WO1995019952A1 - Derives de benzylamine contenant des groupes nitroxy et leur utilisation pour traiter les maladies cardio-vasculaires et l'hypertension intra-oculaire - Google Patents

Derives de benzylamine contenant des groupes nitroxy et leur utilisation pour traiter les maladies cardio-vasculaires et l'hypertension intra-oculaire Download PDF

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WO1995019952A1
WO1995019952A1 PCT/EP1995/000167 EP9500167W WO9519952A1 WO 1995019952 A1 WO1995019952 A1 WO 1995019952A1 EP 9500167 W EP9500167 W EP 9500167W WO 9519952 A1 WO9519952 A1 WO 9519952A1
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substituted
alkyl
phenyl
radical
nitroxyethoxy
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PCT/EP1995/000167
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German (de)
English (en)
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Jan Bron
Geert Jan Sterk
Hendrik Timmerman
Meta E. J. Veerman
Jan Fetze Van Der Werf
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Byk Nederland Bv
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Priority to AU15350/95A priority Critical patent/AU679834B2/en
Priority to EP95906963A priority patent/EP0740649A1/fr
Priority to KR1019960703871A priority patent/KR970700646A/ko
Priority to JP7519335A priority patent/JPH09507672A/ja
Priority to BR9506549A priority patent/BR9506549A/pt
Publication of WO1995019952A1 publication Critical patent/WO1995019952A1/fr
Priority to MXPA/A/1996/002847A priority patent/MXPA96002847A/xx

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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
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    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

  • Benzylamine derivatives containing NHroxy groups and their use for the treatment of cardiovascular diseases and increased intraocular pressure
  • the invention relates to benzylamine derivatives which are used in the pharmaceutical industry for the manufacture of medicaments.
  • substituted nitroxy compounds are described in various ways, which are said to be suitable, for example, for the treatment of cardiovascular diseases.
  • the invention relates to compounds of the formula I (see attached
  • AI means 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cycloalkane, and in which
  • Rl is hydrogen, 1-7C-alkyl or 3-8C-cycloalkyl
  • R2 is hydrogen, 1-7C-alkyl, 3-8C-cycloalkyl or A2-Y, or wherein
  • R1 and R2 together and including the nitrogen atom to which both are bound, represent an unsubstituted or substituted 5-, 6- or 7-ring heterocycle which is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine and Homopiperazine, where
  • Di - l -4C-alkyl-5-7C-cycloal kan means Y is R3, NH 2 , NH-R4 or S-R5, a substituted pyrrolidino radical is substituted by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy and hydroxy, a substituted one Piperidino radical is substituted with one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy and hydroxy, a substituted piperazino radical can be substituted in the 2-, 3-, 5- or 6-position is substituted with a 1-4C-alkyl radical and in the 4-position with a substituent selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, phenyl substituted by R6, R7 and R8, phenyl-1-4C-alkyl substituted by R
  • R3 furyl, naphthyl, tetrahydronaphthyl, by -O-Al-ONO, substitutability ⁇ tes phenyl or by R6, R7 and R8 substituted phenyl bedeu ⁇ tet,
  • R4 is 1-7C-alkyl or the substituents -CH 2 -CH (0H) - (CH 2 0) -Ar and
  • R5 substituted by R6, R7 and R8 phenyl, substituted by R6, R7 and R8 phenyl-1-4C-alkyl, optionally substituted by halogen or 1-4C-A1kyl benzhydryl, dibenzo-5-7C-cycloalkanyl, dibenzocycloheptenyl or Benzo-pyrido-5-7C-cycloal anyl means, and in addition R6 denotes hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylcarbonyl, halogen, amino, mono- or di- (1-4C-alkyl) amino or nitro,
  • R7 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or nitro,
  • R8 represents hydrogen or trifluoromethyl
  • p represents the number 0 or 1
  • Ar denotes a completely or partially unsaturated hydrocarbon ring system which is monocyclic (with 5 to 6) or bicyclic (with 9 to 10 ring atoms) in which 1, 2 or 3 carbon atoms are substituted by heteroatoms from the group nitrogen (N), oxygen (0) or sulfur (S) can be replaced by one or two identical or different substituents from the group 1-4C-A1ky, 1-4C-alkoxy, 1-4C-A1kylthio, 1-4C-A1koxy-1-4C-alkyl , 1-4C-Alkoxy- 1-4C-alkoxy, 3-4C-alkenyl, 3-4C-alkenyloxy, 3-8C-cycloalkyl, 5-10C-cycloalkylalkoxyalkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonylamino , Carbamoyl, carbamoyl -1-4C-alkyl, halogen, hydroxy, oxo
  • 1-15C-Alkylene stands for straight-chain or branched alkylene radicals with 1 to 15 carbon atoms. Examples are methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), trimethylene (-CH 2 CH 2 CH 2 -), tetramethylene (-CH 2 CH 2 CH 2 CH 2 -), pentamethylene ( -CH 2 CH 2 CH 2 CH 2 CH 2 -), hexamethylene (-CH 2 - (CH 2 ) 4 -CH 2 -), octaethylene (-CH 2 - (CH 2 ) 6 -CH 2 -), decamethylene (-CH 2 - (CH 2 ) 8 -CH 2 -), tetradecamethylene (-CH 2 - (CH 2 ) 12 -CH 2 -), 1,2-dimethylethylene [-CH (CH 3 ) -CH ( CH 3 ) -], 1,1-dimethylethylene [-C (CH 3 ) 2 -CH 2 -], isopropy
  • 5-7C-Cycloalkylene stands for cycloalkylene radicals with 5 to 7 carbon atoms. Cyclohexylene radicals are preferred, the 1,2- and 1,4-cyclohexylene radicals being mentioned, for example.
  • Di-1-4C-alkylene-5-7C-cycloalkane stands for cyclic hydrocarbons with 5 to 7 carbon atoms which are substituted by two (identical or different) alkylene residues with 1 to 4 carbon atoms.
  • a preferred di-1-4C-alkylene-5-7C-cycloalkane radical is the 1,4-dimethylenecyclohexane radical.
  • 1-7C-A1kyl stands for straight-chain and branched alkyl radicals with 1 to 7 carbon atoms. Examples include the heptyl, hexyl, neopentyl, isopentyl, pentyl, butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, - Ethyl and the methyl radical.
  • 3-8C-Cycloalkyl stands for the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl radical.
  • 1-4C-A1kyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • 1-4C-Alkoxy represents a radical which, in addition to the oxygen atom, contains one of the 1-4C-alkyl radicals mentioned above.
  • the methoxy and ethoxy radicals may be mentioned, for example.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • 1-4C-Alkoxycarbonyl stands for a radical which, in addition to the carbonyl group, contains one of the 1-4C-alkoxy radicals mentioned above. Examples include methoxycarbonyl and ethoxycarbonyl est.
  • 1-4C-Alkylcarbonyl stands for a radical which, in addition to the carbonyl group, contains one of the 1-4C-alkyl radicals mentioned above.
  • the acetyl radical may be mentioned.
  • dibenzo-5-7C-cycloalkanyl radicals which may be mentioned are the dibenzocyclopentyl radical, the dibenzocyclohexyl radical and in particular the dibenzocycloheptyl radical.
  • the benzopyrido-5-7C-cycloalkanyl radicals which may be mentioned are the benzopyridocyclopentyl radical, the benzopyridocyclohexyl radical and in particular the benzopyridocycloheptyl radical.
  • 4- Mono- or di- (1-4C-alkyl) amino stands for an amino radical which is substituted by one or two identical or different of the 1-4C-alkyl radicals mentioned above.
  • the methylamino, the ethylamino, the dimethylamino, the diethylamino and the diisopropylamino radical may be mentioned.
  • 1-4C-A1kylthio stands for a radical which contains one of the abovementioned 1-4C-alkyl radicals in addition to the sulfur atom.
  • the methylthio radical is preferred.
  • 1-4C-A1koxy-1-4C-al yl stands for one of the above-mentioned 1-4C-A1kyl radicals, which is substituted by one of the above-mentioned 1-4C-alkoxy radicals. Examples include methoxymethyl, methoxyethyl est and butoxyethyl est.
  • 1-4C-Alkoxy-1-4C-alkoxy stands for one of the abovementioned 1-4C-A1k-oxy radicals which is substituted by a further 1-4C-alkoxy radical.
  • the methoxyethoxy radical may be mentioned.
  • 3-4C-alkenyl is, for example, 2-butenyl and especially allyl.
  • 3-4C-alkenyloxy contains a 3-4C-alkenyl residue in addition to the oxygen atom.
  • the allyloxy radical may be mentioned as an exemplary 3-4C alkenyloxy radical.
  • 5-10C-Cycloalkylalkoxyalkyl stands for an Al oxyalkylrest, which is substituted by a Cycloalkylrest.
  • the cyclopropyl methoxyethyl radical may be mentioned.
  • the acetylamido radical (-NH-CO-CH 3 ) may be mentioned.
  • Carbamoyl stands for the rest NH 2 -C0 ⁇ .
  • Carbamoyl-1-4C-alkyl represents one of the 1-4C-A1 alkyl radicals mentioned above which is substituted by carbamoyl.
  • the carbamoyl ethyl est may be mentioned as an exemplary carbamoyl-1C-alkyl radical.
  • 1-4C-Alkylsulfonamido stands for a sulfonamido radical to which one of the aforementioned 1-4C-alkyl radicals is attached.
  • the methylsulfonamido radical may be mentioned.
  • Ureido stands for the residue -NH-C0-NH 2 .
  • 3-methylureido may be mentioned as mono-1-4C-alkylureido, and 3,3-dimethylureido as di-1-4C-alkylureido.
  • Exemplary mono- or di-3-8C-cycloalkylureido residues are, for example, the 3-cyclohexylureido and the 3,3-di-cyclohexylureo residue.
  • 1,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy and in particular 1,1,2 are examples of 1,2-trifluoroethoxy which are wholly or partly substituted by fluorine , 2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and the difluoromethoxy radical.
  • substituted pyrrole idino radicals are the 2-methylpyrrolidino, 2,5-dimethylpyrrolidino and the 3-hydroxypyrrolidino radical.
  • substituted piperidino radicals are 3-hydroxypiperidino, 2-n-propylpiperidino, 5-ethyl-2-methylpiperidino, 4-n-propylpiperidino, 4,4-dimethylpiperidino, 2,6-dimethylpiperidino -, 4-hydroxypiperidino, 2-ethyl-2-methylpiperidino, 2-methylpiperidino, 2,6-dimethylpiperidino and the 2-ethylpiperidino radical.
  • substituted piperazino radicals are 4-methylpiperazino-, 4- [2- (2-trifluoromethylphenyl) ethyl] piperazino-, 4-phenylpiperazino-, 4- (2-methylphenyl) piperazino-, 4- (2,3- Dimethylphenyl) piperazino-, 4- (2-chlorophenyl) piperazino-, 4- (2-methoxyphenyl) piperazino-, 4- (2-ethoxyphenyl) piperazino-, 4- (3-chlorophenyl) piperazino-, 4- ( 4-fluorophenyl) piperazino-, 4- (4-chlorophenyl) piperazino-, 4- (4-methoxyphenyl) piperazino-, 3-methyl-4- (4-chlorophenyl) piperazino-, 3-methyl-4 - (4-chlorophenyl) piperazino, 3-methyl-4 - (4-methoxyphenyl) piperazino, 3-
  • REPLACEMENT BLADE (RULE 26) pylpiperazino-, 4- (3-methylhenyl) piperazino-, 4- (3-methoxyphenyl) piperazino-, 4- (4-methylphenyl) piperazino-, 4- (2,5-dimethylphenyl) piperazino-, 4th -Benzhydrylpiperazino-, 4-n-butylpiperazino-, 4-iso-butylpiperazino-, 4-tert.-butylpiperazino-, 4- (3-trifluoromethylphenyl) piperazino-, 4- (l-phenylethyl) piperazino-, 4- (2-phenylethyl) piperazino-, 4- (2-hydroxyphenyl) piperazino-, 4- (3,4-dimethoxyphenyl) piperazino-, 4-isopropylpiperazino-, 3-methyl-4- (3-methoxyphenyl) piperazino-, 4- (4
  • the substituted morpholino radical for example, is the 3,5-dimethylmorpholino radical.
  • substituted hoopiperazino radicals are 4-methyl, 4-ethoxycarbonyl, 4-acetyl, 4- (2-methoxyphenyl) and 4-benzoyl homopiperazino.
  • Benzhydryl radicals which are optionally substituted by halogen or 1-4C-A1-kyl are, for example, benzhydryl, bis-4,4'-fluorobenzhydryl, bis-4,4'-chlorobenzhydryl, 4-chlorobenzhydryl and the 4-methyl benzhydryl rest called.
  • Exemplary phenyl radicals substituted by R6, R7 and R8 are the radicals 3, 4-di hydroxy, 3-hydroxy-4-methoxy, 3,4-dimethoxy, 2-methoxy, 2-ethoxy, 3- Methoxy, 4-methoxy, 2-hydroxy, 3-hydroxy, 4-hydroxy, 3, 4-di hydroxy, 4-acetyl, 4-fluoro, 4-chloro, 2-chloro, 3-chloro, 3,4-dichloro, 3-trifluoromethyl, 2-trifluoromethyl, 2-methyl, 3-methyl, 4-methyl, 2,3-dimethyl, 2,4-dimethyl , 3,4-dimethyl, 2,5-dimethyl, 4-nitro, 2,6-dinitro-4-trifluoromethyl and 5-chloro-2-methylaminophenyl called.
  • Phenyl 4- (2-methoxyethoxy) phenyl, 2-allylphenyl, 2-acetyl-4-butyramidophenyl, 4-carbamoylmethylphenyl, 4-methylphenyl, 2-tetrahydrofurfuryloxyphenyl, 2-chloro-5-methylphenyl, 2- Acetyl-4- (3,3-diethylureido) phenyl, 2-cyclohexylphenyl, 4-hydroxy-3-carbamoylphenyl, 4- (2-methoxyethyl) phenyl, 2-methoxyphenyl, 4-nitrophenyl, 2-allyloxyphenyl, 2- Cyclopentylphenyl, 2-cyanophenyl, 4-acetamidophenyl, 4-hydroxyphenyl, 2-cyclopropylphenyl, 4-methanesulfonamidophenyl, 4- (3-cycl
  • Suitable salts for the compounds of the formula I are all acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids customarily used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
  • Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, Maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydro ⁇ y-2-naphthoic acid, the acids in the salt production - depending on whether it is a - or multi-base acid and, depending on which salt is desired - be used in an equimolar or a different ratio.
  • acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfur
  • Rl and R2 together and including the nitrogen atom to which both are attached represent an unsubstituted or substituted piperazine radical, where
  • A2 l-10C-alkylene means
  • Y is R3, NH 2 , NH-R4 or S-R5, a substituted piperazino radical in the 4-position is substituted by a substituent selected from the group consisting of 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, picolinoyl, nicotinoyl, isonicotinoyl , Benzhydryl and the rest R4 and where further
  • R3 denotes phenyl or phenyl substituted by -0-A1-0N0-
  • R4 denotes the substituent -CH 2 -CH (0H) - (CH 2 0) -Ar and R5, if desired, benzhydryl or dibenzocycloheptanyl substituted by halogen or 1-4C-A1kyl , Dibenzocycloheptenyl or Benzo-pyrido-cycloheptanyl, and wherein p also means the number 1 and
  • Ar is phenyl, 4- (2-methoxyethoxy) phenyl, 2-allylphenyl, 2-chloro-5-methylphenyl, 2-allyloxyphenyl, 2-cyclopentylphenyl, 2-cyanophenyl or 1-naphthyl, and the salts of these compounds.
  • AI 2-10C-A1 means kylene or dimethylene cyclohexane, and wherein
  • R2 is hydrogen or A2-Y, or wherein
  • R1 and R2 together and including the nitrogen atom to which both are bound, represent an unsubstituted or substituted piperazine radical
  • Y is R3, NH 2 , NH-R4 or S-R5, a substituted piperazino radical in the 4-position is substituted by a substituent selected from the group consisting of 1-4C-alkylcarbonyl, nicotinoyl, benzhydryl and the radical R4, and furthermore
  • R3 denotes phenyl or phenyl substituted by -0-A1-ONO
  • R4 denotes the substituent -CH 2 -CH (0H) - (CH 2 0) -Ar
  • R5 denotes benzhydryl, benzhydryl substituted by 1-4C-A1kyl
  • Ar means phenyl, 2-allyphenyl or 1-naphthyl, and the salts of these compounds.
  • the invention further relates to a process for the preparation of the compounds of the formula I and their salts.
  • the process is characterized in that aldehydes of the formula II (see enclosed formula sheet), in which AI has the meaning given above, with the compounds of the formula III present in the form of ammonium salts (see attached formula sheet), in which Rl and R2 have the meanings given above, reacted in the presence of sodium cyanoborohydride and, if desired, subsequently obtained compounds are converted into the salts or salts obtained into the free compounds.
  • mp stands for melting point
  • RT room temperature
  • h hour
  • Hergestel11 from N- [3- (2-Allylphenoxy) -2-hydroxypropyl] -1,8-octylenediamine and 4- (2-nitroxyethoxy) benzaldehyde in methanol according to process variant A.
  • the hydrochloride of the title compound was obtained from methanol / ethanol / diethyl ether recrystallized mp of the hydrochloride: 151.1-151.7 ⁇ C.
  • the compounds of the formula I have valuable properties which make them commercially viable. In particular, they represent highly effective active substances for the treatment of cardiovascular diseases and diseases of the eye which are based on increased intraocular pressure.
  • the compounds of the formula I represent a desired enrichment of the prior art. Because of the nitrate groups in the molecule, the compounds of the formula I are in principle suitable for prevention and treatment of such disease states in humans which are known to be treated by organic nitrates (such as glycerol trinitrate, isosorbide-5-mononitrate or isosorbide dinitrate) or by compounds which can release nitrogen monoxide (such as molsido in) can.
  • organic nitrates such as glycerol trinitrate, isosorbide-5-mononitrate or isosorbide dinitrate
  • nitrogen monoxide such as molsido in
  • the compounds of formula I can be used for the prevention and treatment of ischemic heart diseases (angina pectoris, heart attack), cardiac compensation disorders, (pul onal) hypertension, (cerebral) thrombosis and atherosclerosis, (peripheral) vasoconstrictions, arrhythmias, certain disorders of the gastrointestinal tract (such as achalasia, irritable bowel syndrome) and increased intraocular pressure.
  • ischemic heart diseases angina pectoris, heart attack
  • cardiac compensation disorders pul onal hypertension
  • (cerebral) thrombosis and atherosclerosis peripheral vasoconstrictions
  • arrhythmias certain disorders of the gastrointestinal tract (such as achalasia, irritable bowel syndrome) and increased intraocular pressure.
  • the compounds of the formula I are notable for thromboxane-antagonistic and antiviral activity and for bronchospasmolytic properties.
  • Another object of the invention is therefore a method for the treatment of mammals, in particular humans, who are suffering from one of the abovementioned diseases.
  • the process is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically compatible amount of one or more compounds of the formula I.
  • the invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.
  • REPLACEMENT BUTT (RULE 26)
  • the invention also encompasses the use of compounds of the formula I in the production of medicaments which are used to combat the diseases mentioned.
  • the invention further relates to medicaments which contain one or more compounds of the formula I.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents gel formers, suppository bases, tablet auxiliaries and other active ingredient carriers
  • antioxidants dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).
  • the active substances can be administered orally, rectally or parenterally (in particular perlingual, buccal, intravenously or percutaneously).
  • the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 10, preferably 0.05 to 5 mg / kg body weight, if desired in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
  • similar or generally lower doses in particular when the active compounds are administered intravenously can be used. If the dosage creeps in, a lower dose is administered at the beginning of the treatment and then slowly switched to a higher dose.
  • the pharmaceutical preparations can also contain one or more other pharmacologically active constituents of other groups of medicaments, such as other antihypertensives, vasodilators, alpha-1 receptor blockers, alpha- 2-receptor stimulators, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dopamine blockers etc.
  • other antihypertensives such as other antihypertensives, vasodilators, alpha-1 receptor blockers, alpha- 2-receptor stimulators, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dopamine block
  • the relaxing effect of the compounds to be tested on spiral strips of the pulmonary artery of the rat was determined.

Abstract

Des composés ont la formule (I), dans laquelle R1 désigne alcylène C1-15, cycloalkylène C5-7 ou di-1-4C-alcylène-5-7C-cycloalcane; R1 désigne hydrogène, alcoyle C1-7 ou cycloalcoyle C3-8 et R2 désigne hydrogène, alcoyle C1-7, cycloalcoyle C3-8 ou A2-Y. Ensemble, R1 et R2, avec l'atome d'azote auquel ils sont tous les deux liés, désignent un hétérocycle pentagonal, hexagonal ou heptagonal substitué ou non sélectionné dans le groupe constitué par la pyrrolidine, la pipéridine, la pipérazine, la morpholine et l'homopipérazine. A2 désigne alcylène C1-15, cycloalcylène C5-7 ou di-1-4C-alcylène-5-7C-cycloalcane; Y désigne R3, NH2, NH-R4 ou S-R5. Un résidu pyrrolidine substitué est substitué par un ou deux substituants identiques ou différents sélectionnés dans le groupe constitué par alcoyle C1-4, alcoxy C1-4 et hydroxyle. Un résidu pipéridine substitué est substitué par un ou deux substituants identiques ou différents sélectionnés dans le groupe constitué d'alcoyle C1-4, alcoxy C1-4 et hydroxyle. Un résidu pipérazine substitué peut être substitué en 2e, 3e, 5e ou 6e position par un résidu alcoyle C1-4 et est substitué en 4e position par un substituant sélectionné dans le groupe constitué d'alcoyle C1-4, alcoxycarbonyle C1-4, alcoylcarbonyle C1-4, phényle substitué par R6, R7 et R8, phényl-1-4C-alcoyle substitué dans le résidu phényle par R7 et R8, benzoyle, picolinoyle, nicotinoyle, isonicotinoyle substitués dans le résidu phényle par R6, R7 et R8, benzhydryle substitué le cas échéant par halogène ou alcoyle C1-4 et le résidu R4. Un résidu morpholine substitué est substitué par un ou deux résidus alcoyle C1-4 identiques ou différents. Un résidu homopipérazine substitué est substitué en 4e position par un substituant sélectionné dans le groupe constitué d'alcoyle C1-4, alcoxycarbonyle C1-4, alcoylcarbonyle C1-4, phényle substitué par R6, R7 et R8, phényl-1-4C-alcoyle substitué dans le résidu phényle par R6, R7 et R8 et benzoyle substitué dans le résidu phényle par R6, R7 et R8. Ces composés sont utiles pour traiter les maladies cardio-vasculaires ainsi que l'hypertension intra-oculaire.
PCT/EP1995/000167 1994-01-19 1995-01-18 Derives de benzylamine contenant des groupes nitroxy et leur utilisation pour traiter les maladies cardio-vasculaires et l'hypertension intra-oculaire WO1995019952A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU15350/95A AU679834B2 (en) 1994-01-19 1995-01-18 Nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases, as well as increased intra-ocular pressure
EP95906963A EP0740649A1 (fr) 1994-01-19 1995-01-18 Derives de benzylamine contenant des groupes nitroxy et leur utilisation pour traiter les maladies cardio-vasculaires et l'hypertension intra-oculaire
KR1019960703871A KR970700646A (ko) 1994-01-19 1995-01-18 니트록시기를 포함한 벤질아민 유도체, 및 심장 혈관 질환과 안압 상승의 치료를 위한 이의 용도(nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases, as well as increased intra-ocular pressure)
JP7519335A JPH09507672A (ja) 1994-01-19 1995-01-18 ニトロキシ基含有ベンジルアミン誘導体及び循環器疾患並びに眼内圧増加の治療のためのその使用
BR9506549A BR9506549A (pt) 1994-01-19 1995-01-18 Derivados de benzilamina contendo grupos nitróxi e sua aplicação para o tratamento de enfermidades cardiovasculares bem como de pressão interna dos olhos elevada
MXPA/A/1996/002847A MXPA96002847A (en) 1994-01-19 1996-07-18 Bencilamine derivatives containing nitrorxi groups and their employment to treat cardiovascular diseases and internal ocular pressure aument

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH157/94-2 1994-01-19
CH15794 1994-01-19

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WO1995019952A1 true WO1995019952A1 (fr) 1995-07-27

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BR (1) BR9506549A (fr)
CA (1) CA2181581A1 (fr)
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009045479A1 (fr) * 2007-10-05 2009-04-09 Acucela Inc. Composés d'alcoxy pour le traitement de maladies
US8067464B2 (en) 2004-10-04 2011-11-29 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US8450527B2 (en) 2007-11-01 2013-05-28 Acucela Inc. Amine derivative compounds for treating ophthalmic diseases and disorders
US9447078B2 (en) 2012-01-20 2016-09-20 Acucela Inc. Substituted heterocyclic compounds for disease treatment
US10471027B2 (en) 2009-07-02 2019-11-12 Acucela, Inc. Pharmacology of visual cycle modulators

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5832447B2 (ja) * 2009-12-07 2015-12-16 ザ ジョンズ ホプキンス ユニバーシティ ビスアシル化ヒドロキシルアミン誘導体
EP2911656B1 (fr) * 2012-10-23 2020-12-02 Nicox SA Composés donneurs d'oxyde nitrique à base de quinone pour une utilisation ophtalmique
RS56968B1 (sr) * 2013-01-18 2018-05-31 Cardioxyl Pharmaceuticals Inc Donori nitroksila sa poboljšanim terapijskim indeksom

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034461A1 (fr) * 1980-02-13 1981-08-26 Kowa Company, Ltd. Composés aromatiques d'aminoéthanol et leurs sels, compositions pharmaceutiques les contenant et procédés pour leur production
EP0359335A2 (fr) * 1988-09-15 1990-03-21 Cedona Pharmaceuticals B.V. Compositions pharmaceutiques à activité relaxante contenant comme substance active un ester nitrate
WO1992004337A1 (fr) * 1990-09-05 1992-03-19 Cedona Pharmaceuticals Bv Derives de thiazolidine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034461A1 (fr) * 1980-02-13 1981-08-26 Kowa Company, Ltd. Composés aromatiques d'aminoéthanol et leurs sels, compositions pharmaceutiques les contenant et procédés pour leur production
EP0359335A2 (fr) * 1988-09-15 1990-03-21 Cedona Pharmaceuticals B.V. Compositions pharmaceutiques à activité relaxante contenant comme substance active un ester nitrate
WO1992004337A1 (fr) * 1990-09-05 1992-03-19 Cedona Pharmaceuticals Bv Derives de thiazolidine

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8067464B2 (en) 2004-10-04 2011-11-29 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US9458088B2 (en) 2007-10-05 2016-10-04 Acucela Inc. Alkoxy compounds for disease treatment
US7982071B2 (en) 2007-10-05 2011-07-19 Acucela Inc. Alkoxy compounds for disease treatment
US11446261B2 (en) 2007-10-05 2022-09-20 Acucela Inc. Alkoxy compounds for disease treatment
WO2009045479A1 (fr) * 2007-10-05 2009-04-09 Acucela Inc. Composés d'alcoxy pour le traitement de maladies
US8829244B2 (en) 2007-10-05 2014-09-09 Acucela Inc. Alkoxy compounds for disease treatment
US8981153B2 (en) 2007-10-05 2015-03-17 Acucela Inc. Alkoxy compounds for disease treatment
US8993807B2 (en) 2007-10-05 2015-03-31 Acucela Inc. Alkoxy compounds for disease treatment
US10639286B2 (en) 2007-10-05 2020-05-05 Acucela Inc. Alkoxy compounds for disease treatment
US9079825B2 (en) 2007-10-05 2015-07-14 Acucela Inc. Alkoxy compounds for disease treatment
US10188615B2 (en) 2007-10-05 2019-01-29 Acucela Inc. Alkoxy compounds for disease treatment
US9737496B2 (en) 2007-10-05 2017-08-22 Acucela Inc. Alkoxy compounds for disease treatment
US8716529B2 (en) 2007-11-01 2014-05-06 Acucela Inc. Amine derivative compounds for treating ophthalmic diseases and disorders
US9452153B2 (en) 2007-11-01 2016-09-27 Acucela Inc. Amine derivative compounds for treating ophthalmic diseases and disorders
US9056849B2 (en) 2007-11-01 2015-06-16 Acucela Inc. Amine derivative compounds for treating ophthalmic diseases and disorders
US8450527B2 (en) 2007-11-01 2013-05-28 Acucela Inc. Amine derivative compounds for treating ophthalmic diseases and disorders
US10471027B2 (en) 2009-07-02 2019-11-12 Acucela, Inc. Pharmacology of visual cycle modulators
US9447078B2 (en) 2012-01-20 2016-09-20 Acucela Inc. Substituted heterocyclic compounds for disease treatment

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CA2181581A1 (fr) 1995-07-20
AU1535095A (en) 1995-08-08
CN1143950A (zh) 1997-02-26
EP0740649A1 (fr) 1996-11-06
MX9602847A (es) 1997-12-31
AU679834B2 (en) 1997-07-10
JPH09507672A (ja) 1997-08-05
BR9506549A (pt) 1997-10-14
KR970700646A (ko) 1997-02-12

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