US20040132716A1 - CGRP antagonists - Google Patents

CGRP antagonists Download PDF

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Publication number
US20040132716A1
US20040132716A1 US10/685,921 US68592103A US2004132716A1 US 20040132716 A1 US20040132716 A1 US 20040132716A1 US 68592103 A US68592103 A US 68592103A US 2004132716 A1 US2004132716 A1 US 2004132716A1
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Prior art keywords
oxo
piperidin
tetrahydro
ethyl
piperidine
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US10/685,921
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Inventor
Klaus Rudolf
Stephan Mueller
Dirk Stenkamp
Philipp Lustenberger
Alexander Dreyer
Eckhart Bauer
Marcus Schindler
Kirsten Arndt
Henri Doods
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Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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Priority to US10/685,921 priority Critical patent/US20040132716A1/en
Assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG reassignment BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ARNDT, KIRSTEN, BAUER, ECKHART, DOODS, HENRI, DREYER, ALEXANDER, LUSTENBERGER, PHILIPP, MUELLER, STEPHAN GEORG, RUDOLF, KLAUS, SCHINDLER, MARCUS, STENKAMP, DIRK
Publication of US20040132716A1 publication Critical patent/US20040132716A1/en
Priority to US11/757,743 priority patent/US7700589B2/en
Priority to US12/706,840 priority patent/US20100152171A1/en
Abandoned legal-status Critical Current

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to CGRP antagonists of general formula
  • A denotes an oxygen or sulphur atom, a phenylsulphonylimino or cyanoimino group
  • X denotes an oxygen or sulphur atom, an imino group optionally substituted by a C 1-6 -alkyl group or a methylene group optionally substituted by a C 1-6 -alkyl group,
  • Y and Z independently of one another each denote a straight-chain or branched C 1-6 -alkyl group wherein each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms,
  • R 1 denotes a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocyclic group,
  • [0011] contain one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen atom
  • [0012] may be substituted at one of the nitrogen atoms by an alkyl group
  • [0013] may be substituted at one or at two carbon atoms by an 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, while the substituents may be identical or different, and
  • an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused to a phenyl, naphthyl, pyridine, diazine, 1,3-oxazole, thienyl, furan, thiazole, pyrrole, N-methylpyrrole or quinoline ring, to a 1H-quinolin-2-one ring optionally substituted at the nitrogen atom by an alkyl group or to an imidazole or N-methylimidazole ring or also two olefinic double bonds of one of the above-mentioned unsaturated heterocycles may each be fused to a phenyl ring,
  • phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups contained in R 1 as well as benzo-, thieno-, pyrido- and diazino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, by alkyl, alkoxy, nitro, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, difluoromethyl, trifluoromethyl, alkoxycarbonyl, carboxy, hydroxy, amino, alkylamino, dialkylamino,
  • R 2 denotes the hydrogen atom
  • a phenylmethyl group or a C 2-7 -alkyl group which may be substituted in the ⁇ position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, 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-( ⁇ -hydroxy-C 2-7 -alkyl)-1-piperazinyl group,
  • heterocyclic groups and phenyl groups may additionally be mono- di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, acetylamino, aminocarbonyl, cyano, methylsulphonyloxy, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl, trifluoromethylsulphonyl, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl or di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl groups and the substituents may be identical or different,
  • R 3 denotes the hydrogen atom or a C 1-3 -alkyl group optionally substituted by a phenyl or pyridinyl group
  • C 1-3 -alkyl group may be linked to an alkyl group present in R 2 or a phenyl or pyridyl ring present in R 2 and the nitrogen atom to which they are bound, forming a ring, or
  • R 2 and R 3 together with the enclosed nitrogen atom denote a group of general formula
  • Y 1 denotes the carbon atom or, if R 5 is a pair of free electrons, it may also denote the nitrogen atom,
  • R 4 denotes the hydrogen atom, an amino, alkylamino, dialkylamino, alkyl, cycloalkyl, amino-C 2-7 -alkyl, alkylamino-C 2-7 -alkyl, dialkylamino-C 2-7 -alkyl, aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino, cycloalkylamino-carbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl or carboxyalkyl group, or, if Y 1 does not denote the nitrogen atom, the carboxy, aminomethyl, alkylaminomethyl or dialkylaminomethyl group,
  • a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group which may each be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by alkyl, alkoxy, methylsulphonyloxy, difluoromethyl, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl, ⁇ -(dialkylamino)alkanoyl, ⁇ -(dialkylamino)alkyl, ⁇ -(dialkylamino)hydroxyalkyl, ⁇ -(carboxy)alkan
  • a 4- to 10-membered azacycloalkyl group a 6- to 10-membered oxaza, thiaza or diazacycloalkyl group, a 6- to 10-membered azabicycloalkyl group, a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group,
  • any methylene group not directly bound to a nitrogen, oxygen or sulphur atom may be substituted by one or two fluorine atoms,
  • the above-mentioned mono- and bicyclic heterocycles as well as the 1-alkyl-4-piperidinylcarbonyl- and 4-alkyl-1-piperazinylcarbonyl group in the ring may be mono- or polysubstituted by a C 1-7 -alkyl group, monosubstituted by a phenyl-C 1-3 -alkyl, alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxy, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulphonyl, cycloalkyl or cycloalkylalkyl group, or substituted by a cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacyclo
  • the phenyl and pyridinyl groups contained in the above-mentioned groups may in turn be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, by alkyl, alkoxy, methylsulphonyloxy, difluoromethyl, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl, ⁇ -(dialkylamino)alkanoyl, ⁇ -(carboxy)alkanoyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, while the substituents may be identical or different,
  • R 5 denotes a hydrogen atom
  • a C 1-4 -alkyl group while an unbranched alkyl group may be substituted in the o) 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,
  • Y 1 does not denote a nitrogen atom, also the fluorine atom, or
  • R 4 together with R 5 and Y 1 denote a 4- to 7-membered cycloaliphatic ring, in which a methylene group may be replaced by a —NH or —N(alkyl)-group
  • R 6 and R 7 which may be identical or different, in each case denote a hydrogen atom, a C 1-3 -alkyl or dialkylamino group or also, if Y 1 does not denote a nitrogen atom, the fluorine atom and
  • R 8 and R 9 which may be identical or different, in each case denote a hydrogen atom or a C 1-3 -alkyl group
  • alkyl and alkoxy groups as well as the alkyl groups present within the other groups specified comprise 1 to 7 carbon atoms and may be straight-chain or branched, while each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms,
  • all the above-mentioned cycloalkyl groups as well as the cycloalkyl groups present within the other groups specified, unless otherwise stated, may comprise 3 to 10 carbon atoms, while each methylene group may be substituted by up to 2 fluorine atoms,
  • aromatic and heteroaromatic groups may additionally be mono- di- or trisubstituted by fluorine, chlorine or bromine atoms, by cyano or hydroxy groups and the substituents may be identical or different and
  • protective groups mentioned in the foregoing and subsequent definitions are meant the protective groups familiar from peptide chemistry, particularly a phenylalkoxycarbonyl group with 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,
  • benzyloxycarbonyl 2-nitro-benzyloxycarbonyl, 4-nitro-benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl- ⁇ , ⁇ -dimethyl-benzyloxycarbonyl or 3,5-dimethoxy- ⁇ , ⁇ -dimethyl-benzyloxycarbonyl group,
  • a second embodiment of the present invention comprises the compounds of the above general formula (I), wherein
  • A, X, Y, Z, R 2 and R 3 are defined as mentioned in the first embodiment hereinbefore and
  • R 1 denotes a mono- or diunsaturated 5- to 7-membered aza, diaza, triaza or thiaza heterocyclic group
  • [0055] contain one or two carbonyl groups adjacent to a nitrogen atom
  • [0056] may be substituted at a carbon atom by a phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl group and
  • an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused to a phenyl, naphthyl, pyridine, diazine, thienyl or quinoline ring or to a 1H-quinolin-2-one ring optionally substituted at the nitrogen atom by a methyl group,
  • phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl groups contained in R 1 as well as the benzo-, pyrido- and diazino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, by alkyl, alkoxy, nitro, difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy groups, while the substituents may be identical or different,
  • alkyl groups or the alkyl groups contained in the above-mentioned groups contain 1 to 7 carbon atoms and may be branched or unbranched, while each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms, and
  • the above-mentioned aromatic and heteroaromatic groups may additionally be mono- di- or trisubstituted by fluorine, chlorine or bromine atoms or by cyano or hydroxy groups and the substituents may be identical or different.
  • a third embodiment of the present invention comprises the compounds of the above general formula (I), wherein
  • A, X, Y, Z, R 2 and R 3 are defined as hereinbefore in the first embodiment and
  • R 1 denotes a monounsaturated 5- to 7-membered diaza or triaza heterocyclic group
  • [0065] contain a carbonyl group adjacent to a nitrogen atom
  • [0066] may additionally be substituted at a carbon atom by a phenyl group and
  • an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused to a phenyl, thienyl or quinoline ring,
  • phenyl groups contained in R 1 as well as benzo-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, by methyl, methoxy, nitro, difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy groups, while the substituents may be identical or different, but are preferably unsubstituted, or monosubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group,
  • alkyl groups as well as the alkyl groups present within the other groups comprise 1 to 7 carbon atoms and may be straight-chain or branched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono- di- or trisubstituted by fluorine, chlorine or bromine atoms or by cyano or hydroxy groups and the substituents may be identical or different.
  • a fourth embodiment of the present invention comprises the compounds of the above general formula (I), wherein
  • A, X, Y, Z, R 2 and R 3 are defined as hereinbefore in the first embodiment and
  • R 1 denotes a 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl, 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl, 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4
  • aromatic and heteroaromatic groups by fluorine, chlorine or bromine atoms, by cyano or hydroxy groups may additionally be mono- di- or trisubstituted and the substituents may be identical or different.
  • a fifth embodiment of the present invention comprises the compounds of the above general formula (I), wherein
  • A, X, Y, Z and R 1 are defined as hereinbefore in the first embodiment and
  • R 2 denotes the hydrogen atom
  • a phenylmethyl group or a C 2-7 -alkyl group which may be substituted in the ⁇ position by a phenyl, pyridinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, [bis-(2-hydroxyethyl)]amino group
  • heterocyclic groups and phenyl groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl or di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl groups and the substituents may be identical or different,
  • R 3 denotes the hydrogen atom or a C 1-3 -alkyl group
  • C 1-3 -alkyl group may be linked to an alkyl group present in R 2 or a phenyl or pyridyl ring present in R 2 and the nitrogen atom to which they are bound, forming a 5- to 7-membered ring, or
  • R 2 and R 3 together with the enclosed nitrogen atom denote a group of general formula
  • Y 1 denotes the carbon atom or, if R 5 denotes a pair of free electrons, it may also denote the nitrogen atom,
  • R 4 denotes the hydrogen atom, an amino, alkylamino or dialkylamino group
  • a phenyl, pyridinyl or diazinyl group which may be substituted in each case by a fluorine, chlorine or bromine atom or by a trifluoromethylcarbonyl, methyl or methoxy group,
  • any methylene group not directly bound to a nitrogen, oxygen or sulphur atom may be substituted by one or two fluorine atoms and
  • the above-mentioned mono- and bicyclic heterocycles may be substituted by a C 1-3 -alkyl group, by a benzyl, C 3-6 -cycloalkylalkyl, C 1-4 -alkanoyl, di-(C 1-3 -alkyl)-amino or C 1-3 -alkylsulphonyl, by an alkoxycarbonyl, alkoxycarbonylalkyl, carboxy or carboxyalkyl group,
  • R 5 denotes a hydrogen atom, a C 1-3 -alkyl group or,
  • Y 1 denotes a nitrogen atom, it may also denote a pair of free electrons
  • R 6 and R 7 which may be identical or different, in each case denote a hydrogen atom or a C 1-3 -alkyl group or di-(C 1-3 -alkyl)-amino group and
  • R 8 and R 9 which may be identical or different, in each case denote a hydrogen atom or a C 1-3 -alkyl group
  • alkyl groups as well as the alkyl groups present within the other groups comprise 1 to 7 carbon atoms and may be straight-chain or branched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by cyano or hydroxy groups and the substituents may be identical or different.
  • a sixth embodiment of the present invention comprises the compounds of the above general formula (I), wherein
  • A, X, Y, Z and R 1 are defined as hereinbefore in the first embodiment and
  • R 2 denotes a phenylmethyl group or a C 2-7 -alkyl group which may be substituted in the ⁇ position by a phenyl, amino, alkylamino or dialkylamino group,
  • phenyl group may be substituted by an amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl or di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl group, or
  • R 3 denotes the hydrogen atom or a C 1-3 -alkyl group
  • R 2 and R 3 together with the nitrogen atom to which they are bound denote a 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl group or
  • R 2 and R 3 together with the enclosed nitrogen atom denote a group of general formula
  • Y 1 denotes the carbon atom or, if R 5 denotes a pair of free electrons, it may also denote the nitrogen atom,
  • R 4 denotes the hydrogen atom
  • a phenyl or pyridinyl group which may be substituted in each case by a fluorine, chlorine or bromine atom, by a trifluoromethylcarbonyl, methyl or methoxy group,
  • R 5 denotes a hydrogen atom or, if Y 1 denotes a nitrogen atom, it may also denote a pair of free electrons,
  • R 6 and R 7 in each case denote a hydrogen atom or a dimethylamino group
  • R 8 and R 9 in each case denote the hydrogen atom
  • alkyl groups as well as the alkyl groups present within the other groups comprise 1 to 7 carbon atoms and may be straight-chain or branched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by cyano or hydroxy groups and the substituents may be identical or different,
  • A denotes an oxygen atom, a cyanoimino or phenylsulphonylimino group
  • X denotes an oxygen atom, an imino or methylene group
  • Y and Z independently of one another each denote a straight-chain or branched C 1-4 -alkyl group wherein each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms,
  • A denotes an oxygen atom or a cyanoimino group
  • X denotes an oxygen atom, an imino or methylene group
  • Y and Z independently of one another each denote a methyl or ethyl group
  • each methylene group may be substituted by up to 2 fluorine atoms and the methyl group may be substituted by up to 3 fluorine atoms,
  • a seventh embodiment of the present invention comprises the compounds of the above general formula (I) wherein
  • A denotes an oxygen atom, a cyanoimino or phenylsulphonylimino group
  • X denotes an oxygen or sulphur atom, an imino group optionally substituted by a C 1-6 -alkyl group or a methylene group optionally substituted by a C 1-6 -alkyl group,
  • Y and Z independently of one another each denote a straight-chain or branched C 1-6 -alkyl group wherein each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms,
  • R 1 denotes a monounsaturated 5- to 7-membered diaza or triaza heterocyclic group
  • [0137] contain a carbonyl group adjacent to a nitrogen atom
  • [0138] may additionally be substituted at a carbon atom by a phenyl group and an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused to a phenyl, thienyl or quinoline ring,
  • phenyl groups contained in R 1 as well as benzo-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, by methyl, methoxy, nitro, difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy groups, while the substituents may be identical or different, but are preferably unsubstituted or are monosubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group,
  • R 2 denotes the hydrogen atom
  • a phenylmethyl group or a C 2-7 -alkyl group which may be substituted in the ⁇ position by a phenyl, pyridinyl, hydroxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or [bis-(2-hydroxyethyl)]amino group,
  • heterocyclic groups and phenyl groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl or di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl groups and the substituents may be identical or different,
  • R 3 denotes the hydrogen atom or a C 1-3 -alkyl group
  • C 1-3 -alkyl group may be linked to an alkyl group present in R 2 or a phenyl or pyridyl ring present in R 2 and the nitrogen atom to which they are bound, forming a 5- to 7-membered ring, or
  • R 2 and R 3 together with the enclosed nitrogen atom denote a group of general formula
  • Y 1 denotes the carbon atom or, if R 5 denotes a pair of free electrons, it may also denote the nitrogen atom,
  • R 4 denotes the hydrogen atom, an amino, alkylamino or dialkylamino group
  • Y 1 does not denote the nitrogen atom, it denotes a dialkylaminomethyl group
  • a phenyl, pyridinyl or diazinyl group which may be substituted in each case by a fluorine, chlorine or bromine atom, by a trifluoromethylcarbonyl, methyl or methoxy group,
  • any methylene group not directly bound to a nitrogen, oxygen or sulphur atom may be substituted by one or two fluorine atoms,
  • the above-mentioned mono- and bicyclic heterocycles may be substituted by a C 1-3 -alkyl group, by a benzyl, C 3-6 -cycloalkylalkyl, C 1-4 -alkanoyl, di-(C 1-3 -alkyl)-amino or C 1-3 -alkylsulphonyl, by an alkoxycarbonyl, alkoxycarbonylalkyl, carboxy or carboxyalkyl group,
  • R 5 denotes a hydrogen atom, a C 1-3 -alkyl group or,
  • Y 1 denotes a nitrogen atom, it may also denote a pair of free electrons,
  • R 6 and R 7 which may be identical or different, in each case denote the hydrogen atom or a C 1-3 -alkyl or di-(C 1-3 -alkyl)-amino group and
  • R 8 and R 9 which may be identical or different, in each case denote the hydrogen atom or a C 1-3 -alkyl group
  • the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned groups contain 1 to 7 carbon atoms and may be branched or unbranched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by cyano or hydroxy groups and the substituents may be identical or different.
  • An eighth embodiment of the present invention comprises the compounds of the above general formula (I), wherein
  • A denotes an oxygen atom, a cyanoimino or phenylsulphonylimino group
  • X denotes an oxygen atom, an imino or methylene group
  • Y and Z independently of one another each denote a straight-chain or branched C 4 -alkyl group wherein each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms,
  • R 1 denotes a 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl, 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl, 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4
  • R 2 denotes a phenylmethyl group or a C 2-7 -alkyl group which may be substituted in the ⁇ position by a phenyl, amino, alkylamino or dialkylamino group,
  • phenyl group may be substituted by an amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl or di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl group, or
  • R 3 denotes the hydrogen atom or a C 1-3 -alkyl group
  • R 2 and R 3 together with the nitrogen atom to which they are bound denote a 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl group or
  • R 2 and R 3 together with the enclosed nitrogen atom denote a group of general formula
  • Y 1 represents the carbon atom or, if R 5 denotes a pair of free electrons, it may also denote the nitrogen atom,
  • R 4 denotes the hydrogen atom
  • a phenyl or pyridinyl group which may be substituted in each case by a fluorine, chlorine or bromine atom, by a trifluoromethylcarbonyl, methyl or methoxy group,
  • R 5 denotes a hydrogen atom or, if Y 1 denotes a nitrogen atom, it may also denote a pair of free electrons,
  • R 6 and R 7 in each case denote a hydrogen atom or a dimethylamino group
  • R 8 and R 9 in each case denote the hydrogen atom
  • alkyl groups as well as the alkyl groups present within the other groups comprise 1 to 7 carbon atoms and may be straight-chain or branched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by cyano or hydroxy groups and the substituents may be identical or different.
  • a ninth embodiment of the present invention comprises the compounds of the above general formula (I), wherein
  • A denotes an oxygen atomor a cyanoimino group
  • X denotes an oxygen atom, an imino or methylene group
  • Y and Z independently of one another in each case denote a methyl or ethyl group wherein each methylene group may be substituted by up to 2 fluorine atoms and the methyl group may be substituted by up to 3 fluorine atoms,
  • R 1 denotes a 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl, 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl, 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4
  • R 2 denotes a phenylmethyl group or a C 2-7 -alkyl group which may be substituted in the ⁇ position by a phenyl, amino, alkylamino or dialkylamino group,
  • phenyl group may be substituted by an amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl or di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl group, or
  • R 3 denotes the hydrogen atom or a C 1-3 -alkyl group
  • R 2 and R 3 together with the nitrogen atom to which they are bound denote a 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl group or
  • R 2 and R 3 together with the enclosed nitrogen atom denote a group of general formula
  • Y 1 denotes the carbon atom or, if R 5 denotes a pair of free electrons, it may also denote the nitrogen atom,
  • R 4 denotes the hydrogen atom
  • a phenyl or pyridinyl group which may be substituted in each case by a fluorine, chlorine or bromine atom, by a trifluoromethylcarbonyl, methyl or methoxy group,
  • R 5 denotes a hydrogen atom or, if Y 1 denotes a nitrogen atom, it may also denote a pair of free electrons,
  • R 6 and R 7 in each case denote a hydrogen atom or a dimethylamino group
  • R 8 and R 9 in each case denote the hydrogen atom
  • alkyl groups as well as the alkyl groups present within the other groups comprise 1 to 7 carbon atoms and may be straight-chain or branched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by cyano or hydroxy groups and the substituents may be identical or different.
  • A is as hereinbefore defined and G denotes a nucleofugic group, preferably the phenoxy, 1H-imidazol-1-yl, H-1,2,4-triazol-1-yl, trichloromethoxy or the 2,5-dioxo-pyrrolidin-1-yloxy group, with the proviso that X denotes the NH group, or
  • A denotes the oxygen atom and G denotes a nucleofugic group which may be identical or different, preferably the chlorine atom or the p-nitrophenoxy or trichloro-ethoxy group, with the proviso that X denotes the oxygen atom,
  • X denotes an oxygen atom or an —NH group
  • Y, Z, R 2 and R 3 are as hereinbefore defined, with the proviso that R 2 and R 3 do not contain any free carboxylic acid, any other free primary or secondary aliphatic amino function or any other free hydroxy function.
  • the fundamentally two-step reactions are normally carried out as one-pot processes, in which, preferably, in the first step, one of the two components (III) or (V) is reacted with equimolar amounts of the carbonic acid derivative of general formula (IV) in a suitable solvent at lower temperature, then at least equimolar amounts of the other component (III) or (V) are added and the reaction is completed at a higher temperature.
  • the reactions with bis-(trichloromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-carbonate) of a tertiary base, for example triethylamine, N-ethyldiisopropylamine, pyridine, 1,5-diaza-bicyclo-[4,3,0]-non-5-ene, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo-[5,4,0]-undec-7-ene.
  • a tertiary base for example triethylamine, N-ethyldiisopropylamine, pyridine, 1,5-diaza-bicyclo-[4,3,0]-non-5-ene, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo-[5,4,0]-undec-7-ene
  • the solvents used which should be anhydrous, may be for example tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile, while if bis-(trichloromethyl)-carbonate is used as the carbonyl component anhydrous chlorohydrocarbons, for example dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred.
  • the reaction temperatures for the first reaction step are between ⁇ 30° C. and +25° C., preferably ⁇ 5° C. and +10° C., for the second reaction step between +15° C.
  • R 1 has the meanings given hereinbefore.
  • the coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropyl carbodiimide
  • HBTU hexafluorophosphate
  • TBTU tetrafluoroborate
  • BOP 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
  • the reaction speed can be increased.
  • the couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30 and +30° C., preferably ⁇ 20 and +25° C.
  • solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30 and +30° C., preferably ⁇ 20 and +25° C.
  • DIEA N-ethyl-diisopropylamine
  • ünig base is preferably used as an additional auxiliary base.
  • anhydride process is used as a further coupling method for synthesising compounds of general formula (I) (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27).
  • the Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc.
  • Y, Z, R 2 and R 3 are as hereinbefore defined, with the proviso that R 2 and R 3 do not contain any free primary or secondary amine
  • Nu denotes a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 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, while the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by one or two methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,
  • 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 ⁇ 10° C. and +30° C., and optionally in the presence of solvents.
  • the auxiliary bases 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 caesium carbonate, alkali metal acetates, e.g.
  • the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • the coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropyl carbodiimide
  • HBTU hexafluorophosphate
  • TBTU tetrafluoroborate
  • BOP 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
  • the reaction speed can be increased.
  • the couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30 and +30° C., preferably ⁇ 20 and +25° C.
  • solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30 and +30° C., preferably ⁇ 20 and +25° C.
  • DIEA N-ethyl-diisopropylamine
  • ünig base is preferably used as an additional auxiliary base.
  • anhydride process is used as a further coupling method for synthesising compounds of general formula (I) (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27).
  • the Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc.
  • Nu denotes a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, while the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by one or two 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,
  • 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 ⁇ 10° C. and +30° C., and optionally in the presence of solvents.
  • the auxiliary bases 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 caesium carbonate, alkali metal acetates, e.g.
  • the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • the new compounds of general formula (I) according to the invention contain one or more chiral centres. If for example there are two chiral centres the compounds may occur in the form of two pairs of diastereomeric antipodes.
  • the invention covers the individual isomers as well as the mixtures thereof.
  • the diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral 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 via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or ( ⁇ )-tartaric acid, (+) or ( ⁇ )-diacetyl tartaric acid, (+) or ( ⁇ )-monomethyl tartrate or camphorsulphonic acid, or an optically active base, for example with (R)-(+)-1-phenylethylamine, (S)-( ⁇ )-1-phenylethylamine or (S)-brucine.
  • an optically active acid for example (+) or ( ⁇ )-tartaric acid, (+) or ( ⁇ )-diacetyl tartaric acid, (+) or ( ⁇ )-monomethyl tartrate or camphorsulphonic acid, or an optically active base, for example with (R
  • 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 resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities.
  • This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts.
  • methanol, ethanol or mixtures thereof for example in a ratio by volume of 50:50, are used.
  • each of the optically active salts is dissolved in water, carefully neutralised with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. dilute hydrochloric acid or aqueous methanesulphonic acid, and in this way the corresponding free compound is obtained in the (+) or ( ⁇ ) form.
  • a base such as sodium carbonate or potassium carbonate
  • a suitable acid e.g. dilute hydrochloric acid or aqueous methanesulphonic acid
  • the starting compounds of general formula (III) may be obtained, if they are not known from the literature or even commercially available, according to the processes described in WO 98/11128 and DE 199 52 146.
  • the starting compounds of general formula (IV) are commercially available.
  • Compounds of general formula (V) may be obtained by methods familiar to the peptide chemist from protected phenylalanines and amines of general formula HNR 2 R 3 .
  • Y and Z are as hereinbefore defined and R denotes an unbranched alkyl group, preferably the methyl or ethyl group, by racemate cleavage.
  • This racemate cleavage can be carried out using enzymatic methods, while only one enantiomer of the racemate is transformed and the mixture produced is then separated using physicochemical methods, preferably using chromatographic methods.
  • a suitable enzyme system for this step consists of the enzyme Alcalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd).
  • the compounds of general formula (X) can then be converted into the enantiomerically pure compounds of general formula (V) by methods familiar to the peptide chemist.
  • [0440] may be prepared from compounds of general formula (X), with the proviso that R denotes the hydrogen atom.
  • the compounds of general formula (XI) may be obtained by diazotisation of compounds of general formula (X) with a suitable diazotising reagent, preferably sodium nitrite in an acidic medium. If enantiomerically pure compounds are used, the corresponding enantiomerically pure hydroxycarboxylic acid compounds are obtained, and the configuration is retained during the reaction.
  • a suitable diazotising reagent preferably sodium nitrite in an acidic medium.
  • Another method of obtaining compounds of general formula (XI) comprises alkylating the compound
  • X denotes a chlorine, bromine or iodine atom, analogously to methods known from the literature (Michael T. Crimmins, Kyle A. Emmitte and Jason D. Katz, Org. Lett. 2, 2165-2167 [2000]).
  • the diastereomeric products obtained can then be separated by physicochemical methods, preferably using chromatographic methods.
  • the hydrolytic cleaving of the chiral auxiliary, coupling with amines of general formula HNR 2 R 3 and cleaving the benzyl protecting group also provides access to enantiomerically pure hydroxycarboxylic acid compounds of general formula (V).
  • the starting compounds of general formula (VI) are obtained for example by reacting amines of general formula HNR 2 R 3 with 2-(alkoxycarbonylmethyl)-3-aryl-propanoic acids and subsequently hydrolytically cleaving the alkyl group.
  • the 2-(alkoxycarbonylmethyl)-3-aryl-propanoic acids required may be prepared analogously to methods known from the literature (David A. Evans, Leester D. Wu, John J. M. Wiener, Jeffrey S. Johnson, David H. B. Ripin and Jason S. Tedrow, J. Org. Chem 64, 6411-6417 [1999]; Saul G. Cohen and Aleksander Milovanovic, J. Am. Chem. Soc.
  • Carboxylic acids of general formula (VIII) may be prepared from generally available starting materials in accordance with the processes described in WO 98/11128.
  • the compounds of general formula I obtained may, if they contain suitable basic functions, be converted, particularly for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids.
  • Suitable acids include for example hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic 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), if they contain a carboxylic acid function, may if desired be converted into the addition salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable addition salts thereof.
  • bases for this include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the present invention relates to racemates if the compounds of general formula (I) have only one chiral element.
  • the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof which are obtained if there is more than one chiral element in the compounds of general formula (I), as well as the individual optically active enantiomers of which the above-mentioned racemates are made up.
  • the new compounds of general formula (I) and the physiologically acceptable salts thereof have valuable pharmacological properties, based on their selective CGRP-antagonistic properties.
  • the invention further relates to pharmaceutical compositions containing these compounds, their use and the preparation thereof.
  • 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 display CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
  • SK-N-MC cells are cultivated in “Dulbecco's modified Eagle medium”. The medium is removed from confluent cultures. 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.
  • PBS buffer Gibco 041-04190 M
  • BSS “Balanced Salts Solution”
  • 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, pH 7.40 the cells are centrifuged twice at 100 ⁇ g and resuspended in BSS. After the number of cells 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 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, and resuspended (1 ml/1000000 cells).
  • 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, and resuspended (1 ml/1000000 cells).
  • the homogenised product is frozen at ⁇ 80° C.
  • the membrane preparations are stable for more than 6 weeks under these conditions.
  • the homogenised product 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 homogenised product are incubated for 180 minutes at ambient temperature with 50 pM 125 I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 ⁇ l. The incubation is ended by rapid filtration through GF/B-glass fibre filters treated with polyethyleneimine (0.1%) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity in the presence of 1 ⁇ M human CGRP-alpha during incubation.
  • assay buffer 50 mM Tris, 150 mM NaCl, 5 mM
  • concentration binding curves are analysed using computer-aided non-linear curve matching.
  • SK-N-MC cells (1 million cells) are washed twice with 250 ⁇ l 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 the substance in 3 to 4 different concentrations, the mixture is incubated for another 15 minutes.
  • 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.
  • cAMP contents of the samples are determined by radioimmunoassay (Messrs. Amersham) and the pA 2 values of antagonistically acting substances are determined graphically.
  • the compounds of general formula I exhibit CGRP-antagonistic properties in the in vitro test model described, in a dosage range between 10 ⁇ 12 and 10 ⁇ 5 M.
  • the compounds of general formula I and the salts thereof with physiologically acceptable acids are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches.
  • the compounds of general formula I also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus (“NIDDM”), cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g.
  • NIDDM non-insulin-dependent diabetes mellitus
  • cardiovascular diseases e.g., morphine tolerance, diarrhoea caused by clostridium toxin
  • skin diseases particularly thermal and radiation-induced skin damage including sunburn
  • inflammatory diseases e.g.
  • the compounds according to the invention have a general pain-relieving effect.
  • the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women and hormone-treated patients with prostate carcinoma are favourably affected by the CGRP-antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects.
  • the dosage required to achieve a corresponding effect is conveniently 0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, when administered intravenously or subcutaneously 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, 1 to 3 ⁇ a day in each case.
  • the treatment with CGRP antagonists and/or CGRP release inhibitors is given as a supplement to conventional hormone substitution, it is advisable to reduce the doses specified above, in which case the dosage may be from 1/5 of the lower limits mentioned above up to 1/1 of the upper limits specified.
  • the compounds prepared according to the invention may be administered either on their own or optionally in combination with other active substances for the treatment of migraine by intravenous, subcutaneous, intramuscular, intrarectal, intranasal route, by inhalation, transdermally or orally, while aerosol formulations are particularly suitable for inhalation.
  • the combinations may be administered either simultaneously or sequentially.
  • Categories of active substance which may be used in the combination include e.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokinine antagonists, anti-convulsants, histamine-H1 receptor antagonists, antimuscarinics, ⁇ -blockers, ⁇ -agonists and ⁇ -antagonists, ergot alkaloids, mild analgesics, non-steroidal antiinflammatories, corticosteroids, calcium antagonists, 5-HT 1B/1D agonists or other anti-migraine agents, which may be formulated together with one or more inert conventional carriers and/or diluents, e.g.
  • active substances which may be used for the combinations mentioned above include for example the non-steroidal antiinflammatories aceclofenac, acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide, lomoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam, sulphasalazine, zomepirac or the pharmaceutically acceptable salts thereof as well as meloxicam and other selective COX2-inhibitors, such as for example rofecoxib and celecoxib.
  • non-steroidal antiinflammatories aceclofenac, acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal
  • the dosage of these active substances is expediently 1/5 of the lowest recommended dose to 1/1 of the normally recommended dose, i.e. for example 20 to 100 mg of sumatriptan.
  • the invention further relates to the use of the compounds according to the invention as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as in RIA and ELISA assays, after suitable radioactive labelling, for example by tritiation of suitable precursors, for example by catalytic hydrogenation with tritium or replacing halogen atoms with tritium, and as a diagnostic or analytical adjuvant in neurotransmitter research.
  • the acid, base and saline solutions used for working up the reaction solutions are aqueous solutions having the concentrations specified.
  • silica gel made by Millipore MATREXTM, 35-70 ⁇ m
  • Alox E. Merck, Darmstadt, standardised aluminium oxide 90, 63-200 ⁇ m, Article no. 1.01097.9050
  • HPLC data are measured using the parameters specified below: Analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond)—C18; 3.5 ⁇ m; 4.6 ⁇ 75 mm; column temperature: 30° C.; flow: 0.8 mL/min; injection volume: 5 ⁇ L; detection at 254 nm Method A: percent by volume of water percent by volume of acetonitrile time (min) (with 0.1% formic acid) (with 0.1% formic acid) 0 90 10 9 10 90 10 10 90 11 90 10
  • the reaction mixture was diluted by the addition of 30 mL EtOAc, extracted with 30 mL of a 15% K 2 CO 3 solution and the organic phase was dried.
  • the organic phase was evaporated down under reduced pressure and the residue purified by chromatography on silica gel.
  • the intermediate product fractions were evaporated down under reduced pressure, the residue remaining (260 mg) was dissolved in 20 mL MeOH and hydrogenated in the autoclave in the presence of 50 mg Pd/C (10%) at 50° C. and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up.
  • the catalyst was filtered off, the solvent eliminated under reduced pressure and the residue purified by chromatography on silica gel.
  • the pH value of the reaction mixture was kept in the range from pH 7.4 to pH 7.6 by the addition of 1 M NaOH. After the addition had ended the mixture was stirred for 3 h at 37° C. and overnight at RT. The reaction mixture was extracted three times with tert-butylmethylether, the combined organic extracts were washed with 15% K 2 CO 3 solution, dried and evaporated down under reduced pressure.

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