WO2005037803A1 - Composes organiques - 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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English (en)
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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

L'invention concerne de nouveaux dérivés de pipérazine de formules générales (I) et (II), les substituants étant tels que définis de manière détaillée dans la description. Les composés selon l'invention peuvent en particulier servir d'inhibiteurs de rénine, et présentent une activité élevée.
PCT/EP2004/052466 2003-10-09 2004-10-07 Composes organiques WO2005037803A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1707206A1 (fr) * 2005-03-31 2006-10-04 Speedel Experimenta AG Dérivés de piperazine pour l'inhibition de la beta-secretase, de la cathepsine d, de la plasmepsin ii et de la protease de vih et pour le traitement de la malaria, de la maladie d'alzheimer et du sida
WO2006128659A2 (fr) * 2005-05-31 2006-12-07 Novartis Ag Composes organiques
WO2007034445A2 (fr) * 2005-09-26 2007-03-29 Actelion Pharmaceuticals Ltd Nouveaux derives de la piperazine
WO2007049224A1 (fr) * 2005-10-25 2007-05-03 Actelion Pharmaceuticals Ltd Nouveaux derives d'hexahydro- ou d'octahydro-cyclopenta[c]pyrrole
WO2008074450A2 (fr) * 2006-12-20 2008-06-26 Nicox S.A. Dérivés nitrés d'inhibiteurs non peptidiques de la rénine
JP2008189592A (ja) * 2007-02-05 2008-08-21 Toa Eiyo Ltd ブトキシアニリン誘導体
WO2009022730A1 (fr) * 2007-08-10 2009-02-19 Nippon Chemiphar Co., Ltd. Antagoniste de récepteur p2x4
WO2009071606A1 (fr) 2007-12-05 2009-06-11 Novartis Ag Composés organiques
JP2013533290A (ja) * 2010-08-13 2013-08-22 バイオラブ・サヌス・ファーマセウティカ・エルティーディーエー． ６，７−ジヒドロ−３Ｈ−オキサゾロ［３，４−ａ］ピラジン−５，８−ジオンの誘導体
WO2013122778A1 (fr) 2012-02-15 2013-08-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Procédés de traitement et de prévention de maladies et de troubles du système nerveux central
JP2017506263A (ja) * 2014-02-24 2017-03-02 バイオラブ・サヌス・ファーマセウティカ・エルティーディーエー． 新規な６，７−ジヒドロ−３Ｈ−オキサゾロ［３，４−ａ］ピラジン−５，８−ジオン誘導体化合物
US12054479B1 (en) 2022-03-14 2024-08-06 Slap Pharmaceuticals Llc Multicyclic compounds

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WO2000064887A1 (fr) * 1999-04-27 2000-11-02 F. Hoffmann-La Roche Ag Inhibiteurs de la renine
WO2000064873A1 (fr) * 1999-04-27 2000-11-02 F. Hoffmann-La Roche Ag Inhibiteurs de renine
WO2003015784A1 (fr) * 2001-08-14 2003-02-27 Glaxo Group Limited 1-arylpiperazines substituees en 2 antagonistes de la tachykinine et/ou des inhibiteurs de la recapture de la serotonine
WO2004089915A1 (fr) * 2003-04-10 2004-10-21 Warner-Lambert Company Llc Derives de piperazine agissant comme inhibiteurs de la renine

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WO2000064887A1 (fr) * 1999-04-27 2000-11-02 F. Hoffmann-La Roche Ag Inhibiteurs de la renine
WO2000064873A1 (fr) * 1999-04-27 2000-11-02 F. Hoffmann-La Roche Ag Inhibiteurs de renine
WO2003015784A1 (fr) * 2001-08-14 2003-02-27 Glaxo Group Limited 1-arylpiperazines substituees en 2 antagonistes de la tachykinine et/ou des inhibiteurs de la recapture de la serotonine
WO2004089915A1 (fr) * 2003-04-10 2004-10-21 Warner-Lambert Company Llc Derives de piperazine agissant comme inhibiteurs de la renine

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1707206A1 (fr) * 2005-03-31 2006-10-04 Speedel Experimenta AG Dérivés de piperazine pour l'inhibition de la beta-secretase, de la cathepsine d, de la plasmepsin ii et de la protease de vih et pour le traitement de la malaria, de la maladie d'alzheimer et du sida
WO2006128659A2 (fr) * 2005-05-31 2006-12-07 Novartis Ag Composes organiques
WO2006128659A3 (fr) * 2005-05-31 2007-11-29 Novartis Ag Composes organiques
JP2008545726A (ja) * 2005-05-31 2008-12-18 ノバルティス アクチエンゲゼルシャフト 有機化合物
WO2007034445A2 (fr) * 2005-09-26 2007-03-29 Actelion Pharmaceuticals Ltd Nouveaux derives de la piperazine
WO2007034445A3 (fr) * 2005-09-26 2008-11-20 Actelion Pharmaceuticals Ltd Nouveaux derives de la piperazine
WO2007049224A1 (fr) * 2005-10-25 2007-05-03 Actelion Pharmaceuticals Ltd Nouveaux derives d'hexahydro- ou d'octahydro-cyclopenta[c]pyrrole
WO2008074450A2 (fr) * 2006-12-20 2008-06-26 Nicox S.A. Dérivés nitrés d'inhibiteurs non peptidiques de la rénine
WO2008074450A3 (fr) * 2006-12-20 2009-01-08 Nicox Sa Dérivés nitrés d'inhibiteurs non peptidiques de la rénine
JP2008189592A (ja) * 2007-02-05 2008-08-21 Toa Eiyo Ltd ブトキシアニリン誘導体
WO2009022730A1 (fr) * 2007-08-10 2009-02-19 Nippon Chemiphar Co., Ltd. Antagoniste de récepteur p2x4
WO2009022731A1 (fr) 2007-08-10 2009-02-19 Nippon Chemiphar Co., Ltd. Antagoniste de récepteur p2x4
JPWO2009022731A1 (ja) * 2007-08-10 2010-11-18 日本ケミファ株式会社 Ｐ２ｘ４受容体拮抗剤
WO2009071606A1 (fr) 2007-12-05 2009-06-11 Novartis Ag Composés organiques
US8003640B2 (en) 2007-12-05 2011-08-23 Novartis Ag Organic compounds
JP2013533290A (ja) * 2010-08-13 2013-08-22 バイオラブ・サヌス・ファーマセウティカ・エルティーディーエー． ６，７−ジヒドロ−３Ｈ−オキサゾロ［３，４−ａ］ピラジン−５，８−ジオンの誘導体
KR20130109110A (ko) * 2010-08-13 2013-10-07 바이오랩 세너스 팔마씨우티카 엘티디에이. 6,7-디히드로-3H-옥사졸로 [3,4-a]피라진-5,8-디온의 유도체
KR101871856B1 (ko) 2010-08-13 2018-06-28 바이오랩 세너스 팔마씨우티카 엘티디에이. 6,7-디히드로-3H-옥사졸로 [3,4-a]피라진-5,8-디온의 유도체
WO2013122778A1 (fr) 2012-02-15 2013-08-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Procédés de traitement et de prévention de maladies et de troubles du système nerveux central
JP2017506263A (ja) * 2014-02-24 2017-03-02 バイオラブ・サヌス・ファーマセウティカ・エルティーディーエー． 新規な６，７−ジヒドロ−３Ｈ−オキサゾロ［３，４−ａ］ピラジン−５，８−ジオン誘導体化合物
US12054479B1 (en) 2022-03-14 2024-08-06 Slap Pharmaceuticals Llc Multicyclic compounds

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