WO2005037803A1 - Organic compounds - Google Patents

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Publication number
WO2005037803A1
WO2005037803A1 PCT/EP2004/052466 EP2004052466W WO2005037803A1 WO 2005037803 A1 WO2005037803 A1 WO 2005037803A1 EP 2004052466 W EP2004052466 W EP 2004052466W WO 2005037803 A1 WO2005037803 A1 WO 2005037803A1
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alkyl
alkoxy
alk
hydrogen
absent
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PCT/EP2004/052466
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French (fr)
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Peter Herold
Robert Mah
Stefan Stutz
Aleksandar Stojanovic
Vincenzo Tschinke
Christiane Marti
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Speedel Experimenta Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel piperazine derivatives, to processes for their preparation and to the use of the compounds as medicaments, especially as renin inhibitors.
  • the invention therefore provides piperazine derivatives of the general formulae (I) and (II)
  • R1 is aryl or heterocyclyl
  • R 2 is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridinyl, diazinyl, triazolyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl, furyl, tetrazolyl or imidazolyl, which radicals may be substituted by 1-3 halogen, hydroxyl, cyano, trifluoromethyl, C ⁇ . 6 -alkyl, halo-Ct- 6 -alkyl, hydroxy-C ⁇ . 6 -alkyl, C ⁇ -6 -alkoxy-C ⁇ -6 -alkyl, cyano-
  • L1, L2, L3, L4 and L5 are each independently a bond, C ⁇ -8 -alkylene, C 2 -8-alkenylene or
  • T1, T2, T3 and T4 are each independently
  • R 3 is hydrogen, C ⁇ -6 -alkyl, C 2 . 6 -alkenyl, C ⁇ -6 -alkoxy, hydroxy-Ci -6 -alkyl, C ⁇ .6-alkoxy-C ⁇ -6 - alkyl, benzyl or an R 4 -Z1-X1- group where R 4 is (a) H-
  • X1 is a bond, is absent, or is -(CH 2 ) ⁇ . 3 -; or, in formula (I), R 3 is also oxo;
  • R 5 and R 6 are each independently hydrogen, C ⁇ -alkyl, C 2-6 -alkenyl, aryl-C 1-6 -al yl or acyl, or, together with the nitrogen atom to which they are bonded, are a 5- or 6-membered heterocyclic ring which may contain an additional nitrogen, oxygen or sulphur atom or a -
  • R 7 and R 8 together with the carbon atom to which they are bonded, are a 3-7-membered ring which may contain one or two oxygen or sulphur atoms or -SO- or -SO 2 - groups;
  • R 9 is hydrogen, C 1-6 -alkyl, C 3 - a -cycloalkyl, C ⁇ -alkoxy-d-e-alkyl, acyl or arylalkyl;
  • R 10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen
  • R 11 is hydrogen or C ⁇ -6 -alkyl
  • R 12 is hydrogen or C ⁇ -6-alkyl
  • U is hydrogen, C ⁇ -6 -alkyl, cycloalkyl, cyano, optionally substituted cycloalkyl, aryl, or heterocyclyl;
  • Q is ethylene or is absent (formula I) or is ethylene or methylene (formula II);
  • Z is absent or is C ⁇ - 6 -alkylene, C 2 .6-alkenylene, hydroxy-C ⁇ - 6 -alkyl'dene, -CH-R 1 -CO-NR 9 -,
  • alkyl and alkoxy radicals are C ⁇ _ e -alkyl and C ⁇ _ 6 -alkoxy radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy respectively.
  • C ⁇ -6 -Alkylenedioxy radicals are preferably methylenedioxy, ethylenedioxy and propylenedioxy.
  • C 1-6 -alkanoyl radicals are acetyl, propionyl and butyryl.
  • Cycloalkyl is a saturated, cyclic hydrocarbon radical having 3-8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C ⁇ -8 -Alkylene radicals are, for example, methylene, ethylene, propylene, 2-methyl propylene, tetra-, penta- and hexamethylene; C 2 .
  • 8 -alkenylene radicals are, for example, vinylene and propenylene; C 2-8 -alkynylene radicals are, for example, ethynylene; acyl radicals are alkanoyl radicals, preferably C ⁇ -6 -alkanoyl radicals, or aroyl radicals such as benzoyl.
  • Aryl denotes mono- or polycyclic aromatic radicals which may be mono- or polysubstituted, for example phenyl, substituted phenyl, naphthyl, substituted naphthyl, tetrahydronaphthyl or substituted tetrahydronaphthyl.
  • substituents on such aryl radicals are C ⁇ -6 -alkyl, trifluoromethyl, nitro, amino, C 2-6 -alkenyl, d- ⁇ -alkoxy, C ⁇ _ 6 -alkylcarbonyloxy, hydroxyl, halogen, cyano, carbamoyl, carboxyl and C ⁇ -6 -alkylenedioxy, and also phenyl, phenoxy, phenylthio, phenyl-C 1-e -alkyl or phenyl-C ⁇ - 6 -alkoxy each optionally substituted by halogen, C ⁇ -6 -alkyl, C ⁇ -6 -alkoxy or dihydroxy-C 1-6 -alkylarninocarbonyl.
  • substituents on aryl or heterocyclyl radicals are C ⁇ - 6 -alkoxycarbonylphenyl, hydroxy-C ⁇ e-alkylphenyl, benzyloxy, pyridylcarbonylamino-C ⁇ -6 -alkyl, C 2 - 6 -alkenyloxy, C ⁇ . 6 -alkoxy-C ⁇ - 6 - alkoxy-Ci- 6 -alkyl, methoxybenzyloxy, hydroxybenzyloxy, phenethyloxy, ethylenedioxybenzyloxy, dioxolanyl-C ⁇ .
  • C 1-6 -alkyl carbamoyl-C ⁇ -6 -alkoxy, C 1-6 -alkylcarbamoyl, di-d- 6 -alkylcarbamoyl, d -6 - alkylsulphonyl, d- 6 -alkylamidinyl, acetamidinyI-C ⁇ . 6 -alkyl, O-methyloximyl-C ⁇ -6 -alkyl, O,N- dimethylhydroxylamino-d_ 6 -alkyl; and also pyridyl, pyridyloxy, pyridylthio, pyridylamino, pyridyl-C ⁇ .
  • heterocyclyl denotes mono- or bicyclic, saturated and unsaturated heterocyclic radicals having from 1 to 4 nitrogen and/or 1 or 2 sulphur or oxygen atoms and which may be mono- or polysubstituted, especially by (in the case of unsaturated heterocyclyl radicals) alkyl, hydroxyl, alkoxy, nitrogen or halogen, or may be substituted by substituents as defined above for aryl radicals, or (in the case of saturated heterocyclyl radicals) may be substituted by alkyl or alkoxy.
  • heterocyclyl radicals are pyridyl, thienyl, pyrazinyl, triazolyl, imidazolyl, benzothiazolyl, furyl, pyrimidinyl, morpholinyl, quinazolinyl, quinolyl, quinoxalinyl, isoquinolyl, benzo[b]thienyl, isobenzofuranyl, benzoimidazolyl, 2-oxobenzoimidazolyl, oxazolyl, thiazolyl, indolyl, pyrrolyl, 2-oxodihydrobenzo[d][1,3]oxazinyl, 4- oxodihydroimidazolyl, 5-oxo-4H-[1 ,2,4]triazinyl, 3-oxo-4H-benzo[1 ,4]thiazinyl, tetrahydroquinoxalinyl, 1 ,1,3-trioxox
  • substituted heterocyclyl radicals are nitrobenzothiazolyl, phenyltetrazolyl, phenyloxadiazolyl, phenylpiperidinyl, phenylpiperazinyl, phenylpyrrolidinyl, thienyloxadiazolyl, furanyloxadiazolyl, benzyloxadiazolyl or phenyloxazolyl.
  • saturated heterocyclyl radicals are dioxolanyl, dioxanyl, dithiolanyl, dithianyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, 2- hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 4- hydroxypiperidinyl, 4-oxopiperidinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4- oxothiomorpholinyl, 2,6-dimethylmorpholinyl, tetrahydropyranyl, 2-oxoimidazolidinyl, 2- oxooxazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxo-[1,3]oxazinyl, 2-oxoazepan
  • the aryl, aroyl and heterocyclyl radicals may additionally be substituted by heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkoxyalkyl or heterocyclyl, for example piperidinoalkyl, piperidinoalkoxy, piperidinoalkoxyalkyl, morpholinoalkyl, morpholinoalkoxy, morpholinoalkoxyalkyl, piperazinoalkyl, piperazinoalkoxy, piperazinoalkoxy, piperazinoalkoxyalkyl, [1,2,4]triazol-1-ylalkyl, [1,2,4]triazol-1-ylalkoxy, [1 ,2,4]triazol-4- ylalkyl, [1 ,2,4]triazol-4-ylalkoxy, [1,2,4]oxadiazol-5-ylalkyl, [l ⁇ oxadiazol- ⁇ -ylalkoxy, 3-
  • Examples of 5- and 6-membered heterocyclic rings represented by NR 5 R 6 are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3- hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 4-hydroxypiperidinyl, 4-oxopiperidinyl, 3,5- dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4-oxothiomorpholinyl, 2,6- dimethylmorpholinyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxo- [1 ,3]oxazinyl, 2-oxotetrahydropyrimidinyl and the like.
  • Examples of 3-7-membered rings represented by CR 7 R 8 are cyclopentyl, cyclohexyl, cycloheptyl, 1,3-dioxolanyl, 1,3- dioxanyl, 1,3-dithiolanyl and 1,3-dithianyl.
  • polyhydroxyalkyl denotes Ci-d-alkyl radicals which may be substituted by 2-6 hydroxyl groups, for example glyceryl, arabityl, sorbityl, etc.
  • the compounds of the formula (I) or formula (II) have at least one asymmetric carbon atom and may therefore be in the form of optically pure enantiomers, enantiomer mixtures or as racemates.
  • Compounds having a second asymmetric carbon atom may be in the form of optically pure diastereomers, diastereomer mixtures, diastereomeric racemates, mixtures of diastereomeric racemates or as meso compounds.
  • the invention encompasses all of these forms.
  • Enantiomer mixtures, racemates, diastereomer mixtures, diastereomeric racemates or mixtures of diastereomeric racemates may be separated by customary methods, for example by optical resolution, column chromatography, thin-layer chromatography, HPLC and the like.
  • salts encompasses salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like.
  • the compounds of the formulae (I) and (II) also include those compounds in which one or more atoms are replaced by their stable, non-radioactive isotopes; for example a hydrogen atom by deuterium.
  • Preferred inventive compounds are those of the general formulae (IA) or (IIA)
  • a further, preferred group of compounds of the formula (I) or (II), or more preferably of the formula (IA) or (IIA), are compounds where R 1 is aryl or heterocyclyl; R 2 is phenyl, cyclohexyl, tetrazolyl, or phenyl, cyclohexyl or tetrazolyl each substituted by halogen, hydroxyl, cyano, trifluoromethyl, d-6-alkyl, halo-C ⁇ -6-alkyl, hydroxy-C ⁇ -6 -alkyl, C 1-6 - alkoxy-C 1-6 -alkyl, cyano-d_ 6 -alkyl, carboxy-C ⁇ -6-alkyl, C ⁇ - 6 -alkanoyloxy-C ⁇ -6 -alkyl, C ⁇ . 6 - alkoxycarbonyloxy-C ⁇ - 6 -alkyl, d -6 -alkoxycarbonyl, d
  • L1, L2, L3, L4 and L5 are each independently a bond, C ⁇ - 8 -alkylene, C 2 - 8 -alkenylene or
  • T1, T2, T3 and T4 are each independently
  • R 3 is hydrogen, C ⁇ _e-alkyl, C 2- 6-alkenyl, d-e-alkoxy, hydroxy-C ⁇ -6-alkyl, C ⁇ -6 -alkoxy-C ⁇ -6 -alkyl or benzyl; or, in formula (I) or (IA), R 3 is also oxo;
  • R 5 and R 6 are each independently hydrogen, d -6 -alkyl or acyl, or, together with the nitrogen atom to which they are bonded, are a 5- or 6-membered heterocyclic ring which may contain an additional nitrogen, oxygen or sulphur atom;
  • R 7 and R 8 together with the carbon atom to which they are bonded, are a 3-7-membered ring which may contain one or two oxygen or sulphur atoms;
  • R 9 is hydrogen, Ci-e-alkyl, C 3 - 8 -cycloalkyl, acyl orarylalkyl;
  • R 11 is hydrogen or Ci-e-alkyl
  • R 12 is hydrogen or C ⁇ -6 -alkyl
  • U is hydrogen, C ⁇ -6 -alkyl, cycloalkyl, cyano, aryl or heterocyclyl;
  • Q is ethylene or is absent (formulae (I) and (IA)) or is ethylene or methylene (formulae (II) and (IIA));
  • X is a >CHOR 9 , >CO or >CH-R 11 group
  • Z is d-e-alkylene, -CH-R 11 -CO-NR 9 , -O-, -NR 9 -, -alk-O-, -alk-S-, -alk-NR 9 - or is absent; and where, if Z is -O-, X is >CHR 11 and either R 2 contains an L1-T1-L2-T2-L3-T3-L4-T4-L5-U substituent or R 3 is a substituent other than hydrogen as defined above;
  • X is preferably -CH 2 - or -CO-.
  • Z is preferably -O-, -alk-O-, -N-fCg-g-cycloalky -d. 6 -alkylene- or is absent.
  • R 1 radicals are phenyl and phenyl substituted by C ⁇ -6-alkyl, C ⁇ -6-alkoxy, halogen, hydroxyl, hydroxy-d -6 -alkoxy, d-6-alkylsulphinyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, carboxyl, C ⁇ -6 -alkoxycarbonyl, C ⁇ -6-alkoxy-d- ⁇ - alkoxy-d.e-alkyl, Co- ⁇ -alkylcarbonylamino, Co-6-alkylcarbonylamino-d_ 6 -alkyl, C-o- ⁇ - alkylcarbonylamino-C 1-6 -alkoxy, (N-C 1-6 -alkyl)-Co- 6 -alkylcarbonylamino-d- 6 -alkyl, (N-C ⁇ _ 6 - alkyl)-Co- 6 -alkylcarbonylamino-C
  • R 1 radicals are naphthyl, and naphthyl substituted by hydroxyl, oxo, halogen, carbamoyl, carboxyl, C ⁇ -6-alkoxy, hydroxy-Ci-e-alkoxy, Ci -6 -alkoxy-Ci -6 -alkoxy, di- C 1-6 -alkylamino, 2,3-dihydroxypropoxy, 2,3-dihydroxypropoxy-C ⁇ .e-alkoxy, 2,3- dimethoxypropoxy, methoxybenzyloxy, hydroxybenzyloxy, phenethyloxy, methylenedioxybenzyloxy, dioxolanyl-d ⁇ -alkoxy, C3-8-cycloalkyl-C ⁇ -6-alkoxy, hydroxy-C ⁇ -6 - alkoxy, pyridylcarbamoyloxy-Ci- 6 -alkoxy, 3-morpholino-2-hydroxypropoxy, benzyloxy-C
  • R 1 radicals encompasses the abovementioned substituted phenyl and naphthyl radicals, and also tetrahydronaphthyl and methyl-substituted tetrahydronaphthyl.
  • R radicals which are likewise preferred are pyridyl, benzoimidazolyl, di-C 1-6 - alkoxypyrimidinyl, 2- and 5-benzo[b]thienyl, 6- and 7-quinolyl, 6- and 7-isoquinolyl, 6- and 7-tetrahydroquinolyl, 6- and 7-tetrahydroisoquinolyl, 6-quinoxalinyl, 6- and 7-quinazolinyl, indolyl, dihydro-2H-benzo[1,4]oxazinyl, 3-oxo-4H-benzo[1,4]oxazinyl, 2-oxobenzooxazolyl, 2-oxo-1 ,3-dihydroindolyl, 2,3-dihydroindolyl, indazolyl and benzofuranyl, and also 6- and 7- quinolyl, 6- and 7-isoquinolyl, 6- and 7-tetrahydroquinolyl,
  • 6 -alkyl di-d- 6 -alkylamino-C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkylsulphonyl-d. 6 -alkyl, C 1 -6- alkylsulphonyl-Ci-e-alkoxy, carboxy-C ⁇ . 6 -alkyl, carboxy-d_ 6 -alkoxy, carboxy-C ⁇ -6 -alkoxy-C ⁇ .
  • R 2 radicals are phenyl and phenyl substituted by halogen, hydroxyl, cyano, trifluoromethyl, d -6 -alkyl, halo-C ⁇ - 6 -alkyl, hydraxy-d_ 6 -alkyl, C 1-6 -alkoxy-d-e-alkyl, cyano- d- ⁇ -alkyl, carboxy-C ⁇ -6 -alkyl, d -6 -alkanoyloxy-d-6-alkyl, C 1-6 -alkoxycarbonyloxy-C ⁇ _ 6 - alkyl, d -6 -alkoxycarbonyl, C ⁇ -6 -alkoxy or d -6 -alkylenedioxy.
  • R 2 radicals which are likewise preferred are phenyl substituted by an L1-T1-L2-T2-L3-T3- L4-T4-L5-U radical where L1 and L2 are preferably absent or d -8 -alkylene and L3 is absent and U is hydrogen, d_ 6 -alkyl, C 3 .
  • R 2 radicals are phenyl or phenyl substituted by 2-benzothiazolylthio-C 1-6 -alkyl, 2 ⁇ benzyloxy-3-methoxypropoxy, 2-benzoyloxy-3- ethoxypropoxy, 2,3-dihydroxypropoxy, 2-hydroxy-3-benzylamino-propoxy, 2-hydroxy-3- phenoxypropoxy, 2-hydroxy-3-phenylthiopropoxy, 2-methoxy-3-phenoxypropoxy, 2- methoxy-3-benzyloxypropoxy, 2-methyl-3-fluorophenylbutyryloxy-C ⁇ _ 6 -alkoxy, 2-methyl-3- phenoxypropoxy, 2-C 2 -6-alkenyloxy-4-phenylbutyl, 3,4,5-trimethoxyphenyloxadiazolyl-C ⁇ - 6
  • C ⁇ _ 6 -alkoxy carbamoyloxy-C - 6 -alkyl, carboxy-Ci- ⁇ -alkoxy, carboxy-d -6 -alkyl, cyano, cyano- d- 6 -alkoxy, cyano-C ⁇ - 6 -alkyl, cyanophenyl-C ⁇ - 6 -alkoxy, cyclohexylcarbonyloxy-C -6 -alkyl, cyclohexyloxy-Ci- 6 -alkoxy, cyclopropylcarbonyloxy-C ⁇ -6 -alkyl, dioxolanyl-C ⁇ .6-alkoxy, furyloxadiazolyl-C - 6 -alkoxy, furoyloxy-C .
  • 6 -alkyl phenylaminocarbonyloxy-C ⁇ _ 6 -alkoxy, phenylaminocarbonyloxy-C ⁇ . 6 -alkyl, phenylhydroxy- C -e-alkyl, phenyloxadiazolyl-d -6 -alkoxy, phenyloxadiazolyl-C ⁇ -6 -alkyl, phenyloxazolyl-d -6 - alkoxy, phenyloxy-C ⁇ . 6 -alkoxy, phenylsulphamoyl-C ⁇ - 6 -alkyl, phenylsulphinyl-C ⁇ .
  • 6 -alkyl phenylsulphonyl-d- 6 -alkoxy, phenylsulphonyl-C ⁇ -6 -alkyl, phenyltetrazolylthio-C ⁇ . 6 -alkyl, phenylthio-d- ⁇ -alkoxy, phenylthio-d -6 -alkyl, pyrazinylcarbonyloxy-C . 6 -alkyl, pyridylaminocarbonyloxy-C ⁇ .
  • R 1 radicals are phenyl, 3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl and 4H-benzo[1,4]oxazin-3-on-6-yl which may be substituted by 1-3 halogen or C ⁇ -6 -alkoxy-C ⁇ - 6 -alkyl.
  • R 2 radicals are phenyl substituted by C 1-6 -alkoxy, C ⁇ _ B - alkoxybenzyloxy-d-e-alkoxy, halophenoxy-C 1-6 -alkoxy or halophenylpyrrolidin-3-yIoxy.
  • Examples of preferred X radicals are methylene and >CO.
  • Z radicals are -O- and -N ⁇ Cs- B -cycloalkylJ-d-e-alkylene-.
  • the compounds of the formula (I) or (II) may be prepared in a similar manner to the preparation processes disclosed in the literature. Details on the specific preparation variants can be taken from the examples.
  • the compounds of the formula (I) or (II) may also be prepared in optically pure form.
  • the separation into antipodes can be effected by methods known per se, either preferably at an earlier synthetic stage by salt formation with an optically active acid, for example (+)- or (-)-mandelic acid, and separation of the diastereomeric salts by fractional crystallization, or preferably at a relatively late stage by derivatizing with a chiral auxiliary building block, for example (+)- or (-)-camphanoyl chloride, and separation of the diastereomeric products by chromatography and/or crystallization and subsequent cleavage of the bond to give the chiral auxiliary.
  • the pure diastereomeric salts and derivatives may be analysed to determine the absolute configuration of the piperidine present with common spectroscopic methods, and X-ray spectroscopy on single crystals constitutes a particularly suitable method.
  • a preferred method for the preparation of optically pure compounds of the formula (IA) or (IIA) consists in the construction of the basic piperazine structure by reacting an oxazolidine with an amine to give a piperazinedione according to the following exemplary scheme:
  • Another preferred method for the preparation of optically pure compounds of the formula (IA) or (IIA) consists in the construction of the basic piperazi ⁇ one structure by reacting a substituted epoxide derivative with a 2-amino-acetamide derivative, followed by alcohol activation and subsequent ring closure to give a piperazinone according to the following exemplary scheme:
  • Prodrug derivatives of the compounds described in the present context are derivatives thereof which, on in vivo application, release the original compound by a chemical or physiological process.
  • a prodrug may be converted to the original compound, for example, when a physiological pH is attained or by enzymatic conversion.
  • Prodrug derivatives may, for example, be esters of freely available carboxylic acids, S- and O-acyl derivatives of thiols, alcohols or phenols, and the acyl group is as defined in the present context.
  • ester derivatives which are converted by solvolysis in physiological medium to the corresponding carboxylic acid
  • a certain compound in this invention also encompasses its prodrug derivative and salt form, where these are possible and appropriate.
  • the compounds of the formula (I) or (II), or preferably of the formula (IA) or (IIA), and their pharmaceutically useable salts have inhibiting action on the natural enzyme renin.
  • the latter passes from the kidneys into the blood and there brings about the cleavage of angiotensinogen to form the decapeptide angiotensin I which is then cleaved in the lung, the kidneys and other organs to the octapeptide angiotensin II.
  • Angiotensin II increases the blood pressure both directly by arterial constriction and indirectly by the release of the hormone aldosterone which inhibits the release of the sodium ion from the adrenal glands, which is associated with a rise in the extracellular liquid volume.
  • This rise can be attributed to the action of angiotensin II itself or of the heptapeptide angiotensin III formed therefrom as a cleavage product.
  • Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I and, as a consequence thereof, the formation of a smaller amount of angiotensin ll.
  • the reduced concentration of this active peptide hormone is the immediate cause of the hypotensive action of renin inhibitors.
  • One experimental method of detecting the action of renin inhibitors is by means of in vitro tests, in which the reduction of the formation of angiotensin I in different systems (human plasma, purified human renin together with synthetic or natural renin substrate) is measured.
  • One in vitro test which is used is the one according to Nussberger et. al (1987) J. Cardiovascular Pharmacol., Vol. 9, p. 39-44 which follows. This test measures the formation of angiotensin I in human plasma. The amount of angiotensin I formed is determined in a subsequent radioimmunoassay. Which action inhibitors have on the formation of angiotensin I is tested in this system by the addition of different concentrations of these substances.
  • the IC 6 o refers to that concentration of the particular inhibitor which reduces the formation of angiotensin I by 50%.
  • the compounds of the present invention exhibit inhibiting actions in the in vitro systems at minimum concentrations of about 10 "3 to about 10 "10 mol/l.
  • renin inhibitors bring about a blood pressure decrease.
  • Human renin differs from renin of other species.
  • primates marmosets, Callithrixjacchus
  • human renin and primate renin are substantially homologous in the enzymatically active region.
  • One in vivo test which is used is as follows: the test compounds are tested on normotensive marmosets of both genders and having a bodyweight of about 350 g which are conscious, able to move freely and in their normal cages. Blood pressure and heart rate are measured using a catheter in the descending aorta and recorded radiometrically.
  • the endogenous release of renin is stimulated by the combination of 1-week low-salt diet with a single intra-muscular injection of furosemide (5-(aminosulphonyl)-4- chloro-2-[(2-furanylmethyl)amino]benzoicacid) (5 mg/kg).
  • furosemide 5-(aminosulphonyl)-4- chloro-2-[(2-furanylmethyl)amino]benzoicacid
  • the test substances are administered either directly into the femoral artery by means of an injection cannular or into the stomach by gavage as a suspension or solution, and their effect on blood pressure and heart rate was evaluated.
  • the compounds of the present invention effectively reduce blood pressure in the in vivo test described at doses of about 0.003 to about 0.3 mg/kg i.v. and at doses of about 0.3 to about 30 mg/kg p.o.
  • the compounds of the formula (I) or (II), or preferably of the formula (IA) or (IIA), and their pharmaceutically useable salts may find use as curative compositions, for example in the form of pharmaceutical preparations.
  • the pharmaceutical preparations may be administered enterally, such as orally, for example in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, for example in the form of nasal sprays, rectally, for example in the form of suppositories, ortransdermally, for example in the form of ointments or patches.
  • the administration may also be parenteral, such as intramuscular or intravenous, for example in the form of injection solutions.
  • the compounds of the formula (I) or (II), or preferably of the formula (IA) or (IIA), and the pharmaceutically useable salts thereof may be processed with pharmaceutically inert, inorganic or organic excipients.
  • excipients used for example for tablets, sugar- coated tablets and hard gelatine capsules, may be lactose, corn starch, or derivatives thereof, talc, stearic acid or salts thereof etc.
  • Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc.
  • Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.
  • Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, bile acids, lecithin, etc.
  • Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.
  • the pharmaceutical preparations may additionally also comprise preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourings, salts for altering the osmotic pressure, buffers, coatings or antioxidants. They may also comprise other therapeutically valuable substances.
  • the present invention further provides the use of the compounds of the formula (I) or (II), or preferably of the formula (IA) or (IIA), and the pharmaceutically useable salts thereof, in the treatment or prevention of hypertension and heart failure, and also glaucoma, cardiac infarction, kidney failure and restenoses of mammals, especially of human beings.
  • the compounds of the formula (I) or (ll), or preferably of the formula (IA) or (UA), and the pharmaceutically useable salts thereof, may also be used in combination with one or more agents having cardiovascular action, for example ⁇ - and ⁇ -blockers such as phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol etc.; vasodilators such as hydralazine, minoxidil, diazoxide, nitroprusside, flosequinan etc.; calcium antagonists such as amrinone, bencyclan, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil.
  • agents having cardiovascular action for example ⁇ - and ⁇ -blockers such as
  • gallopamil, nifedipine etc. ACE inhibitors such as cilazapril, captopril, enalapril, lisinopril etc.
  • potassium activators such as pinacidil
  • anti-serotoninergics such as keta ⁇ serin
  • thromboxane-synthetase inhibitors neutral endopeptidase inhibitors (NEP inhibitors); angiotensin II antagonists
  • diuretics such as hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamteren, chlorthalidone etc.
  • sympatholytics such as methyldopa, clonidine, guanabenz, reserpine; and other agents which are suitable for the treatment
  • the dose may vary within wide limits and has of course to be adapted to the individual circumstances in each individual case.
  • the starting materials are prepared as follows: a) tert-Butyl 4-(4-r3-(2-methoxybenzyloxy)propoxylphenyl ⁇ -3-r4-(3-methoxypropy ⁇ -3-oxo- 3,4-dihvdro-2H-benzon ,4loxazin-6-yloxymethvnpiperazine-1-carboxylate
  • reaction mixture is concentrated by evaporation - the residue is admixed with 120 ml of dioxane, 120 ml of 1 N NaOH and 7.12 g of di-tert-butyl dicarbonate and stirred at room temperature over 16 hours.
  • the reaction mixture is diluted with brine and extracted with ethyl acetate (5x) - the combined organic phases are dried over sodium sulphate and concentrated by evaporation.
  • the title compound is obtained as a yellow solid from the residue by means of flash chromatography (SiO 2 60F).
  • a mixture of 0.064 g of copper(l) iodide, 2.00 g of 6-bromo-4-(3-methoxypropyl)-4H- benzo[1,4]oxazin-3-one and 2.02 g of sodium iodide is initially charged under argon in a Schlenk apparatus, admixed with 0.088 ml of rac-N,N'-dimethylcycl ⁇ hexane-1,2-diamine and 6 ml of dioxane, and stirred at 110°C over 19 hours.
  • the reaction mixture is cooled to room temperature, diluted with aqueous ammonia (30%), poured into water and extracted with dichloromethane (3x).
  • the solution is introduced by cannula at 0°C into a solution of 0.062 g of benzylcyclopropylamine, 0.022 ml of pyridine and 1,6 mg of 4-dimethylaminopyridine in 2 ml of dichloromethane.
  • the reaction mixture is warmed slowly to room temperature over 10 hours.
  • the solution is admixed with 3 ml of 1 M HCI and the organic phase is removed.
  • the aqueous phase is extracted with dichloromethane (2 x 5 ml).
  • the combined organic phases are dried over sodium sulphate and concentrated by evaporation.
  • the title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO 2 60F).
  • the starting materials are prepared as follows: a) tert-Butyl 3-r(2-chlorobenzv ⁇ cyclopropylcarbamovn-4- ⁇ 4-f2-(2,5-difluorophenoxy)- ethoxylphenyl ⁇ piperazine-1-carboxylate
  • Example 1a Analogously to Example 1a, 0.1 g of tert-butyl 3-[(2-chlorobenzyl)cyclopropylcarbamoyl]- piperazine-1-carboxylate and 0.1547 g of 2-[2-(4-bromophenoxy)ethoxy]-1,4- difluorobenzene are reacted. The title compound is obtained as a yellow oil.
  • N.B. Instead of tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate is used as the ligand.
  • Example 3c Analogously to Example 3c, 1 g of 1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2- carboxylic acid (Example 3) and 0.8049 g of (2-chlorobenzyl)cyclopropyIamine are reacted. The title compound is obtained as a white foam.
  • the starting materials are prepared as follows: a) (rac)-tert-Butyl 3-r(benzyl)cyclopropylcarbamoyl]-4- ⁇ 4-[2-(2-5 difluorophenoxy)ethoxylphenyl)piperazine-1-carboxylate Analogously to Example 1a, 0.15 g of (rac)-tert-butyl 3-[(benzyl)cyclopropylcarbamoyl]- piperazine-1 -carboxylate and 0.2541 g of 2-[2-(4-bromophenoxy)ethoxy]-1 ,4- difluorobenzene are reacted. The title compound is obtained as a yellow wax.
  • the reaction mixture is worked up after 6 hours by diluting with water and ethyl acetate - the decanted organic layer is dried over sodium sulphate and concentrated by evaporation. .
  • the title compound is obtained from the residue by means of flash chromatography (SiO 2 60F).
  • the starting materials are prepared as follows: a) (rac)-1- ⁇ 4-l3-(2-Methoxy-benzyloxy)-propoxyl-phenyll-6-[4-(3-methoxy-propyl)-3,4- dihydro-2H-benzo 1 ,41oxazin-6-yloxymethyll-4-(toluene-4-sulfonyl)-piperazin-2-one 0.0036 g of sodium hydride (60% dispersion in mineral oil) are added to a solution of 0.070 g of (rac)-toluene-4-sulphonic acid 2-[( ⁇ 4-[3-(2-methoxy-benzyloxy)-propoxy]- phenylcarbamoyl ⁇ -methyl)-(toluene-4-sulfonyl)-amino]-1-[4-(3-methoxy-propyl)-3,4-dihydro- 2H-be ⁇ zo[1,4]oxa
  • reaction mixture is cooled to 0°C and treated with 1.56 ml of 2,4,6-tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (50% in ethyl acetate). After 3 hours, the reaction is diluted with tert-butyl methyl ether, washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a red-brown oil and used without purification in the next step.
  • reaction mixture is worked up after 1.5 hours by diluting with water and extracting with tert-butyl methyl ether (3X) - the combined organic layers are washed with brine, dried over sodium sulphate and concentrated by evaporation.
  • the title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO 2 60 F).
  • the organic phase is washed with 1 N HCI, water and brine, dried over sodium sulphate and concentrated by evaporation.
  • the crude ester-amide intermediate is dissolved in 30 ml of methanol and treated with 1.2 ml of 1 N aqueous potassium hydroxide solution. After 2 hours, the reaction mixture is concentrated by evaporation - the residue is diluted with ethyl acetate, water and 1 N HCI.
  • the separated organic phase is washed with water and brine, dried over sodium sulphate and concentrated by evaporation.
  • the title compound is obtained as a light brown oil from the residue by means of flash chromatography (SiO 2 60F).
  • the starting material is prepared as follows: a) (R)-1-(3-Fluoro-phenyl)-pyrrolidin-3-ol

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Abstract

Novel piperazine derivatives of the general formulae (I) and (II), with the substituent definitions as illustrated in detail in the description are described. The compounds are suitable especially as renin inhibitors and have high potency.

Description

Organic compounds
The present invention relates to novel piperazine derivatives, to processes for their preparation and to the use of the compounds as medicaments, especially as renin inhibitors.
Especially with regard to renin inhibition, there is still a need for highly potent active ingredients. In this context, improvement of the pharmaco kinetic properties is at the forefront. These properties directed to better bioavailability are, for example, absorption, metabolic stability, solubility or lipophilicity.
The invention therefore provides piperazine derivatives of the general formulae (I) and (II)
Figure imgf000002_0001
(I) (ll) where
R1 is aryl or heterocyclyl;
R2 is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridinyl, diazinyl, triazolyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl, furyl, tetrazolyl or imidazolyl, which radicals may be substituted by 1-3 halogen, hydroxyl, cyano, trifluoromethyl, Cι.6-alkyl, halo-Ct-6-alkyl, hydroxy-Cι.6-alkyl, Cι-6-alkoxy-Cι-6-alkyl, cyano-
C1-6-alkyl, carboxy-Cι-6-alkyl, Cι-6-alkanoyloxy-Cι-6-alkyl, Cι.6-alkoxycarbonyloxy-Cι_6-alkyl,
C^e-alkoxycarbonyl, or C1-6_alkoxy, or a Ci-β-alkylenedioxy group, and/or by an L1-T1-L2-
T2-L3-T3-L4-T4-L5-U radical;
L1, L2, L3, L4 and L5 are each independently a bond, Cι-8-alkylene, C2-8-alkenylene or
C2.8-alkynylene, or are absent;
T1, T2, T3 and T4 are each independently
(a) a bond, or are absent, or are one of the groups
(b) -CH(OH)-
(c) -CH(OR6)-
(d) -CH(NR5R8)-
(e) -CO- (f) -CR7R8-
(g) -O- or -NR6-
( ) -S(θXκr (i) -SO2NR6- (j) -NR6SO2- (k) -CONR6- (I) -NR6CO- (m) -O-CO- (n) -CO-O-
(0) -O-CO-O- (p) -O-CO-NR6-
(q) -N(R6)-CO-N(R6)-
(r) -N(R6)-CO-O-
(s) pyrrolidinylene, piperidinylene or piperazinylene
(t) -C(R11)(R12)-, where the bonds starting from (b)-(t) lead to a saturated or aromatic carbon atom of the adjacent group if the bond starts from a heteroatom, and where not more than two (b)-(f) groups, three (g)-(h) groups and one (i)-(t) group are present;
R3 is hydrogen, Cι-6-alkyl, C2.6-alkenyl, Cι-6-alkoxy, hydroxy-Ci-6-alkyl, Cι.6-alkoxy-Cι-6- alkyl, benzyl or an R4-Z1-X1- group where R4 is (a) H-
(b) C1-6-alkyl-
(c) C2-6-alkenyl-
(d) hydroxy-Ci.e-alkyl-
(e) polyhydroxy-C1-6-alkyl-
(f) Cι-6-alkyl-O-C1-6-alkyl-
(g) aryl-
(h) heterocyclyl- (i) arylalkyl- (j) heterocyclylalkyl- (k) aryloxyalkyl-
(1) heterocyclyloxyalkyl- (m) (R5,R6)N-(CH2)1.3- (n) (R5,R6)N- (o) d-6-alkyl-S(O)0-2-
(p) aryl-S(O)0_2-
(q) heterocyclyl-S(O)o-2-
(r) HO-SO3- or salts thereof
(s) H2N-C(NH)-NH-
(t) NC-, and the bonds starting from (n)-(t) lead to a carbon atom of the adjacent group and this carbon atom is saturated if the bond starts from a heteroatom;
Z1
(a) is a bond, is absent, or is one of the groups
(b) Cι-6-alkylene-
(c) C2-6-alkenylene- (d) -O-, -N(R11)-, -S(O)o.2-
(e) -CO-
(f) -O-CO-
(g) -O-CO-O-
(h) -O-CO-N(R11)-
(i) -N(R11)-CO-O-
(j) -CO-N(R11)-
(k) -N(R11)-CO-
(l) -N(R11)-CO-N(R11)-
(m) -CH(OR9)- and the bonds starting from (d) and (f)-(m) lead to a carbon atom of the adjacent group and this carbon atom is saturated if the bond starts from a heteroatom;
X1 is a bond, is absent, or is -(CH2)ι.3-; or, in formula (I), R3 is also oxo;
R5 and R6 are each independently hydrogen, C^-alkyl, C2-6-alkenyl, aryl-C1-6-al yl or acyl, or, together with the nitrogen atom to which they are bonded, are a 5- or 6-membered heterocyclic ring which may contain an additional nitrogen, oxygen or sulphur atom or a -
SO- or -SO2- group, and the additional nitrogen atom may optionally be substituted by C1-6- alkyl radicals;
R7 and R8, together with the carbon atom to which they are bonded, are a 3-7-membered ring which may contain one or two oxygen or sulphur atoms or -SO- or -SO2- groups;
R9 is hydrogen, C1-6-alkyl, C3-a-cycloalkyl, C^-alkoxy-d-e-alkyl, acyl or arylalkyl;
R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen;
R11 is hydrogen or Cι-6-alkyl; R12 is hydrogen or Cι-6-alkyl;
U is hydrogen, Cι-6-alkyl, cycloalkyl, cyano, optionally substituted cycloalkyl, aryl, or heterocyclyl;
Q is ethylene or is absent (formula I) or is ethylene or methylene (formula II);
X is a bond or a >CH-R11, >CR9R1\ >CHOR9, >CO or >C=NOR10 group;
Z is absent or is Cι-6-alkylene, C2.6-alkenylene, hydroxy-Cι-6-alkyl'dene, -CH-R1 -CO-NR9-,
-O-, -S-, -NR8-, -O-alk-, -S-alk-, -NR9-alk-, -alk-O-, -alk-S- or -alk-NR9-, where alk is d-6- alkylene; and where
(a) if Z is -O- or -S-, X is >CR9R11 and either R2 contains an L1-T1-L2-T2-L3-T3-L4-T4-L5- U substituent or R3 is a substituent other than hydrogen as defined above;
(b) if Z is -O-alk-, -S-alk-, or -NR9-alk-, X is >CR9R11 ; and
(c) if X is a bond, Z is C2-6-alkenylene, -alk-O-, -alk-S- or -alk-NR9-, and pharmaceutically usable salts thereof.
Examples of alkyl and alkoxy radicals are Cι_e-alkyl and Cι_6-alkoxy radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy respectively. Cι-6-Alkylenedioxy radicals are preferably methylenedioxy, ethylenedioxy and propylenedioxy. Examples of C1-6-alkanoyl radicals are acetyl, propionyl and butyryl. Cycloalkyl is a saturated, cyclic hydrocarbon radical having 3-8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cι-8-Alkylene radicals are, for example, methylene, ethylene, propylene, 2-methyl propylene, tetra-, penta- and hexamethylene; C2. 8-alkenylene radicals are, for example, vinylene and propenylene; C2-8-alkynylene radicals are, for example, ethynylene; acyl radicals are alkanoyl radicals, preferably Cι-6-alkanoyl radicals, or aroyl radicals such as benzoyl. Aryl denotes mono- or polycyclic aromatic radicals which may be mono- or polysubstituted, for example phenyl, substituted phenyl, naphthyl, substituted naphthyl, tetrahydronaphthyl or substituted tetrahydronaphthyl. Examples of substituents on such aryl radicals are Cι-6-alkyl, trifluoromethyl, nitro, amino, C2-6-alkenyl, d-β-alkoxy, Cι_6-alkylcarbonyloxy, hydroxyl, halogen, cyano, carbamoyl, carboxyl and Cι-6-alkylenedioxy, and also phenyl, phenoxy, phenylthio, phenyl-C1-e-alkyl or phenyl-Cι-6-alkoxy each optionally substituted by halogen, Cι-6-alkyl, Cι-6-alkoxy or dihydroxy-C1-6-alkylarninocarbonyl. Further examples of substituents on aryl or heterocyclyl radicals are Cι-6-alkoxycarbonylphenyl, hydroxy-C^e-alkylphenyl, benzyloxy, pyridylcarbonylamino-Cι-6-alkyl, C2-6-alkenyloxy,
Figure imgf000005_0001
Cι.6-alkoxy-Cι-6- alkoxy-Ci-6-alkyl, methoxybenzyloxy, hydroxybenzyloxy, phenethyloxy, ethylenedioxybenzyloxy, dioxolanyl-Cι.6-alkoxy, C3-8-cycloalkyl-Cι-6-alkyl, C3_8-cycloalkyl- Cι-6-alkoxy, hydroxy-C1-6-alkoxy, carbamoyloxy-d-6-alkoxy, pyridylcarbamoyloxy-d-e- alkoxy, benzoyloxy-Cι-6-alkoxy, Cι_6-alkoxycarbonyl, Co-6-alkylcarbonylamino, C0-δ- alkylcarbonylamino-Cι-6-alkyl, C0-s-alkylcarbonylamino-C1-6-alkoxy, (N-d-6-alkyl)-Co-.- alkylcarbonylamino-Cι-e-alkyl, (N-d-e-alM.-Co-e-alkylcarbonylamino-d-e-alkoxy, C3-8- cycloalkylcarbonylamino-d-e-alkyl, C3-8-cycloalkylcarbonylamino-d-6-alkoxy, Cι_6-alkoxy- Ci-e-alkyl, hydroxy-Cι-6-alkyl, hydroxy-Ci-e-alkoxy-Ci-e-alkyl, hydroxy-d-e-alkoxy-d-β- alkoxy, Cι-6-alkoxycarbonylamino-Cι-e-alkyl, Ci-6-alkoxycarbonylamino-Ci.6-alkoxy, d-6- alkylaminocarbonylamino-d-β-alkyl, d-6-alkylaminocarbonylamino-Cι.6-alkoxy, C1-6- alkylaminocarbonyl-Cι-6-alkyl, C^β-alkylaminocarbonyl-d-e-alkoxy, d-6- alkylaminocarbonyl-Cι-6-alkoxy-Cι-6-alkyl, di-Cι-6-alkylaminocarbonyl-d-6-alkyl, di-C1-6- alkylaminocarbonyl-Cι-6-alkoxy, Cι-6-alkylcarbonyloxy-C1-6-alkyl, C1-6-alkylcarbonyloxy-d_6- alkoxy, cyano-Cι-6-alkyl, cyano-Cι-6-alkoxy, 2-oxooxazolidinyl-Cι-6-alkyl, 2-oxooxazolidinyl- Cι_e-alkoxy, Cι.6-alkoxycarbonyl-Cι-6-alkyl, Cι-6-alkoxycarbonyl-C1-6-alkoxy, C -6- alkylsulphonylamino-Cι-6-alkyl, Cι-6-alkylsulphonylamino-d-B-alkoxy, (N-C -6-alkyl)-Cι-6- alkylsulphonylamino-Cι-6-alkyl, (N-d-6-al )-Cι-6-alkylsulphonylamino-Cι-6-alkoxy, C1-6- alkylamino-C1-6-alkyl, d-δ-alkylamino-Ci-e-alkoxy, di-Cι.6-alkylamino-Cι-6-alkyl, di-d-6- alkylamino-d_6-alkoxy, d_6-alkylsulphonyl-Cι-6-alkyl, d-6-alkylsulphonyl-d-6-alkoxy, carboxy-Cι-6-alkyl, carboxy-d β-alkoxy, carboxy-Cι-δ-alkoxy-Cι-6-alkyl, Cι-6-alkoxy-d-6- alkylcarbonyl, acyl-Cι-6-alkoxy-d-6-alkyl, (N-Ci-β-alky -d-e-alkoxycarbonylamino, (N- hydroxy)-d-6-alkylaminocarbonyl-d-6-alkyl, (N-hydroxy)-Cι.6-alkylaminocarbonyl-C1.6- alkoxy, (N-hydroxy)aminocarbonyl-d-6-alkyl, (N-hydroxy)aminocarbonyl-Cι-6-alkoxy, Cι_6- alkoxyaminocarbonyl-d-6-alkyl, 6-alkoxyaminocarbonyl-d-6-alkoxy, (N-C1-6-alkoxy)-Cι-6- al kylaminocarbonyl-d-6-al kyl , (N -
Ci-e-alkoxyJ-d-e-alkylaminocarbonyl-d-B-alkoxy^N-acylJ-C^e-alkoxy-d-e-alkylamino, Cι-6- alkoxy-Ci-6-alkylcarbamoyl, (N-d-e-alkyO-d-e-alkoxy-d-e-alkylcarbamoyl, Cι-6-aIkoxy-Cι-6- alkylcarbonyl, Cι-6-alkoxy-Cι-6-alkylcarbonylamino, (N-d-θ-alky -d-e-alkoxy-d-e- alkylcarbonylamino, 1 -Ci-e-alkoxy-C^e-alkylimidazol^-yl, 1 -Cι-6-alkoxy-Cι-6-alkyItetrazol-5- yl, 5-Cι-6-alkoxy-Cι-6-alkyltetrazol-1-yll 2-Cι-6-alkoxy-Cι.6-alkyl-4-oxoimidazol-1-yl, carbamoyl-
C1-6-alkyl, carbamoyl-Cι-6-alkoxy, C1-6-alkylcarbamoyl, di-d-6-alkylcarbamoyl, d-6- alkylsulphonyl, d-6-alkylamidinyl, acetamidinyI-Cι.6-alkyl, O-methyloximyl-Cι-6-alkyl, O,N- dimethylhydroxylamino-d_6-alkyl; and also pyridyl, pyridyloxy, pyridylthio, pyridylamino, pyridyl-Cι.6-alkyl, pyridyl-C1-6-alkoxy, pyrimidinyl, pyrimidinyloxy, pyrimidinylthio, pyrimidinylamino, pyrimidinyl-C1-6-alkyl, pyrimidinyl-d_6-alkoxy, thienyl, thienyl-C1-6-alkyl, thienyl-d-6-alkoxy, furyl, furyl-d-6-alkyl, furyl-d-6-alkoxy each optionally substituted by halogen, Ci-e-alkyl, d e-alkoxy or dihydroxy-Cι-6-alkylaminocarbonyl. The term heterocyclyl denotes mono- or bicyclic, saturated and unsaturated heterocyclic radicals having from 1 to 4 nitrogen and/or 1 or 2 sulphur or oxygen atoms and which may be mono- or polysubstituted, especially by (in the case of unsaturated heterocyclyl radicals) alkyl, hydroxyl, alkoxy, nitrogen or halogen, or may be substituted by substituents as defined above for aryl radicals, or (in the case of saturated heterocyclyl radicals) may be substituted by alkyl or alkoxy.
Examples of heterocyclyl radicals are pyridyl, thienyl, pyrazinyl, triazolyl, imidazolyl, benzothiazolyl, furyl, pyrimidinyl, morpholinyl, quinazolinyl, quinolyl, quinoxalinyl, isoquinolyl, benzo[b]thienyl, isobenzofuranyl, benzoimidazolyl, 2-oxobenzoimidazolyl, oxazolyl, thiazolyl, indolyl, pyrrolyl, 2-oxodihydrobenzo[d][1,3]oxazinyl, 4- oxodihydroimidazolyl, 5-oxo-4H-[1 ,2,4]triazinyl, 3-oxo-4H-benzo[1 ,4]thiazinyl, tetrahydroquinoxalinyl, 1 ,1,3-trioxodihydro-2H-1λ6-benzo[1,4]thiazinyl, 1-oxopyridyl, dihydro-2H-benzo[1,4]oxazinyl, 2-oxotetrahydrobenzo[e][1 ,4]diazepinyl3 2- oxodihydrobenzo[e][1,4]diazepinyl, 1H-pyrrolizinyl, phthalazinyl, 1-oxo-3H-isobenzofuranyl, 4-oxo-3H-thieno[2,3-d]pyrimidinyl, 3-oxo-4H-benzo[1,4]oxazinyl, [1,5]naphthyridyl, dihydro- 2H-benzo[1 ,4]thiazinyl, 1 , 1-dioxodihydrα-2H-benzo[1 ,4]thiazinyl, 2-oxo-1 H-pyrido[2,3- b][1 ,4]oxazinyl, dihydro-1 H-pyrido[2,3-b][1 ,4]oxazinyl, 1 H-pyrrolo[2,3-b]pyridyl, benzo[1,3]dioxolyl, benzooxazolyl, 2-oxobenzooxazolyl, 2-oxo-1 ,3-dihydroindolyl, 2,3- dihydroindolyl, indazolyl or benzofuranyl.
Examples of substituted heterocyclyl radicals are nitrobenzothiazolyl, phenyltetrazolyl, phenyloxadiazolyl, phenylpiperidinyl, phenylpiperazinyl, phenylpyrrolidinyl, thienyloxadiazolyl, furanyloxadiazolyl, benzyloxadiazolyl or phenyloxazolyl. Examples of saturated heterocyclyl radicals are dioxolanyl, dioxanyl, dithiolanyl, dithianyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, 2- hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 4- hydroxypiperidinyl, 4-oxopiperidinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4- oxothiomorpholinyl, 2,6-dimethylmorpholinyl, tetrahydropyranyl, 2-oxoimidazolidinyl, 2- oxooxazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxo-[1,3]oxazinyl, 2-oxoazepanyl, 2- oxotetrahydropyri idinyl and the like.
In the case of R1, R4 and R9, the aryl, aroyl and heterocyclyl radicals may additionally be substituted by heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkoxyalkyl or heterocyclyl, for example piperidinoalkyl, piperidinoalkoxy, piperidinoalkoxyalkyl, morpholinoalkyl, morpholinoalkoxy, morpholinoalkoxyalkyl, piperazinoalkyl, piperazinoalkoxy, piperazinoalkoxyalkyl, [1,2,4]triazol-1-ylalkyl, [1,2,4]triazol-1-ylalkoxy, [1 ,2,4]triazol-4- ylalkyl, [1 ,2,4]triazol-4-ylalkoxy, [1,2,4]oxadiazol-5-ylalkyl, [l^^oxadiazol-δ-ylalkoxy, 3- methyl[1 ,2,4]oxadiazol-5-ylalkyl, 3-methyl[1 ,2,4]oxadiazol-5-ylalkoxy, 5-methyl[1 ,2,4]- oxadiazol-3-ylalkyl, 5-methyl[1,2,4]oxadiazol-3-ylalkoxy, tetrazol-1-ylaIkyl, tetrazol-1- ylalkoxy, tetrazol-2-ylalkyl, tetrazol-2-ylalkoxy, tetrazol-5-ylalkyl, tetrazol-5-ylalkoxy, 5-methyltetrazol-1-ylalkyl, 5-methyltetrazol- 1-ylalkoxy, thiazol-4-ylalkyl, thiazol-4-ylalkoxy, oxazol-4-ylalkyl, oxazol-4-ylalkoxy, 2-oxopyrrolidinylalkyl, 2-oxopyrrolidinylalkoxy, imidazolylalkyl, imidazolylalkoxy, 2-methylimidazolylalkyl, 2-methylimidazolylalkoxy, N- methylpiperazinoalkyl, N-methylpiperazinoalkoxy, N-methylpiperazinoalkoxyalkyl, and also alkylaminoalkyl, alkylaminoalkoxy, alkylaminoalkoxyalkyl, mono- and polyhydroxyalkyl, -alkoxy, -alkoxyalkyl and -alkoxyalkoxy, carbamoylalkyloxy, C1-6-alkoxy, amino-Cι-6-alkoxy, hydroxy-Cι-6-alkoxy, dioxolanyl, dioxanyl, dithiolanyl, dithianyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, 4-methyIpiperazinyl, morpholinyl, thiomorpholinyl, 2- hydroxy ethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 3- acetamidomethylpyrrolidinyl, 3-Cι-B-alkoxy-d-B-alkylpyrrolidinyl, 4-hydroxypiperidinyl, 4- oxopiperidinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4-oxothiomorpholinyl, 2,6-dimethylmorpholinyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxo[1,3]oxazinyl, 2-oxotetrahydropyrimidinyl and the like, or by the -O-CH2CH(OH)CH2NR>: radical where NRX is a mono- or di-Ci-e-alkylamino, piperidino, morpholino, piperazino or N-methylpiperazino radical.
Examples of 5- and 6-membered heterocyclic rings represented by NR5R6 are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3- hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 4-hydroxypiperidinyl, 4-oxopiperidinyl, 3,5- dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4-oxothiomorpholinyl, 2,6- dimethylmorpholinyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxo- [1 ,3]oxazinyl, 2-oxotetrahydropyrimidinyl and the like. Examples of 3-7-membered rings represented by CR7R8 are cyclopentyl, cyclohexyl, cycloheptyl, 1,3-dioxolanyl, 1,3- dioxanyl, 1,3-dithiolanyl and 1,3-dithianyl.
The term polyhydroxyalkyl denotes Ci-d-alkyl radicals which may be substituted by 2-6 hydroxyl groups, for example glyceryl, arabityl, sorbityl, etc.
The compounds of the formula (I) or formula (II) have at least one asymmetric carbon atom and may therefore be in the form of optically pure enantiomers, enantiomer mixtures or as racemates. Compounds having a second asymmetric carbon atom may be in the form of optically pure diastereomers, diastereomer mixtures, diastereomeric racemates, mixtures of diastereomeric racemates or as meso compounds. The invention encompasses all of these forms. Enantiomer mixtures, racemates, diastereomer mixtures, diastereomeric racemates or mixtures of diastereomeric racemates may be separated by customary methods, for example by optical resolution, column chromatography, thin-layer chromatography, HPLC and the like.
The term "pharmaceutically usable salts" encompasses salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like.
The compounds of the formulae (I) and (II) also include those compounds in which one or more atoms are replaced by their stable, non-radioactive isotopes; for example a hydrogen atom by deuterium.
The compound groups mentioned hereinbelow are not to be regarded as closed, but rather it is possible in a sensible manner, for example to replace general by more specific definitions, for parts of these groups of compounds to be exchanged with one another or for the definitions given above or to be omitted.
Preferred inventive compounds are those of the general formulae (IA) or (IIA)
Figure imgf000009_0001
IA IIA where R1, R2, R3, Q, X and Z are each as defined for the compounds of the formulae (I) or (II) above.
A further, preferred group of compounds of the formula (I) or (II), or more preferably of the formula (IA) or (IIA), are compounds where R1 is aryl or heterocyclyl; R2 is phenyl, cyclohexyl, tetrazolyl, or phenyl, cyclohexyl or tetrazolyl each substituted by halogen, hydroxyl, cyano, trifluoromethyl, d-6-alkyl, halo-Cι-6-alkyl, hydroxy-Cι-6-alkyl, C1-6- alkoxy-C1-6-alkyl, cyano-d_6-alkyl, carboxy-Cι-6-alkyl, Cι-6-alkanoyloxy-Cι-6-alkyl, Cι.6- alkoxycarbonyloxy-Cι-6-alkyl, d-6-alkoxycarbonyl, d-6-alkoxy, d-6-alkylenedioxy, or by an
L1-T1-L2-T2-L3-T3-L4-T4-L5-U radical; or naphthyl or acenaphthyl;
L1, L2, L3, L4 and L5 are each independently a bond, Cι-8-alkylene, C2-8-alkenylene or
C2.8-alkynylene, or are absent;
T1, T2, T3 and T4 are each independently
(a) a bond, or are absent, or are one of the groups
(b) -CH(OH)-
(c) -CH(OR6)-
(d) -CH(NR5R6)-
(e) -CO-
(f) -CR7R8-
(g) -O- or -NR6- (h) -S(O)o-2-
(i) -SO2NR5-
G) -NR6SO2-
(k) -CONR6-
(I) -NR6CO-
(m) -O-CO-
(n) -CO-O-
(0) -O-CO-O-
(p) -O-CO-NR6-
(q) -N(R6)-CO-N(R6)-
(r) -N(R6)-CO-O-
(s) pyrrolidinylene, piperidinylene or piperazinylene
(t) -C(R11)(R12)-, where the bonds starting from (b)-(t) lead to a saturated or aromatic carbon atom of the adjacent group if the bond starts from a heteroatom, and where not more than two (b)-(f) groups, three (g)-(h) groups and one (i)-(t) group are present;
R3 is hydrogen, Cι_e-alkyl, C2-6-alkenyl, d-e-alkoxy, hydroxy-Cι-6-alkyl, Cι-6-alkoxy-Cι-6-alkyl or benzyl; or, in formula (I) or (IA), R3 is also oxo; R5 and R6 are each independently hydrogen, d-6-alkyl or acyl, or, together with the nitrogen atom to which they are bonded, are a 5- or 6-membered heterocyclic ring which may contain an additional nitrogen, oxygen or sulphur atom;
R7 and R8, together with the carbon atom to which they are bonded, are a 3-7-membered ring which may contain one or two oxygen or sulphur atoms;
R9 is hydrogen, Ci-e-alkyl, C3-8-cycloalkyl, acyl orarylalkyl;
R11 is hydrogen or Ci-e-alkyl;
R12 is hydrogen or Cι-6-alkyl;
U is hydrogen, Cι-6-alkyl, cycloalkyl, cyano, aryl or heterocyclyl;
Q is ethylene or is absent (formulae (I) and (IA)) or is ethylene or methylene (formulae (II) and (IIA));
X is a >CHOR9, >CO or >CH-R11 group;
Z is d-e-alkylene, -CH-R11-CO-NR9, -O-, -NR9-, -alk-O-, -alk-S-, -alk-NR9- or is absent; and where, if Z is -O-, X is >CHR11 and either R2 contains an L1-T1-L2-T2-L3-T3-L4-T4-L5-U substituent or R3 is a substituent other than hydrogen as defined above;
and pharmaceutically usable salts thereof.
Preference is further given to compounds of the formulae (I), (IA), (II) and (IIA) in which Q is absent. X is preferably -CH2- or -CO-. Z is preferably -O-, -alk-O-, -N-fCg-g-cycloalky -d. 6-alkylene- or is absent.
Preferred R1 radicals are phenyl and phenyl substituted by Cι-6-alkyl, Cι-6-alkoxy, halogen, hydroxyl, hydroxy-d-6-alkoxy,
Figure imgf000011_0001
d-6-alkylsulphinyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, carboxyl, Cι-6-alkoxycarbonyl, Cι-6-alkoxy-d-Θ- alkoxy-d.e-alkyl, Co-β-alkylcarbonylamino, Co-6-alkylcarbonylamino-d_6-alkyl, C-o-β- alkylcarbonylamino-C1-6-alkoxy, (N-C1-6-alkyl)-Co-6-alkylcarbonylamino-d-6-alkyl, (N-Cι_6- alkyl)-Co-6-alkylcarbonylamino-C1-6-alkoxy, Cs-s-cycloalkylcarbonylamino-d-e-alkyl, C3.8- cycloalkylcarbonylamino-C -6-alkoxy, Cι-6-alkoxy-Cι.6-alkyl, hydroxy-C1-6-alkyl, hydroxy-Cι- 6-alkoxy-Cι-B-alkyl, hydroxy-d-β-alkoxy-d-β-alkoxy, d-Θ-alkoxycarbonylamino-d-6-alkyl, d_ 6-alkoxycarbonylamino-Cι-6-alkoxy, d_6-alkylaminocarbonylamino-Cι-6-alkyl, d-6- alkylaminocarbonylamino-Cι-6-alkoxy, Ci-e-alkylaminocarbonyl-d-e-alkyl, d_e- alkylaminocarbαnyl-d.6-alkoxy, d-6-alkylaminocarbonyl-Cι-6-alkoxy-d-6-alkyl, di-Cι-6- alkylaminocarbonyl-C1-6-alkyl, di-Ci-β-alkylaminocarbonyl-d-e-alkoxy, C1-6- alkylcarbonyloxy-Ci-6-alkyl, d-6-alkylcarbonyloxy-Cι_6-alkoxy, cyano-Cι-6-alkyl, cyano-d-6- alkoxy, 2-oxooxazolidinyl-C1-6-alkyl, 2-oxooxazolidinyl-Cι_6-alkoxy, Cι_6-alkoxycarbonyl-Cι.6- alkyl, d-6-alkoxycarbonyl-Cι_6-alkoxy, Cι-6-alkylsulphonylamino-Cι-6-alkyl, Cι.6- alkylsulphonylamino-d-6-alkoxy, (N-d-e-alky -Ci-β-alkylsuIphonylamino-Ci-e-alkyl, (N-C1-6- alkyl)-Ci-6-alkylsulphonylamino-Ci-6-alkoxy,
Figure imgf000012_0001
C1-6-alkylamino-C1-6- alkoxy, di-Cι-6-aIkylamino-Cι-6-alkyl, di-d-e-alkylamino-d-e-alkoxy, d-6-alkylsulphonyl-Cι.6- alkyl, d-Θ-alkylsulphonyl-d_6-alkoxy, carboxy-C1-6-alkyl, carboxy-C1-Θ-alkoxy, carboxy-d.6- alkoxy-Ci-e-alkyl, Cι-B-alkoxy-Cι-6-alkylcarbonyl, acyl-Cι-6-alkoxy-Cι-6-alkyl, (N-Cι-6-alkyl)- d-e-alkoxycarbonylamino, (N-hydroxyJ-Ci-e-alkylaminocarbonyl-d-e-alkyl, (N-hydroxy)-d- 6-alkylaminocarbonyl-C1-6-alkoxy, (N-hydroxy)aminocarbonyl-Cι-6-alkyl, (N- hydroxy)aminocarbonyl-Cι-6-alkoxy, Cι-6-alkoxyaminocarbonyl-Cι-6-alkyl, 6-alkoxyaminocarbonyl-Cι-6-alkoxy, (N-C1.6-alkoxy)-Cι-6-alkylaminocarbonyl-C1-6-alkyl, (N- C .6-alkoxy)-Cι-6-alkylaminocarbonyl-C1-B-alkoxy, (N-acyl)-Ci-6-alkoxy-Ci-6-alkylamino, C1-6- alkoxy-d-e-alkylcarbamoyl, (N-Cι-6-alkyl)-Cι.6-alkoxy-C1-6-alkylcarbamoyl, d-6-alkoxy-Cι.6- alkylcarbonyl, d-6-alkoxy-Cι-6-alkylcarbonylamino, (N-d-β-alky -d-e-alkoxy-Ci-θ- alkylcarbonylamino, 1-Cι-6-alkoxy-Cι-6-alkylimidazol-2-yl, 1-Cι-6-alkoxy-Cι.6-alkyltetrazol-5- yl, 5-Cι.6-alkoxy-Cι..6-alkyltetrazol-1 -yl, 2-Cι-6-alkoxy-d.6-alkyl-4-oxoimidazol-1 -yl, carbamoyl-
Cι-6-alkyl, carbamoyl-C1-6-alkoxy, d-6-alkylcarbamoyl, di-d-β-alkylcarbamoyl, Ci-β- alkylsulphonyl, piperidinoalkyl, piperidinoalkoxy, piperidinoalkoxyalkyl, morpholinoalkyl, morpholinoalkoxy, morpholinoalkoxyalkyl, piperazinoalkyl, piperazinoalkoxy, piperazinoalkoxyalkyl, [1,2,4]triazol-1-ylalkyl, [1,2,4]triazol-1-ylalkoxy, [1 ,2,4]triazol-4- ylalkyl, [1,2,4]triazol-4-ylalkoxy, [1,2,4]oxadiazol-5-ylalkyl, [1 ,2,4]oxadiazol-5-ylalkoxy, 3-methyl[1,2,4]oxadiazol-5-ylalkyl, 3-methyl[ ,2,4]oxadiazol-5-ylalkoxy, 5-methyl[1 ,2,4]- oxadiazol-3-ylalkyl, 5-methyl[1,2,4]oxadiazol-3-ylalkoxy, tetrazol-1-ylalkyl, tetrazol-1- ylalkoxy, tetrazol-2-ylalkyl, tetrazol-2-ylalkoxy, tetrazol-5-ylalkyl, tetrazol-5-ylalkoxy, 5- methyltetrazol-1-ylalkyl, 5-methyltetrazol-l-ylalkoxy, thiazol-4-ylalkyl, thiazol-4-ylalkoxy, oxazol-4-ylalkyl, oxazol-4-ylalkoxy, 2-oxopyrrolidinylalkyl, 2-oxopyrrolidinylalkoxy, imidazolylalkyl, imidazolylalkoxy, 2-methylimidazolylalkyl, 2-methylimidazolylalkoxy, N- methylpiperazinoalkyl, N-methylpiperazinoalkoxy, N-methylpiperazinoalkoxyalkyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3,4- dihydroxypyrrolidinyl, 3-acetamidomethylpyrrolidinyl, 3-Cι-6-alkoxy-C1-6-alkylpyrrolidinyl, 4- hydroxypiperidinyl, 4-oxopiperidinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4- oxothiomorpholinyl, 2,6-dimethylmorpholinyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2- oxopyrrolidinyl, 2-oxo[1 ,3]oxazinyl and 2-oxotetrahydropyrimidinyl. Further preferred R1 radicals are naphthyl, and naphthyl substituted by hydroxyl, oxo, halogen, carbamoyl, carboxyl, Cι-6-alkoxy, hydroxy-Ci-e-alkoxy, Ci-6-alkoxy-Ci-6-alkoxy, di- C1-6-alkylamino, 2,3-dihydroxypropoxy, 2,3-dihydroxypropoxy-Cι.e-alkoxy, 2,3- dimethoxypropoxy, methoxybenzyloxy, hydroxybenzyloxy, phenethyloxy, methylenedioxybenzyloxy, dioxolanyl-d β-alkoxy, C3-8-cycloalkyl-Cι-6-alkoxy, hydroxy-Cι-6- alkoxy, pyridylcarbamoyloxy-Ci-6-alkoxy, 3-morpholino-2-hydroxypropoxy, benzyloxy-Cι.6- alkoxy, picolyloxy, Ci-e-alkoxycarbonyl, d-e-alkoxy-d-β-alkoxy-d-e-alkyl, Co-6- alkylcarbonylamino, Co-6-alkylcarbonylamino-Cι-6-alkyl, Co-6-alkyicarbonylamino-d-6- al koxy, (N-d-6-alkyl)-C0-6-altylcarbonylamino-Cι-6-alkyl, (N-d-6-alkyl)-Co-6- alkylcarbonylamino-C1-6-alkoxy, C3-8-cycloalkylcarbonylamino-C1.6-alkyl, C3_8- cycloalkylcarbonylamino-C1-6-alkoxy,
Cι-6-alkoxy-Cι-6-alkyl, hydroxy-d-6-alkyl, hydroxy-Cι_6-alkoxy-C1-6-alkyl, hydroxy-Ci-e- alkoxy-d-6-alkoxy, Cι-6-alkoxycarbonylamino-d-6-alkyl, Cι-6-alkoxycarbonylamino-Cι-6- alkoxy, C1-6-alkylaminocarbonyIamino-Cι-6-alkyl, Cι-6-alkylaminocarbonylamino-d-6-alkoxy, d-β-alkylaminocarbonyl-d-e-alkyl, d.6-alkylaminocarbonyl-Cι_6-alkoxy, C1-6- alkylaminocarbonyl-Ci-6-alkoxy-Ci.6-alkyl, di-Cι-6-alkylaminocarbonyl-Cι-6-alkyl, di-Cι-6- alkylaminocarbonyl-d-6-alkoxy, Cι-6-alkylcarbonyloxy-C1-6-alkyl, C1-6-alkylcarbonyloxy-C1-6- alkoxy, cyano-d-β-alkyl, cyano-Cι-6-alkoxy, 2-oxooxazolidinyl-C1-6-alkyl, 2-oxooxazolidinyl- Ci-e-alkoxy, d-6-alkoxycarbonyl-d.6-alkyl, Cι-6-alkoxycarbonyl-d-6-alkoxy, Ci-e- alkylsulphonylamino-C1-6-alkyl, C.-β-alkylsulphonylamino-d-θ-alkoxy, (N-d-6-alkyl)-d-e- alkylsulphonylamino-Ci_6-alkyl, (N-Cι-6-alkyl)-Cι-6-alkylsulphonylamino-Cι-6-alkoxy, d-6- alkylamino-Cι.6-alkyl, C1-6-alkylamino-Cι-6-alkoxy, di-Cι-6-alkylamino-Cι-6-alkyl, di-C1-6- alkylamino-Cι-6-alkoxy, d-6-alkylsulphonyl-Cι-6-alkyl, Cι-6-alkylsulphonyl-Cι-6-alkoxy, carboxy-Cι-6-alkyl, carboxy-C1-6-alkoxy, carboxy-Cι-6-alkoxy-Cι.6-alkyI, Cι-6-alkoxy-d-6- alkylcarbonyl, acyl-Cι-6-alkoxy-d-6-alkyl, (N-Cι-6-alkyl)-Cι-6-alkoxycarbonylamino, (N- hydroxy)-Cι-6-alkylaminocarbonyl-Cι-6-alkyl, (N-hydroxy)-d-6-alkylaminocarbonyl-Cι,6- alkoxy, (N-hydroxy)aminocarbonyl-d.6-alkyl, (N-hydroxy)aminocarbonyl-C1-6-alkoxy, C1-6- alkoxyaminocarbonyl-C -6-alkyl, 6-alkoxyaminocarbonyI-C1-6-alkoxy, (N-d-e-alkoxyJ-d-e- alkylaminocarbonyl-Cι-6-alkyl, (N-
Ci-B-alkoxyJ-Cve-alkylaminocarbonyl-C^s-alkoxy^N-acy -Ci-e-alkoxy-d-Θ-alkylamino, C1-6- alkoxy-d-6-alkylcarbamoyl, (N-Ci-B-alkyO-d-e-alkoxy-d-e-alkylcarbamoyl, Cι-6-alkoxy-C1-6- alkylcarbonyl, Cι-6-alkoxy-Cι-6-alkylcarbonylamino, (N-Cι-6-alkyl)-C1-6-alkoxy-Cι-6-alkyl- carbonylamino, l-d-e-alkoxy-d-β-alkylimidazol^-yl, 1-d.e-alkoxy-C1-6-alkyltetrazol-5-yl, 5- Cι-eralkoxy-d.6-alkyltetrazol-1 -yl, 2-d.6-alkoxy-Cι-6-alkyl-4-oxoimidazol-1 -yl, carbamoyl-d- 6-alkyl, carbamoyl-d-β-alkoxy, Cι-6-alkylcarbamoyl, di-Cι-6-alkylcarbamoyl, Cι.6- alkylsulphonyl, piperidinoalkyl, piperidinoalkoxy, piperidinoalkoxyalkyl, morpholinoalkyl, morpholinoalkoxy, morpholinoalkoxyalkyl, piperazinoalkyl, piperazinoalkoxy, piperazinoalkoxyalkyl, [1,2,4]triazol-1-ylalkyl, [1,2,4]triazol-1-ylalkoxy, [1 ,2,4]triazol-4- ylalkyl, [1,2,4]triazol-4-ylalkoxy, [1,2,4]oxadiazol-5-ylalkyl, [1,2,4]oxadiazol-5-ylalkoxy, 3- methyl[1 ,2,4]oxadiazol-5-ylalkyl, 3-methyl[1 ,2,4]oxadiazol-5-ylalkoxy, 5-methyl[1 ,2,4]- oxadiazol-3-ylalkyl, 5-methyl[1,2,4]oxadiazol-3-ylalkoxy, tetrazol-1-ylaIkyl, tetrazol-1- ylalkoxy, tetrazol-2-ylalkyl, tetrazol-2-ylalkoxy, tetrazol-5-ylalkyl, tetrazol-5-ylalkoxy, 5- methyltetrazol-1-ylalkyl, 5-methyltetrazol-1-ylalkoxy, thiazol-4-ylalkyl, thiazol-4-ylalkoxy, oxazol-4-ylalkyl, oxazol-4-ylalkoxy, 2-oxopyrrolidinylalkyl, 2-oxopyrrolidinylalkoxy, imidazolylalkyl, imidazolylalkoxy, 2-methylimidazolylalkyl, 2-methylimidazolylalkoxy, N- methylpiperazinoalkyl, N-methylpiperazinoalkoxy, N-methylpiperazinoalkoxyalkyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3,4- dihydroxypyrrolidinyl, 3-acetamidomethylpyrrolidinyl, 3-Cι_6-alkoxy-d_6-alkylpyrrolidinyl, 4- hydroxypiperidinyl, 4-oxopiperidinyl, 3,5-dimethylmorpholinyl, 4,4-dioxothiomorpholinyl, 4- oxothiomorpholinyl, 2,6-dimethylmorpholinyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2- oxopyrrolidinyl, 2-oxo-[1,3]oxazinyl and 2-oxotetrahydropyrimidinyl; tetrahydronaphthyl or methyl-substituted tetrahydronaphthyl and indanyl.
A group of particularly preferred R1 radicals encompasses the abovementioned substituted phenyl and naphthyl radicals, and also tetrahydronaphthyl and methyl-substituted tetrahydronaphthyl.
R radicals which are likewise preferred are pyridyl, benzoimidazolyl, di-C1-6- alkoxypyrimidinyl, 2- and 5-benzo[b]thienyl, 6- and 7-quinolyl, 6- and 7-isoquinolyl, 6- and 7-tetrahydroquinolyl, 6- and 7-tetrahydroisoquinolyl, 6-quinoxalinyl, 6- and 7-quinazolinyl, indolyl, dihydro-2H-benzo[1,4]oxazinyl, 3-oxo-4H-benzo[1,4]oxazinyl, 2-oxobenzooxazolyl, 2-oxo-1 ,3-dihydroindolyl, 2,3-dihydroindolyl, indazolyl and benzofuranyl, and also 6- and 7- quinolyl, 6- and 7-isoquinolyl, 6- and 7-tetrahydroquinolyl, 6- and 7-tetrahydroisoquinolyl, 6-quinoxalinyl, 6- and 7-quinazolinyl, indolyl, dihydro-2H-benzo[1,4]oxazinyl, 3-oxo-4H- benzo[1,4]oxazinyl, 2-oxobenzooxazolyl, 2-oxo-1,3-dihydroindolyl, 2,3-dihydroindolyl, indazolyl and benzofuranyl each substituted by hydroxyl, oxo, halogen, carbamoyl, carboxyl, C1-6-alkoxy, hydroxy-Cι-6-alkoxy, Cι-6-alkoxy-d.6-alkoxy, di-Cι-6-alkylamino, 2,3- dihydroxypropoxy, 2,3-dihydroxypropoxy-Cι-6-alkoxy, 2,3-dimethoxypropoxy, methoxybenzyloxy, hydroxybenzyloxy, phenethyloxy, methylenedioxybenzyloxy, dioxolanyl-d-e-alkoxy, cyclopropyl-C1-e-alkoxy, hydroxy-Ci-e-alkoxy, pyridylcarbamoyloxy- C1-6-alkoxy, 3-morpholino-2-hydroxypropoxy, benzyloxy-Ci-6-alkoxy, picolyloxy, d-6- alkoxycarbonyl, Cι.6-alkoxy-d-6-alkoxy-C1-B-alkyl, Co-e-alkylcarbonylamino, Co-e- alkylcarbonylamino-Cι-6-alkyl, Co-e-alkylcarbonylamino-d-β-alkoxy, (N-C1-6-alkyl)-C0-6- alkylcarbonylamino-Cι-6-alkyl, (N-d-e-alky -Co-B-alkylcarbonylamino-d-e-alkoxy, C3-8- cycloalkylcarbonylamino-Cι-6-alkyl, C3.8-cycloalkylcarbonylamino-Cι-6-alkoxy, Cι-6-alkoχy- Cι.6-alkyl, hydroxy-Cι-6-alkyl, hydroxy-d-e-alkoxy-d-B-alkyl, hydroxy-d-e-alkoxy-d e- alkoxy, Cι-6-alkoxycarbonylamino-Cι.6-alkyl, Cι.6-alkoxycarbonylamino-d-6-alkoxy, C1-6- alkylaminocarbonylamino-d-6-alkyl, Cι-6-alkylaminocarbonylamino-Cι-6-alkoxy, Cι-6- alkylaminocarbonyl-d-6-alkyl, d-6-alkylaminocarbonyl-Cι-6-alkoxy, C1-6- alkylaminocarbonyl-d-6-alkαxy-Cι-6-alkyl, di-Cι-6-alkylaminocarbonyl-d-6-alkyl, di-Cι-6- alkylaminocarbonyl-Cι_6-alkαxy, d-6-alkylcarbonyloxy-Cι-6-alkyl, Cι-6-alkylcarbonyloxy-Cι-6- alkoxy, cyano-Cι-6-alkyl, cyano-Cι-6-alkoxy, 2-oxooxazolidinyl-C1-6-alkyl, 2-oxooxazolidinyl- C1-6-alkoxy, d-6-alkoxycarbαnylrCι-6-alkyl, Cι.6-alkoxycarbonyl-C1-e-alkoxy, d-e- alkylsulphonylamino-Ci-6-alkyl, Cι-6-alkylsulphonylamino- C -6-alkoxy, (N-C1-6-alkyl)-Cι-6-alkylsulphonylamino-C1-6-alkyl, ( -d-B-alkyO-d-β- alkylsulphonylamino-Cι-6-alkoxy, d-e-alkylamino-d-e-alkyl, d-B-alkylamino-d-e-alkoxy, di- Ci-6-alkylamino-Ci.6-alkyl, di-d-6-alkylamino-Cι-6-alkoxy, Cι-6-alkylsulphonyl-d.6-alkyl, C1-6- alkylsulphonyl-Ci-e-alkoxy, carboxy-Cι.6-alkyl, carboxy-d_6-alkoxy, carboxy-Cι-6-alkoxy-Cι. e-alkyl, C1-6-alkoxy-Ci-6-alkylcarbonyl, acyl-C1-6-alkoxy-Cι.6-alkyl, (N-Cι-6-alkyl)-Cι..6- alkoxycarbonylamino, (N-hydroxy)-C1-6-alkylaminocarbonyl-Ci-6-alkyl, (N-hydroxy)-Cι-6- alkylaminocarbonyl-d_6-alkoxy, (N-hydroxy)-aminocarbonyl-C1-6-alkyl, (N- hydroxy)aminocarbonyl-C1-6-alkoxy, Cι-6-alkoxyaminocarbonyl-Cι.6-alkyl, 6- alkoxyaminocarbonyl-d-e-alkoxy, (N-d-6-alkoxy)-Cι-6-alkylaminocarbonyl-Cι-6-alkyl, (N-Ci- 6-alkoxy)-Cι-6-alkylaminocarbonyl-Cι-6-alkoxy, (N-acyl)-Cι_6-alkoxy-Cι-6-alkylamino, C1-6- alkoxy-Cι-6-alkylcarbamoyl, (N-Cι-6-alkyl)-Cι-6-alkoxy-C -6-alkylcarbamoyl, Cι-6-alkoxy-Cι-6- alkylcarbonyl, Cι-6-alkoxy-Cι-6-alkylcarbonylamino, (N-d-B-alky - -e-alkoxy-d-B- alkylcarbonylamino, 1 -d-6-alkoxy-d-6-alkylimidazol-2-yl, 1 -d-6-alkoxy-d_6-alkyltetrazol- 5-yl, 5-Ci_6-alkoxy-Ci-6-alkyltetrazol-1-yl, 2-Cι-6-alkoxy-Cι-6-alkyl-4-oxoimidazol-1 -yl, carbamoyl-d e-alkyl, carbamoyl-C1-6-alkoxy, d-6-alkylcarbamoyl, di-C1-6-alkylcarbamoyl, Cι_6-alkylsulphonyl, piperidinoalkyl, piperidinoalkoxy, piperidinoalkoxyalkyl, morpholinoalkyl, morpholinoalkoxy, morpholinoalkoxyalkyl, piperazinoalkyl, piperazinoalkoxy, piperazinoalkoxyalkyl, [1,2,4]triazol-1-ylalkyl, [1,2,4]triazol-1-ylalkoxy, [1,2,4]triazol-4-ylalkyl, [1,2,4]triazol-4-ylalkoxy, [1,2,4]oxadiazol-5-ylalkyl, [1 ,2,4]oxadiazol-5-ylalkoxy, 3-methyl[1 ,2,4]oxadiazol-5-ylalkyl, 3-methyl[1 ,2,4]oxadiazol-5- ylalkoxy, 5-methyl[1,2,4]-oxadiazol-3-ylalkyl, 5-methyl[1 ,2,4]oxadiazol-3-ylalkoxy, tetrazol- 1-ylalkyl, tetrazol-1-ylalkoxy, tetrazol-2-ylalkyl, tetrazol-2-ylalkoxy, tetrazol-5-ylalkyl, tetrazol-5-ylalkoxy, 5-methyltetrazol-1-ylalkyl, 5-methyltetrazol-1-ylalkoxy, thiazol-4-ylalkyl, thiazol-4-ylalkoxy, oxazol-4-ylalkyl, oxazol-4-ylalkoxy, 2-oxopyrrolidinylalkyl, 2- oxopyrrolidinylalkoxy, imidazolylalkyl, imidazolylalkoxy, 2-methylimidazolylalkyl, 2- methylimidazolylalkoxy, N-methylpiperazinoalkyl, N-methylpiperazinoalkoxy, N- methylpiperazinoalkoxyalkyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, 4- methylpiperazinyl, morpholinyl, thiomorpholinyl, 2-hydroxymethylpyrrolidinyl, 3- hydroxypyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 3-acetamidomethylpyrrolidinyl, 3-Cι_6-alkoxy- Cι-6-alkylpyrrolidinyl, 4-hydroxypiperidinyl, 4-oxopiperidinyl, 3,5-dimethylmorpholinyl, 4,4- dioxothiomorpholinyl, 4-oxothiomorpholinyl, 2,6-dimethylmorpholinyl, 2-oxoimidazolidinyl, 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxo-[1,3]oxazinyl and 2-oxotetrahydropyrimidinyl. Preferred R2 radicals are phenyl and phenyl substituted by halogen, hydroxyl, cyano, trifluoromethyl, d-6-alkyl, halo-Cι-6-alkyl, hydraxy-d_6-alkyl, C1-6-alkoxy-d-e-alkyl, cyano- d-β-alkyl, carboxy-Cι-6-alkyl, d-6-alkanoyloxy-d-6-alkyl, C1-6-alkoxycarbonyloxy-Cι_6- alkyl, d-6-alkoxycarbonyl, Cι-6-alkoxy or d-6-alkylenedioxy.
R2 radicals which are likewise preferred are phenyl substituted by an L1-T1-L2-T2-L3-T3- L4-T4-L5-U radical where L1 and L2 are preferably absent or d-8-alkylene and L3 is absent and U is hydrogen, d_6-alkyl, C3.6-cycloalkyl, phenylpiperidinyl, phenylpiperazinyl, phenylpyrrolidinyl, phenyl each substituted by d-6-alkyl, d-e-alkoxy, Cι-6-alkylthio, Cι-6- alkylsulphinyl, Cι_6-alkylenedioxy, halogen, benzoyl-d-e-alkyl, halogen-d-6-alkyl, C1-6- alkanoyloxy or hydroxyl; or is naphthyl; or is pyridyl, thienyl, pyrazinyl, triazolyl, imidazolyl, phenyloxadiazolyl, thieπyloxadiazolyl, furyloxadiazolyl, phenyloxazolyl, benzthiazolyl, furyl, pyrimidinyl, nitrobenzthiazolyl, phenyltetrazolyl, piperidinyl, tetrahydropyranyl or morpholinyl.
In the groups T1-T4, preference is given to the definitions (a)-(c), (e)-(h), (k)-(n) and (r)-(t). Examples of particularly preferred R2 radicals are phenyl or phenyl substituted by 2-benzothiazolylthio-C1-6-alkyl, 2~benzyloxy-3-methoxypropoxy, 2-benzoyloxy-3- ethoxypropoxy, 2,3-dihydroxypropoxy, 2-hydroxy-3-benzylamino-propoxy, 2-hydroxy-3- phenoxypropoxy, 2-hydroxy-3-phenylthiopropoxy, 2-methoxy-3-phenoxypropoxy, 2- methoxy-3-benzyloxypropoxy, 2-methyl-3-fluorophenylbutyryloxy-Cι_6-alkoxy, 2-methyl-3- phenoxypropoxy, 2-C2-6-alkenyloxy-4-phenylbutyl, 3,4,5-trimethoxyphenyloxadiazolyl-Cι-6- alkoxy, β-nitro^-benzothiazolylthio-d-e-alkyl, benzamido-C1-6-alkoxy, benzamido-C θ- alkyl, benzo[1,3]dioxolyloxy-d-6-alkoxy, benzoyl-d.6-alkoxy and ketals thereof, benzoyl- C1-6-alkyl and ketals thereof, benzoyl-Cι-6-alkylaminocarbonyl-Cι_6-alkyl, benzoyl-Cι-6- alkoxycarbonyl-d.6-alkyl, benzoyl-d-e-alkylaminocarbonyl, benzoyloxy, benzoyloxy-Ci-6- alkylbenzoyloxy-C1-6-alkoxy, benzoyloxy-C1-6-alkoxy, benzoyloxy-d-6-alkyl, benzthiazolylthio-Cι.6-alkoxy, benzothiazolylthio-Cι-6-alkyl, benzylcarbamoyl-d_6-alkoxy, benzyloxy-C1-6-alkoxycarbonyloxy-Ci-6-alkyl, benzyloxy-Ci-β-alkoxy, benzylthio-d_6-alkoxy, carbamoyloxy-
Cι_6-alkoxy, carbamoyloxy-C -6-alkyl, carboxy-Ci-β-alkoxy, carboxy-d-6-alkyl, cyano, cyano- d-6-alkoxy, cyano-Cι-6-alkyl, cyanophenyl-Cι-6-alkoxy, cyclohexylcarbonyloxy-C -6-alkyl, cyclohexyloxy-Ci-6-alkoxy, cyclopropylcarbonyloxy-Cι-6-alkyl, dioxolanyl-Cι.6-alkoxy, furyloxadiazolyl-C -6-alkoxy, furoyloxy-C .6-aIkoxy, halophenoxy-Cι-6-alkyl, halobenzoyl-Ci. 6-alkoxy, halobenzoyloxy-Cι-6-alkyl, halobenzoyloxy-Cι-6-alkoxy, halobenzyloxy-Ci-6-alkoxy, halogen, halogen-d-6-alkyI, halophenoxy, halophenoxy-C -6-alkoxy, halophenyloxadiazolyl-Cι-6-alkoxy, hydroxyl, hydroxybenzoyloxy-Cι-6-alkyl, hydroxybenzoyloxy-Cι-6-alkoxy, hydroxy-Cι-Θ-alkoxy, hydroxy-Cι_6-alkyl, imidazolylcarbonyIoxy-Cι-6-alkyl, methoxybenzoyl-Cι-6-alkyl, methoxybenzyloxy-d.6- alkoxy, methylenedioxybenzoyl-C1-6-alkoxy, morpholino-Ci_6-alkoxy, morpholinocarbonyloxy-Cι-6-alkoxy, morpholinocarbonyloxy-Cι-6-alkyl, N-methylaminophenylcarbonyloxy-Ci-e-alkyl, N-methylbenzylamino-Cι_6-alkoxy, N-methylpyrrolylcarbonyloxy-Cι-6-alkoxy, N-Cι-6-alkylbenzamido-Cι-6-alkyl, naphthyl-d-6- alkoxy, nicotinoyloxy-Ci-B-alkoxy, nicotinoyloxy-Cι-6-alkyl, Cι-6-alkanoylbenzoyloxy-Cι-6- alkyl, Cι-6-alkanoyloxy-Cι.6-alkoxy, Cι_6-alkanoyloxy-Cι.6-alkyl, Ci-6-alkenylbenzyloxy-Ci.6- alkoxy, d-6-alkenyloxy, Cι.6-alkenyloxybenzyloxy-Cι-6-alkoxy, Cι-6-alkoxy, Ci-e- alkoxybenzoyloxy-Ci-e-alkyl, Cι-6-alkoxycarbonyl, Cι-s-alkoxy-Cι.6-alkyl, d-6- alkoxybenzoylamino-Cι-6-alkyl, Cι-6-alkoxybenzylcarbonyloxy-Cι_6-alkyl, d-6- alkoxybenzyloxy-d-β-alkoxy, Cι-6-alkoxybenzylthio-Cι_6-alkoxy, Cι.6-alkoxycarbonyl-Cι-6- alkoxy, Cι-6-alkoxycarbonyl-Cι-6-alkyl, d-e-alkoxyphenyloxadiazolyl-d-β-alkoxy, d-6- alkoxyphenyloxy-Cι-6-alkoxy, Cι.6-alkyl, d-B-alkylbenzyloxy-d-β-alkoxy, d-6-alkylphenoxy- Cι-6-alkoxy, Cι-6-alkylenedioxy, Cι-6-alkylenedioxybenzyloxy-C -6-alkoxy, Ci-e- alkylsuIphonylbenzoyl-Cι-6-alkoxy, Cι-6-alkylthiobenzoyloxy-Cι-6-alkoxy, Cι-6- alkylthiobenzyloxy-d-6-alkoxy, benzoyloxybenzyl-d-6-alkoxy, hydroxybenzyl-d_6-alkoxy, Cι-β-alkoxybenzyl-d-6-alkoxy, d-6-alkoxybenzylcarbonyloxy-Cι-6-alkoxy, phenoxybenzyloxy-C^e-alkoxy, phenoxycarbonyl-Cι-6-alkyl, phenoxy-Cι-6-alkenyloxy, phenoxy-Cι-6-alkinyloxy, phenyl-C1-6-alkanoylamino-Cι-6-alkyl, phenyl-Cι-6-alkenyloxy, phenyl-C1-6-alkoxy, phenyl-d-6-alkyl, phenyl-Cι-6-alkylaminocarbonyl, phenyl-d-6- alkylcarbonyl-C1-6-alkoxy, phenyl-C1-e-alkylaminocarbonyl-C .6-alkyl, phenylaminocarbonyloxy-Cι_6-alkoxy, phenylaminocarbonyloxy-Cι.6-alkyl, phenylhydroxy- C -e-alkyl, phenyloxadiazolyl-d-6-alkoxy, phenyloxadiazolyl-Cι-6-alkyl, phenyloxazolyl-d-6- alkoxy, phenyloxy-Cι.6-alkoxy, phenylsulphamoyl-Cι-6-alkyl, phenylsulphinyl-Cι.6-alkyl, phenylsulphonyl-d-6-alkoxy, phenylsulphonyl-Cι-6-alkyl, phenyltetrazolylthio-Cι.6-alkyl, phenylthio-d-β-alkoxy, phenylthio-d-6-alkyl, pyrazinylcarbonyloxy-C .6-alkyl, pyridylaminocarbonyloxy-Cι.6-alkoxy, pyridylaminocarbonyloxy-d-6-alkyl, pyridylcarbamoyloxy, pyridyl-Ci-B-alkoxy-d-e-alkoxy, pyridyl-C1-6-alkoxy-C1.6-alkyl, pyridyloxadiazolyl-d-e-alkoxy, pyridylthio-Ci-s-alkyl, pyrimidinyloxy-Cι-6-alkoxy, pyrimidinylthio-Cι-6-alkyl, thienoyloxy-Cι-6-alkoxy, thienoyloxy-C -6-alkyl, thienyloxadiazolyl- Cι_6-alkoxy, triazolyl-Cι.6-alkoxy, trifluoromethylbenzyloxy-Cι.6-alkoxy, or trifluoromethyl.
Examples of particularly preferred R1 radicals are phenyl, 3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl and 4H-benzo[1,4]oxazin-3-on-6-yl which may be substituted by 1-3 halogen or Cι-6-alkoxy-Cι-6-alkyl.
Examples of particularly preferred R2 radicals are phenyl substituted by C1-6-alkoxy, Cι_B- alkoxybenzyloxy-d-e-alkoxy, halophenoxy-C1-6-alkoxy or halophenylpyrrolidin-3-yIoxy.
Examples of preferred X radicals are methylene and >CO.
Examples of particularly preferred Z radicals are -O- and -N^Cs-B-cycloalkylJ-d-e-alkylene-.
The compounds of the formula (I) or (II) may be prepared in a similar manner to the preparation processes disclosed in the literature. Details on the specific preparation variants can be taken from the examples.
The compounds of the formula (I) or (II) may also be prepared in optically pure form. The separation into antipodes can be effected by methods known per se, either preferably at an earlier synthetic stage by salt formation with an optically active acid, for example (+)- or (-)-mandelic acid, and separation of the diastereomeric salts by fractional crystallization, or preferably at a relatively late stage by derivatizing with a chiral auxiliary building block, for example (+)- or (-)-camphanoyl chloride, and separation of the diastereomeric products by chromatography and/or crystallization and subsequent cleavage of the bond to give the chiral auxiliary. The pure diastereomeric salts and derivatives may be analysed to determine the absolute configuration of the piperidine present with common spectroscopic methods, and X-ray spectroscopy on single crystals constitutes a particularly suitable method.
A preferred method for the preparation of optically pure compounds of the formula (IA) or (IIA) consists in the construction of the basic piperazine structure by reacting an oxazolidine with an amine to give a piperazinedione according to the following exemplary scheme:
Figure imgf000019_0001
Further details and alternative preparation processes are specified in Tetrahedron Asymmetry 12 (2001), 1293-1302 and literature cited there.
Another preferred method for the preparation of optically pure compounds of the formula (IA) or (IIA) consists in the construction of the basic piperaziπone structure by reacting a substituted epoxide derivative with a 2-amino-acetamide derivative, followed by alcohol activation and subsequent ring closure to give a piperazinone according to the following exemplary scheme:
Figure imgf000019_0002
Alternative preparation processes are specified in Tetrahedron Letters 39 (1998), 7459- 7462 and literature cited there.
Prodrug derivatives of the compounds described in the present context are derivatives thereof which, on in vivo application, release the original compound by a chemical or physiological process. A prodrug may be converted to the original compound, for example, when a physiological pH is attained or by enzymatic conversion. Prodrug derivatives may, for example, be esters of freely available carboxylic acids, S- and O-acyl derivatives of thiols, alcohols or phenols, and the acyl group is as defined in the present context. Preference is given to pharmaceutically useable ester derivatives which are converted by solvolysis in physiological medium to the corresponding carboxylic acid, for example lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or disubstituted lower alkyl esters such as lower ω-(amino, mono- or dialkylamino, carboxyl, lower alkoxycarbonyl) - alkyl esters or such as lower α-(alkanoyloxy, al oxycarbonyl or dialkylaminocarbonyl) - alkyl esters; as such, pivaloyloxymethyl esters and similar esters are utilized in a conventional manner.
Owing to the close relationship between a free compound, a prodrug derivative and a salt compound, a certain compound in this invention also encompasses its prodrug derivative and salt form, where these are possible and appropriate.
The compounds of the formula (I) or (II), or preferably of the formula (IA) or (IIA), and their pharmaceutically useable salts have inhibiting action on the natural enzyme renin. The latter passes from the kidneys into the blood and there brings about the cleavage of angiotensinogen to form the decapeptide angiotensin I which is then cleaved in the lung, the kidneys and other organs to the octapeptide angiotensin II. Angiotensin II increases the blood pressure both directly by arterial constriction and indirectly by the release of the hormone aldosterone which inhibits the release of the sodium ion from the adrenal glands, which is associated with a rise in the extracellular liquid volume. This rise can be attributed to the action of angiotensin II itself or of the heptapeptide angiotensin III formed therefrom as a cleavage product. Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I and, as a consequence thereof, the formation of a smaller amount of angiotensin ll. The reduced concentration of this active peptide hormone is the immediate cause of the hypotensive action of renin inhibitors.
One experimental method of detecting the action of renin inhibitors is by means of in vitro tests, in which the reduction of the formation of angiotensin I in different systems (human plasma, purified human renin together with synthetic or natural renin substrate) is measured. One in vitro test which is used is the one according to Nussberger et. al (1987) J. Cardiovascular Pharmacol., Vol. 9, p. 39-44 which follows. This test measures the formation of angiotensin I in human plasma. The amount of angiotensin I formed is determined in a subsequent radioimmunoassay. Which action inhibitors have on the formation of angiotensin I is tested in this system by the addition of different concentrations of these substances. The IC6o refers to that concentration of the particular inhibitor which reduces the formation of angiotensin I by 50%. The compounds of the present invention exhibit inhibiting actions in the in vitro systems at minimum concentrations of about 10"3 to about 10"10 mol/l.
In salt-depleted animals, renin inhibitors bring about a blood pressure decrease. Human renin differs from renin of other species. To test inhibitors of human renin, primates (marmosets, Callithrixjacchus) are used because human renin and primate renin are substantially homologous in the enzymatically active region. One in vivo test which is used is as follows: the test compounds are tested on normotensive marmosets of both genders and having a bodyweight of about 350 g which are conscious, able to move freely and in their normal cages. Blood pressure and heart rate are measured using a catheter in the descending aorta and recorded radiometrically. The endogenous release of renin is stimulated by the combination of 1-week low-salt diet with a single intra-muscular injection of furosemide (5-(aminosulphonyl)-4- chloro-2-[(2-furanylmethyl)amino]benzoicacid) (5 mg/kg). 16 hours after the injection of furosemide, the test substances are administered either directly into the femoral artery by means of an injection cannular or into the stomach by gavage as a suspension or solution, and their effect on blood pressure and heart rate was evaluated. The compounds of the present invention effectively reduce blood pressure in the in vivo test described at doses of about 0.003 to about 0.3 mg/kg i.v. and at doses of about 0.3 to about 30 mg/kg p.o.
The compounds of the formula (I) or (II), or preferably of the formula (IA) or (IIA), and their pharmaceutically useable salts may find use as curative compositions, for example in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered enterally, such as orally, for example in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, for example in the form of nasal sprays, rectally, for example in the form of suppositories, ortransdermally, for example in the form of ointments or patches. The administration may also be parenteral, such as intramuscular or intravenous, for example in the form of injection solutions.
To prepare tablets, coated tablets, sugar-coated tablets and hard gelatine capsules, the compounds of the formula (I) or (II), or preferably of the formula (IA) or (IIA), and the pharmaceutically useable salts thereof, may be processed with pharmaceutically inert, inorganic or organic excipients. Such excipients used, for example for tablets, sugar- coated tablets and hard gelatine capsules, may be lactose, corn starch, or derivatives thereof, talc, stearic acid or salts thereof etc. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc.
Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.
Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, bile acids, lecithin, etc.
Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.
The pharmaceutical preparations may additionally also comprise preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourings, salts for altering the osmotic pressure, buffers, coatings or antioxidants. They may also comprise other therapeutically valuable substances.
The present invention further provides the use of the compounds of the formula (I) or (II), or preferably of the formula (IA) or (IIA), and the pharmaceutically useable salts thereof, in the treatment or prevention of hypertension and heart failure, and also glaucoma, cardiac infarction, kidney failure and restenoses of mammals, especially of human beings.
The compounds of the formula (I) or (ll), or preferably of the formula (IA) or (UA), and the pharmaceutically useable salts thereof, may also be used in combination with one or more agents having cardiovascular action, for example σ- and β-blockers such as phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol etc.; vasodilators such as hydralazine, minoxidil, diazoxide, nitroprusside, flosequinan etc.; calcium antagonists such as amrinone, bencyclan, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil. gallopamil, nifedipine etc.; ACE inhibitors such as cilazapril, captopril, enalapril, lisinopril etc.; potassium activators such as pinacidil; anti-serotoninergics such as ketaπserin; thromboxane-synthetase inhibitors; neutral endopeptidase inhibitors (NEP inhibitors); angiotensin II antagonists; and also diuretics such as hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamteren, chlorthalidone etc.; sympatholytics such as methyldopa, clonidine, guanabenz, reserpine; and other agents which are suitable for the treatment of hypertension, heart failure or vascular diseases in humans and animals which are associated with diabetes or renal disorders such as acute or chronic renal failure. Such combinations may be employed separately or in preparations which comprise a plurality of components.
Further substances which can be used in combination with the compounds of the formulae (I), (IA), (ll) or (UA) are the compounds of classes (i) to (ix) on page 1 of WO 02/40007 (and also the preferences and examples further listed therein) and the substances specified on pages 20 and 21 of WO 03/027091.
The dose may vary within wide limits and has of course to be adapted to the individual circumstances in each individual case. In general, for oral administration, a daily dose of about 3 mg to about 3 g, preferably about 10 mg to about 1 g, for example about 300 mg, per adult (70 kg), divided into preferably 1-3 individual doses which may, for example, be of equal size, may be appropriate, although the upper limit specified may also be exceeded if this should be found to be appropriate; typically, children receive a lower dose corresponding to their age and bodyweight.
The examples which follow illustrate the present invention. All temperatures are reported in degrees Celsius, pressures in mbar. Unless stated otherwise, the reactions take place at room temperature. The abbreviation "Rf = xx (A)" means, for example, that the Rf value xx is obtained in the solvent system A. The ratio of the solvents relative to one another is always reported in parts by volume. Chemical names of end products and intermediates were obtained with the aid of the program AutoNom 2000 (Automatic Nomenclature). Unless stated otherwise, the absolute stereochemistry of the 2-substituted piperazine unit is (2R).
HPLC gradients on Hypersil BDS C-18 (5 μm); column: 4 x 125 mm
I 90% water*/10% acetonitrile* to 0% water*/100% acetonitrile* in 5 minutes + 2.5 minutes (1.5 ml/min); *: containing 0.1 % trifluoroacetic acid
II 95% water*/5% acetonitrile* to 0% water*/100% acetonitrile* in 40 minutes (0.8 ml/min); *: containing 0.1% trifluoroacetic acid
The following abbreviations are used:
Rf ratio of distance which a substance travels to distance of the eluent front from the start point in thin layer chromatography Rt retention time of a substance in HPLC (in minutes) m.p. melting point (temperature)
General method A: (de-Boc I)
The solution of 1 mmol of "Boc derivative" in 5 ml of chloroform is admixed successively with 15 ml of methanol and 2.5 ml of 2N HCI and stirred at 60°C over 18 hours. The reaction mixture is cooled to room temperature, poured onto 1M aqueous sodium hydrogencarbonate solution (40 ml) and extracted with tert-butyl methyl ether (2 x 60 ml). The organic phases are washed with brine (1 x 60 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO 60F).
General method B: (de-Cbz)
The solution of 1 mmol of "Cbz derivative" in 15 ml of tetrahydrofuran is hydrogenated in the presence of 100-200 mg of 10% Pd/C at 15-20°C over 2-4 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO260 F).
General method C: (9-BBN reduction)
The solution of 1 mmol of "lactam" in 3 ml of tetrahydrofuran is admixed with 9-BBN (0.5M in tetrahydrofuran) (3.2-6.4 equiv.) and stirred at reflux over 1-2 hours (checking of conversion with HPLC). The reaction mixture is cooled to room temperature, admixed with ethanolamine (3.2-6.4 equiv.) and concentrated by evaporation. The residue is stirred in 1:1 ethyl acetate-heptane (30 ml) at 0°C overnight and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO260F).
General method D: (de-Boc II)
A solution of 0.033 mmol of "Boc derivative " in 1 ml of dichloromethane is admixed with 0.3 ml of trifluoroacetic acid. The reaction mixture is stirred at room temperature over 1 hour. The reaction mixture is concentrated by evaporation and taken up in 5 ml of dichloromethane. The organic phase is washed with 5 ml of 0.5 M NaOH. The aqueous phase is extracted with dichloromethane (2 * 5 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F). Example 1:
6-(1-(4-f3-(2-Methoxybenzyloxy)propoxy1phenyl}piperazin-2-ylmethoxy)-4-(3- methoxypropyl)-4H-benzori,41oxazin-3-one
Analogously to method A, 0.112 g of tert-butyl 4-{4-[3-(2- methoxybenzyloxy)propoxy]phenyl}-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H- benzo[1,4]oxazin-6-yloxymethyl]piperazine-1-carboxylate is used to prepare the title compound.
The starting materials are prepared as follows: a) tert-Butyl 4-(4-r3-(2-methoxybenzyloxy)propoxylphenyl}-3-r4-(3-methoxypropyπ-3-oxo- 3,4-dihvdro-2H-benzon ,4loxazin-6-yloxymethvnpiperazine-1-carboxylate
A mixture of 0.085 g of 1-(3-(2-methoxybenzyloxy)propoxy)-4-bromobenzene, 0.070 g of tert-butyl 3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxymethyl]- piperazine-1-carboxylate, 0.023 g of sodium tert-butoxide and 0.008 g of tris(dibenzylidenacetone)dipalladium(0)achloroform complex is initially charged under argon in a Schlenk apparatus, admixed with a solution of 0.003 g of tri-tert-butylphosphine in 2 ml of toluene (prepared in a Schlenk apparatus under argon) and stirred at 120°C over 1 hour. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf = 0.44 (1:1 EtOAc-heptane); Rt = 4.92.
b) tert-Butyl 3-[4-(3-methoxypropyl)-3-oxo-3.4-dihvdro-2H-benzof1,41oxazin-6- yloxymethyll piperazine- 1 -carboxylate
A solution of 1.43 g of tert-butyl 4-benzyl-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H- benzo[1,4]oxazin-6-yloxymethyl]piperazine-1-carboxylate in 100 ml of ethanol is hydrogenated in the presence of 0.145 g of 10% Pd/C at room temperature over 16 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO260F). Rf = 0.63 (9:1 dichloromethane-methanol); Rt = 3.28. c) tert-Butyl 4-benzyl-3-r4-(3-methoxypropyπ-3-oxo-3.4-dihvdro-2H-benzo[1 ,41oxazin-6- yloχymethyllpiperazine-1-Garboχylate
A suspension of 0.041 g of copper(l) iodide, 0.079 g of [1, 0]phenanthroline, 0.986 g of caesium carbonate, 0.75 g of 6-iodo-4-(3-methoxypropyl)-4H-benzo[1 ,4]oxazin-3-one and 1.32 g of tert-butyl 4-benzyl-3-hydroxymethylpiperazine-1-carboxylate in 10 ml of toluene is stirred in a sealed Supelco bottle at 110°C over 40 hours. The reaction mixture is cooled to room temperature and filtered through silica gel, and the filtercake is washed with ethyl acetate. The filtrate is concentrated by evaporation - the title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO260F). Rf = 0.40 (1:1 EtOAc-heptane); Rt = 3.83.
d) tert-Butyl 4-benzyl-3-hvdroxymethylpiperazine-1 -carboxylate
6.29 g of 2-mercaptobenzoic acid and a solution of 0.57 g of 1 ,4-bis(diphenyl- phosphino)butane, 0.78 g of bis(dibenzylidenacetone)palladium in 5 ml of tetrahydrofuran are added at room temperature to the solution of 6.70 g of (4-allyl-1-benzylpiperazin-2- yl)methanol in 15 ml of tetrahydrofuran. After 30 minutes, the reaction mixture is concentrated by evaporation - the residue is admixed with 120 ml of dioxane, 120 ml of 1 N NaOH and 7.12 g of di-tert-butyl dicarbonate and stirred at room temperature over 16 hours. The reaction mixture is diluted with brine and extracted with ethyl acetate (5x) - the combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow solid from the residue by means of flash chromatography (SiO260F). Rf = 0.22 (1:1 EtOAc-heptane); Rt = 3.00.
e) (4-Allyl-1-benzyl-piperazin-2-yl)methanol
A solution of 10.70 g of 7-allyl-3-phenyltetrahydrooxazolo[3,4-a]pyrazine-5,8-dione (cis/trans mixture) in 800 ml of tetrahydrofuran is added at room temperature to the suspension of 14.64 g of lithium aluminium hydride in 1500 ml of tetrahydrofuran. The reaction mixture is stirred at reflux over 19 hours and subsequently cooled to 0°C. 15 ml of water, 15 ml of 3 N NaOH and once again 15 ml of water are successively added dropwise and the suspension is stirred at room temperature over 2 hours. The reaction mixture is clarified by filtration through Hyflo and concentrated by evaporation. The residue is diluted with dichloromethane and washed successively with 1 N NaOH (2x) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO260F). Rf = 0.60 (5:1 EtOAc-ethanol); Rt = 1.93. f) 7-AHyl-3-phenyltetrahvdrooxazolo.3,4-alpyraane-5,8-dione (cis/trans mixture)
A solution of 46 g of methyl 3-(2-chloroacetyl)-2-phenyloxazolidine-4-carboxylate (cis/trans mixture) [Tet Asym. (2001), 12, 1293-1302], 8.03 g of allylamine and 19.3 ml of triethylamine in 1 of acetonitrile is stirred at reflux over 48 hours and subsequently concentrated by evaporation. The residue is taken up in ethyl acetate, washed with 1 N HCI (2x), dried over sodium sulphate and concentrated by evaporation. The title compounds are obtained as colourless oils from the residue by means of flash chromatography (SiO260F). Diastereomer I: Rf = 0.36 (1:1 EtOAc-heptane); Rt = 3.20. Diastereomer II: Rf = 0.36 (1 :1 EtOAc-heptane); Rt = 3.08.
g) 6-lodo-4-,3-methoxypropyl)-4H-benzo.1 ,41oxazin-3-one
A mixture of 0.064 g of copper(l) iodide, 2.00 g of 6-bromo-4-(3-methoxypropyl)-4H- benzo[1,4]oxazin-3-one and 2.02 g of sodium iodide is initially charged under argon in a Schlenk apparatus, admixed with 0.088 ml of rac-N,N'-dimethylcyclαhexane-1,2-diamine and 6 ml of dioxane, and stirred at 110°C over 19 hours. The reaction mixture is cooled to room temperature, diluted with aqueous ammonia (30%), poured into water and extracted with dichloromethane (3x). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow solid from the residue by means of flash chromatography (SiO260F). Rf = 0.55 (1:1 EtOAc-heptane); Rt = 4.48.
h) 6-Bromo-4-(3-methoxypropyl.-4H-benzo[1,41oxazin-3-one
A suspension of 9.87 g of 6-bromo-4H-benzo[1 ,4]oxazin-3-one and 9.52 ml of 1-chloro-3- methoxypropane, 43.30 g of potassium fluoride on alumina, 0.14 g of potassium iodide and
500 ml of acetonitrile is stirred at reflux over 40 hours. The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation to dryness. The title compound is obtained as yellow-brown crystals from the residue by means of recrystallization from ethyl acetate.
Rf = 0.43 (1:1 EtOAc-heptane); Rt = 4.27; m.p. 192-195°C.
i) 1-(3-(2-Methoxybenzyloxy)propoxy)-4-bromobenzene A suspension of 5.1 g of 4-bromophenol, 11.36 g of 3-(2-methoxybenzyloxy)propyl toluene-4-sulphonate and 14.13 g of caesium carbonate in 50 ml of acetonitrile is stirred at 85°C over 6 hours. The reaction mixture is cooled to room temperature, diluted with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (2x).The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO260F). Rf = 0.58 (1 :3 EtOAc-heptane); Rt = 5.60.
j) 3-(2-Methoxybenzyloxy)propyl toluene-4-sulphonate
57.04 g of p-toluenesulphonyl chloride are added in portions at room temperature to the solution of 50 g of 3-(2-methoxybenzyloxy)propan-1-ol, 53 ml of triethylamine and 3.25 g of
4-dimethylaminopyridine in 500 ml of dichloromethane. The reaction mixture is stirred at room temperature over 1 hour, diluted with dichloromethane and subsequently washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F).
Rf = 0.36 (1 :3 EtOAc-heptane); Rt = 4.93.
Example 2:
6-(1-(4-r3-(2-Methoxybenzyloxy)propoxylphenyl}piperazin-2-ylmethoxy)-4-(3- methoxypropyl)-3,4-dihvdro-2H-benzoH.41oxazine
Analogously to method C, 0.070 g of 6-(1-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}- piperazin-2-ylmethoxy)-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 1) is used to prepare the title compound.
EΞxample 3:
N-Benzyl-N-cvclopropyl-1-(4-methoxyphenyl.piperazine-2-carboxamide Analogously to method D, 0.0153 g of tert-butyl 3-(benzylcyclopropylcarbamoylH-(4- methoxyphenyl)piperazine-1-carboxylate is used to prepare the title compound.
The starting materials are prepared as follows: a) tert-Butyl 3-(benzylcvclopropylcarbamoyl.-4-(4-methoxyphenvQpiperazine-1- carboxylate Analogously to Example 1a, 0.026 g of 4-bromoanisole and 0.0325 g of tert-butyl 3- (benzylcyclopropylcarbamoyl)piperazine-l-carboxylate are reacted. The title compound is obtained as a yellowish oil. Rf = 0.40 (1:1 EtOAc-heptane); Rt = 4.20. b) tert-Butyl 3-(benzylcyclopropylcarbamoyl)piperazine-1-carboxylate The solution of 0.0685 g of 1-benzyl 4-tert-butyl 2-
(benzylcyclopropyIcarbamoyl)piperazine-1,4-dicarboxyIate in 3 ml of methanol is hydrogenated in the presence of 0.060 g of 10% Pd/C at room temperature over 2 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The crude title compound is obtained as a colourless oil from the residue.
Rf = 0.05 (1:1 EtOAc-heptane); Rt = 3.58.
c) 1 -Benzyl 4-tert-butyl 2-(benzylcvclopropylcarbamoyl)piperazine- ,4-dicarboxylate 0.069 ml of chloro-N,N-trimethylpropenylamine is added at 0°C to a solution of 0.1 g of 1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2-carboxylic acid in 2 ml of dichloromethane. The solution is stirred at 0°C for 3 hours. Subsequently, the solution is introduced by cannula at 0°C into a solution of 0.062 g of benzylcyclopropylamine, 0.022 ml of pyridine and 1,6 mg of 4-dimethylaminopyridine in 2 ml of dichloromethane. The reaction mixture is warmed slowly to room temperature over 10 hours. The solution is admixed with 3 ml of 1 M HCI and the organic phase is removed. The aqueous phase is extracted with dichloromethane (2 x 5 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO260F).
Rf = 0.56 (1:1 EtOAc-heptane); Rt = 5.28.
d) 1-Benzyloxycarbonyl-4-tert-butoxylcarbonylpiperazine-2-carboxylic acid 0.37 ml of benzyl chloroformate is added to a mixture of 0.5 g of 1-tert- butoxycarbonylpiperazine-3-carboxylic acid, 7 ml of ethyl acetate and 7 ml of saturated aqueous sodium hydrogencarbonate solution. The reaction mixture is stirred at room temperature for 1.5 hours. 15 ml of water and 15 ml of ethyl acetate are added and the phases are separated. The organic phase is washed with 20 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO260F).
Rf = 0.25 (EtOAc + 1% AcOH); Rt = 4.12. Example 4: N-(2-Chlorobenzyl)cvclopropyl-1-(4-f2-(2,5-difluorophenoxy)ethoxylphenyl}piperazine-2- carboxamide
Analogously to method D, 0.061 g of tert-butyl 3-[(2-chlorobenzyl)cyclopropylcarbamoyl]-4-
{4-[2-(2,5-difluorophenoxy)ethoxy]phenyl}piperazine-1-carboxylate is used to prepare the title compound.
The starting materials are prepared as follows: a) tert-Butyl 3-r(2-chlorobenzvπcyclopropylcarbamovn-4-{4-f2-(2,5-difluorophenoxy)- ethoxylphenyl}piperazine-1-carboxylate
Analogously to Example 1a, 0.1 g of tert-butyl 3-[(2-chlorobenzyl)cyclopropylcarbamoyl]- piperazine-1-carboxylate and 0.1547 g of 2-[2-(4-bromophenoxy)ethoxy]-1,4- difluorobenzene are reacted. The title compound is obtained as a yellow oil.
Rf = 0.64 (1:1 EtOAc-heptane); Rt = 5.18.
N.B.: Instead of tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate is used as the ligand.
b) tert-Butyl 3-f(2-chlorobenzyl)cvclopropylcarbamovnpiperazine-1-carboxylate Analogously to Example 3b, 1.17 g of 1 -benzyl 4-tert-butyl 2-[(2-chIorobenzyl)cyclopropyl- carbamoyl]piperazine-1,4-dicarboxylate are reacted. The crude title compound is obtained as a colourless oil.
Rf = 0.26 (dichloromethane-methanol-25% cone, ammonia = 200:10:1); Rt = 3.76.
c) -Benzyl 4-tert-butyl 2-)T2-chlorobenzyl,cvclopropylcarbarnoyripiperazine-1.4- dicarboxylate
Analogously to Example 3c, 1 g of 1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2- carboxylic acid (Example 3) and 0.8049 g of (2-chlorobenzyl)cyclopropyIamine are reacted. The title compound is obtained as a white foam. Rf = 0.29 (1:1 EtOAc-heptane); Rt = 5.54.
d) (2-Chlorobenzyl)cyclopropylamine
2 ml of acetic acid are added to a solution of 2 g of cyclopropylamine, 4.924 g of 2- chlorobenzaldehyde and 6.8 g of sodium cyanoborohydride in 25 ml of ethanol. The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation. The title compound is obtained as an orange-yellow oil from the residue by means of flash chromatography (SiO260F). Rf = 0.60 (dichloromethane-methanol-25% cone, ammonia = 200:20:1); Rt = 2.44. e) 2-r2-(4-Bromophenoxy)ethoxyl-1,4-difluorobenzene
A solution of 4.78 g of 2-(2,5-difluorophenoxy)ethyl toluene-4-sulphonate, 3.17 g of 4-bromophenol and 9.11 g of caesium carbonate in 100 ml of acetonitrile is heated to reflux for 5 hours. The mixture is cooled to room temperature and poured onto saturated aqueous sodium hydrogencarbonate solution. Extraction is effected with tert-butyl methyl ether (3 * 50 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as beige crystals from the residue. Rf = 0.58 (1:1 EtOAc-heptane); Rt = 5.33.
f) 2-(2,5-Difluorophenoxy.ethyl toluene-4-sulphonate
A solution of 32.6 g of ethylene glycol bis(toluene~ -sulphonate), 3.34 g of 2,5- difluorophenol and 15.9094 g of caesium carbonate in 120 ml of acetonitrile is heated to reflux for 1 hour. The mixture is cooled to room temperature and poured onto saturated aqueous sodium hydrogencarbonate solution. Extraction is effected with tert-butyl methyl ether (3 * 60 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf = 0.30 (1:2 EtOAc-heplane); Rt = 4.79.
Example 5:
(rac)-N-Benzylcvclopropyl-1-{4-[2-(2,5-difluorophenoxy)ethoxylphenyl piperazine-2- carboxamide
Analogously to method D, 0.0893 g of (rac)-tert-butyl 3-[(benzyl)cycIopropylcarbamoyl]-4-
{4-[2-(2,5-difluorophenoxy)ethoxy]phenyl}piperazine-1-carboxylate is used to prepare the title compound.
The starting materials are prepared as follows: a) (rac)-tert-Butyl 3-r(benzyl)cyclopropylcarbamoyl]-4-{4-[2-(2-5 difluorophenoxy)ethoxylphenyl)piperazine-1-carboxylate Analogously to Example 1a, 0.15 g of (rac)-tert-butyl 3-[(benzyl)cyclopropylcarbamoyl]- piperazine-1 -carboxylate and 0.2541 g of 2-[2-(4-bromophenoxy)ethoxy]-1 ,4- difluorobenzene are reacted. The title compound is obtained as a yellow wax. Rf = 0.50 (1:1 EtOAc-heptane); Rt = 4.91. N.B.: Instead of tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate is used as the ligand.
b) (rac.-tert-Butyl 3-.(benzv0cvclopropylcarbamoyllpiperazine-1-carboxylate Analogously to Example 3b, 1.19 g of (rac)-1 -benzyl 4-tert-butyl 2-[(benzyl)cyclopropyl- carbamoyl]piperazine-1,4-dicarboχylate are reacted. The crude title compound is obtained as a colourless oil.
Rf = 0.23 (dichloromethane-methanol-25% cone, ammonia = 200:10:1); Rt = 3.66.
c) (rac)-1 -Benzyl 4-tert-butyl 2-[(benzyl)cvclopropylcarbamoyllpiperazine-1 ,4- dicarboxylate
Analogously to Example 3c, 1 g of (rac)-1-benzyloxycarbonyl-4-tert-butyloxycarbonyl- piperazine-2-carboxylic acid and 0.6124 g of benzylcyclopropylamine are reacted. The title compound is obtained as a colourless oil. Rf = 0.63 (1:1 EtOAc-heptane); Rt = 5.28.
Example 6:
(rac_-1-f4-r3-(2-Methoxy-benzyloxy)-propoxy1-phenyl)-6-[4-(3-methoxy-propyl.-3,4-dihvdro-
2H-benzoπ ,41oxazin-6-yloxymethyn-piperazin-2-one
0.027 g of dibasic sodium phosphate and 0.086 g of 10% sodium amalgam are added to a solution of 0.029 g of (rac)-1-{4-[3-(2-Methoxy-benzyloxy)-propoxy]-phenyl}-6-[4-(3- methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxymethyl]-4-(toluene-4-sulfonyl)- piperazin-2-one in 2 ml of methanol. Additional 10% sodium amalgam (0.090 g) is added after 1.5 hours and again after 2.5 hours. The reaction mixture is worked up after 6 hours by diluting with water and ethyl acetate - the decanted organic layer is dried over sodium sulphate and concentrated by evaporation. . The title compound is obtained from the residue by means of flash chromatography (SiO260F).
The starting materials are prepared as follows: a) (rac)-1-{4-l3-(2-Methoxy-benzyloxy)-propoxyl-phenyll-6-[4-(3-methoxy-propyl)-3,4- dihydro-2H-benzo 1 ,41oxazin-6-yloxymethyll-4-(toluene-4-sulfonyl)-piperazin-2-one 0.0036 g of sodium hydride (60% dispersion in mineral oil) are added to a solution of 0.070 g of (rac)-toluene-4-sulphonic acid 2-[({4-[3-(2-methoxy-benzyloxy)-propoxy]- phenylcarbamoyl}-methyl)-(toluene-4-sulfonyl)-amino]-1-[4-(3-methoxy-propyl)-3,4-dihydro- 2H-beπzo[1,4]oxazin-6-yloxymethyl]-ethyl ester in 3 ml of tetrahydrofuran. After 30 minutes, the reaction mixture is poured into a mixture of ethyl acetate and a 1 M aqueous potassium bisulphate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO260F). Rf = 0.37 (2:1 EtOAc-heptane); Rt = 5.46.
b) (rac)-Toluene-4-sulphonic acid 2-r(f4-r3-(2-methoxy-benzyloxy)-propoxy1- phenylcarbamoyl -methvπ-(toluene-4-sulfonyl)-amino1-1-r4-(3-methoxy-propyl)-3.4- dihydro-2H-benzori ,41oxazin-6-yloxymethyll-ethyl ester
A solution of 0.142 g of (rac)-2-{2-hydroxy-3-[4-(3-methoxy-propyl)-3,4-dihydro-2H- benzo[1,4]oxazin-6-yloxy]-propylamino}-N-{4-[3-(2-methoxy-benzyloxy)-propoχy]-phenyl}- acetamide, 0.184 g of p-toluenesulphonyl chloride, 0.134 ml of triethylamine and 0.001 g of dimethyl-pyridin-4-yl-amine in 5 ml of dichloromethane is stirred at room temperature for 76 hours. The reaction mixture is then concentrated by evaporation - the title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO260F). Rf = 0.20 (1:1 EtOAc-heptane); Rt = 5.75.
c) (rac)-2-f2-Hvdroxy-3-f4-(3-methoxy-propyl)-3,4-dihvdro-2H-benzori,41oxazin-6-yloxyl- propylamino}-N-f4-.3-,2-methoxy-benzyloxy)-propoxyl-phenyl}-acetamide
A solution of 0.197 g of (rac)-4-(3-Methoxy-propyl)-6-oxiranylmethoxy-3,4-dihydro-2H- benzo[1,4]oxazine, 0.974 g of 2-amino-N-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}- acetamide and 0.297 ml of triethylamine in 20 ml of methanol is stirred at 55°C. After 12 hours, the reaction mixture is cooled to room temperature and concentrated by evaporation. The title compound is obtained as a red-orange oil from the residue by means of flash chromatography (SiO260F). Rf = 0.62 (dichloromethane-methanol-25% cone, ammonia = 200:20:1); Rt = 4.37.
d) 2-Amino-N-{4-f3-(2-methoxy-benzyloxy)-propoxy1-phenylVacetamide
1 ml of a HCI in dioxane solution (4 N) is added to a solution of 1.67 g of ({4-[3-(2-Methoxy- benzyloxy)-propoxy]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl ester in 5 ml of dioxane. An additional 1 ml of the 4 N HCI/dioxane solution is added after 2.5 hours. After stirring overnight, the reaction mixture is concentrated by evaporation. The title compound is obtained as a yellow oil and used without purification in the next step. Rf = 0.42 (dichloromethane-methanol-25% cone, ammonia = 200:20:1); Rt = 3.51. e) ((4-r3-(2- ethoxy-benzyloxyVpropoxyl-phenylcarbamoyl)-methyl)-carbamic acid tert- butyl ester 0.684 g of tert-butoxycarbonylamino-acetic acid and 2.71 ml of triethylamine are added at room temperature to a solution of 1.10 g of 4-[3-(2-methoxy-benzyloxy)-propoxy]- phenylamine in 50 ml of dichloromethane. The reaction mixture is cooled to 0°C and treated with 1.56 ml of 2,4,6-tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (50% in ethyl acetate). After 3 hours, the reaction is diluted with tert-butyl methyl ether, washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a red-brown oil and used without purification in the next step. Rf = 0.29 (1:1 EtOAc-heptane); Rt = 4.65.
f) 4-f3-(2-Methoxy-benzyloxy,-propoxyl-phenylamine
A Schlenk apparatus is charged under argon with a mixture of 2.0 g of 1-(3-(2- methoxybenzyloxy)propoxy)-4-bromobenzene (Example 1i), 0.064 g of tri-tert- butylphosphine, 0.166 g of bis(dibenzylidenacetone)palladium(0), 6.33 ml of lithium bis(trimethylsilyl)amide (1 M in hexanes) in 15 ml of toluene. After 16 hours, the reaction mixture is diluted with diethyl ether and washed with 1 N HCI and 1 N NaOH, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a dark brown oil from the residue by means of flash chromatography (SiO260F). Rf = 0.30 (1:1 EtOAc-heptane); Rt = 3.41.
g) (rac)-4-(3-Methoxy-propyπ-6-oxiranylmethoxy-3.4-dihvdro-2H-benzoπ,41oxazine 0.983 g of sodium hydride (60% dispersion in mineral oil) is added to a solution of 4.99 g of 4-(3-Methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ol in 200 ml of N,N- dimethylformamide. After stirring for 30 minutes, 5.0 g of (rac)-toluene-4-sulfonic acid oxiranylmethyl ester is added in portions. The reaction mixture is worked up after 1.5 hours by diluting with water and extracting with tert-butyl methyl ether (3X) - the combined organic layers are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO260 F).
Rf = 0.35 (1:1 EtOAc-heptane); Rt = 3.85.
h) 4-(3-Methoxy-propyl -3,4-dihvdro-2H-benzof1 ,4loxazin-6-ol 4.5 ml of a borane«tetrahydrofuran solution (1 M) is added dropwise via syringe to a solution of 0.527 g of 1-(6-Hydroxy-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-methoxy-propan- 1-one in 13 ml of tetrahydrofuran. After stirring overnight, the reaction mixture is concentrated by evaporation - the residue is diluted with methanol and the mixture is re- concentrated by evaporation. This procedure is repeated - the title compound is obtained as a light brown oil from the residue by means of flash chromatography (SiO2 60F). Rf = 0.33 (1:1 EtOAc-heptane); Rt = 3.03.
i) 1-(6-Hvdroxy-2,3-dihydro-benzof1,41oxazin-4-yl)-3-methoxy-propan-1-one A suspension of 0.58 g of 3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ol in 25 ml of dichloromethane is treated with 0.613 ml of pyridine and then cooled to 0°C. 0.906 ml of 3- methoxypropionyl chloride are added and the reaction mixture is allowed to slowly warm to room temperature. After stirring for 2.5 hours, the reaction mixture is concentrated by evaporation -the residue is partitioned between ethyl acetate and water. The organic phase is washed with 1 N HCI, water and brine, dried over sodium sulphate and concentrated by evaporation. The crude ester-amide intermediate is dissolved in 30 ml of methanol and treated with 1.2 ml of 1 N aqueous potassium hydroxide solution. After 2 hours, the reaction mixture is concentrated by evaporation - the residue is diluted with ethyl acetate, water and 1 N HCI. The separated organic phase is washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a light brown oil from the residue by means of flash chromatography (SiO2 60F). Rf = 0.54 (EtOAc); Rt = 2.62.
According to the process described in Example 6, the following compound is prepared in an analogous manner:
Example 7:
1-f4-[1-(3-Fluoro-phenyl)-ρyrrolidin-3(S)-yloxyl-phenylV6(R.S)-|"4-(3-methoxy-propylV3,4- dihvd-0-2H-benzori ,41oxazin-6-yloxymethyl]-piperazin-2-one
The starting material is prepared as follows: a) (R)-1-(3-Fluoro-phenyl)-pyrrolidin-3-ol
Analogously to Example 1a, 2.96 g of (R)-pyrrolidin-3-ol and 3.0 ml of 1 -bromo-3-fluoro- benzene are reacted. The title compound is obtained as a dark brown oil.
Rf = 0.22 (2:3 EtOAc-heptane); Rt = 3.55.
N.B.: Instead of tri-tert-butylphosphine, (rac^^'-bistdiphenylphosphinej-l.l'-binaphthyl is used as the ligand.
Figure imgf000036_0001
Figure imgf000037_0001
Thin-layer chromatography eluent systems: A Dichloromethane-methanol-25% cone, ammonia = 200:20: 1 B Dichloromethane-methanol-25% cone, ammonia = 200:20:0.5 C Dichloromethane-methanol-25% cone, ammonia = 200: 10:1 D Dichloromethane-methanol-25% cone, ammonia = 90:10:1 E Dichloromethane-methanol-water-conc. acetic acid = 750:270:50:5

Claims

Claims:
1. Compound of the formula (I) or (II)
Figure imgf000038_0001
where
R1 is aryl or heterocyclyl;
R2 is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridinyl, diazinyl, triazolyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl, furyl, tetrazolyl or imidazolyl, which radicals may be substituted by 1-3 halogen, hydroxyl, cyano, trifluoromethyl, C1-6-alkyl, halo-d-6-alkyl, hydroxy-Cι-6-alkyl, Cι-6-alkoxy-C1-6-alkyl, cyano- Ci_6-alkyl, carboxy-Cι-6-alkyl, d-e-alkanoyloxy-d-e-alkyl, Ci-e-alkoxycarbonyloxy-d-e-alkyl, C -6-alkoxycarbonyl, or d-6-alkoxy, or a Ci-e-alkylenedioxy group, and/or by an L1-T1-L2- T2-L3-T3-L4-T4-L5-U radical;
L1, L2, L3, L4 and L5 are each independently a bond, Cι-8-alkylene, C2-8-alkenylene or C2-8-alkynylene, or are absent; T1, T2, T3 and T4 are each independently
(a) a bond, or are absent, or are one of the groups
(b) -CH(OH)-
(c) -CH(OR6)-
(d) -CH(NR5R6)-
(e) -CO-
(f) -CR7R8- (g) -O- or -NR6-
Figure imgf000038_0002
(i) -SO2NR6- 0) -NR6SO2- (k) -CONR6- (I) -NR6CO- (m) -O-CO- (n) -CO-O-
(0) -O-CO-O- (p) -O-CO-NR6-
(q) -N(R6)-CO-N(R6)-
(r) -N(R6)-CO-O-
(s) pyrrolidinylene, piperidinylene or piperazinylene
(t) -C(R11)(R12)-, where the bonds starting from (b)-(t) lead to a saturated or aromatic carbon atom of the adjacent group if the bond starts from a heteroatom, and where not more than two (b)-(f) groups, three (g)-(h) groups and one (i)-(t) group are present;
R3 is hydrogen, d-6-alkyl, C2-6-alkenyI, Cι.6-alkoxy, hydroxy-Cι-6-alkyl, Cι-β-alkoxy-Cι-6- alkyl, benzyl or an
R4-Z1-X1- group where R4 is
(a) H-
(b) Cι_6-alkyl-
(c) C2-6-alkenyl-
(d) hydroxy-Ci-6-alkyl-
(e) polyhydroxy-Ci-6-alkyl-
(f) Cι-6-alkyl-O-C1-6-alkyl- (g) aryl-
(h) heterocyclyl- (i) arylalkyl- (j) heterocyclylalkyl- (k) aryloxyalkyl-
(1) heterocyclyloxyalkyl- (m) (R5,R6)N-(CH2)1.3- (n) (R5,R6)N-
(o) Cι.6-alkyl-S(O)o-2-
(p) aryl-S(O)0-2-
(q) heterocyclyl-S(O)o-2-
(r) HO-SO3- or salts thereof
(s) H2N-C(NH)-NH-
(t) NC-, and the bonds starting from (n)-(t) lead to a carbon atom of the adjacent group and this carbon atom is saturated if the bond starts from a heteroatom;
Z1 (a) is a bond, is absent, or is one of the groups
(b) Cι.s-alkylene-
(c) C2-6-alkenylene- (d) -O-, -N(R11)-, -S(O)o-2-
(e) -CO-
(f) -O-CO-
(g) -O-CO-O-
(h) -O-CO-N(R11)-
(i) -N(R11)-CO-O-
(j) -CO-N(R11)-
(k) -N(R11)-CO-
(l) -N(R11)-CO-N(R11)-
(m) -CH(OR9)-
and the bonds starting from (d) and (f)-(m) lead to a carbon atom of the adjacent group and this carbon atom is saturated if the bond starts from a heteroatom; X1 is a bond, is absent, or is -(CH2)ι-3-; or, in formula (I), R3 is also oxo;
R5 and R6 are each independently hydrogen, Cι-6-alkyl, C2-6-alkenyl, aryl-Cι.6-alkyl or acyl, or, together with the nitrogen atom to which they are bonded, are a 5- or 6-membered heterocyclic ring which may contain an additional nitrogen, oxygen or sulphur atom or a - SO- or -SO2- group, and the additional nitrogen atom may optionally be substituted by Ci-e- alkyl radicals;
R7 and R8, together with the carbon atom to which they are bonded, are a 3-7-membered ring which may contain one or two oxygen or sulphur atoms or -SO- or -SO2- groups; R9 is hydrogen, Cι-6-alkyl, C3.8-cycloalkyl, Ci.8-alkoxy-d.6-alkyl, acyl or arylalkyl; R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen; R11 is hydrogen or Ci-e-alkyl; R12 is hydrogen or Cι-6-alkyl;
U is hydrogen, Cι-6-alkyl, cycloalkyl, cyano, optionally substituted cycloalkyl, aryl, or heterocyclyl;
Q is ethylene or is absent (formula I) or is ethylene or methylene (formula II); X is a bond or a >CH-R11, >CR9R11, >CHOR9, >CO or >C=NOR10 group; Z is absent or is Cι-Θ-alkylene, C2-8-alkenylene, hydroxy-Cι.6-alkylidene, -CH-R11-CO-NR9-, -O-, -S-, -NR9-, -O-alk-, -S-alk-, -NR9-alk-, -alk-O-, -alk-S- or -alk-NR9-, where alk is d_6-alkylene; and where (a) if Z is -O- or -S-, X is -CR9R11- and either R2 contains an L1-T1-L2-T2-L3-T3-L4-T4-L5- U substituent or R3 is a substituent other than hydrogen as defined above;
(b) if Z is -O-alk-, -S-alk- or -NR9-alk-, X is -CR9R11-; and
(c) if X is a bond, Z is C2.6-alkenylene, -alk-O-, -alk-S- or -alk-NR9-, and pharmaceutically usable salts thereof.
2. Compound according to Claim 1 of the formula (IA) or (IIA)
Figure imgf000041_0001
IA IIA where R , R2, R3, Q, X and Z are each as defined for the compounds of the formulae (I) or (II) according to Claim 1.
3. Compound according to Claim 1 or 2 where
R1 is aryl or heterocyclyl;
R2 is phenyl, cyclohexyl, tetrazolyl, or phenyl, cyclohexyl or tetrazolyl each substituted by halogen, hydroxyl, cyano, trifluoromethyl, Cι_6-alkyl, halo-Cι-6-alkyl, hydroxy-Cι_6-alkyl, d-e-alkoxy-d-θ-alkyl, cyano-d.6-alkyl, carboxy-d-s-alkyl, Cι-6-alkanoyloxy-C _6-alkyl, d-6-alkoxycarbonyloxy-Cι-6-alkyl, Cι-6-alkoxycarbonyl, Cι-6-alkoxy, C _6-alkylenedioxy, or by an L1-T1-L2-T2-L3-T3-L4-T4-L5-U radical; or naphthyl or acenaphthyl;
L1, L2, L3, L4 and L5 are each independently a bond, Cι-8-alkylene, C2-8-alkenylene or
C2-8-alkynylene, or are absent;
T1, T2, T3 and T4 are each independently
(a) a bond, or are absent, or are one of the groups
(b) -CH(OH)-
(c) -CH(OR6)-
(d) -CH(NR5R6)-
(e) -CO-
(f) -CR7R8-
(g) -O- or -NR6- (h) -S(O)0-2- (i) -SO2NR6- (j) -NR6SO2-
(k) -CONR6- (I) -NR6CO-
(m) -O-CO-
(n) -CO-O-
(o) -O-CO-O-
(p) -O-CO-NR8-
(q) -N(R6)-CO-N(R6)-
(r) -N(R6)-CO-O-
(s) pyrrol idinylene, piperidinylene or piperazinylene
(t) -C(R11)(R12)-,
where the bonds starting from (b)-(t) lead to a saturated or aromatic carbon atom of the adjacent group if the bond starts from a heteroatom, and where not more than two (b)-(f) groups, three (g)-(h) groups and one (i)-(t) group are present;
R3 is hydrogen, Cι-6-alkyl, C2-e-alkenyl, d.6-alkoxy, hydroxy-C1-6-alkyl, Cι_e-alkoxy-Cι-6-alkyl or benzyl; or, in formula (I) or (IA), R3 is also oxo;
R5 and R6 are each independently hydrogen, dialk l or acyl, or, together with the nitrogen atom to which they are bonded, are a 5- or 6-membered heterocyclic ring which may contain an additional nitrogen, oxygen or sulphur atom;
R7 and R8, together with the carbon atom to which they are bonded, are a 3-7-membered ring which may contain one or two oxygen or sulphur atoms;
R9 is hydrogen, d_B-alkyl, C3_8-cycloalkyl, Cι.e-alkoxy-Cι-6-alkyl, acyl or arylalkyl;
R11 is hydrogen or Cι-6-alkyl;
R12 is hydrogen or Cι-6-alkyl;
U is hydrogen, Cι-6-alkyl, cycloalkyl, cyano, aryl or heterocyclyl;
Q is ethylene or is absent (formula (I)) or is ethylene or methylene (formula (II));
X is a >CHOR9, >CO or >CH-R11 group;
Z is Ci-e-alkylene, -CH-R11-CO-NR9, -0-, -NR9-, -alk-O-, -alk-S-, -alk-NR9- or is absent; and where, if Z is -O-, X is >CHR11 and either R2 contains an L1-T1-L2-T2-L3-T3-L4-T4-L5-U substituent or R3 is a substituent other than hydrogen as defined above; and pharmaceutically usable salts thereof.
4. Compound according to one of Claims 1 to 3, characterized in that Q is absent.
5. Compound according to one of Claims 1 to 4, characterized in that X is -CH2- or >CO.
6. Compound according to one of Claims 1 to 4, characterized in that Z is -O-, -alk-O-, -N-(C3-8-cycloalkyl)-Ci-6-alkylene- or is absent.
7. Compound according to one of Claims 1 to 6, characterized in that Q is absent, X is -CH2- and Z is -O-.
8. Compound according to one of Claims 1 to 7, characterized in that R1 is phenyl, 3,4-dihydro-2H-benzo[1,4]oxazin-6-yl or4H-benzo[1,4]oxazin-3-on-6ryl which may be substituted by 1-3 halogen or d-6-alkoxy-d-e-alkyl.
9. Compound according to one of Claims 1 to 8, characterized in that R2 is phenyl substituted by Cι-6-alkoxy, Cι-6-alkoxybenzyloxy-Cι.6-alkoxy, halophenoxy-C1-6-alkoxy or halophenylpyrrolidin-3-yloxy.
10. Pharmaceutical preparation comprising a compound of the formula (I), (IA), (II) or (IIA) according to Claims 1 and 2.
11. Use of a compound of the formula (I), (IA), (ll) or (IIA) according to Claims 1 and 2 in the treatment and prevention of hypertension, heart failure, glaucoma, cardiac infarction, kidney failure or restenoses.
12. Use of a compound of the formula (I), (IA), (II) or (IIA) according to Claims 1 and 2 for the preparation of a medicament for use in the treatment and prevention of hypertension, heart failure, glaucoma, cardiac infarction, kidney failure or restenoses.
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