) 1-[N2-[N-[[[2-(3-Bromophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (45) 1-[N2-[N-[(1,2,4,5-Tetrahydro-3H-3-benzazepin-3-yl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (46) 1-[N2-[N-[[[2-[3-(Trifluoromethyl)phenyl]ethyl]amino]-carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (47) 1-[N2-[N-[[[2-(3-Fluorophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (48) 1-[N2-[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-fluorophenyl)-piperazine
    • (49) 1-[N2-[4-Amino-3,5-dibromo-N-[[(2-phenylethyl)amino]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (50) 1-[N2-[N-[4-(2-Methoxyphenyl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (51) 1-[N2-[N-[4-(3-Methoxyphenyl)-1,2,5,6-tetrahydro-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (52) 1-[N2-[N-[4-(2-Methoxyphenyl)-1,2,5,6-tetrahydro-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (53) 1-[N2-[N-[(4-Biphenylyl)acetyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (54) 1-[N2-[N-[4-(4-Bromophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (55) 1-[N2-[N-[4-(1H-Indol-3-yl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (56) 1-[N2-[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (57) 1-[N2-[N-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (58) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (59) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (60) 1-[N2-[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (61) 1-[N2-[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (62) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(2-pyridinyl)-piperazine
    • (63) 1-[N2-[N-[[[2-(2-Cyclohexyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (64) 1-[N2-[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (65) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (66) 1-[N2-[N-[4-(Aminocarbonyl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (67) 1-[N2-[N-[[[2-(1H-Indol-3-yl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (68) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-methoxyphenyl)-piperazine
    • (69) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-pyridinyl)-piperazine
    • (70) 1-[N2-[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-methoxyphenyl)-piperazine
    • (71) 1-[N2-[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-pyridinyl)-piperazine
    • (72) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D,L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (73) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D,L-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (74) 1-[N2-[N-[4-(2,3-Dichlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (75) 1-[N2-[N-[4-(3,5-Dichlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (76) 1-[N2-[N-[4-(2-Cyanphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (77) 1-[N2-[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D,L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (78) 1-[N2-[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D,L-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (79) 1-[N2-[N-[4-[4-Chloro-3-(trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (80) 1-[N2-[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (81) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (82) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (83) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (84) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-[1-(1-methylethyl)-4-piperidinyl]-piperidine
    • (85) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-phenylpiperazine
    • (86) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-6-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (87) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-5-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (88) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-5,6-dichloro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (89) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-3-(methoxycarbonylmethyl)-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (90) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine
    • (91) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (92) 1-[4-Amino-3,5-dibromo-N-[[4-(benzoylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (93) 1-[4-Amino-3,5-dibromo-N-[[4-(aminocarbonyl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (94) 1-[4-Amino-3,5-dibromo-N-[(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (95) 1-[3,5-Dibromo-N-[[4-(benzoylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (96) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-6-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (97) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (98) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosinamide
    • (99) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-methylpiperazine
    • (100) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)piperazine
    • (101) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-phenylpiperazine
    • (102) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N,N-diethyl-D-tyrosinamide
    • (103) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-[(4-(dimethylamino)butyl]-D-tyrosinamide
    • (104) 1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (105) 1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (106) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]piperazine
    • (107) 1-[4-Amino-3,5-dibromo-N-[(4-cyan-4-phenyl-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (108) 1-[3,5-Dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]dec-8-yl)carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (109) 1-[3,5-Dibromo-N-[(4-cyan-4-phenyl-1-piperidinyl)carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (110) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine
    • (111) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyrimidinyl)-piperazine
    • (112) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-pyridinyl)-piperazine
    • (113) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4(pyrazinyl)-piperazine
    • (114) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine
    • (115) 1-[3,5-Dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]dec-8-yl)carbonyl]-D-tyrosyl]-4-(2-pyridinyl)-piperazine
    • (116) 1-[4-Amino-3,5-dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (117) 1-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (118) 1-[3,5-Dibromo-N-[[4-(aminocarbonyl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (119) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(pyrazinyl)-piperazine
    • (120) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-pyrimidinyl)-piperazine
    • (121) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxo-imidazo-[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (122) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (123) cis-1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-cyclohexyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (124) trans-1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-cyclohexyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (125) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (126) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (127) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (128) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine
    • (129) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(pyrazinyl)-piperazine
    • (130) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-methoxyphenyl)-piperazine
    • (131) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(2-methoxyphenyl)-piperazine
    • (132) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine
    • (133) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-methoxyphenyl)-piperazine
    • (134) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (135) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (136) 1-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (137) 1-[4-Amino-N-[[4-(1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (138) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3(2H)-dioxo-1H-isoindol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (139) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (140) 1-[N2-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (141) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (142) 1-[N2-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (143) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (144) 1-[3,5-Dibromo-N-[(4′(3′H)-oxospiro[piperidine-4,2′(1′H)-quinazolin]-1-yl)carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (145) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo-[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (146) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-3-(4-pyridinyl)alanyl]-4-(4-pyridinyl)-piperazine
    • (147) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (148) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (149) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (150) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-(methoxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (151) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (152) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (153) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (154) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (155) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperazine
    • (156) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-fluorophenyl)-piperazine
    • (157) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-fluorophenyl)-piperazine
    • (158) 1-[4-Amino-3,5-dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (159) 1-[4-Amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (160) 1-[3,5-Dibromo-N-[[4-(aminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (161) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyrimidinyl)-piperazine
    • (162) 1-[3,5-Dibromo-N-[[4-[2(3H)-oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (163) 1-[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (164) 1-[4-Amino-3,5-dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (165) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyrimidinyl)-piperazine
    • (166) 1-[3,5-Dibromo-N-[[4-(methylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (167) 1-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)-methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (168) 1-[N2-[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (169) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(3-pyridinyl)-piperazine
    • (170) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(3-pyridinyl)-piperazine
    • (171) 1-[3,5-Dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (172) 1-[3,5-Dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (173) 1-[2,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (174) 1-[2,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (175) 1-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (176) 1-[N2-[3,5-Dibromo-N-[[4-(methylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (177) 1-[N2-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (178) 1-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)-methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (179) 1-[N2-[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (180) 1-[N2-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (181) 1-[N2-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (182) 1-[N2-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)amino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (183) 1-[N2-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (184) 1-[N2-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (185) 1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (186) 1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]-carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (187) 1-[N-[[4-(N-(Aminocarbonyl)phenylamino]-1-piperidinyl]-carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (188) 1-[N2-[N-[[4-[2(3H)-oxobenzoxazol-3-yl]-1-piperidinyl]-carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (189) 1-[4-Amino-3,5-dibromo-N-[[4-(1H-indol-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (190) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (191) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (192) 1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]-carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (193) 1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-phenylpiperazine
    • (194) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-cyclohexyl-4-piperidinyl)-piperazine
    • (195) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine
    • (196) 1-[N2-[N-[[4-(2-Cyanophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine
    • (197) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    • (198) 1-[N2-[N-[[4-(2-Cyanophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    • (199) 1-[3,5-Dichloro-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (200) 1-[3,5-Dichloro-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (201) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (202) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-morpholinyl)-piperidine
    • (203) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(ethoxycarbonyl)-piperidine
    • (204) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(dimethylamino)-piperidine
    • (205) 1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (206) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-pyrrolidinyl)-piperidine
    • (207) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(methoxycarbonyl)-4-phenylpiperidine
    • (208) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (209) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine
    • (210) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine
    • (211) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hydroxycarbonyl)-piperidine
    • (212) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (213) 1-[N2-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    • (214) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperazine
    • (215) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-piperidine
    • (216) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-piperidine
    • (217) 1-[N2-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (218) 1-[N2-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (219) (R)-1-[2-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methylamino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine
    • (220) (R)-1-[2-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]amino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine
    • (221) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (222) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-[(2-[4-(1-piperidinyl)-1-piperidinyl]ethyl]-D-tyrosinamide
    • (223) 1-[3,5-Dibromo-N-[[4-[5-[(4-morpholinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (224) 1-[3,5-Dibromo-N-[[4-[5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]-carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (225) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (226) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (227) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (228) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (229) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo-[4,5-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (230) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (231) 1-[4-Amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (232) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    • (233) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (234) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (235) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1′-piperidinyl)-piperidine
    • (236) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (237) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    • (238) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (239) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (240) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (241) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (242) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (243) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (244) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (245) (R)-1-[2-[N-[[4-(3,4-dihydro-2(1H)-oxopyrido[2,3-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]amino]-3-(4-amino-3,5-dibromophenyl)-propyl]-4-(1-piperidinyl)-piperidine
    • (246) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(1,3-dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (247) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (248) 1-[N2-[3,5-Dibromo-N-[[4-[2(3H)-oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (249) 1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]-carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-4-[(1-piperidinyl)methyl]-piperidine
    • (250) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (251) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (252) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (253) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (254) 1-[N2-[3,5-Dibromo-N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (255) 1-[N2-[3,5-Dibromo-N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (256) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (257) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-glycyl]-4-(4-pyridinyl)-piperazine
    • (258) 1-[4-Amino-3,5-dibromo-N-[[4-(benzoylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (259) 1-[4-Amino-3,5-dibromo-N-[[4-(benzoylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (260) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-β-alanyl]-4-(4-pyridinyl)-piperazine
    • (261) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N-methylglycyl]-4-(4-pyridinyl)-piperazine
    • (262) 1-[4-Amino-3,5-dibromo-N-[[4-[N-(phenylaminocarbonyl)-phenylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (263) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-[3-(2-thienyl)-D-alanyl]-4-(1-piperidinyl)-piperidine
    • (264) 4-Amino-3,5-dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methyl-N-[3-(4-methyl-1-piperazinyl)propyl]-D-phenylalaninamide
    • (265) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-glycyl]-4-(1-piperidinyl)-piperidine
    • (266) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-alanyl]-4-(4-pyridinyl)-piperazine
    • (267) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-[N-(methylaminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine
    • (268) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-alanyl]-4-(1-piperidinyl)-piperidine
    • (269) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)piperidine
    • (270) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (271) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-[N-(methylaminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    • (272) 1-[N2-[[4-(1,3-Dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-1-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-piperidinyl)-piperidine
    • (273) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N-methylglycyl]-4-(1-piperidinyl)-piperidine
    • (274) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinoxalin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (275) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinoxalin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (276) 1-[4-Amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-(4-fluorophenyl)amino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (277) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (278) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (279) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-dimethylamino)propyl]-piperidine
    • (280) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (281) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tryptyl]-4-(1-piperidinyl)-piperidine
    • (282) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (283) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    • (284) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (285) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperidine
    • (286) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-[2-(4-methyl-1-piperazinyl)ethyl]-D-tyrosinamide
    • (287) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (288) 1-[3,5-Dibromo-N-[[4-(7,9-dihydro-6,8-dioxo-1H-purin-9-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (289) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (290) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperidine
    • (291) (R,S)-1-[2-(4-Amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(4-pyridinyl)-piperidine
    • (292) (R)-1-[3-(3,5-Dibromo-4-hydroxyphenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    • (293) 1-[N6-Acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (294) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (295) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (296) (R,S)-1-[2-(4-Amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine
    • (297) (R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    • (298) (R)-1-[3-(4-Amino-3-bromophenyl)-2-[N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    • (299) (R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    • (300) (R)-1-[3-(4-Amino-3-bromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    • (301) (R)-1-[3-(3,5-Dibromo-4-hydroxyphenyl)-2-[N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    • (302) (R,S)-1-[2-(4-Amino-3,5-dibromobenzoyl)-4-[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine
    • (303) 1-[4-Amino-N-[[4-[2-(aminocarbonylamino)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (304) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (305) 1-[4-Amino-N-[[4-[2-(methylsulphonylamino)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (306) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (307) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (308) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (309) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (310) 1-[4-Amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (311) 1-[4-Amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (312) 1-[4-Amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (313) 1-[4-Amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (314) 1-[4-Amino-3,5-dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (315) 1-[4-Amino-3,5-dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (316) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (317) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine
    • (318) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperazine (319) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-fluorophenyl)-piperazine
    • (320) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-fluorophenyl)-piperazine
    • (321) 1-[3,5-Dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (322) trans-1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-cyclohexyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (323) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-6,7-dimethoxy-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (324) 1-[N-[[4-(5-Chloro-3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (325) 1-[3,5-Dibromo-N-[[3-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-pyrrolidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (326) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (327) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (328) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-8-methoxy-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (329) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (330) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (331) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (332) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (333) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (334) 1-[N-[[4-(1,3-dihydro-4-[3-(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-3-(4-pyridinyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine
    • (335) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (336) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (337) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (338) (R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[(N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    • (339) (R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    • (340) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (341) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (342) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (343) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (344) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (345) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (346) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (347) 1-[4-Amino-3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (348) 1-[4-Amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (349) 1-[4-Amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (350) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (351) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (352) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (353) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (354) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (355) 1-[4-Amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (356) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    • (357) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (358) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (359) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (360) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (361) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (362) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (363) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (364) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (365) 1-[N2-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (366) 1-[4-Amino-3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine
    • (367) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine
    • (368) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine
    • (369) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[4-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperazine
    • (370) 1-[4-Amino-3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine
    • (371) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine
    • (372) 4-(1-Acetyl-4-piperidinyl)-1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-piperidine
    • (373) 1-[4-Amino-N-[[4-(6-bromo-3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (374) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (375) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (376) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (377) 1-[4-Amino-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (378) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6— (1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (379) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperazine
    • (380) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine
    • (381) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(3-pyridinyl)-piperazine
    • (382) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(3-pyridinyl)-piperazine (383) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(3-pyridinyl)-piperazine
    • (384) 1-[3,5-Dibromo-N-[[4-[1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (385) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(3-pyridinyl)-piperazine
    • (386) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (387) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine
    • (388) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine
    • (389) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(phenylaminocarbonylamino)-piperidine
    • (390) 1-[4-Amino-3,5-dibromo-N-[[4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (391) 1-[3,5-Dibromo-N-[[4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (392) 1-[3,5-Dibromo-N-[[4-[4-phenyl-2(1H)-oxopyrimidin-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (393) 4-Cyano-1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-phenylpiperidine
    • (394) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyrimidinyl)-piperazine
    • (395) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyrimidinyl)-piperazine
    • (396) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyrimidinyl)-piperazine
    • (397) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyrimidinyl)-piperazine
    • (398) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (399) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    • (400) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (401) 2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole
    • (402) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (403) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (404) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-ethylphenyl)-piperazine
    • (405) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-1,2,5,6-tetrahydropyridine
    • (406) 1-[3,5-Dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (407) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (408) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazine
    • (409) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazine
    • (410) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorobenzoyl)-piperidine
    • (411) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-cyano-4-phenylpiperidine
    • (412) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperidine
    • (413) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(hexahydro-1-methyl-4-pyridinyl)carbonyl]-piperazine
    • (414) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine
    • (415) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine
    • (416) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (417) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (418) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    • (419) 1-[N-[4-[[1,3-Dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    • (420) 1-[3,5-Dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (421) 1-[3,5-Dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (422) 1-[3,5-Dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (423) 1-[3,5-Dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (424) 1-[4-Amino-3,5-dibromo-N-[[4-[7-(methylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (425) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-morpholinyl)-piperidine
    • (426) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(dimethylamino)-piperidine
    • (427) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-pyrrolidinyl)-piperidine
    • (428) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-morpholinyl)-piperidine
    • (429) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(dimethylamino)-piperidine
    • (430) 1-[4-Amino-3,5-dibromo-N-[[4-[7-[(4-methyl-1-piperazinyl)carbonyl]-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (431) 1-[4-Amino-3,5-dibromo-N-[[4-(2,5-dioxo-4-phenylmidazolidin-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (432) 1-[3,5-Dibromo-N-[[4-(2,5-dioxo-4-phenylmidazolidin-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (433) 1-[4-Amino-3,5-dibromo-N-[[4-[2,5-dioxo-4-(phenylmethyl)-imidazolidin-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (434) 1-[3,5-Dibromo-N-[[4-[2,5-dioxo-4-(phenylmethyl)imidazolidin-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (435) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidine
    • (436) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (437) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (438) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-cyclohexylpiperazine
    • (439) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-cyclohexylpiperazine
    • (440) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (441) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (442) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (443) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (444) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (445) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    • (446) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (447) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (448) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (449) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (450) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-N-methyl-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    • (451) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperazine
    • (452) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperazine
    • (453) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (454) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (455) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (456) 1-[3,4-Dichloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (457) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperidine
    • (458) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (459) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (460) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-cycloheptylpiperazine
    • (461) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-cyclopentylpiperazine
    • (462) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-4-methoxy-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (463) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (464) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (465) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (466) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (467) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (468) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (469) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (470) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (471) 1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(4-biphenylyl)-D,L-alanyl]-4-(1-piperidinyl)-piperidine
    • (472) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-biphenylyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (473) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (474) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (475) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (476) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (477) 1-[3,4-Dichloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (478) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (479) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (480) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (481) 1-[4-Amino-3,5-dibromo-N-[[4-[4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (482) 1-[4-Amino-3,5-dibromo-N-[[4-[4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (483) 1-[4-Amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (484) 1-[4-Amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (485) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-benzoyl-4-piperidinyl)-piperidine
    • (486) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine
    • (487) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(3-carboxy-1-oxopropyl)-4-piperidinyl]-piperidine
    • (488) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine
    • (489) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidine
    • (490) 1-[3,5-Dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (491) 1-[3,5-Dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (492) 1-[3,5-Dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (493) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine
    • (494) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(carboxymethyl)-4-piperidinyl]-piperidine
    • (495) 1-[(4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (496) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(4-pyridinyl)carbonyl]-piperazine
    • (497) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-methyl-1-piperazinyl)piperidine
    • (498) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine
    • (499) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine
    • (500) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-piperazine
    • (501) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-methyl-1-piperazinyl)piperidine
    • (502) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine
    • (503) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine
    • (504) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine
    • (505) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)carbonyl]-piperidine
    • (506) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (507) 1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (508) (R,S)-1-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (509) 1-[4-Amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    • (510) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    • (511) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (512) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (513) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (514) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    • (515) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine
    • (516) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine
    • (517) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine
    • (518) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    • (519) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (520) 1-[4-Amino-N-[[4-[4-[3,5-bis-(trifluoromethyl)phenyl]-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (521) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine
    • (522) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine
    • (523) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-(methylsulphonyloxy)-D-phenylalanyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine
    • (524) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine
    • (525) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidine
    • (526) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine
    • (527) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-(2-methyl-4-thiazolyl)-D,L-alanyl]-4-(1-piperidinyl)-piperidine
    • (528) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-(2-methyl-4-thiazolyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine
    • (529) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (530) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (531) (R,S)-1-[2-[(3-Methoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (532) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (533) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido-[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (534) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (535) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperazinyl)-piperidine
    • (536) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (537) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    • (538) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (539) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    • (540) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (541) (R,S)-1-[2-[(3-Ethoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    • (542) (R,S)-1-[2-[(3-Ethoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (543) (R,S)-1-[2-[(3-Ethoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (544) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (545) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    • (546) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (547) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (548) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    • (549) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (550) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-[2-(dimethylamino)ethoxy]phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    • (551) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperidine
    • (552) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine
    • (553) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine
    • (554) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine
    • (555) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine
    • (556) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine
    • (557) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine
    • (558) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(4-pyridinyl)carbonyl]-piperazine
    • (559) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (560) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine
    • (561) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine
    • (562) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine
    • (563) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine
    • (564) 1-[4-Amino-N-[(4-amino-1-piperidinyl)carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (565) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    • (566) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    • (567) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (568) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    • (569) 1-[3,5-Dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (570) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (571) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (572) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (573) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (574) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (575) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (576) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (577) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (578) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (579) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (580) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (581) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (582) 1-[4-Amino-3,5-dibromo-N-[[4-(2,3-dihydro-4(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (583) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    • (584) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    • (585) 1-[4-Amino-N-[[4-[4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (586) 1-[4-Amino-N-[[4-[4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (587) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    • (588) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    • (589) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (590) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (591) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3,4-difluoro-5-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (592) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3,4-difluoro-5-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (593) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(ethoxycarbonyl)-piperidine
    • (594) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(ethoxycarbonylmethyl)-piperidine
    • (595) (R,S)-2-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-6-methyl-2,6-diazaspiro[3,4]octane
    • (596) (R,S)-1-[(4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(hydroxycarbonylmethyl)-piperidine
    • (597) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (598) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (599) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (600) (R,S)-1-[4-[4-(Aminocarbonylamino)-1-piperidinyl]-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (601) (R,S)-1-[4-[4-(Aminocarbonylamino)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (602) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methoxyphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (603) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-carboxypiperidine
    • (604) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (605) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-fluor-3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (607) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-fluor-3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (607) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine
    • (608) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (609) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (610) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    • (611) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(4-pyridinyl)-piperidine
    • (612) (R,S)-1-[2-[(4-Amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (613) 1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (614) 1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (615) 1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(cyclopentyl)-piperazine
    • (616) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-methylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (617) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    • (618) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    • (619) 1-[3-Bromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (620) 1-[3-cyano-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (621) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (622) 1-[N-[[4-(1,3-Dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (623) 1-[3-Methyl-N-[[4-[3,4-dihydro-2(1H)-oxothieno[3,4-d]-pyrimidin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (624) 1-[N-[[4-[1,3-Dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (625) 1-[N-[[4-[1,3-Dihydro-4-[(3-(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (626) 1-[3-Bromo-N-[[4-[1,3-dihydro-4-[(3-(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (627) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxothieno[3,4-d]-pyrimidin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (628) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (629) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperazine
    • (630) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperazine
    • (631) (R,S)-4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)-phenyl]methyl]-N-[2-(4-methyl-1-piperazinyl)ethyl]-butanamide
    • (632) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(1H-tetrazol-5-yl)-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (633) 1-[3-Bromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    • (634) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(2-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (635) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[2-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (636) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-nitro-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (637) (R,S)-1-[2-[(4-Amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (638) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[2-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (639) (R,S)-1-[2-[[3,5-Bis-(trifluoromethyl)phenyl]methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (640) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dimethoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (641) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(2-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (642) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dimethoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (643) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(4-piperidinyl)-piperidine
    • (644) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (645) (R,S)-1-[2-[(3-Bromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (646) (R,S)-1-[2-[(3-Bromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (647) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-propen-3-yl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (648) (R,S)-1-[2-[3-(Biphenylyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (649) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(pyridinyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (650) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(2-thiazolyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (651) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(2-furyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (652) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-propylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (653) (R,S)-1-[4-(2,4-Dihydro-5-phenyl-3(3H)-oxotriazol-2-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (654) (R,S)-1-[4-[1,3-Dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl]-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (655) (R,S)-1-[2-[(4-Quinolinyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (656) (R,S)-1-[2-[(4-Quinolinyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (657) 1-[2-[(1,2,3,4-Tetrahydro-1-naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine (mixture of diastereomers)
    • (658) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (659) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (660) (R,S)-1-[2-[(4-Quinolinyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (661) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (662) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (663) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (664) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    • (665) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (666) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (667) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    • (668) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine
    • (669) (R,S)-1-[2-[3,5-Dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine
    • (670) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (671) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    • (672) (R,S)-1-[2-[(3,4-Dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-[4-(dimethylaminomethyl)phenyl]-piperidine
  • and the salts thereof.
  • The compounds of general formula I are prepared by methods which are known in principle, particularly using processes derived from peptide chemistry (cf. for example Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2). The amino protecting groups used may be those described in Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/1, of which urethane protecting groups such as the fluorenylmethoxycarbonyl, phenylmethoxycarbonyl or tert.-butyloxycarbonyl group are preferred. Any functional groups present in the groups R2 and/or A of the compounds of general formula I or in the precursors thereof are additionally protected by suitable protecting groups in order to prevent side reactions (cf. for example: G. B. Fields et al., Int. J. Peptide Protein Res. 35, 161 (1990); T. W. Greene, Protective Groups in Organic Synthesis). Examples of side-chain-protected amino acids of this kind include, in particular, Arg(NO2), Arg(Mtr), Arg(di-z), Arg(Pmc), Lys(Boc), Lys(Z), Orn(Boc), Orn(Z), Lys(Cl-Z) which are commercially obtainable, possibly in the form of derivatives. Particular care should be taken to ensure that so-called orthogonal combinations of protecting groups are used to protect the α-amino and the side chain amino group, e.g.:
  • Protection of the N
    (side chain) Nα-protection
    p-Toluenesulphonyl Phenylmethoxycarbonyl
    tert.Butyloxycarbonyl
    Phenylmethoxycarbonyl (4-Methoxyphenyl)methoxycarbonyl
    tert.Butoxycarbonyl
    Adamantyloxycarbonyl
    Biphenylylisopropyloxycarbonyl
    Isonicotinoyloxycarbonyl
    o-Nitrophenylsulphenyl
    Formyl
    tert. Butoxycarbonyl Phenylmethoxycarbonyl
    p-Toluenesulphonyl
    o-Nitrophenylsulphenyl
    Biphenylylisopropyloxycarbonyl
    9-Fluorenylmethoxycarbonyl
    Acetyl, Trifluoroacetyl, tert.Butyloxycarbonyl
    Formyl, (2-Chlorophenyl)-
    methoxycarbonyl, (4-Chloro-
    phenyl)methoxycarbonyl,
    4-(Nitrophenyl)methoxycarbonyl,
    Phthaloyl
  • Instead of protecting amino groups in the side chain, amino acids or derivatives thereof which carry precursor functions and in particular are substituted by nitro or cyano in the side chain, such as 5-o-cyanonorvalin may also be used.
  • The basic functions in the side chains of α-amino acids which are not commercially obtainable and which are characterised, for example, by (aminoiminomethyl) groups, may be protected in the same way as is used for protecting the side chains of arginine and its derivatives (cf. also M. Bodanszky, “Peptide Chemistry”, Springer-Verlag, 1988, p. 94-97); protecting groups which are particularly suitable for the (aminoiminomethyl)- group are the p-toluenesulphonyl, mesitylene sulphonyl- (Mts), methoxytrimethylphenylsulphonyl- (Mtr), 2,2,5,7,8-pentamethylchroman-6-sulphonyl- (Pmc), pentachlorophenoxycarbonyl- and nitro-protecting groups.
  • For the actual coupling, the methods known from peptide chemistry are used (see Houben-Weyl, for example, Methoden der Organischen Chemie, Vol. 15/2). It is preferable to use carbodiimides such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)N,N—N′,N′-tetramethyluronium-hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By the addition of 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) racemisation may additionally be suppressed, if desired, or the reaction rate may be increased. The couplings are normally carried out with equimolar amounts of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between −30 and +30° C., preferably between −20 and +20° C. If necessary, N-ethyl-diisopropylamine (DIEA) is preferred as an additional auxiliary base (Hünig base).
  • The so-called “anhydride method” (cf. also M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27) was used as another coupling method for the synthesis of compounds of general formula I. The “mixed anhydride method” is preferred, in the variant according to Vaughan (J. R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride is obtained from the optionally N2-protected α-amino acid which is to be coupled, and the mono-isobutylcarbonate, using isobutylchlorocarbonate in the presence of base such as 4-methylmorpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines are carried out in a one-pot process using the above-mentioned solvents at temperatures between −20 and +20° C., preferably between 0 and +20° C.
  • Any protecting groups present in the side chains of α-amino acid partial structures are finally cleaved, after the formation of the N- and C-terminally substituted amino acid derivative, with suitable reagents which are also known from the literature in principle, specifically arylsulphonyl and hetarylsulphonyl protecting groups, preferably by acidolysis, i.e. by the action of strong acids, preferably trifluoroacetic acid, nitro- and arylmethoxycarbonyl protecting groups are preferably cleaved by hydrogenolysis, e.g. using hydrogen in the presence of palladium black and with glacial acetic acid as solvent. If the substrate contains functions which are sensitive to hydrogenolysis, e.g. halogen atoms such as chlorine, bromine or iodine, a phenylmethanol or hetarylmethanol function or some other benzyl heteroatom bond, particularly a benzyl-oxygen bond, the nitro group may also be cleaved non-hydrogenolytically, e.g. with zinc/2N trifluoroacetic acid (cf. also A. Turan, A. Patthy and S. Bajusz, Acta Chim. Acad. Sci. Hung, Tom. 85 (3), 327-332 [1975]; C.A. 83, 206526y [1975]), with tin(II)-chloride in 60% aqueous formic acid (see also: SUNSTAR KK, JA-A-3271-299), with zinc in the presence of acetic acid (cf. also: A. Malabarba, P. Ferrari, G. Cietto, R. Pallanza and M. Berti, J. Antibiot. 42 (12), 1800-1816 (1989)) or excess aqueous 20% titanium(III)-chloride in aqueous methanol and in the presence of aqueous ammonium acetate buffer at 24° C. (see also: R. M. Freidinger, R. Hirschmann and D. F. Veber, J. Org. Chem. 43 (25), 4800-4803 [1978]).
  • Any precursor functions which may be present in the side chain of the α-amino acid may also subsequently be converted by hydrogenolysis into the desired amino functions; nitroalkyl groups yield aminoalkyl groups under conditions which will be familiar to the chemist, whilst the cyano group is converted into the aminomethyl group.
  • Alternatively, nitrile functions may also be reduced with complex hydrides which are selective in relation to other critical functions contained in the molecule, particularly amide groups (cf. also: J. Seyden-Penne, “Reductions by the Alumino- and Borohydrides in Organic Synthesis”, VCH Publishers Inc., 1991, p. 132ff.), e.g. with sodium borohydride in methanol and in the presence of cobalt(II)-chloride, with sodium borohydride in tetrahydrofuran in the presence of trifluoroacetic acid or with tetrakis-(n-butyl)-ammonium borohydride in dichloromethane; the reduction of aliphatic nitro function to the primary amino-function is also possible with sodium borohydride in the presence of tin(II)-chloride or copper(II)-acetylacetonate, without affecting the carboxamide groups present in type I compounds (see also: J. Seyden-Penne, ibid. p. 137ff.).
  • The following methods are particularly suitable for preparing the compounds of general Formula I according to the invention:
  • a) In order to prepare compounds of general formula I, wherein
  • R denotes an unbranched C1-7-alkyl group which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
      • by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, wherein the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl- or 1-methylimidazolyl-groups and the substituents may be identical or different,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
      • or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one, two or three nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the above-mentioned 5-membered heteroaromatic monocyclic rings and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group, and
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl groups in the ω-position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
  • or the group of formula
  • Figure US20090163480A1-20090625-C00018
  • wherein
    R5, R6, R7, RN, Y1, o and p are as hereinbefore defined,
    Y2 denotes a CH— group and
    Z denotes an NR1— group, wherein R1 is as hereinbefore defined:
  • coupling carboxylic acids of general formula VII,

  • RCO2H  (VII)
  • wherein
    R is as hereinbefore defined,
  • with compounds of general formula VIII,
  • Figure US20090163480A1-20090625-C00019
  • wherein
    R2, R3, R4, R11, A, X, m and n are as hereinbefore defined, and
  • Z denotes an NR1— group, wherein R1 is as hereinbefore defined, and, if necessary, subsequently cleaving any protecting groups or modifying precursor functions in accordance with the methods described hereinbefore.
  • The coupling is carried out using the methods known from peptide chemistry described above, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
  • b) In order to prepare compounds of general formula I wherein R is defined as in a), Z denotes the NR1— group and R1, R2, R3, R4, R11, A, X, m and n are as hereinbefore defined:
  • coupling compounds of general formula IX,

  • R—CO-Nu  (IX)
  • wherein
    R is defined as in a) and
    Nu denotes a leaving group, for example a halogen atom such as the chlorine, bromine- or iodine atom, an alkylsulphonyloxy group having 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms or by methyl- or nitro groups, wherein the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl- optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yloxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azide group,
  • with compounds of general formula VIII,
  • Figure US20090163480A1-20090625-C00020
  • wherein
    R2, R3, R4, R11, A, X, m and n are as hereinbefore defined and
  • Z denotes an NR1— group, whilst R1 is as hereinbefore defined,
  • and, if necessary, subsequently cleaving protecting groups or modifying precursor functions using the methods described above.
  • The reaction is carried out under Schotten-Baumann or Einhorn-conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between −50° C. and +120° C., preferably between −10° C. and +30° C., optionally in the presence of solvents. Auxiliary bases which may be used are preferably alkali-metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetate, e.g. sodium- or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-Diazabicyclo[2,2,2]octane or 1,8-diazabicyclo-[5,4,0]undec-7-ene, whilst the solvents which may be used include, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or -acetates are used as auxiliary bases, water may also be added to the reaction mixture as a cosolvent.
  • c) In order to prepare compounds of general formula I wherein
  • R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl- group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
      • by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
        whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, is C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group,
  • or the group of formula
  • Figure US20090163480A1-20090625-C00021
  • wherein
    R5, R6, R7, RN, Y1, o and p are as hereinbefore defined,
    Y2 denotes the N-atom and
    Z denotes the NR1— group, wherein R1 is as hereinbefore defined:
  • reacting amines of general formula X

  • R—H  (X)
  • wherein
    R is as hereinbefore defined, with carbonic acid derivatives of general XI
  • Figure US20090163480A1-20090625-C00022
  • wherein
    X1 is a nucleofugic group, preferably the 1H-imidazol-1-yl, 1H-1,2,4-triazol-1-yl, trichloromethoxy- or 2,5-dioxopyrrolidin-1-yloxy group,
  • and with compounds of general formula VIII,
  • Figure US20090163480A1-20090625-C00023
  • wherein
    R2, R3, R4, R11, A, X, m and n are as hereinbefore defined and
    Z denotes an NR1— group, wherein R1 is as hereinbefore defined,
  • and, if necessary, subsequently cleaving any protecting groups or modifying any precursor functions using the method described hereinbefore.
  • The theoretically two-step reactions are generally carried out as one-pot processes, preferably by reacting one of the two components X or VIII with equimolar amounts of the carbonic acid derivative of general formula XI in a suitable solvent at fairly low temperature, in the first step, and then adding at least equimolar amounts of the other component VIII or X and finishing the reaction at elevated temperature. The reactions with bis-(trichloromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-carbonat) of a tertiary base, e.g. triethylamine, N-ethyl-diisopropylamine, pyridine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo-[5,4,0]undec-7-ene. Examples of solvent, which should be anhydrous, include tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile, if bis-(trichloromethyl)-carbonate is used as the carbonyl component, anhydrous chlorohydrocarbons such as dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred. The reaction temperatures are between −30 and +25° C. for the first step of the reaction, preferably between −5 and +10° C., and between +15° C. and the boiling temperature of the solvent used, preferably between +20° C. and +70° C. for the second step of the reaction (cf. also: H. A. Staab and W. Rohr, “Synthesen mit heterocyclischen Amiden (Azoliden)”, Neuere Methoden der Präparativen Organischen Chemie, Band V, p. 53-93, Verlag Chemie, Weinheim/Bergstr., 1967; P. Majer and R. S. Randad, J. Org. Chem. 59, 1937-1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara and H. Ogura, Tetrahedron Letters 24 (42), 4569-4572 (1983)).
  • d) In order to prepare compounds of general formula I wherein the carbonyl group linked to the groups R and Z denotes a urea carbonyl group, in which the urea carbonyl is flanked by at least one NH— group, and wherein
  • R denotes an unbranched C1-6-alkylamino group optionally additionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl- group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
      • by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
  • or the group of formula
  • Figure US20090163480A1-20090625-C00024
  • wherein
      • R5, R6, R7, RN, Y1, o and p are as hereinbefore defined and
      • Y2 denotes the N-atom,
  • Z denotes the group NR1 and
      • R1 denotes a hydrogen atom or, provided that, R denotes an unbranched alkylamino group unsubstituted at the nitrogen atom and optionally substituted in the ω-position, R1 may also denote an alkyl or phenylalkyl group:
  • Reacting amines of general formula X′,

  • R—H  (X′)
  • wherein R is as hereinbefore defined,
    with carbonic acid derivatives of general formula XI′,
  • Figure US20090163480A1-20090625-C00025
  • wherein
  • X2 denotes a phenoxy group, if X3 is the (1H)-1,2,3,4-tetrazol-1-yl group, the 4-nitrophenoxy group, if X3 is the 4-nitrophenoxy group, and the chlorine atom if X3 is the 2,4,5-trichlorophenoxy group, and with compounds of general formula VIII′,
  • Figure US20090163480A1-20090625-C00026
  • wherein
  • R2, R3, R4, R11, X, A, m and n are as hereinbefore defined and
  • R1 denotes a hydrogen atom or, provided that R is an unbranched alkylamino group unsubstituted at the nitrogen and optionally substituted in the ω-position, R1 may also denote an alkyl or phenylalkyl group, and
  • if necessary, subsequently cleaving protecting groups or modifying precursor functions using the methods described hereinbefore.
  • The reactions are in two steps, in principle, with intermediate formation of urethanes, which can be isolated. However, the reactions may also be carried out as one-pot reactions. Preferably, in the first step, one of the two components X′ or VIII′ is reacted with equimolar amounts of the carbonic acid derivative of general formula XI′ in a suitable solvent at low temperature, then at least equimolar amounts of the other component VIII′ or X′ are added and the reaction is completed at elevated temperature. The reactions are preferably carried out in anhydrous solvents, e.g. in tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile or anhydrous chlorohydrocarbons e.g. dichloromethane, 1,2-dichloroethane or trichloroethylene. The reaction temperatures are between −15 and +40° C., preferably between −10 and +25° C. for the first step, between +20° C. and the boiling temperature of the solvent used, preferably between +20° C. and 100° C. for the second reaction step (cf. also: R. W. Adamiak and J. Stawinski, Tetrahedron Letters 1977, 22, 1935-1936; A. W. Lipkowski, S. W. Tam and P. S. Portoghese, J. Med. Chem. 29, 1222-1225 (1986); J. Izdebski and D. Pawlak, Synthesis 1989, 423-425).
  • e) In order to prepare compounds of general formula I wherein Z denotes the group NH and
  • R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
      • by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
  • or the group of formula
  • Figure US20090163480A1-20090625-C00027
  • wherein
    R5, R6, R7, RN, Y1, o and p are as hereinbefore defined and Y2 denotes an N-atom:
  • Reacting isocyanates of general formula XII,
  • Figure US20090163480A1-20090625-C00028
  • wherein
    R2, R3, R4, R11, A, X, m and n are as hereinbefore defined,
  • with amines of general formula X,

  • R—H  (X)
  • wherein
    R is as hereinbefore defined and, if necessary, subsequently cleaving protecting groups or modifying precursor functions using the processes described above.
  • The reaction is carried out at temperatures between 0° C. and 150° C., preferably between 20° C. and 100° C., optionally in the presence of anhydrous solvents, e.g. tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone or mixtures thereof.
  • f) In order to prepare compounds of general formula I wherein
  • R denotes an unbranched C1-6-alkylamino group unsubstituted at the nitrogen atom, which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl- group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
      • by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group, and
  • Z denotes the NR1— group wherein R1 is as hereinbefore defined:
  • Reacting isocyanates of general formula XIII,

  • R═C═O  (XIII)
  • wherein R is as hereinbefore defined, with compounds of general formula VIII,
  • Figure US20090163480A1-20090625-C00029
  • wherein R2, R3, R4, R11, A, X, m and n are as hereinbefore defined and
  • Z denotes an NR1— group, wherein R1 is as hereinbefore defined,
  • and, if necessary, subsequently cleaving any protecting groups or modifying the precursor functions using the methods described hereinbefore.
  • The reaction is carried out at temperatures between 0 and 150° C., preferably at temperatures between 20 and 100° C., and optionally in the presence of anhydrous solvents, e.g. tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone.
  • g) In order to prepare compounds of general formula I wherein R, Z, R2, R3, R4, R11, A, m and n have the meanings given hereinbefore and X is as hereinbefore defined, provided that A does not denote a bond or X denotes an oxygen atom, if A denotes a single bond:
  • Coupling carboxylic acids of general formula XIV,
  • Figure US20090163480A1-20090625-C00030
  • wherein
    R, Z, R11, m and n are as hereinbefore defined,
    R2′ has the meanings given for R2 hereinbefore or denotes a group R2 substituted by the above-mentioned protecting groups, A′ has the meanings given for A hereinbefore or, if A denotes the divalent group of an amino acid, it optionally bears in the side chain a precursor group for the group R9, e.g. a cyanopropyl group,
  • to compounds of general formula XV,

  • H—NR3R4  (XV)
  • wherein
    R3 and R4 are as hereinbefore defined,
  • and if necessary subsequent cleaving of protective groups or modification of precursor functions using the methods described above.
  • The coupling is carried out using the methods known from peptide chemistry and described hereinbefore, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
  • If the starting compound XIV used is enantiomerically pure, partial racemisation of the C-terminal amino acid must be expected during the coupling step and possibly quantitative racemisation must be expected if triethylamine is used as the auxiliary base and dimethylformamide, dimethylacetamide or N-methyl-pyrrolidone is used as solvent.
  • h) In order to prepare compounds of general formula I wherein X denotes the oxygen atom:
  • Coupling carboxylic acids of general formula XVI,
  • Figure US20090163480A1-20090625-C00031
  • wherein
    R, Z, R11, m and n are as hereinbefore defined and
    R2′ has the meanings given for R2 hereinbefore or denotes a group R2 substituted by the above-mentioned protecting groups,
  • to compounds of general formula XVII,
  • Figure US20090163480A1-20090625-C00032
  • wherein
    A′ has the meanings given for A hereinbefore or, if A denotes the divalent group of an amino acid, A′ optionally bears in the side chain a precursor group for the group R9, e.g. a cyanopropyl group, and
  • R3 and R4 are as hereinbefore defined,
  • and if necessary subsequently cleaving protecting groups or modifying precursor functions using the methods described above.
  • The coupling is carried out using the methods known from peptide chemistry and described above, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
  • If the starting compound XVI used is enantiomerically pure, during the coupling step partial racemisation must be expected or, if triethylamine is used as the auxiliary base and dimethylformamide, dimethylacetamide or N-methyl-pyrrolidone is used as solvent, quantitative racemisation must be expected based on the chiral centre of XVI.
  • i) In order to prepare compounds of general formula I wherein
  • R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
      • by a C4-10-cycloalkyl group,
      • by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
      • by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl- group,
      • by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
      • by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
  • whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
  • or the group of formula
  • Figure US20090163480A1-20090625-C00033
  • wherein
      • R5, R6, R7, RN, Y1, o and p are as hereinbefore defined and
      • Y2 denotes an N-atom,
  • Z represents the methylene group,
  • X denotes two hydrogen atoms,
    A denotes a single bond,
    m denotes the value 1 and
    n denotes the value 0:
  • Coupling carboxylic acids of general formula XVIII,
  • Figure US20090163480A1-20090625-C00034
  • wherein
    R2, R3 and R4 are as hereinbefore defined,
  • with amines of general formula X,

  • R—H  (X)
  • wherein R is as hereinbefore defined.
  • The coupling is carried out using the methods known from peptide chemistry and described above, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
  • j) In order to prepare compounds of general formula I wherein R3 and R4 have the meanings given hereinbefore with the exception of the hydrogen atoms, Z denotes a methylene group, X denotes two hydrogen atoms, A denotes a single bond, m is the number 1 and n is the number 0:
  • Reacting secondary amines of general formula XVa,

  • H—NR3′R4′  (XVa)
  • wherein
    R3′ and R4′ have the meanings given for R3 and R4 hereinbefore with the exception of hydrogen atoms,
  • with formaldehyde and CH-acid compounds of general formula XIX,
  • Figure US20090163480A1-20090625-C00035
  • wherein
    R is as hereinbefore defined and
    R2 is as hereinbefore defined, but with the proviso that any acid functions present such as hydroxy groups are appropriately protected by suitable protecting groups.
  • The reaction is preferably carried out in a slightly acidic medium, using alcohols, e.g. methanol or ethanol, or lower aliphatic carboxylic acids, such as glacial acetic acid, as solvents and at temperatures between room temperature and the boiling point of the solvent in question. In a preferred variant, an inorganic acid salt such as the hydrochloride of a secondary amine of general formula XVa is heated with paraformaldehyde and a ketone of general formula XIX in glacial acetic acid to temperatures between 50° C. and 80° C.
  • k) In order to prepare compounds of general formula I wherein R, R2, R3, R4, R11, X, Z, m and n are as hereinbefore defined and A denotes the divalent group of formula III
  • Figure US20090163480A1-20090625-C00036
  • (linked to the NR3R4— group via the —CX— group)
    wherein
      • R8 denotes the hydrogen atom or an alkyl or phenylalkyl group and
      • R9 denotes an unbranched C1-5-alkyl group substituted in the ω-position by an aminoiminomethylamino group:
  • Reacting compounds of general formula XX,
  • Figure US20090163480A1-20090625-C00037
  • wherein
      • R, R2, R3, R4, R11, X, Z, m and n are as hereinbefore defined,
      • R8 denotes a hydrogen atom or an alkyl or phenylalkyl group and
      • R9 denotes an unbranched C1-5-alkyl group substituted in the ω-position by a primary amino group,
  • with carbonic acid derivatives of general formula XXI,
  • Figure US20090163480A1-20090625-C00038
  • wherein
    Nu2 is a leaving group, e.g. an alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl group each having 1 to 10 carbon atoms in alkyl moiety, e.g. a methoxy, ethoxy, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, methylsulphonyl or ethylsulphonyl group, the chlorine atom, the SO2H, SO3H— or OPOCl2— group, or the group of general formula XXII,
  • Figure US20090163480A1-20090625-C00039
  • wherein
    R15 and R16, which may be identical or different, denote hydrogen atoms or C1-3-alkyl groups.
  • Occasionally, for example when Nu2 is an alkoxy group, instead of using the compounds of general formula XXI it is advantageous to use the inorganic acid salts thereof, e.g. the neutral sulphates or hydrochlorides thereof.
  • The reactions are carried out analogously to methods known from the literature (see G. B. L. Smith, J. Amer. Chem. Soc. 51, 476 [1929]; B. Rathke, Chem. Ber. 17, 297 [1884]; R. Phillips and H. T. Clarke, J. Amer. Chem. Soc. 45, 1755 [1923]; S. J. Angyal and W. K. Warburton, J. Amer. Chem. Soc. 73, 2492 [1951]; H. Lecher and F. Graf, Chem. Ber. 56, 1326 [1923]; J. Wityak, S. J. Gould, S. J. Hein and D. A. Keszler, J. Org. Chem. 52, 2179 [1987]; T. Teraji, Y. Nakai, G. J. Durant, WO-A-81/00109, Chem. Abstr. 94, 192336z [1981]; C. A. Maryanoff, R. C. Stanzione, J. N. Plampin and J. E. Mills, J. Org. Chem. 51, 1882-1884 [1986]; A. E. Miller and J. J. Bischoff, Synthesis 1986, 777; R. A. B. Bannard, A. A. Casselman, W. F. Cockburn and G. M. Brown, Can. J. Chem. 36, 1541 [1958]; Aktieselskabet Grea, Kopenhagen, DE 28 26 452-C2; K. Kim. Y-T. Lin and H. S. Mosher, Tetrah. Letters, 29, 3183-3186 [1988]; H. B. Arzeno et al., Synth. Commun. 20, 3433-3437 [1990]; H. Bredereck and K. Bredereck, Chem. Ber. 94, 2278 [1961]; H. Eilingsfeld, G. Neubauer, M. Seefelder and H. Weidinger, Chem. Ber. 97, 1232 [1964]; P. Pruszynski, Can. J. Chem. 65, 626 [1987]; D. F. Gavin, W. J. Schnabel, E. Kober and M. A. Robinson, J. Org. Chem. 32, 2511 [1967]; N. K. Hart, S. R. Johns, J. A. Lamberton and R. I. Willing, Aust. J. Chem. 23, 1679 [1970]; CIBA Ltd., Belgisches Patent 655 403; Chem. Abstr. 64, 17481 [1966]; R. A. B. Bannard, A. A. Casselman, W. F. Cockburn and G. M. Brown, Can. J. Chem. 36, 1541 [1958]; J. P. Greenstein, J. Org. Chem. 2, 480 [1937]; F. L. Scott and J. Reilly, J. Amer. Chem. Soc. 74, 4562 [1952]; W. R. Roush and A. E. Walts, J. Amer. Chem. Soc. 106, 721 [1984], M. S. Bernatowicz, Y. Wu and G. R. Matsueda, J. Org. Chem. 57, 2497-2502 [1992]; H. Tsunematsu, T. Imamura and S. Makisumi, J. Biochem. 94, 123-128 [1983]) at temperatures between 0° C. and +100° C., preferably between +40° C. and +80° C., using inert solvents, e.g. dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof and, depending on the nature of the Nu2- group, frequently in the presence of auxiliary bases, especially alkali metal carbonates such as sodium- or potassium carbonate, or tertiary amines, preferably N-ethyl-diisopropylamine or triethylamine.
  • The amino acids of general formula I modified according to the invention contain at least one chiral centre. If the group A is also chiral, the compounds may occur in the form of two diastereomeric pairs of antipodes. The invention includes the individual isomers as well as the mixtures thereof.
  • The diastereomers are separated on the basis of their different physicochemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
  • Racemates covered by general formula I may be separated, for example, by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated by means of the diastereomeric optically active salts which are formed on reacting with an optically active acid, e.g. (+)- or (−)-tartaric acid, (+)- or (−)-diacetyl tartaric acid, (+)- or (−)-monomethyl-tartrate or (+)-camphor sulphonic acid or an optically active base such as (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine or (S)-brucine.
  • According to a conventional process for separating isomers, the racemate of a compound of general formula I is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the crystalline, diastereomeric, optically active salts obtained are separated on the basis of their different solubilities. This reaction may be carried out in solvents of any kind provided that they are sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof are used, e.g. in a ratio by volume of 50:50. Then each of the optically active salts is dissolved in water, neutralised with a base such as sodium carbonate or potassium carbonate, sodium hydroxide solution or potassium hydroxide solution, and in this way the corresponding free compound is obtained in the (+)- or (−)-form.
  • The (R)-enantiomer alone or a mixture of two optically active diastereomeric compounds coming within the scope of general formula I may also be obtained by carrying out the syntheses described above with a suitable reaction component in the (R)-configuration.
  • The starting materials of general formulae VII, IX, X, X′, XI, XI′, XIII, XV, XVa, XVII, XXI, XXII required to synthesis the compounds of general formula I as well as the amino acids used are commercially available or may be prepared by methods known from the literature.
  • Compounds of general formula VIII wherein Z denotes the group NR1 and those of general formula VIII′ wherein X denotes the oxygen atom may be obtained from commonly available starting materials using methods familiar to peptide chemists.
  • Isocyanates of general formula XII can easily be obtained from α-amino acid derivatives of general formula VIII′ wherein R1 denotes a hydrogen atom and the other groups are as hereinbefore defined, or from the hydrochlorides thereof by reacting with phosgene, diphosgene or triphosgene in the presence of pyridine (see also: J. S. Nowick, N. A. Powell, T. M. Nguyen and G. Noronha, J. Org. Chem. 57, 7364-7366 [1992]).
  • Carboxylic acids of general formulae XIV and XVI may be obtained from the corresponding carboxylic acid esters by saponification, preferably in the presence of lithium hydroxide.
  • The carboxylic acids of general formula XVIII are obtained by saponifying corresponding carboxylic acid esters which are in turn prepared from suitable secondary amines, 4-aryl-4-oxobutanoic acid esters and formaldehyde by Mannich reaction.
  • Compounds of general formula XIX may be obtained from suitable 4-oxobutanoic acids and amines of general formula X using conventional methods.
  • The intermediate compounds of general formula XX come under general formula I and are thus within the scope of the present application. These compounds may be obtained, for example, using processes a) to h) described herein.
  • The compounds of general formula I may be converted into their physiologically acceptable salts with inorganic or organic acids, particularly for pharmaceutical applications. Examples of suitable acids for this purpose include hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
  • Moreover, if the new compounds of formula I thus obtained contain an acid function, for example a carboxy group, they may if desired be converted into the addition salts thereof with inorganic or organic bases, more particularly for pharmaceutical use, into the physiologically acceptable addition salts thereof. Bases which may be considered include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • The new compounds of general formula I and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP-receptor binding studies. The compounds exhibit CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
  • The following experiments were carried out to demonstrate the affinity of compounds of general formula I for human CGRP-receptors and their antagonistic properties:
  • A. Binding Studies with SK-N-MC-Cells Expressing Human CGRP-Receptor
  • SK-N-MC-cells are cultivated in Dulbecco's modified Eagle Medium. The medium of confluent cultures is removed. The cells are washed twice with PBS-buffer (Gibco 041-04190 M), detached by the addition of PBS-buffer mixed with 0.02% EDTA and isolated by centrifuging. After resuspension in 20 ml of Balanced Salts Solution [BSS (in mM): NaCl 120, KCl 5.4, NaHCO3 16.2, MgSO4 0.8, NaHPO4 1.0, CaCl2 1.8, D-Glucose 5.5, HEPES 30, pH7.40] the cells are centrifuged twice at 100×g and resuspended in BSS. After the cell number has been determined the cells are homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000×g. The supernatant is discarded and the pellet is recentrifuged and resuspended (1 ml/1000000 cells) in Tris-buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40), enriched with 1% bovine serum albumin and 0.1% bacitracin. The homogenate is frozen at −80° C. The membrane preparations are stable for more than 6 weeks under these conditions.
  • After thawing, the homogenate is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230 μl of the homogenate are incubated at ambient temperature for 180 minutes with 50 pM of 125I-Iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 μl. Incubation is ended by rapid filtration using GF/B-glass fibre filters treated with polyethyleneimine (0.1%) by means of a cell harvester. The protein-bound radioactivity is measured using a gammacounter. The non-specific binding is defined as the radioactivity bound after the presence of 1 μM of human CGRP-alpha during incubation.
  • The concentration binding curves are analysed using a computer-aided non-linear curve adaptation.
  • The compounds of general formula I show IC50 values ≦10000 nM in the test described.
    • B. CGRP-Antagonism in SK-N-MC-Cells
  • SK-N-MC-cells (1 million cells) are washed twice with 250 μl of incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP (10 μl) as agonist in increasing concentrations (10−11 to 10−6 M) or additionally of substance in 3 to 4 different concentrations, incubation is continued for a further 15 minutes.
  • Intracellular cAMP is then extracted by the addition of 20 μl of 1M HCl and centrifugation (2000×g, 4° C. for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at −20° C.
  • The cAMP contents of the samples are determined by radioimmunoassay (Amersham) and the pA2-values of antagonistically acting substances are determined graphically.
  • The compounds of general formula I display CGRP-antagonistic properties in a dosage range between 10−11 and 10−5 M in the in vitro test model described.
  • In view of their pharmacological properties the compounds of general formula I and the salts thereof with physiologically acceptable acids or bases are thus suitable for acute and prophylactic treatment of headache, particularly migraine and cluster headaches. Moreover, the compounds of general formula I also have a beneficial effect on the following diseases: non-insulin-dependent diabetes mellitis (NIDDM), cardiovascular diseases, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g. inflammatory joint diseases (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases which involve excessive vasodilation and resultant reductions in circulation, e.g. shock and sepsis, as well as morphine tolerance. In addition, the compounds of general formula I have the effect of alleviating pain in general.
  • The dosage needed to achieve such effects is appropriately 0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, by intravenous or subcutaneous route, and 0.01 to 10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight, when administered orally, nasally or by inhalation, in each case 1 to 3 times a day.
  • For this purpose, the compounds of general formula I prepared according to the invention may be formulated, optionally in combination with other active substances, such as antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin-antagonists, anti-convulsants, histamine-H1-receptor antagonists, antimuscarinics, β-blockers, α-agonists and α-antagonists, ergot alkaloids, mild analgesics, non-steroidal antiphlogistics, corticosteroids, calcium-antagonists, 5-HT1D-agonists or other antimigraine agents, together with one or more inert conventional carriers and/or diluents, e.g. corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metering aerosol or suppositories.
  • Thus, additional active substances which may be considered for the above-mentioned combinations include, for example, meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidon, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenyloin, valproate, amitryptilin, lidocaine, diltiazem or sumatriptan and other 5-HT1D-agonists such as naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan. The dosage for these active substances is appropriately 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dosage, i.e. 20 to 100 mg of sumatriptan, for example.
  • The invention further relates to the use of the compounds of general formula I as valuable auxiliary agents for the production and purification (by affinity chromatography) of anti-bodies and, after suitable radiolabelling, e.g. by direct labelling with 125I or 131I or by tritiation of suitable precursors for example by replacing halogen atoms with tritium, in RIA- and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.
  • The Examples which follow are intended to illustrate the invention:
    • Preliminary Remarks:
  • There are satisfactory elementary analyses, IR, UV, 1H-NMR and generally mass spectra as well, for all the compounds. Unless otherwise specified, Rf values were determined using TLC ready-made plates of silica gel 60 F254 (E. Merck, Darmstadt, Product No. 5729) without chamber saturation. If there are no details of configuration, it is undecided whether this is the pure enantiomer or whether partial or total racemisation has occurred. The following eluants or eluant mixtures were used for chromatography:
    • FM1=dichloromethane/cyclohexane/methanol/ammonia 7/1.5/1.5/0.2 (v/v/v/v)
    • FM2=dichloromethane/methanol/ammonia 7.5/2.5/0.5 (v/v/v)
    • FM3=dichloromethane/methanol 8/2 (v/v)
    • FM4=dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia=59/25/7.5/7.5/1 (v/v/v/v/v)
    • FM5=ethyl acetate/dichloromethane=7/3 (v/v)
    • FM6=ethyl acetate/petroleum ether=1/1 (v/v)
    • FM7=dichloromethane/methanol/conc. aqueous ammonia=80/20/1 (v/v/v)
  • The following abbreviations were used in the descriptions of the experiments:
    • Mp.: melting point
    • (D): (decomposition)
    • DIEA: N,N-diisopropyl-ethylamine
    • Boc: (1,1-dimethylethoxy)carbonyl
    • TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
    • HOBt: 1-hydroxybenzotriazole-hydrate
    • CDT: 1,1′-carbonyldi(1,2,4-triazole)
    • THF: tetrahydrofuran
    • DMF: dimethylformamide
    • Fmoc: (9-fluorenylmethoxy)carbonyl
    • EE: ethyl acetate
    • PE: petroleum ether
    • LM: solvent
    • Lfd. No.: item number
  • The meanings of the symbols made up of letters and numbers used in the Examples are given in the following summary:
  • Figure US20090163480A1-20090625-C00040
    Figure US20090163480A1-20090625-C00041
    Figure US20090163480A1-20090625-C00042
    Figure US20090163480A1-20090625-C00043
    Figure US20090163480A1-20090625-C00044
    Figure US20090163480A1-20090625-C00045
    Figure US20090163480A1-20090625-C00046
    Figure US20090163480A1-20090625-C00047
    Figure US20090163480A1-20090625-C00048
    Figure US20090163480A1-20090625-C00049
    Figure US20090163480A1-20090625-C00050
    Figure US20090163480A1-20090625-C00051
    Figure US20090163480A1-20090625-C00052
    Figure US20090163480A1-20090625-C00053
    Figure US20090163480A1-20090625-C00054
    Figure US20090163480A1-20090625-C00055
    Figure US20090163480A1-20090625-C00056
    Figure US20090163480A1-20090625-C00057
    Figure US20090163480A1-20090625-C00058
    Figure US20090163480A1-20090625-C00059
    Figure US20090163480A1-20090625-C00060
    Figure US20090163480A1-20090625-C00061
    Figure US20090163480A1-20090625-C00062
    Figure US20090163480A1-20090625-C00063
    Figure US20090163480A1-20090625-C00064
    Figure US20090163480A1-20090625-C00065
    Figure US20090163480A1-20090625-C00066
    Figure US20090163480A1-20090625-C00067
    Figure US20090163480A1-20090625-C00068
    Figure US20090163480A1-20090625-C00069
    Figure US20090163480A1-20090625-C00070
    Figure US20090163480A1-20090625-C00071
    Figure US20090163480A1-20090625-C00072
    Figure US20090163480A1-20090625-C00073
    Figure US20090163480A1-20090625-C00074
    Figure US20090163480A1-20090625-C00075
    Figure US20090163480A1-20090625-C00076
    • A. Preparation of Intermediate Compounds EXAMPLE A1
  • Preparation of compounds of the general structure:
  • Figure US20090163480A1-20090625-C00077
    • 1,3-dihydro-4-(3-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one a) 4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • To a mixture of 20.0 g (0.10 mol) of 4-amino-1-(1,1-dimethylethoxycarbonyl)piperidine, 8.2 g (0.1 mol) of anhydrous sodium acetate and 150 ml of dichloromethane was added dropwise, with stirring and whilst maintaining a reaction temperature of from 0° C. to +10° C., a solution of 25.0 g (0.109 mol) of 3-methoxy-phenacylbromide in 50 ml of dichloromethane was added dropwise. The mixture was stirred for 5 hours at room temperature, then 19.5 g (0.296 mol) of sodium cyanate, 18 ml of glacial acetic acid and 10 ml of water were added and stirring was continued for 12 hours at room temperature. The mixture was stirred into 1 l of ice water, the dichloromethane phase was separated off, washed twice with 200 ml of water, 5% aqueous sodium hydrogen carbonate solution, 20% aqueous citric acid solution and once more with water, dried over magnesium sulphate and evaporated down in vacuo. The residue was taken up in methanol.
  • It was left to stand overnight, the precipitate which crystallised out was suction filtered, washed thoroughly with tert. butyl-methylether and after drying in vacuo 11.5 g (30.8% of theory) of colourless crystals were obtained.
  • MS: M+=373
  • The following were obtained accordingly:
    • (1) 4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • Rf: 0.51 (FM4)
    • (2) 4-[1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • yield: 23.8% of theory
    • (3) 4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • IR(KBr): 1685.7 cm−1 (C═O)
    • (4) 4-[1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • Rf: 0.23 (dichloromethane/methanol 9/1 v/v)
  • IR(KBr): 1687.6 cm−1 (C═O)
  • MS: M+=357
    • (5) 4-[1,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • yield: 29.1% of theory
  • MS: M+=388
    • (6) 4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • yield: 13.1% of theory
  • IR(KBr): 1685 cm−1 (C═O)
  • MS: M+=421/423 (Br)
    • (7) 4-[1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • IR(KBr): 1680, 1699 cm−1 (C═O)
  • MS: M+=419
    • (8) 4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • IR(KBr): 1682 cm−1 (C═O)
  • MS: M+=388
    • (9) 4-[4-(4-biphenylyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • yield: 21.6% of theory, colourless crystals
  • Rf: 0.6 (ethyl acetate)
  • IR(KBr): 1681.8 cm−1 (C═O)
    • (10) 4-[1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • yield: 30% of theory, crystals
  • IR(KBr): 1679.9 cm−1 (C═O)
    • (11) 4-[1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • Rf: 0.86 (FM1)
    • (12) 4-[4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • yield: 62% of theory, colourless crystals
  • Rf: 0.34 (ethyl acetate)
  • IR(KBr): 1687 cm−1 (C═O)
    • (13) 4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • yield: 21% of theory
  • Rf: 0.6 (ethyl acetate/methanol 9/1 v/v)
    • (14) 4-[1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • Yield: 60% of theory
  • IR(KBr): 1682 cm−1 (C═O)
  • MS: M+=359
    • (15) 4-[4-[3,5-bis-(trifluoromethyl)phenyl]-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • Yield: 3.2% of theory
  • IR(KBr): 1687.6 cm−1 (C═O)
  • Rf: 0.95 (dichloromethane/methanol 9/1 v/v)
    • (16) 4-[4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
  • Yield: 4.6% of theory
  • IR(KBr): 1684 cm−1 (C═O)
  • Rf: 0.48 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV254 ready-made films for TLC)
    • b) 1,3-dihydro-4-(3-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one
  • The solution of 11.5 g (0.0308 mol) of 4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine in 150 ml of dichloromethane was mixed with 15 ml of trifluoroacetic acid and then stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 10 ml of water and made distinctly ammoniacal. The resulting precipitate was suction filtered, washed thoroughly with water and dried overnight at 50° C. in vacuo. 7.0 g (83.1% of theory) of colourless crystals were obtained, Rf value 0.2 (dichloromethane/methanol 9/1 v/v).
  • The following were obtained accordingly:
    • (1) 1,3-dihydro-4-phenyl-1-(4-piperidinyl)-2H-imidazol-2-one,
  • Rf: 0.22 (FM1; Macherey-Nagel POLYGRAM® SIL G/UV254 ready-made films for TLC)
  • IR(KBr): 1672 cm−1 (C═O)
    • (2) 1,3-dihydro-4-(4-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one
  • IR(KBr): 1670 cm−1 (C═O)
  • MS: M+=273
    • (3) 1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-1-(4-piperidinyl)-2H-imidazol-2-one
  • IR(KBr): 1687.6 cm−1 (C═O)
    • (4) 1,3-dihydro-5-methyl-4-phenyl-1-(4-piperidinyl)-2H-imidazol-2-one
  • yield: 76.2% of theory
  • IR(KBr): 1679.9 cm−1 (C═O)
  • MS: M+=257
    • (5) 1,3-dihydro-4-(3-nitrophenyl)-1-(4-piperidinyl)-2H-imidazol-2-one
  • yield: 94% of theory
  • IR(KBr) 1677.8 (C═O); 1137.8, 1197.6, 1349.9 (NO2) cm−1
    • (6) 4-(3-bromophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one
  • yield: quantitative
  • IR(KBr): 1676 cm−1 (C═O)
    • (7) 1,3-dihydro-4,5-diphenyl-1-(4-piperidinyl)-2H-imidazol-2-one
  • IR(KBr): 1670 cm−1 (C═O)
  • MS: M+=319
    • (8) 1,3-dihydro-4-(4-fluorophenyl)-1-(4-piperidinyl)-2H-imidazol-2-one
  • yield: 30% of theory
  • Rf: 0.2 (eluant: ethyl acetate/methanol/conc. ammonia 9/1/0.3 v/v/v)
  • IR(KBr): 1682 cm−1 (C═O)
    • (9) 4-(4-biphenylyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one
  • yield: quantitative
  • IR(KBr) of the trifluoroacetate: 1679.9 cm−1 (C═O)
    • (10) 1,3-dihydro-4-(2-naphthyl)-1-(4-piperidinyl)-2H-imidazol-2-one
  • yield: 28.2% of theory
  • Rf: 0.03 (FM1)
  • IR(KBr) of the trifluoroacetate: 1678 cm−1 (C═O)
    • (11) 7-(2-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one
  • yield: 18.8% of theory
  • Rf: 0.22 (FM1)
  • IR(KBr) of the trifluoroacetate: 1681.6 cm−1 (C═O)
    • (12) 4-(3,4-dichlorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one
  • yield: quantitative
  • IR(KBr) of the trifluoroacetate: 3197 (N—H); 1685 (C═O) cm−1
    • (13) 4-(3-chlorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one
  • Yield: 98% of theory
  • Rf: 0.25 (eluant: ethyl ethanoate/methanol/conc. ammonia 9/1/0.3 v/v/v)
    • (14) 1,3-dihydro-4-(3-hydroxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one
  • Yield: 90% of theory
  • Rf: 0.075 (FM1)
  • IR(KBr): 1670 (C═O) cm−1
  • MS: M+=259
    • (15) 4-[3,5-bis-(trifluoromethyl)phenyl]-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one
  • Yield: 71% of theory
  • Rf: 0.15 (FM1)
  • IR(KBr): 1701 (C═O) cm−1
  • MS: M+=379
    • (16) 4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one
  • Yield: 44% of theory
  • Rf: 0.71 (FM1; Macherey-Nagel POLYGRAM® SIL G/UV254 ready-made films for TLC)
  • IR(KBr): 1676 (C═O) cm−1
    • EXAMPLE A2 2,4-dihydro-5-phenyl-2-(4-piperidinyl)-3H-1,2,4-triazol-3-one a) 1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinone-(1,1-dimethylethoxycarbonyl)hydrazone
  • A mixture of 16.0 g (0.05 mol) of 1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinone, 7.25 g (0.055 mol) of tert. butyl hydrazinoformate and 250 ml of ethanol was refluxed for 1 hour. The solvent was distilled off in vacuo, the oily residue remaining was triturated with diethylether. The crystalline precipitate thus formed was suction filtered and washed with a little diethylether. After the product had been dried in vacuo 21.7 g (99.7% of theory) of colourless crystals were obtained,
  • m.p. 156-158° C. (decomposition).
    • b) N-(1,1-dimethylethoxycarbonyl)-N′-[1-(9H-fluoren-9-ylmethoxycarbonyl-4-piperidinyl]-hydrazine
  • A solution of 21.7 g (0.05 mol) of 1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinone-(1,1-dimethylethoxycarbonyl)-hydrazone in 200 ml of glacial acetic acid was hydrogenated in the presence of 2.0 g platinum (IV) oxide at room temperature and 3 bar of hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the filtrate was evaporated down in vacuo and the residue was dissolved in a little diethylether. The crystals precipitated after standing for 3 hours at room temperature were suction filtered, washed with a little diethylether and dried in vacuo at room temperature. 21.8 g (99.6% of theory) of colourless crystals of
  • m.p. 135-137° C. and Rf=0.235 (eluant 3) were obtained.
  • ESI-MS: (M+H)+=438
    • c) [1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine-hydrochloride
  • 21.8 g (0.0498 mol) of N-(1,1-dimethylethoxycarbonyl)-N′-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine were dissolved in 100 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The excess trifluoroacetic acid was removed in vacuo, the residue was dissolved in 50 ml of water and made alkaline with 10% aqueous sodium carbonate solution. The solution was extracted thoroughly with dichloromethane, the combined extracts were dried over magnesium sulphate and evaporated down in vacuo. The residue thus obtained was taken up in ethyl acetate and converted into the hydrochloride by the addition of ethereal hydrogen chloride solution. After recrystallisation from anhydrous ethanol 6.2 g (33.3% of theory) of colourless crystals of melting point 160-162° C. were obtained.
  • C20H23N3O2+HCl (373.88)
  • Calculated: C, 64.25; H, 6.47; N, 11.24; C, 19.48.
  • Found: 64.14 6.46 10.99 9.46.
    • d) 2,4-dihydro-5-phenyl-2-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one
  • The solutions of 5.56 g (0.0165 mol) of [1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine in 60 ml of tetrahydrofuran and 3.7 g (0.0177 mol) of N-(ethoxycarbonyl)-benzo-thionamide in 30 ml of tetrahydrofuran were combined and refluxed for 1 hour, whereupon hydrogen sulphide was released. The solvent was distilled off in vacuo, the oily residue remaining was boiled with a little acetonitrile. The mixture was allowed to cool, then additionally cooled from outside with ice water and the resulting precipitate was suction filtered. 4.0 g (52% of theory) of colourless crystals were obtained, melting point 142° C. and Rf=0.38 (eluant 4).
  • IR (KBr): 1685.7 cm−1 (C═O)
    • e) 2,4-dihydro-5-phenyl-2-(4-piperidinyl)-3H-1,2,4-triazol-3-one
  • A mixture of 9.0 g (0.0193 mol) of 2,4-dihydro-5-phenyl-2-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one, 50 ml of tetrahydrofuran and 70 ml of diethylamine was stirred at room temperature until the end of the reaction monitored by thin layer chromatography. The solvent was removed in vacuo, the residue remaining was mixed with 300 ml of water and subjected to ultrasound treatment for 30 minutes. The insoluble matter was separated off by suction filtering and the aqueous filtrate was evaporated down in vacuo. The residue thus obtained was boiled with a little methanol and after cooling it was suction filtered. After drying 0.58 g (12.3% of theory) of colourless crystals of melting point 294° C. (D) and Rf=0.1 (eluant 1) were obtained.
  • IR (KBr): 1681.8 cm−1 (C═O)
    • EXAMPLE A3
  • Preparation of compounds of general structure:
  • Figure US20090163480A1-20090625-C00078
    • 3,4-dihydro-3-(4-piperidinyl)-2(1H)-pyrido[2,3-d]-1-pyrimidinone a) N-(2-Pyridinyl)-2,2-dimethylpropanamide
  • To a solution of 94.1 g (1.0 mol) of 2-aminopyridine and 173 ml (1.25 mol) of triethylamine in 400 ml of dichloromethane were added dropwise, whilst cooling with ice water, 132.5 g (1.099 mol) of pivaloyl chloride in 150 ml of dichloromethane. The mixture was stirred for 2 hours at room temperature and filtered to remove the triethylamine hydrochloride formed. The filtrate was washed with water and twice with 5% aqueous sodium hydrogen carbonate solution, then dried over sodium sulphate. After working up in the usual way 157.5 g (88.4% of theory) of colourless crystals of melting point 74-76° C. were obtained.
  • The following was obtained in the same way:
    • N-(4-Pyridinyl)-2,2-dimethylpropanamide
  • Yield: 74% of theory
  • Mp. 137-140° C. (diisopropylether)
  • IR (KBr): 1687 cm−1 (C═O)
    • b) N-(3-formyl-2-pyridinyl)-2,2-dimethylpropanamide
  • Whilst maintaining a reaction temperature of −78° C., 781 ml (1.25 mol) of a 1.6-molar solution of n-butyllithium in n-hexane were added dropwise to a solution of 89.1 g (0.5 mol) of N-(2-pyridinyl)-2,2-dimethylpropanamide in 300 ml of anhydrous tetrahydrofuran. The mixture was allowed to heat slowly up to 0° C. and stirred for 3 hours at this temperature. Then the mixture was again cooled to −78° C. and whilst maintaining this temperature the solution of 109.6 g (1.5 mol) of dimethylformamide in 150 ml of anhydrous tetrahydrofuran was added dropwise thereto. The mixture was allowed to come up to 0° C. and then stirred into 1 l of ice water. It was initially acidified with 12% aqueous hydrochloric acid, then made alkaline by the addition of solid potassium carbonate and extracted thoroughly with diethylether. The combined ether extracts were dried over sodium sulphate and evaporated down. The crystalline residue, after recrystallisation from diisopropylether, had an m.p. of 83° C. Yield: 94.0 g (91.2% of theory).
  • The following were obtained in the same way:
    • (1) N-(4-formyl-3-pyridinyl)-2,2-dimethylpropanamide
  • Yield: 52% of theory
  • Rf: 0.5 (dichloromethane/methanol/conc. ammonia 90/10/0.1 v/v/v)
  • IR (KBr) of the hydrochloride: 1695 cm−1 (C═O)
  • MS: M+=206
    • (2) N-(3-formyl-4-pyridinyl)-2,2-dimethylpropanamide
  • The reddish oil obtained in a quantitative yield was further processed without more purification
    • c) N-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-2-pyridinyl]-2,2-dimethylpropanamide
  • A solution of 8.2 g (0.0398 mol) of N-(3-formyl-2-pyridinyl)-2,2-dimethylpropanamide and 7.6 g (0.04 mol) of 4-amino-1-(phenylmethyl)piperidine in 80 ml of methanol was combined in batches with a total of 1.7 g (0.045 mol) of sodium borohydride and refluxed for a total of 24 hours. The solvent was removed in vacuo, the residue was distributed between water and ethyl acetate. The organic phase was dried over sodium sulphate and freed from solvent. The residue was triturated with diisopropylether and suction filtered. 6.0 g (39.6% of theory) of colourless crystals of melting point 138° C. were obtained.
  • The following were obtained in the same way:
    • (1) N-[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-pyridinyl]-2,2-dimethylpropanamide
  • Yield: 94% of theory
  • Rf: 0.4 (dichloromethane/methanol/conc. ammonia 90/10/0.1 V/V/V)
  • The yellowish oil was used in the following stage without further purification
    • (2) N-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-4-pyridinyl]-2,2-dimethylpropanamide
  • Yield: 11.6% of theory
  • IR(KBr): 1689 (C═O) cm−1
    • d) 2-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]-amino]methyl]-pyridine
  • A mixture of 6.0 g (0.0158 mol) of N-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-2-pyridinyl]-2,2-dimethylpropanamide and 100 ml of conc. hydrochloric acid was refluxed for 3 hours. The mixture was evaporated down in vacuo, the residue remaining was dissolved in a little water and made alkaline by the addition of solid potassium carbonate. It was extracted thoroughly with ethyl acetate, the combined extracts were dried over sodium sulphate and evaporated down in vacuo. The residue was thoroughly triturated with diisopropylether and yielded 4.2 g (89.7% of theory) of colourless crystals of melting point 114° C.
  • The following were obtained in the same way:
    • (1) 3-amino-4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-pyridine
  • Yield: 96% of theory
  • Rf: 0.42 (dichloromethane/methanol/conc. ammonia 90/10/0.1 v/v/v)
  • The yellowish oil was used in the following stage without further purification
    • (2) 4-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-pyridine
  • Yield: quantitative
  • The yellowish oil was used in the following stage without further purification
    • e) 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone
  • A mixture of 4.2 g (0.0142 mol) of 2-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-pyridine, 2.4 g (0.0148 mol) of N,N′-carbonyldiimidazole and 50 ml of dimethylformamide was heated to 100° C. for 30 minutes. The still warm mixture was stirred into 300 ml of ice water, the precipitate formed was suction filtered and recrystallised from acetonitrile. After drying in vacuo 4.5 g (98.3% of theory) of colourless crystals of melting point 187° C. were obtained.
  • The following were obtained in the same way:
    • (1) 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[3,4-d]-pyrimidinone
  • Colourless crystals
  • Yield: 33% of theory
  • IR (KBr): 1676 cm−1 (C═O)
  • MS: M+=322
    • (2) 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[4,3-d]-pyrimidinone
  • Mp. 155° C. (D)
  • Yield: 99% of theory
  • IR (KBr): 1680 cm−1 (C═O)
    • f) 3,4-dihydro-3-(4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone
  • A solution of 4.7 g (0.0146 mol) of 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone in 50 ml of methanol was hydrogenated at a temperature of 5° C. and in the presence of 2.0 g of 20% palladium/charcoal until the uptake of hydrogen ceased. After removal of the catalyst and solvent 3.3 g (97.3% of theory) of a colourless oil of Rf=0.35 (FM1) were obtained.
  • IR (KBr): 1660.6 cm−1 (C═O)
  • The following were obtained in the same way:
    • (1) 3,4-dihydro-3-(4-piperidinyl]-2(1H)-pyrido[3,4-d]-pyrimidinone
  • Colourless crystals
  • Yield: 95% of theory
  • IR (KBr): 1662 cm−1 (C═O)
  • MS: M+=232
    • (2) 3,4-dihydro-3-(4-piperidinyl]-2(1H)-pyrido[4,3-d]-pyrimidinone
  • Yellowish resin
  • Yield: 97% of theory
  • IR (KBr): 1672 cm−1 (C═O)
  • Rf: 0.12 (FM1)
    • EXAMPLE A4 Methyl 3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate a) (E)-1-(dimethylamino)-2-[4-(methoxycarbonyl)-2-nitrophenyl]-ethene
  • A mixture of 98.3 g (0.504 mol) of methyl 4-methyl-3-nitrobenzoate, 78.0 g (0.655 mol) of N,N-dimethylformamide dimethylacetal and 1 l of dimethylformamide was heated to 140° C. for 3 hours. The solvent was distilled off in vacuo, the residue was triturated thoroughly with 1 l methanol. After drying in vacuo 119.5 g (94.7% of theory) of a red amorphous substance was obtained, which was further processed without any more purification.
    • b) 4-(Methoxycarbonyl)-2-nitrobenzaldehyde
  • To a mixture of 119.5 g (0.478 mol) of (E)-1-(dimethylamino)-2-[4-(methoxycarbonyl)-2-nitrophenyl]-ethene and 1.3 l of water/tetrahydrofuran mixture (1/1 v/v) were added, in batches, 308.0 g (1.44 mol) of sodium metaperiodate, whilst the reaction temperature was regulated at under +30° C. by external cooling with ice water. The mixture was stirred for a further 2.5 hours at room temperature and then filtered. The precipitate was thoroughly washed with ethyl acetate. The organic phase was separated off, the aqueous phase was thoroughly extracted with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulphate and evaporated down in vacuo. The oil which crystallised after one day was further processed without any more purification. Yield: 87 g (87% of theory).
    • c) Methyl 4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-nitrobenzoate
  • To a solution of 41.0 g (0.215 mol) of 4-amino-1-(phenylmethyl)-piperidine and 45.0 g (0.215 mol) of 4-(methoxycarbonyl)-2-nitrobenzaldehyde in 1 l methanol were added in batches, at room temperature, 8.3 g (0.22 mol) of sodium borohydride and the mixture was then stirred for 30 minutes at the same temperature. The mixture was stirred into 1 l of ice water and thoroughly extracted with tert. butyl-methylether. The combined extracts were dried over sodium sulphate and evaporated down in vacuo, the residue was dissolved in as little methanol as possible and converted into the hydrochloride by treatment with methanolic hydrogen chloride solution. The crystalline salt was suction filtered, washed with methanol and diethylether, then taken up in water and made alkaline with saturated aqueous potassium carbonate solution. The mixture obtained was extracted thoroughly with ethyl acetate, the combined ethyl acetate extracts were dried over sodium sulphate and evaporated down. 58.2 g (70.6% of theory) of a brownish-yellow oil were obtained, which was further processed without any more purification.
    • d) Methyl 3-amino-4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-benzoate
  • A solution of 58.0 g (0.151 mol) of methyl 4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-nitrobenzoate in 800 ml of methanol was hydrogenated in the presence of 10 g of 5% rhodium/charcoal for 7 hours at room temperature. The catalyst was filtered off, the filtrate was evaporated down in vacuo. 50.0 g (93.7% of theory) of colourless crystals were obtained, which were further processed without any more purification.
    • e) Methyl 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-oxoquinazolin-7-carboxylate
  • Prepared analogously to Example A3e) from methyl 3-amino-4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-benzoate and N,N′-carbonyl-diimidazole in a yield of 66.3% of theory.
  • Slightly yellowish crystals.
  • IR (KBr): 1714.6; 1664.5 cm−1 (C═O)
    • f) Methyl 3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazolin-7-carboxylate
  • A solution of 35.5 g (0.0936 mol) of methyl 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-oxoquinazolin-7-carboxylate in 400 ml of methanol was hydrogenated in the presence of 5 g of 10% palladium/charcoal for 5 hours at 50° C. The catalyst was filtered off, the filtrate was evaporated down in vacuo. The residue was triturated with 150 ml of ethyl acetate and then suction filtered. After drying in vacuo 20.4 g (75.3% of theory) of colourless crystals were obtained, which were further processed without any more purification.
  • IR (KBr): 1718.5; 1672.2 cm−1 (C═O)
  • The following were prepared analogously:
    • (1) 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone
  • Rf: 0.3 (FM1)
  • IR (KBr): 1662.5 cm−1 (C═O)
    • (2) 3,4-dihydro-8-methoxy-3-(4-piperidinyl)-2(1H)-quinazolinone
  • Rf: 0.35 (FM1)
    • (3) 3,4-dihydro-6,7-dimethoxy-3-(4-piperidinyl)-2(1H)-quinazolinone
  • Rf: 0.40 (FM1)
    • EXAMPLE A5 3,4-dihydro-3-(4-piperidinyl)-1H-thieno[3,4-d]pyrimidin-2-one-trifluoroacetate a) Methyl 4-(ethoxycarbonylamino)-thiophene-3-carboxylate
  • A mixture of 50.0 g (0.258 mol) of methyl 4-aminothiophen-3-carboxylate-hydrochloride, 700 ml of toluene, 26 g (0.257 mol) of triethylamine and 27 ml (0.283 mol) of ethyl chlorocarbonate was refluxed for 5 hours. The insoluble matter was filtered off, the filtrate was evaporated down in vacuo and the residue was crystallised from petroleum ether. 59.0 g (99.8% of theory) of colourless crystals of melting point 52° C. were obtained.
  • In the same way, crystalline methyl 3-(ethoxycarbonylamino)-thiophen-2-carboxylate was obtained from methyl 3-aminothiophene-2-carboxylate and ethyl chlorocarbonate in a yield of 98.7% of theory.
  • IR (KBr): 1739.7; 1622 cm−1 (C═O, C═C)
    • b) 4-(ethoxycarbonylamino)-thiophene-1-carboxaldehyde
  • Into an ice-cold suspension of 12.9 g (0.34 mol) of lithium aluminium hydride in 800 ml of tert. butyl-methylether was added dropwise, at a reaction temperature of about 0° C., a solution of 59.1 g (0.258 mol) of methyl 4-(ethoxycarbonylamino)-thiophene-3-carboxylate in 200 ml of tert. butyl-methylether, and the mixture was then stirred for a further 2 hours at 10° C. Then 13 ml of water, 13 ml of 2N aqueous sodium hydroxide solution and 39 ml of water were added dropwise one after another and the mixture was stirred for 1 hour at room temperature. It was filtered, and 500 g of activated manganese (IV) oxide were added in batches to the filtrate with stirring. After the completion of the reaction, which could be monitored by thin layer chromatography, the mixture was filtered again and the filtrate was then evaporated down in vacuo. The crystalline residue which solidified was further processed without any more purification. yield: 28.2 g (54.9% of theory).
  • In the same way 3-(ethoxycarbonylamino)-thiophene-2-carboxaldehyde was obtained from methyl 3-(ethoxycarbonylamino)-thiophene-2-carboxylate in a yield of 71.9% of theory.
    • c) 4-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonylamino)-thiophene
  • A mixture of 28.2 g (0.142 mol) of 4-(ethoxycarbonyl-amino)-thiophene-3-carboxaldehyde, 28.2 g (0.141 mol) of 4-amino-1-(1,1-dimethyl-ethoxycarbonyl)piperidine and 300 ml of toluene was refluxed using a water separator until water formation had ceased. The solvent was removed in vacuo, the residue was dissolved in 300 ml of methanol and at room temperature combined batchwise with 5.5 g (0.145 mol) of sodium borohydride. The mixture was stirred for a further hour at room temperature, then evaporated down in vacuo and the residue was distributed between water and tert. butyl-methylether. The organic phase was dried over sodium sulphate and freed from solvent in vacuo. The oily residue was further processed without purification.
  • Yield: 54.0 g (99.9% of theory).
  • In the same way 2-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonylamino)-thiophene was obtained from 3-(ethoxycarbonylamino)-thiophene-2-carboxaldehyde, 4-amino-1-(1,1-dimethylethoxycarbonyl)piperidine and sodium borohydride in a yield of 100% of theory.
  • IR (KBr): 1728.1; 1693.4 cm−1 (C═O)
    • d) 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,4-d]pyrimidin-2-one
  • A solution of 54.0 g (0.141 mol) of 4-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonylamino)-thiophene in 300 ml of dimethylformamide was refluxed for 4 hours. After the end of the reaction, which could be monitored by thin layer chromatography, the still warm mixture was stirred into 1 l of ice water. The crystalline precipitate was suction filtered and dried at 30° C. in a circulating air drier.
  • Yield: 47.5 g (99.8% of theory).
  • In the same way 3,4-dihydro-3-[1-(1,1-dimethyl-ethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,2-d]pyrimidin-2-one was obtained from 2-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonyl-amino)-thiophene in a yield of 71% of theory. Colourless crystals of melting point 200° C. (acetonitrile).
  • IR (KBr): 1683.8; 1654.8 cm−1 (C═O)
    • e) 3,4-dihydro-3-(4-piperidinyl)-1H-thieno[3,4-d]pyrimidin-2-one-trifluoroacetate
  • A mixture of 10.0 g (0.0296 mol) of 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,4-d]pyrimidin-2-one and 50 ml of trifluoroacetic acid was stirred at room temperature for 30 minutes. The residue remaining after removal of the excess trifluoroacetic acid was triturated with diethylether and suction filtered. 5.8 g (55.8% of theory) of colourless crystals were obtained, which were used without further purification.
  • IR (KBr): 1664.5 cm−1 (C═O)
  • In the same way, crystalline 3,4-dihydro-3-(4-piperidinyl)-1H-thieno[3,2-d]pyrimidin-2-one-trifluoracetate was obtained from 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno-[3,2-d]pyrimidin-2-one and trifluoroacetic acid in a yield of 100% of theory.
  • IR (KBr): 1685.7; 1656.8 cm−1 (C═O)
    • EXAMPLE A6 3,4-dihydro-3-(4-piperidinyl)-2(1H)quinolone-hydrochloride
  • A mixture of 1.1 g (4.949 mmol) of 3-(4-pyridinyl)-2(1H)-quinolone (D. R. Bragg and D. G. Wibberley, J. Chem. Soc. 1961, 5074-5077), 100 ml of ethanol, 5 ml (5 mmol) of 1N hydrochloric acid and 0.2 g platinum (IV) oxide was hydrogenated for 4 hours at room temperature. The catalyst was filtered off, the filtrate evaporated down in vacuo and the residue was triturated with isopropanol. The precipitated crystals were suction filtered, washed with isopropanol and diethylether and dried in vacuo. Yield: 0.64 g (56.2% of theory).
  • IR (KBr): 1666.4 cm−1 (C═O)
  • MS: M+=230
      • m/e=146, 84
    EXAMPLE A7 3-(4-Piperidinyl-2(1H)-quinolone
  • A mixture of 8.6 g (0.0387 mol) of 3-(4-pyridinyl)-2(1H)-quinolone, 1.2 l of ethanol, 39 ml (0.039 mol) of 1N hydrochloric acid and 8.0 g of 10% palladium/charcoal was hydrogenated at a temperature of 40° C. until about 0.08 mol of hydrogen had been taken up. The mixture was freed from catalyst, the filtrate was evaporated down in vacuo, the residue was taken up in 200 ml of water and made ammoniacal. Common salt was added up to saturation point and the mixture was continuously extracted with dichloromethane using a perforator. The dichloromethane phase was evaporated down, the residue remaining was separated from by-products by chromatography over silica gel using FM1 as eluant. The appropriate fractions were combined, freed from solvent, dissolved in a little isopropanol and converted with ethanolic hydrogen chloride solution into the hydrochloride. Colourless crystals. Yield: 2.68 g (26.2% of theory).
  • MS: M+=228
  • IR (KBr): 1651 cm−1 (C═O)
    • EXAMPLE A8 5-chloro-3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone
  • An ice-cold solution of 6.3 g (0.0177 mol) of 5-chloro-3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-quinazolinone (prepared analogously to Example A4e)) in 50 ml of dichloromethane was mixed dropwise with 3.34 g (0.0234 mol) of α-chloroethyl chlorocarbonate whilst maintaining a reaction temperature of 0° C., after which the mixture was allowed to come back slowly to room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 50 ml of methanol and refluxed for 4 hours. After cooling, the colourless precipitate formed was suction filtered. Yield: 2.0 g (42.50% of theory).
  • IR (KBr): 1666.4 cm−1 (C═O)
    • EXAMPLE A9 6-bromo-3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone-hydrobromide
  • To a solution of 6.16 g (0.075 mol) of sodium acetate and 11.565 g (0.05 mol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a mixture of 150 ml of glacial acetic acid and 35 ml of water a solution of 8.8 g (0.055 mol) of anhydrous bromine in 20 ml of glacial acetic acid was added dropwise, with stirring and whilst maintaining a reaction temperature of 13 to 15° C. The mixture was filtered and the filtrate was evaporated down in vacuo. To remove any inorganic components the residue was taken up five times in 50 ml of dichloromethane, filtered and evaporated down, then triturated with a little acetonitrile, whereupon crystallisation occurred. The crystals were suction filtered, washed with acetonitrile/diethylether (1/1 v/v) and after drying in vacuo 5.5 g of colourless crystals of melting point 288° C. (decomposition) were obtained. By working up the mother liquors a further 4.5 g of material of the same quality was obtained. Total yield: 10.0 g (51% of theory).
  • C13H17Br2N3O (391.10)
  • Calculated: C, 39.92; H, 4.38; Br, 40.86; N, 10.74.
  • Found: 39.72 4.36 41.56 10.24.
  • IR (KBr): 1670.3 cm−1 (C═O)
    • EXAMPLE A10 3-(4-piperidinyl)-2,4(1H,3H)-quinazolindione a) 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzamide
  • To an ice-cold solution of 28 ml (134 mmol) of 4-amino-1-(phenylmethyl)piperidine in 200 ml of tetrahydrofuran were added, batchwise, 21.9 g (134 mmol) of isatoic acid anhydride. The resulting suspension was stirred for 2½ hours at room temperature and 2½ hours at reflux temperature, then freed from solvent. The residue was dissolved in 100 ml of hot ethanol, the resulting solution was filtered whilst hot after the addition of 5 g of activated charcoal. The crystal mass precipitated after cooling was suction filtered, washed with diisopropylether and dried in vacuo at 50° C. 28.3 g of colourless crystals were obtained. A further 5.1 g of a product of the same quality were isolated from the combined mother liquors. Total yield: 33.4 g (80.6% of theory).
  • IR (KBr): 1620 cm−1 (C═O)
  • MS: M+=309
    • b) 3-[1-(phenylmethyl)-4-piperidinyl]-2,4(1H,3H)-quinazolindione
  • Prepared analogously to Example A3e) from 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzamide and N,N′-carbonyldiimidazole in a yield of 97.8% of theory. Colourless crystals of melting point 223° C.
  • IR (KBr): 1720; 1647 cm−1 (C═O)
  • MS: M+=335
    • c) 3-(4-piperidinyl)-2,4(1H,3H)-quinazolindione
  • Prepared analogously to Example A3f) from 3-[1-(phenylmethyl)-4-piperidinyl]-2,4(1H,3H)-quinazolindione by hydrogenolysis in the presence of palladium/charcoal in a yield of 70% of theory.
  • Rf: 0.075 (FM1)
  • IR (KBr): 1703; 1657 cm−1 (C═O)
    • EXAMPLE A11 3,4-dihydro-3-[1-(4-piperidinyl)-4-piperidinyl]-2(1H)-quinazolinone a) 3,4-dihydro-3-[1-[1-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-2(1H)-quinazolinone
  • A mixture of 5.75 g (0.0249 mol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone, 4.75 g (0.0251 mol) of 1-(phenylmethyl)-4-piperidinone and 100 ml of ethanol was treated for 30 minutes in an ultrasound bath, then mixed with 9.5 ml (0.031 mol) of titanium (IV) isopropoxide, whereby after 10 minutes a crystal mass was formed. Then heating was continued using the ultrasound bath for a further 2½ hours to a maximum of 35° C., the mixture was allowed to cool to room temperature and 1.05 g (0.0167 mol) of sodium cyanoborohydride were then added in batches, whilst maintaining the pH at 5-6 using dilute methanolic hydrogen chloride solution, and it was then kept for 24 hours at room temperature. After this time another 1.05 g (0.0167 mol) of sodium cyanoborohydride were added and the same procedure was used as above. After a total of 48 hours reaction time the mixture was decomposed by the addition of water and worked up in the usual way. The crude product obtained was purified by column chromatography over silica gel using FM4 as eluant. 7.05 g (70% of theory) of a colourless crystalline substance were obtained.
  • In the same way exo-4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-(phenylmethyl)piperazine was obtained from tropinone and 1-(phenylmethyl)piperazine in a yield of 48.9% of theory. Colourless, amorphous substance, Rf=0.36 (FM1).
    • b) 3,4-dihydro-3-[1-(4-piperidinyl)-4-piperidinyl]-2(1H)-quinazolinone
  • Prepared analogously to Example A3f) from 3,4-dihydro-3-[1-[1-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-2(1H)-quinazolinone by hydrogenolysis, but using Pearlman's catalyst, in a yield of 92% of theory. Colourless crystals, Rf=0.48 (Macherey-Nagel, POLYGRAM® SIL G/UV254 ready-made films for TLC; eluant: dichloromethane/methanol/cyclohexane/conc. ammonia 68/20/10/5 v/v/v/v).
  • IR (KBr): 1660.6 cm−1 (C═O)
  • MS: M+=314
    • EXAMPLE A12 3-(4-piperidinyl)-3,4,4a,5,6,7,8,8a-octahydro-2(1H)-quinazolinone-acetate
  • A solution of 5.0 g (17.17 mmol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone-acetate in 70 ml of methanol was hydrogenated at room temperature and in the presence of 1.0 g rhodium (III) oxide-platinum (IV) oxide hydrate catalyst (46.45% rhodium, 20.15% platinum) until the hydrogen uptake had ceased. The catalyst and solvent were removed, the residue was triturated with 10 ml of diisopropylether and a few drops of isopropanol and the resulting crystals were suction filtered. After drying in vacuo 4.4 g (86.2% of theory) of colourless crystals were obtained, Rf=0.3 (eluant: dichloromethane/methanol/conc. ammonia 7.5/2.5/0.5 v/v/v).
  • IR (KBr): 1641 cm−1 (C═O)
  • MS: M+=237
    • EXAMPLE A13 1,1-dioxido-2-(4-piperidinyl)-3(4H)-1,2,4-benzothiadiazinone a) 2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide
  • Whilst carrying out external cooling with ice water a solution of 44.3 g (0.2 mol) of 2-nitrobenzenesulphonyl chloride in 250 ml of chloroform was added dropwise to a solution of 38.0 g (0.2 mol) of 4-amino-1-(phenylmethyl)piperidine and 22.0 g (0.22 mol) of triethylamine in 250 ml of chloroform. After the cooling was stopped the mixture was stirred for a further 30 minutes at room temperature, the reaction mixture was then extracted twice with 1 l water. The aqueous extracts were extracted once more with 100 ml of dichloromethane, the combined organic phases were then dried over sodium sulphate and evaporated down in vacuo. The highly viscous light-brown substance obtained in a yield of 75.0 g (99.9% of theory) was further processed without any more purification.
  • IR (KBr): 3363.7 (NH); 1541.0 (NO2); 1365.5 (NO2 or SO2); 1346.2 (NO2 or SO2); 1168.8 (SO2) cm−1
    • b) 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide
  • To a solution of 75.0 g (0.2 mol) of 2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide in 2.0 l ethanol was added dropwise, at room temperature, a solution of 174.0 g (0.828 mol) of sodium dithionite-dihydrate in 700 ml of water. After the heat of the exothermic reaction had died away the mixture was refluxed for 4.5 hours, then the ethanol was distilled off and the aqueous phase remaining was extracted thoroughly with dichloromethane.
  • The combined dichloromethane extracts were dried over sodium sulphate and evaporated down, the residue remaining was purified by column chromatography over silica gel using dichloromethane/methanol/conc. ammonia 80/20/0.25 (v/v/v) as eluant. 6.5 g (8.6% of theory) of a highly viscous oil were obtained.
  • IR(KBr): 1319.2, 1153.4 cm−1 (SO2)
    • c) 1,1-dioxido-2-[1-(phenylmethyl)-4-piperidinyl]-3(4H)-1,2,4-benzothiadiazinone
  • Prepared analogously to Example A3e) from 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide and N,N′-carbonyldiimidazole in a yield of 78% of theory. Colourless crystals of melting point 169-171° C.
  • IR(KBr) 1693.4 (C═O); 1359.7, 1340.4, 1188.1 (SO2) cm−1
    • d) 1,1-dioxido-2-(4-piperidinyl)-3(4H)-1,2,4-benzothiadiazinone
  • Prepared analogously to Example A3f), but using Pearlman's catalyst instead of palladium/charcoal, in a yield of 90% of theory. Colourless, amorphous substance.
  • IR(KBr): 1705.0 (C═O) cm−1
    • EXAMPLE A14 3,4-dihydro-2,2-dioxido-3-(4-piperidinyl)-2,1,3-benzothiadiazine a) 3,4-dihydro-2,2-dioxido-3-[1-(phenylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazine
  • A solution of 11.0 g (0.0372 mol) of 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenemethanamine in 200 ml of pyridine was added dropwise within 1.5 hours and at reflux temperature to a solution of 3.4 g (0.0354 mol) of sulphamide in 200 ml of pyridine and the mixture was then refluxed for 6 hours. The mixture was freed from solvent, the residue was purified by column chromatography using ethyl acetate/methanol 9/1 (v/v) as eluant. 5.5 g (43.5% of theory) of a colourless amorphous substance were obtained.
  • IR(KBr): 1344.3, 1166.9 cm−1 (SO2)
    • b) 3,4-dihydro-2,2-dioxido-3-(4-piperidinyl)-2,1,3-benzothiadiazine
  • Prepared analogously to Example A3f) from 3,4-dihydro-2,2-dioxido-3-[1-(phenylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazine by catalytic hydrogenation in the presence of palladium/charcoal in a quantitative yield. Colourless, amorphous substance.
  • IR(KBr): 1263.3, 1105.1 cm−1 (SO2)
    • EXAMPLE A15 D,L-4-phenyl-1-(4-piperidinyl)-imidazolidine-2,5-dione a) N2-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide
  • A mixture of 10.0 g (0.0398 mol) of N2-(1,1-dimethylethoxycarbonyl)-D,L-phenylglycine, 7.57 g (0.0398 mol) of 4-amino-1-(phenylmethyl)piperidine, 10 ml of triethylamine, 12.8 g (0.0399 mol) of TBTU and 5.4 g (0.0353 mol) of N-hydroxybenzotriazole-hydrate in 200 ml of THF-DMF mixture (1/1 v/v) was stirred overnight at room temperature. The residue remaining after removal of the solvent was taken up in ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down in vacuo. 14.8 g (87.8% of theory) of a colourless, amorphous substance were obtained.
  • IR(KBr): 1701.1, 1676.0, 1652.9 cm−1 (C═O)
  • Analogously N2-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamide was obtained from N2-(1,1-dimethylethoxycarbonyl)-D,L-phenylalanine and 4-amino-1-(phenylmethyl)piperidine in a yield of 85% of theory. Colourless, amorphous substance, Rf=0.83 (eluant: dichloromethane/cyclohexane/methanol/conc. ammonia=70/15/15/2 v/v/v/v).
  • IR(KBr): 1683.8, 1651.0 cm−1 (C═O)
    • b) N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide-bis-trifluoroacetate
  • Prepared analogously to Example A5e) from N2-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide and trifluoroacetic acid in a quantitative yield. Colourless, amorphous substance, Rf=0.56 (FM1)
  • Analogously N-[1-(phenylmethyl)-4-piperidinyl]1-D,L-phenylalaninamide-bis-trifluoracetate was obtained from N2-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamide in a yield of 92% of theory.
  • IR(KBr): 1670.3 cm−1 (C═O)
    • c) D,L-4-phenyl-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione
  • Prepared analogously to Example A3e) from N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide and N,N′-carbonyldiimidazole in a yield of 57.3% of theory. Colourless crystals, Rf=0.68.
  • IR(KBr): 1774.4, 1712.7 cm−1 (C═O)
  • Analogously D,L-4-(phenylmethyl)-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione was obtained from N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamide in a yield of 93% of theory. Colourless, fine crystals, Rf=0.6 (eluant: dichloromethane/methanol/cyclohexane/conc. ammonia=7/1.5/1.5/0.2 v/v/v/v).
  • IR(KBr): 1764.8, 1708.8 cm−1 (C═O)
  • MS: M+=363
    • d) D,L-4-phenyl-1-(4-piperidinyl)-imidazolidine-2,5-dione
  • Prepared analogously to Example A3f) from D,L-4-phenyl-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione by hydrogenolysis in the presence of palladium/charcoal in a yield of 84.3% of theory. Colourless, amorphous substance, Rf=0.5.
  • IR(KBr): 1766.7, 1706.9 cm−1 (C═O)
  • Analogously D,L-4-(phenylmethyl)-1-(4-piperidinyl)-imidazolidine-2,5-dione was obtained from D,L-4-(phenylmethyl)-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione. Colourless crystals, Rf=0.24 (eluant: dichloromethane/methanol/cyclohexane/conc. ammonia=7/1.5/1.5/0.2 v/v/v/v).
  • IR(KBr): 1766.7, 1705.0 cm−1 (C═O)
    • EXAMPLE A16 1,3-dihydro-3-(4-piperidinyl)-2(2H)-imidazo[4,5-c]quinolone a) 1-[2-(acetylamino)phenyl]-2-bromoethanone
  • 45.0 g (0.282 mol) of dry bromine were added dropwise to a boiling solution of 50.0 g (0.282 mol) of 1-[2-(acetylamino)phenyl]ethanone in 400 ml of chloroform at room temperature. The solvent was distilled off, the residue was distributed between dichloromethane and saturated ice-cold sodium hydrogen carbonate solution. The organic phase was dried over sodium sulphate, evaporated down in vacuo, the residue was triturated with diethylether and suction filtered. After drying in vacuo 35.4 g (49% of theory) of colourless crystals were obtained, Rf=0.48 (eluant: petroleum ether/ethyl acetate 2/1 v/v).
  • IR(KBr): 1685.69, 1664.47 cm−1 (C═O)
  • MS: M+=255/257 (Br)
    • b) 4-[2-(acetylamino)phenyl]-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-one
  • To a solution of 26.3 g (0.138 mol) of 4-amino-1-(phenylmethyl)piperidine and 17.8 g (0.138 mol) of DIEA in 300 ml of dichloromethane was added dropwise a solution of 35.4 g (0.138 mol) of 1-[2-(acetylamino)phenyl]-2-bromoethanone in 150 ml of dichloromethane and the mixture was kept for a further 2 hours at room temperature. With external cooling with ice 13.5 g (0.20 mol) of sodium cyanate and 12 ml of glacial acetic acid were then added and the mixture was stirred overnight in a thawing ice bath. It was washed with water and saturated sodium hydrogen carbonate solution, dried over sodium sulphate and freed from solvent. The residue was triturated with 50 ml of ethyl acetate-methanol mixture (9/1 v/v), the resulting crystals were suction filtered, washed with ethyl acetate and dried in vacuo. 37.0 g (68.7% of theory) of colourless crystals were obtained, Rf=0.41 (eluant: dichloromethane/methanol 9/1 v/v).
  • IR(KBr): 1678 cm−1 (C═O)
  • MS: M+=390 (Br)
    • c) 4-(2-aminophenyl)-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one
  • A mixture of 3.0 g (7.68 mmol) of 4-[2-(acetylamino)phenyl]-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one, 50 ml of 5 N sodium hydroxide solution and 25 ml of ethanol was refluxed for 3 hours. After cooling the organic phase was separated off, dried over sodium sulphate and evaporated down in vacuo. A colourless amorphous substance was obtained in a quantitative yield, Rf=0.53 (eluant: dichloromethane/methanol 9/1 v/v).
    • d) 1,3-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(2H)-imidazo[4,5-c]quinolone
  • A solution of 2.67 g (7.66 mmol) of 4-(2-aminophenyl)-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one in 50 ml of chloroform was mixed with 3.0 g of paraformaldehyde and refluxed for 3.5 hours. The residue remaining after evaporation of the solvent was taken up in 100 ml of methanol and acidified with methanolic hydrogen chloride solution. After stirring for one hour at room temperature the mixture was poured into 300 ml of saturated sodium hydrogen carbonate solution. The resulting mixture was extracted thoroughly with ethyl acetate, the combined extracts were dried over sodium sulphate and evaporated down in vacuo. The residue was purified by column chromatography over silica gel using FM4 as eluant. From the appropriate fractions 0.5 g (18.2% of theory) of a colourless, amorphous substance were isolated, Rf=0.24 (FM4).
  • IR(KBr): 1689 cm−1 (C═O)
  • MS: M+=358 (Br)
    • e) 1,3-dihydro-3-(4-piperidinyl)-2(2H)-imidazo[4,5-c]quinolone
  • Prepared analogously to Example A3f) from 1,3-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(2H)-imidazo[4,5-c]quinolone by hydrogenolysis in the presence of palladium/charcoal in a yield of 98.5% of theory. Colourless crystals, Rf=0.63 (FM1).
    • EXAMPLE A17 Preparation of β-(methoxycarbonyl)-arenebutanoic acids 3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid a) 4-(phenylmethoxy)-benzaldehyde
  • To a solution of 36.6 g (0.3 mol) of 4-hydroxybenzaldehyde in 100 ml of ethanol were added dropwise, one after another, a solution of 12.0 g (0.3 mol) of sodium hydroxide in 100 ml of water and a solution of 36.5 ml of (0.307 mol) of benzylbromide in 100 ml of ethanol and the mixture was then kept for 1 hour at 50° C. The ethanol was extensively distilled off, finally in vacuo, the remaining aqueous emulsion was divided between water and ethyl acetate. The ethyl acetate phase was dried over sodium sulphate and evaporated down in vacuo. The residue remaining crystallised on trituration with petroleum ether and was recrystallised from diisopropylether. 48.0 g (75.4% of theory) of colourless crystals of melting point 118-122° C. were obtained.
    • b) 3-(methoxycarbonyl)-4-[(4-phenylmethoxy)phenyl]-3-butenoic acid
  • To a freshly prepared solution of 2.3 g (0.1 mol) of sodium in 300 ml of anhydrous methanol were added 14.6 g (0.1 mol) of dimethyl succinate and after half an hour's stirring a solution of 21.2 g (0.1 mol) of 4-(phenylmethoxy)-benzaldehyde in 100 ml of anhydrous methanol were added dropwise. Then the mixture was refluxed for 6 hours, the methanol was distilled off under normal pressure and the remaining residue was kept for 30 minutes at a reaction temperature of 80° C. The viscous slurry obtained was stirred into 1 l of a glacial acetic acid-water mixture (1/1 v/v), the resulting mixture was extracted thoroughly with ethyl acetate. The combined ethyl acetate extracts were in turn extracted with saturated potassium carbonate solution. The potassium carbonate extracts were carefully acidified with acetic acid and then extracted thoroughly with ethyl acetate. These extracts were washed with water, dried over sodium sulphate and freed from solvent in vacuo. The residue was purified by column chromatography over silica gel using dichloromethane/petroleum ether/glacial acetic acid 25/74/1 (v/v/v). The colourless, partly crystallised mixture of diastereomers was obtained in a yield of 16.0 g (49% of theory). Rf=0.68 (eluant: ethyl acetate/petroleum ether 1:2 v/v).
  • IR(KBr): 1699.2 cm−1 (C═O)
  • The following were obtained analogously:
  • (1) 3-(methoxycarbonyl)-4-[3-(trifluoromethyl)phenyl]-3-butenoic acid was obtained from 3-(trifluoromethyl)benzaldehyde and dimethyl succinate in a yield of 21% of theory.
  • IR(KBr): 1738, 1726 cm−1 (C═O)
  • ESI-MS: (M−H)−=287
      • (M+H)+=289
      • (M+Na)+=311
  • (2) 3-(methoxycarbonyl)-4-(1-naphthyl)-3-butenoic acid was obtained from 1-naphtaldehyde and dimethyl succinate in a yield of 60% of theory.
  • Colourless oil
  • IR(KBr): 1712 cm−1 (C═O)
  • MS: M+=270
  • (3) 3-(methoxycarbonyl)-4-[3,5-dimethyl-4-phenylmethoxyphenyl]-3-butenoic acid was obtained from 3,5-dimethyl-4-phenylmethoxybenzaldehyde and dimethyl succinate in a yield of 66% of theory.
  • Colourless oil which could be further processed without purification.
  • (4) 4-(4-amino-3,5-dibromophenyl)-3-(methoxycarbonyl)-3-butenoic acid was obtained from 4-amino-3,5-dibromobenzaldehyde and dimethyl succinate in a yield of 21% of theory.
  • (5) 3-(Methoxycarbonyl)-4-(3-phenylmethoxyphenyl)-3-butenoic acid was obtained from 3-phenylmethoxybenzaldehyde and dimethyl succinate in a yield of 37% of theory.
    • c) 4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid
  • Prepared analogously to Example A3f) from 3-(methoxycarbonyl)-4-[(4-phenylmethoxy)phenyl]-3-butenoic acid by hydrogenolysis in the presence of palladium/charcoal in a yield of 96% of theory. Colourless oil, Rf=0.5 (eluant: ethyl acetate/petroleum ether/glacial acetic acid 66.3/33.3/0.4 v/v/v).
  • The following were obtained analogously:
  • (1) β-(methoxycarbonyl)-3-(trifluoromethyl)-benzenebutanoic acid was obtained from 3-(methoxycarbonyl)-4-[3-(trifluoromethyl)phenyl]-3-butenoic acid in a yield of 80% of theory. Rf=0.59 (eluant: ethyl acetate/petroleum ether 1/1/v/v).
  • ESI-MS: (M−H)−=289
  • (2) β-(methoxycarbonyl)-1-naphthalinebutanoic acid was obtained from 3-(methoxycarbonyl)-4-(1-naphthyl)-3-butenoic acid, however using platinum(IV)-oxide as a catalyst, in a yield of 31% of theory.
  • IR (KBr): 1734, 1711 (C═O) cm−1
  • MS: M+=272
  • β-(methoxycarbonyl)-1,2,3,4-tetrahydro-1-naphthaline-butanoic acid was isolated as a by-product in a yield of 8.4% of theory
  • IR (KBr): 1736, 1712 (C═O) cm−1
  • MS: M+=276
  • (3) 3,5-dimethyl-4-hydroxy-β-(methoxycarbonyl)-benzene butanoic acid was obtained from 3-(methoxycarbonyl)-4-[3,5-dimethyl-4-phenylmethoxyphenyl]-3-butenoic acid in a yield of 48% of theory.
  • Rf=0.11 (FM1)
  • IR (KBr): 1716 (C═O) cm−1
  • MS: M+=266
  • (4) 3-Hydroxy-β-(methoxycarbonyl)-benzene butanoic acid was obtained from 3-(Methoxycarbonyl)-4-(3-phenylmethoxyphenyl)-3-butenoic acid in a yield of 59% of theory.
  • Rf=0.24 (petroleum ether/ethyl acetate/glacial acetic acid 6/4/0.2 v/v/v)
  • IR (KBr): 1714 (C═O) cm−1
  • MS: M+=238
  • (5) 4-Amino-β-(methoxycarbonyl)-benzene butanoic acid was obtained from 3-(methoxycarbonyl)-4-(4-amino-3,5-dibromophenyl)-3-butenoic acid and in the presence of triethylamine in a quantitative yield.
  • Rf=0.53 (eluant: dichloromethane/methanol/glacial acetic acid 90/10/1.5 v/v/v))
  • IR (KBr): 1728 (C═O) cm−1
  • MS: M+=237
    • d) 3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid
  • To a solution of 12.0 g (0.05 mol) of 4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid in 200 ml of glacial acetic acid were added 150 ml of water and 8.0 g sodium acetate and then a solution of 15.58 g (0.0975 mol) of bromine in 60 ml of glacial acetic acid was added dropwise. The mixture was stirred for a further hour at room temperature, then evaporated down to two thirds in vacuo and the residue was divided between water and ethyl acetate. The ethyl acetate extracts were washed with water, dried over sodium sulphate and evaporated down in vacuo. After stirring with diisopropylether a colourless crystal was obtained. Yield: 12.0 g (62.2% of theory). Rf=0.4 (eluant: ethyl acetate/petroleum ether/glacial acetic acid 49.8/49.8/0.4 v/v/v).
  • IR(KBr): 1724 cm−1 (C═O)
  • MS: M+=394/396/398 (Br2)
    • EXAMPLE A18 1-(3-pyridinyl)piperazine a) 1-(phenylmethyl)-3-(3-pyridinyl)piperazine
  • To a solution of 5.0 g (0.0515 mol) of 3-fluoropyridine and 43.5 ml of 1-(phenylmethyl)piperazine in 300 ml of anhydrous diethylether was added dropwise, at boiling temperature, within 2.5 hours, 56 ml (0.112 mol) of a 2 molar solution of phenyllithium in a cyclohexane-diethylether mixture (7/3 v/v) and the resulting mixture was then kept at reflux temperature for a further 4 hours. The crude reaction product obtained as an oil after working up in the usual way was purified by column chromatography over silica gel (30-60 μm) using FM1/cyclohexane (7/3 v/v) as eluant. 12.0 g (92% of theory) of a colourless oil were obtained, Rf 0.52 (FM4; Macherey-Nagel, POLYGRAM® SIL G/UV254 Pre-coated plastic sheets for TLC).
  • MS: M+=253
    • 1-(3-Pyridinyl)piperazine
  • Prepared analogously to Example A3f) from 1-(phenylmethyl)-3-(3-pyridinyl)piperazine by hydrogenolysis in the presence of palladium/charcoal in a yield of 55% of theory. Colourless oil, Rf 0.35 (FM1).
  • IR(KBr): 1652.9 cm−1 (C═N)
    • EXAMPLE A19 1-(1-cyclohexyl-4-piperidinyl)piperazine-tris-trifluoroacetate a) 1-(1,1-dimethylethoxycarbonyl)-4-[1-(phenylmethyl)-4-piperidinyl]piperazine
  • A solution of 15.0 g (0.8054 mol) of 1-(1,1-dimethylethoxycarbonyl)piperazine and 14.26 ml (0.08053 mol) of 1-(phenylmethyl)-4-piperidinone in 250 ml of methanol was adjusted to a pH of between 5 and 6 by dropwise addition of acetic acid and mixed in batches with a total of 4.13 g (0.0624 mol) of 95% sodium cyanoborohydride, whilst taking care to maintain a pH of 5 to 6 by further dropwise addition of acetic acid. After stirring for 18 hours at room temperature the mixture was evaporated down in vacuo, the residue was made alkaline with soda and divided between water and ethyl acetate. After working up the ethyl acetate phase in the usual way 21.76 g (75.2% of theory) of a highly viscous colourless oil were obtained, Rf 0.66 (FM1).
    • b) 1-(1,1-dimethylethoxycarbonyl)-4-(4-piperidinyl)piperazine
  • Prepared analogously to Example A3f) from 1-(1,1-dimethylethoxycarbonyl)-4-[1-(phenylmethyl)-4-piperidinyl]piperazine by hydrogenolysis, but using Pearlman's catalyst instead of palladium/charcoal, in a yield of 79.7% of theory.
  • Colourless crystals, Rf=0.3 (FM1).
    • c) 1-(1,1-dimethylethoxycarbonyl)-4-(1-cyclohexyl-4-piperidinyl)piperazine
  • Prepared analogously to Example A19a) from 1-(1,1-dimethylethoxycarbonyl)-4-(4-piperidinyl)piperazine and cyclohexanone in a yield of 99% of theory. Colourless, highly viscous oil.
  • MS: M+=251
    • d) 1-(1-cyclohexyl-4-piperidinyl)piperazine-tris-trifluoroacetate
  • Prepared analogously to Example A5e) from 1-(1,1-dimethylethoxycarbonyl)-4-(1-cyclohexyl-4-piperidinyl)piperazine and trifluoroacetic acid in a quantitative yield. Colourless crystals, Rf=0.2 (FM1)
    • EXAMPLE A20 1-(1-ethyl-4-piperidinyl)piperazine-trihydrochloride a) 1-(1-ethyl-4-piperidinyl)-4-(phenylmethyl)piperazine
  • Prepared analogously to Example A19a) from 1-ethyl-4-piperidinone and 1-(phenylmethyl)piperazine in a yield of 71% of theory. Colourless, amorphous substance, Rf=0.46 (FM4).
    • b) 1-(1-ethyl-4-piperidinyl)piperazine-trihydrochloride
  • A mixture of 36.3 g (0.126 mol) of 1-(1-ethyl-4-piperidinyl)-4-(phenylmethyl)piperazine, 300 ml of 1N hydrochloric acid and 200 ml of methanol was hydrogenated at room temperature and in the presence of 4.0 g of 10% palladium/charcoal until the uptake of hydrogen had ceased. After working up in the usual way 22.9 g (59.3% of theory) of a colourless, crystalline substance was obtained.
  • MS: M+=197
  • In the same way exo-1-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)piperazine-trihydrochloride was obtained from exo-4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-(phenylmethyl)piperazine (see Example A11a)) by hydrogenolysis in the presence of palladium/charcoal in a yield of 91% of theory.
  • MS: M+=209
    • EXAMPLE A21 1-ethyl-4-(4-piperidinyl)piperidine a) 1-(phenylmethoxycarbonyl)-4-(4-piperidinyl)piperidine
  • To a mixture of 72.375 g (0.3 mol) of bipiperidine-dihydrochloride, 1500 ml of methanol, 75 ml of water and 100 mg of bromophenol blue were added dropwise, simultaneously, with stirring and at room temperature, a solution of 51.18 g (0.3 mol) of benzyl chlorocarbonate in 75 ml of toluene and 6 N sodium hydroxide solution (about 80 ml) were added, so that the indicator colour changed continuously. After all had been added, which took about 4 hours, the mixture was diluted with 300 ml of water and the organic solvent was distilled off in vacuo. The aqueous phase remaining was acidified with hydrochloric acid, whilst being externally cooled, extracted thoroughly with diethylether and then made alkaline with 50% potassium hydroxide solution. The mixture was extracted thoroughly with dichloromethane, the combined dichloromethane extracts were dried over magnesium sulphate and evaporated down in vacuo. The colourless, highly viscous, slowly crystallising oil remaining was further processed without any more purification.
  • Yield: 87.3 g (96.2% of theory).
  • IR(KBr): 1701.1 cm−1 (C═O)
    • b) 1-ethyl-4-[1-(phenylmethoxycarbonyl)-4-piperidinyl]piperidine
  • To a solution of 18.14 g (0.061 mol) of 1-(phenylmethoxycarbonyl)-4-(4-piperidinyl)piperidine in 450 ml of a methanol/water mixture (1/1 v/v) were added, with stirring, whilst maintaining a temperature of 15 to 20° C., 10.05 g (0.152 mol) of 95% sodium cyanoborohydride and 50 mg of bromocresol purple. Then a solution of 10.57 g (0.24 mol) of acetaldehyde in 50 ml of methanol and 1N hydrochloric acid were alternately added dropwise so that the colour of the mixture changed continuously from blue to yellow. After all had been added and the reaction had finished the mixture was adjusted to pH 2 with hydrochloric acid and extracted twice with 200 ml of diethylether. The aqueous phase was then made alkaline and extracted thoroughly with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulphate and evaporated down in vacuo. The colourless crystallising residue remaining was purified by column chromatography over silica gel (30-60 μm) using FM1 as eluant. Yield of colourless crystals of melting point 93-96° C.: 7.9 g (39.2% of theory).
  • IR(KBr): 1699.2 cm−1 (C═O)
    • c) 1-ethyl-4-(4-piperidinyl)piperidine
  • A solution of 7.6 g (0.023 mol) of 1-ethyl-4-[1-(phenylmethoxycarbonyl)-4-piperidinyl]piperidine in a mixture of 70 ml of methanol, 30 ml of water and 10 ml of glacial acetic acid was hydrogenated in the presence of 10% palladium/charcoal at room temperature and 3 bar of hydrogen pressure until the uptake of hydrogen had ceased. After working up in the usual way the desired compound was obtained as a colourless oil in a quantitative yield.
    • EXAMPLE A22 Hexahydro-1-methyl-4-(4-piperidinyl)-1H-1,4-diazepine a) Hexahydro-1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-1H-1,4-diazepine
  • Prepared analogously to Example A11a) from hexahydro-1-methyl-1H-1,4-diazepine and 1-(phenylmethyl)-4-piperidinone in a yield of 35% of theory. Colourless viscous oil.
  • MS: M+=287
  • The following were prepared in the same way:
    • (1) 1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-piperazine
  • from 1-methylpiperazine and 1-(phenylmethyl)-4-piperidinone
  • Yield: 39.9% of theory, colourless viscous oil
    • (2) 1-acetyl-4-[1-(phenylmethyl)-4-piperidinyl]piperazine
  • from 1-acetylpiperazine and 1-(phenylmethyl)-4-piperidinone
  • Yield: 24.2% of theory, colourless viscous oil
  • Rf: 0.46 (eluant: ethyl acetate/methanol/conc. ammonia 50/50/2 v/v/v)
  • IR(KBr): 1647 cm−1 (C═O)
  • MS: M+=301
    • (3) 4-(dimethylamino)-1-[1-(phenylmethyl)-4-piperidinyl]-piperidine
  • from 4-(dimethylamino)piperidine and 1-(phenylmethyl)-4-piperidinone
  • Yield: 28.9% of theory; colourless viscous oil
  • Rf: 0.58 (eluant: ethyl acetate/methanol/conc. ammonia 50/50/2 v/v/v)
  • MS: M+=301
    • (4) 1-(1,1-dimethylethoxycarbonyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine
  • from 1-(1,1-dimethylethoxycarbonyl)-4-piperidinone and 1-(phenylmethyl)piperazine
  • Yield: 86.6% of theory. Colourless, amorphous substance
  • Rf: 0.58 (eluant: dichloromethane/methanol 9/1 v/v)
    • b) Hexahydro-1-methyl-4-(4-piperidinyl)-1H-1,4-diazepine
  • Prepared analogously to Example A3f) from hexahydro-1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-1H-1,4-diazepine by hydrogenolysis, but using Pearlman's catalyst instead of palladium/charcoal, in a quantitative yield. Colourless viscous oil.
  • MS: M+=197
  • The following were obtained in the same way:
    • (1) 1-methyl-4-(4-piperidinyl)piperazine
  • from 1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]piperazine in a quantitative yield. Colourless viscous oil.
  • MS: M+=183
    • (2) 1-acetyl-4-(4-piperidinyl)piperazine
  • from 1-acetyl-4-[1-(phenylmethyl)-4-piperidinyl]piperazine in a yield of 81.9% of theory. Colourless crystals.
  • IR(KBr): 1631 cm−1 (C═O)
    • (3) 4-(dimethylamino)-1-(4-piperidinyl)piperidine
  • from 4-(dimethylamino)-1-[1-(phenylmethyl)-4-piperidinyl]-piperidine in a yield of 76.8% of theory. Colourless, amorphous substance.
    • (4) 1-(1,1-dimethylethoxycarbonyl)-4-(1-piperazinyl)piperidine-hydrochloride
  • from 1-(1,1-dimethylethoxycarbonyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine-hydrochloride.
  • Yield: 96% of theory. Colourless crystals
  • Rf: 0.23 (eluant: dichloromethane/methanol 9/1 v/v)
    • EXAMPLE A23 4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine-bis-trifluoroacetate a) 1-(1,1-dimethylethoxycarbonyl)-4-piperidinecarboxylic acid
  • To a mixture of 25.9 g (0.2 mol) of piperidine-4-carboxylic acid, 200 ml (0.2 mol) of 1N sodium hydroxide solution and 200 ml of tetrahydrofuran were added 48.0 g (0.22 mol) of di-tert.-butyl pyrocarbonate and the mixture was stirred overnight at room temperature. The tetrahydrofuran was distilled off, finally in vacuo, and the remaining aqueous solution was acidified with citric acid. The colourless crystals precipitated were suction filtered and dried at 40° C. in a circulating air drier. Yield: 45.5 g (99.2% of theory).
  • IR(KBr): 1733.9, 1662.5 cm−1 (C═O)
    • b) 1-(1,1-dimethylethoxycarbonyl)-4-[(4-methyl-1-piperazinyl)-carbonyl]-piperidine
  • Prepared analogously to Example A15a) from 1-(1,1-dimethylethoxycarbonyl)-4-piperidinecarboxylic acid and 1-methylpiperazine in the presence of TBTU in a yield of 76% of theory. Colourless, amorphous substance, Rf=0.64 (eluant: dichloromethane/methanol/conc. ammonia 50/50/1 v/v/v).
  • IR(KBr): 1693, 1678 cm−1 (C═O)
  • The following were prepared in the same way:
    • (1) 1-methyl-4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-piperidine
  • from 1-methyl-4-piperidinecarboxylic acid and 1-(1,1-dimethylethoxycarbonyl)piperazine in a yield of 97% of theory.
  • Colourless crystals.
  • IR(KBr): 1683.8, 1629.8 cm−1 (C═O)
    • (2) 1-(1,1-dimethylethoxycarbonyl)-4-(isonicotinoyl)piperazine
  • from 1-(1,1-dimethylethoxycarbonyl)-piperazine and 4-pyridinecarboxylic acid in a yield of 76.8% of theory. Colourless crystals of melting point 139.2-140.2° C. and Rf=0.84 (eluant: dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v).
  • IR(KBr): 1689.5, 1625.9 cm−1 (C═O)
    • c) 4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine-bis-trifluoroacetate
  • prepared analogously to Example A5e) from 1-(1,1-dimethylethoxycarbonyl)-4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine and trifluoroacetic acid in a yield of 89% of theory.
  • Colourless, amorphous substance.
  • The following were prepared in the same way:
    • (1) 1-methyl-4-[(1-piperazinyl)carbonyl]-piperidine
  • from 1-methyl-4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-piperidine and trifluoroacetic acid in a yield of 57% of theory. Colourless, amorphous substance.
  • IR(KBr): 1679.9, 1645.2 cm−1 (C═O)
  • MS: M+=211
    • (2) 4-(isonicotinoyl)piperazine-trifluoroacetate
  • from 1-(1,1-dimethylethoxycarbonyl)-4-(isonicotinoyl)piperazine and trifluoroacetic acid in a yield of 98.3% of theory. Colourless, amorphous substance.
  • IR(KBr): 1676.0 cm−1 (C═O)
    • EXAMPLE A24
  • Preparation of compounds of the general structure:

  • Boc-A-NR3R4
    • 1-[N2-(1,1-dimethylethoxycarbonyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine
  • To a mixture of 18.8 g (0.0494 mol) of Boc-Lys(Z)-OH, 6.5 g (0.05 mol) of DIEA, 16 g (0.05 mol) of TBTU, 6.6 g (0.049 mol) of HOBt and 100 ml of dimethylformamide were added dropwise, with stirring, 8.1 g (0.0494 mol) of 1-(4-pyridinyl)piperazine, dissolved in 40 ml of DMF, and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was then washed three times successively with 70 ml of saturated aqueous sodium hydrogen carbonate solution and once with 70 ml of saturated aqueous saline solution, dried over sodium sulphate and evaporated down in vacuo. 24.2 g (93.2% of theory) of a yellowish oil were obtained, which was used for the following reactions without further purification.
  • IR (KBr): 1650, 1713 cm−1 (C═O)
  • Rf (FM1): 0.59
  • The following were prepared analogously:
  • A NR3R4 Remarks % Yield Rf Eluant IR [cm−1]
    A9 C1 THF as LM 63.2 0.4 FM1 (KBr): C═O
    KHSO4/ 1705.0; 1649
    A4 C1 NaCl soln 93.2 0.59 FM1 (KBr): C═O
    1647.7; 1712.7
    A5 C1 66 0.55 FM1 (KBr): C═O
    1655; 1709
    A5 C8 54 0.8 FM1 (KBr): C═O
    1653; 1713
    A6 C8 91 0.8 FM1 (KBr): C═O
    1645; 1710.8
    A10 C1 63 0.5 FM1 (KBr): C═O
    1665; 1695
    A10 C8 30 0.41 FM4 (KBr): C═O
    1662; 1699
    • EXAMPLE A25
  • Preparation of compounds of general formula:

  • Cbz-A-NR3R4
    • 1-[N2-(phenylmethoxycarbonyl)-N6-(1,1-dimethyl-ethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine
  • To a mixture of 100 g (0.263 mol) of Z-Lys(Boc)-OH, 86.1 g (0.268 mol) of TBTU and 36.3 g (0.263 mol) of HOBt in 600 ml of dimethylformamide were added 43.0 g (0.263 mol) of 1-(4-pyridinyl)-piperazine and 47.2 ml (0.268 mol) of DIEA with stirring and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo and the residue divided between ethyl acetate and aqueous saturated sodium hydrogen carbonate solution. The aqueous phase was extracted twice more with a mixture of ethyl acetate/methanol (10/1, v/v) and the combined organic phases were washed once with saturated sodium hydrogen carbonate solution. The organic phase was, after drying over sodium sulphate, evaporated down in vacuo and the residue was taken up in 750 ml of ethyl acetate and washed four times with 100 ml of water, six times with 100 ml of 1% potassium hydrogen sulphate solution, once with 100 ml of water, twice with 100 ml of 31 aqueous ammonia solution and twice with 100 ml of water. The organic phase was evaporated down after drying over sodium sulphate. 120 g (87% of theory) of the desired product were obtained as an oil, which was used without further purification for the subsequent reactions.
  • IR (KBr): 1709 cm−1 (C═O)
  • Rf (FM1): 0.59
  • EI-MS: M+=525
  • The following were prepared analogously:
  • %
    A NR3R4 Remarks Yield MS Rf Eluant IR [cm−1]
    A3 C4 100
    A3 C3 Triethylamine as 100 0.8 FM1 (KBr): C═0
    base 1643.3; 1710.8
    A11 C1 98.8 0.5 FM1 (KBr): C═O
    1705.0; 1643.3
    A3 C1 81 EI: M+ = 525 0.59 FM1 (KBr): C═O
    1708.8;
    A3 C5 LC/SiO2/FM4 95 YED: M = 525 0.67 FM4
    A3 C6 THF, LC/SiO2/FM4 92 0.82 FM4 (KBr): C═O
    1710.8; 1641.3
    A3 C8 Further reacted as 100
    crude product
    • EXAMPLE A26
  • Preparation of compounds of general formula:

  • H-A-NR3R4
    • 1-[N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine
  • To a mixture of 24.2 g (46 mmol) of 1-[N2-(1,1-dimethylethoxycarbonyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine and 150 ml of methylene chloride were added 50 ml of trifluoroacetic acid and the reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralised by the addition of saturated aqueous sodium hydrogen carbonate solution, the organic phase was dried and evaporated down in vacuo. 12 g (62% of theory) of the desired compound were obtained as a colourless oil.
  • IR (KBr): 1648 cm−1 (C═O)
  • Rf (FM1): 0.5
  • The following were prepared analogously:
  • A NR3R4 Remarks % Yield Rf Eluant IR [cm−1]
    A9 C1 100 0.4 FM2 (KBr): C═O
    1676.0; 1645.2
    A4 C1 61.5 0.48 FM1 (KBr): C═O
    1647.7; 1712.7
    A5 C1 55 0.42 FM1 (KBr): C═O
    1651
    A5 C8 further 100 0.19 FM1
    reacted as
    crude
    product
    A6 C1 82 0.3 FM1 (KBr): C═O
    1647; 1676
    A6 C8 further 100 0.23 FM1 (KBr): C═O
    reacted as 1674
    crude
    product
    A10 C1 38 0.55 FM1 (KBr): C═O
    1643
    A10 C8 further 100 0.15 FM1
    reacted as
    crude
    product
    • EXAMPLE A27
  • Preparation of compounds of general formula:

  • H-A-NR3R4
    • 1-[N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
  • A solution of 120 g (0.228 mol) of 1-[N2-(phenylmethoxycarbonyl)-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine in 1000 ml of methanol and 240 ml of 1M aqueous potassium hydrogen sulphate solution was hydrogenated in the presence of 30 g palladium on charcoal (10%) at 20° C. and 3 bar of hydrogen pressure until the uptake of hydrogen had ceased. The catalyst was filtered off, the filtrate evaporated down in vacuo, the residue was taken up in isopropanol/methanol and adjusted to pH 7-8 by the addition of a concentrated aqueous ammonia solution. The solution was filtered and evaporated to dryness. 87 g (97% of theory) of an oil were obtained.
  • IR (KBr): 1634, 1701 cm−1 (C═O)
  • Rf: 0.79 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1 (v/v/v)
  • The following were prepared analogously:
  • A NR3R4 Remarks % Yield MS Rf Eluant IR [cm−1]
    A3 C4 93 ESI: M + H = 391 (M + Na = 413) 0.6 FM1 (KBr): C═0
    1637.5; 1706.9
    A3 C3 100 0.3 FM1 (KBr): C═0
    1641.3; 1705
    A11 C1 78.5 0.2 FM1 (KBr): C═O
    1701.1; 1641.3
    A7 C1 without KHSO4 80.2 0.2 FM7
    A3 C1 97 0.79 ethyl (KBr): C═O
    acetate/methanol/ 1633.6; 1701.1
    conc. aqueous
    ammonia 6/4/1
    (v/v/v)
    A3 C5 without KHSO4 53 0.39 FM4 (KBr): C═O
    1733.9; 1624.0
    A3 C6 without KHSO4 89 0.38 FM4 (KBr): C═O
    1706.9; 1645.2
    A3 C8 further reacted as 100 0.3 FM1
    crude product
    • EXAMPLE A28
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00079
    • 1-[N2-[N-(1,1-dimethylethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
  • To a mixture of 2.58 g (5.88 mmol) of N-[(1,1-dimethylethoxy)-carbonyl]-3,5-dibromo-D-tyrosine, 1.03 g (8 mmol) of DIEA, 1.93 g (6 mmol) of TBTU, 0.79 g (5.8 mmol) of HOBt and 100 ml of dimethylformamide were added dropwise, 2.5 g (5.88 mmol) of 1-[N6-[(phenylmethoxy)-carbonyl]-L-lysyl]-4-(4-pyridinyl)piperazine, dissolved in 50 ml of dimethylformamide, with stirring. The reaction mixture was stirred overnight at room temperature, then evaporated down in vacuo and the residue was taken up in ethyl acetate. The organic phase was washed twice with aqueous saturated sodium hydrogen carbonate solution and once with aqueous saturated saline solution, dried and evaporated down in vacuo. The purification was carried out by column chromatography (aluminium oxide, activity stage III (6% water content) (ICN Biomedicals), eluant: ethyl acetate/methanol/ammonia=8/2/0.5 (v/v/v), followed by methanol/ammonia=7/3 (v/v)). 4.0 g (80% of theory) of an amorphous substance were obtained.
  • IR (KBr): 1643, 1709 cm−1 (C═O)
  • Rf: 0.52 (FM1)
  • ESI-MS: (M+H)+=845/847/849 (Br2)
  • The following were prepared analogously (in each case n=1):
  • R2 A NR3R4 Remarks % Yield MS Rf Eluant IR [cm−1]
    AS7 A0 C4 LM: THF; 100
    reacted as
    crude product
    AS1 A0 C11 reacted as 69
    crude product
    AS4 A0 C20 59 ESI: (M + H)+ = (KBr): C═0
    600/2/4 (Br2) 1639; 1707
    AS1 A0 C4 71
    AS4 A0 C11 53 0.5 FM1
    AS7 A0 C1 reacted as 100 (KBr): C═0
    crude product 1644
    AS4 A7 C1 NEt3 as base; 100 0.4 FM8
    reacted as
    crude product
    AS1 A4 C1 80 ESI: (M + H)+ = 0.52 FM1 (KBr): C═O
    845/7/9 (Br2) 1643.3;
    1708.8
    AS4 A0 C5 Boc-AS4 83 EI: M+ = 0.69 FM5 (KBr): C═O
    LC/SiO2/FM5 581/3/5 (Br2) 1706.9;
    1641.3
    AS4 A0 C15 LC/SiO2/FM4 86 EI: M+ = 0.83 FM4 (KBr): C═O
    382/4/6 (Br2) 1706.9;
    1641.3
    AS1 A0 C5 LC/SiO2/FM5 81 0.5 FM5 (KBr): C═O
    1705.0;
    1637.5
    AS4 A0 C16 LC/SiO2/FM4 85 EI: (M + H)+ = 0.42 FM4 (KBr): C═O
    THF 582/4/6 (Br2) 1706.9;
    1643.3
    AS1 A0 C15 THF 76 0.53 FM4 (KBr): C═O
    LC/SiO2/FM4 1701.1;
    1637.5
    AS4 A0 C3 LC/SiO2/FM6 83 ESI: (M + H)+ = 0.71 FM6 (KBr): C═O
    598/600/2 (Br2) 1706.9;
    1641.3
    AS1 A0 C16 LC/SiO2/FM4 85 0.35 FM1 (KBr): C═O
    1705;
    1641.3
    AS1 A0 C6 LC/SiO2/FM6 84 0.54 FM6 (KBr): C═O
    1701.1;
    1635.5
    AS4 A0 C18 LC/SiO2/FM4 95 0.66 FM4 (KBr): C═O
    1705;
    1641.3
    AS1 A0 C37 90 0.43 FM1 (KBr): C═O
    1645;
    1714.5
    AS4 A0 C37 95 0.51 FM4 (KBr): C═O
    1643.3;
    1705
    AS4 A0 C22 75 (KBr): C═O
    1635.5;
    1708.8
    AS4 A0 C21 92 M+ = 0.42 FM4 (KBr): C═O
    582/4/6 (Br2) 1643; 1705
    AS4 A5 C1 69 ESI: (M + H)+ = (KBr): C═O
    939/41/43 (Br2) 1653; 1709
    AS4 A0 C23 85 (KBr): C═O
    1645; 1709
    AS4 A10 C1 65 M+: 652/4/6 (KBr): C═O
    1649; 1707
    AS4 A0 C24 79 M+: 589/91/93 (KBr): C═O
    1643; 1707
    AS4 A5 C8 76 (KBr): C═O
    1643; 1713
    AS4 A6 C1 95 (KBr): C═O
    1645; 1710.8
    AS4 A6 C8 88 M+: 657/9/61 (KBr): C═O
    1628; 1713
    AS4 A10 C8 46 ESI: (M + H)+ = (KBr): C═O
    858/60/62 (Br2) 1647; 1707
    AS4 A0 C26 46 (KBr): C═O
    1637.5; 1707
    AS1 A0 C1 further 100
    reacted as
    crude product
    AS1 A0 C8 55 0.3 dichloro- (KBr): C═O
    methane/ 1632
    methanol
    9/1
    AS1 A0 C18 84 ESI: (M + H)+ = 0.4 FM4 (KBr): C═O
    613/5/7 (Br2) 1641; 1707
    AS1 A0 C3 81 (KBr): C═O
    1638; 1701
    AS1 A0 C21 70 0.28 FM4 (KBr): C═O
    1643; 1707
    AS4 A0 C6 47 (KBr): C═O
    1639; 1707
    AS4 A0 C19 90 (KBr): C═O
    1639; 1707
    AS9 A0 C1 further 47
    reacted as
    crude product
    AS1 A7 C1 NEt3 as base; 83 0.28 FM1
    further
    reacted as
    crude product
    AS4 A0 C38 67 0.5 FM1
    AS4 A0 C37 84
    AS4 A0 C39 100 (raw) 0.68 FM1
    AS4 A0 C40 36
    AS1 A0 C42 90 0.43 FM1 (KBr): C═0
    1645/1715
    AS4 A0 C42 100 0.51 FM4 (KBr): C═0
    1643/1705
    AS1 A0 C43 78 0.9 EE/MeOH (KBr): C═0
    95/5 1636/1676/
    1659
    AS1 A0 C44 47 0.9 EE/MeOH (KBr): C═0
    95/5 1638/1701
    AS1 A0 C45 72 EI: M+ = 0.9 EE/MeOH (KBr): C═0
    591/3/5 (Br2) 9/1 1638/1695
    AS1 A0 C47 80 EI: M+ = 0.95 EE/MeOH (KBr): C═0
    596/98/600 9/1 1636/1705
    (Br2)
    AS1 A0 C49 89 0.9 EE/MeOH (KBr): C═0
    9/1 1636/1684
    AS4 A0 C44 69 0.9 EE/MeOH (KBr): C═0
    9/1 1643/1707;
    CN 2235
    AS1 A0 C50 93 EI: M+ = 0.9 EE/MeOH (KBr): C═0
    598/600/602 9/1 1636/1705
    (Br2)
    AS1 A0 C51 100 0.1 EE/MeOH/ (KBr): C═0
    NH4OH 1638/1707
    5/5/0.1
    AS4 A0 C52 63 0.56 FM1 (KBr): C═0
    1641/1705
    AS4 A0 C53 83 EI: M+ = (KBr): C═0
    601/3/5 (Br2) 1638/1705
    AS4 A0 C64 41 ESI: (M + H)+ = (KBr): C═0
    610/12/14 1639/1701
    (Br2)
    AS1 A0 C53 66 0.45 CH2Cl2/ (KBr): C═0
    MeOH/ 1639/1709
    NH4OH
    70/30/1
    AS4 A0 C51 88 0.35 CH2Cl2/ (KBr): C═0
    MeOH/ 1641/1691
    NH4OH
    50/50/0.5
    AS4 A0 C66 77 EI: M+ = 0.75 CH2Cl2/ (KBr): C═0
    629/31/33 MeOH/ 1641/1707
    (Br2) NH4OH
    9/1/0.1
    AS16 A0 C8 100 0.8 FM1
    AS16 A0 C1 56 0.5 EE/MeOH/ (KBr): C═0
    NH4OH 1695
    9/1/1
    AS4 A0 C8 100
    AS1 A0 C53 70.0 EI: M+ = 0.10 CH2Cl2/MeOH/ (KBr): C═0
    502/4/6 (Br2) NH4OH 70/30/1 1676
    AS4 A0 C70 47.0 (KBr): C═0
    1645/1707
    AS1 A0 C64 31.0 0.50 CH2Cl2/MeOH/ (KBr): C═0
    NH4OH 90/10/1 1639/1707
    AS1 A0 C70 20.0
    AS4 A0 C72 50.0 0.50 CH2Cl2/MeOH/
    NH4OH 90/10/1
    AS19 A0 C8 98.0
    AS35 A0 C8 92.0 0.70 FM1
    AS36 A0 C8 65.0
    • EXAMPLE A29
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00080
    • 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyridinyl)-piperazine
  • A mixture of 39 g (0.089 mol) of 4-amino-3,5-dibromo-N-[(1,1-dimethylethoxy)carbonyl]-D-phenylalanine, 35.7 g (0.111 mol) of TBTU, 12.3 g (0.089 mol) of HOBt, 14.5 g. (0.089 mol) of 1-(4-pyridinyl)-piperazine and 19.6 ml of (0.111 mol) of DIEA in 1000 ml of tetrahydrofuran was stirred overnight at room temperature. The reaction mixture was extracted once with saturated aqueous saline solution and twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted once with tetrahydrofuran and the combined tetrahydrofuran phases were washed once with saturated aqueous saline solution. After drying the organic phase with sodium sulphate it was evaporated down in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was filtered after drying again and evaporated down in vacuo. 52.5 g of the intermediate compound were obtained as a viscous oil, which was then mixed with 300 ml of methylene chloride and 8.0 ml of trifluoroacetic acid and stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo, the residue formed was triturated with ether. 45.8 g (72% of theory) of the desired product were obtained as a white amorphous solid.
  • IR (KBr): 1643, 1674 cm−1 (C═O)
  • Rf: 0.36 (ethyl acetate/methanol=6/4 (v/v))
  • The following were prepared analogously (in each case n=1):
  • R2 A NR3R4 Remarks % Yield MS Rf Eluant IR [cm−1]
    AS7 A0 C8 Crude product; 84
    Boc-cleaving
    with pure TFA
    AS4 A0 C8 63 ESI: (M + H)+ = (KBr): C═0
    486/88/90 (Br2) 1632
    AS4 A0 C4 63 ESI: (M + H)+ = (KBr): C═0
    481/3/5 (Br2) 1620
    AS1 A9 C1 55 0.25 FM2 (KBr): C═O
    1674.1;
    1643.3
    AS4 A0 C8 81 ESI: (M + H)+ = 0.6 FM2 (KBr): C═O
    486/8/90 (Br2) 1629.8
    AS4 A0 C1 72 0.38 ethyl acetate/ (KBr): C═O
    methanol = 6/4 1643.3;
    (v/v) 1674.1
    AS1 A0 C20 30
    AS4 A0 C65 41 EI: M+ = (KBr): C═0
    515/17/19 (Br2) 1618
    AS1 A0 C65 15 ESI: (M + H)+ = 0.08 FM1 (KBr): C═0
    517/19/21 (Br2) 1635
    AS4 A0 C78 77.0 ESI: (M + H)+ = 0.30 CH2Cl2/MeOH/ (KBr): C═0
    529/31/33 (Br2) NH4OH = 90/10/1 1674
    AS1 A0 C78 60.0 ESI: (M + H)+ = 0.10 CH2Cl2/MeOH/ (KBr): C═0
    531/33/35 (Br2) NH4OH = 80/20/1 1670
    AS4 A0 C71 43.0 0.20 CH2Cl2/MeOH/ (KBr): C═0
    NH4OH = 90/10/1 1678
    AS31 A0 C20 39.0 EI: M+ = 382 0.30 CH2Cl2/MeOH/ (KBr): C═0
    NH4OH = 80/20/1 1678
    AS31 A0 C53 83.0 EI: M+ = 383 (KBr): C═0
    1678
    • EXAMPLE A30
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00081
    • 1-[N2-[N-(9-fluorenylmethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
  • A mixture of 63 g (0.1123 mol) of N-[(9-fluorenylmethoxy)-carbonyl]-3,5-dibromo-D-tyrosine, 44 g (0.1123 mol) of 1-[N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine, 39.7 g (0.1235 mol) of TBTU, 15.5 g (0.1123 mol) of HOBt, 21.7 ml (0.1235 mol) of DIEA and 600 ml of dimethylformamide was stirred for 20 hours at room temperature. The reaction mixture was evaporated down in vacuo and the residue divided between ethyl acetate/methanol (10/1 v/v) and saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed once with saturated aqueous sodium hydrogen carbonate solution and after drying evaporated down in vacuo. The residue was recrystallised twice from isopropanol (22.6 g; 22% of theory), the mother liquors were combined, evaporated down and purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM; eluant: ethyl acetate/methanol=8/2 (v/v)). A further 28.0 g (26.7% of theory) of the desired end product were obtained. Total yield: 49% of theory.
  • IR (KBr): 1641, 1705 cm−1 (C═O)
  • Rf: 0.46 (ethyl acetate/methanol=6/4 (v/v))
  • ESI-MS: (M+H)+=933/935/937 (Br2)
  • The following were prepared analogously:
  • R2 A NR3R4 Remarks % Yield MS Rf Eluant IR [cm−1]
    AS1 A3 C1 48 ESI: (M + H)+ = 0.46 Ethyl acetate/ (KBr): C═O
    933/5/7 (Br2) methanol = 6/4 1641.3; 1705.5
    (v/v)
    AS1 A3 C5 THF/SiO2/FM4 80 ESI: (M + H)+ = 0.72 FM1 (KBr): C═O
    933/5/7 (Br2) 1701.1; 1635.5
    AS1 A3 C6 THF 60 ESI: M− = 0.47 FM4 (KBr): C═O
    960/2/4 (Br2) 1712.7; 1631.7
    AS5 A3 C1 THF 61 ESI: (M + H)+ = 0.36 FM4 (KBr): C═O
    LC/SiO2/FM4 917/19/21 (Br2) 1708.8; 1645.2
    Diastereomers
    AS10 A0 C1 THF 90 0.52 FM4
    AS1 A3 C18 73 0.46 FM1 (KBr): C═O
    1635.5; 1712.7
    AS10 A3 C1 THF 85 (KBr): C═O
    1643.3; 1708.8
    AS10 A3 C4 THF 82 (KBr): C═O
    1639.4; 1710.8
    AS10 A3 C1 THF 85 (KBr): C═O
    1643; 1709
    AS4 A3 C18 94 ESI: (M + H)+ = (KBr): C═O
    963/5/7 (Br2) 1633.6; 1711
    AS15 A0 C8 90 (KBr): C═O
    1635.5; 1617.5
    AS12 A0 C8 44 ESI: (M + H)+ = (KBr): C═O
    577 1630; 1714.6
    AS10 A0 C4 88 0.49 FM4 (KBr): C═O
    1635.5; 1716.5
    AS1 A3 C1 70 0.7 FM7
    • EXAMPLE A31
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00082
    • 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
  • To a mixture of 63 g (0.1123 mol) of N-[(9-fluorenylmethoxy)-carbonyl]-3,5-dibromo-D-tyrosine, 44 g (0.1123 mol) of 1-[N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine, 39.7 g (0.1235 mol) of TBTU, 15.5 g (0.1123 mol) of HOBt and 1500 ml of tetrahydrofuran were slowly added dropwise 21.7 ml (0.1235 mol) of DIEA and the reaction mixture was then stirred for 2 hours at room temperature. After the addition of 200 ml of diethylamine the mixture was again stirred overnight at room temperature. The reaction mixture was mixed with 1000 ml of saturated saline solution, stirred thoroughly and the aqueous phase was separated off. After extracting the aqueous phase three times with 500 ml of tetrahydrofuran and combining the organic phases the mixture was washed three times with 500 ml of saturated aqueous saline solution, three times with 200 ml of saturated aqueous sodium hydrogen carbonate solution and once with 500 ml of saturated aqueous saline solution. The organic phase was dried and then evaporated down in vacuo. The residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc. aqueous ammonia=8/1/0.25 (v/v/v)). 40.0 g (50% of theory) of the desired end product were obtained.
  • IR (KBr): 1641, 1699 cm−1 (C═O)
  • Rf: 0.2 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1 (v/v/v))
  • ESI-MS: (M+H)+=711/713/715 (Br2)
  • The following were prepared analogously (in each case n=1):
  • R2 A NR3R4 Remarks % Yield MS Rf Eluant IR [cm−1]
    AS4 A3 C8 crude 43
    AS4 A3 C1 crude 100 0.4 FM1
    AS4 A3 C4 79 ESI: (M + H)+ = 0.7 FM7 (KBr): C═0
    709/11/13 1637.5;
    (Br2) 1705
    AS4 A0 C69 82 ESI: (M + H)+ = (KBr): C═0
    587/9/81 1618/1645/
    (Br2) 1690
    AS4 A0 C46 38 0.55 CH2Cl2/ (KBr): C═0
    MeOH/ 1614/1639
    NH4OH
    90/10/1
    AS4 A0 C48 54 EI: M+ = 0.52 CH2Cl2/ (KBr): C═0
    522/4/6 (Br2) MeOH/ 1638
    NH4OH
    90/10/2
    AS11 A0 C53 71.0 EI: M+ = 469 0.20 CH2Cl2/ (KBr): C═0
    MeOH/ 1637/1732
    NH4OH
    90/10/1
    AS11 A0 C20 45.0 EI: M+ = 468 0.40 CH2Cl2/ (KBr): C═0
    MeOH/ 1635/1732
    NH4OH
    90/10/1
    AS31 A0 C72 100.0 EI: M+ = 411 0.45 FM1 (KBr): C═0
    1664
    AS11 A0 C72 33.0 EI: M+ = 497 0.30 FM1 (KBr): C═0
    1630/1641
    • EXAMPLE A32
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00083
    • 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
  • To a mixture of 4 g (4.7 mmol) of 1-[N2-[N-(1,1-dimethylethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine and 80 ml of methylene chloride were added 20 ml of trifluoroacetic acid and the reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralised by the addition of saturated aqueous sodium hydrogen carbonate solution, the organic phase was dried over sodium sulphate and evaporated down in vacuo. 2.2 g (64% of theory) of an amorphous solid were obtained.
  • IR (KBr): 1643, 1680 cm−1 (C═O)
  • Rf: 0.5 (FM1)
  • ESI-MS: (M+H)+=745/747/749 (Br2)
  • The following were prepared analogously (in each case n=1):
  • %
    R2 A NR3R4 Remarks Yield MS Rf Eluant IR [cm−1] Mp. (° C.)
    AS7 A0 C4 crude product; 51 0.30 FM1
    pure TFA
    AS1 A0 C11 95 ESI: (M + H)+ = (KBr): C═0
    503/5/7 1676
    (Br2)
    AS4 A0 C20 100 ESI: (M + H)+ =
    500/2/4
    (Br2)
    AS1 A0 C4 100 ESI: (M + H)+ = (KBr): C═0
    481/3/5 1678
    (Br2)
    AS4 A0 C11 74
    AS7 A0 C1 reacted as 100
    crude
    product
    AS4 A7 C1 reacted as 100 0.40 EE/MeOH
    crude 7/3 v/v
    product
    AS1 A4 C1 64 ESI: (M + H)+ = 0.50 FM1 (KBr): C═O
    745/7/9 1643.3;
    (Br2) 1679.9
    AS4 A0 C5 89 0.32 FM4 (KBr): C═O
    1637.5
    AS4 A0 C15 93 0.33 FM4 (KBr): C═O
    1618.2
    AS1 A0 C5 89 0.25 FM4 (KBr): C═O 154-157
    1639.4
    AS4 A0 C16 LC/SiO2/ 90 0.30 FM4 (KBr): C═O
    FM4 1635.5
    AS1 A0 C15 89 0.20 FM4 (KBr): C═O 160-164
    1639.4
    AS4 A0 C3 LC/SiO2/ 98 0.37 FM4 (KBr): C═O
    FM4 1683.8;
    AS4 A0 C6 89 0.28 FM4 (KBr): C═O
    1637.5
    AS1 A0 C16 95 0.57 FM1 (KBr): C═O
    1683.8
    AS1 A0 C6 LC/SiO2/ 56 EI: M+ = 0.24 FM4 (KBr): C═O
    FM4 511/3/5 (Br2) 1637.5
    AS4 A0 C18 90 EI: M+ = 0.50 FM1 (KBr): C═O
    512/4/6 (Br2) 1624.0
    AS4 A0 C37 93 0.24 FM4 (KBr): C═O
    1635.5; 1684
    AS4 A0 C22 88 M+ = 502/4/6 (KBr): C═O
    (Br2) 1618.2
    AS4 A0 C21 52 M+ = 482/4/6 0.55 FM1 (KBr): C═O
    (Br2) 1681.8
    AS1 A0 C37 89 0.32 FM1 (KBr): C═O
    1681.8
    AS4 A5 C1 crude (KBr): C═O
    1645; 1676
    AS4 A0 C23 88 (KBr): C═O
    1643
    AS4 A10 C1 47 ESI: (M + H)+ = (KBr): C═O
    553/5/7 1653
    (Br2)
    AS4 A5 C8 67 M+ = 543/5/7 (KBr): C═O
    1645
    AS4 A6 C1 59 (KBr): C═O
    1643
    AS4 A0 C24 94 M+ = (KBr): C═O
    489/91/93 1618; 1637.5
    AS4 A6 C8 70 (KBr): C═O
    1639.4
    AS4 A10 C8 82 M+ = 557/9/61 (KBr): C═O
    1651
    AS4 A0 C26 88 (KBr): C═O
    1626
    AS1 A0 C1 96 ESI: (M + H)+ = 0.18 FM1 (KBr): C═O
    483/5/7 (Br2) 1680
    AS1 A0 C8 crude 69
    AS1 A0 C18 82 0.27 FM1 (KBr): C═O
    1684
    AS1 A0 C3 100 0.38 FM1 (KBr): C═O
    1682
    AS1 A0 C21 89 0.26 FM1 (KBr): C═O
    1595; 1615
    AS4 A0 C3 99 0.37 FM4 (KBr): C═O
    1618; 1636;
    1683
    AS4 A0 C19 98 ESI: (M + H)+ = 0.47 FM4 (KBr): C═O
    498/500/502 1638; 1682
    (Br2)
    AS9 A0 C1 Crude 96
    product
    AS1 A7 C1 37 0.42 FM7
    AS4 A0 C38 80 0.25 FM1
    AS4 A0 C37 86
    AS4 A0 C39 73
    AS4 A0 C40 92 EI: M+ = 515/7/9 (KBr): C═0
    1674
    AS1 A0 C42 100 0.32 FM1 (KBr): C═0
    crude 1682
    AS4 A0 C42 95 0.24 FM4 (KBr): C═0
    1636/1684
    AS1 A0 C43 66 0.1 FM7 (KBr): C═0
    1659
    AS1 A0 C44 59 0.15 CH2Cl2/ (KBr): C═0
    MeOH/ 1676
    NH4OH
    90/10/1
    AS1 A0 C45 82 ESI: (M + H)+ = 0.10 EE/MeOH (KBr): C═0
    492/4/6 (Br2) 9/1 1678
    AS1 A0 C47 89 0.52 FM7 (KBr): C═0
    1634/1666
    AS1 A0 C49 84 0.15 CH2Cl2/ (KBr): C═0
    MeOH/ 1678
    NH4OH
    AS4 A0 C44 93 EI: M+ = 504/6/8 0.45 EE/ (KBr): C═0
    (Br2) MeOH 9/1 1653; CN
    2239
    AS1 A0 C50 100 EI: M+ = 0.10 EE/ (KBr): C═0
    498/500/502 MeOH 9/1 1636
    (Br2)
    AS1 A0 C51 100 EI: M+ = 530/2/4 0.05 EE/ (KBr): C═0
    (Br2) MeOH/ 1678
    NH4OH
    5/5/0.1
    AS4 A0 C52 97 0.15 FM1 (KBr): C═0
    1620/1688
    AS4 A0 C53 58 ESI: (M + H)+ = 0.05 EE/MeOH/ (KBr): C═0
    502/4/6 (Br2) NH4OH 5/5/0.1 1678
    AS4 A0 C64 100 (KBr): C═0
    1647/1678
    AS1 A0 C53 70 EI: M+ = 502/4/6 0.15 CH2Cl2/MeOH/ (KBr): C═0
    (Br2) NH4OH 70/30/1 1676
    AS4 A0 C51 100 0.05 CH2Cl2/MeOH/ (KBr): C═0
    NH4OH 1680
    AS4 A0 C66 100 0.27 CH2Cl2/MeOH/
    NH4OH
    AS16 A0 C8 76 0.40 FM1
    AS16 A0 C1 28 0.20 EE/MeOH/
    NH4OH 9/1/1
    AS4 A0 C70 96 0.20 EE/MeOH/ (KBr): C═0
    NH4OH 1676
    80/20/0.5
    AS1 A0 C64 100 EI: M+ = (KBr): C═0
    510/1214 1674
    AS1 A0 C70 100 (KBr): C═0
    1674
    AS4 A0 C72 100 ESI: (M + H)+ = 0.10 CH2Cl2/MeOH/ (KBr): C═0
    530/2/4 (Br2) NH4OH 80/20/1 1678
    AS19 A0 C8 100
    AS35 A0 C8 72 0.60 FM1
    AS36 A0 C8 80 0.52 FM1 (KBr): C═0
    1674
    • EXAMPLE A33 4-(4-pyridinyl)-1-[3-(4-pyridinyl)-D,L-alanyl]-piperazine-hydrochloride
  • 16.4 g (0.04 mol) of 1-[N-[(1,1-dimethylethoxy)carbonyl]-3-(4-pyridinyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine, dissolved in 100 ml of methanol, were mixed with 20 ml of ethereal hydrochloric acid and the reaction mixture was heated to 40° C. The desired compound crystallised out of the reaction mixture.
  • yield: 9.2 g (60% of theory)
  • Rf: 0.1 (FM1)
  • Mp.: 198-200° C.
    • EXAMPLE A34
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00084
    • 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
  • A mixture of 50 g (53.5 mmol) of 1-[N2-[N-(9-fluorenylmethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine and 300 ml of diethylamine was heated to 60° C. with stirring. 100 ml of methanol were added and stirring was continued for a further 5 hours at 60° C. The reaction mixture was evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=6/4 (v/v)). 26 g (68% of theory) of a white foam were obtained.
  • IR (KBr): 1641, 1691 cm−1 (C═O)
  • Rf: 0.2 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1 (v/v/v))
  • ESI-MS: (M+H)+=710/712/714 (Br2)
  • The following were prepared analogously:
  • %
    R2 A NR3R4 n Remarks Yield MS Rf Eluant IR [cm−1]
    AS1 A3 C4 1 85 ESI: M + H = 0.2 FM1 (KBr): C═0
    710/2/4 (Br2) 1635.5;
    1695.3
    AS1 A3 C8 1 98 (KBr): C═0
    1635; 1705
    AS1 A3 C1 1 68 EI: 0.2 ethyl (KBr): C═O
    M+ = 710/2/4 acetate/ 1641.3;
    (Br2) methanol/ 1691.5
    NH4OH =
    6/4/1
    (v/v/v)
    AS1 A3 C5 1 THF as solvent; purified by 56 ESI: M + H = 0.3 FM1 (KBR): C═O
    column chromatography: 711/3/5 (Br2) 1695.3;
    silica gel/FM1 1635.5
    AS1 A3 C6 1 THF as solvent; purified by 90 EI: M+ = 0.49 FM1 (KBr): C═O
    column chromatography: 739/41/43 1695.3;
    silica gel/FM1 (Br2) 1629.8
    AS5 A3 C1 1 THF as solvent; purified by 93 0.25/ FM4 (KBr): C═O
    column chromatography: 0.37 1705.0;
    silica gel/FM4; 1643.3
    diastereomers
    AS10 A0 C1 1 71 0.5 FM1 (KBr): C═O
    1641.3
    AS1 A3 C18 1 94 (KBr): C═O
    1647; 1722.5
    AS10 A3 C1 1 49 M+ = 694/6/8 (KBr): C═O
    (Br2) 1643; 1703
    AS10 A3 C4 1 46 ESI: M + H = (KBr): C═O
    694/6/8 (Br2) 1639.4; 1705
    AS10 A3 C4 1 46 ESI: M + H = (KBr): C═O
    694/6/8 (Br2) 1639.4; 1705
    AS10 A3 C1 1 49 M+ = (KBr): C═O
    694/68/70 1643; 1703
    (Br2)
    AS4 A3 C18 1 46 ESI: M + H = (KBr): C═O
    741/3/5 (Br2) 1641.3; 1705
    AS15 A0 C8 1 100 M+: 321 (KBr): C═O
    1637.5
    AS12 A0 C8 1 81 (KBr): C═O
    1630
    AS10 A0 C4 1 THF as solvent 68 0.38 FM4 (KBr): C═O
    1635.5
    AS1 A3 C1 0 crude product 100 0.3 FM7
    • EXAMPLE A35 1-[N2-[N-[[[2-(2-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
  • To a solution of 1.0 g (1.34 mmol) of 1-[N2-(−3,5-dibromo-D-tyrosyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine in 80 ml of tetrahydrofuran were added 0.28 g (1.6 mmol) of 2-methoxyphenethyl isocyanate and the mixture was stirred for 3 days at room temperature. The reaction mixture was evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/methanol/cyclohexane/ammonia=350/75/75/10 (v/v/v/v)). 0.5 g (40% of theory) of a colourless amorphous solid was obtained.
  • IR (KBr): 1639 cm−1 (C═O)
  • Rf: 0.49 (FM1)
  • ESI-MS: (M+H)+=922/924/926 (Br2)
    • EXAMPLE A36
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00085
    • methyl 4-amino-3,5-dibromo-N2-[[(2-phenylethyl)amino]-carbonyl]-D-phenylalanine
  • A mixture of 1.27 g (7.73 mmol) of CDT in 150 ml of tetrahydrofuran was mixed, whilst cooling with ice, with 0.72 ml (5.15 mmol) of triethylamine and 2.0 g (5.15 mmol) of methyl-4-amino-3,5-dibromo-D-phenylalanine-hydrochloride, stirred for a further 30 minutes whilst cooling with ice and stirred for 1 hour at room temperature. Then 0.82 ml (6.44 mmol) of benzene ethanamine were added and the mixture was refluxed for 5 hours. The reaction mixture was evaporated down in vacuo, the residue was taken up in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. After drying the organic phase the solvent was removed in vacuo, the residue was stirred with ether and the precipitate was filtered off. 1.69 g (66% of theory) of an amorphous solid were obtained.
  • IR (KBr): 1632, 1732 cm−1 (C═O)
  • Rf: 0.63 (ethyl acetate)
  • ESI-MS: (M+H)+=498/500/502 (Br2)
  • The following were prepared in the same way (in each case n=1):
  • %
    RCO R2 Remarks Yield MS Rf Eluant IR [cm−1]
    N6 AS1 further reacted 100 0.60 FM1
    as crude product
    N15 AS6 DMF/THF = 1/1 100 ESI: 0.65 FM1 (KBr): C═O
    (v/v) as solvent (M + H)+ = 517/9 1745.5; 1676.0
    (Br)
    N2 AS1 99 0.53 FM1 (KBr): C═O
    1716.5
    N8 AS4 66 ESI: (M + H)+ = 0.63 ethyl acetate (KBr): C═O
    498/500/502 1631.7; 1732.0
    (Br2)
    N15 AS4 92 0.85 ethyl acetate/ (KBr): C═O
    methanol = 8/2 1620.1; 1737.8
    (v/v)
    N23 AS4 95 EI: M+ = 0.86 ethyl acetate/ (KBr): C═O
    572/4/6/8 methanol = 8/2 1732.0; 1641.3
    (Br2, Cl) (v/v)
    N2 AS2 100 EI: M+ = 406 0.86 FM1 (KBr): C═O
    1629.8; 1722.3;
    1741.6
    N15 AS1 DIEA 47 0.75 FM1
    N15 AS3 38 0.60 t.-butyl- (KBr): C═O
    methylether/ 1695.5
    petroleum ether =
    9/1 (v/v)
    N66 AS21 76 0.60 EE (KBr): C═0
    1662/1734
    N66 AS1 100
    N66 AS4 63 0.56 FM1
    N122 AS1 95
    N122 AS4 88
    N66 AS17 22 ESI: (M + H)+ = 0.25 FM1 (KBr): C═0
    623/5/7 (Br2) 1663/1740
    N66 AS18 65 0.53 EE
    N66 AS19 79 0.50 FM1 (KBr): C═0
    1663/1734
    N66 AS5 90 ESI: (M + H)+ = 0.78 FM1 (KBr): C═0
    607/09/11 (Br2) 1637/1663/
    1740
    N66 AS22 68 0.74 FM1
    N66 AS23 100 (KBr): C═0
    1738/1662
    N66 AS25 100 ESI: (M + H)+ = 0.52 FM1
    472
    N66 AS49 100 0.80 FM1
    • EXAMPLE A37
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00086
    • 4-amino-3,5-dibromo-N2-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanine
  • To a solution of 2.8 g (4.9 mmol) of methyl 4-amino-3,5-dibromo-N2-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanine in a mixture of 30 ml of methanol and 20 ml of water were added 0.25 g (10.0 mmol) of lithium hydroxide and the mixture was then stirred for 3 hours at room temperature. After the addition of 2.0 g (50 mmol) of sodium hydroxide the mixture was diluted with 50 ml of water. The reaction mixture was stirred for 15 minutes in an ultrasound bath, then stirred overnight at room temperature and evaporated down in vacuo. The residue was mixed with 100 ml of water and the aqueous phase was extracted twice with 50 ml of ether. By the addition of 2 M aqueous hydrochloric acid the aqueous phase was adjusted to a pH of 3-4 and extracted three times with ethyl acetate. The combined ethyl acetate phases were washed once with water, then dried and evaporated down in vacuo. 1.6 g (58% of theory) of a yellowish-brown oil were obtained.
  • IR (KBr): 1616, 1724 cm−1 (C═O)
  • Rf: 0.33 (ethyl acetate/methanol=8/2 (v/v))
  • ESI-MS: (M+H)+=557/559/561/563 (Br2, Cl)
  • The following were prepared in the same way (in each case n=1):
  • %
    RCO Z R2 Remarks Yield MS Rf Eluant IR [cm−1]
    N8 N—H AS4 62 ESI: (M − H)− = 0.61 Ethyl acetate/ (KBr): C═O
    482/4/6 (Br2) methanol = 6/4 1612.4,
    (v/v) 1724.3; —OH,
    —NH— 3386.8;
    3483.2
    N15 N—H AS4 64 ESI: (M − H)− = 0.10 Ethyl acetate/ (KBr): C═O
    578/80/82 methanol = 8/2 1703.0
    (Br2); (M + H)+ = (v/v)
    580/2/4 (Br2);
    (M + Na)+ =
    602/4/6 (Br2)
    N23 N—H AS4 58 ESI: (M − H)− = 0.33 Ethyl acetate/ (KBr): C═O
    557/59/61/63 methanol = 8/2 1616.3;
    (Br2, Cl) (v/v) 1724.3
    N15 N—H AS1 No addition 59 ESI: (M − H)− = 0.72 EE/MeOH/ (KBr): C═O
    of sodium 579/81/83 (Br2) NH4OH = 6/4/1 1695.3
    hydroxide (v/v/v)
    N66 N—H AS21 95 0.48 EE/AcOH (KBr): C═O
    10/0.02 (v/v) 1639
    N66 CH2 AS1 85 0.38 CH2Cl2/MeOH/
    AcOH 9/1/0.15
    (v/v/v)
    N71 CH2 AS1 66.6 ESI: (M + H)+ = 0.38 CH2Cl2/MeOH/ (KBr): C═O
    606/08/10 (Br2) AcOH 9/1/0.15 1622/1680
    (v/v/v)
    N66 N—H AS18 100 ESI: (M − H)− = 0.26 EE/AcOH 9/0.01
    557 (v/v)
    N66 N—H AS19 98 0.22 CH2Cl2/MeOH/ (KBr): C═O
    AcOH 9/1/0.15 1665/1740
    (v/v/v)
    N66 N—H AS5 73 ESI: (M − H)− = 0.23 FM1 (KBr): C═O
    577/79/81 (Br2) 1632/1705
    N66 N—H AS22 78 0.30 FM1 (KBr): C═O
    1668/1739
    N66 CH2 AS21 79 0.34 EE/AcOH 9/0.01 (KBr): C═O
    (v/v) 1643/1703
    N66 CH2 AS1 90 0.30 EE/MeOH 9/1
    (v/v)
    N15 CH2 AS1 78 ESI: (M − H)− = 0.30 EE/AcOH 9/0.01 (KBr): C═O
    578/80/82 (Br2) (v/v) 1728/1672
    N66 N—H AS25 99
    N66 CH2 AS2 100 (KBr): C═O
    1645/1712
    N66 CH2 AS23 70
    N139 CH2 AS2 50 (KBr): C═O
    1630/1662/
    1707
    N66 CH2 AS27 93 0.20 FM1
    N66 CH2 AS28 LiOH 100 0.30 FM1
    N66 CH2 AS4 72 0.53 FM1 (KBr): C═O
    1639/1701
    N66 CH2 AS36 74 ESI: (M − H)− = 0.36 FM1 (KBr): C═O
    434 1645/1701
    N66 CH2 AS38 69
    N66 CH2 AS48 47 EI: M+ = 0.30 FM1 (KBr): C═O
    489 1645
    N66 N—H AS49 47 0.10 FM1
    N66 CH2 AS18 60 0.15 EE
    N66 CH2 AS39 96
    N109 CH2 AS21 81
    N113 CH2 AS21 76 0.20 EE/AcOH
    99/1
    N134 CH2 AS21 89 0.15 EE/AcOH
    99/1
    N66 CH2 AS47 100 ESI: (M + H)+ = (KBr): C═O
    476 1645/1716
    N66 CH2 AS7 60 0.20 FM1 (KBr): C═O
    1649/1722
    N66 CH2 AS52 95 ESI: (M + H)+ = 0.15 FM1 (KBr): C═O
    480 1643/1722
    • EXAMPLE A38
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00087
    • 3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine
  • A mixture of 24 g (46.3 mmol) of methyl 3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine and 5.0 g (50 mmol) of lithium hydroxide in 200 ml of water was stirred for 1 hour at 60 C. The solid product was suction filtered and the filtrate was washed with 200 ml of ethyl acetate. By the addition of 1 M aqueous hydrochloric acid the aqueous phase was adjusted to a pH of 3-4 and extracted 3 times with 150 ml of ethyl acetate. The combined ethyl acetate phases were washed once with water, dried over sodium sulphate and evaporated down in vacuo. The residue was triturated with ether. 9.1 g (38% of theory) of a colourless solid were obtained.
  • IR (KBr): 1719 cm−1 (C═O)
  • Rf: 0.57 (ethyl acetate/methanol/glacial acetic acid=9.5/0.5/0.2 (v/v/v))
  • The following were prepared in the same way (in each case n=1):
  • %
    RCO Z R2 Remarks Yield MS Rf Eluant IR [cm−1]
    N6 N—H AS1 100 0.20 FM1 (KBr): C═O
    1625.9; 1730
    N15 N—H AS6 H2O/MeOH = 85 ESI: 0.53 EE/MeOH/ (KBr): C═O
    1/1 (v/v) as (M − H)− = AcOH = 9/1/0.1 1695.3
    solvent 501/3 (Br) (v/v/v)
    N2 N—H AS1 75 0.57 EE/methanol/ (KBr): C═O
    glacial acetic 1718.5
    acid = 9.5/0.5/0.2
    (v/v/v)
    N2 N—H AS2 71 0.20 FM1 (KBr): C═O
    1625.9;
    1693.4;
    1718.5; —NH—
    3357.9
    N15 N—H AS3 H2O/MeOH = 57 0.30 EE/MeOH = 1/1 (KBr): C═O
    1/1 (v/v) as (v/v) 1693.4
    solvent
    N66 AS1 75 0.05 EE/MeOH 8/2
    N66 AS4 85
    N122 AS1 44
    N122 AS4 85
    N66 N—CH3 AS1 58 ESI: (M − H)− = 0.20 EE (KBr): C═O
    607/09/11 1607/1655/
    (Br2) 1711
    N66 N—H AS17 55 0.03 FM1
    N15 CH2 AS1 78 ESI: (M − H)− = 0.30 EE/MeOH 9/1 (KBr): C═O
    578/80/82 (v/v) 1672/1728
    (Br2)
    N66 N—H AS23 79.0 0.22 FM1 (KBr): C═O
    1738/1664
    • EXAMPLE A39 methyl N6-[(1,1-dimethylethoxy)carbonyl]-N2-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine
  • To a mixture of 10 g (19.4 mmol) of 3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine, 2.6 g (20 mmol) of DIEA, 6.4 g (20 mmol) of TBTU, 2.64 g (19.5 mmol) of HOBt and 200 ml of dimethylformamide was added dropwise, with stirring, a solution of 5.04 g (19.4 mmol) of H-Lys(Boc)-OMe in 50 ml of dimethylformamide and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo and the residue was taken up in 250 ml of ethyl acetate. The ethyl acetate phase was then washed twice with 100 ml of saturated aqueous sodium hydrogen carbonate solution, once with 100 ml of 20% aqueous citric acid solution and finally once with 100 ml of saturated aqueous saline solution. The organic phase was dried with sodium sulphate, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/petroleum ether=2/1 (V/V)). After removal of the solvent in vacuo the residue was triturated with ether, the amorphous solid obtained (9.5 g; 66% of theory) was suction filtered and dried.
  • IR (KBr): 1632; 1657, 1682, 1734 cm−1 (C═O)
  • Rf: 0.64 (ethyl acetate)
  • ESI-MS: (M+H)+=757/759/761 (Br2)
      • (M+Na)+=779/781/783 (Br2)
    EXAMPLE A40 N6-[(1,1-dimethylethoxy)carbonyl]-N2-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine
  • A mixture of 7.75 g (10.4 mmol) of methyl N6-[(1,1-dimethylethoxy)carbonyl]-N2-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine, 3.5 g (140 mmol) of lithium hydroxide and 150 ml of water was stirred overnight at room temperature. The aqueous phase was washed once with ethyl acetate, acidified by the addition of 1 M aqueous potassium hydrogen sulphate solution and then extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated down in vacuo. 6.9 g (91% of theory) of a yellowish oil were obtained.
  • IR (KBr): 1653 cm−1 (C═O)
  • Rf: 0.7 (ethyl acetate/methanol/glacial acetic acid=9/0.5/0.5 (v/v/v))
  • ESI-MS: (M−H)−=741/743/745 (Br2)
    • EXAMPLE A41 1-[N2-[N-(phenylmethoxycarbonyl)-3,5-dichloro-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
  • A mixture of 5 g (13.0 mmol) of 3,5-dichloro-N-[(phenylmethoxy)carbonyl]-D-tyrosine, 5.1 g (13.0 mmol) of 1-[N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 1.81 g (14 mmol) of DIEA, 4.17 g (13 mmol) of TBTU, 1.75 g (13.0 mmol) of HOBt and 200 ml of tetrahydrofuran was stirred at room temperature overnight. The reaction mixture was evaporated down in vacuo, the residue was taken up in ethyl acetate/methanol (95/5) and washed twice with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=6/4 (v/v)). 6.0 g (61% of theory) of a yellowish oil were obtained.
  • Rf: 0.47 (FM1)
  • ESI-MS: (M+H)+=757/759/761 (Cl2)
    • EXAMPLE A42
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00088
    • 1-[N2-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-[(1,1-dimethylethoxy)-carbonyl]-L-lysyl]-4-(1-methyl-4-piperidinyl)-piperazine
  • To a mixture of 1.1 g (1.5 mmol) of N6-[(dimethylethoxy)-carbonyl]-N2-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine, 0.79 g (6.1 mmol) of DIEA, 0.52 g (1.6 mmol) of TBTU, 0.2 g (1.5 mmol) of HOBt and 100 ml of dimethylformamide was added dropwise a solution of 0.44 g (1.5 mmol) of 1-(1-methyl-4-piperidinyl)-piperazine in 30 ml of dimethylformamide at room temperature, the mixture was then stirred overnight and evaporated down in vacuo. The residue was taken up in ethyl acetate/methanol (95/5), washed twice with 70 ml of aqueous saturated sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down in vacuo. 1.1 g (81% of theory) of a colourless foam were obtained.
  • Rf: 0.34 (ethyl acetate/methanol/conc. aqueous ammonia=7/2/1 (v/v/v))
  • The following was prepared analogously (n=1):
  • Re- % IR
    RCO R2 A NR3R4 marks Yield Rf Eluant [cm−1]
    N15 AS1 A11 C1 KHSO4 70 0.40 FM3 (KBr):
    solution C═O
    1697.3;
    1641.3
    • EXAMPLE A43 1-[N2-(3,5-dichloro-D-tyrosyl)-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazin
  • A solution of 6 g (7.9 mmol) of 1-[N2-[N-[(phenylmethoxy)carbonyl]-3,5-dichloro-D-tyrosyl]-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in a mixture of 200 ml of methanol and 20 ml of aqueous 1 M potassium hydrogen sulphate solution was hydrogenated in the presence of 0.5 g palladium black as catalyst at room temperature under 3 bar of hydrogen pressure for 40 minutes. The catalyst was filtered off, the reaction mixture was evaporated to dryness in vacuo and the residue adjusted to a pH of about 10 by the addition of 2 ml of concentrated aqueous ammonia solution. The product was extracted several times with isopropanol, the combined isopropanol extracts were evaporated down in vacuo and the residue was purified by column chromatography (LiChroprep, Si60 particle size: 20-40 μm, Messrs. Merck (Darmstadt); eluant: methylene chloride/methanol/ammonia=350/75/75/10 (v/v/v/v)). 2.5 g (51% of theory) of a colourless amorphous solid substance were obtained.
  • IR (KBr): 1641, 1705 cm−1 (C═O)
  • Rf: 0.27 (FM1)
    • EXAMPLE A44
  • Preparation of compounds of general formula:

  • Fmoc-A-NR3R4
    • 1-[N2-[(9-fluorenylmethoxy)carbonyl]-NG-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-L-arginyl]-4-(4-pyridinyl)-piperazine
  • To a mixture of 7.0 g (10.6 mmol) of Fmoc-Arg(Pmc)-OH, 1.42 g (11.0 mmol) of DIEA, 3.53 g (11.0 mmol) of TBTU, 1.35 g (11.0 mmol) of HOBt and 50 ml of DMF was added dropwise with stirring a solution of 1.74 g (10.6 mmol) of 1-(4-pyridinyl)-piperazine in 20 ml of DMF. The reaction mixture was stirred for a further 3.5 hours at room temperature and then evaporated down at 40° C. in a high vacuum. The residue was dissolved in ethyl acetate, the organic phase was washed twice with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down in vacuo. The residue was triturated with diethylether, suction filtered and dried. 7.85 g (96% of theory) of the desired end product were obtained, which was reacted without further purification.
  • Rf: 0.5 (FM1)
  • The following was prepared analogously:
  • %
    A NR3R4 Yield Rf Eluant IR [cm−1]
    A3 C18 60 0.55 FM4 (KBr): C═O
    1643; 1711
    • EXAMPLE A45
  • Preparation of compounds of general formula:

  • H-A-NR3R4
    • 1-[NG-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-L-arginyl]-4-(4-pyridinyl)-piperazine
  • A solution of 8.5 g (11.1 mmol) of 1-[N2-[(9-fluorenylmethoxy)carbonyl]-NG-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-L-arginyl]-4-(4-pyridinyl)-piperazine in 100 ml of THF was mixed with 16 ml of diethylamine and then stirred for 2.5 hours at room temperature. The reaction mixture was evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: FM1). 3.3 g (54% of theory) of an amorphous solid were obtained.
  • Rf: =0.19 (FM1)
  • IR(KBr): 1637 cm−1 (C═O)
  • The following was prepared analogously:
  • %
    A NR3R4 Yield Rf Eluant IR [cm−1]
    A3 C18 80 (KBr): C═O
    1637.5; 1705
    • EXAMPLE A46 1-[N6,N6-dimethyl-N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
  • 9.6 g (18.3 mmol) of 1-[N6-[(1,1-dimethylethoxy)carbonyl]-N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine were stirred overnight in 200 ml of a 5% solution of trifluoroacetic acid in dichloromethane. The reaction mixture was then evaporated down in vacuo. 13.47 g (97% of theory) of the desired 1-[N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine were obtained as the trifluoroacetate salt. Then 7.0 g (9.1 mmol) of the crude product were dissolved in 200 ml of water and 4.1 ml of a 40% formaldehyde solution (45.6 mmol) were added whilst cooling with an ice bath. The reaction mixture was stirred for 10 minutes at room temperature, carefully mixed with 1.5 g (40 mmol) of sodium borohydride whilst cooling with an ice bath, then mixed with 4.1 ml of a 40% formaldehyde solution (45.6 mmol) whilst cooling externally with ice, after which the reaction mixture was stirred for a further 10 minutes at room temperature and again mixed with 1.5 g (40 mmol) of sodium borohydride whilst cooling with an ice bath. The pH of the reaction mixture was monitored continuously during the reaction and kept between pH 3 and pH 6 by dropwise addition of trifluoroacetic acid. The mixture was then stirred for 30 minutes at 5° C., adjusted to pH 10 by the addition of potassium carbonate and extracted four times with 50 ml of ethyl acetate. The combined organic phases were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc. aqueous ammonia=6.5/3/0.3 (v/v/v)). 2.3 g (56% of theory) of a colourless oil were obtained.
  • IR (KBr): 1711, 1649 cm−1 (C═O)
  • Rf: 0.2 (FM7)
  • ESI-MS: (M+H)+=454
    • EXAMPLE A47
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00089
    • methyl (R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-benzenebutanoate
  • A mixture of 10 g (27 mmol) of methyl 4-amino-3,5-dibromo-γ-oxo-benzenebutanoate, 5.4 g (27 mmol) of 4-(4-pyridinyl)-piperidine and 1.5 g (45 mmol) of paraformaldehyde was suspended in 20 ml of glacial acetic acid and heated with stirring in an oil bath (bath temperature: 100° C.). After 3 hours a further 1.5 g (45 mmol) of paraformaldehyde were added and the mixture was stirred for a further 3 hours at 100° C. and then for 1 hour at 125° C. The solvent was removed in vacuo and the residue was taken up in 800 ml of water. The aqueous phase was made alkaline by the addition of sodium carbonate and extracted twice with 500 ml of ethyl acetate. The combined ethyl acetate extracts were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=9:1)). 1.0 g (6.8% of theory) of the desired end product were obtained as an oil.
  • IR(KBr): 1716.5 cm−1
  • Rf: 0.7 (FM1)
  • The following was prepared analogously:
  • %
    A NR3R4 Yield Rf Eluant IR [cm−1]
    AS4 C8 35 0.68 FM1 KBr: C═O
    1672.2;
    1733.9
    • EXAMPLE A48
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00090
    • (R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-benzenebutanoic acid
  • A mixture of 1.0 g (1.9 mmol) of methyl (R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-phenylbutanoate, 5 ml of 1 N sodium hydroxide solution and 50 ml of dioxane was stirred overnight at room temperature and for 1 hour at 60° C. The reaction mixture was then neutralised by the addition of 5 ml of 1N hydrochloric acid, evaporated down in vacuo and the residue was dried in a vacuum drying chamber. 0.97 g (100% of theory) of the desired product was obtained, which was further reacted without any purification.
  • Rf: 0.15 (FM1)
  • The following was prepared analogously:
  • %
    A NR3R4 Yield Rf Eluant IR [cm−1]
    AS4 C8 96 0.2 FM1 KBr: C═O
    1660
    • EXAMPLE A49 3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid
  • To a solution of 12 g (0.043 mol) of 4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid in 200 ml of acetic acid were added 150 ml of water and 8 g of sodium acetate, a solution of 5 ml of bromine in 60 ml of acetic acid was added dropwise with stirring, then the reaction mixture was extensively evaporated down in vacuo and the residue was stirred into water. The aqueous phase was repeatedly extracted with ethyl acetate, and the combined organic phases were washed with water. The organic extracts were dried, evaporated down in vacuo and the solid residue was recrystallised from diisopropylether. 12 g (70% of theory) of the desired end product were obtained.
  • Rf: 0.4 (ethyl acetate/petroleum ether/glacial acetic acid=5/5/0.4 (v/v/v)
  • ESI-MS: (M+H)+=394/6/8 (Br2)
    • EXAMPLE A50
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00091
    • methyl (R,S)-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-4-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]-4-oxo-butanoate
  • A solution of 2.0 g (5 mmol) of 3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid in 80 ml of THF was mixed with 1.6 g (5 mmol) of TBTU, 0.76 g (5 mmol) of HOBt, 1.25 g (5 mmol) of 4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)piperidine and 1.03 g (8 mmol) of DIEA with stirring. The reaction mixture was stirred for 6 hours at room temperature and then evaporated down in vacuo. The residue was mixed with saturated aqueous sodium hydrogen carbonate solution and extracted several times with ethyl acetate. The combined organic extracts were washed successively with saturated aqueous sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated down in vacuo. 3.0 g (50% of theory) of the desired product was obtained, which was further reacted without purification.
  • IR (KBr): 1714.8 cm−1 (C═O)
  • Rf: 0.7 (ethyl acetate/petroleum ether=7/3 (v/v))
  • The following were prepared analogously:
  • %
    RCO R2 Yield MS Rf Eluant IR [cm−1]
    N66 AS1 98 0.66 FM1
    N66 AS2 100 0.77 FM1 (KBr): C═O
    1664/1734
    N139 AS2 100 EI: M+ = 0.30 FM1 (KBr): C═O
    486 1643/1672/
    1732
    N66 AS4 28 EI: M+ = 0.33 FM4 (KBr): C═O
    606/08/10 1666/1734
    (Br2)
    N66 AS36 63 0.56 FM4
    N66 AS38 92
    N66 AS48 100 0.68 FM1
    N66 AS18 22
    N66 AS39 100
    N109 AS21 39 0.35 EE (KBr): C═O
    1639/1734
    N113 AS21 57 0.15 EE/PE 95/5
    N134 AS21 80 0.15 EE
    N66 AS7 100 0.75 FM1
    N66 AS53 40
    • EXAMPLE A51 (R)-1-[2-amino-3-(3,5-dibromo-4-hydroxyphenyl)propyl]-4-(1-piperidinyl)-piperidine
  • To a suspension of 3.8 g (100 mmol) of lithium aluminium hydride in 400 ml of THF were added in batches, with stirring and at room temperature, 14.4 g (20 mmol) of 1-(3,5-dibromo-D-tyrosyl)-4-(1-piperidinyl)-piperidine within 30 minutes. The reaction mixture was kept for 30 minutes at room temperature and refluxed for 2 hours and then neutralised by the careful addition of 1 ml of water and 5.1 ml of concentrated aqueous hydrochloric acid. After the addition of 100 ml of methanol the solid precipitate was suction filtered and the filtrate was evaporated down in vacuo. The residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 5.4 g (57% of theory) of the desired product was obtained as an amorphous solid.
  • IR (KBr): 3420 cm−1 (NH2)
  • Rf: 0.4 (FM2)
  • ESI-MS: M+=473/475/477 (Br2)
  • The following was prepared analogously:
  • (R)-1-[2-amino-3-(4-amino-3,5-dibromophenyl)propyl]-4-(1-piperidinyl)-piperidine from 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(1-piperidinyl)-piperidine in a yield of 56.5% of theory, Rf 0.12 (eluant: dichloromethane/methanol/cyclohexane/conc. ammonia 7/1.5/1.5/0.2 (v/v/v/v)).
    • EXAMPLE A52 (R)-1-[3-(4-amino-3,5-dibromophenyl)-2-[N-[(1,1-dimethylethoxy)carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
  • To a solution of 10 g (0.017 mol) of 1-[4-amino-3,5-dibromo-N-[(1,1-dimethylethoxy)carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine in 350 ml of dioxane were added 3.1 g (0.082 mol) of sodium borohydride and the reaction mixture was cooled to 5° C. Then a solution of 4.92 g (0.082 mol) of acetic acid in 100 ml of dioxane was added dropwise with stirring. The reaction mixture was stirred for a further hour at room temperature and for 3 hours at 85° C. Then ice water was added, the organic solvent was removed in vacuo and the aqueous residue was repeatedly extracted with methylene chloride. The combined organic phases were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/methanol/cyclohexane/conc. aqueous ammonia=3600/150/150/20 (v/v/v/v). 4.1 g (42% of theory) of a colourless foam were obtained.
  • IR (KBr): 1705 cm−1 (C═O)
    • EXAMPLE A53 (R)-1-[2-amino-3-(4-amino-3,5-dibromophenyl)propyl]-4-(1-piperidinyl)-piperidine
  • To a mixture of 4 g (7 mmol) of (R)-1-[3-(4-amino-3,5-dibromophenyl)-2-[N-[(1,1-dimethylethoxy)carbonyl]-amino]propyl]-4-(1-piperidinyl)-piperidine and 100 ml of methylene chloride, 40 ml of trifluoroacetic acid were slowly added dropwise, with stirring, at 10° C. The reaction mixture was stirred for 2 hours at room temperature and then evaporated down in vacuo. The residue was mixed with ice water, made basic by the addition of concentrated aqueous ammonia solution and extracted three times with 200 ml of diethylether. The combined ether extracts were dried and evaporated down in vacuo. 3.4 g (100% of theory) of an amorphous solid were obtained.
  • IR (KBr): 1683.8, 1616.3 (C═O)
  • Rf: 0.02 (FM 4)
    • EXAMPLE A54 methyl (R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)phenyl]-methyl]-butanoate
  • Prepared analogously to Example A15a) from methyl (R,S)-3-carboxy-2-[[3-(trifluoromethyl)phenyl]methyl]-propanoate and 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a yield of 27.3% of theory. Colourless, amorphous substance, Rf=0.25 (eluant: ethyl acetate).
  • MS: M+=503
  • The following was obtained in the same way:
  • methyl (R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-butanoate from methyl (R,S)-3-carboxy-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-propanoate and 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a yield of 98% of theory, Rf=0.66 (eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 7/1.5/1.5/0.2 (v/v/v/v)).
    • EXAMPLE A55 (R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-butanoic acid
  • A mixture of 3.0 g (4.92 mmol) of methyl (R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-butanoate, 30 ml (30 mmol) of 1N sodium hydroxide solution and 20 ml of methanol was stirred for 3 hours at room temperature, then diluted with 100 ml of water and 30 ml of 1N hydrochloric acid were added dropwise. The precipitate was suction filtered and dried at 50° C. in a circulating air drier. Colourless, amorphous substance, Rf=0.38 (eluant: dichloromethane/methanol/glacial acetic acid 9/1/0.15 (v/v/v)). Yield: 2.5 g (85.4% of theory).
  • The following was obtained in the same way:
  • (R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[[3-(trifluromethyl)phenyl]methyl]-butanoic acid from methyl(R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)-phenyl]methyl]-butanoate in a yield of 79% of theory, Rf=0.34 (eluant: ethyl acetate/glacial acetic acid 99.8/0.2 (v/v)).
  • IR(KBr): 1703, 1643 cm−1 (C═O)
    • EXAMPLE A56 Methyl 3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-N-methyl-D-tyrosine a) 1-(chlorocarbonyl)-4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]piperidine
  • To a mixture of 7.0 ml (about 14 mmol) of a 20% solution of phosgene in toluene and 2.02 g (20 mmol) of triethylamine in 300 ml of tetrahydrofuran was added in batches, while maintaining a reaction temperature of about 0° C., a suspension of 1.5 g (5.60 mmol) of 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]piperidine-hydrochloride in 100 ml of tetrahydrofuran. The mixture was stirred for another hour at a temperature between 0° C. and +5° C., filtered to remove the resulting triethylamine-hydrochloride and the filtrate was freed from solvent. The residue was triturated with diisopropyl ether and suction filtered. After drying in vacuo 0.7 g (42.6% of theory) of colourless crystals were obtained, Rf=0.17 (eluant: dichloromethane/acetone 9.5/0.5 (v/v)), which was further processed without any further purification.
    • b) Methyl 3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-N-methyl-D-tyrosine
  • To a solution of 4.9 g (13.3 mmol) of methyl 3,5-dibromo-N-methyl-D-tyrosine and 4.04 g (40 mmol) of triethylamine in 500 ml of tetrahydrofuran was added dropwise, at room temperature, within 3 hours, a solution of 3.92 g (13.34 mmol) of 1-(chlorocarbonyl)-4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]piperidine in 1 l tetrahydrofuran. The mixture was then heated for 12 hours to reflux temperature, left to cool and filtered to remove the precipitated triethylamine. The filtrate was evaporated down, the residue was divided between ethyl acetate and 20% aqueous citric acid. The organic phase was dried over sodium sulphate, again evaporated down in vacuo, the residue was purified by column chromatography over silica gel using ethyl acetate/petroleum ether 9/1 (v/v) as eluant. Working up the appropriate fractions yielded 3.2 g (38.5% of theory) of a colourless, amorphous substance, Rf=0.45 (eluant: ethyl acetate)
  • IR(KBr): 1739.7, 1660.6 cm−1 (C═O)
  • ESI-MS: (M+H)+=623/625/627 (Br2)
      • (M+Na)+=645/647/649 (Br2)
      • (M+K)+=661/663/665 (Br2)
    EXAMPLE A57 Methyl 3,5-dibromo-4-methoxy-D-phenylalanine
  • To a mixture of 5.5 g (14.12 mmol) of 3,5-dibromo-4-methoxy-D-phenylalanine-hydrochloride and 55 ml of methanol were added 150 ml of a saturated methanolic hydrogen chloride solution and the mixture was stirred for 20 hours at room temperature. The residue remaining after evaporation of the solvent was stirred with 50 ml of water and adjusted to pH 8 with saturated sodium hydrogen carbonate solution. The precipitate was suction filtered, stirred with 10 ml of isopropanol and left to stand overnight. The insoluble matter was filtered off and the filtrate was evaporated down in vacuo. The residue was further reacted as a crude product. Yield: 1.0 g (28.7% of theory) of a colourless oil, Rf=0.55 (eluant: dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia=300/80/25/25/3 (v/v/v/v/v)).
    • EXAMPLE A58 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyrimidinyl)-piperazine a) 1-(2-chloro-4-pyrimidinyl)-4-(phenylmethyl)piperazine
  • A mixture of 9.9 g (0.0664 mol) of 2,4-dichloropyrimidine, 200 ml of water and 11.7 ml (0.0673 mol) of 1-(phenylmethyl)piperazine was heated to 40° C. for 2 hours in an ultrasound bath. After cooling the mixture was made alkaline with potassium carbonate and extracted thoroughly with ethyl acetate. The crude product obtained after working up in the usual way was purified by column chromatography over silica gel (30-60 μm) using FM2 and FM4 (2/1 v/v) as eluant. Working up the appropriate fractions yielded 7.4 g (38.6% of theory) of a colourless oil, Rf=0.51 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
  • MS: M+=288/290 (Cl)
    • b) 1-(4-pyrimidinyl)piperazine
  • A solution of 7.4 g (0.0256 mol) of 1-(2-chloro-4-pyrimidinyl)-4-(phenylmethyl)piperazine in 100 ml of ethanol was hydrogenated in the presence of 2 g of 10% palladium/charcoal for 4 hours at 40° C. under 5 bar of hydrogen pressure. The crude product obtained after conventional working up was purified by column chromatography over silica gel (30-60 μm) using FM1/cyclohexane 9/1 (v/v) as eluant. Colourless crystals, Rf=0.3 (FM1/cyclohexane 9/1 (v/v)); Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC). Yield: 1.7 g (40.7% of theory).
    • c) 1-[4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanyl)-4-(4-pyrimidinyl)piperazine
  • Prepared analogously to Example A15a) from 4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanine and 1-(4-pyrimidinyl)piperazine in the presence of TBTU in a yield of 92% of theory. Colourless, amorphous substance, Rf=0.42 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
  • IR(KBr): 1705.0, 1643.3 cm−1 (C═O)
  • MS: M+=582/584/586 (Br2)
    • d) 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyrimidinyl)piperazine
  • Prepared analogously to Example A1b) from 1-[4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanyl)-4-(4-pyrimidinyl)piperazine in a yield of 52% of theory. Colourless, amorphous substance, Rf=0.55 (FM1; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
  • IR(KBr): 1681.8 cm−1 (C═O)
  • MS: M+=482/484/486 (Br2)
    • EXAMPLE A59
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00092
    • (R,S)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-4-oxobutanoic acid
  • A mixture of 4.8 g (8.3 mMol) of ethyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)-phenyl]methyl]-2-(ethoxycarbonyl)-4-oxobutanoate, 200 ml of ethanol and 41.5 ml of 1N sodium hydroxide solution was refluxed for 3 hours.
  • The ethanol was removed in vacuo, then the residue was diluted with 50 ml of water and adjusted to pH 3 with 1N aqueous hydrochloric acid. The precipitated substance was suction filtered, thoroughly washed with water and then dried in vacuo. 3.8 g (96% of theory) of colourless crystals of Mp. 139
    Figure US20090163480A1-20090625-P00001
    141° C. were obtained, Rf=0.65 (eluant: EE/MeOH/glacial acetic acid 90/10/1 v/v/v).
  • IR(KBr): 1724, 1647 cm−1 (C═O)
  • MS: no M+, m/e=246, 231, 147
  • The following were prepared analogously:
  • %
    R2 Remarks Yield MS Rf Eluant IR [cm−1]
    AS29 100
    AS16 17 ESI: (M + H)+ = 0.30 EE/MeOH/
    488/90/92 (Cl2) AcOH 80/10/1
    AS5 62 0.60 CH2Cl2/MeOH/
    NH4OH 90/10/1
    AS32 100 ESI: (M + Na)+ = 0.67 EE/MeOH/ (KBr): C═O
    614/6/8 (Br2) AcOH 90/10/1 1645/1728
    AS33 90 EI: M+ = 525 0.20 EE/MeOH/ (KBr): C═O
    AcOH 90/10/1 1643/1701
    AS31 100 0.20 CH2Cl2/MeOH/
    NH4OH 80/20/1
    AS17 100 ESI: (M + H)+ = 0.50 EE/MeOH/ (KBr): C═O
    608/10/12 (Br2) AcOH 90/10/1 1643
    AS34 76 ESI: (M − H)− = 0.65 EE/MeOH/
    506 AcOH 90/10/1
    AS19 70 0.46 EE/MeOH/ (KBr): C═O
    AcOH 9/1/0.5 1643/1701
    AS46 78 ESI: (M − H)− = 0.20 FM1 (KBr): C═O
    471 1647
    AS50 97 0.05 EE
    AS2 LiOH instead 86 ESI: (M + H)+ = (KBr): C═O
    of NaOH 472 1643/1705
    AS29 100 ESI: (M − H)− = (KBr): C═O
    448 1645/1705
    AS31 87
    • EXAMPLE A60
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00093
    • Ethyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-2-(ethoxycarbonyl)-4-oxobutanoate
  • A mixture of 2.31 g (10 mMol) of 4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-piperidine, 3.64 g (10 mMol) of β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoic acid, 5 ml of triethylamine, 3.5 g (11 mMol) of TBTU, 200 ml of tetrahydrofuran and 20 ml dimethylformamide was stirred for 5 hours at room temperature. The solvent was removed in vacuo and the residue taken up in dichloromethane, the resulting solution was dried over sodium sulphate and freed from the solvent. After purification by column chromatography on 400 g of silica gel (Amicon, 35-70 μm, ethyl acetate as eluant), 4.8 g (83% of theory) of a colourless, amorphous substance were obtained, Rf=0.63 (eluant: EE).
  • IR(KBr): 1734, 1668, 1653 cm−1 (C═O)
  • MS: M+=577 (Br2)
  • The following were prepared analogously:
  • %
    R2 Yield MS Rf Eluant IR [cm−1]
    AS29 75 0.8 FM1
    AS16 59 0.5 EE
    AS5 65 EI: M+ = 0.7 FM4 (KBr): C═O
    677/79/81 1649/1668/
    (Br2) 1734
    AS32 74 0.5 FM4 (KBr): C═O
    1647/1668/
    1734
    AS33 85 0.5 EE (KBr): C═O
    1649/1734
    AS31 82 EI: M+ = 574 0.5 CH2Cl2/MeOH/ (KBr): C═O
    NH4OH 90/10/1 1658/1741
    AS17 93 EI: M+ = 0.5 EE (KBr): C═O
    707/09/11 1645/1666/
    (Br2) 1736/1759
    AS34 75 EI: M+ = 607 0.8 EE (KBr): C═O
    1649/1668/
    1736
    AS19 67 0.8 FM1 (KBr): C═O
    1647/1668/
    1734
    AS46 80 EI: M+ = 572 0.8 FM1 (KBr): C═O
    1737
    AS50 78 EI: M+ = 0.6 EE (KBr): C═O
    677/9/81 (Br2) 1645/1666/
    1730
    AS2 51
    • EXAMPLE A61
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00094
    • β,β-bis-(ethoxycarbonyl)-1-methyl-1H-indol-3-butanoic acid
  • Produced analogously to Example A1b) from tert.-butyl β,β-bis-(ethoxycarbonyl)-1-methyl-1H-indol-3-butanoate through the action of trifluoroacetic acid in dichloromethane in a yield of 63.5% of theory. Colourless crystals of Mp. 127-130° C. (diisopropylether).
  • IR(KBr): 1738, 1712 cm−1 (C═O)
  • The following were prepared analogously:
  • R2 % Yield MS Rf Eluant IR [cm−1]
    AS29 100
    AS16 100 0.7 EE/MeOH/
    AcOH
    97.5/2.2/0.25
    AS5 100 0.5 PE/EE 2/1
    AS32 100 0.58 PE/EE 2/1 (KBr): C═O
    1759/1711
    AS33 100 (KBr): C═O
    1736
    AS17 52 (KBr): C═O
    1707/1726/
    1755
    AS34 90 0.8 EE/MeOH/ (KBr): C═O
    AcOH 1705/1743
    97.5/2.5/0.25
    AS19 100 0.76 PE/EE/ (KBr): C═O
    AcOH 6/3/1 1738
    AS46 92 0.35 FM1 (KBr): C═O
    1732
    AS50 71 (KBr): C═O
    1712/1734/
    1759
    AS2 31 EI: M+ = 272 0.42 PE/EE/ (KBr): C═O
    AcOH 6/4/0.2 1711/1734
    • EXAMPLE A62
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00095
    • Tert.-butyl β,β-bis-(ethoxycarbonyl)-3,5-dimethylbenzene-butanoate
  • To a solution of 13.8 g (50.2 mMol) of diethyl [(1,1-dimethylethoxycarbonyl)methyl]-malonate in 400 ml of anhydrous tetrahydrofuran, 2.3 g (52.7 mMol) of sodium hydride was added whilst being externally cooled with iced water. After stirring for 30 minutes, and maintaining a reaction temperature of 0 to +5° C., the solution of 10.0 g (50.2 mMol) of 3,5-dimethylbenzylbromide in 80 ml tetrahydrofuran was added dropwise and the mixture allowed to warm to room temperature within 14 hours. The reaction mixture was freed from the solvent in vacuo, 200 ml of 10% citric acid was added to the residue and the resulting mixture was thoroughly extracted with ethyl acetate. After the usual working up, the combined extracts yielded 19.7 g (100% of theory) of a colourless oil of Rf=0.67 (eluant: dichloromethane), which was used in the following steps without further purification.
  • The following were prepared analogously:
  • R2 Remarks % Yield MS Rf Eluant IR [cm−1]
    AS29 100
    AS16 62 0.6 CH2Cl2
    AS5 91 ESI: (M + H)+ = 0.8 PE/EE (KBr): C═O
    521/3/5 (Br2) 2/1 1734
    AS32 96 0.76 PE/EE (KBr): C═O
    2/1 1734
    AS33 78 0.55 CH2Cl2 (KBr): C═O
    1736
    AS31 with use of 3- 74 EI: M+ = 417 0.7 toluene/ (KBr): C═O
    (dimethylaminomethyl)- t-BME 4/1 1734
    1-methyl-1H-indol-
    methoiodide
    AS17 70 EI: M+ = 0.5 CH2Cl2 (KBr): C═O
    550/52/54 (Br2) 1734
    AS34 93 EI: M+ = 450 0.5 CH2Cl2/ (KBr): C═O
    PE 1/1 1736
    AS19 87 0.89 CH2Cl2 (KBr): C═O
    1736
    AS46 54 EI: M+ = 415 0.7 FM4
    AS50 60 EI: M+ = 0.7 CH2Cl2 (KBr): C═O
    520/22/24 (Br2) 1734
    • EXAMPLE A63 (phenylmethyl)-β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoate
  • Prepared analogously to Example A62 from diethyl[(phenylmethoxycarbonyl)methyl]-malonate and 4-(1,1-dimethylethyl)-benzylbromide in the presence of sodium hydride in a yield of 53% of theory.
  • Colourless oil of Rf=0.21 (eluant: dichloromethane/petroleum ether 2/1 v/v).
  • IR(KBr): 1738 cm−1 (C═O)
    • EXAMPLE A64 Methyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]-methyl]-4-oxobutanoate
  • To a solution of 2.0 g (4.43 mMol) of methyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-hydroxyphenyl)-methyl]-4-oxobutanoate in 30 ml of anhydrous dimethylformamide, 0.2 g (4.4 mMol) of a 55% suspension of sodium hydride in paraffin oil was added. After stirring for 30 minutes at room temperature, 0.5 ml (4.8 mMol) of isopropyliodide was added dropwise, and kept for two hours each at room temperature and at 70° C. The residue remaining after removal of the volatile constituents was divided between water and ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and was again evaporated down. The raw product was purified by column chromatography on silica gel (60 μm), first using dichloromethane, later methanol/conc. ammonia (9/1 v/v) as eluants. Yield was 0.9 g (42% of theory) of a colourless, amorphous substance of Rf=0.32 (FM4).
  • IR(KBr): 1734, 1668 cm−1 (C═O)
  • MS: M+=493
  • In the same way, methyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-ethoxyphenyl)methyl]-4-oxobutanoate was obtained from methyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-hydroxyphenyl)methyl]-4-oxobutanoate and ethyliodide in a yield of 67% of theory. Colourless, amorphous substance of Rf=0.29 (FM4).
  • IR(KBr): 1734, 1666 cm−1 (C═O)
  • MS: M+=479
    • EXAMPLE A65 β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoic acid
  • Prepared analogously to example A58b) from phenyl methyl β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoate by catalytic hydrogenation in the presence of palladium/charcoal in a yield of 95% of theory. Colourless, highly-viscous oil of Rf=0.16 (eluant: dichloromethane).
  • IR(KBr): 1739 cm−1 (C═O)
    • EXAMPLE A66 1-methyl-4-[(1-piperazinyl)carbonyl]-piperazine-bis-(trifluoroacetate) a) 4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-1-methylpiperazine
  • To a solution of 1.1 g of triphosgene (3.7 mMol) in 20 ml of dichloromethane, a mixture of 1.2 g (10 mMol) of 1-methyl-piperazine, 0.38 ml (22 mMol) of DIEA and 35 ml of dichloromethane was added dropwise at room temperature within 30 minutes, and then the solution of 1.9 g (10 mMol) of 1-(1,1-dimethylethoxycarbonyl)piperazine and 0.38 ml of DIEA in 20 ml dichloromethane were added. After stirring for an hour at room temperature, insoluble matter was filtered off and the filtrate evaporated down in vacuo. After purification of the raw product on silica gel (Amicon, 35-70 μm), using dichloromethane/methanol/conc. ammonia (80/20/1 v/v/v) for elution, 700 mg (22% of theory) of colourless crystals were obtained of Mp. 130° C.
  • IR(KBr): 1691, 1641 cm−1 (C═O)
    • b) 1-methyl-4-[(1-piperazinyl)carbonyl]-piperazine-bis-(trifluoroacetate)
  • Prepared analogously to Example A1b), but omitting the treatment with aqueous ammonia, from 4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-1-methylpiperazine and trifluoroacetic acid in a yield of 99.6% of theory. Colourless, amorphous substance of Rf=0.17 (eluant: dichloromethane/methanol/conc. ammonia 50/50/0.5).
  • IR(KBr): 1678 cm−1 (C═O)
  • MS: M+=212
    • EXAMPLE A67 1-[4-[4-(dimethylamino)butyl]phenyl]-piperazine-dihydrochloride a) N,N-dimethyl-4-fluoro-γ-oxobenzenebutanoic acid amide
  • To a solution of 30.5 g (0.155 Mol) of 4-fluoro-γ-oxobenzenebutanoic acid in 470 ml tetrahydrofuran, 35.0 g (0.216 Mol) of N,N′-carbonyldiimidazole was added with stirring and at room temperature and held at room temperature for a further 2.5 hours. Then, 13.7 g (0.304 Mol) of dimethylamine was added under strong external cooling by means of an ice-ethanol mixture. After the mixture had stood at room temperature for 12 hours, the solvent was removed in vacuo, the residue was divided between dichloromethane and 10% aqueous citric acid solution, the organic phase was dried over sodium sulphate and once again evaporated down in vacuo. After purification by column chromatography (eluant: ethyl acetate) on silica gel the crude product yielded 30.22 g (87% of theory) of colourless crystals of Rf=0.31 (eluant: ethyl acetate/glacial acetic acid 99.99/0.01).
  • IR(KBr): 1680, 1647 cm−1 (C═O)
    • b) N,N-dimethyl-γ-oxo-4-[4-(phenylmethyl)-1-piperazinyl]-benzenebutanoic acid amide
  • The mixture of 33.48 g (0.15 Mol) of N,N-dimethyl-4-fluoro-γ-oxobenzenebutanoic acid amide, 29.6 g (0.168 Mol) of 1-(phenylmethyl)piperazine and 6 ml of DIEA was refluxed for 6 hours. Another 30 g (0.17 Mol) of (phenylmethyl)piperazine was added, and the mixture was refluxed for a further 7 hours. The mixture was taken up in a little dichloromethane, and purified by column chromatography on silica gel, using dichloromethane/methanol/conc. ammonia 99/1/0.5 for elution. The residue obtained from the appropriate fractions was stirred with diisopropylether, the formed crystals were then recrystallised from ethanol. 42.22 g (74% of theory) of colourless crystals were obtained, Rf=0.69 (eluant: dichloromethane/methanol/conc. ammonia 95/5/0.5 v/v/v).
  • IR(KBr): 1662, 1643 cm−1 (C═O)
    • c) 4-[4-[4-(dimethylamino)-1-hydroxybutyl]phenyl]-1-(phenylmethyl)piperazine
  • Prepared analogously to example A51 from N,N-dimethyl-γ-oxo-4-[4-(phenylmethyl)-1-piperazinyl]-benzenebutanoic acid amide by reduction with lithium aluminium hydride in a yield of 61% of theory. Colourless, amorphous substance of Rf=0.62 (eluant: ethyl acetate/methanol 1/1 v/v).
  • MS: M+=367
    • d) 1-[4-[4-(dimethylamino)butyl]phenyl]-piperazine-dihydrochloride
  • Prepared analogously to example A20b) from 4-[4-[4-(dimethylamino)-1-hydroxybutyl]phenyl]-1-(phenylmethyl)piperazine by catalytic hydrogenation in the presence of palladium/charcoal and hydrochloric acid in a quantitative yield. Colourless, amorphous substance of Rf=0.37 (eluant: ethyl acetate/methanol 50/50/0.5 v/v/v).
    • B. Preparation of the Final Compounds EXAMPLE 1
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00096
    • 1-[N-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperazine No. 83
  • A mixture of 2 g (3.44 mmol) of 3,5-dibromo-N2-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]-carbonyl]-D-tyrosine, 0.59 g (3.6 mmol) of 1-(4-pyridinyl)-piperazine, 1.27 g (3.96 mmol) of TBTU, 0.47 g (3.44 mmol) of HOBt, 0.7 ml (3.96 mmol) of DIEA and 100 ml tetrahydrofuran was stirred overnight at ambient temperature. The reaction mixture was extracted once with saturated aqueous saline solution, twice with saturated aqueous sodium hydrogen carbonate solution and again with saturated aqueous saline solution. The organic phase was dried, evaporated down in vacuo and the crude product was then purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=9/1/(v/v/)). 550 mg (22% of theory) of an amorphous solid were obtained.
  • IR (KBr): 1601, 1636, 1696 cm−1 (C═O)
  • Rf: 0.67 (FM2)
  • ESI-MS: (M+H)+=726/728/730 (Br2)
  • The following were prepared analogously (in each case n=1):
  • %
    No. RCO Z R2 A NR3R4 Remarks Yield MS Rf Eluant IR [cm−1]
    N6 N—H AS1 A3 C4 88 ESI: (M + H)+ = 0.8 FM1 (KBr): C═O
    928/30/32 1629.8;
    (Br2) 1708.8
    193 N15 N—H AS6 A0 C7 DMF as 26 ESI: 0.9 EE/MeOH/ (KBr): C═O
    solvent (M + H)+ = AcOH 1693.4;
    647/9 (Br) 75/23/2 v/v/v 1622.0
    194 N66 N—H AS1 A0 C67 49 ESI: 0.33 FM1 (KBr): C═O
    (M + H)+ = 1622/1664
    828/30/32
    (Br2)
    202 N15 N—H AS1 A0 C36 DMF as 9 ESI: 0.49 FM1 (KBr): C═O
    solvent; (M + H)+ = 1695.3;
    DIEA 733/5/7 1622.0
    (Br2) NH 3417.7
    203 N15 N—H AS1 A0 C29 DMF as 41 ESI: 0.58 EE/MeOH (KBr): C═O
    solvent; (M − H)− = 9/1 v/v 1695.3
    DIEA 718/20/22
    (Br2)
    204 N15 N—H AS1 A0 C30 DMF as 27 ESI: 0.1 FM1 (KBr): C═O
    solvent; (M + H)+ = 1695.3;
    DIEA 691/3/5 1624.0
    (Br2)
    205 N15 N—H AS6 A0 C8 DMF as 23 ESI: 0.46 FM1 (KBr): C═O
    solvent; (M + H)+ = 1695.3;
    DIEA 653/5 (Br) 1622.0
    206 N15 N—H AS1 A0 C31 DMF as 33 ESI: 0.25 FM1 (KBr): C═O
    solvent; (M + H)+ = 1695.3;
    DIEA 717/19/21 1624.0
    (Br2)
    207 N15 N—H AS1 A0 C32 DMF as 55 ESI: 0.46 FM1 (KBr): C═O
    solvent; (M − H)− = 1690; 1650
    DIEA 780/2/4
    (Br2)
    212 N15 N—H AS1 A7 C1 DMF as 37 ESI: 0.27 FM1 (KBr): C═O
    solvent; (M + H)+ = 1697.3;
    DIEA 882/4/6 1639.4
    (Br2) NH 3423.4
    217 N15 N—H AS6 A3 C1 51 0.9 FM1 (KBr): C═O
    1693.4;
    1641.3
    222 N15 N—H AS1 A0 C27 THF/DMF 10 ESI: 0.35 FM1 (KBr): C═O
    1/1 as (M + H)+ = 1695.3
    solvent; NEt3 774/6/8
    as base (Br2)
    286 N15 N—H AS1 A0 C28 THF/DMF 9 ESI: 0.4 FM1 (KBr): C═O
    1/1 as (M + H)+ = 1699.2
    solvent; NEt3 706/8/10
    as base (Br2)
    81 N15 N—H AS4 A0 C4 64 ESI: (M + H)+ = 0.75 FM1 (KBr): C═O
    724/6/8 1618.2;
    (Br2); 1703.0
    (M + Na)+ =
    746/48/50
    (Br2)
    82 N15 N—H AS4 A0 C1 53 ESI: (M + H)+ = 0.55 FM3 (KBr): C═O
    725/7/9 1620.1; 1703.0
    (Br2)
    84 N66 N—H AS21 A0 C68 31 ESI: (M + H)+ = 0.52 FM1 (KBr): C═O
    683 1608/1628/
    1666
    85 N15 N—H AS4 A0 C7 42 ESI: (M + H)+ = 0.8 FM1 (KBr): C═O
    724/6/8 1618.2; 1697.3;
    (Br2); —NH—, —NH2
    (M + Na)+ = 3379.1
    746/48/50
    (Br2)
    90 N15 N—H AS1 A0 C8 40 ESI: (M + H)+ = 0.78 FM2 (KBr): C═O
    731/3/5 1624.0; 1697.3
    (Br2)
    N2 N—H AS2 A3 C1 DMF as 73 ESI: (M + H)+ = 0.42 FM1 (KBr): C═O
    solvent; 766 1654.2; 1708.8
    DIEA
    354 N15 N—H AS1 A0 C4 21 ESI: (M + H)+ = 0.76 FM2 (KBr): C═O
    725/7/9 1622.0; 1695.3;
    (Br2); —OH, —NH—
    (M + Na)+ = 3417.7
    747/49/51
    (Br2)
    98 N15 N—H AS1 A0 C9 60 ESI: (M + H)+ = 0.41 FM2 (KBr): C═O
    580/2/4 1624.0; 1685.7;
    (Br2); (M − H)− = —OH, —NH—
    578/80/82 3421.5
    (Br2);
    (M + Na)+ =
    602/4/6
    (Br2)
    102 N15 N—H AS1 A0 C12 43 ESI: (M + H)+ = 0.76 FM2 (KBr): C═O
    636/38/40 1622.0; 1695.3;
    (Br2);
    (M + Na)+ =
    658/60/62
    (Br2)
    99 N15 N—H AS1 A0 C10 54 ESI: (M + H)+ = 0.61 FM2 (KBr): C═O
    663/5/7 1622.9; 1700.9;
    (Br2) —OH, —NH—
    3421.5
    100 N15 N—H AS1 A0 C11 54 ESI: (M + H)+ = 0.5 FM2 (KBr): C═O
    746/48/50 1624.0; 1695.3;
    (Br2) —NH—, —OH
    3423.4;
    101 N15 N—H AS1 A0 C7 62 ESI: (M + H)+ = 0.82 FM2 (KBr): C═O
    725/7/9 1622.0; 1695.3;
    (Br2); —OH, —NH—
    (M + Na)+ = 3253.7
    747/49/51
    (Br2)
    103 N15 N—H AS1 A0 C13 37 ESI: (M + H)+ = 0.72 FM2 (KBr): C═O
    679/81/83 1625.9;
    (Br2) 1693.4;
    1666.4; —OH,
    —NH— 3409.9
    106 N15 N—H AS1 A0 C14 72 ESI: (M + H)+ = 0.66 FM1 (KBr): C═O
    832/4/6 1674.1;
    (Br2); 1689.5
    (M + Na)+ =
    854/6/8 (Br2)
    104 N15 N—H AS6 A0 C4 36 ESI: (M + H)+ = 0.71 FM1 (KBr): C═O
    647/9 (Br); 1695.3
    (M + Na)+ =
    669/71 (Br);
    (M − H)− 645/7
    (Br)
    105 N15 N—H AS6 A0 C1 25 ESI: (M + H)+ = 0.25 FM3 (KBr): C═O
    648/50 (Br) 1695.3
    N2 N—H AS1 A12 C1 DMF as 72 ESI: 0.4 FM1 KBr: C═O
    solvent; (M + H)+ = 1641
    DIEA 1082/4/6
    (Br2)
    199 N15 N—H AS3 A0 C8 THF/DMF = 86 ESI: (M + H)+ = 0.37 ethyl KBr: C═O
    9/1 (v/v) 643/5/7 acetate/ 1697; 1624
    as solvent (Br2) methanol/
    petroleum
    ether =
    1/2/1 (v/v/v)
    200 N15 N—H AS3 A0 C1 40 ESI: (M + H)+ = 0.45 ethyl KBr: C═O
    638/40/42 acetate/ 1695; 1636
    (Br2) methanol/
    petroleum
    ether =
    1/2/1 (v/v/v)
    419 N66 N—H AS21 A0 C38 28 ESI: (M + H)+ = 0.1 FM1 (KBr): C═O
    682 1628/1662
    425 N66 N—H AS1 A0 C36 42 ESI: (M + H)+ = 0.4 FM1 (KBr): C═O
    747/49/51 1624/1657
    (Br2)
    426 N66 N—H AS4 A0 C30 66 ESI: (M + H)+ = 0.45 FM1 (KBr): C═O
    704/6/8 1618/1663
    (Br2)
    427 N66 N—H AS1 A0 C31 38 ESI: (M + H)+ = 0.2 FM1 (KBr): C═O
    731/3/5 1630/1653
    (Br2)
    428 N66 N—H AS4 A0 C36 40 ESI: (M + H)+ = 0.6 FM1 (KBr): C═O
    746/48/50 1618/1662
    (Br2)
    429 N66 N—H AS1 A0 C30 47 ESI: (M + H)+ = 0.15 FM1 (KBr): C═O
    705/7/9 1635/1653
    (Br2)
    435 N66 N—H AS4 A0 C31 20 ESI: (M + H)+ = 0.55 FM1 (KBr): C═O
    730/2/4 1608/1631
    (Br2)
    436 N66 N—H AS1 A0 C11 15 ESI: (M + H)+ = 0.1 FM1 (KBr): C═O
    760/2/4 (Br2) 1624/1653
    437 N66 N—H AS4 A0 C11 25 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    759/61/63 1622/1661
    (Br2)
    438 N66 N—H AS4 A0 C54 13 ESI: (M + H)+ = 0.7 FM1 (KBr): C═O
    744/6/8 1620/1660
    (Br2)
    439 N66 N—H AS1 A0 C54 31 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    745/7/9 1626/1661
    (Br2)
    443 N122 N—H AS1 A0 C11 44 ESI: (M + H)+ = 0.1 FM1 (KBr): C═O
    790/2/4 1624/1680
    (Br2)
    444 N122 N—H AS1 A0 C8 62 ESI: (M + H)+ = 0.18 FM1 (KBr): C═O
    775/7/9 1624/1678
    (Br2)
    445 N122 N—H AS1 A0 C1 60 ESI: (M + H)+ = 0.2 FM1 (KBr): C═O
    770/2/4 1630/1680
    (Br2)
    446 N122 N—H AS1 A0 C20 59 ESI: (M + H)+ = 0.15 FM1 (KBr): C═O
    789/91/93 1622/1680
    (Br2)
    447 N122 N—H AS4 A0 C1 54 ESI: (M + H)+ = 0.6 FM1 (KBr): C═O
    769/71/73 1622/1682
    (Br2)
    448 N122 N—H AS4 A0 C20 68 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    788/90/92 1620/1682
    (Br2)
    449 N122 N—H AS4 A0 C8 59 ESI: (M + H)+ = 0.58 FM1 (KBr): C═O
    774/6/8 1620/1682
    (Br2)
    450 N66 N—CH3 AS1 A0 C4 36 ESI: (M + H)+ = 0.39 FM1 (KBr): C═O
    753/5/7 1653
    (Br2)
    451 N66 CH2 AS1 A0 C1 20 ESI: (M + H)+ = 0.3 FM1 (KBr): C═O
    739/41/43 1638
    (Br2)
    452 N71 CH2 AS1 A0 C1 16 ESI: (M + H)+ = 0.4 FM1 (KBr): C═O
    751/53/55 1638/1680
    (Br2)
    453 N66 CH2 AS1 A0 C11 17 ESI: (M + H)+ = 0.13 FM1 (KBr): C═O
    758/60/62 1636
    (Br2)
    454 N66 CH2 AS1 A0 C20 33 ESI: (M + H)+ = 0.23 FM1 (KBr): C═O
    757/59/61 1632
    (Br2)
    455 N71 CH2 AS1 A0 C8 35 EI: M+ = 0.42 FM1 (KBr): C═O
    755/7/9 (Br2) 1624/1684
    457 N71 CH2 AS1 A0 C4 49 ESI: (M + H)+ = 0.77 FM1 (KBr): C═O
    750/2/4 1626/1682
    (Br2)
    458 N71 CH2 AS1 A0 C37 25 ESI: (M + H)+ = 0.2 FM1 (KBr): C═O
    769/71/73 1638/1682
    (Br2)
    459 N66 CH2 AS1 A0 C37 50 EI: M+ = 0.2 FM1 (KBr): C═O
    757/59/61 1636
    (Br2)
    460 N66 N—H AS1 A0 C55 72 ESI: (M + H)+ = 0.27 EE/MeOH/ (KBr): C═O
    759/61/63 NH4OH = 1626/1661
    (Br2) 8/1.5/0.1
    v/v/v
    461 N66 N—H AS1 A0 C56 77 ESI: (M + H)+ = 0.77 FM1 (KBr): C═O
    731/3/5 1626/1661
    (Br2)
    462 N66 N—H AS17 A0 C8 51 ESI: (M + H)+ = 0.44 FM1 (KBr): C═O
    759/61/63 1628/1663
    (Br2)
    463 N66 N—H AS18 A0 C1 59 ESI: (M + H)+ = 0.7 FM1 (KBr): C═O
    704 1661
    464 N66 N—H AS18 A0 C8 51 ESI: (M + H)+ = 0.76 FM1 (KBr): C═O
    709 1628/1663
    465 N66 N—H AS18 A0 C37 73 ESI: (M + H)+ = 0.7 FM1 (KBr): C═O
    723 1628/1663
    469 N66 N—H AS19 A0 C8 34 ESI: (M + H)+ = 0.34 FM1 (KBr): C═O
    651/53 (Br) 1626/1664
    471 N66 N—H AS20 A0 C8 41 ESI: (M + H)+ = 0.68 FM1 (KBr): C═O
    649 1624/1684
    472 N66 N—H AS5 A0 C8 26 ESI: (M + H)+ = 0.73 FM1 (KBr): C═O
    729/31/33 1626/1664
    (Br2)
    475 N66 N—H AS18 A0 C20 58 ESI: (M + H)+ = 0.22 FM1 (KBr): C═O
    723 1628/1664
    476 N66 N—H AS18 A0 C11 44 ESI: (M + H)+ = 0.27 MeOH (KBr): C═O
    724 1630/1662
    478 N66 N—H AS19 A0 C37 62 ESI: (M + H)+ = 0.8 FM1 (KBr): C═O
    665/7 (Br) 1626/1662
    479 N66 N—H AS19 A0 C20 55 ESI: (M + H)+ = 0.64 FM1 (KBr): C═O
    665/7 (Br) 1664
    480 N66 N—H AS19 A0 C4 55 ESI: (M + H)+ = 0.77 FM1 (KBr): C═O
    645/7 (Br) 1628/1662
    506 N66 N—H AS21 A0 C20 46 ESI: (M + H)+ = 0.75 FM1 (KBr): C═O
    655 1626/1664
    507 N66 N—H AS22 A0 C8 65 ESI: (M + H)+ = 0.78 FM1 (KBr): C═O
    607/9 (Cl) 1624/1664
    508 N66 CH2 AS21 A0 C20 15 ESI: (M + H)+ = 0.15 MeOH (KBr): C═O
    654 1639/1670
    246 N15 CH2 AS1 A0 C8 19 ESI: (M + H)+ = 0.35 EE/MeOH/ (KBr): C═O
    730/2/4 NH4OH 1635/1707
    (Br2) 9/1/0.5 v/v/v
    285 N15 CH2 AS1 A0 C4 42 ESI: (M + H)+ = 0.45 EE/MeOH/ (KBr): C═O
    724/6/8 NH4OH 1684/1711
    (Br2) 9/1/0.5 v/v/v
    289 N66 CH2 AS1 A0 C8 40 ESI: (M + H)+ = 0.38 EE/MeOH/ (KBr): C═O
    744/6/8 NH4OH 1635/1668
    (Br2) 9/1/0.5 v/v/v
    290 N66 CH2 AS1 A0 C4 30 ESI: (M + H)+ = 0.45 EE/MeOH/ (KBr): C═O
    738/40/42 NH4OH 1634/1664
    (Br2) 9/1/0.5 v/v/v
    511 N66 N—H AS23 A0 C8 DMF 80 ESI: (M + H)+ = 0.57 FM1 (KBr): C═O
    603 1664/1626
    512 N66 N—H AS23 A0 C11 DMF 60 ESI: (M + H)+ = 0.30 FM1 (KBr): C═O
    618 1645
    513 N66 N—H AS23 A0 C1 DMF 54 ESI: (M + H)+ = 0.50 FM1 (KBr): C═O
    598 1662/1712
    514 N66 N—H AS23 A0 C38 DMF 65 ESI: (M + H)+ = 0.20 FM1 (KBr): C═O
    644 1664/1626/
    1712
    515 N66 N—H AS23 A0 C40 DMF 7 ESI: (M + H)+ = 0.40 FM1 (KBr): C═O
    632 1630/1662
    527 N66 N—H AS25 A0 C8 49 ESI: (M + H)+ = 0.48 FM1 (KBr): C═O
    594 1647
    528 N66 N—H AS25 A0 C1 29 ESI: (M + H)+ = 0.48 FM1 (KBr): C═O
    589 1646
    529 N66 CH2 AS2 A0 C8 27 ESI: (M + H)+ = 0.50 FM1 (KBr): C═O
    622 1635/1668/
    1716
    530 N66 CH2 AS2 A0 C20 5 EI: M+ = 635 0.49 FM1 (KBr): C═O
    1637/1668/
    1714
    531 N66 CH2 AS23 A0 C8 30 EI: M+ = 601 0.50 FM1
    N66 CH2 AS23 95
    538 N139 CH2 AS2 A0 C20 49 EI: M+ = 636 0.30 FM1 (KBr): C═O
    1635/1674
    539 N139 CH2 AS2 A0 C53 52 EI: M+ = 637 0.30 FM1 (KBr): C═O
    1637/1674
    540 N139 CH2 AS2 A0 C8 60 0.37 FM1 (KBr): C═O
    1635/1674
    541 N66 CH2 AS27 A0 C53 32 EI: M+ = 630 0.65 FM1 (KBr): C═O
    1639/1670
    542 N66 CH2 AS27 A0 C8 32 EI: M+ = 615 0.80 FM1 (KBr): C═O
    1639/1670
    543 N66 CH2 AS27 A0 C20 21 EI: M+ = 629 0.59 FM1 (KBr): C═O
    1639/1672
    544 N66 CH2 AS28 A0 C20 35 EI: M+ = 643 0.50 FM1 (KBr): C═O
    1641/1670
    545 N66 CH2 AS28 A0 C53 54 EI: M+ = 644 0.50 FM1 (KBr): C═O
    1639/1670
    546 N66 CH2 AS28 A0 C8 53 EI: M+ = 629 0.60 FM1 (KBr): C═O
    1639/1672
    547 N66 CH2 AS29 A0 C8 14 EI: M+ = 599 0.53 FM1 (KBr): C═O
    1630
    548 N66 CH2 AS29 A0 C53 12 EI: M+ = 614 0.48 FM1
    549 N66 CH2 AS29 A0 C20 15 EI: M+ = 613 0.48 FM1 (KBr): C═O
    1637/1668
    550 N66 CH2 AS30 A0 C53 4 0.48 FM1
    574 N66 CH2 AS16 A0 C20 55 EI: M+ = 0.80 CH2Cl2/ (KBr): C═O
    653/5/7 (Cl2) MeOH/ 1635/1670
    NH4OH
    80/20/1
    575 N66 CH2 AS16 A0 C53 54 EI: M+ = 0.20 EE/MeOH/ (KBr): C═O
    654/6/8 (Cl2) NH4OH 1635/1668
    70/30/3
    578 N66 CH2 AS5 A0 C53 32 EI: M+ = 0.30 FM5 (KBr): C═O
    742/4/6 (Br2) 1637/1670
    579 N66 CH2 AS5 A0 C20 37 EI: M+ = 0.50 FM5 (KBr): C═O
    741/3/5 (Br2) 1635/1670
    589 N66 CH2 AS32 A0 C53 49 EI: M+ = 0.33 FM5 (KBr): C═O
    756/58/60 1639/1670
    (Br2)
    590 N66 CH2 AS32 A0 C20 36 EI: M+ = 0.47 FM5 (KBr): C═O
    755/7/9 (Br2) 1658/1672
    591 N66 CH2 AS33 A0 C20 43 EI: M+ = 689 0.40 EE/MeOH/ (KBr): C═O
    NH4OH 1637/1670
    50/50/0.5
    592 N66 CH2 AS33 A0 C53 52 EI: M+ = 690 0.20 EE/MeOH/ (KBr): C═O
    NH4OH 1633/1668
    70/30/5
    593 N66 CH2 AS16 A0 C29 11 EI: M+ = 0.65 EE/MeOH (KBr): C═O
    628/30/32 9/1 1606/1637/
    (Cl2) 1668/
    1728
    594 N66 CH2 AS16 A0 C73 48 EI: M+ = 0.50 EE/MeOH (KBr): C═O
    628/30/32 9/1 1637/1668/
    (Cl2) 1736
    595 N66 CH2 AS16 A0 C74 10 EI: M+ = 0.30 EE/MeOH/
    597/99/601 NH4OH
    (Cl2) 50/50/0.5
    597 N66 CH2 AS31 A0 C53 25 EI: M+ = 639 0.30 CH2Cl2/ (KBr): C═O
    MeOH/ 1635/1668
    NH4OH
    90/10/1
    598 N66 CH2 AS31 A0 C20 31 EI: M+ = 638 0.10 CH2Cl2/ (KBr): C═O
    MeOH/ 1635/1668
    NH4OH
    90/10/0.3
    600 N73 CH2 AS31 A0 C20 10 ESI: (M + H)+ = 0.15 CH2Cl2/ (KBr): C═O
    551 MeOH/ 1628
    NH4OH
    90/10/1
    602 N66 CH2 AS17 A0 C53 56 EI: M+ = 0.25 EE/MeOH/ (KBr): C═O
    772/4/6 (Br2) NH4OH 1637/1668
    50/50/0.5
    603 N66 CH2 AS16 A0 C33 93 EI: M+ = 0.75 EE/MeOH/ (KBr): C═O
    600/02/04 AcOH 70/30/1 1635/1716
    (Br2)
    604 N66 CH2 AS17 A0 C20 47 EI: M+ = 0.20 EE/MeOH/ (KBr): C═O
    771/3/5 (Br2) NH4OH 1635/1668
    50/50/0.5
    605 N66 CH2 AS34 A0 C53 70 EI: M+ = 672 0.25 EE/MeOH/ (KBr): C═O
    NH4OH 1633/1666
    60/40/0.5
    606 N66 CH2 AS34 A0 C20 45 EI: M+ = 671 0.15 EE/MeOH/ (KBr): C═O
    NH4OH 1635/1668
    50/50/0.5
    607 N66 N—H AS21 A0 C40 27 ESI: (M + H)+ = 0.65 FM1 (KBr): C═O
    670 1608/1628/
    1664
    608 N66 N—H AS21 A0 C11 34 ESI: (M + H)+ = 0.50 FM1 (KBr): C═O
    656 1606/1628/
    1664
    609 N66 N—H AS21 A0 C8 30 ESI: (M + H)+ = 0.80 FM1 (KBr): C═O
    641 1626/1664
    610 N66 N—H AS21 A0 C1 55 ESI: (M + H)+ = 0.80 FM1 (KBr): C═O
    636 1635/1662
    611 N66 N—H AS21 A0 C4 80 ESI: (M + H)+ = 0.70 FM1 (KBr): C═O
    635 1606/1628/
    1664
    612 N66 CH2 AS4 A0 C8 43 EI: M+ = 0.85 FM1 (KBr): C═O
    742/4/6 (Br2) 1668/1631/
    1606
    613 N66 N—H AS22 A0 C20 62 ESI: (M + H)+ = 0.73 FM1 (KBr): C═O
    621/23 (Cl) 1626/1664
    614 N66 N—H AS22 A0 C37 55 ESI: (M + H)+ = 0.68 FM1 (KBr): C═O
    621/23 (Cl) 1626/1664
    615 N66 N—H AS22 A0 C56 77 ESI: (M + H)+ = 0.76 FM1 (KBr): C═O
    593 1628/1664
    616 N66 CH2 AS36 A0 C8 32 ESI: (M + H)+ = 0.76 FM1 (KBr): C═O
    585 1637/1668
    617 N66 CH2 AS21 A0 C37 15 EI: M+ = 653 0.15 MeOH (KBr): C═O
    1639/1670
    618 N66 CH2 AS21 A0 C38 24 EI: M+ = 680 0.10 MeOH (KBr): C═O
    1639/1670
    628 N66 CH2 AS21 A0 C8 31 EI: M+ = 639 0.25 MeOH (KBr): C═O
    1639/1670
    629 N66 CH2 AS21 A0 C11 43 EI: M+ = 654 0.10 MeOH (KBr): C═O
    1641/1668
    630 N66 CH2 AS21 A0 C1 74 EI: M+ = 634 0.10 MeOH (KBr): C═O
    1641/1668
    631 N66 CH2 AS21 A0 C28 63 EI: M+ = 614 0.30 MeOH (KBr): C═O
    1666
    634 N66 CH2 AS38 A0 C8 35 ESI: (M + H)+ = 0.25 MeOH (KBr): C═O
    622 1635/1668
    635 N66 CH2 AS48 A0 C8 40 EI: M+ = 639 0.68 FM1 (KBr): C═O
    1643/1670
    636 N66 N—H AS49 A0 C20 25 ESI: (M + H)+ = 0.40 EE/MeOH/ (KBr): C═O
    632 NH4OH 1664
    9/1/0.5
    637 N66 CH2 AS4 A0 C20 11 ESI: (M + H)+ = 0.60 FM1 (KBr): C═O
    757/59/61 1635/1668
    (Br2)
    638 N66 CH2 AS48 A0 C20 11 ESI: (M + H)+ = 0.66 FM1 (KBr): C═O
    654 1641/1668
    639 N66 CH2 AS18 A0 C20 4 EI: M+ = 721 0.10 MeOH (KBr): C═O
    1637/1670
    640 N66 CH2 AS39 A0 C20 38 EI: M+ = 645 0.80 CH2Cl2/ (KBr): C═O
    MeOH/ 1635/1670
    NH4OH
    8/2/0.3
    641 N66 CH2 AS38 A0 C20 49 EI: M+ = 635 0.80 CH2Cl2/ (KBr): C═O
    MeOH/ 1635/1668
    NH4OH
    8/2/0.3
    642 N66 CH2 AS39 A0 C8 45 EI: M+ = 631 0.10 EE/MeOH/ (KBr): C═O
    NH4OH 1635/1670
    9/1/0.3
    N66 CH2 AS21 A0 C69 70 EI: M+ = 739 (KBr): C═O
    1684
    644 N109 CH2 AS21 A0 C20 46 ESI: (M + H)+ = 0.10 MeOH (KBr): C═O
    659 1643
    645 N66 CH2 AS19 A0 C20 21 EI: M+ = 0.53 FM1 (KBr): C═O
    763/5 (Br) 1669/1634
    646 N66 CH2 AS19 A0 C8 45 EI: M+ = 0.60 FM1 (KBr): C═O
    649/651 (Br) 1637/1668
    653 N113 CH2 AS21 A0 C20 55 EI: M+ = 666 0.60 FM1 (KBr): C═O
    1630/1701
    654 N134 CH2 AS21 A0 C20 22 EI: M+ = 690 0.60 FM1 (KBr): C═O
    1714
    655 N66 CH2 AS46 A0 C20 43 EI: M+ = 636 0.50 FM1 (KBr): C═O
    1630/1664
    656 N66 CH2 AS46 A0 C8 71 EI: M+ = 622 0.60 FM1 (KBr): C═O
    1635
    657 N66 CH2 AS47 A0 C20 63 EI: M+ = 639 0.50 FM1 (KBr): C═O
    1635/
    1668/
    1716
    658 N66 CH2 AS50 A0 C20 70 ESI: (M + H)+ = 0.20 EE/MeOH/ (KBr): C═O
    741/3/5 NH4OH 1635/1668
    (Br2) 50/50/0.5
    659 N66 CH2 AS50 A0 C53 60 ESI: (M + H)+ = 0.20 EE/MeOH/ (KBr): C═O
    743/5/7 NH4OH 1635/1668
    (Br2) 50/50/0.5
    660 N66 CH2 AS46 A0 C53 41 EI: M+ = 637 0.65 FM1 (KBr): C═O
    1630
    661 N66 CH2 AS7 A0 C8 75 EI: M+ = 615 0.70 FM1 (KBr): C═O
    1626/1660
    662 N66 CH2 AS7 A0 C53 41 EI: M+ = 630 0.55 FM1 (KBr): C═O
    1628/1662
    663 N66 CH2 AS7 A0 C20 78 EI: M+ = 629 0.60 FM1 (KBr): C═O
    1628/1662
    664 N66 CH2 AS52 A0 C8 66 EI: M+ = 629 0.75 FM1 (KBr): C═O
    1635
    665 N66 CH2 AS52 A0 C53 37 EI: M+ = 644 0.70 FM1 (KBr): C═O
    1633/1664
    666 N66 CH2 AS52 A0 C20 61 EI: M+ = 643 0.80 FM1 (KBr): C═O
    1635/1664
    667 N66 CH2 AS2 A0 C53 47 EI: M+ = 636 0.60 FM1 (KBr): C═O
    1630/1664
    N66 CH2 AS2 A0 C69 78 0.75 FM1
    669 N66 CH2 AS32 A0 C71 44 EI: M+ = 0.20 EE/MeOH/ (KBr): C═O
    834/6/8 (Br2) NH4OH 1641/1670
    50/50/0.5
    670 N66 CH2 AS51 A0 C20 Preliminary 47 EI: M+ = 641 0.15 EE/MeOH/ (KBr): C═O
    stage NH4OH 1635/1664
    special 50/50/0.5
    cases
    671 N66 CH2 AS51 A0 C53 45 EI: M+ = 642 0.15 EE/MeOH/ (KBr): C═O
    NH4OH 1637/1670
    50/50/0.5
    672 N66 CH2 AS16 A0 C76 55 EI: M+ = 0.66 FM1 (KBr): C═O
    689/91/93 1635
    (Cl2)
    • EXAMPLE 2
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00097
    • 1-[N2-[4-amino-N-[[4-(2-chlorophenyl)-1-piperazinyl]-carbonyl]-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)piperazine-bis-(trifluoroacetate) No. 61
  • A mixture of 0.56 g (1.0 mmol) of 4-amino-N2-[[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-phenylalanine, 0.41 g (1.05 mmol) of 1-[N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine, 0.35 g (1.10 mmol) of TBTU, 0.14 g (1.0 mmol) of HOBt, 0.2 ml (1.10 mmol) of DIEA and 100 ml of dimethylformamide was stirred overnight at ambient temperature. The reaction mixture was evaporated down in vacuo and divided between methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic phase was then extracted once with saturated aqueous sodium hydrogen carbonate solution and with water, dried and evaporated down in vacuo. The crude product was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=8/2 (v/v/)), taken up in 30 ml of methylene chloride and stirred with 3 ml of trifluoroacetic acid for 3 hours at ambient temperature. The reaction mixture was evaporated down in vacuo, the residue was triturated with ether and the obtained amorphous solid (0.43 g, 37% of theory) was suction filtered.
  • IR (KBr): 1643, 1678 cm−1 (C═O)
  • Rf: 0.6 (FM1)
  • ESI-MS: (M+H)+=832/834/836/838 (Br2,Cl)
  • The following were prepared analogously (in each case n=1):
  • No. RCO R2 A NR3R4 % Yield MS Rf Eluant IR [cm−1]
    48 N6 AS1 A1 C3 79 ESI: M + H = 0.3 FM1 (KBr): C═O
    946/48/50 1652.9; 1674.1
    (Br2)
    213 N15 AS6 A1 C8 14.7 ESI: M + H = 0.45 FM2 (KBr): C═O
    781/3 (Br) 1691.5; 1629.8
    49 N8 AS4 A1 C1 57.14 ESI: M + H = 0.5 FM1 (KBr): C═O
    757/59/61 1643.3; 1676.0
    (Br2)
    58 N15 AS4 A1 C4 21 ESI: M + H = 0.57 FM1 (KBr): C═O
    852/4/6 (Br2) 1635.5; 1695.3
    59 N15 AS4 A1 C1 45.6 ESI: M + H = 0.44 FM1 (KBr): C═O
    853/5/7 (Br2) 1635.5; 1695.3
    60 N23 AS4 A1 C4 19.2 ESI: M + H = 0.65 FM1 (KBr): C═O
    831/3/5/7 1633.6
    (Br2, Cl)
    61 N23 AS4 A1 C1 36.6 ESI: M + H = 0.6 FM1 (KBr): C═O
    832/4/6/8 1643.3; 1678.0
    (Br2, Cl)
    • EXAMPLE 3
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00098
    • 1-[N2-[3,5-dibromo-N-[[[(2-methoxyphenyl)methyl]amino]-carbonyl]-D,L-tyrosyl]-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
  • A tetrahydrofuran solution (50 ml) of 1.0 g (1.34 mmol) of 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine was added dropwise over a period of 40 minutes to a suspension of 0.33 g (2.01 mmol) of CDT in 50 ml of tetrahydrofuran cooled to −10° C. and stirred. The reaction mixture was then stirred for 2 hours at ambient temperature and mixed with 0.22 ml (1.675 mmol) of 2-methoxy-benzenemethanamine. Then the mixture was refluxed for 2 hours and stirred overnight at ambient temperature. The reaction mixture was evaporated down in vacuo, the residue was triturated with ether and the solid obtained (1.1 g; 90% of theory) was suction filtered and dried.
  • IR (KBr): 1641, 1717 cm−1 (C═O)
  • ESI-MS: (M+H)+=908/910/912 (Br2)
      • (M+H+Na)++=466.7 (Br2)
  • The following were prepared analogously:
  • % Mp.
    No. RCO R2 n X A NR3R4 Remarks Yield MS Rf Eluant IR [cm−1] (° C.)
    195 N15 AS1 1 O A3 C8 21 ESI: (M + H)+ = 0.8 FM7 (KBr): C═O
    959/61/63 1699.2;
    (Br2) 1635.5
    196 N51 AS1 1 O A3 C8 26; 1 ESI: (M + H)+ = 0.85 FM7 (KBr): C═O
    929/31/33 1710; CN
    (Br2) 2219.8
    201 N101 AS4 1 O A0 C8 DIEA 34 ESI: (M + H)+ = 0.58 FM1 (KBr): C═O
    746/8/50 1693.4;
    (Br2) 1618.2
    215 N15 AS1 1 O A0 C34 NEt3 as 92 ESI: (M − H)− = 0.36 FM1 (KBr): C═O
    base 778/80/82 1695.3
    (Br2)
    216 N15 AS1 1 O A0 C35 NEt3 as 69 ESI: (M − H)− = 0.3 FM1 (KBr): C═O
    base 779/81/82 1701.1
    (Br2)
    221 N15 AS4 1 O A7 C1 NEt3 as 39 ESI: (M + H)+ = 0.38 FM1 (KBr): C═O
    base 881/3/5 1697.3;
    (Br2) 1637.5
    288 N85 AS1 1 O A0 C8 THF/DMF 30 ESI: (M + H)+ = 0.3 MeOH (KBr): C═O
    as solvent; 749/51/53 1683.8;
    NEt3 as (Br2) 1624.0;
    base OH 3429.2
    293 N66 AS1 1 O A9 C1 DIEA 11 ESI: (M + H)+ = 0.4 FM1 (KBr): C═O
    910/2/4 1645.2
    (Br2)
    295 N66 AS1 1 O A7 C1 NEt3 as 70 ESI: (M + H)+ = 0.45 FM1 (KBr): C═O
    base 896/8/900 1716.5;
    (Br2) 1647.1
    303 N86 AS4 1 O A0 C8 DIEA 20 ESI: (M + H)+ = 0.7 FM 2 (KBr): C═O
    747/9/51 1618.2
    (Br2)
    304 N87 AS4 1 O A0 C8 THF as 30 ESI: (M + H)+ = 0.75 FM1 (KBr): C═O
    solvent; 802/4/6 1720.4;
    NEt3 as (Br2) 1668.3;
    base 1620.1;
    NH, NH2
    3431.2;
    3379.1
    305 N88 AS4 1 O A0 C8 DIEA 45 ESI: (M + H)+ = 0.6 FM1 (KBr): C═O
    782/4/6 1616, SO2
    (Br2) 1323.1;
    1151.4
    308 N90 AS4 1 O A0 C8 DIEA 27 ESI: (M + H)+ = 0.5 FM1 (KBF): C═O
    750/2/4 1637.5
    (Br2)
    80 N15 AS1 1 O A3 C1 62 ESI: (M + H)+ = 0.8 FM2 (KBr): C═O
    954/6/8 1697.3;
    (Br2) 1639.4
    N8 AS1 1 O A3 C1 66 ESI: (M + H)+ = 0.22 EtOAc/ (KBr): C═O
    858/60/62 methanol = 1641.3
    (Br2) 6/4 (v/v)
    N9 AS1 1 O A3 C1 59 ESI: (M + H)+ = 0.22 EtOAc/ (KBr): C═O
    888/90/92 methanol = 1652.9
    (Br2) 6/4 (v/v)
    N2 AS1 1 O A4 C1 40 ESI: (M + H)+ = 0.45 FM1 (KBr): C═O
    922/4/6 (Br2); 1641.3;
    (M + Na)+ = 1710.8;
    944/6/8 (Br2) OH, NH
    3396.4
    N4 AS1 1 O A4 C1 73 ESI: (M + H)+ = 0.13 FM1 (KBr): C═O
    952/4/6 (Br2) 1641.3;
    1714.6
    62 N15 AS1 1 O A3 C5 purified by 65 ESI: (M + H)+ = 0.27 FM1 (KBR): C═O
    column 1003/5/7 (Br2); 1685.7;
    chromato- (M + Na)+ = 1635.5; OH,
    graphy: silica 1025/7/9 (Br2) NH: 3419.6
    gel/FM4
    N15 AS1 1 O A3 C6 purified by 86 ESI: (M + H)+ = 0.45 FM1 (KBr): C═O
    column 983/5/7 (Br2) 1695.3;
    chromato- 1633.6
    graphy: silica
    gel/FM4
    73 N15 AS5 1 O A3 C1 purified by 64 ESI: (M + H)+ = 0.75 FM1 (KBr):
    column 938/40/42 (Br2) C═O1699.2;
    chromato- 1641.3
    graphy: silica
    gel/FM4;
    diastereomers
    78 N45 AS5 1 O A3 C1 purified by 44 ESI: (M + H)+ = 0.73 FM1 (KBr): C═O
    column 952/4/6 (Br2) 1712.7,
    chromato- 1637.5; —NH—
    graphy: silica 3300.0
    gel/FM4;
    diastereomers
    110 N15 AS4 1 O A0 C5 purified by 82 ESI: (M + H)+ = 0.79 FM1 (KBr): C═O
    column 725/7/9 (Br2) 1620.1;
    chromato- 1514.0
    graphy: silica
    gel/FM4
    111 N15 AS4 1 O A0 C15 purified by 58 ESI: M+ = 0.77 FM1 (KBr): C═O
    column 726/28/30 (Br2) 1697.3;
    chromato- 1620.1
    graphy: silica
    gel/FM4
    114 N45 AS4 1 O A0 C5 purified by 75 ESI: (M + H)+ = 0.78 FM1 (KBr): C═O
    column 739/41/43 (Br2) 1710.8;
    chromato- 1620.1
    graphy: silica
    gel/FM4
    112 N15 AS1 1 O A0 C5 purified by 45 ESI: (M + H)+ = 0.33 FM1 (KBr): C═O
    column 726/28/30 (Br2) 1695.3;
    chromato- 1624.0
    graphy: silica
    gel/FM4
    115 N45 AS1 1 O A0 C5 purified by 28 ESI: (M + H)+ = 0.35 FM1 (KBr): C═O
    column 740/2/4 (Br2) 1710.8;
    chromato- 1622
    graphy: silica
    gel/FM4
    113 N15 AS4 1 O A0 C16 purified by 56 ESI: (M + H)+ = 0.68 FM1 (KBr): C═O 173-176
    column 726/8/30 (Br2) 1699.2;
    chromato- 1618.2
    graphy: silica
    gel/FM4
    119 N45 AS4 1 O A0 C16 purified by 81 ESI: (M + H)+ = 0.69 FM1 (KBr): C═O 148-152
    column 762/4/6 (Br2) 1710.8;
    chromato- 1618.2
    graphy: silica
    gel/FM4
    120 N15 AS1 1 O A0 C15 purified by 27 ESI: (M + H)+ = 0.31 FM1 (KBr): C═O 173-175
    column 749/51/53 (Br2) 1695.3
    chromato-
    graphy: silica
    gel/FM4
    128 N15 AS4 1 O A0 C3 purified by 61 ESI: (M + Na)+ = 0.72 FM1 (KBr): C═O 174-177
    column 764/6/8 (Br2) 1699.2;
    chromato- 1618.2
    graphy: silica
    gel/FM4
    130 N15 AS4 1 O A0 C6 purified by 60 ESI: (M + H)+ = 0.7 FM1 (KBr): C═O 150-154
    column 754/6/8 (Br2) 1703;
    chromato- 1620.1
    graphy: silica
    gel/FM4
    129 N15 AS1 1 O A0 C16 purified by 18 ESI: (M − H)− = 0.27 FM1 (KBr): C═O 173-176
    column 725/7/9 (Br2) 1693.4;
    chromato- 1627.8
    graphy: silica
    gel/FM4
    131 N45 AS4 1 O A0 C6 purified by 69 ESI: (M + H)+ = 0.73 FM1 (KBr): C═O 159-162
    column 768/70/72 (Br2) 1712.7;
    chromato- 1620.1
    graphy: silica
    gel/FM4
    132 N45 AS4 1 O A0 C3 purified by 27 ESI: (M + Na)+ = 0.72 FM1 (KBr): C═O 142-146
    column 778/80/2 (Br2) 1712.7;
    chromato- 1618.2
    graphy: silica
    gel/FM4
    133 N15 AS1 1 O A0 C6 purified by 24 ESI: (M + H)+ = 0.33 FM1 (KBr): C═O 161-164
    column 755/7/9 (Br2) 1697.3;
    chromato- 1624.0
    graphy: silica
    gel/FM4
    134 N15 AS4 1 O A0 C18 purified by 69 ESI: (M + H)+ = 0.59 FM1 (KBr): C═O 171-174
    column 756/8/60 (Br2) 1699.2;
    chromato- 1618.2
    graphy: silica
    gel/FM4
    135 N15 AS1 1 O A0 C18 Purified by 17 ESI: (M + H)+ = 0.25 FM1 (KBr): C═O 74-77
    column 757/9/61 (Br2) 1691.5; 1625.9
    chromato-
    graphy: silica
    gel/FM4
    N29 AS1 1 O A3 C1 61 ESI: (M + H)+ = 0.62 FM7 (KBr): C═O
    903/5/7 (Br2) 1641.3
    N36 AS1 1 O A3 C1 33 ESI: (M + H)+ = 0.49 FM7 (KBr): C═O
    915/7/9 (Br2) 1641.3
    44 N34 AS1 1 O A3 C1 35 ESI: (M + H)+ = 0.3 FM1 (KBr): C═O
    936/38/40/42 1641.3
    (Br3)
    378 N15 AS1 0 O A3 C1 30 ESI: (M + H)+ = 0.13 FM1 (KBr): C═O
    940/2/4 (Br2) 1701.1; 1641.3
    N48 AS1 1 O A3 C1 52 0.58 FM7 (KBr): C═O
    1641.3
    N77 AS1 1 O A3 C4 32 ESI: (M + H)+ = (KBr): C═O
    955/7/9 (Br2) 1645; 1713
    294 N66 AS4 1 O A7 C1 NEt3 as base 31 ESI: (M + H)+ = 0.3 FM1 (KBr): C═O
    895/7/9 (Br2) 1653; 1772.5;
    1716.5
    323 N104 AS1 1 O A0 C4 DIEA 18 ESI: (M + H)+ = 0.4 FM1 (KBr): C═O
    799/801/803 1624
    (Br2)
    324 N105 AS1 1 O A0 C4 DIEA 24 ESI: (M + H)+ = 0.38 FM1 (KBr): C═O
    773/5/7/9 1624/1667
    (Br2/Cl)
    325 N106 AS1 1 O A0 C4 DIEA 22 ESI: (M + H)+ = 0.35 FM1 (KBr): C═O
    725/7/9 (Br2) 1626/1662.5
    326 N71 AS1 1 O A0 C1 DIEA 20 ESI: (M + H)+ = 0.16 FM1 (KBr): C═O
    752/4/6 (Br2) 1624/1680
    327 N71 AS4 1 O A0 C4 DIEA 24 ESI: (M + H)+ = 0.48 FM1 (KBr): C═O
    750/2/4 (Br2) 1618/1682
    328 N107 AS1 1 O A0 C4 DIEA 17 ESI: (M + H)+ = 0.38 FM1 (KBr): C═O
    769/71/73 (Br2) 1651
    329 N108 AS4 1 O A0 C4 DIEA 16 ESI: (M + H)+ = 0.31 FM1 (KBr): C═O
    781/83/85 (Br2) 1620/1674
    330 N108 AS4 1 O A0 C1 DIEA/DMF 15 ESI: (M + H)+ = 0.45 FM1 (KBr): C═O
    781/83/85 (Br2) 1620/1678
    331 N108 AS4 1 O A0 C20 DIEA/DMF 15 ESI: (M + H)+ = 0.4 FM1 (KBr): C═O
    800/802/804 1616/1680
    (Br2)
    332 N109 AS1 1 O A0 C4 DIEA/DMF 39 ESI: (M + H)+ = 0.32 FM1 (KBr): C═O
    745/7/9 (Br2) 1665
    333 N110 AS1 1 O A0 C4 DIEA/DMF 52 ESI: (M + H)+ = 0.34 FM1 (KBr): C═O
    745/7/9 (Br2) 1636
    334 N111 AS14 1 O A0 C1 DIEA/DMF 18 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    649 1626/1688
    335 N109 AS4 1 O A0 C4 DIEA/DMF 46 ESI: (M + H)+ = 0.47 FM1 (KBr): C═O
    744/6/8 (Br2) 1618
    336 N110 AS1 1 O A0 C8 DIEA/DMF 25 ESI: (M + H)+ = 0.22 FM1 (KBr): C═O
    751/3/5 (Br2) 1645
    337 N109 AS1 1 O A0 C8 DIEA/DMF 32 ESI: (M + H)+ = 0.21 FM1 (KBr): C═O
    751/3/5 (Br2) 1645
    338 N109 AS4 1 H2 A0 C8 DIEA/ 38 ESI: (M + H)+ = 0.44 FM1 (KBr): C═O
    DMF 736/8/40 (Br2) 1653
    339 N110 AS4 1 H2 A0 C8 DIEA/ 39 ESI: (M + H)+ = 0.44 FM1 (KBr): C═O
    DMF 736/8/40 (Br2) 1653
    340 N66 AS1 1 O A0 C20 DIEA/ 33 ESI: (M + H)+ = 0.12 FM1 (KBr): C═O
    DMF 759/61/63 (Br2) 1618/1657
    341 N71 AS1 1 O A0 C20 DIEA/ 31 ESI: (M + H)+ = 0.1 FM1 (KBr): C═O
    DMF 771/3/5 (Br2) 1620/1680
    342 N112 AS4 1 O A0 C20 DIEA/ 27 ESI: (M + H)+ = 0.47 FM1 (KBr): C═O
    DMF 776/8/80 (Br2) 1618/1682
    343 N112 AS1 1 O A0 C20 DIEA/ 26 ESI: (M + H)+ = 0.11 FM1 (KBr): C═O
    DMF 777/9/81 (Br2) 1624/1678
    344 N71 AS1 1 O A0 C37 DIEA/ 52 ESI: (M + H)+ = 0.65 FM1 (KBr): C═O
    DMF 771/3/5 (Br2) 1622/1680
    345 N66 AS1 1 O A0 C37 DIEA/ 50 ESI: (M + H)+ = 0.7 FM1 (KBr): C═O
    DMF 759/61/63 (Br2) 1626/1659
    346 N71 AS4 1 O A0 C37 DIEA/ 37 ESI: (M + H)+ = 0.75 FM1 (KBr): C═O
    DMF 770/72/74 (Br2) 1620/1682
    347 N6 AS4 1 O A0 C37 DIEA/ 45 ESI: (M + H)+ = 0.8 FM1 (KBr): C═O
    DMF 758/60/62 (Br2) 1620/1663
    348 N113 AS4 1 O A0 C20 DIEA/ 24 ESI: (M + H)+ = 0.8 FM1 (KBr): C═O
    DMF 771/3/5 (BR2) 1616/1701
    349 N113 AS4 1 O A0 C8 DIEA/ 40 ESI: (M + H)+ = 0.8 FM1 (KBr): C═O
    DMF 757/59/61 (Br2) 1616/1699
    350 N111 AS4 1 O A0 C20 33 ESI: (M + H)+ = 0.63 FM1 (KBr): C═O
    838/40/42 (Br2) 1620/1688
    351 N111 AS4 1 O A0 C8 39 ESI: (M + H)+ = 0.64 FM1 (KBr): C═O
    824/6/8 (Br2) 1620/1688
    352 N111 AS1 1 O A0 C8 36 ESI: (M + H)+ = 0.37 FM1 (KBr): C═O
    825/7/9 (Br2) 1644/1688
    353 N112 AS1 1 O A0 C8 24 ESI: (M + H)+ = 0.28 FM1 (KBr): C═O
    763/5/7 (Br2) 1624/1684
    355 N113 AS4 1 O A0 C11 DIEA/ 6 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    DMF 772/4/6 (Br2) 1620/1697
    356 N66 AS4 1 O A0 C38 DIEA/ 31 ESI: (M + H)+ = 0.23 FM1 (KBr): C═O
    DMF 785/7/9 (Br2) 1624/1664
    357 N112 AS4 1 O A0 C11 DIEA/ 5 ESI: (M + H)+ = 0.37 FM1
    DMF 777/79/81 (Br2)
    358 N111 AS1 1 O A0 C11 DIEA/ 13 ESI: (M + H)+ = 0.09 FM1 (KBr): C═O
    DMF 840/42/44 (Br2) 1624/1686
    359 N111 AS4 1 O A0 C11 DIEA/ 24 0.39 FM1 (KBr): C═O
    DMF 1622/1686
    360 N109 AS4 1 O A0 C8 DIEA/ 25 ESI: (M + H)+ = 0.7 FM1 (KBr): C═O
    DMF 750/52/54 (Br2) 1618/1657
    361 N110 AS4 1 O A0 C11 DIEA/ 35 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    DMF 750/52/54 (Br2) 1622/1649
    362 N110 AS4 1 O A0 C8 DIEA/ 24 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    DMF 750/52/54 (Br2) 1649
    363 N111 AS4 1 O A0 C37 DIEA/ 25 0.53 FM1 (KBr): C═O
    DMF 1622/1688
    364 N111 AS1 1 O A0 C37 DIEA/ 24 ESI: (M + H)+ = 0.3 FM1 (KBr): C═O
    DMF 839/41/43 (Br2) 1624/1686
    366 N66 AS4 1 O A0 C39 67 ESI: (M + H)+ = 0.53 FM1 (KBr): C═O
    772/4/6 (Br2) 1618/1665
    367 N71 AS4 1 O A0 C39 DIEA/ 12 ESI: (M + H)+ = 0.52 FM1 (KBr): C═O
    DMF 784/6/8 (Br2) 1618/1684
    368 N111 AS4 1 O A0 C39 DIEA/ 37 ESI: (M + H)+ = 0.8 FM1 (KBr): C═O
    DMF 852/4/6 (Br2) 1618/1686
    369 N114 AS4 1 O A0 C8 15 ESI: (M + H)+ = 0.58 FM1 (KBr): C═O
    824/6/8 (Br2) 1618/1686
    370 N66 AS4 1 O A0 C40 DIEA/ 35 ESI: (M + H)+ = 0.44 FM1 (KBr): C═O
    DMF 773/5/7 (Br2) 1622/1660
    371 N111 AS4 1 O A0 C40 DIEA/ 58 ESI: (M + H)+ = 0.44 FM1 (KBr): C═O
    DMF 853/5/7 (Br2) 1622/1687
    373 N115 AS4 1 O A0 C8 DIEA/ 43 ESI: (M + H)+ = 0.7 FM1 (KBr): C═O
    DMF 822/4/6/8 (Br3) 1620/1670
    374 N116 AS4 1 O A0 C20 27 ESI: (M + H)+ = 0.53 FM1 (KBr): C═O
    784/6/8 (Br) 1618/1680
    375 N117 AS4 1 O A0 C20 23 ESI: (M + H)+ = 0.52 FM1 (KBr): C═O
    815/7/9 (Br) 1620/1687
    376 N118 AS4 1 O A0 C20 30 0.56 FM1 (KBr): C═O
    1620/1684
    377 N119 AS4 1 O A0 C20 74 ESI: (M + H)+ = 0.61 FM1 (KBr): C═O
    848/50/52/54 1616/1685
    (Br3)
    418 N111 AS4 1 O A0 C38 DIEA/ 23 ESI: (M + H)+ = 0.27 FM1 (KBr): C═O
    DMF 865/7/9 (Br) 1622/1687
    490 N113 AS1 1 O A0 C20 DIEA/ 37 ESI: (M + H)+ = 0.1 FM1 (KBr): C═O
    DMF 772/4/6 (Br2) 1622/1699
    491 N113 AS1 1 O A0 C8 DIEA/ 94 ESI: (M + H)+ = 0.37 FM1 (KBr): C═O
    DMF 758/60/62 (Br2) 1624/1691
    492 N113 AS1 1 O A0 C11 DIEA/ 42 ESI: (M + H)+ = 0.1 FM1 (KBr): C═O
    DMF 773/5/7 (Br2) 1678
    495 N133 AS4 1 O A0 C20 45 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    846/48/50 (Br2) 1620/1682
    379 N71 AS1 1 O A0 C3 39 ESI: (M + H)+ = 0.41 FM4 (KBr): C═O
    769/71/73 (Br2) 1680
    380 N71 AS4 1 O A0 C3 40 ESI: (M + H)+ = 0.47 FM4 (KBr): C═O
    768/70/72 (Br2) 1618/1682
    381 N71 AS1 1 O A0 C42 11 ESI: (M + H)+ = 0.53 FM1 (KBr): C═O
    752/54/56 (Br2) 1624/1682
    382 N66 AS1 1 O A0 C42 18 ESI: (M + H)+ = 0.16 FM4 (KBr): C═O
    740/42/44 (Br2) 1630/1653
    383 N66 AS4 1 O A0 C42 47 ESI: (M + H)+ = 0.25 FM4 (KBr): C═O
    739/41/43 (Br2) 1626/1659
    384 N93 AS1 1 O A0 C1 11 ESI: (M + H)+ = 0.20 FM7 (KBr): C═O
    790/92/94 (Br2) 1636/1705
    385 N71 AS4 1 O A0 C42 37 ESI: (M + H)+ = 0.30 FM4 (KBr): C═O
    751/53/55 (Br2) 1620/1680
    386 N71 AS4 1 O A0 C18 26 ESI: (M + H)+ = 0.27 FM4 (KBr): C═O
    782/4/6 (Br2) 1620/1682
    387 N66 AS4 1 O A0 C5 62 ESI: (M + H)+ = 0.38 FM4 (KBr): C═O
    739/41/43 (Br2) 1626/1663
    388 N71 AS4 1 O A0 C5 55 ESI: (M + H)+ = 0.39 FM4 (KBr): C═O
    751/3/5 (Br2) 1618/1684
    389 N66 AS1 1 O A0 C43 59 ESI: (M + H)+ = 0.32 CH2Cl2/MeOH/ (KBr): C═O
    796/98/800 NH4OH 9/1/0.1 1653
    (Br2)
    390 N135 AS4 1 O A0 C18 5 ESI: (M + H)+ = 0.71 FM1 (KBr): C═O
    853/5/7 (Br2) 1622/1653
    391 N135 AS1 1 O A0 C18 6 ESI: (M + H)+ = 0.54 FM1 (KBr): C═O
    854/6/8 (Br2) 1659
    392 N120 AS1 1 O A0 C4 12 ESI: (M + H)+ = 0.41 CH2Cl2/MeOH/ (KBr): C═O
    763/5/7 (Br2) NH4OH 9/1/0.1 1618/1639
    393 N66 AS1 1 O A0 C44 28 ESI: (M + H)+ = 0.50 CH2Cl2/MeOH/ (KBr): C═O
    763/5/7 (Br2) NH4OH 9/1/0.1 1659
    394 N66 AS4 1 O A0 C21 37 ESI: (M + H)+ = 0.35 EE/MeOH/ (KBr): C═O
    740/42/44 (Br2) AcOH 75/25/0.5 1659
    396 N71 AS1 1 O A0 C21 49 ESI: (M + H)+ = 0.30 EE/MeOH/ (KBr): C═O
    753/5/7 (Br2) AcOH 75/25/0.5 1622/1678
    397 N66 AS1 1 O A0 C21 62 ESI: (M + H)+ = 0.35 EE/MeOH/ (KBr): C═O
    741/3/5 (Br2) AcOH 75/25/0.5 1649
    398 N121 AS4 1 O A0 C8 80 ESI: (M + H)+ = 0.55 CH2Cl2/MeOH/ (KBr): C═O
    743/5/7 (Br2) NH4OH 9/1/0.1 1618/1668
    399 N122 AS4 1 O A0 C18 40 ESI: (M + H)+ = 0.62 FM1 (KBr): C═O
    800/2/4 (Br2) 1622/1682
    400 N136 AS4 1 O A0 C8 11 ESI: (M + H)+ = 0.65 FM1 (KBr): C═O
    741/3/5 (Br2) 1622/1653
    401 N66 AS1 1 O A0 C45 19 ESI: (M + H)+ = 0.65 CH2Cl2/MeOH/ (KBr): C═O
    749/51/53 (Br2) NH4OH 9/1/0.1 1659
    402 N136 AS4 1 O A0 C1 10 ESI: (M + H)+ = 0.42 CH2Cl2/MeOH/ (KBr): C═O
    736/8/40 (Br2) NH4OH 9/1/0.1 1649
    403 N121 AS4 1 O A0 C1 25 ESI: (M + H)+ = 0.43 CH2Cl2/MeOH/ (KBr): C═O
    738/40/42 (Br2) NH4OH 9/1/0.1 1626/1676
    404 N66 AS4 1 O A0 C46 58 ESI: (M + H)+ = 0.29 CH2Cl2/MeOH/ (KBr): C═O
    766/8/70 (Br2) NH4OH 9/1/0.1 1624/1663
    405 N66 AS1 1 O A0 C47 40 ESI: (M − H)− = 0.3 EE/MeOH 9/1 (KBr): C═O
    752/4/6 (Br2) 1659
    406 N136 AS1 1 O A0 C1 16 ESI: (M + H)+ = 0.34 FM7 (KBr): C═O
    737/39/41 (Br2) 1645
    407 N121 AS1 1 O A0 C1 15 ESI: (M + H)+ = 0.36 FM7 (KBr): C═O
    739/41/43 (Br2) 1638
    408 N71 AS4 1 O A0 C48 47 ESI: (M + H)+ = 0.17 CH2Cl2/MeOH/ (KBr): C═O
    792/4/6 (Br2) NH4OH 9/1/0.1 1620/1680
    409 N66 AS4 1 O A0 C48 31 ESI: (M + H)+ = 0.43 CH2Cl2/MeOH/ (KBr): C═O
    780/2/4 (Br2) NH4OH 9/1/0.1 1665/1736
    410 N66 AS1 1 O A0 C49 51 0.24 EE/MeOH 9/1 (KBr): C═O
    1661
    411 N71 AS4 1 O A0 C44 45 ESI: (M + Na)+ = 0.35 EE/MeOH 9/1 (KBr): C═O
    796/98/800 1728
    (Br2)
    412 N66 AS1 1 O A0 C50 58 ESI: (M + H)+ = 0.47 EE/MeOH 9/1 (KBr): C═O
    756/58/60 (Br2) 1642/1661
    413 N66 AS1 1 O A0 C51 16 ESI: (M + H)+ = 0.47 EE/MeOH/ (KBr): C═O
    788/90/92 (Br2) NH4OH 5/5/0.1 1631
    414 N66 AS4 1 O A0 C52 34 ESI: (M + H)+ = 0.54 FM1 (KBr): C═O
    747/49/51 (Br2) 1622/1662
    415 N71 AS4 1 O A0 C52 35 ESI: (M + H)+ = 0.52 FM1 (KBr): C═O
    759/61/63 (Br2) 1620/1682
    416 N66 AS4 1 O A0 C53 53 ESI: (M + H)+ = 0.45 CH2Cl2/MeOH/ (KBr): C═O
    759/61/63 (Br2) NH4OH 9/1/0.1 1620/1664
    417 N71 AS4 1 O A0 C53 39 ESI: (M + H)+ = 0.43 (KBr): C═O
    771/3/5 (Br2) 1620/1684
    496 N66 AS4 1 O A0 C64 57 0.5 CH2Cl2/MeOH/ (KBr): C═O
    NH4OH 9/1/0.1 1635
    497 N66 AS1 1 O A0 C53 60 ESI: (M + H)+ = 0.31 CH2Cl2/MeOH/ (KBr): C═O
    760/2/4 (Br2) NH4OH 1676
    50/50/0.5
    498 N66 AS4 1 O A0 C65 60 ESI: (M + H)+ = 0.39 FM1 (KBr): C═O
    760/2/4 (Br2) 1676
    499 N71 AS4 1 O A0 C65 53 ESI: (M + H)+ = 0.39 FM1 (KBr): C═O
    785/7/9 (Br2) 1618/1684
    500 N66 AS4 1 O A0 C51 71 ESI: (M + H)+ = 0.15 CH2Cl2/MeOH/ (KBr): C═O
    787/89/91 (Br2) NH4OH 9/1/0.1 1628
    501 N71 AS1 1 O A0 C53 71 ESI: (M + H)+ = 0.25 CH2Cl2/MeOH/ (KBr): C═O
    772/4/6 (Br2) NH4OH 1676
    50/50/0.5
    502 N66 AS1 1 O A0 C65 42 ESI: (M + H)+ = 0.15 FM1 (KBr): C═O
    774/6/8 (Br2) 1626/1657
    503 N71 AS1 1 O A0 C65 48 ESI: M + H)+ = 0.12 FM1 (KBr): C═O
    786/88/90 (Br2) 1620/1682
    504 N66 AS4 1 O A0 C66 67 ESI: (M + H)+ = 0.65 CH2Cl2/MeOH/ (KBr): C═O
    787/89/91 (Br2) NH4OH 1624
    50/50/0.5
    297 N71 AS4 1 H2 A0 C8 9 ESI: (M + H)+ = 0.2 FM1 (KBr): C═O
    742/4/6 (Br2) 1684
    298 N71 AS13 1 H2 A0 C8 6 ESI: (M + H)+ = 0.16 FM1 (KBr): C═O
    664/6 (Br) 1622/1682
    299 N66 AS4 1 H2 A0 C8 21 ESI: (M + H)+ = 0.25 FM1 (KBr): C═O
    730/2/4 (Br2) 1666
    300 N66 AS13 1 H2 A0 C8 14 ESI: (M + H)+ = 0.19 FM1 (KBr): C═O
    652/4 (Br) 1666
    301 N71 AS1 1 H2 A0 C8 26 ESI: (M + H)+ = 0.2 FM1 (KBr): C═O
    743/5/7 (Br2) 1682
    420 N87 AS1 1 O A0 C4 45 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    797/99/801 1624/1665/
    (Br2) 1719
    422 N87 AS1 1 O A0 C8 35 ESI: (M + H)+ = 0.54 FM1 (KBr): C═O
    805/7/9 (Br2) 1628/1668/
    1720
    431 N125 AS4 1 O A0 C8 89 ESI: (M + H)+ = 0.75 FM1 (KBr): C═O
    772/4/6 (Br2) 1713/1773
    432 N125 AS1 1 O A0 C4 59 ESI: (M + H)+ = 0.65 FM1 (KBr): C═O
    767/69/71 (Br2) 1622/1711/
    1773
    433 N126 AS4 1 O A0 C4 33 ESI: (M + H)+ = 0.65 FM1 (KBr): C═O
    780/2/4 (Br2) 1709/1769
    434 N126 AS1 1 O A0 C8 53 ESI: (M + H)+ = 0.53 FM1 (KBr): C═O
    787/89/91 (Br2) 1626/1707
    440 N127 AS4 1 O A0 C8 67 ESI: (M + H)+ = 0.67 FM1 (KBr): C═O
    780/2/4 (Br2) 1618
    441 N127 AS4 1 O A0 C20 89 ESI: (M + H)+ = 0.24 EE/MeOH/ (KBr): C═O
    794/6/8 (Br2) NH4OH 1618
    8/1.5/0.3
    442 N127 AS4 1 O A0 C4 83 ESI: (M + H)+ = 0.37 EE/MeOH/ (KBr): C═O
    774/6/8 (Br2) NH4OH 1616/1732
    8/1.5/0.3
    456 N66 AS16 1 O A0 C8 83 ESI: (M + H)+ = 0.32 EE/MeOH/ (KBr): C═O
    641/3/5 (Cl2) NH4OH 1624/1665
    8/1.5/0.1
    466 N128 AS4 1 O A0 C8 13 ESI: (M + H)+ = 0.63 FM1 (KBr): C═O
    832/4/6 (Br2) 1684
    467 N129 AS4 1 O A0 C8 16 ESI: (M + H)+ = 0.63 FM1 (KBr): C═O
    806/08/10 (Br2) 1618/1682
    468 N129 AS1 1 O A0 C8 28 ESI: (M + H)+ = 0.29 FM1 (KBr): C═O
    807/09/11 (Br2) 1630/1680
    470 N128 AS1 1 O A0 C8 81 ESI: (M + H)+ = 0.63 FM1 (KBr): C═O
    835/7/9 (Br2) 1684
    473 N130 AS1 1 O A0 C8 40 ESI: (M + H)+ = 0.51 FM1 (KBr): C═O
    787/89/91 (Br2) 1624/1678
    474 N130 AS4 1 O A0 C8 17 ESI: (M + H)+ = 0.71 FM1 (KBr): C═O
    786/88/90 (Br2) 1618/1684
    477 N66 AS16 1 O A0 C1 33 ESI: (M + H)+ = 0.53 EE/MeOH/ (KBr): C═O
    636/38/40 (Cl2) NH4OH 9/1/1 1661
    (v/v/v)
    481 N131 AS4 1 O A0 C37 30 ESI: (M + H)+ = 0.15 CH2Cl2/ (KBr): C═O
    838/40/42/44 MeOH 7/3 1618/1685
    (Br2; Cl2) (v/v)
    482 N131 AS4 1 O A0 C20 24 ESI: (M + H)+ = 0.15 CH2Cl2/ (KBr): C═O
    838/40/42/44 MeOH 7/3 1618/1685
    (Br2; Cl2) (v/v)
    483 N132 AS4 1 O A0 C20 62 ESI: (M + H)+ = 0.55 FM1 (KBr): C═O
    804/6/8/10 1684
    (Br2; Cl)
    484 N132 AS4 1 O A0 C37 85 ESI: (M + H)+ = 0.60 FM1 (KBr): C═O
    804/6/8/10 1616/1686
    (Br2; Cl)
    505 N134 AS4 1 O A0 C8 81 ESI: (M + H)+ = 0.74 FM1 (KBr): C═O
    781/3/5 (Br2) 1616/1714
    292 N66 AS1 1 H2 A0 C8 6 ESI: (M + H)+ = 0.25 FM1 (KBr): C═O
    731/3/5 (Br2) 1607/1664
    245 N72 AS4 1 H2 A0 C8 19 ESI: (M + H)+ = 0.30 FM1 (KBr): C═O
    731/3/5 (Br2) 1668
    220 N15 AS1 1 H2 A0 C8 6 ESI: (M + H)+ = 0.30 FM1 (KBr): C═O
    717/19/21 (Br2) 1697.3
    307 N87 AS4 1 O A0 C4 27 ESI: (M + H)+ = 0.50 FM1 (KBr): C═O
    796/98/800 1618/1670/
    (Br2) 1718
    178 N74 AS1 1 O A0 C4 33 ESI: (M + H)+ = 0.60 EE/MeOH/ (KBr): C═O
    679/81/83 (Br2) AcOH 1624
    50/50/1
    (v/v/v)
    395 N71 AS4 1 O A0 C21 22 ESI: (M + H)+ = 0.25 EE/MeOH/
    752/4/6 (Br2) AcOH
    50/25/0.5
    (v/v/v)
    509 N119 AS4 1 O A0 C38 DMF 45 ESI: (M + H)+ = 0.2 FM1 (KBr): C═O
    875/7/9/81 1687/1618
    (Br3)
    510 N118 AS4 1 O A0 C38 DMF 34 ESI: (M + H)+ = 0.4 FM1 (KBr): C═O
    827/29/31 (Br2) 1682/1620
    519 N137 AS4 1 O A0 C20 THF/ 62 ESI: (M + H)+ = 0.1 FM1 (KBr): C═O
    DMF 786/88/90 (Br2) 1618/1678
    520 N138 AS4 1 O A0 C20 THF/DMF 31 ESI: (M + H)+ = 0.45 FM1 (KBr): C═O
    906/08/10 1693
    (Br2)
    N66 AS4 1 O A0 C69 DMF 100
    533 N139 AS1 1 O A0 C8 44 ESI: (M + H)+ = 0.1 FM5 (KBr): C═O
    746/48/50 1628
    (Br2)
    534 N139 AS4 1 O A0 C20 60 ESI: (M + H)+ = 0.2 FM5 (KBr): C═O
    759/61/63 1618/1672
    (Br2)
    535 N139 AS1 1 O A0 C53 34 ESI: (M + H)+ = 0.1 FM5 (KBr): C═O
    761/63/65 1624/1670
    (Br2)
    536 N140 AS4 1 O A0 C8 40 ESI: (M + H)+ = 0.37 FM1 (KBr): C═O
    745/7/9 1616/1676
    (Br2)
    537 N140 AS1 1 O A0 C8 33.4 ESI: (M + H)+ = 0.3 FM1 (KBr): C═O
    746/48/50 1614/1672
    (Br2)
    551 N66 AS1 1 O A0 C66 41 ESI: (M + H)+ = 0.3 EE/MeOH/ (KBr): C═O
    788/90/92 NH4OH 1628
    (Br2) 50/50/0.5
    552 N66 AS4 1 O A0 C78 83 ESI: (M + H)+ = 0.6 CH2Cl2/MeOH/ (KBr): C═O
    787/89/91 NH4OH 1620
    (Br2) 80/20/1
    553 N66 AS1 1 O A0 C78 30 ESI: (M + H)+ = 0.5 CH2Cl2/MeOH/ (KBr): C═O
    788/90/92 NH4OH 1626
    (Br2) 80/20/1
    554 N71 AS4 1 O A0 C78 67 ESI: (M + H)+ = 0.5 CH2Cl2/MeOH/ (KBr): C═O
    799/801/803 NH4OH 1622/1684
    (Br2) 80/20/1
    555 N71 AS1 1 O A0 C78 26 ESI: (M + H)+ = 0.5 CH2Cl2/MeOH/ (KBr): C═O
    800/02/04 NH4OH 1624/1684
    (Br2) 80/20/1
    556 N66 AS4 1 O A0 C70 71 ESI: (M + H)+ = 0.6 CH2Cl2/MeOH/ (KBr): C═O
    788/90/92 NH4OH 1653
    (Br2) 50/50/0.5
    557 N71 AS4 1 O A0 C70 27 ESI: (M + H)+ = 0.8 CH2Cl2/MeOH/
    800/02/04 NH4OH
    (Br2) 50/50/0.5
    558 N66 AS1 1 O A0 C64 61 ESI: (M + H)+ = 0.3 CH2Cl2/MeOH/ (KBr): C═O
    790/92/94 NH4OH 1635
    (Br2) 90/10/1
    559 N141 AS4 1 O A0 C20 80 ESI: (M + H)+ = 0.3 CH2Cl2/MeOH/ (KBr): C═O
    626/28/30 NH4OH 1618/1714
    (Br2) 90/10/1
    560 N66 AS4 1 O A0 C71 59 ESI: (M + H)+ = 0.3 CH2Cl2/MeOH/ (KBr): C═O
    837/39/41 NH4OH 1628/62
    (Br2) 90/10/1
    561 N71 AS4 1 O A0 C71 56 ESI: (M + H)+ = 0.2 CH2Cl2/ (KBr): C═O
    849/51/53 (Br2) MeOH/ 1618/1684
    NH4OH
    90/10/1
    562 N66 AS1 1 O A0 C70 15 ESI: (M + H)+ = 0.6 CH2Cl2/ (KBr): C═O
    789/91/93 (Br2) MeOH/ 1676
    NH4OH
    50/50/0.5
    563 N71 AS1 1 O A0 C70 27 ESI: (M + H)+ = 0.6 CH2Cl2/ (KBr): C═O
    801/3/5 (Br2) MeOH/ 1678
    NH4OH
    70/30/1
    565 N66 AS4 1 O A0 C72 51 ESI: (M + H)+ = 0.2 CH2Cl2/ (KBr): C═O
    787/89/91 (Br2) MeOH/ 1622/1658
    NH4OH
    80/20/1
    566 N71 AS4 1 O A0 C72 65 ESI: (M + H)+ = 0.2 CH2Cl2/ (KBr): C═O
    799/801/803 MeOH/ 1620/1682
    (Br2) NH4OH
    80/20/1
    567 N136 AS4 1 O A0 C53 65 ESI: (M + H)+ = 0.5 CH2Cl2/ (KBr): C═O
    756/58/60 (Br2) MeOH/ 1641
    NH4OH
    80/20/1
    568 N136 AS4 1 O A0 C72 76 ESI: (M + H)+ = 0.2 CH2Cl2/ (KBr): C═O
    784/6/8 (Br2) MeOH/ 1637
    NH4OH
    80/20/1
    569 N136 AS1 1 O A0 C53 63 ESI: (M + H)+ = 0.4 CH2Cl2/ (KBr): C═O
    757/59/61 (Br2) MeOH/ 1643
    NH4OH
    80/20/1
    570 N66 AS31 1 O A0 C20 88 ESI: (M + H)+ = 0.6 CH2Cl2/ (KBr): C═O
    640 MeOH/ 1622/1664
    NH4OH
    80/20/1
    571 N66 AS31 1 O A0 C53 82 ESI: (M + H)+ = 0.8 CH2Cl2/ (KBr): C═O
    641 MeOH/ 1664
    NH4OH
    80/20/1
    572 N71 AS31 1 O A0 C20 100 ESI: (M + H)+ = 0.4 CH2Cl2/ (KBr): C═O
    652 MeOH/ 1620/1684
    NH4OH
    80/20/1
    573 N71 AS31 1 O A0 C53 48 ESI: (M + H)+ = 0.4 CH2Cl2/ (KBr): C═O
    653 MeOH/ 1622/1684
    NH4OH
    80/20/1
    576 N66 AS11 1 O A0 C53 35 ESI: (M + H)+ = 0.65 CH2Cl2/ (KBr): C═O
    727 MeOH/ 1664/1732
    NH4OH
    80/20/1
    577 N71 AS11 1 O A0 C53 73 ESI: (M + H)+ = 0.18 EE/ (KBr): C═O
    739 MeOH/ 1684/1734
    NH4OH
    50/50/0.5
    580 N66 AS11 1 O A0 C20 65 ESI: (M + H)+ = 0.5 CH2Cl2/ (KBr): C═O
    706 MeOH/ 1664/1732
    NH4OH
    80/20/1
    581 N71 AS11 1 O A0 C20 38 ESI: (M + H)+ = 0.2 CH2Cl2/ (KBr): C═O
    738 MeOH/ 1684/1734
    NH4OH
    90/10/1
    582 N143 AS4 1 O A0 C20 61 ESI: (M + H)+ = 0.5 CH2Cl2/ (KBr): C═O
    758/60/62 MeOH/ 1615
    NH4OH
    90/10/1
    583 N66 AS31 1 O A0 C72 50 ESI: (M + H)+ = 0.35 FM1 (KBr): C═O
    669 1664
    584 N71 AS31 1 O A0 C72 68 ESI: (M + H)+ = 0.35 FM1 (KBr): C═O
    681 1622/1684
    585 N144 AS4 1 O A0 C8 50 ESI: (M + H)+ = 0.43 FM5 (KBr): C═O
    927/29/31/33 1616/1684
    (Br4)
    586 N144 AS4 1 O A0 C53 85 ESI: (M + H)+ = 0.67 FM1 (KBr): C═O
    942/4/6/8 (Br4) 1680
    587 N66 AS11 1 O A0 C72 37 ESI: (M + H)+ = 0.35 FM1 (KBr): C═O
    755 1622/1685/
    1732
    588 N71 AS11 1 O A0 C72 81 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    767 1684/1732
    619 N71 AS19 1 O A0 C8 27.9 0.3 EE/MeOH/ (KBr): C═O
    NH4OH 1622/1684
    9/1/0.3
    620 N66 AS35 1 O A0 C8 36 ESI: (M − H)− = 0.25 MeOH (KBr): C═O
    598 1628/1664
    621 N66 AS36 1 O A0 C8 32 ESI: (M − H)− = 0.56 FM1 (KBr): C═O
    587 1626/1666
    622 N71 AS36 1 O A0 C8 32 ESI: (M − H)− = 0.44 FM1 (KBr): C═O
    599 1622/1684
    623 N109 AS36 1 O A0 C8 37 ESI: (M − H)− = 0.6 FM1 (KBr): C═O
    593 1626/1649
    624 N118 AS36 1 O A0 C8 55 ESI: (M − H)− = 0.6 FM1 (KBr): C═O
    629 1622/1684
    625 N111 AS36 1 O A0 C8 47 ESI: (M − H)− = 0.61 FM1 (KBr): C═O
    667 1624/1687
    626 N111 AS19 1 O A0 C8 20 ESI: (M − H)− = 0.28 EE/MeOH/ (KBr): C═O
    731/3 (Br) NH4OH 1624/1687
    9/1/0.3
    627 N109 AS19 1 O A0 C8 16 ESI: (M − H)− = 0.28 EE/MeOH/ (KBr): C═O
    657/9 (Br) NH4OH 1653
    9/1/0.3
    633 N118 AS19 1 O A0 C8 20 ESI: (M + H)+ = 0.18 EE/MeOH/ (KBr): C═O
    693/5 (Br) NH4OH 1622/1684
    9/1/0.3
    N66 AS1 1 O A0 C69 100 0.3 FM4 (KBr): C═O
    1668
    • EXAMPLE 4
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00099
    • 1-[4-amino-3,5-dibromo-N-[4-(1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine No. 91
  • A mixture of 0.35 g (2.1 mmol) of CDT, 1.0 g (1.4 mmol) of 4-(1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl)-piperidine, 0.5 ml of (2.8 mmol) of DIEA and 100 ml of tetrahydrofuran was stirred for 1 hour whilst cooling with ice and then for 30 minutes at ambient temperature. With stirring 0.46 g (1.75 mmol) of 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyridinyl)piperazine and 0.32 ml of (1.8 mmol) of DIEA were added and refluxed for 3 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and the organic phase was washed twice with aqueous saturated sodium hydrogen carbonate solution. The combined aqueous phases were then extracted once with ethyl acetate/tetrahydrofuran=1/1 (v/v) and the combined organic phases were washed once with saturated aqueous saline solution. After drying the organic phase and eliminating the solvent in vacuo the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=9/1 (v/v)). 120 mg (12% of theory) of a colourless foam were obtained.
  • IR (KBr): 1626. 1686 cm−1 (C═O)
  • Rf: 0.62 (FM3)
  • ESI-MS: (M+H)+=731/733/735 (Br2)
      • (M+H+Na)++=377/378/379 (Br2)
  • The following were prepared analogously (in each case n=1):
  • % M.p.
    No. RCO R2 A NR3R4 n Remarks Yield MS Rf Eluant IR [cm−1] (° C.)
    N16 AS1 A3 C1 1 NEt3 as base 31 ESI: (M + H)+ = 0.2 FM1 (KBr): C = 0
    974/6/8 (Br2) 1641.3;
    1695.3
    86 N53 AS4 A0 C1 1 DMF as solvent 23 ESI: (M + H)+ = 0.5 FM1 (KBr): C = 0
    739/41/43 (Br2) 1641.3;
    1697.3
    87 N54 AS4 A0 C1 1 DMF als 81 ESI: (M + H)+ = 0.5 FM1 (KBr): C = 0
    Lösemittel 739/41/43 (Br2) 1620.1;
    1697.3
    92 N57 AS4 A0 C1 1 DMF as solvent 60 ESI: (M + H)+ = 0.6 FM1 (KBr): C = 0
    712/4/6 (Br2) 1597; 1635.5
    93 N47 AS4 A0 C1 1 23 ESI: (M + H)+ = 0.4 FM1 (KBr): C = 0
    636/8/40 (Br2) 1622; 1675
    94 N45 AS4 A0 C1 1 45 ESI: (M + H)+ = 0.6 FM1 (KBr): C = 0
    739/41/43 (Br2) 1598.9;
    1620.1
    95 N57 AS1 A0 C1 1 DMF as solvent 13 ESI: (M + H)+ = 0.2 FM 1 (KBr): C = 0
    713/5/7 (Br2) 1637.5
    96 N53 AS1 A0 C1 1 DMF as solvent 15 ESI: (M + H)+ = 0.2 FM 1 (KBr): C = 0
    740/2/4 (Br2) 1633.6;
    1687.6
    97 N54 AS1 A0 C1 1 DMF as solvent 31 ESI: (M + H)+ = 0.2 FM 1 (KBr): C = 0
    740/2/4 (Br2) 1635.5;
    1695.3
    107 N59 AS4 A0 C1 1 76 ESI: (M + H)+ = 0.7 FM 1 (KBr): C = 0
    694/6/8 (Br2) 1597; 1635.5
    108 N45 AS1 A0 C1 1 37 ESI: (M + H)+ = 0.3 FM 1 (KBr): C = 0
    740/2/4 (Br2) 1633.6;
    1708.8
    109 N59 AS1 A0 C1 1 30 ESI: (M + H)+ = 0.3 FM 1 (KBr): C = 0
    695/7/9 (Br2) 1647.4
    116 N60 AS4 A0 C1 1 DMF as solvent 80 ESI: (M + H)+ = 0.6 FM 1 (KBr): C = 0
    753/5/7 (Br2) 1623.7;
    1676.1;
    1712.7
    117 N60 AS1 A0 C1 1 DMF as solvent 50 ESI: (M + H)+ = 0.4 FM 1 (KBr): C = 0
    754/6/8 (Br2) 1617; 1650;
    1670; 1712.7
    118 N47 AS1 A0 C1 1 29 ESI: (M + H)+ = 0.1 FM 1 (KBr): C = 0
    637/9/41 (Br2) 1639.4
    121 N61 AS1 A0 C1 1 12.4 ESI: (M + H)+ = 0.2 FM 1 (KBr): C = 0
    727/9/31 (Br2) 1635.5; 1705
    122 N61 AS4 A0 C1 1 42 ESI: (M + H)+ = 0.6 FM 1 (KBr): C = 0
    726/8/30 (Br2) 1620.1;
    1706.9
    125 N15 AS7 A0 C1 1 NEt3 as base 4.4 ESI: (M + H)+ = 0.6 FM 1 (KBr): C = 0
    598 1708.8
    126 N15 AS7 A0 C4 1 NEt3 as base 57 ESI: (M + H)+ = 0.6 FM 1 (KBr): C = 0 188.0
    597 1622; 1708.8
    127 N15 AS7 A0 C8 1 NEt3 as 16 ESI: (M + H)+ = 0.6 FM 1 (KBr): C = 0  168-170
    base 603 1622;
    1697.3
    137 N94 AS4 A0 C4 1 42 ESI: (M + H)+ = 0.8 FM1 (KBr): C = 0
    708/10/12 (Br2) 1618
    138 N95 AS4 A0 C8 1 NEt3 as 29 ESI: (M + H)+ = 0.8 FM1 (KBr): C = 0
    base 743/5/7 (Br2) 1713
    139 N61 AS1 A3 C1 1 41 ESI: (M + H)+ = 0.4 FM1 (KBr): C = 0
    955/7/9 (Br2) 1640; 1709
    140 N60 AS1 A3 C1 1 66 ESI: (M + H)+ = 0.5 FM1 (KBr): C = 0
    982/4/6 (Br2) 1645; 1712
    143 N66 AS1 A0 C4 1 DMF as 69 ESI: (M + H)+ = 0.4 FM1 (KBr): C = 0
    solvent 739/41/43 (Br2) 1624; 1659
    144 N96 AS1 A0 C4 1 54 ESI: (M + H)+ = 0.54 FM1 (KBr): C = 0
    725/7/9 (Br2) 1616
    145 N61 AS1 A0 C4 1 48 ESI: (M + H)+ = 0.6 FM1 (KBr): C = 0
    724/6/8 (Br2) 1624; 1709
    146 N15 AS14 A0 C1 1 DMF as 53 ESI: (M + H)+ = 0.15 FM1 (KBr): C = 0
    solvent 555 1636; 1701
    147 N61 AS4 A0 C11 1 30 ESI: (M + H)+ = 0.7 FM1 (KBr): C = 0
    746/48/50 (Br2) 1620; 1713
    148 N66 AS1 A0 C8 1 THF/DMF 58 ESI: (M + H)+ = 0.68 FM1 (KBr): C = 0
    as solvent 745/7/9 (Br2) 1628; 1663
    149 N69 AS1 A0 C4 1 THF/DMF 61 ESI: (M + H)+ = 0.68 FM1 (KBr): C = 0
    as solvent 739/41/43 (Br2) 1624; 1675
    150 N97 AS1 A0 C4 1 THF/DMSO 32 ESI: (M + H)+ = 0.4 FM1 (KBr): C = 0
    as solvent 783/85/87 (Br2) 1709
    152 N71 AS1 A0 C4 1 40 ESI: (M + H)+ = 0.68 FM1 (KBr): C = 0
    751/53/55 (Br2) 1622; 1684
    153 N65 AS1 A0 C4 1 51 ESI: (M + H)+ = 0.68 FM1 (KBr): C = 0
    751/53/55 (Br2) 1626; 1678
    N66 AS1 A3 C1 1 37
    225 N66 AS1 A0 C1 1 THF/DMF 48 ESI: (M + H)+ = 0.35 FM1 (KBr): C = 0
    as solvent 740/42/44 (Br2) 1650; 1670
    226 N66 AS4 A0 C8 1 THF/DMF 88 ESI: (M + H)+ = 0.6 FM1 (KBr): C = 0
    as solvent 744/6/8 (Br2) 1618; 1661
    227 N69 AS4 A0 C8 1 THF/DMF 72 ESI: (M + H)+ = 0.6 FM1 (KBr): C = 0
    as solvent 744/6/8 (Br2) 1618; 1680
    228 N69 AS1 A0 C8 1 THF/DMF 69 ESI: (M + H)+ = 0.45 FM1 (KBr): C = 0
    as solvent 745/7/9 (Br2) 1628
    229 N70 AS1 A0 C4 1 THF/DMF 39 ESI: (M + H)+ = 0.3 FM1 (KBr): C = 0
    as solvent 727/29/31 (Br2) 1730
    230 N66 AS4 A0 C20 1 49 ESI: (M + H)+ = 0.55 FM1 (KBr): C = 0
    758/60/62 (Br2) 1614
    231 N99 AS4 A0 C8 1 THF/DMF as 68 ESI: M + H)+ = 0.6 FM1 (KBr): C = 0
    solvent 758/60/62 (Br2) 1624
    239 N71 AS1 A0 C8 1 THF/DMF as 59 ESI: (M + H)+ = 0.45 FM1 (KBr): C = 0
    solvent 757/59/61 (Br2) 1626; 1680
    240 N71 AS4 A0 C11 1 35 ESI: (M + H)+ = 0.68 FM1 (KBr): C = 0
    771/3/5 (Br2) 1615; 1684
    241 N71 AS4 A0 C8 1 88 ESI: (M + H)+ = 0.68 FM1 (KBr): C = 0
    756/58/60 (Br2) 1620; 1682
    242 N71 AS4 A0 C1 1 40 ESI: (M + H)+ = 0.64 FM1 (KBr): C = 0
    751/3/5 (Br2) 1615; 1684
    243 N71 AS4 A0 C20 1 38 ESI: (M + H)+ = 0.65 FM1 (KBr): C = 0
    770/2/4 (Br2) 1618; 1684
    244 N71 AS1 A0 C11 1 36 ESI: (M + H)+ = 0.35 FM1 (KBr): C = 0
    772/4/6 (Br2) 1622; 1684
    N5 AS1 A3 C1 1 NEt3 as base 24 ESI: (M + H)+ = 0.06 FM1 (KBr): C═O
    890/2/4 (Br2) 1641.3
    N10 AS1 A3 C1 1 NEt3 as base 55 ESI: (M + H)+ = 0.38 FM1 (KBr): C═O
    874/6/8 (Br2) 1641.3
    N12 AS1 A3 C1 1 NEt3 as base 35480 ESI: (M + H)+ = 0.43 FM1 (KBr): C═O
    902/4/6 (Br2) 1639.4
    N22 AS1 A3 C1 1 NEt3 as base 35.5 0.5 FM1
    N23 AS1 A3 C1 1 NEt3 as base 31 0.5 FM1
    N24 AS1 A3 C1 1 NEt3 as base 35607 0.5 FM1
    N46 AS1 A3 C1 1 NEt3 as base 36.2 0.5 FM1 (KBr): C═O
    1641.3
    83 N15 AS1 A0 C1 1 36.7 ESI: (M + H)+ = 0.62 FM2 (KBr): C═O
    726/28/30 (Br2) 1641.3;
    1695.3
    84 N15 AS1 A0 C4 1 36.3 ESI: (M + H)+ = 0.69 FM2 (KBr): C═O
    725/7/9 (Br2); 1624.0;
    (M + Na)+ = 1699.2
    747/49/51 (Br2)
    88 N55 AS4 A0 C1 1 93.6 ESI: (M + H)+ = 0.75 FM3 (KBr): C═O
    793/5/7/9 1641.3;
    (Br2; Cl2) 1708.8
    89 N56 AS4 A0 C1 1 30 ESI: (M + H)+ = 0.81 FM1 (KBr): C═O
    797/799/801 1641.3;
    (Br2) 1697.3;
    1749.3
    136 N15 AS9 A0 C1 1 14.6 ESI: (M + H)+ = 0.55 FM3 (KBr): C═O
    570 1635.5;
    1701.1
    91 N64 AS4 A0 C1 1 11.7 ESI: (M + H)+ = 0.62 FM3 (KBr): C═O
    731/733/735 1625.9;
    1685.7
    N16 AS1 A3 C5 1 Purification 74 ESI: (M + H)+ = 0.48 FM4 (KBr): C═O
    by column 974/976/978 1685.7;
    chromato- (Br2) 1635.5
    graphy: silica
    gel/FM4
    155 N15 AS1 A0 C3 1 34 ESI: (M + H)+ = 0.45 FM1 (KBr): C═O 165-9
    743/5/7 (Br2) 1626; 1695
    156 N15 AS1 A0 C19 1 40 ESI: (M + H)+ = 0.47 FM1 (KBr): C═O 155-9
    743/5/7 (Br2) 1624; 1695
    157 N15 AS4 A0 C19 1 54 ESI: (M + H)+ = 0.79 FM1 (KBr): C═O 151-4
    742/4/6 (Br2) 1616; 1697
    158 N79 AS4 A0 C1 1 15 ESI: (M + H)+ = 0.63 FM1 (KBr): C═O 132-5
    727/29/31 (Br2) 1616; 1695;
    1732
    159 N77 AS4 A0 C8 1 34 ESI: (M + H)+ = 0.63 FM1 (KBr): C═O
    732/4/6 (Br2) 1632
    160 N73 AS1 A0 C4 1 12 ESI: (M − H)− = 0.14 FM1 (KBr): C═O
    649/651/653 1626
    (Br2)
    170 N15 AS4 A0 C37 1 62 ESI: (M − H)− = 0.45 FM1 (KBr): C═O  165-70
    725/7/9 (Br2) 1620; 1701
    171 N79 AS1 A0 C1 1 60 ESI: (M + H)+ = 0.21 FM1 (KBr): C═O 193-7
    728/30/32 (Br2) 1637.5
    172 N79 AS1 A0 C8 1 27 ESI: (M + H)+ = 0.32 FM1 (KBr): C═O 163-9
    733/5/7 (Br2) 1622
    185 N77 AS4 A0 C4 1 66 ESI: (M + H)+ = 0.49 FM1 (KBr): C═O
    726/28/30 (Br2) 1624
    186 N77 AS4 A0 C1 1 76 ESI: (M + H)+ = 0.63 FM1 (KBr): C═O
    727/29/31 (Br2) 1635.5
    187 N77 AS1 A0 C4 1 67 ESI: (M + H)+ = 0.33 FM1 (KBr): C═O
    727/29/31 (Br2) 1627.8
    188 N78 AS1 A3 C1 1 63 ESI: (M + H)+ = 0.45 FM1 (KBr): C═O
    955/7/9 (Br2) 1637.5;
    1774.4; 1701
    189 N103 AS4 A0 C8 1 50 ESI: (M + H)+ = 0.71 FM1 (KBr): C═O
    713/5/7 (Br2) 1616.3
    192 N77 AS1 A0 C1 1 47 ESI: (M + H)+ = 0.2 FM1 (KBr): C═O
    728/30/32 (Br2) 1643.3
    247 N15 AS10 A3 C4 1 60 ESI: (M + H)+ = 0.6 FM1 (KBr): C═O
    937/39/41 (Br2) 1639.4; 1701
    249 N15 AS4 A0 C22 1 52 ESI: (M + H)+ = 0.59 FM1 (KBr): C═O
    744/6/8 (Br2) 1695.3
    161 N15 AS4 A0 C21 1 32 ESI: (M + H)+ = 0.61 FM1 (KBr): C═O 163-7
    726/28/30 (Br2) 1622; 1701
    162 N78 AS1 A0 C4 1 15 ESI: (M + H)+ = 0.48 FM1 (KBr): C═O
    726/28/30 (Br2) 1624; 1772.5
    163 N73 AS1 A0 C1 1 43 ESI: (M + H)+ = 0.07 FM1 (KBr): C═O
    752/4/6 (Br2) 1637.5
    164 N79 AS4 A0 C8 1 48 ESI: (M + H)+ = 0.6 FM1 (KBr): C═O  127-32
    732/4/6 (Br2) 1616.3
    165 N15 AS1 A0 C21 1 27 ESI: (M + H)+ = 0.26 FM1 (KBr): C═O 184-9
    727/29/31 (Br2) 1697.3
    166 N76 AS1 A0 C4 1 17 ESI: (M + H)+ = 0.23 FM1 (KBr): C═O
    665/7/9 (Br2) 1616; 1734
    167 N75 AS1 A0 C4 1 20 ESI: (M + H)+ = 0.18 FM1 (KBr): C═O
    665/7/9 (Br2) 1624
    168 N73 AS1 A3 C4 1 39 ESI: (M + H)+ = 0.15 FM1 (KBr): C═O
    879/81/83 (Br2) 1631.7
    169 N15 AS1 A0 C37 1 17 ESI: (M + H)+ = 0.31 FM1 (KBr): C═O  156-61
    726/28/30 (Br2) 1627.8; 1697.3
    173 N15 AS10 A0 C4 1 66 ESI: (M + H)+ = 0.68 FM1 (KBr): C═O 283-4
    709/11/13 (Br2) 1627.8; 1656.8;
    1695.3
    174 N15 AS10 A0 C1 1 42 ESI: (M + H)+ = 0.61 FM1 (KBr): C═O 266-9
    710/2/4 (Br2) 1706.9
    175 N77 AS1 A0 C8 1 36 ESI: (M + H)+ = 0.24 FM1 (KBr): C═O
    733/5/7 (Br2) 1641.3
    176 N76 AS1 A3 C4 1 47 ESI: (M + H)+ = 0.21 FM1 (KBr): C═O
    893/5/7 (Br2) 1635.5
    177 N75 AS1 A3 C4 1 53 ESI: (M + H)+ = 0.14 FM1 (KBr): C═O
    893/5/7 (Br2) 1637.5
    180 N74 AS1 A3 C4 1 44 ESI: (M + H)+ = 0.26 FM1 (KBr): C═O
    907/9/11 (Br2) 1631.7; 1689.5
    190 N15 AS1 A3 C18 1 44 ESI: (M + H)+ = 0.38 FM1 (KBr): C═O
    985/7/9 (Br2) 1635.5; 1695.3
    191 N15 AS10 A3 C1 1 64 ESI: (M + H)+ = 0.56 FM1 (KBr): C═O
    938/40/42 (Br2) 1645.2; 1701
    N15 AS10 A3 C4 1 91 ESI: (M + H)+ = (KBr): C═O
    937/39/41 (Br2) 1643.3; 1701
    N15 AS10 A3 C1 1 64 ESI: (M + H)+ = (KBr): C═O
    938/40/42 (Br2) 1645; 1701
    254 N77 AS1 A3 C1 1 37 ESI: (M + H)+ = 0.3 FM1 (KBr): C═O
    956/8/60 (Br2) 1641
    N15 AS4 A3 C18 1 90 ESI: (M + H)+ = (KBr): C═O
    984/6/8 (Br2) 1641.3; 1699
    257 N15 AS4 A5 C1 1 17 ESI: (M + H)+ = 0.53 FM1 (KBr): C═O
    782/4/6 (Br2) 1643; 1697
    258 N100 AS4 A0 C1 1 69 ESI: (M + H)+ = 0.54 FM1 (KBr): C═O
    755/7/9 (Br2) 1627.8; 1705
    259 N100 AS4 A0 C8 1 70 ESI: (M + H)+ = 0.54 FM1 (KBr): C═O
    760/2/4 (Br2) 1695
    260 N15 AS4 A0 C23 1 39 ESI: (M + H)+ = 0.36 FM1 (KBr): C═O
    796/798/800 1635.5; 1699
    (Br2)
    261 N15 AS4 A10 C1 1 26 ESI: (M + H)+ = 0.38 FM1 (KBr): C═O
    796/798/800 1631.4; 1701
    (Br2)
    265 N15 AS4 A5 C8 1 20 ESI: (M + H)+ = 0.41 FM1 (KBr): C═O
    787/9/91 (Br2) 1635.5; 1697
    266 N15 AS4 A6 C1 1 24 ESI: (M + H)+ = 0.43 FM1 (KBr): C═O
    796/798/800 1647; 1689, 5
    (Br2)
    262 N80 AS4 A0 C1 1 25 ESI: (M + H)+ = 0.54 FM1 (KBr): C═O
    803/5/7 (Br2) 1637.5
    263 N15 AS15 A0 C8 1 64 ESI: (M + H)+ = 0.43 FM1 (KBr): C═O
    565 1627.8; 1707
    264 N15 AS4 A0 C24 1 62 ESI: (M + H)+ = 0.4 FM1 (KBr): C═O
    733/5/7 (Br2) 1622; 1701
    267 N81 AS4 A3 C8 1 46 ESI: (M + H)+ = 0.55 FM1 (KBr): C═O
    974/6/8 (Br2) 1641; 1707
    268 N15 AS4 A6 C8 1 27 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    801/3/5 (Br2) 1633.6; 1697
    269 N82 AS4 A0 C8 1 86 ESI: (M + H)+ = 0.66 FM1 (KBr): C═O
    742/4/6 (Br2) 1620; 1649
    270 N82 AS4 A0 C1 1 56 ESI: (M + H)+ = 0.59 FM1 (KBr): C═O
    737/39/41 (Br2) 1641
    272 N15 AS11 A0 C8 1 76 ESI: (M + H)+ = 0.6 FM1 (KBr): C═O
    698 1627.8;
    1714.6
    273 N15 AS4 A10 C8 1 68 ESI: (M + H)+ = 0.52 FM1 (KBr): C═O
    801/3/5 (Br2) 1637.5; 1701
    274 N102 AS4 A0 C1 1 76 ESI: (M + H)+ = 0.56 FM1 (KBr): C═O
    738/40/42 (Br2) 1664.5
    275 N102 AS4 A0 C8 1 55 ESI: (M + H)+ = 0.59 FM1 (KBr): C═O
    743/5/7 (Br2) 1618; 1664.5
    276 N83 AS4 A0 C1 1 30 ESI: (M + H)+ = 0.48 FM1 (KBr): C═O
    745/7/9 (Br2) 1633.6
    277 N84 AS4 A0 C8 1 63 ESI: (M + H)+ = 0.54 FM1 (KBr): C═O
    744/6/8 (Br2) 1616; 1691.5
    278 N84 AS4 A3 C4 1 88 ESI: (M + H)+ = 0.53 FM1 (KBr): C═O
    966/8/70 (Br2) 1633.6;
    1691.5
    279 N15 AS4 A0 C26 1 75 ESI: (M + H)+ = 0.44 FM1 (KBr): C═O
    732/4/6 (Br2) 1618; 1709
    281 N15 AS12 A0 C8 1 21 ESI: (M + H)+ = 0.42 FM1 (KBr): C═O
    598 1697
    282 N66 AS1 A0 C18 1 19 ESI: (M + H)+ = 0.51 FM1 (KBr): C═O
    770/2/4 (Br2) 1624; 1660.6;
    1734
    284 N66 AS1 A0 C18 1 29 ESI: (M + H)+ = 0.3 FM1 (KBr): C═O
    771/3/5 (Br2) 1630; 1655
    314 N93 AS4 A0 C8 1 81 ESI: (M + H)+ = 0.5 FM1 (KBr): C═O
    794/6/8 (Br2) 1618; 1701
    315 N93 AS4 A0 C1 1 77 ESI: (M + H)+ = 0.49 FM1 (KBr): C═O
    789/91/93 (Br2) 1627.6; 1705
    316 N65 AS1 A0 C18 1 15 ESI: (M + H)+ = 0.3 FM1 (KBr): C═O
    783/5/7 (Br2) 1624; 1681.8
    317 N66 AS4 A0 C3 1 51 ESI: (M + H)+ = 0.62 FM1 (KBr): C═O
    778/80/82 (Br2) 1627.6;
    1662.5
    318 N66 AS1 A0 C3 1 40 ESI: (M + H)+ = 0.41 FM1 (KBr): C═O
    557/559/561 1659
    (Br2)
    319 N66 AS4 A0 C19 1 55 ESI: (M + H)+ = 0.68 FM1 (KBr): C═O
    778/780/782 1664.5
    (Br2)
    320 N65 AS4 A0 C19 1 61 ESI: (M + H)+ = 0.62 FM1 (KBr): C═O
    768/70/72 (Br2) 1618; 1682
    321 N93 AS1 A0 C4 1 29 ESI: (M + H)+ = 0.35 FM1 (KBr): C═O
    789/91/93 (Br2) 1622; 1705
    N15 AS1 A3 C5 1 47 0.32 FM1
    N19 AS1 A3 C1 1 80 ESI: (M + H)+ = (KBr): C═O
    933/5/7 (Br2) 1641.3
    • EXAMPLE 5
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00100
    • 1-[N2-[N-(4-phenyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine No. 17
  • To a solution of 800 mg (0.86 mmol) of 1-[N2-[N-(4-phenyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in methanol were added 2 ml of methanol saturated with hydrogen chloride and the mixture was stirred overnight at ambient temperature. The reaction mixture was mixed with ethyl acetate until the hydrochloride was totally precipitated and the precipitate formed was filtered off. After washing the precipitate with water it was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc. aqueous ammonia=5/5/0.5 (v/v/v)). 0.38 g (55% of theory) of an amorphous solid were obtained.
  • IR (KBr): 1639 cm−1 (C═O)
  • Rf: 0.55 (FM2)
  • ESI-MS: (M+H)+=799/801/803 (Br2)
      • (M+2H)++=400/401/402 (Br2)
  • The following were prepared analogously (in each case n=1):
  • No. RCO R2 A n NR3R4 % Yield MS Rf Eluant IR [cm−1]
    11 N8 AS1 A1 1 C1 70 ESI: (M + H)+ = 0.43 FM2 (KBr): C═O
    758/60/62 (Br2) 1656.8
    12 N9 AS1 A1 1 C1 60 ESI: (M + H)+ = 0.46 FM2 (KBr): C═O
    788/90/92 (Br2) 1643.3
    8 N5 AS1 A1 1 C1 53.7 ESI: (M + H)+ = 0.2 methanol/ (KBr): C═O
    790/2/4 (Br2) glacial acetic 1641.3
    acid/water =
    9/1/1 (v/v/v)
    15 N11 AS1 A1 1 C1 56 ESI: (M + H)+ = 0.4 FM2
    773/5/7 (Br2)
    6 N2 AS1 A1 1 C11 66.4 ESI: (M + H)+ = 0.39 FM2 (KBr): C═O
    808/10/12 (Br2) 1656.8
    7 N2 AS1 A1 1 C2 46.2 ESI: (M + H)+ = 0.13 FM2 (KBr): C═O
    794/6/8 (Br2) 1637.5
    13 N2 AS2 A1 1 C1 84.7 ESI: (M + H)+ = 0.46 FM2 (KBr): C═O
    666 1641.3
    • EXAMPLE 6
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00101
    • 1-[4-amino-3,5-dibromo-N2-[N-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine-bis-(trifluoroacetate) No 61
  • To a mixture of 0.42 g (0.45 mmol) of 1-[4-amino-3,5-dibromo-N2-[N-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanyl]-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in 30 ml of methylene chloride were added 3 ml of trifluoroacetic acid. The reaction mixture was stirred for 3 hours at ambient temperature and then evaporated down in vacuo. The remaining residue was triturated with ether and the resulting beige amorphous solid (0.43 g; 37% of theory) was suction filtered.
  • IR (KBr): 1643, 1678 cm−1 (C═O)
  • Rf: 0.6 (FM1)
  • ESI-MS: (M+H)+=832/834/836/838 (Br2,Cl)
  • The following were prepared analogously:
  • %
    No. RCO Z R2 A NR3R4 n Remarks Yield MS Rf Eluant IR [cm−1]
    21 N6 N—H AS1 A1 C4 1 65 ESI: (M + H)+ = 0.3 FM1 (KBr): C = 0
    828/30/32 (Br2) 1635.5
    22 N16 N—H AS1 A1 C1 1 98 ESI: (M + H)+ = 0.2 FM1 (KBr): C = 0
    874/6/8 (Br2) 1643.3; 1676
    141 N61 N—H AS1 A1 C1 1 46 ESI: (M + H)+ = 0.1 FM1 (KBr): C = 0
    855/7/9 (Br2) 1634; 1705
    142 N60 N—H AS1 A1 C1 1 50 ESI: (M + H)+ = 0.1 FM1 (KBr): C = 0
    882/4/6 (Br2) 1643; 1711
    154 N66 N—H AS1 A1 C1 1 60 ESI: (M + H)+ = 0.1 FM1 (KBr): C = 0
    868/70/72 (Br2) 1645; 1653
    197 N15 N—H AS1 A1 C8 1 21 ESI: (M + H)+ = 0.18 FM7 (KBr): C═O
    859/61/63 (Br2) 1678;
    1201.6; CF3
    1180.4;
    1134.1
    198 N51 N—H AS1 A1 C8 1 27 ESI: (M + H)+ = 0.22 FM7 (KBr): C═O
    829/31/33 (Br2) 1676; CN
    2221.9, CF3
    1203.5;
    1180.4; 1132
    218 N15 N—H AS6 A1 C1 1 25.7 ESI: (M + H)+ = 0.45 FM1 (KBr): C═O
    776/8 (Br) 1695.3;
    1635.5
    287 N15 N—H AS1 A8 C1 1 36.5 ESI: (M + H)+ = 0.5 FM2 (KBr): C═O
    840/2/4 (Br2) 1695.3;
    1637.5
    19 N15 N—H AS1 A1 C1 1 44 ESI: (M + H)+ = 0.43 FM2 (KBr): C═O
    854/6/8 (Br2) 1695.3;
    1637.5
    14 N10 N—H AS1 A1 C1 1 25.5 ESI: (M + H)+ = 0.33 FM2 (KBr): C═O
    774/6/8 (Br2) 1683.8
    16 N12 N—H AS1 A1 C1 1 64.4 ESI: (M + H)+ = 0.55 FM2 (KBr): C═O
    802/4/6 (Br2) 1639.4
    29 N22 N—H AS1 A1 C1 1 91.2 ESI: (M + H)+ = 0.5 FM2 (KBr): —NH—
    867/69/71 (Br2) 3427.3; C═O
    1643.3;
    1678.0
    30 N23 N—H AS1 A1 C1 1 83.3 ESI: (M + H)+ = 0.5 FM2 (KBr): C═O
    833/5/7/9 (Br2, Cl) 1643.3;
    1676.0
    31 N24 N—H AS1 A1 C1 1 100 ESI: (M + H)+ = 0.51 FM2 (KBr): C═O
    843/5/7 (Br2) 1645.2;
    1676.0
    63 N46 N—H AS1 A1 C1 1 100 ESI: (M + H)+ = 0.58 FM2 (KBr): C═O
    764/6/8 (Br2) 1643.3;
    1676.0
    68 N15 N—H AS1 A1 C6 1 80 ESI: (M + H)+ = 0.18 FM1 (KBr): C═O
    833/5/7 (Br2) 1683.8
    69 N15 N—H AS1 A1 C5 1 74 ESI: (M + H)+ = 0.18 FM1 (KBr): C═O
    854/6/8 (Br2) 1683.8; 1639.4
    70 N45 N—H AS1 A1 C6 1 89 ESI: (M + H)+ = 0.2 FM1 (KBr): C═O
    897/9/901 (Br2) 1695.3; 1676.0
    71 N16 N—H AS1 A1 C5 1 82 ESI: (M + H)+ = 0.22 FM1 (KBr): C═O
    874/6/8 (Br2) 1678.0;
    1639.4
    72 N15 N—H AS5 A1 C1 1 97 ESI: (M + H)+ = 0.16/0.2 FM1 (KBr): C═O
    838/40/42 (Br2) 1685.7;
    1643.3
    77 N45 N—H AS5 A1 C1 1 66 ESI: (M + H)+ = 0.33/0.4 FM1 (KBr): C═O
    852/4/6 (Br2) 1683.8; 1645.2
    NH3 3427.3
    24 N18 N—H AS1 A1 C1 1 94 ESI: (M + H)+ = 0.11 FM1 (KBr): C═O
    775/7/9 (Br2) 1676.0;
    1643.3
    25 N19 N—H AS1 A1 C1 1 92 ESI: (M + H)+ = 0.13 FM1 (KBr): C═O
    833/5/7 (Br2) 1676.0;
    1643.3
    26 N20 N—H AS1 A1 C1 1 98 EI: M+ = 762/4/6 0.11 FM1 (KBr): C═O
    (Br2) 1676.0;
    1643.3
    27 N21 N—H AS1 A1 C1 1 98 ESI: (M + H)+ = 0.04 FM1 (KBr): C═O
    814/6/8 (Br2) 1676.0;
    1645.2
    41 N34 N—H AS1 A1 C1 1 97 ESI: (M + H)+ = 0.08 FM1 (KBr): C═O
    835/38/40/42 1676.0;
    (Br3) 1643.3
    42 N35 N—H AS1 A1 C1 1 83 ESI: (M + H)+ = 0.09 FM1 (KBr): C═O
    803/5/7 (Br2) 1676.0;
    1643.3
    43 N36 N—H AS1 A1 C1 1 87 ESI: (M + H)+ = 0.04 FM1 (KBr): C═O
    815/7/9 (Br2) 1676.0;
    1645.2
    53 N42 N—H AS1 A1 C1 1 89 ESI: (M + H)+ = 0.11 FM1 (KBr): C═O
    805/7/9 (Br2) 1676.0;
    1634.3
    54 N43 N—H AS1 A1 C1 1 84 ESI: (M + H)+ = 0.11 FM1 (KBr): C═O
    835/7/9/41 (Br3) 1678.0;
    1643.3
    55 N44 N—H AS1 A1 C1 1 95 ESI: (M + H)+ = 0.07 FM1 (KBr): C═O
    796/8/800 (Br2) 1676.0;
    1643.3
    67 N48 N—H AS1 A1 C1 1 90 ESI: (M + H)+ = 0.06 FM1 (KBr): C═O
    797/99/801 (Br2) 1682.9;
    1643.3
    184 N77 N—H AS1 A1 C4 1 88 ESI: (M + H)+ = 0.11 FM1 (KBr): C═O
    855/7/9 (Br2) 1637.5; 1676
    248 N78 N—H AS1 A1 C1 1 97 ESI: (M + H)+ = 0.14 FM1 (KBr): C═O
    855/7/9 (Br2) 1643.3; 1676;
    1772.5
    181 N75 N—H AS1 A1 C4 1 95 ESI: (M + H)+ = 0.04 FM1 (KBr): C═O
    793/5/7 (Br2) 1637.5; 1676
    182 N76 N—H AS1 A1 C4 1 93 ESI: (M + H)+ = 0.04 FM1 (KBr): C═O
    793/5/7 (Br2) 1637.5; 1678
    183 N74 N—H AS1 A1 C4 1 91 ESI: (M + H)+ = 0.08 FM1 (KBr): C═O
    807/9/11 (Br2) 1635.5; 1678
    250 N15 N—H AS1 A1 C18 1 98 ESI: (M + H)+ = 0.14 FM1 (KBr): C═O
    885/7/9 (Br2) 1633.6; 1680
    251 N15 N—H AS10 A1 C4 1 84 ESI: (M + H)+ = 0.27 FM1 (KBr): C═O
    837/39/41 (Br2) 1635.5;
    1693.4
    252 N15 N—H AS10 A1 C4 1 87 ESI: (M + H)+ = 0.31 FM1 (KBr): C═O
    837/39/41 (Br2) 1637.5;
    1685.7
    253 N15 N—H AS10 A1 C1 1 82 ESI: (M + H)+ = 0.18 FM1 (KBr): C═O
    838/40/42 (Br2) 1690
    255 N77 N—H AS1 A1 C1 1 94 ESI: (M + H)+ = 0.08 FM1 (KBr): C═O
    856/8/60 (Br2) 1645; 1676
    256 N15 N—H AS4 A1 C18 1 74 ESI: (M + H)+ = 0.28 FM1 (KBr): C═O
    884/6/8 (Br2) 1633.6;
    1683.8
    271 N81 N—H AS4 A1 C8 1 76 ESI: (M + H)+ = 0.2 FM1 (KBr): C═O
    874/6/8 (Br2) 1674
    280 N84 N—H AS4 A1 C4 1 66 ESI: (M + H)+ = 0.26 FM1 (KBr): C═O
    866/8/70 (Br2) 1635.5;
    1685.7
    N15 N—H AS1 A1 C1 0 98 ESI: (M + H)+ = 0.2 ButOH/ (KBr): C═O
    840/2/4 (Br2) AcOH/H2O = 1643; 1680
    4/1/1
    (v/v/v)
    179 N73 N—H AS1 A1 C4 1 86 ESI: (M + H)+ = 0.03 FM1 (KBR): C═O
    779/81/83 (Br2) 1642.8; 1676
    N66 N—H AS4 A0 1 75 ESI: (M + H)+ = 0.3 FM1 (KBr): C = 0
    744/6/8 (Br2) 1620/1666
    516 N66 N—H AS1 A1 C1 1 Isomer to 82 0.1 FM1
    No. (154)
    517 N66 N—H AS1 A1 C1 1 Isomer to 80 0.1 FM1
    No. (154)
    518 N66 N—H AS1 A1 C1 1 Isomer to 89 0.1 FM1
    No. (154)
    521 N66 N—H AS4 A0 C17 1 THF/DMF 75 ESI: (M + H)+ = 0.15 FM1 (KBr): C = 0
    744/6/8 (Br2) 1666/1620
    522 N66 N—H AS1 A0 C17 1 THF/DMF 100 ESI: (M + H)+ = 0.15 FM1 (KBr): C = 0
    745/7/9 (Br2) 1624/1655
    643 N66 CH2 AS21 A0 C17 1 53 ESI: (M + H)+ = 0.35 FM1 (KBr): C = 0
    640 1635/1668
    N66 CH2 AS2 A0 C17 1 100 EI: M+ = 621 0.35 FM1 (KBr): C = 0
    1670
    • EXAMPLE 7
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00102
    • 1-[N2-[N-[[[(2-methoxyphenyl)methyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
  • A mixture of 910 mg (1.0 mmol) of 1-[N2-[N-[[[2-(2-methoxyphenyl)methyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-N6-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 50 ml of glacial acetic acid, 25 ml of a 33% solution of hydrogen bromide in glacial acetic acid and 2 ml of anisole was stirred overnight at ambient temperature. The reaction mixture was stirred into diethylether and the sticky precipitate formed was suction filtered. The crude product was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 0.37 g (48% of theory) of an amorphous solid were obtained.
  • IR (KBr): 1630 cm−1 (C═O)
  • ESI-MS: (M+H)+=774/776/778 (Br2)
      • (M+2H)++=387.7/388.7/389.7 (Br2)
  • The following were prepared analogously (in each case n=1):
  • %
    No. RCO R2 A NR3R4 Yield MS Rf Eluant IR [cm−1]
    1 N1 AS1 A1 C1 46.9 ESI: (M + H)+ = 0.36 FM1 (KBr): C═O
    788/90/92 (Br2) 1627.8
    2 N2 AS1 A1 C1 100 ESI: (M + H)+ = 0.48 FM2 (KBr): C═O
    788/90/92 (Br2) 1641.3; NH,
    NH+ 3419.6
    4 N4 AS1 A1 C1 2.8 ESI: (M + H)+ = 0.52 FM2
    818/20/22 (Br2)
    • EXAMPLE 8
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00103
    • 1-[N2-[N-[4-(4-fluorophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
  • To a solution of 0.18 g (0.001 mol) 4-(4-fluorophenyl)-butanoic acid in a mixture of 4 ml of dimethylformamide and 10 ml of tetrahydrofuran was added with stirring a mixture of 0.71 g (0.001 mol) 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 0.32 g (0.001 mol) TBTU and 0.13 g (0.001 mol) DIEA and the mixture was stirred in a nitrogen atmosphere for 2 days. The reaction mixture was then evaporated down in vacuo and the remaining residue was taken up in dichloromethane. The organic phase was with 20% aqueous citric acid solution and then extracted with 10% aqueous sodium hydrogen carbonate solution, dried over sodium sulphate, filtered and evaporated down in vacuo. After stirring the residue with ether 0.68 g (77% of theory) of the desired product remain as an amorphous residue.
  • IR (KBr): 1641, 1676 cm−1 (C═O)
  • Rf: 0.65 (FM2)
  • ESI-MS: (M+H)+=875/877/879 (Br2)
      • (M+H+Na)++=449/450/451 (Br2)
  • The following were prepared analogously (in each case n=1):
  • %
    No. RCO R2 A NR3R4 Remarks Yield MS Rf Eluant IR [cm−1]
    123 N62 AS1 A0 C1 DMF/THF as 20 ESI: (M + H)+ = 0.3 FM 1 (KBr): C = 0
    solvent 725/7/9 (Br2) 1641.3;
    1691.5
    124 N63 AS1 A0 C1 DMF/THF as 53 ESI: (M + H)+ = 0.2 FM 1 (KBr): C = 0
    solvent 725/7/9 (Br2) 1641.3;
    1691.5
    322 N63 AS1 A0 C8 DMF/THF as 19 EI: M+ = 0.3 FM 1 (KBr): C = 0
    solvent 729/31/33 (Br2) 1629.8;
    1695.3
    N11 AS1 A3 C1 46 ESI: (M + H)+ = (KBr): C═O
    873/5/7 (Br2) 1625.9;
    1645.2
    N18 AS1 A3 C1 THF/DMF as 77 ESI: (M + H)+ = 0.78 FM7 (KBr): C═O
    solvent 875/7/9 (Br2) 1641.3
    N20 AS1 A3 C1 THF/DMF as 88 ESI: (M + H)+ = 0.67 FM7 (KBr): C═O
    solvent 863/5/7 (Br2) 1643.3
    N21 AS1 A3 C1 THF/DMF as 78 ESI: (M + H)+ = 0.47 FM7 (KBr): C═O
    solvent 917/6/8 (Br2) 1643.3
    N46 AS1 A3 C1 THF/DMF as 80 ESI: (M + H)+ = 0.65 FM7 (KBr): C═O
    solvent 905/7/9 (Br2) 1643.3
    N43 AS1 A3 C1 THF/DMF as 75 0.75 FM7 (KBr): C═O
    solvent 1645.2
    N44 AS1 A3 C1 THF/DMF as 79 ESI: (M + H)+ = 0.65 FM7 (KBr): C═O
    solvent 896/98/900 1629.8
    (Br2)
    • EXAMPLE 9
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00104
    • 1-[N2-[N-[[[(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dichloro-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine-bis-(trifluoroacetate No. 20
  • To a suspension of 0.33 g (2 mmol) of CDT and 1 ml of triethylamine in about 30 ml of tetrahydrofuran, cooled to −10° C., was added dropwise, with stirring, a solution of 1.0 g (1.6 mmol) of 1-[N2(-3,5-dichloro-D-tyrosyl]-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in 50 ml of tetrahydrofuran within 60 minutes. The reaction mixture was stirred for 1 hour at 0° C., then stirred for 2 hours at ambient temperature, mixed with a tetrahydrofuran solution of 0.24 g (1.6 mmol) of (3-methoxyphenyl)-ethanamine, refluxed for 3 hours and stirred overnight at ambient temperature. After elimination of the solvent in vacuo the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: FM1). The resulting intermediate compound was stirred in a mixture of 5 ml of trifluoroacetic acid and 80 ml of dichloromethane overnight, the solvent was eliminated in vacuo and the residue triturated with ether. 709 mg (43% of theory) of the desired compound as an amorphous solid.
  • IR (KBr): 1643, 1676 cm−1 (C═O)
  • Rf: 0.41 (FM2)
  • ESI-MS: (M+H)+=700/702/704 (Br2)
      • (M+2H)++=350.7/351.7/352.7 (Br2)
  • The following were prepared analogously (in each case n=1):
  • %
    No. RCO R2 A NR3R4 Remarks Yield MS Rf Eluant IR [cm−1]
    23 N17 AS1 A1 C1 NEt3 as base 55 ESI: (M + H)+ = 0.2 FM1 (KBr): C = 0
    798/800/802 (Br2) 1643.3;
    1676
    47 N39 AS1 A1 C1 NEt3 as base 69.4 ESI: (M + H)+ = 0.1 FM1 (KBr): C = 0
    676/78/80 (Br2) 1645.2;
    1676
    50 N64 AS1 A1 C1 NEt3 as base 76 ESI: (M + H)+ = 0.2 FM1 (KBr): C = 0
    828/830/832 (Br2) 1643.3;
    1678
    51 N40 AS1 A1 C1 NEt3 as base; 79.7 ESI: (M + H)+ = 0.2 FM1 (KBr): C = 0
    dehydration 826/828/30 (Br2) 1643.3;
    1678
    52 N41 AS1 A1 C1 NEt3 as base; 21.8 ESI: (M + H)+ = 0.2 FM1 (KBr): C = 0
    dehydration 826/828/30 (Br2) 1645.2;
    1679.9
    56 N16 AS1 A1 C4 NEt3 as base 5 ESI: (M + H)+ = 0.3 FM1 (KBr): C = 0
    873/75/77 (Br2) 1637.5;
    1676
    57 N45 AS1 A1 C4 NEt3 as base 32 ESI: (M + H)+ = 0.2 FM1 (KBr): C = 0
    867/9/71 (Br2) 1635.5;
    1678
    66 N47 AS1 A1 C4 NEt3 as base 28.4 ESI: (M + H)+ = 0.1 FM1 (KBr): C = 0
    764/6/8 (Br2) 1635.5;
    1676
    46 N38 AS1 A1 C1 NEt3 as base 86 ESI: (M + H)+ = 0.35 FM1 (KBr): C = 0
    826/28/30 (Br2) 1645.2;
    1684
    232 N66 AS4 A1 C8 69 ESI: (M + H)+ = 0.33 FM1 (KBr): C = 0
    872/4/6 (Br2) 1645
    233 N66 AS4 A1 C1 THF/DMF as 16 ESI: (M + H)+ = 0.32 FM1 (KBr): C = 0
    solvent 867/69/71 (Br2) 1653
    234 N66 AS4 A1 C4 68 ESI: (M + H)+ = 0.42 FM1 (KBr): C = 0
    867/69/71 (Br2) 1645
    235 N66 AS1 A1 C8 26 ESI: (M + H)+ = 0.27 FM1 (KBr): C = 0
    873/5/7 (Br2) 1645
    236 N71 AS1 A1 C1 30 ESI: (M + H)+ = 0.22 FM1 (KBr): C = 0
    880/2/4 (Br2) 1636; 1678
    237 N71 AS4 A1 C8 28 ESI: (M + H)+ = 0.25 FM1
    884/6/8 (Br2)
    238 N71 AS4 A1 C1 20 ESI: (M + H)+ = 0.3 FM1 (KBr): C = 0
    879/81/83 (Br2) 1641; 1682
    18 N14 AS1 A1 C1 Cleaving of Boc 26.3 ESI: (M + H)+ = 0.55 FM2 (KBr): C═O
    protecting group with 813/5/7 (Br2) 1641.3;
    methanolic HCl 1716.5
    solution
    17 N13 AS1 A1 C1 Cleaving of Boc 55.2 ESI: (M + H)+ = 0.55 FM2 (KBr): C═O
    protecting group with 799/801/803 (Br2) 1639.4
    methanolic HCl
    solution
    9 N6 AS1 A1 C1 Cleaving of Boc 41.3 ESI: (M + H)+ = 0.44 FM2 (KBr): C═O
    protecting group with 829/31/33 (Br2) 1639.4
    methanolic HCl
    solution
    10 N7 AS1 A1 C1 Cleaving of Boc 57.6 ESI: (M + H)+ = 0.32 FM2 (KBr): C═O
    protecting group with 829/31/33 (Br2) 1639.4
    methanolic HCl
    solution
    20 N2 AS3 A1 C1 43 ESI: (M + H)+ = 0.41 FM2 (KBr): C═O
    700/2/4 (Br2) 1643.3;
    1676.0
    283 N102 AS4 A3 C4 NEt3 as base 65 ESI: (M + H)+ = 0.24 FM1 (KBr): C═O
    864/6/8 (Br2) 1637.5;
    1676
    • EXAMPLE 10
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00105
    • 1-[N2-[N-[4-(2,3-dichlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine-tris-(trifluoroacetate) No. 74
  • To a solution of 0.35 g (2.1 mmol) of CDT in 50 ml of tetrahydrofuran were added with cooling (0° C.) and stirring 1.0 g (1.4 mmol) of 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine and the mixture was stirred for 30 minutes at 0° C. and for a further 30 minutes at ambient temperature. After the addition of 0.47 g (1.75 mmol) of 1-(2,3-dichlorophenyl)piperazine-hydrochloride and 0.25 ml of triethylamine the reaction mixture was refluxed for 5 hours and after cooling mixed with 70 ml of saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated off, the aqueous phase was extracted twice with 50 ml of tetrahydrofuran. The combined organic phases were washed with saturated aqueous saline solution, dried over magnesium sulphate, filtered and evaporated down in vacuo. The residue was triturated with ether, suction filtered and then stirred for 2 hours with a mixture of 50 ml of dichloromethane and 5 ml of trifluoroacetic acid. After evaporation of the reaction mixture in vacuo and trituration of the residue with ether, 0.8 g (47% of theory) of an amorphous solid are left.
  • IR (KBr): 1643.3, 1676 cm−1 (C═O)
  • Rf: 0.78 (FM7)
  • ESI-MS: (M+H)+=867/869/871/873/875 (Br2, Cl2)
      • (M+2H)++=434/435/436/437 (Br2, Cl2)
  • The following were prepared in the same way (in each case n=1):
  • %
    No. RCO R2 A NR3R4 Yield MS Rf Eluant IR [cm−1]
    36 N29 AS1 A1 C1 17.3 ESI: (M + H)+ = 0.35 MeOH/NH4OH = (KBr): C═O
    889/91/93 (Br2) 9/1 (v/v) 1643.3;
    1674.1
    208 N15 AS1 A1 C1 53.5 ESI: (M + H)+ = 0.43 FM2 (KBr): C═O
    854/6/8 (Br2) 1691.5;
    1635.5
    209 N15 AS1 A1 C1 47.7 ESI: (M + H)+ = 0.55 FM2 (KBr): C═O
    854/6/8 (Br2) 1695.3;
    1637.5
    210 N15 AS1 A1 C1 28 ESI: (M + H)+ = 0.48 FM2 (KBr): C═O
    854/6/8 (Br2) 1689.5;
    1639.4
    75 N50 AS1 A1 C1 16.5 ESI: (M + H)+ = 0.63 FM2 (KBr): C═O
    867/69/71/73/75 1643.3;
    (Br2, Cl2) 1676.0;
    74 N49 AS1 A1 C1 47 ESI: (M + H)+ = 0.65 FM2 (KBr): C═O
    867/69/71/73/75 1643.3;
    (Br2, Cl2) 1676.0
    76 N51 AS1 A1 C1 13.4 ESI: (M + H)+ = 0.58 FM2 (KBr): C═O
    824/6/8 (Br2) 1643.3;
    1676.0; CN
    2219.9
    79 N52 AS1 A1 C1 11.4 ESI: (M + H)+ = 0.59 FM2 (KBr): C═O
    901/3/5/7 (Br2, 1645.2;
    Cl) 1676.3
    45 N37 AS1 A1 C1 43 ESI: (M + H)+ = 0.6 FM2 (KBr): C═O
    784/6/8 (Br2) 1643.3;
    1678.0
    39 N32 AS1 A1 C1 48.3 ESI: (M + H)+ = 0.57 FM2 (KBr): C═O
    795/7/9 (Br2) 1643.3;
    1678.0
    38 N31 AS1 A1 C1 54.1 ESI: (M + H)+ = 0.6 FM2 (KBr): C═O
    844/6/8 (Br2) 1643.3;
    1678.0; NO2
    1543.0
    37 N30 AS1 A1 C1 61.6 ESI: (M + H)+ = 0.6 FM2 (KBr): C═O
    813/5/7 (Br2) 1643.3;
    1676.0
    35 N28 AS1 A1 C1 74.8 ESI: (M + H)+ = 0.55 FM2 (KBr): C═O
    800/2/4 (Br2) 1639.4;
    34 N27 AS1 A1 C1 36.8 ESI: (M + H)+ = 0.43 FM2 (KBr): C═O
    800/2/4 (Br2) 1641.3;
    1714.6; NH+
    3409.9
    32 N25 AS1 A1 C1 50.0 ESI: (M + H)+ = 0.44 FM2 (KBr): C═O
    737/39/41 (Br2) 1645.2;
    1678.3
    33 N26 AS1 A1 C1 42 ESI: (M + H)+ = 0.33 FM2 (KBr): C═O
    767/69/71 (Br2) 1676.0
    40 N33 AS1 A1 C1 14.5 ESI: (M + H)+ = 0.58 FM2 (KBr): C═O
    802/4/6 (Br2) 1643.3;
    1676.0
    28 N6 AS3 A1 C1 67.2 ESI: (M + H)+ = 0.43 FM2 (KBr): C═O
    741/3/5 (Cl2) 1641.3;
    1716.5
    64 N23 AS1 A1 C4 39 ESI: (M + H)+ = 0.68 FM2 (KBr): C═O
    832/4/6/8 1627.8;
    (Br2, Cl) 1678.0
    65 N15 AS1 A1 C4 41 ESI: (M + H)+ = 0.61 FM2 (KBr): C═O
    853/5/7 (Br2) 1631.7;
    1695.3
    365 N111 AS1 A1 C1 36.9 ESI: (M + H)+ = 0.09 FM1 (KBr): C = 0
    839/41/43 (Br2) 1626/1676
    • EXAMPLE 11 1-[N2-[N-[[[2-(2,5-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5 dibromo-D,L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine No. 3
  • A mixture of 0.8 g (0.84 mmol) of 1-[N2-[N-[[[2-(2,5-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 50 ml of glacial acetic acid, 25 ml of a 33% solution of hydrogen bromide in glacial acetic acid and 2 ml of anisole was stirred for 12 hours at ambient temperature. The reaction mixture was stirred into diethylether and the resulting precipitate was suction filtered. The solid residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 0.3 g (44% of theory) of the desired product was obtained as an amorphous solid.
  • IR (KBr): 1643.3 cm−1 (C═O)
  • Rf: 0.17 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1)
  • ESI-MS: (M+H)+=818/820/822 (Br2)
      • (M+2H)++=409.5/410.5/411.5 (Br2)
    EXAMPLE 12 1-[N2-[3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosyl]-L-arginyl]-4-(4-pyridinyl)-piperazine-bis-(trifluoroacetate) No. 4
  • A stirred mixture of 20 ml of trifluoroacetic acid, 1.3 ml of anisole and 0.9 ml of ethanedithiol was mixed with 2.1 g (1.9 mmol) of solid 1-[N2-[3,5-dibromo-N-[[[2-(3-methoxyphenyl)-ethyl]amino]carbonyl]-NG-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-D-tyrosyl]-L-arginyl]-4-(4-pyridinyl)-piperazine whilst cooling with ice and stirred for a further 45 minutes whilst cooling with ice, then for 3 hours at ambient temperature. The resulting precipitate was suction filtered and discarded, the filtrate was evaporated down in vacuo, the residue remaining was mixed with toluene and again evaporated down in vacuo. The resulting solid residue was triturated with a mixture of diethylether and acetone and the white solid formed was suction filtered and dried. 1.7 g (65% of theory) of the desired title compound were obtained.
  • IR (KBr): 1674, 1645 cm−1 (C═O)
  • Rf: 0.15 (FM: BuOH/AcOH/H2O 4/1/1 (v/v/v))
  • ESI-MS: (M+H)+=816/818/820 (Br2)
      • (M+2H)++=408.6/409.6/410.6 (Br2)
    EXAMPLE 13
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00106
    • (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(4-pyridinyl)-piperidine No. 291
  • A mixture of 0.97 g (1.8 mmol) of (R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-benzenebutanoic acid, 0.48 g (1.8 mmol) of 4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-piperidine, 2 ml of triethylamine, 0.58 g (1.8 mmol) of TBTU, 0.24 g (1.8 mmol) of HOBt, 25 ml of THF and 25 ml of DMF was stirred for 4 hours at ambient temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in a mixture of ethyl acetate and methanol (95/5 (v/v)) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried and evaporated down in vacuo. The residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=9/1 (v/v); then MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/ethanol=9/1 (v/v)). 0.2 g (15% of theory) of the desired product were obtained as a white amorphous solid.
  • IR (KBr): 1668.3 cm−1 (C═O)
  • Rf: 0.5 (FM2)
  • ESI-MS: (M+H)+=737/739/741 (Br2)
      • (M+Na)+=759/761/763 (Br2)
  • The following were prepared analogously:
  • %
    No. RCO R2 NR3R4 Yield MS Rf Eluant IR [cm−1]
    291 N66 AS4 C4 15 ESI: (M + H)+ = 0.36 CH2Cl2/ (KBr): C = 0
    737/39/41 (Br2) EtOH 1668
    296 N66 AS4 C8 14 ESI: (M + H)+ = 0.66 FM1 (KBr): C = 0
    743/5/7 (Br2) 1668
    302 N71 AS4 C8 19 ESI: (M + H)+ = 0.54 FM1 (KBr): C = 0
    755/7/9 (Br2) 1682
    • EXAMPLE 14 1-[4-amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine No. 312 a) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine No. 307
  • Prepared analogously to Example 3 from methyl 3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate, 1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and CDT in a yield of 27.2% of theory. Colourless, amorphous substance, Rf 0.5 (eluant: dichloromethane/cyclohexane/methanol/conc. ammonia=7/1.5/1.5/0.2 (v/v/v/v)).
  • IR(KBr): 1718.5, 1670.3, 1618.2 cm−1 (C═O)
  • ESI-MS: (M+H)+=796/798/800 (Br2)
      • (M+Na)+=818/820/822 (Br2)
  • The following were obtained accordingly:
  • From methyl-3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate, 1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine and CDT in a yield of 30.3% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine (No. 304), Rf=0.75 (FM1).
  • IR(KBr) 1720.4, 1668.3, 1620.1 cm−1 (C═O)
  • ESI-MS: (M+H)+=802/804/806 (Br2)
      • (M+Na)+=824/826/828 (Br2)
  • From methyl-3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate, 1-(3,5-dibromo-D-tyrosyl)-4-(1-piperidinyl)-piperidine and CDT in a yield of 35% of theory: 1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine (No. 422), Rf 0.54 (eluant: dichloromethane/cyclohexane/methanol/conc. ammonia=7/1.5/1.5/0.2 (v/v/v/v)).
  • IR(KBr): 1720.4, 1668.3, 1627.8 cm−1 (C═O)
  • ESI-MS: (M+H)+=803/805/807 (Br2)
      • (M+Na)+=825/827/829 (Br2)
  • From methyl-3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate, 1-(3,5-dibromo-D-tyrosyl)-4-(4-pyridinyl)-piperidine and CDT in a yield of 45% of theory: 1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine (No. 420), Rf 0.56 (FM1).
  • IR(KBr): 1718.5, 1664.5, 1624.0 cm−1 (C═O)
  • ESI-MS: (M+H)+=797/799/801 (Br2)
      • (M+Na)+=819/821/823 (Br2)
    b) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine No 309
  • Prepared analogously to Example A37) from 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine by saponification with lithium hydroxide in a yield of 95% of theory. Colourless, amorphous substance, Rf 0.25 (eluant: dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 (v/v/v)).
  • IR(KBr) 1666.4, 1614.3 cm−1 (C═O)
  • ESI-MS: (M−H)−=780/782/784 (Br2)
  • The following were obtained accordingly:
  • From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine in a yield of 60.2% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine (No. 306), Rf 0.15 (FM1).
  • IR(KBr): 1635.5 cm−1, broad (C═O)
  • ESI-MS: (M+H)+=788/790/792 (Br2)
      • (M+Na)+=810/812/814 (Br2)
  • From 1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine in a yield of 62% of theory: 1-[3,5-dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine (No. 423), Rf 0.03 (eluant: dichloromethane/cyclohexane/methanol/conc. ammonia=7/1.5/1.5/0.2 (v/v/v/v)).
  • IR(KBr): 1635.5 cm−1, broad (C═O)
  • ESI-MS: (M+H)+=789/791/793 (Br2)
  • From 1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(methoxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine in a yield of 80% of theory: 1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine (No. 151). Colourless, amorphous substance.
  • IR(KBr): 1701.1, 1625.9 cm−1 (C═O)
  • ESI-MS: (M+H)+=767/769/771 (Br2)
      • (M+2H)++=383/384/385 (Br2)
  • From 1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine in a yield of 82% of theory: 1-[3,5-dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H) oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine (No. 421), Rf 0.03 (FM1). Colourless, amorphous substance.
  • IR(KBr): 1625 wide cm−1 (C═O)
  • ESI-MS: (M+H)+=783/785/787 (Br2)
      • (M+Na)+=805/807/809 (Br2)
    c) 1-[4-amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine No. 312
  • Prepared analogously to Example 1 from 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and ammonium carbonate in the presence of TBTU in a yield of 40.6% of theory. Colourless, amorphous substance, Rf 0.8 (eluant: dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 (v/v/v)).
  • IR(KBr): 1670.3, 1616.3 cm−1 (C═O)
  • ESI-MS: (M+H)+=781/783/785 (Br2)
      • (M+Na)+=803/805/807 (Br2)
  • The following were obtained accordingly:
  • From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and ethanolamine in a yield of 34.6% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine, (No. 313) Rf=0.7 (eluant: dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 v/v/v).
  • IR(KBr): 1662.5, 1618.2 cm−1 (C═O)
  • ESI-MS: (M+H)+=825/827/829 (Br2)
      • (M+Na)+=847/849/851 (Br2)
      • (M+2H)++=413/414/415 (Br2)
      • (M+H+Na)++=424/425/426 (Br2)
  • From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and 1-methylpiperazine in a yield of 44.9% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[7-[(4-methyl-1-piperazinyl)carbonyl]-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine, (No. 430) Rf=0.28 (eluant: ethyl acetate/methanol/conc. ammonia=8/1.5/0.3 v/v/v).
  • IR(KBr): 1618.2 cm−1 (C═O)
  • ESI-MS: (M+H)+=864/866/868 (Br2)
      • (M+Na)+=886/888/890 (Br2)
      • (M+2H)++=432/433/434.7 (Br2)
  • From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and methylammonium chloride in a yield of 37% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[7-(methylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine, (No. 424) Rf=0.49 (FM1)
  • IR(KBr): 1662.5, 1622 cm−1 (C═O)
  • ESI-MS: (M+H)+=795/797/799 (Br2)
      • (M+Na)+=817/819/821 (Br2)
  • From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine and ammonium carbonate in a yield of 12% of theory: 1-[4-amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine (No. 310), Rf=0.7 (eluant: dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 (v/v/v)).
  • IR(KBr): 1670.3, 1618.2 cm−1 (C═O)
  • ESI-MS: (M+H)=787/789/791 (Br2)
  • From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine and ethanolamine in a yield of 11.4% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine (No. 311), Rf=0.65 (eluant: dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 (v/v/v)).
  • IR(KBr): 1660.6, 1620.1 cm−1 (C═O)
  • ESI-MS: (M+H)+=831/833/835 (Br2)
      • (M+2H)++=416/417/418 (Br2)
      • (M+H+Na)++=427/428/429 (Br2)
    EXAMPLE 15 4-(1-acetyl-4-piperidinyl)-1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-phenylalanyl]-piperidine No. 372 a) 1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine
  • A mixture of 5.60 g (0.01 mol) of 4-amino-3,5-dibromo-N2-(9-fluorenylmethoxycarbonyl)-D-phenylalanine, 1.35 g (0.01 mol) HOBt, 3.21 g (0.01 mol) TBTU, 1.29 g (0.01 mol) DIEA, 2.68 g (0.01 mol) 4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine and 150 ml of tetrahydrofuran was stirred for 2 hours at room temperature. After the reaction was complete 20 ml of diethylamine were added and the mixture was stirred for a further 18 hours at room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 200 ml of dichloromethane and washed successively with 100 ml of saturated sodium chloride solution and saturated sodium hydrogen carbonate solution and dried over magnesium sulphate. The reddish oil remaining after elimination of the solvent was purified by column chromatography on silica gel (30-60 μm) using firstly dichloromethane, then FM4 as eluant. The title compound was obtained in the form of a colourless amorphous substance and in a yield of 4.31 g (73.3% of theory).
  • IR(KBr): 1687.6 cm−1 (C═O)
  • MS: M+=586/588/590 (Br2)
    • b) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine
  • Prepared analogously to Example 4 from 1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine, CDT and 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a quantitative yield. Colourless, amorphous substance.
  • IR(KBr): 1676 cm−1 (C═O)
  • MS: (M+H)+=844/846/848 (Br2)
      • (M+Na)+=866/868/870 (Br2)
    c) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine No. 521
  • Prepared analogously to Example A1b), but using sodium hydroxide solution instead of ammonia, from 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine by treating with trifluoroacetic acid in a yield of 75% of theory. Colourless, amorphous substance.
  • IR(KBr): 1666.4, 1620.1 cm−1 (C═O)
  • MS: (M+H)+=744/746/748 (Br2)
      • (M+2H)++=372/373/374.5 (Br2)
    d) 4-(1-acetyl-4-piperidinyl)-1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-piperidine No. 372
  • A solution of 0.372 g (0.499 mmol) of 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine and 0.07 g (5.5 mmol) of DIEA in 50 ml of dichloromethane was mixed with 0.043 g (5.48 mmol) of acetylene chloride dropwise whilst cooling externally with ice-water and then stirred for 1 hour at room temperature. The solvent was eliminated in vacuo, the residue was stirred with water and filtered. The filter residue was dried in vacuo and purified by column chromatography on silica gel (30-60 μm) using FM4 as eluant. The suitable eluates were evaporated down, the residue was triturated with diethylether and suction filtered. 230 mg (58.5% of theory) of colourless crystals were obtained.
  • IR(KBr): 1622 cm−1 (C═O)
  • MS: (M+H)+=786/788/790 (Br2)
      • (M+Na)+=808/810/812 (Br2)
  • The following were obtained accordingly:
    • 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-benzoyl-4-piperidinyl)-piperidine No. (485)
  • Colourless crystals
  • Rf 0.74 (FM1)
  • IR(KBr): 1626, 1668 cm−1 (C═O)
  • ESI-MS: (M+H)+=848/850/852 (Br2)
    • EXAMPLE 16 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine No. 486
  • A solution of 0.372 g (0.499 mmol) of 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine and 0.07 g (5.5 mmol) of DIEA in 50 ml of dichloromethane was mixed dropwise with 0.063 g (5.5 mmol) of methanesulphonylchloride whilst cooling externally with ice-water and then stirred for 1 hour at room temperature. The solvent was eliminated in vacuo, the residue was stirred with water and filtered. The filter residue was dried in vacuo and purified by column chromatography over silica gel (30-60 μm) using initially dichloromethane, then FM4 as eluant. The suitable eluates were evaporated down, the residue was triturated with diethylether and suction filtered. 220 mg (53.5% of theory) of colourless crystals were obtained.
  • IR(KBr): 1668, 1618 cm−1 (C═O)
  • MS: (M+H)+=822/824/826 (Br2)
      • (M+Na)+=844/846/848 (Br2)
      • (M+K)+=860/862/864 (Br2)
  • The following were obtained accordingly:
  • (1) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-(methylsulphonyloxy)-D-phenylalanyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine (No. (523)) in a yield of 12% of theory.
  • Rf 0.54 (FM1)
  • IR(KBr): 1628, 1665 cm−1 (C═O)
  • ESI-MS: (M+H)+=901/903/905 (Br2)
  • (2) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine (No. (524) in a yield of 12% of theory.
  • Rf 0.50 (FM1)
  • ESI-MS: (M+H)+=823/825/827 (Br2)
  • (3) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine (No. (668) in a yield of 56% of theory.
  • Rf 0.70 (FM1)
  • IR(KBr): 1630, 1666 cm−1 (C═O)
  • MS: M+=699
    • EXAMPLE 17 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(3-carboxy-1-oxopropyl)-4-piperidinyl]-piperidine No 487
  • A mixture of 0.372 g (0.499 mmol) of 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine, 0.11 g (1.1 mmol) of succinic anhydride and 150 ml of tetrahydrofuran was refluxed for 1 hour. The reaction mixture was freed from solvent in vacuo, the residue was purified by column chromatography on silica gel (30-60 μm) using FM1 as eluant. The suitable eluates were evaporated down, the residue was triturated with diethylether and suction filtered. 175 mg (41.5% of theory) of colourless crystals were obtained.
  • IR(KBr): 1668, 1608 cm−1 (C═O)
  • MS: (M−H)−=842/844/846 (Br2)
      • (M+Na)+=868/870/872 (Br2)
    EXAMPLE 18 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine No. 488
  • A mixture of 0.372 g (0.499 mmol) of 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine, 0.05 g (0.499 mmol) of hexanal, 0.03 g (0.5 mmol) of glacial acetic acid and 150 ml of tetrahydrofuran was stirred for 1 hour at room temperature. After the addition of 0.116 g (0.52 mmol) of 95% sodium triacetoxyborohydride the mixture was kept for a further 2.5 hours at room temperature. The solvent was eliminated in vacuo, the residue was divided between 20% aqueous sodium carbonate solution and dichloromethane, the organic phase was dried over magnesium sulphate and evaporated down. The residue was purified by column chromatography on silica gel (30-60 μm) using FM4 as eluant. The suitable eluates were evaporated down, the residue was triturated with diethylether and suction filtered. 100 mg (24.2% of theory) of colourless crystals were obtained.
  • IR(KBr): 1666, 1620 cm−1 (C═O)
  • MS: (M+H)+=828/830/832 (Br2)
      • (M+Na)+=850/852/854 (Br2)
  • The following were obtained accordingly:
  • (1) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidine (No. (489) in a yield of 23% of theory.
  • Rf 0.65 (FM1)
  • IR(KBr): 1622, 1666 cm−1 (C═O)
  • ESI-MS: (M+H)+=798/800/802 (Br2)
  • (2) 1-[4-ammo-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine (No. (493) in a yield of 43% of theory.
  • Rf 0.72 (FM1)
  • IR(KBr): 1620, 1666 cm−1 (C═O)
  • ESI-MS: (M+H)+=730/732/734 (Br2)
  • (3) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidine (No. (525) in a yield of 46.5% of theory.
  • Rf 0.50 (FM1)
  • IR(KBr): 1622, 1662 cm−1 (C═O)
  • ESI-MS: (M+H)+=799/801/803 (Br2)
    • EXAMPLE 19
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00107
    • 1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine No. 532
  • The mixture of 200 mg (3 mmol) 1-[3-bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenyl-alanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, 108 mg (0.33 mMol) vinyl-tributyl tin (ALDRICH No. 27143-8), 50 mg tetrakis-(triphenylphosphine)-palladium (Merck No. 818193), a trace of 2,6-di-tert.-butyl-4-methylphenol and 10 ml anhydrous toluene was refluxed for 5 hours. The cooled reaction mixture was filtered over an activated charcoal filter, the filtrate was evaporated in a vacuum. The residue was purified for elution by column chromatography over silica gel, initially using pure dichloromethane, then methanol/conc. ammonia (9/1 v/v). The suitable eluates were triturated and suction filtered with tert.-butyl-methylether. Yield was 60 mg (32.6% of theory) of colourless crystals of Rf 0.25 (FM1)
  • MS: M+=612
  • The following were prepared analogously: (in each case, n=1):
  • %
    No. RCO Z R2 A NR3R4 Yield MS Eluant Rf IR [cm−1]
    647 N66 CH2 AS40 A0 C8 75 EI: M+ = 611 FM1 0.6 (KBr): C = 0
    1639/1668
    648 N66 CH2 AS41 A0 C8 56 EI: M+ = 647 FM1 0.7 (KBr): C = 0
    1639/1668
    649 N66 CH2 AS42 A0 C8 8 EI: M+ = 648 FM1 0.6 (KBr): C = 0
    1635/1668
    650 N66 CH2 AS43 A0 C8 11 EI: M+ = 654 FM1 0.6 (KBr): C = 0
    1635/1666
    651 N66 CH2 AS44 A0 C8 84 EI: M+ = 637 FM1 0.6 (KBr): C = 0
    1633/1664
    652 N66 CH2 AS45 A0 C8 83 EI: M+ = 613 FM1 0.6 (KBr): C = 0
    1637/1667
    • EXAMPLE 20
  • Preparation of compounds of general formula:
  • Figure US20090163480A1-20090625-C00108
    • (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine No. 599
  • Produced analogously to Example 1 from (R,S)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-4-oxobutanoic acid, 4-(4-methyl-1-piperazinyl)piperidine and TBTU in a yield of 10% of theory. Colourless, amorphous substance of Rf=0.2 (dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v).
  • IR(KBr): 1722, 1662, 1637 cm−1 (C═O)
  • MS: M+=711
  • Accordingly, (R,S)-1-[4-[4-(aminocarbonylamino)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine (No. 601) was obtained from (R,S)-4-[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-4-oxobutanoic acid, 4-(4-methyl-1-piperazinyl)piperidine and TBTU in a yield of 20% of theory. Colourless, amorphous substance of Rf=0.25 (dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v).
  • ESI-MS: (M+H)+=624
      • (M+Na)+=646
      • (M+H+Na)++=323.8
    EXAMPLE 21 1-[3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hydroxycarbonyl)-piperidine No. 211
  • Produced analogously to Example A38 from 1-[3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(ethoxycarbonyl)-piperidine and aqueous lithium hydroxide solution in a yield of 79% of theory. Colourless, amorphous substance of Rf 0.54 (ethyl ethanoate/methanol/glacial acetic acid 9/1/0.3 v/v/v).
  • IR(KBr): 1691.5, 1622.0 cm−1 (C═O)
  • ESI-MS: (M−H)−=690/2/4 (Br2)
    • EXAMPLE 22 1-[3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperazine No. 214
  • Produced analogously to Example A24 from 3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosine, 1-(1,1-dimethylethoxycarbonyl)-4-(1-piperazinyl)piperidine and TBTU, and additional conversion of the obtained intermediate product with trifluoroacetic acid (in accordance with Example A1b) in a yield of 4.2% of theory.
  • Colourless, amorphous substance of Rf 0.25 (FM1)
  • IR(KBr): 1624.0 cm−1 (C═O)
  • ESI-MS: (M+H)+=732/4/6 (Br2)
    • EXAMPLE 23 (R)-1-[2-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methylamino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine No. 219 a) 1-(chlorocarbonyl)-4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-piperidine
  • To a solution of 3.0 g (13.8 mmol) 4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)piperidine and 2.7 ml (15 mMol) DIEA in 100 ml toluene, a solution of 1.8 ml (14.9 mMol) diphosgene in 15 ml toluene was added dropwise under external cooling with iced water, and the mixture was additionally kept at room temperature for 17 hours. The precipitate was suction filtered, washed with petroleum ether and dissolved in 50 ml dichloromethane. The obtained solution was agitated twice each with 50 ml 7% aqueous sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated in a vacuum. Yield was 3.0 g (78% of theory) of a colourless substance of Rf 0.25 (dichloromethane/acetone 9/1 v/v), which was further processed without more purification.
    • b) (R)-1-[3-(3,5-dibromo-4-hydroxyphenyl)-2-(N-methylamino)-propyl]-4-(1-piperidinyl)-piperidine
  • To a suspension of 2.3 g (60 mmol) lithium aluminium hydride in 100 ml anhydrous tetrahydrofuran, a solution of 11.0 g (18.66 mmol) 1-[3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-tyrosyl]-4-(1-piperidinyl)piperidine in 100 ml anhydrous tetrahydrofuran was added dropwise at room temperature whilst being stirred. It was stirred for a further 15 minutes at room temperature and then refluxed for 3 hours. 3 ml 20% aqueous ammonium chloride solution was added to the cooled mixture, then it was dried with magnesium sulphate. The filter cake was filtered and washed with 300 ml of an ethyl ethanoate-methanol mixture (1/1 v/v), and the combined filtrates were evaporated in a vacuum. The residue was purified by column chromatography over silica gel using ethyl ethanoate/methanol (8/2 v/v) for elution.
  • 1. 2.9 g (31% of theory) of a colourless substance of Rf 0.13 (eluant: methanol) was isolated from the suitable fractions, which was identified as 1-(3,5-dibromo-N-methyl-D-tyrosyl)-4-(1-piperidinyl)piperidine:
  • IR(KBr): 1668.3 cm−1 (C═O)
  • MS: M+=501/3/5 (Br2)
  • and
  • 2. 1.8 g (20% of theory) of a colourless substance of Rf 0.05 (eluant: methanol), which was identified as the sought compound:
  • ESI-MS: (M+H)+=488/490/492 (Br2)
      • (M+2H)++=244/245/246.5 (Br2)
    c) (R)-1-[2-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methylamino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-piperidinyl)-piperidine No. 219
  • A solution of 0.57 g (2.02 mmol) 1-(chlorocarbonyl)-4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-piperidine in 30 ml dimethylformamide was added dropwise to the mixture of 0.9 g (1.84 mmol) (R)-1-[3-(3,5-dibromo-4-hydroxyphenyl)-2-(N-methylamino)-propyl]-4-(1-piperidinyl)-piperidine and 0.65 ml (3.7 mmol) DIEA in a mixture of 50 ml tetrahydrofuran and 20 ml dimethylformamide. It was stirred overnight at room temperature and the deposit was evaporated in a vacuum. The residue was treated with 300 ml of a tetrahydrofuran ethyl ethanoate mixture (1/1 v/v) and the resulting solution was agitated twice each with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate and evaporated in a vacuum. The residue was purified over silica gel by column chromatography using dichloromethane/methanol (8.5/1.5 v/v) for elution. 390 mg (29% of theory) of a colourless substance of Rf 0.46 (dichloromethane cyclohexane/methanol/conc. ammonia 75/15/15/2 v/v/v/v) were isolated from the suitable fractions:
  • IR(KBr): 1695.3, 1624.0 cm−1 (C═O)
  • ESI-MS: (M+H)+=731/3/5 (Br2)
    • EXAMPLE 24 1-[3,5-dibromo-N-[[4-[5-[(4-morpholinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine No. 223
  • 100 mg (0.6 mMol) N,N′-carbonyldiimidazole was added to a solution of 400 mg (0.5 mMol) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine in 10 ml anhydrous tetrahydrofuran at room temperature, heated to 50° C. for 30 minutes and then 90 mg (1 mMol) morpholine was added. After heating to 50-60° C. for two hours, the solution was removed in a vacuum and the residue was purified over silica gel (30-60 μm) by column chromatography, initially using dichloromethane, then dichloromethane/methanol 9/1 (v/v), and finally dichloromethane/methanol/conc. ammonia 9/1/0.2 (v/v/v) as eluants. 250 mg (60% of theory) of an amorphous, colourless substance was yielded from the suitable extracts.
  • IR(KBr): 1712.7, 1625.9 cm−1 (C═O)
  • ESI-MS: (M+H)+=838/840/842 (Br2)
      • (M+2H)++=419/420/421.5 (Br2)
  • The following were obtained accordingly:
  • 1-[3,5-dibromo-N-[[4-[5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]-carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine (No. 224) from 1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine, 1-methylpiperazine and N,N′-carbonyldiimidazole in a yield of 52% of theory. Colourless, amorphous substance.
  • IR(KBr): 1710.8, 1625.9 cm−1 (C═O)
  • ESI-MS: (M+H)+=851/853/855 (Br2)
      • (M+2H)++=426/427/428 (Br2)
    EXAMPLE 25 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(carboxymethyl)-4-piperidinyl]-piperidine No. 494
  • Produced analogously to Example A37, but using tetrahydrofuran instead of methanol, from 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine by the action of aqueous lithium hydroxide solution in a yield of 51% of theory. Colourless, amorphous substance.
  • ESI-MS: (M−H)−=800/802/804 (Br2)
      • (M+H)+=802/804/806 (Br2)
      • (M+Na)+=824/826/828 (Br2)
    EXAMPLE 26 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine No. 526
  • Produced analogously to Example 18 from 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine, ethyl glyoxylate and sodium triacetoxyborohydride and additional saponification with soda lye of the 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine, obtained as an intermediate product but not characterised, according to Example A55. A colourless, amorphous substance is obtained in a yield of 35% of theory.
  • IR(KBr): 1625.9 wide cm−1 (C═O)
  • ESI-MS: (M+H)+=803/805/807 (Br2)
      • (M+Na)+=825/827/829 (Br2)
    EXAMPLE 27 1-[4-amino-N-[(4-amino-1-piperidinyl)carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine No. 564
  • 653 mg (10.4 mMol) 95% sodium cyanoborohydride (Aldrich 15.615-9) was stirred into the mixture of 930 mg (1.48 mMol) 1-[4-amino-3,5-dibromo-N-[(4-oxo-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine, 1143 mg (14.8 mmol) ammonium acetate (Merck No. 1115) and 30 ml anhydrous methanol at room temperature, and was stirred overnight. The deposit was adjusted to pH≦2 with conc. hydrochloric acid and was evaporated in a vacuum. The residue is taken up in water and made alkaline with 40% soda lye. Exhaustive extraction with dichloromethane followed, then the combined extracts were dried over sodium sulphate and evaporated in a vacuum. The residue was purified over 100 g silica gel (Amicon, 35-70 μm) by column chromatography using dichloromethane/methanol/conc. ammonia (60/40/5 v/v/v) for elution. From the suitable fractions, 250 mg (27% of theory) of the sought substance was isolated as a colourless, amorphous product of Rf 0.15 (dichloromethane/methanol/conc. ammonia 50/50/0.5 v/v/v).
  • IR (KBr): 1618 wide cm−1 (C═O)
  • ESI-MS: (M+H)+=627/629/631 (Br2)
      • (M+Na)+=649/651/653 (Br2)
      • (M+2H)++=314/315/316 (Br2)
    EXAMPLE 28 (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(hydroxycarbonylmethyl)-piperidine No. 596
  • Produced analogously to Example A55 from (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(ethoxycarbonylmethyl)-piperidine by saponification with soda lye in a yield of 86% of theory. Colourless, amorphous substance of Rf 0.76 (ethyl ethanoate/methanol/glacial acetic acid 70/30/1 v/v/v).
  • IR(KBr): 1716, 1635 cm−1 (C═O)
  • ESI-MS: (M−H)−=613/615/617 (Cl2)
      • (M+H)+=615/617/619 (Cl2)
      • (M+Na)+=637/639/641 (Cl2)
    EXAMPLE 29 1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-carbonyl]-3-(1H-tetrazol-5-yl)-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine No. 632
  • 8.5 g (35 mMol) tributyl tin(IV)-azide (Synthesis 1976, 330) was added to a solution of 1.6 g (2.68 mMol) 1-[3-cyano-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine in 400 ml toluene and the mixture was refluxed for 4 days. The residue remaining after dispellation of the solvent was stirred with ethyl ethanoate, the obtained precipitate was suction filtered and purified over silica gel by column chromatography using FM1 as an eluent. After the usual further processing, yield is 400 mg (24% of theory) of colourless crystals of Rf 0.2 (FM1)
  • IR(KBr): 1653 cm−1 (C═O)
  • ESI-MS: (M+H)+=641
      • (M+Na)+=663
  • The following Examples describe the preparation of pharmaceutically useful forms which contain as active substance any desired compound of general formula I:
    • EXAMPLE I Capsules for Powder Inhalation Containing 1 mg of Active Substance Composition:
  • 1 capsule for powder inhalation contains:
  •
    Active substance  1.0 mg
    Lactose 20.0 mg
    Hard gelatine capsules 50.0 mg
    71.0 mg
    • Method of Preparation:
  • The active substance is ground to the particle size required for inhalants. The ground active substance is homogeneously mixed with the lactose. The mixture is packed into hard gelatine capsules.
    • EXAMPLE II Inhalable Solution for Respimat® Containing 1 mg of Active Substance Composition:
  • 1 stroke contains:
  •
    Active substance 1.0 mg
    Benzalkonium chloride 0.002 mg
    Disodium edetate 0.0075 mg
    Purified water ad 15.0 μl
    • Method of Preparation:
  • The active substance and benzalkonium chloride are dissolved in water and transferred into Respimat® cartridges.
    • EXAMPLE III Inhalable Solution for Nebulisers Containing 1 mg of Active Substance Composition:
  • 1 vial contains:
  •
    Active substance 0.1 g
    Sodium chloride 0.18 g
    Benzalkonium chloride 0.002 g
    Purified water ad 20.0 ml
    • Method of Preparation:
  • Active substance, sodium chloride and benzalkonium chloride are dissolved in water.
    • EXAMPLE IV Propellant Gas Metering Aerosol Containing 1 mg of Active Substance Composition:
  • 1 stroke contains:
  •
    Active substance 1.0 mg
    Lecithin 0.1%
    Propellant gas ad 50.0 μl
    • Method of Preparation:
  • The micronised active substance is homogeneously suspended in a mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with metering valve.
    • EXAMPLE V Nasal Spray Containing 1 mg of Active Substance Composition:
  • Active substance 1.0 mg
    Sodium chloride 0.9 mg
    Benzalkonium chloride 0.025 mg
    Disodium edetate 0.05 mg
    Purified water ad 0.1 ml
    • Method of Preparation:
  • The active substance and adjuvants are dissolved in water and transferred into a suitable container.
    • EXAMPLE VI Injectable Solution Containing 5 mg of Active Substance Per 5 ml Composition:
  • Active substance 5 mg
    Glucose 250 mg
    Human-serum-albumin 10 mg
    Glycofurol 250 mg
    Water for injections ad 5 ml
    • Preparation:
  • Glycofurol and glucose are dissolved in water for injections (WfI); human-serum-albumin is added; active substance is dissolved with heating; solution is made up to required volume with WfI; transferred into ampoules under nitrogen gas.
    • EXAMPLE VII Injectable Solution Containing 100 mg of Active Substance Per 20 ml Composition:
  • Active substance 100 mg
    Monopotassium dihydrogen phosphate = KH2PO4 12 mg
    Disodium hydrogen phosphate = Na2HPO4•2H2O 2 mg
    Sodium chloride 180 mg
    Human-serum-albumin 50 mg
    Polysorbate 80 20 mg
    Water for injections ad 20 ml
    • Preparation:
  • Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (WfI); human-serum-albumin is added; active substance is dissolved with heating; solution is made up to required volume with WfI; transferred into ampoules.
    • EXAMPLE VIII Lyophilisate Containing 10 mg of Active Substance Composition:
  • Active substance 10 mg
    Mannitol 300 mg 
    Human-serum-albumin 20 mg
    • Preparation:
  • Mannitol is dissolved in water for injections (WfI); human-serum-albumin is added; active substance is dissolved with heating; solution is made up to required volume with WfI; transferred into vials and freeze-dried.
  • Solvent for lyophilisate:
  •
    Polysorbate 80 = Tween 80 20 mg
    Mannitol 200 mg
    Water for injections ad 10 ml
    • Preparation:
  • Polysorbate 80 and mannitol are dissolved in water for injections (WfI) and transferred into ampoules.
    • EXAMPLE IX Tablets Containing 20 mg of Active Substance Composition:
  • Active substance 20 mg
    Lactose 120 mg 
    Corn starch 40 mg
    Magnesium stearate  2 mg
    Povidon K 25 18 mg
    • Preparation:
  • Active substance, lactose and corn starch are homogeneously mixed; granulated with an aqueous solution of Povidon; mixed with magnesium stearate; pressed in a tablet press; weight of tablet 200 mg.
    • EXAMPLE X Capsules Containing 20 mg of Active Substance Composition:
  • Active substance 20 mg
    Corn starch 80 mg
    Highly dispersed silicic acid  5 mg
    Magnesium stearate 2.5 mg 
    • Preparation:
  • Active substance, corn starch and silicic acid are homogeneously mixed; mixed with magnesium stearate; then the mixture is packed into size 3 hard gelatine capsules using a capsule filling machine.
    • EXAMPLE XI Suppositories Containing 50 mg of Active Substance Composition:
  • Active substance  50 mg
    Hard fat (adeps solidus) q.s. ad 1700 mg
    • Preparation:
  • Hard fat is melted at about 38° C.; ground active substance is homogeneously dispersed in the molten hard fat; then after cooling to about 35° C. the melt is poured into chilled moulds.
    • EXAMPLE XII Aqueous Solution for Nasal Application Containing 10 mg Active Substance Composition:
  • Active substance 10.0 mg
    Hydrochloric acid in quantity required
    for formation of a neutral salt
    Methylparahydroxybenzoate (PHB) 0.01 mg
    Propylparahydroxybenzoate (PHB) 0.005 mg
    Purified water ad 1.0 ml
    • Preparation:
  • The active substance is dissolved in purified water; Hydrochloric acid is added until the solution is clear; PHB methyl and propyl esters are added; the solution is made up to required volume with purified water; the solution is sterile-filtered and is transferred into an appropriate container.
    • EXAMPLE XIII Aqueous Solution for Nasal Application Containing 5 mg Active Substance Composition:
  • Active substance 5 mg
    1,2-propandiol 300 mg
    Hydroxyethylcellulose 5 mg
    Sorbic acid 1 mg
    Purified water ad 1 ml
    • Preparation:
  • The active substance is dissolved in 1,2-propandiol; a hydroxyethyl-cellulose solution is prepared in purified water containing sorbic acid and is added to the active substance solution; the solution is sterile-filtered and is transferred into an appropriate container.
    • EXAMPLE XIV Aqueous Solution for Intravenous Application Containing 5 mg Active Substance Composition:
  • Active substance 5 mg
    1,2-propandiol 300 mg
    Mannitol 50 mg
    Water for injections (WfI) ad 1 ml
    • Preparation:
  • The active substance is dissolved in 1,2-propandiol; the solution is approximately made up to the required volume with WfI; the mannitol is added and the solution is made up to required volume with WfI; the solution is sterile-filtered, transferred into individual containers and autoclaved.
    • EXAMPLE XV Liposomal Formulation for Intravenous Injection Containing 7.5 mg Active Substance Composition:
  • Active substance 7.5 mg
    Egg-lecithin, e.g. lipoid E 80 100.0 mg
    Cholesterol 50.0 mg
    Glycerine 50.0 mg
    Water for injections ad 1.0 ml
    • Preparation:
  • The active substance is dissolved in a mixture of lecithin and cholesterol; the solution is added to a mixture of glycerine and WfI and is homogenised by means of high-pressure homogenisation or microfluidiser technology; the liposomal formulation obtained in this manner is transferred into an appropriate container under aseptic conditions.
    • EXAMPLE XVI Suspension for Nasal Application Containing 20 mg Active Substance Composition:
  • Active substance 20.0 mg
    Carboxymethylcellulose (CMC) 20.0 mg
    Sodium monohydrogen phosphate/sodium- q.s.
    dihydrogen phosphate buffer pH 6.8
    Sodium chloride 8.0 mg
    Methylparahydroxybenzoate 0.01 mg
    Propylparahydroxybenzoate 0.003 mg
    Purified water ad 1.0 ml
    • Preparation:
  • The active substance is suspended in an aqueous CMC solution; the other components are added to the suspension one after another and the suspension is made up to required volume with purified water.
    • EXAMPLE XVII Aqueous Solution for Subcutaneous Application Containing 10 mg Active Substance Composition:
  • Active substance 10.0 mg
    Sodium monohydrogen phosphate/sodium 7.0
    dihydrogen phosphate buffer q.s. ad pH
    Sodium chloride 4.0 mg
    Water for injections ad 0.5 ml
    • Preparation:
  • The active substance is dissolved in the phosphate buffer solution, after addition of the sodium chloride the solution is made up to required volume with water. The solution is sterile-filtered and is autoclaved after being transferred into an appropriate container.
    • EXAMPLE XVIII Aqueous Solution for Subcutaneous Application Containing 5 mg Active Substance Composition:
  • Active substance 5.0 mg
    Polysorbate 80 0.5 mg
    Water for injections ad 0.5 ml
    • Preparation:
  • The active substance is suspended in the polysorbate 80 solution and is reduced to a particle size of approx. 1 μm by means of a suitable dispersion technique (e.g. wet milling, high-pressure homogenisation, micro-fluidisation, etc.). The suspension is transferred into an appropriate container under aseptic conditions.

Claims (13)

1. Modified amino acids of general formula
Figure US20090163480A1-20090625-C00109
wherein
R denotes an unbranched C1-7-alkyl group which may be substituted in the ω-position
by a C4-10-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxo-thieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]-quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, wherein the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups and the substituents may be identical or different,
by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one, two or three nitrogen atoms,
whilst a 1,4-butadienylene group may be attached both to the above-mentioned 5-membered heteroaromatic monocyclic rings and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
by a C4-10-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
by a 6-membered heteroaromatic ring linked via a carbon atom, containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl and alkylamino groups in the ω-position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
or the group of formula
Figure US20090163480A1-20090625-C00110
wherein
p denotes the number 1 or 2,
o denotes the number 2 or 3 or, if Y1 and Y2 are not simultaneously nitrogen atoms, o may also denote 1.
Y1 denotes the nitrogen atom if R5 is a free pair of electrons, or the carbon atom,
Y2 is the nitrogen atom or the group >CH,
R5 is a free pair of electrons if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 denotes a hydrogen atom, a C1-3-alkyl group, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl, aminocarbonylamino, phenylmethyl or phenyl group,
R6 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom, R6 together with R5 may denote an additional bond,
R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together constitute an additional bond, R7 together with RN may also denote a 1,4-butadienylene group,
RN denotes a hydrogen atom or a C1-6-alkyl group which may be mono- or disubstituted in the ω-position
by a C5-7-cycloalkyl group, by a 1-naphthyl, 2-naphthyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl, alkylaminocarbonyl, acetylamino, cyano, aminocarbonylamino or alkylaminocarbonylamino group or by phenyl, pyridinyl or diazinyl groups, whilst these substituents may be identical or different,
a C5-7-cycloalkyl group, a phenyl, pyridinyl, cyano, amino, benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, phenylalkylamino-carbonylamino, pyridinylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino, N-(aminocarbonyl-aminocarbonyl)-N-phenylamino, N-(pyridinyl)-N-(aminocarbonyl)amino, N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino, 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl or diazinylamino group,
a saturated, mono- or di-unsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza- or S,S-dioxidothiadiaza-heterocycle.
wherein the above-mentioned heterocycles may be linked via a carbon or nitrogen atom and
may contain one or two carbonyl groups adjacent to a nitrogen atom,
may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl, aroyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
may be substituted at one or two carbon atoms by a branched or unbranched alkyl group or by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, wherein the substituents may be the same or different,
and wherein a C3-6-alkylene group may additionally be attached to the above-mentioned heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring,
or if Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 may also denote the 1,4-butadienylene group,
or, if Y1 is a carbon atom, RN together with R5, including Y1, also denotes a carbonyl group or a saturated or monounsaturated 5- or 6-membered 1,3-diaza-heterocycle which may optionally contain one or two carbonyl groups in the ring and, if it is unsaturated, may be benzofused at the double bond and may be substituted at one of the nitrogen atoms by a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
whilst the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl- or 1-methylimidazolyl groups contained in the residues mentioned under R5, R7 and RN, as well as benzo, thieno, pyrido- and diazino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)-carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino, benzoylaminocarbonylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group
and unless otherwise specified the alkyl groups contained in the above-mentioned radicals may contain 1 to 5 carbon atoms,
X denotes an oxygen atom or 2 hydrogen atoms,
Z denotes a methylene group or the group —NR1, wherein
R1 denotes a hydrogen atom or an alkyl or phenylalkyl group,
R11 denotes a hydrogen atom, a C1-3-alkyl group, an alkoxycarbonyl group having a total of 2 to 4 carbon atoms or a phenylmethyl group,
n denotes the number 1 or 2 or, if m is 1, n may also be 0,
m denotes the number 0 or 1,
R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
whilst the above-mentioned aromatic and heteroaromatic groups in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched alkyl groups, C3-8-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, and the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group,
A denotes a bond or the divalent group of formula
Figure US20090163480A1-20090625-C00111
(which is linked to the NR3R4 group via the —CX group)
wherein
R8 and R9 together denote an n-propylene group or
R8 denotes a hydrogen atom or an alkyl or phenylalkyl group and
R9 denotes a hydrogen atom or a branched or unbranched C1-5-alkyl group which, if it is unbranched, may be substituted in the ω-position by a hydroxy, mercapto, amino, alkylamino, dialkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, hexahydro-1-azepinyl, methylthio, hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-naphthyl, 2-naphthyl- or pyridinyl group, whilst the above-mentioned heterocycles, phenyl and naphthyl groups may in turn be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, trifluoromethoxy, methylsulphonyloxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different, and wherein the hydroxy, mercapto, amino, guanidino, indolyl and imidazolyl groups contained in the groups mentioned for R9 may be substituted with the protecting groups commonly used in peptide chemistry, preferably with the acetyl, benzyloxycarbonyl or tert. butyloxycarbonyl group,
R3 denotes a hydrogen atom,
a C1-7-alkyl group which may be substituted in the (ω-position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino, 4-alkyl-1-piperazinyl or 4-ω-hydroxyalkyl)-1-piperazinyl group,
a phenyl or pyridinyl group,
wherein the above-mentioned heterocyclic groups and phenyl groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, methylsulphonyloxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and the substituents may be identical or different,
R4 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a phenyl or pyridinyl group or
R3 and R4 together with the enclosed nitrogen atom denote a group of general formula
Figure US20090163480A1-20090625-C00112
wherein
Y3 denotes a carbon atom or, if R12 denotes a free pair of electrons, Y3 may also be the nitrogen atom,
r denotes the number 0, 1 or 2,
q denotes the number 0, 1 or 2,
R10 denotes a hydrogen atom or an amino, alkylamino, dialkylamino, alkyl, cycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino, cycloalkylaminocarbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or carboxy group,
a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group which may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, amino-carbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(dialkylamino)alkyl, ω-(dialkylamino)hydroxyalkyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different,
a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or 3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, which may be substituted by a phenyl group or fused at the double bond to a benzene, pyridine or diazine ring,
a 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl group,
a 4- to 10-membered azacycloalkyl group, a 5- to 10-membered oxaza, thiaza- or diazacycloalkyl group or a 6- to 10-membered azabicycloalkyl group,
wherein the above-mentioned mono- and bicyclic heterocycles may be bound via a nitrogen or carbon atom and
may be substituted by a C1-7-alkyl group, by an alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulphonyl, cycloalkyl- or cycloalkylalkyl group, by a cycloalkylcarbonyl, aza-cycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group optionally substituted in the ring,
whilst the alicyclic parts contained in these substituents may comprise 3 to 10 ring members and the heteroalicyclic parts may comprise 4 to 10 ring members and
the above-mentioned phenyl and pyridinyl groups may in turn be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different, or
R10 together with R12 and Y3 denotes a 4- to 7-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(alkyl)- group,
whilst a hydrogen atom bound to a nitrogen atom within the group R10 may be replaced by a protecting group,
R12 denotes a hydrogen atom,
a C1-4-alkyl group, wherein an unbranched alkyl group may be substituted in the ω-position by a phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl- or hexahydro-1H-1-azepinyl group,
an alkoxycarbonyl, cyano or aminocarbonyl group or a free pair of electrons, if Y3 denotes a nitrogen atom, and
R13 and R14 in each case denote a hydrogen atom or,
if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom or
if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes a partially hydrogenated or aromatic 5- to 7-membered mono- or bicyclic carbocycle or heterocycle,
whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 7 carbon atoms, unless otherwise specified,
all the above-mentioned cycloalkyl groups and the cycloalkyl groups present within the other groups named may contain 5 to 10 carbon atoms, unless otherwise specified,
their tautomers, diastereomers, enantiomers, mixtures thereof and the salts thereof.
2. Modified amino acids of general formula I according to claim 1, wherein the partial amino acid structure of the formula
Figure US20090163480A1-20090625-C00113
is in the D- or (R)-configuration and is in the L- or (S)-configuration with regard to the partial amino acid structure of formula
Figure US20090163480A1-20090625-C00114
which may be present in the group A, or wherein the partial structure of formula VI
Figure US20090163480A1-20090625-C00115
is spatially constructed analogously to the (R)-configured partial structure of formula V.
3. Modified amino acids of general formula I according to at least one of claims 1 or 2, wherein
R denotes an unbranched C1-5-alkyl group which may be substituted in the ω-position
by a C4-7-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-positions by lower straight-chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups, and the substituents may be identical or different,
by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
or by a 6-membered heteroaromatic ring linked via a carbon atom and containing one or two nitrogen atoms,
whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
or an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a C1-3-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
by a C4-7-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxo-imidazo[4,5-b]-pyridin-3-yl group,
by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
or by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1 or 2 nitrogen atoms, whilst a 1,4-butadienylene group may be attached to both the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl and alkylamino groups in the ω-position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C5-7-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
or the group of formula
Figure US20090163480A1-20090625-C00116
wherein
p denotes the number 1 or 2,
o denotes the number 2 or, if Y1 and Y2 are not simultaneously nitrogen atoms, o may also denote 1.
Y1 denotes the nitrogen atom if R5 is a free pair of electrons, or the carbon atom,
Y2 is the nitrogen atom or the group >CH,
R5 is a free pair of electrons if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 denotes a hydrogen atom, a C1-3-alkyl group, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl, aminocarbonylamino, phenylmethyl or phenyl group,
R6 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom, R6 together with R5 may denote an additional bond,
R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together constitute an additional bond, R7 together with RN may also denote a 1,4-butadienylene group,
RN denotes the hydrogen atom or a C1-3-alkyl group, which may be monosubstituted in the ω-position
by a C5-7-cycloalkyl group or by a 1-naphthyl, 2-naphthyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl, alkylaminocarbonyl, acetylamino, cyano, aminocarbonylamino or alkylaminocarbonylamino group, or may be mono- or disubstituted by phenyl, pyridinyl or diazinyl groups, whilst these substituents may be identical or different,
a cyclohexyl, phenyl, pyridinyl, cyano, amino, benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [N-phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino, N-(aminocarbonylaminocarbonyl)-N-phenylamino, N-(pyridinyl)-N-(aminocarbonyl)amino, N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino, diazinylamino or 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl group,
a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza- or S,S-dioxidothiadiaza heterocycle,
whilst the above-mentioned heterocycles may be linked via a carbon or nitrogen atom and
may contain one or two carbonyl groups adjacent to a nitrogen atom,
may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl, aroyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
may be substituted at one or two carbon atoms by a branched or unbranched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, whilst the substituents may be identical or different,
and wherein a C3-4-alkylene group may additionally be attached to the above-mentioned heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring,
or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 may also denote the 1,4-butadienylene group or,
if Y1 denotes a carbon atom, RN together with R5, with the inclusion of Y1, may also denote a carbonyl group or a saturated or monounsaturated 5- or 6-membered 1,3-diazaheterocycle which may contain one or two carbonyl groups in the ring adjacent to a nitrogen atom and, if it is unsaturated, may also be benzo-fused at the double bond and substituted at one of the nitrogen atoms by a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
whilst the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups contained in the residues mentioned under R5, R7 and RN, as well as benzo, thieno, pyrido- and diazino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C4-7-cycloalkyl groups, nitro, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the alkyl groups contained in the above-mentioned groups may contain 1 to 3 carbon atoms unless otherwise specified,
X denotes the oxygen atom or 2 hydrogen atoms,
Z denotes the methylene group or the group —NR1— wherein
R1 denotes a hydrogen atom or a C1-3-alkyl group,
R11 denotes a hydrogen atom, a C1-3-alkyl group or an alkoxycarbonyl group having 2 to 4 carbon atoms altogether,
n denotes the number 1 or 2 or, if m is 1, n may also be 0,
m denotes the number 0 or 1,
R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
whilst the above-mentioned aromatic and heteroaromatic groups in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, or by branched or unbranched alkyl groups, C4-7-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, and the substituents may be identical or different,
A denotes a bond or the divalent group of formula
Figure US20090163480A1-20090625-C00117
(linked to the R3R4N— group of general formula (I) via the carbonyl group)
wherein
R8 and R9 together denote an n-propylene group or
R8 denotes a hydrogen atom or a C1-3-alkyl group and
R9 denotes a hydrogen atom or a branched or unbranched C1-4-alkyl group which, if it is unbranched, may be substituted in the ω-position
by a hydroxy, mercapto, amino, alkylamino, dialkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, hexahydro-1-azepinyl, methylthio, hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-naphthyl, 2-naphthyl- or pyridinyl group, whilst the above-mentioned heterocycles and phenyl groups may in turn be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, trifluoromethoxy, methylsulphonyloxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and any hydroxy, mercapto, amino, guanidino, indolyl and imidazolyl groups contained in the groups mentioned for R9 may be substituted by a protecting group,
R3 denotes a hydrogen atom,
a C1-4-alkyl group which may be substituted in the ω-position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-azepin-1-yl, [bis-(2-hydroxyethyl)]amino, 4-methyl-1-piperazinyl- or 4-(ω-hydroxyalkyl)-1-piperazinyl group,
a phenyl or pyridinyl group,
wherein the above-mentioned heterocyclic radicals and phenyl groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, methylsulphonyloxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and the substituents may be identical or different,
R4 denotes a hydrogen atom or a methyl or ethyl group optionally substituted by a phenyl or pyridinyl group
or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula
Figure US20090163480A1-20090625-C00118
wherein
Y3 denotes a carbon atom or, if R12 denotes a free pair of electrons, Y3 may also be the nitrogen atom,
r denotes the number 0, 1 or 2,
q denotes the number 0, 1 or 2,
R10 denotes a hydrogen atom or an amino, alkylamino, dialkylamino, alkyl, cycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino, cycloalkylaminocarbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or carboxy group,
a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group which may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(dialkylamino)alkyl, ω-(dialkylamino)hydroxyalkyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different,
a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or 3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, which may be substituted by a phenyl group or fused at the double bond to a benzene, pyridine or diazine ring,
a 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl group,
a 4- to 10-membered azacycloalkyl group, a 5- to 10-membered oxaza, thiaza or diazacycloalkyl group or a 6- to 10-membered azabicycloalkyl group,
wherein the above-mentioned mono- and bicyclic heterocycles may be bound via a nitrogen or carbon atom and
may be substituted by a C1-7-alkyl group, by an alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulphonyl, cycloalkyl or cycloalkylalkyl group, by a cycloalkylcarbonyl, aza-cycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group optionally alkyl substituted in the ring,
whilst the alicyclic parts contained in these substituents may comprise 3 to 10 ring members and the heteroalicyclic parts may comprise 4 to 10 ring members and
the above-mentioned phenyl and pyridinyl groups may in turn be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different, or
R10 together with R12 and Y3 denotes a 4- to 7-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(alkyl)- group,
whilst a hydrogen atom bound to a nitrogen atom within the group R10 may be replaced by a protecting group,
R12 denotes a hydrogen atom, a C1-2-alkyl group which may be substituted in the ω-position by a phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl or hexahydro-1H-azepin-1-yl- group,
an alkoxycarbonyl, cyano- or aminocarbonyl group or a free pair of electrons, if Y3 denotes a nitrogen atom, and
R13 and R14 in each case denote a hydrogen atom or,
if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom or
if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes a partially hydrogenated or aromatic 5- to 7-membered mono- or bicyclic carbocycle or heterocycle,
whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise specified,
all the above-mentioned cycloalkyl groups and the cycloalkyl groups present within the other groups named may contain 5 to 7 carbon atoms, unless otherwise specified,
their tautomers, their diastereomers, their enantiomers and their salts.
4. Modified amino acids of general formula I according to at least one of claims 1 or 2, wherein
R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
by a C5-7-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may be substituted in the carbon skeleton by a phenyl, pyridinyl or diazinyl group,
by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, wherein a nitrogen of an imino group may be substituted by an alkyl group,
or may be substituted by a pyridinyl group,
whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and to the pyridinyl group, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
or an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a methyl or ethyl group, and which may be substituted in the ω-position
by a C5-7-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2(1H)-oxoquinolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
or by a pyridinyl group,
whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and to the pyridinyl group, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkyl and alkylamino groups in the ω-position as well as optionally partially hydrogenated mono- and bicyclic heteroaromatic rings may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups, whilst the substituents may be the same or different,
or the group of formula
Figure US20090163480A1-20090625-C00119
wherein
p denotes the number 1 or 2,
o denotes the number 2 or, if Y1 and Y2 are not simultaneously nitrogen atoms, it may also denote the number 1,
Y1 denotes the nitrogen atom if R5 denotes a free pair of electrons, or the carbon atom,
Y2 denotes the nitrogen atom or the group >CH,
R5 denotes a free pair of electrons if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 denotes a hydrogen atom, a C1-3-alkyl group, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl or aminocarbonylamino group or a phenylmethyl or phenyl group optionally substituted at the aromatic moiety by a fluorine, chlorine or bromine atom or by a methyl, methoxy, ethoxy, trifluoromethyl, hydroxy, amino or acetylamino group,
R6 denotes the hydrogen atom or, if Y1 is not a nitrogen atom, R6 together with R5 may also denote an additional bond,
R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, R7 together with RN may also denote the 1,4-butadienylene group,
RN denotes the hydrogen atom or a C1-3-alkyl group, which may be monosubstituted in the ω-position
by a C5-7-cycloalkyl group or by a 1-naphthyl, 2-naphthyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl, methylaminocarbonyl, acetylamino, cyano, aminocarbonylamino or alkylaminocarbonylamino group, or may be mono- or disubstituted by phenyl, pyridinyl or diazinyl groups, whilst these substituents may be identical or different,
a cyclohexyl, phenyl, pyridinyl, cyano, amino, benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [N-phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino, N-(aminocarbonylaminocarbonyl)-N-phenylamino, N-(pyridinyl)-N-(aminocarbonyl)amino, N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino, diazinylamino or 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl group,
a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S,S-dioxidothiadiaza heterocycle,
whilst the above-mentioned heterocycles may be linked via a carbon or nitrogen atom and
may contain one or two carbonyl groups adjacent to a nitrogen atom,
may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
may be substituted at one or two carbon atoms by a methyl, phenyl, phenylmethyl, naphthyl, biphenylyl, thienyl, pyridinyl or diazinyl group, wherein the substituents may be identical or different,
and wherein a C3-4-alkylene group may additionally be attached to the above-mentioned heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the above-mentioned heterocycles may be fused to a thiophene, benzene, pyridine, quinoline or diazine ring,
or, if Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 may also denote a 1,4-butadienylene group or,
if Y1 denotes a carbon atom, RN together with R5 with the inclusion of Y1 may also denote a carbonyl group or a saturated or monounsaturated 5- or 6-membered 1,3-diazaheterocycle which may contain one or two carbonyl groups in the ring adjacent to a nitrogen atom and, if it is unsaturated, may also be benzo-fused at the double bond and may be substituted at one of the nitrogen atoms by a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
whilst the phenyl, pyridinyl or diazinyl groups contained in the groups mentioned under RN and the thieno, benzo, pyrido- or diazino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by methyl groups, nitro, methoxy, ethoxy, methylsulphonylamino, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, methylaminocarbonylamino, acetyl, cyano or trifluoromethoxy groups, whilst the substituents may be identical or different,
and the alkyl groups contained in the above-mentioned residues may contain 1 to 3 carbon atoms, unless otherwise specified,
X denotes an oxygen atom or 2 hydrogen atoms,
Z denotes a methylene group or the group —NR1— wherein
R1 is a hydrogen atom or a methyl group,
R11 denotes the hydrogen atom or a methyl or methoxycarbonyl group,
n denotes the number 1 or 2 or, if m is the number 1, n may also denote 0,
m denotes the number 0 or 1,
R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, pyridinyl or quinolinyl group,
wherein the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by branched or unbranched C1-5 alkyl groups, allyl, vinyl, methoxy, ethoxy, propoxy, 1-methylethoxy, dimethylaminoethoxy, trifluoromethyl, hydroxy, nitro, amino, acetylamino, propionylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetyl, cyano, methylsulphonyloxy or trifluoromethoxy groups, by tetrazolyl, phenyl pyridinyl, thiazolyl or furyl groups and the substituents may be identical or different, or
A denotes a bond or the divalent group of formula
Figure US20090163480A1-20090625-C00120
(linked to the NR3R4— group of general formula (I) via the carbonyl group)
wherein
R8 and R9 together denote an n-propylene group or
R8 denotes the hydrogen atom or the methyl group and
R9 denotes a hydrogen atom or an unbranched C1-4-alkyl group which may be substituted in the ω-position
by a hydroxy, amino, methylamino, dimethylamino, hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl or pyridinyl group, wherein the phenyl and pyridinyl group may in turn be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl or cyano group and wherein any hydroxy, amino and guanidino groups contained in the groups given for R9 may be substituted by a protecting group, e.g. the phenylmethoxycarbonyl or tert. butyloxycarbonyl group,
R3 denotes a hydrogen atom,
a C1-4-alkyl group optionally substituted in the ω-position by a cyclohexyl, phenyl, pyridinyl, hydroxy, amino, methylamino, dimethylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-(1-piperidinyl)-1-piperidinyl group,
a phenyl or pyridinyl group,
whilst the above-mentioned phenyl and pyridinyl groups may additionally be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl or cyano group,
R4 denotes the hydrogen atom or a C1-2-alkyl group optionally substituted by a phenyl or pyridinyl group
or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula
Figure US20090163480A1-20090625-C00121
wherein
Y3 denotes a carbon atom or, if R12 denotes a free pair of electrons, Y3 may also be a nitrogen atom,
r denotes the number 0, 1 or 2,
q denotes the number 0, 1 or 2,
with the proviso that the sum of the numbers given for r and q is 0, 1, 2 or 3,
R10 denotes a hydrogen atom, an alkyl, cycloalkyl, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonylamino, alkoxycarbonyl, alkoxycarbonylmethyl, carboxymethyl or carboxy group,
a phenyl, pyridinyl, diazinyl, pyridinylcarbonyl or phenylcarbonyl group which may be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by methyl, ethyl, propyl, methoxy, hydroxy, ω-(dialkylamino)-alkyl, ω-(dialkylamino)hydroxyalkyl or alkanoyl groups, whilst the substituents may be identical or different,
a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or 3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, which may be substituted by a phenyl group or may be fused at the double bond to a benzene, pyridine or diazine ring,
a 5- to 7-membered azacycloalkyl group, a 4- to 7-membered oxaza- or diazacycloalkyl group or a 7- to 9-membered azabicycloalkyl group,
wherein the above-mentioned mono- and bicyclic heterocycles are bound via a nitrogen or a carbon atom and
may be substituted by a C1-7-alkyl group, or by an alkanoyl, dialkylamino, phenylcarbonyl, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety, alkylsulphonyl, cycloalkyl or cycloalkylalkyl group or by an azacycloalkylcarbonyl or diazacycloalkylcarbonyl group optionally alkyl-substituted in the ring,
whilst the alicyclic groups contained in these substituents may comprise 3 to 7 ring members and the heteroalicyclic groups may comprise 4 to 7 ring members and
the above-mentioned phenylcarbonyl group may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino or acetylamino group, or
R10 together with R12 and Y3 denotes a 4- to 6-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(CH3)— group,
whilst a hydrogen atom bound to a nitrogen atom within the group R10 may be replaced by a protecting group, e.g. the phenylmethoxycarbonyl or tert. butyloxycarbonyl group,
R12 denotes a hydrogen atom, a C1-2-alkyl group which may be substituted in the ω-position by a phenyl, pyridinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-methyl-1-piperazinyl group,
a methoxycarbonyl or ethoxycarbonyl, cyano or aminocarbonyl group or a free pair of electrons, if Y3 denotes a nitrogen atom, and
R13 and R14 each denote a hydrogen atom or,
if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom, or
if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes a partially hydrogenated
or aromatic 5- or 6-membered mono- or bicyclic carbocycle or heterocycle, containing one or two nitrogen atoms,
whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups named may contain 1 to 3 carbon atoms, unless otherwise stated, and
all the above-mentioned cycloalkyl groups and the cycloalkyl groups present within the other groups named may contain 5 to 7 carbon atoms, unless otherwise specified,
their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.
5. Modified amino acids of general formula I according to at least one of claims 1 or 2, wherein
R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
by a C5-7-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group, whilst the above-mentioned aromatic groups may additionally be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, amino or acetylamino group,
by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl or isoquinolinyl group,
or an unbranched C1-4-alkylamino group which is optionally additionally substituted at the nitrogen atom by a methyl or ethyl group and which may be substituted in the ω-position
by a C5-7-cycloalkyl group,
by a phenyl group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms, or by methyl, nitro, methoxy, trifluoromethyl, hydroxy, amino or acetylamino groups, whilst the substituents may be identical or different,
by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl or isoquinolinyl group,
or the group of formula
Figure US20090163480A1-20090625-C00122
wherein
p denotes the number 1 or 2,
o denotes the number 2 or, if Y1 and Y2 are not simultaneously nitrogen atoms, it may also denote the number 1,
Y1 denotes the nitrogen atom if R5 denotes a free pair of electrons, or the carbon atom,
Y2 denotes the nitrogen atom or the group >CH,
R5 denotes a free pair of electrons, if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 may denote the hydrogen atom, a C1-2-alkyl group or the cyano or phenyl group,
R6 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom, R6 together with R5 may also denote an additional bond,
R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, R7 together with RN may also denote the 1,4-butadienylene group,
RN denotes the hydrogen atom or a C1-3-alkyl group, which may be substituted in the ω-position
by one or two phenyl or pyridinyl groups, wherein the substituents may be identical or different,
or by a hydroxy or methoxy group,
a phenyl group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl groups, nitro, methoxy, ethoxy, trifluoromethyl, hydroxy or cyano groups, whilst the substituents may be identical or different, or a phenyl group substituted by a methylenedioxy group,
a 2-pyridinyl or 4-pyridinyl group,
an amino, benzoylamino, aminocarbonyl, methylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonylamino, methylaminocarbonylamino, N-(aminocarbonyl)-N-methylamino, N-(methylaminocarbonyl)-N-methylamino, N-(aminocarbonyl)-N-(4-fluorophenyl)amino, N-(methylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [N-phenyl(methylamino)]-carbonylamino, N-(phenylaminocarbonyl)-N-methylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino group or a phenylamino group optionally substituted in the phenyl ring by an aminocarbonylamino or methylsulphonylamino group,
a 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, a 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl, 1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl, 1H-indol-3-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl, 1,3(2H)-dioxo-1H-isoindol-2-yl, 1H-benzimidazol-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 2(3H)-oxobenzoxazol-3-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-d]pyrimidin-3-yl, 2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[2,3-d]pyrimidin-3-yl, 2(1H)-oxoquinolin-3-yl, 3,4-dihydro-2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinazolin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 2,4(1H,3H)-dioxothieno[3,4-d]-pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl, 1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl, 2,5-dioxo-4-phenylmidazolidin-1-yl, 2,5-dioxo-4-(phenylmethyl)-imidazolidin-1-yl, 3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl, 1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl, 1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl, 1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 4-phenyl-2(1H)-oxopyrimidin-1-yl, 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2[1H]-oxopyrido[4,3-d]pyrimidin-3-yl or 2,3-dihydro-4(1H)-oxoquinazolin-3-yl group,
wherein the above-mentioned mono- and bicyclic heterocycles may be substituted at one of the nitrogen atoms by a methoxycarbonylmethyl group and/or
the above-mentioned mono- and bicyclic heterocycles may be mono-, di- or trisubstituted in the carbon skeleton and/or at the phenyl groups contained in these groups by fluorine, chlorine or bromine atoms, or by methyl, trifluoromethyl, methoxy, hydroxy, amino, nitro, phenyl, phenylmethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (1-piperidinyl)carbonyl or (4-methyl-1-piperazinyl)carbonyl groups wherein the substituents may be identical or different and multiple substitution with the last three substituents is ruled out,
or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 also denotes the 1,4-butadienylene group,
or, provided that Y1 denotes a carbon atom, RN together with R5 with the inclusion of Y1 may also denote a carbonyl group or a saturated or monounsaturated five- or six-membered 1,3-diaza-heterocycle,
which may contain a carbonyl group in the ring, adjacent to a nitrogen atom,
may be substituted by a phenyl group at one of the nitrogen atoms
and, if it is unsaturated, may also be benzo-condensed at the double bond,
X denotes an oxygen atom or 2 hydrogen atoms,
Z denotes a methylene group or the group —NR1, wherein
R1 denotes a hydrogen atom or a methyl group,
R11 denotes a hydrogen atom, a methoxycarbonyl, ethoxycarbonyl or methyl group,
n denotes the number 1 and m denotes the number 0 or
n denotes the number 0 and m denotes the number 1,
R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 2-thienyl, 3-thienyl, thiazolyl or alkylthiazolyl group having 1 to 3 carbon atoms in the alkyl moiety, a pyridinyl or quinolinyl group,
wherein the above-mentioned phenyl and naphthyl groups may be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched C1-5-alkyl groups, by C1-3-alkoxy groups, by vinyl, allyl, trifluoromethyl, methylsulphonyloxy, 2-(dimethylamino)ethoxy, hydroxy, cyano, nitro or amino groups, by tetrazolyl, phenyl, pyridinyl, thiazolyl or furyl groups and the substituents may be identical or different, and multiple substitution with the last five substituents is ruled out,
A denotes a bond or the divalent group of formula
Figure US20090163480A1-20090625-C00123
(linked to the group —NR3R4 of formula (I) via the carbonyl group)
wherein
R8 and R9 together denote an n-propylene group or
R8 denotes the hydrogen atom or the methyl group and
R9 denotes the hydrogen atom or an unbranched C1-4-alkyl group,
which may be substituted in the ω-position by an amino, methylamino, dimethylamino, aminoiminomethylamino or aminocarbonylamino group, whilst in the above-mentioned substituents a hydrogen atom bound to a nitrogen atom may be replaced by a protecting group, e.g. the phenylmethoxycarbonyl or tert. butyloxycarbonyl group,
R3 denotes a hydrogen atom or
a C1-4-alkyl group optionally substituted in the ω-position by an amino, methylamino, dimethylamino- or 4-(1-piperidinyl)-1-piperidinyl group,
R4 denotes a hydrogen atom or a methyl or ethyl group
or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula
Figure US20090163480A1-20090625-C00124
wherein
Y3 denotes the carbon atom or, if R12 denotes a free pair of electrons, Y3 may also denote a nitrogen atom,
r denotes the number 1,
q denotes the number 1,
R10 denotes the hydrogen atom, an alkyl, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonylamino, alkoxycarbonyl, alkoxycarbonylmethyl, carboxymethyl or carboxy group or a cycloalkyl group having 4 to 7 carbon atoms in the ring,
a benzoyl, pyridinylcarbonyl, phenyl, pyridinyl or diazinyl group, each of which may be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom, or by an acetyl, methyl, ethyl or methoxy group, or by a dimethylaminoalkyl group having 1 to 4 carbon atoms in the alkyl moiety optionally hydroxysubstituted in the alkyl moiety,
a 1,3-dihydro-2-oxo-2H-imidazolyl group bound via a nitrogen atom, which may be fused to a benzene or pyridine ring at the double bond,
a 1-pyrrolidinyl, 1-piperidinyl, 4-(dimethylamino)-1-piperidinyl, 4-piperidinyl or 4-morpholinyl group, wherein the nitrogen atom of the 4-piperidinyl group may be substituted by an alkanoyl- or alkyl group each having 1 to 7 carbon atoms or by a benzoyl, methylsulphonyl, 3-carboxy-propionyl, cyclopropylmethyl, alkoxycarbonylmethyl or carboxymethyl group or by a protecting group, e.g. the phenylmethoxycarbonyl or tert. butyloxycarbonyl group, or it may represent a hexahydro-1H-1-azepinyl, 8-methyl-8-azabicyclo[3,2,1]oct-3-yl, 4-alkyl-1-piperazinyl, hexahydro-4-alkyl-1H-1,4-diazepin-1-yl, 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group,
or
R10 together with R12 and Y3 denotes a 5-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(CH3)— group,
R12 denotes a hydrogen atom, a C1-2-alkyl group which may be substituted in the ω-position by a 1-pyrrolidinyl, 1-piperidinyl or 4-methyl-1-piperazinyl group,
a methoxycarbonyl or ethoxycarbonyl or a cyano group,
a free pair of electrons if Y3 denotes a nitrogen atom, and
R13 and R14 each denote a hydrogen atom or,
provided that Y3 is a carbon atom, R12 together with R14 may also denote an additional carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom or,
provided that Y3 is a carbon atom, R12 together with R14 may also denote an additional carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes an indole group fused on via the 5-membered ring,
whilst all the above-mentioned alkyl groups and the alkyl groups present within the other named groups may contain 1 to 3 carbon atoms, unless otherwise specified,
their tautomers, their diastereomers, their enantiomers and their salts.
6. Modified amino acids of general formula I according to claims 1 to 5, characterised in that these are described in Examples 1 to 29.
7. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 6 with inorganic or organic acids or bases.
8. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 6 or a physiologically acceptable salt according to claim 7 optionally together with one or more inert carriers and/or diluents.
9. Use of a compound according to at least one of claims 1 to 7 for the preparation of a pharmaceutical composition which is suitable for the acute and prophylactic treatment of headaches, for treating non-insulin dependent diabetes mellitus, cardiovascular disorders, skin diseases, inflammatory diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and consequently reduced blood circulation, e.g. shock and sepsis, and morphine tolerance.
10. Process for preparing a pharmaceutical composition according to claim 8, characterised in that a compound according to at least one of claims 1 to 7 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
11. Process for preparing the compounds of general formula I according to claims 1 to 7, characterised in that
a) In order to prepare compounds of general formula I, wherein
R denotes an unbranched C1-7-alkyl group which may be substituted in the ω-position
by a C4-10-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl- or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, wherein the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl- or 1-methylimidazolyl-groups and the substituents may be identical or different,
by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, and
or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one, two or three nitrogen atoms,
whilst a 1,4-butadienylene group may be attached both to the above-mentioned 5-membered heteroaromatic monocyclic rings and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group, and
whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl groups in the ω-position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
or the group of formula
Figure US20090163480A1-20090625-C00125
wherein
R5, R6, R7, RN, Y1, o and p are as defined in claims 1 to 6,
Y2 denotes a CH— group and
Z denotes an NR1— group, wherein R1 is as defined in claims 1 to 6:
a carboxylic acid of general formula VII,

RCO2H  (VII)
wherein
R is as defined in claims 1 to 6,
is coupled with a compound of general formula VIII,
Figure US20090163480A1-20090625-C00126
wherein
R2, R3, R4, R11, A, X, m and n are defined as in claims 1 to 6, and
Z denotes an NR1— group, wherein R1 is defined as in claims 1 to 6,
and, if necessary, any protecting groups are subsequently cleaved from a compound thus obtained, or precursor functions are modified, or
b) In order to prepare compounds of general formula I wherein R is defined as in a), Z denotes the NR1— group and R1, R2, R3, R4, R11, A, X, m and n are defined as in claims 1 to 6:
a compound of general formula IX,

R—CO-Nu  (IX)
wherein
R is defined as in a) and
Nu denotes a leaving group,
is coupled with a compound of general formula VIII,
Figure US20090163480A1-20090625-C00127
wherein
R2, R3, R4, R11, A, X, m and n are defined as in claims 1 to 6 and
Z denotes an NR1— group, whilst R1 is defined as in claims 1 to 6,
and, if necessary, protecting groups are subsequently cleaved from a compound thus obtained or precursor functions are modified or
c) in order to prepare compounds of general formula I wherein
R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
by a C4-10-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl group,
by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl- group,
by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphynyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group,
or the group of formula
Figure US20090163480A1-20090625-C00128
wherein
R5, R6, R7, RN, Y1, o and p are defined as in claims 1 to 6,
Y2 denotes the N-atom and
Z denotes the NR1— group, wherein R1 is defined as in claims 1 to 6:
an amine of general formula X

R—H  (X)
wherein
R is as hereinbefore defined, is reacted with a carbonic acid derivative of general XI
Figure US20090163480A1-20090625-C00129
wherein
X1 is a nucleofugic group,
and with a compound of general formula VIII,
Figure US20090163480A1-20090625-C00130
wherein
R2, R3, R4, R11, A, X, m and n are defined as in claims 1 to 6, and
Z denotes an NR1— group, wherein R1 is defined as in claims 1 to 6,
and, if necessary, protecting groups are subsequently cleaved from a compound thus obtained or precursor functions are modified, or
d) In order to prepare compounds of general formula I wherein the carbonyl group linked to the groups R and Z denotes a urea carbonyl group, in which the urea carbonyl is flanked by at least one NH— group, and wherein
R denotes an unbranched C1-6-alkylamino group optionally additionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
by a C4-10-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl group,
by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl- group,
by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphynyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group,
or the group of formula
Figure US20090163480A1-20090625-C00131
wherein
R5, R6, R7, RN, Y1, o and p are as defined in claims 1 to 6 and Y2 denotes the N-atom,
Z denotes the group NR1 and
R1 denotes a hydrogen atom or, provided that R denotes an unbranched alkylamino group unsubstituted at the nitrogen atom and optionally substituted in the ω-position, R1 may also denote an alkyl or phenylalkyl group:
an amine of general formula X′,

R—H  (X′)
wherein R is as hereinbefore defined,
is reacted with carbonic acid derivatives of general formula XI′,
Figure US20090163480A1-20090625-C00132
wherein
X2 denotes a phenoxy group, if X3 is the (1H)-1,2,3,4-tetrazol-1-yl- group, the 4-nitrophenoxy group, if X3 is the 4-nitrophenoxy group, and the chlorine atom if X3 is the 2,4,5-trichlorophenoxy group, and with a compound of general formula VIII′,
Figure US20090163480A1-20090625-C00133
wherein
R2, R3, R4, R11, X, A, m and n are defined as in claims 1 to 6, and
R1 denotes a hydrogen atom or, provided that R is an unbranched alkylamino group unsubstituted at the nitrogen and optionally substituted in the ω-position, R1 may also denote an alkyl or phenylalkyl group,
and, if necessary protecting groups are subsequently cleaved from a compound thus obtained or precursor functions are modified or
e) in order to prepare compounds of general formula I wherein Z denotes the group NH and
R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
by a C4-10-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl group,
by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphynyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
or the group of formula
Figure US20090163480A1-20090625-C00134
wherein
R5, R6, R7, RN, Y1, o and p are defined as in claims 1 to 6 and
Y2 denotes an N-atom,
an isocyanate of general formula XII,
Figure US20090163480A1-20090625-C00135
wherein
R2, R3, R4, R11, A, X, m and n are defined as in claims 1 to 6,
is reacted with an amine of general formula X,

R—H  (X)
wherein
R is as hereinbefore defined,
and, if necessary, protecting groups are subsequently cleaved from a compound thus obtained or precursor functions are modified, or
f) in order to prepare compounds of general formula I wherein
R denotes an unbranched C1-6-alkylamino group unsubstituted at the nitrogen atom, which may be substituted in the ω-position
by a C4-10-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl group,
by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphynyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group, and
Z denotes an NR1— group wherein R1 is defined as in claims 1 to 6,
an isocyanate of general formula XIII,

R═C═O  (XIII)
wherein R is as hereinbefore defined, is reacted with a compound of general formula VIII,
Figure US20090163480A1-20090625-C00136
wherein R2, R3, R4, R11, A, X, m and n are defined as in claims 1 to 6, and
Z denotes an NR1— group, wherein R1 is defined as in claims 1 to 6,
and, if necessary, protecting groups are subsequently cleaved from a compound thus obtained or precursor functions are modified, or
g) in order to prepare compounds of general formula I, wherein
X is defined as in claims 1 to 6, provided that A does not denote a bond, or X denotes an oxygen atom if A denotes a single bond:
a carboxylic acid of general formula XIV,
Figure US20090163480A1-20090625-C00137
wherein
R, Z, R11, m and n are defined as in claims 1 to 6,
R2′ has the meanings given for R2 in claims 1 to 6 or denotes a group R2 substituted by a protecting group,
A′ has the meanings given for A in claims 1 to 6 or, if A denotes the divalent group of an amino acid, A′ optionally bears a precursor group for the group R9 in the side chain,
is coupled with a compound of general formula XV,

H—NR3R4  (XV)
wherein
R3 and R4 have the meanings given in claims 1 to 6,
and, if necessary, protecting groups are subsequently cleaved from a compound thus obtained or precursor functions are modified or
h) in order to prepare compounds of general formula I wherein X denotes an oxygen atom,
a carboxylic acid of general formula XVI,
Figure US20090163480A1-20090625-C00138
wherein
R, Z, R11, m and n are defined as in claims 1 to 6 and
R2′ has the meanings given for R2 in claims 1 to 6 or denotes a group R2 substituted by a protecting group,
is coupled with a compound of general formula XVII,
Figure US20090163480A1-20090625-C00139
wherein
A′ has the meanings given for A in claims 1 to 6 or, if A denotes the divalent group of an amino acid, A′ optionally bears a precursor group for the group R9 in the side chain, and
R3 and R4 have the meanings given in claims 1 to 6,
and, if necessary, protecting groups are subsequently cleaved from a compound thus obtained or precursor functions are modified or
i) in order to prepare compounds of general formula I wherein
R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
by a C4-10-cycloalkyl group,
by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl- group,
by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,
whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphynyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group,
or the group of formula
Figure US20090163480A1-20090625-C00140
wherein
R5, R6, R7, RN, Y1, o and p are defined as in claims 1 to 6 and Y2 denotes the N-atom,
Z represents a methylene group,
X denotes two hydrogen atoms,
A denotes a single bond,
m denotes the value 1 and
n denotes the value 0,
a carboxylic acid of general formula XVIII,
Figure US20090163480A1-20090625-C00141
wherein
R2, R3 and R4 are defined as in claims 1 to 6,
is coupled with an amine of general formula X,

R—H  (X)
wherein R is as hereinbefore defined, or
j) in order to prepare compounds of general formula I wherein
R3 and R4 have the meanings given in claims 1 to 6 with the exception of hydrogen atoms, Z denotes a methylene group, X denotes two hydrogen atoms, A denotes a single bond, m denotes the number 1 and n denotes the number 0,
a secondary amine of general formula XVa,

H—NR3′R4′  (XVa)
wherein
R3′ and R4′ have the meanings given for R3 and R4 in claims 1 to 6, with the exception of hydrogen atoms,
is reacted with formaldehyde and a CH-acid compound of general formula XIX,
Figure US20090163480A1-20090625-C00142
wherein
R is defined as in claims 1 to 6 and
R2 is defined as in claims 1 to 6, but with the proviso that any acid functions present are appropriately protected by suitable protecting groups, or
k) in order to prepare compounds of general formula I wherein A denotes the divalent group of formula III
Figure US20090163480A1-20090625-C00143
(linked to the NR3R4— group via the —CX— group)
wherein
R8 denotes a hydrogen atom or an alkyl or phenylalkyl group and
R9 denotes an unbranched C1-5-alkyl group substituted in the ω-position by an aminoiminomethylamino group,
a compound of general formula XX,
Figure US20090163480A1-20090625-C00144
wherein
R, R2, R3, R4, R11, X, Z, m and n are defined as in claims 1 to 6,
R8 denotes a hydrogen atom or an alkyl or phenylalkyl group and
R9 denotes an unbranched C1-5-alkyl group substituted in the ω-position by a primary amino group,
is reacted with a carbonic acid derivative of general formula XXI,
Figure US20090163480A1-20090625-C00145
wherein
Nu2 is a leaving group or the group of general formula XXII,
Figure US20090163480A1-20090625-C00146
wherein
R15 and R16, which may be identical or different, denote hydrogen atoms or C1-3-alkyl groups, and
if desired a protecting group used during the reactions described hereinbefore is cleaved again and/or
if desired a compound of general formula I thus obtained is resolved into its stereoisomers and/or
a compound of general formula I thus obtained is converted into the salts thereof, more particularly for pharmaceutical use into the physiologically acceptable salts thereof.
12. Use of the compounds of general formula I according to claims 1 to 7 for the production and purification of antibodies.
13. Use of the labelled compounds of general formula I according to claims 1 to 7 in RIA and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.
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