WO1995019952A1 - Nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases, as well as increased intra-ocular pressure - Google Patents

Nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases, as well as increased intra-ocular pressure Download PDF

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Publication number
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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Prior art keywords
substituted
alkyl
phenyl
radical
nitroxyethoxy
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PCT/EP1995/000167
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German (de)
French (fr)
Inventor
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 KR1019960703871A priority Critical patent/KR970700646A/en
Priority to EP95906963A priority patent/EP0740649A1/en
Priority to AU15350/95A priority patent/AU679834B2/en
Priority to BR9506549A priority patent/BR9506549A/en
Priority to JP7519335A priority patent/JPH09507672A/en
Publication of WO1995019952A1 publication Critical patent/WO1995019952A1/en
Priority to MXPA/A/1996/002847A priority patent/MXPA96002847A/en

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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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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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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
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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

Compounds have formula (I), in which A1 stands for 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cycloalkane; R1 stands for hydrogen, 1-7C-alkyl or 3-8C-cycloalkyl; R2 stands for hydrogen, 1-7C-alkyl, 3-8C-cycloalkyl or A2-Y; R1 and R2, together with the nitrogen atom to which both are bound, represent a non-substituted or substituted 5-, 6- or 7-ring heterocycle selected from the group made of pyrrolidine, piperidine, piperazine, morpholine and homopiperazine; A2 stands for 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cycloalkane; Y stands for R3, NH2, NH-R4 or S-R5. One substituted pyrrolidine residue is substituted by one or two identical or different substituents selected from the group that consists of 1-4C-alkyl, 1-4C-alkoxy and hydroxy. One substituted piperidine residue is substituted by one or two identical or different substituents selected from the group that consists of 1-4C-alkyl, 1-4C-alkoxy and hydroxy. One substituted piperazine residue may be substituted at positions 2, 3, 5 or 6 by a 1-4C-alkyl residue and at position 4 is substituted by a substituent selected from the group that consists of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, phenyl substituted by R6, R7 and R8, phenyl-1-4C-alkyl substituted at the phenyl residue by R6, R7 and R8, benzoyl, picolinoyl, nicotinoyl, isonicotinoyl substituted in the phenyl residue by R6, R7 and R8, possibly halogen-substituted or 1-4C-alkyl-substituted benzhydryl and the residue R4. One substituted morpholine residue is substituted by one or two identical or different 1-4C-alkyl residues, and one substituted homopiperazine residue is substituted at position 4 by a substituent selected from the group that consists of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, phenyl substituted by R6, R7 and R8, phenyl-1-4C-alkyl substituted in the phenyl residue by R6, R7 and R8 and benzoyl substituted in the phenyl residue by R6, R7 and R8. These compounds are useful for treating cardiovascular diseases and increased intra-ocular pressure.

Description

NHroxy-Gruppen enthaltende Benzylamlnderivate und ihre, Verwendung zur Behandlung von cardiovasculären Erkrankungen sowie erhαtem AugeninnendruckBenzylamine derivatives containing NHroxy groups and their use for the treatment of cardiovascular diseases and increased intraocular pressure
Anwendungsgebiet der ErfindungField of application of the invention
Die Erfindung betrifft Benzylaminderivate, die in der pharmazeutischen Industrie für die Herstellung von Medikamenten verwendet werden.The invention relates to benzylamine derivatives which are used in the pharmaceutical industry for the manufacture of medicaments.
Bekannter technischer HintergrundKnown technical background
Im Stand der Technik werden auf verschiedene Weise substituierte Nitroxy- verbindungen beschrieben, die sich beispielsweise zur Behandlung cardio- vasculärer Erkrankungen eignen sollen.In the prior art, substituted nitroxy compounds are described in various ways, which are said to be suitable, for example, for the treatment of cardiovascular diseases.
Beschreibung der ErfindungDescription of the invention
Gegenstand der Erfindung sind Verbindungen der Formel I (siehe beiliegendesThe invention relates to compounds of the formula I (see attached
Formelblatt) , worinFormula sheet), wherein
AI l-15C-Alkylen, 5-7C-Cycloalkylen oder Di-l-4C-alkylen-5-7C-cycloalkan bedeutet, und worinAI means 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cycloalkane, and in which
Rl Wasserstoff, 1-7C-Alkyl oder 3-8C-Cycloalkyl undRl is hydrogen, 1-7C-alkyl or 3-8C-cycloalkyl and
R2 Wasserstoff, 1-7C-Alkyl, 3-8C-Cycloalkyl oder A2-Y bedeutet, oder worinR2 is hydrogen, 1-7C-alkyl, 3-8C-cycloalkyl or A2-Y, or wherein
Rl und R2 gemeinsam und unter Einschluß des Stickstoffatoms, an das beide gebunden sind, einen unsubstituierten oder substituierten 5-, 6- oder 7-Ring Heterocyclus darstellen, der ausgewählt ist aus der Gruppe be¬ stehend aus Pyrrolidin, Piperidin, Piperazin, Morpholin und Homopipera¬ zin, wobeiR1 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
A2 l - 15C-Al kyl en , 5-7C-Cycl oal kyl en oderA2 l - 15C-alkyl, 5-7C-cycloalcyl or
Di - l -4C-al kyl en-5-7C-cycl oal kan bedeutet , Y R3, NH2, NH-R4 oder S-R5 bedeutet, ein substituierter Pyrrolidinorest substituiert ist mit einem oder zwei gleichen oder verschiedenen Substituenten ausgewählt aus der Gruppe bestehend aus 1-4C-Alkyl, l-4C-Alkoxy und Hydroxy, ein substituierter Piperidinorest substituiert ist mit einem oder zwei gleichen oder verschiedenen Substituenten ausgewählt aus der Gruppe bestehend aus 1-4C-Alkyl, l-4C-Alkoxy und Hydroxy, ein substituierter Piperazinorest in 2-, 3-, 5- oder 6-Position substituiert sein kann mit einem 1-4C-Alkylrest und in 4-Position substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus 1-4C-A1kyl , l-4C-Alkoxycarbonyl , l-4C-Alkylcarbonyl , durch R6, R7 und R8 substituiertem Phenyl, durch R6, R7 und R8 im Phenylrest substituiertem Phenyl -l-4C-alkyl , durch R6, R7 und R8 im Phenylrest substituiertem Benzoyl, Picolinoyl, Nicotinoyl, Iso- nicotinoyl, gewünschtenfalls durch Halogen oder 1-4C-Alkyl sub¬ stituiertem Benzhydryl und dem Rest R4, ein substituierter Morphol inorest substituiert ist mit einem oder zwei gleichen oder verschiedenen 1-4C-Alkylresten und ein substituierter Homopiperazinorest in 4-Position substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus 1-4C-A1kyl , l-4C-Alkoxycarbonyl , l-4C-Alkylcarbonyl , durch R6, R7 und R8 substituiertem Phenyl, durch R6, R7 und R8 im Phenylrest substituiertem Phenyl -l-4C-alkyl und durch R6, R7 und R8 im Phe¬ nylrest substituiertem Benzoyl, wobei weiterhinDi - 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 R6, R7 and R8 in the phenyl radical, benzoyl, picoloyoyl, nicotinoyl, isonicotinoyl substituted by R6, R7 and R8 in the phenyl radical, if desired benzhydryl and substituted by halogen or 1-4C-alkyl the rest R4, a substituted morphol inorest is substituted with one or two identical or different 1-4C-alkyl radicals and a substituted homopiperazinorest in 4-position is substituted with a substituent selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1- 4C-alkylcarbonyl, by R6, R7 and R8 substituted phenyl, by R6, R7 and R8 in the phenyl radical substituted phenyl -l-4C-alkyl and R6, R7 and R8 in Phe ¬ nylrest substituted benzoyl, wherein further
R3 Furyl, Naphthyl, Tetrahydronaphthyl, durch -O-Al-ONO-, substituier¬ tes Phenyl oder durch R6, R7 und R8 substituiertes Phenyl bedeu¬ tet,R3 furyl, naphthyl, tetrahydronaphthyl, by -O-Al-ONO, substitutability ¬ tes phenyl or by R6, R7 and R8 substituted phenyl bedeu¬ tet,
R4 1-7C-Alkyl oder den Substituenten -CH2-CH(0H)-(CH20) -Ar bedeutet undR4 is 1-7C-alkyl or the substituents -CH 2 -CH (0H) - (CH 2 0) -Ar and
R5 durch R6, R7 und R8 substituiertes Phenyl, durch R6, R7 und R8 substituiertes Phenyl -l-4C-alkyl , gewünschtenfalls durch Halogen oder 1-4C-A1 kyl substituiertes Benzhydryl, Dibenzo-5-7C-cycloal - kanyl , Dibenzocycloheptenyl oder Benzo-pyrido-5-7C-cycloal anyl bedeutet, und wobei außerdem R6 Wasserstoff, 1-4C-Alkyl, l-4C-Alkoxy, l-4C-Alkylcarbonyl , Halogen, Amino, Mono- oder Di -(1-4C-alkyl )amino oder Nitro bedeutet,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 Wasserstoff, 1-4C-Alkyl, l-4C-Alkoxy, Halogen oder Nitro bedeutet,R7 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or nitro,
R8 Wasserstoff oder Trifluormethyl bedeutet, p die Zahl 0 oder 1 bedeutet undR8 represents hydrogen or trifluoromethyl, p represents the number 0 or 1 and
Ar ein ganz oder teilweise ungesättigtes Kohlenwasserstoffringsystem bedeutet, das monocyclisch (mit 5 bis 6) oder bicyclisch (mit 9 bis 10 Ringatomen) ist, in dem 1, 2 oder 3 Kohlenstoffatome durch Heteroatome aus der Gruppe Stickstoff (N), Sauerstoff (0) oder Schwefel (S) ersetzt sein können und das durch einen oder zwei gleiche oder verschiedene Substituenten aus der Gruppe 1-4C-A1ky , l-4C-Alkoxy, 1-4C-A1kylthio, 1-4C-A1koxy-l-4C-alkyl , l-4C-Alkoxy- l-4C-alkoxy, 3-4C-Alkenyl , 3-4C-Alkenyloxy, 3-8C-Cycloalkyl , 5-10C-Cycloalkylalkoxyalkyl, l-4C-Alkylcarbonyl , 1-4C-Alkylcar- bonylamino, Carbamoyl , Carbamoyl -1-4C-alkyl , Halogen, Hydroxy, Oxo, Nitro, Cyan, l-4C-Alkylsufonamido, Amino, Mono- oder Di-(1- 4C-alkyl)amino, Ureido, Mono- oder Di-(l-4C-alkyl)ureido, Mono- oder Di-(3-8C-cycloalkyl )ureido, Trifluormethyl, ganz oder teil¬ weise durch Fluor substituiertes l-4C-Alkoxy, l-4C-Alkoxycarbonyl , Tetrahydrofurfuryloxy oder Morpholino substituiert sein kann, und die Salze dieser Verbindungen.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, nitro, cyano, 1-4C-alkylsufonamido, amino, mono- or di- (1-4C-alkyl) amino, ureido, mono- or di- (1-4C-Alkyl) ureido, mono- or di- (3-8C-cycloalkyl) ureido, trifluoromethyl, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, tetrahydrofurfuryloxy or morpholino can, and the salts this r connections.
l-15C-Alkylen steht für geradkettige oder verzweigte Alkylenreste mit 1 bis 15 Kohlenstoffatomen. Beispielsweise seien die Reste Methylen (-CH2-), Ethylen (-CH2CH2-), Trimethylen (-CH2CH2CH2-) , Tetramethylen (-CH2CH2CH2CH2-), Pentamethylen (-CH2CH2CH2CH2CH2-), Hexamethylen (-CH2-(CH2)4-CH2-), Octa ethylen (-CH2-(CH2)6-CH2-), Decamethylen (-CH2-(CH2)8-CH2-), Tetradecamethylen (-CH2-(CH2)12-CH2-), 1,2-Dimethyl- ethylen [-CH(CH3)-CH(CH3)-], 1,1-Dimethylethylen [-C(CH3)2-CH2-], Isopro- pyliden [-C(CH3)2-], 2,2-Dimethylpropylen [-CH2-C(CH3)2-CH2-], 2-Methyl- propylen [-CH2-CH(CH3)-CH2-] und 2-Methylethylen [-CH2-CH(CH3)-] genannt.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 -], isopropylidene [-C (CH 3 ) 2 -], 2,2-dimethylpropylene [-CH 2 -C (CH 3 ) 2 -CH 2 -], 2-methyl-propylene [-CH 2 -CH (CH 3 ) -CH 2 -] and 2-methylethylene [-CH 2 -CH (CH 3 ) -].
5-7C-Cycloalkylen steht für Cycloalkylenreste mit 5 bis 7 Kohlenstoff¬ atomen. Bevorzugt sind Cyclohexylenreste, wobei beispielsweise der 1,2- und der 1,4-Cyclohexylenrest genannt seien. Di-l-4C-alkylen-5-7C-cycloalkan steht für cyclische Kohlenwasserstoffe mit 5 bis 7 Kohlenstoffatome, die durch zwei (gleiche oder verschiedene) Alky¬ lenreste mit 1 bis 4 Kohlenstoffatomen substituiert sind. Ein bevorzugter Di-l-4C-alkylen-5-7C-cycloalkanrest ist der 1,4-Dimethylencyclohexanrest.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 steht für geradkettige und verzweigte Alkylreste mit 1 bis 7 Kohlenstoffatomen. Beispielsweise seien genannt der Heptyl-, Hexyl-, Neo- pentyl-, Isopentyl-, Pentyl-, Butyl-, iso-Butyl-, sec.-Butyl-, tert.-Bu- tyl-, Propyl-, Isopropyl-,- Ethyl- und der Methylrest.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 steht für den Cyclopropyl-, Cyclobutyl-, Cyclopentyl-, Cy- clohexyl-, Cycloheptyl- und Cyclooctylrest.3-8C-Cycloalkyl stands for the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl radical.
1-4C-A1kyl steht für geradkettige oder verzweigte Alkylreste mit 1 bis 4 Kohlenstoffatomen. Beispielsweise seien genannt der Butyl-, iso-Butyl-, sec.-Butyl-, tert.-Butyl-, Propyl-, Isopropyl-, Ethyl- und der Methylrest.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.
l-4C-Alkoxy steht für einen Rest, der neben dem Sauerstoffatom einen der vorstehend genannten 1-4C-Alkylreste enthält. Beispielsweise seien der Methoxy- und der Ethoxyrest genannt.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 im Sinne der vorliegenden Erfindung ist Brom, Chlor und Fluor.Halogen in the sense of the present invention is bromine, chlorine and fluorine.
l-4C-Alkoxycarbonyl steht für einen Rest, der neben der Carbonylgruppe einen der vorstehend genannten l-4C-Alkoxyreste enthält. Beispielsweise seien der Methoxycarbonyl- und der Ethoxycarbonyl est genannt.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.
l-4C-Alkylcarbonyl steht für einen Rest, der neben der Carbonylgruppe einen der vorstehend genannten 1-4C-Alkylreste enthält. Beispielsweise sei der Acetylrest genannt.1-4C-Alkylcarbonyl stands for a radical which, in addition to the carbonyl group, contains one of the 1-4C-alkyl radicals mentioned above. For example, the acetyl radical may be mentioned.
Als Dibenzo-5-7C-cycloalkanylreste seien der Dibenzocyclopentyl -, der Di- benzocyclohexyl- und insbesondere der Dibenzocycloheptylrest genannt.The dibenzo-5-7C-cycloalkanyl radicals which may be mentioned are the dibenzocyclopentyl radical, the dibenzocyclohexyl radical and in particular the dibenzocycloheptyl radical.
Als Benzo-pyrido-5-7C-cycloalkanylreste seien der Benzo-pyridocyclopentyl -, der Benzo-pyridocyclohexyl- und insbesondere der Benzo-pyridocycloheptyl- rest genannt.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- oder Di-(l-4C-alkyl)amino steht für einen Aminorest, der durch einen oder zwei gleiche oder verschiedene der vorstehend genannten 1-4C-A1kyl- reste substituiert ist. Beispielsweise seien der Methylamino-, der Ethyl- amino-, der Dimethylamino-, der Diethylamino- und der Di-isopropylaminorest genannt.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. For example, the methylamino, the ethylamino, the dimethylamino, the diethylamino and the diisopropylamino radical may be mentioned.
1-4C-A1kylthio steht für einen Rest, der neben dem Schwefelatom einen der vorstehend genannten 1-4C-Alkylreste enthält. Bevorzugt ist der Methylthio- rest.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-l-4C-al yl steht für einen der vorstehend genannten 1-4C-A1kyl - reste, der durch einen der vorstehend genannten l-4C-Alkoxyreste substitu¬ iert ist. Beispielsweise seien der Methoxymethyl-, der Methoxyethyl est und der Butoxyethyl est genannt.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.
l-4C-Alkoxy-l-4C-alkoxy steht für einen der vorstehend genannten 1-4C-A1k- oxyreste, der durch einen weiteren l-4C-Alkoxyrest substituiert ist. Bei¬ spielsweise sei der Methoxyethoxyrest genannt.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. For example, the methoxyethoxy radical may be mentioned.
3-4C-Alkenyl ist beispielsweise 2-Butenyl und insbesondere Allyl.3-4C-alkenyl is, for example, 2-butenyl and especially allyl.
3-4C-Alkenyloxy enthält neben dem Sauerstoffatom einen 3-4C-Alkenylrest. Als beispielhafter 3-4C-Alkenyloxyrest sei der Allyloxyrest genannt.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 steht für einen Al oxyalkylrest, der durch einen Cycloalkylrest substituiert ist. Beispielsweise sei der Cyclopropyl- methoxyethylrest genannt.5-10C-Cycloalkylalkoxyalkyl stands for an Al oxyalkylrest, which is substituted by a Cycloalkylrest. For example, the cyclopropyl methoxyethyl radical may be mentioned.
Als l-4C-Alkylcarbonylaminorest sei beispielsweise der Acetylamidorest (-NH-C0-CH3) genannt.As the 1-4C-alkylcarbonylamino radical, for example, the acetylamido radical (-NH-CO-CH 3 ) may be mentioned.
Carbamoyl steht für den Rest NH2-C0~.Carbamoyl stands for the rest NH 2 -C0 ~.
Carbamoyl -l-4C-al kyl steht für einein der vorstehend genannten 1-4C-A1 kyl - reste, der durch Carbamoyl substituiert ist. Als beispielhafter Carbamoyl- l-4C-alkylrest sei der Carbamoyl ethyl est genannt. l-4C-Alkylsulfonamido steht für einen Sulfonamidorest, an den einer der vorstehend genannten 1-4C-Alkylreste gebunden ist. Beispielsweise sei der Methylsulfonamidorest genannt.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. For example, the methylsulfonamido radical may be mentioned.
Ureido steht für den Rest -NH-C0-NH2. Als Mono-l-4C-alkylureido sei bei¬ spielsweise 3-Methylureido, als Di-l-4C-alkylureido 3,3-Dimethylureido ge¬ nannt. Als beispielhafte Mono- oder Di-3-8C-cycloalkylureidoreste seien beispielsweise der 3-Cyclohexylureido- und der 3,3-Di-cyclohexylureidorest genannt.Ureido stands for the residue -NH-C0-NH 2 . For example, 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.
Als ganz oder teilweise durch Fluor substituiertes l-4C-Alkoxy seien bei¬ spielsweise der 1,2,2-Trifluorethoxy, der 2,2,3,3,3-Pentafluorpropoxy-, der Perfluorethoxy- und insbesondere der 1,1,2,2-Tetrafluorethoxy-, der Triflu- ormethoxy-, der 2,2,2-Trifluorethoxy- und der Difluormethoxyrest genannt.For example, 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.
Als substituierte Pyrrol idinoreste seien beispielsweise der 2-Methylpyrro- lidino-, 2,5-Dimethylpyrrolidino- und der 3-Hydroxypyrrolidinorest genannt.Examples of substituted pyrrole idino radicals are the 2-methylpyrrolidino, 2,5-dimethylpyrrolidino and the 3-hydroxypyrrolidino radical.
Als substituierte Piperidinoreste seien beispielsweise der 3-Hydroxypiperi- dino-, 2-n-Propylpiperidino-, 5-Ethyl -2-methylpiperidino-, 4-n-Propylpipe- ridino-, 4,4-Dimethylpiperidino-, 2,6-Dimethylpiperidino-, 4-Hydroxypiperi- dino-, 2-Ethyl-2-methylpiperidino-, 2-Methylpiperidino-, 2,6-Dimethylpipe- ridino- und der 2-Ethylpiperidinorest genannt.Examples of 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.
Als substituierte Piperazinoreste seien beispielsweise der 4-Methylpipera- zino-, 4-[2-(2-Trifluormethylphenyl)ethyl ]piperazino-, 4-Phenylpiperazino-, 4-(2-Methylphenyl )piperazino-, 4-(2,3-Dimethylphenyl )piperazino-, 4-(2-Chlorphenyl)piperazino-, 4-(2-Methoxyphenyl)piperazino-, 4-(2-Ethoxy- phenyl)piperazino-, 4-(3-Chlorphenyl)piperazino-, 4-(4-Fluorphenyl )pipera- zino-, 4-(4-Chlorphenyl)piperazino-, 4-(4-Methoxyphenyl)piperazino-, 3-Me- thyl-4-(4-chlorphenyl)piperazino-, 3-Methyl-4-(4-methoxyphenyl )piperazino-, 3-Methyl -4-(4-methylphenyl )piperazino-, 4-(2,4-Dimethylphenyl )piperazino-, 4-Acetylpiperazino-, 4-(3,4-Dichlorphenyl )piperazino-, 4-(3,4-Dimethylphe¬ nyl )piperazino-, 4-(3-Pyridincarbonyl )piperazino-, 3-Methyl -4-phenylpipe- razino-, 3-Methyl -4-(3-chlorphenyl )piperazino-, 4-Benzylpiperazino-, 4-Pro-Examples of 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-methoxyphenyl) piperazino, 3-methyl -4- (4-methylphenyl) piperazino, 4- (2,4-dimethylphenyl) piperazino, 4-acetylpiperazino, 4- (3,4-dichlorophenyl) piperazino -, 4- (3,4-Dimethylphe¬ nyl) piperazino-, 4- (3-pyridinecarbonyl) piperazino-, 3-methyl -4-phenylpiperrazino-, 3-methyl -4- (3-chlorophenyl) piperazino- , 4-benzylpiperazino-, 4-pro
<T<T
ERSÄTZBLATT (REGEL 26) pylpiperazino-, 4- (3-Methyl henyl )piperazino-, 4-(3-Methoxyphenyl)piperazi- no-, 4- (4-Methyl phenyl )piperazino-, 4-(2,5-Dimethylphenyl)piperazino-, 4-Benzhydrylpiperazino-, 4-n-Butylpiperazino-, 4-iso-Butylpiperazino-, 4-tert.-Butylpiperazino-, 4- (3-Trifluormethyl phenyl )piperazino-, 4-(l-Phe- nyl ethyl )piperazino-, 4-(2-Phenylethyl)piperazino-, 4-(2-Hydroxyphenyl)pi- perazino-, 4-(3,4-Dimethoxyphenyl )piperazino-, 4-Isopropylpiperazino-, 3-Methyl-4-(3-methoxyphenyl)piperazino-, 4-(4-Hydroxyphenyl)piperazino-, 3-Methyl -4- (3-methyl phenyl )piperazino-, 4-(3-Hydroxyphenyl)piperazino-, 4- (2, 6-Dinitro-4- trifluormethyl phenyl )piperazino-, 4-(2-Hydroxy-3-phenoxy- propyl)piperazino-, 4-(4-Nitrophenyl)piperazino-, 4- (4-Acetyl phenyl )pipe- razino-, 4-Ethoxycarbonylpiperazino- und der 4-(4-Chlorbenzhydryl)pipera- zinorest genannt.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-hydroxyphenyl) piperazino-, 3-methyl -4- (3-methylphenyl) piperazino-, 4- (3-hydroxyphenyl) piperazino-, 4- (2, 6-dinitro-4-trifluoromethyl phenyl) piperazino-, 4- (2-hydroxy-3-phenoxypropyl) piperazino-, 4- (4-nitrophenyl) piperazino-, 4- (4-acetylphenyl) pipe-razino-, 4-ethoxycarbonylpiperazino- and the like 4- (4-Chlorobenzhydryl) piperazine residue called.
Als substituierter Morpholinorest sei beispielsweise der 3,5-Dimethylmor- pholinorest genannt.The substituted morpholino radical, for example, is the 3,5-dimethylmorpholino radical.
Als substituierte Ho opiperazinoreste seien beispielsweise der 4-Methyl-, der 4-Ethoxycarbonyl-, der 4-Acetyl-, der 4-(2-Methoxyphenyl)- und der 4- Benzoyl homopiperazinorest genannt.Examples of substituted hoopiperazino radicals are 4-methyl, 4-ethoxycarbonyl, 4-acetyl, 4- (2-methoxyphenyl) and 4-benzoyl homopiperazino.
Als gewünschtenfalls durch Halogen oder 1 -4C-A1 kyl substituierte Benzhy- drylreste seien beispielsweise der Benzhydryl-, der Bis-4,4'-fluorbenz- hydryl-, der Bis-4,4'-chlorbenzhydryl-, der 4-Chlorbenzhydryl- und der 4-Methyl benzhydryl rest genannt.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.
Als beispielhafte, durch R6, R7 und R8 substituierte Phenylreste seien die Reste 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-Fluor-, 4-Chlor, 2-Chlor-, 3-Chlor-, 3,4-Dichlor-, 3-Trifluormethyl -, 2-Trifluormethyl-, 2-Methyl-, 3-Methyl-, 4-Methyl-, 2,3-Dimethyl-, 2,4-Dimethyl-, 3,4-Dimethyl-, 2,5-Dimethyl-, 4-Nitro-, 2,6-Dinitro-4-trifluormethyl- und 5-Chlor-2-methylaminophenyl ge¬ nannt.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.
Als beispielhafte ausgewählte Substituenten Ar seien die folgenden Reste genannt: Phenyl, 4-(2-Methoxyethoxy)-phenyl , 2-Allylphenyl , 2-Acetyl-4-butyramido- phenyl , 4-Carbamoylmethylphenyl , 4-Methylphenyl , 2-Tetrahydrofurfuryloxy- phenyl, 2-Chlor-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-Cyanphenyl , 4-Acetamidophenyl , 4-Hydroxyphenyl , 2-Cyclopropylphenyl , 4-Methansulfonamidophenyl , 4-(3-Cyclohexylureido)-phenyl , 2-Methylthio- phenyl , 4-Carbamoylphenyl , 4-Cyclopropyl ethoxyethylphenyl , 2,5-Dichlor- phenyl, 2-Butyryl-4-fluorphenyl , 2-Trifluor ethylphenyl , 2-Chlorphenyl , 2-Fluorphenyl, 2-Methylphenyl , 2-Acetylphenyl , 5,6,7,8-Tetrahydro-2-naph- . thyl, 4-Carbazolyl, 1-Naphthyl, 5,8-Dihydro-l-naphthyl , 5,6-Dihydro-l- naphthyl, l-Inden-4-yl , l-Inden-7-yl , 2-Methyl-4-indolyl , 6,7-Dihydroxy- 5,6,7,8-tetrahydro-l-naphthyl, 4-Indolyl, 3,4-Dihydro-2-hydroxychinolin- 5-yl (= 3,4-Dihydrocarbostyril-5-yl), 8-Hydroxycarbostyril-5-yl , 2-Naph- thyl, 2-Thiazolyl, 4-Morpholino-l,2,5-thiadiazol-3-yl , 7-Ethyl-2-benzo- furanyl, 2-Acetyl-7-benzofuranyl , 5-Methyl-2H-benzopyron-8-yl , 1,4-Benzo- dioxan-5-yl, 4-Indanyl und 5,6,7,8-Tetrahydro-5-oxo-l-naphthyl .The following radicals may be mentioned as exemplary selected substituents Ar: 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-cyclohexylureido) phenyl, 2-methylthiophenyl, 4-carbamoylphenyl, 4-cyclopropyl ethoxyethylphenyl, 2.5 -Dichlorophenyl, 2-butyryl-4-fluorophenyl, 2-trifluoroethylphenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl, 2-acetylphenyl, 5,6,7,8-tetrahydro-2-naph-. thyl, 4-carbazolyl, 1-naphthyl, 5,8-dihydro-l-naphthyl, 5,6-dihydro-l-naphthyl, l-inden-4-yl, l-inden-7-yl, 2-methyl- 4-indolyl, 6,7-dihydroxy-5,6,7,8-tetrahydro-l-naphthyl, 4-indolyl, 3,4-dihydro-2-hydroxyquinolin-5-yl (= 3,4-dihydrocarbostyril-5 -yl), 8-hydroxycarbostyril-5-yl, 2-naphthyl, 2-thiazolyl, 4-morpholino-l, 2,5-thiadiazol-3-yl, 7-ethyl-2-benzofuranyl, 2- Acetyl-7-benzofuranyl, 5-methyl-2H-benzopyron-8-yl, 1,4-benzo-dioxan-5-yl, 4-indanyl and 5,6,7,8-tetrahydro-5-oxo-l- naphthyl.
Als Salze kommen für die Verbindungen der Formel I alle Säureadditionssalze in Betracht. Besonders erwähnt seien die pharmakologisch verträglichen Salze der in der Galenik üblicherweise verwendeten anorganischen und orga¬ nischen Säuren. Pharmakologisch unverträgliche Salze, die beispielsweise bei der Herstellung der erfindungsgemäßen Verbindungen im industriellen Maßstab als Verfahrensprodukte zunächst anfallen können, werden durch dem Fachmann bekannte Verfahren in pharmakologisch verträgliche Salze überge¬ führt. Als solche eignen sich wasserlösliche und wasserunlösliche Säure¬ additionssalze mit Säuren wie beispielsweise Salzsäure, Bromwasserstoffsäu¬ re, Phosphorsäure, Salpetersäure, Schwefelsäure, Essigsäure, Zitronensäure, D-Gluconsäure, Benzoesäure, 2-(4-Hydroxybenzoyl)-benzoesäure, Buttersäure, Sulfosalicylsäure, Maleinsäure, Laurinsäure, Äpfelsäure, Fumarsäure, Bern¬ steinsäure, Oxalsäure, Weinsäure, Embonsäure, Stearinsäure, Toluolsulfon- säure, Methansulfonsäure oder 3-Hydroχy-2-naphtoesäure, wobei die Säuren bei der Salzherstellung - je nachdem, ob es sich um eine ein- oder mehrba- sige Säure handelt und je nachdem, welches Salz gewünscht wird - im äquimo- laren oder einem davon abweichenden Mengenverhältnis eingesetzt werden.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-hydroχy-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.
9 Hervorzuheben sind solche Verbindungen der Formel I, worin AI 2-10C-Alkylen oder Dimethylencyclohexan bedeutet, und worin Rl Wasserstoff und R2 Wasserstoff oder A2-Y bedeutet, oder worin9 To be emphasized are those compounds of the formula I in which AI is 2-10C-alkylene or dimethylenecyclohexane, and in which R1 is hydrogen and R2 is hydrogen or A2-Y, or in which
Rl und R2 gemeinsam und unter Einschluß des Stickstoffatoms, an das beide gebunden sind, einen unsubstituierten oder substituierten Piperazinrest darstellen, wobeiRl and R2 together and including the nitrogen atom to which both are attached represent an unsubstituted or substituted piperazine radical, where
A2 l-10C-Alkylen bedeutet,A2 l-10C-alkylene means
Y R3, NH2, NH-R4 oder S-R5 bedeutet, ein substituierter Piperazinorest in 4-Position substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus l-4C-Alkoxycarbonyl , l-4C-Alkylcarbonyl , Picolinoyl, Nicotinoyl, Isonicotinoyl , Benzhydryl und dem Rest R4 und wobei weiterhinY 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 Phenyl oder durch -0-A1-0N0- substituiertes Phenyl bedeutet, R4 den Substituenten -CH2-CH(0H)-(CH20) -Ar bedeutet und R5 gewünschtenfalls durch Halogen oder 1-4C-A1kyl substituiertes Benzhydryl, Dibenzocycloheptanyl , Dibenzocycloheptenyl oder Benzo-pyrido-cycloheptanyl bedeutet, und wobei außerdem p die Zahl 1 bedeutet undR3 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 Phenyl, 4-(2-Methoxyethoxy)-phenyl , 2-Allylphenyl , 2-Chlor-5- methylphenyl , 2-Allyloxyphenyl , 2-Cyclopentylphenyl , 2-Cyanphenyl oder 1-Naphthyl bedeutet, und die Salze dieser Verbindungen.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.
Besonders hervorzuheben sind solche Verbindungen der Formel I, worinParticularly noteworthy are those compounds of the formula I in which
AI 2-10C-A1 kylen oder Dimethylencyclohexan bedeutet, und worinAI 2-10C-A1 means kylene or dimethylene cyclohexane, and wherein
Rl Wasserstoff undRl hydrogen and
R2 Wasserstoff oder A2-Y bedeutet, oder worinR2 is hydrogen or A2-Y, or wherein
Rl und R2 gemeinsam und unter Einschluß des Stickstoffatoms, an das beide gebunden sind, einen unsubstituierten oder substituierten Piperazinrest darstellen,R1 and R2, together and including the nitrogen atom to which both are bound, represent an unsubstituted or substituted piperazine radical,
ERSATZBUTT(REGEL26) wobei . A2 l-10C-Alkylen bedeutet,REPLACEMENT BUTT (RULE 26) in which . A2 l-10C-alkylene means
Y R3, NH2, NH-R4 oder S-R5 bedeutet, ein substituierter Piperazinorest in 4-Position substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus l-4C-Alkylcarbonyl , Nicotinoyl, Benzhydryl und dem Rest R4 und wobei weiterhinY 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 Phenyl oder durch -0-A1-ONO„ substituiertes Phenyl bedeutet, R4 den Substituenten -CH2-CH(0H)-(CH20) -Ar bedeutet und R5 durch 1-4C-A1kyl substituiertes Benzhydryl, Benzhydryl,R3 denotes phenyl or phenyl substituted by -0-A1-ONO, R4 denotes the substituent -CH 2 -CH (0H) - (CH 2 0) -Ar and R5 denotes benzhydryl, benzhydryl substituted by 1-4C-A1kyl,
Dibenzocycloheptanyl , Dibenzocycloheptenyl oder durch Chlor substituiertes Benzo-pyrido-cycloheptanyl bedeutet, und wobei außerdem p die Zahl 1 bedeutet undMeans dibenzocycloheptanyl, dibenzocycloheptenyl or chloro-substituted benzopyridocycloheptanyl, and where p also denotes the number 1 and
Ar Phenyl, 2-Ally phenyl oder 1-Naphthyl bedeutet, und die Salze dieser Verbindungen.Ar means phenyl, 2-allyphenyl or 1-naphthyl, and the salts of these compounds.
Weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung der Verbindungen der Formel I und ihrer Salze. Das Verfahren ist dadurch ge¬ kennzeichnet, daß man Aldehyde der Formel II (siehe beiliegendes Formel - blatt), worin AI die oben angegebene Bedeutung hat, mit den in Form von Ammoniumsalzen vorliegenden Verbindungen der Formel III (siehe beiliegendes Formelblatt), worin Rl und R2 die oben angegebenen Bedeutungen haben, in Gegenwart von Natriumcyanoborhydrid umsetzt, und gewünschtenfalls an¬ schließend erhaltene Verbindungen in die Salze oder erhaltene Salze in die freien Verbindungen überführt.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.
Das Verfahren wird auf eine dem Fachmann an sich bekannte Weise durchge¬ führt, beispielsweise so, wie in der folgenden allgemeinen Herstellungsvor¬ schrift beschrieben.The process is carried out in a manner known per se to the person skilled in the art, for example as described in the following general manufacturing instructions.
In den folgenden Beispielen, die der näheren Erläuterung der Erfindung dienen sollen, steht Fp. für Schmelzpunkt, RT für Raumtemperatur und h für Stunde(n) .In the following examples, which are intended to explain the invention in more detail, mp stands for melting point, RT for room temperature and h for hour (s).
1010
ERSATZBUTT (REGEL 26) BeispieleREPLACEMENT BUTT (RULE 26) Examples
AI 1 gemei ne Herstel 1 ungsvorschr i f tenAI 1 according to manufac turing regulations
Variante Aoption A
10 mmol des Aldehyds II und 10 mmol der (als Ammoniumsalz vorliegenden) Aminoverbindung III werden in einem geeigneten Lösungsmittel (wie z.B. Methanol, Ethanol oder Tetrahydrofuran) gelöst, mit 10 mmol Natriumcyano- borhydrid versetzt und bei RT für eine h gerührt. Nach nochmaliger Zugabe von 10 mmol Natriumcyanoborhydrid wird für weitere 20 h gerührt. Das Lö¬ sungsmittel wird abgezogen und der Rückstand in einem Gemisch aus Wasser und Ethylacetat gelöst. Die organische Phase wird abgetrennt, über Magne¬ siumsulfat getrocknet und eingeengt. Der Rückstand wird durch Chromato- grafie und/oder Umkristallisation gereinigt.10 mmol of the aldehyde II and 10 mmol of the amino compound III (present as the ammonium salt) are dissolved in a suitable solvent (such as methanol, ethanol or tetrahydrofuran), mixed with 10 mmol of sodium cyanoborohydride and stirred at RT for one hour. After adding 10 mmol of sodium cyanoborohydride again, the mixture is stirred for a further 20 h. The solvent is drawn off and the residue is dissolved in a mixture of water and ethyl acetate. The organic phase is separated off, dried over magnesium sulfate and concentrated. The residue is purified by chromatography and / or recrystallization.
Variante BVariant B
Anstelle von 10 mmol der (als Ammoniumsalz vorliegenden) Aminoverbindung III werden 40 mmol eingesetzt.Instead of 10 mmol of the amino compound III (present as ammonium salt), 40 mmol are used.
Variante CVariant C
Anstelle von 10 mmol der (als Ammoniumsalz vorliegenden) Aminoverbindung III werden 100 mmol eingesetzt.Instead of 10 mmol of the amino compound III (present as ammonium salt), 100 mmol are used.
1. 2-(2-Nitroxyethoxy)-N-(2-phenylethγ1)benzylamin1. 2- (2-nitroxyethoxy) -N- (2-phenylethγ1) benzylamine
Hergestellt aus 2-(2-Nitroxyethoxy)benzaldehyd und 2-Phenyl ethyl ammonium- chlorid nach Verfahrensvariante A. Gereinigt durch Chromatografie an Kie¬ selgel (Ethylacetat). Die Titelverbindung wurde als Tosylat isoliert und aus Diethylether umkristallisiert. Fp. des Tosylats: 147-149°C.Manufactured from 2- (2-nitroxyethoxy) benzaldehyde and 2-phenyl ethyl ammonium chloride according to process variant A. Purified by chromatography on silica gel (ethyl acetate). The title compound was isolated as tosylate and recrystallized from diethyl ether. Mp of tosylate: 147-149 ° C.
4141
ERSATZBUTT (REGEL 26) 2. N-f2-r(4-Methyl-a1pha-phenylbenzyl Uhiol-ethyl)-4-(2-nitroxyethoχy)- benzylaminREPLACEMENT BUTT (RULE 26) 2. N-f2-r (4-methyl-a1pha-phenylbenzyl Uhiol-ethyl) -4- (2-nitroxyetho χ y) - benzylamine
Hergestellt aus 4-(2-Nitroxyethoxy)benzaldehyd und 2-[(4-Methyl-alpha-phe- nylbenzyl)thio]ethylammoniumchlorid in Tetrahydrofuran nach Verfahrens¬ variante A. Gereinigt durch Chromatografie an Kieselgel (Dichlormethan) . Fp. des Hydrochlorids: 98-103βC.Prepared from 4- (2-nitroxyethoxy) benzaldehyde and 2 - [(4-methyl-alpha-phenylbenzyl) thio] ethylammonium chloride in tetrahydrofuran according to process variant A. Purified by chromatography on silica gel (dichloromethane). Mp of the hydrochloride: 98-103 β C.
3. N-r2-(7-Chlor-10.11-dihydro-5H-benzor4.51cvc1oheptari.2blpyridin-5- thio)-ethy11-4-(2-nitroχyethoxy)benzylamin3. N-r2- (7-chloro-10.11-dihydro-5H-benzor4.51cvc1oheptari.2blpyridin-5-thio) -ethy11-4- (2-nitroχyethoxy) benzylamine
Hergestellt aus 4-(2-Nitroxyethoxy)benzaldehyd und N-[2-(7-Chlor-10,ll-di- hydro-5H-benzo[4,5]cyclohepta[l,2b]pyridin-5-thio)ethyl]amin x 2 HC1 in Tetrahydrofuran nach Verfahrensvariante A. Gereinigt durch Chromatografie an Kieselgel (Ethylacetat/Methanol 7:1). Als Dihydrochlorid aus Ethylacetat umkristallisiert. Fp. des Dihydrochlorids: 148-151βC.Made from 4- (2-nitroxyethoxy) benzaldehyde and N- [2- (7-chloro-10, ll-di-hydro-5H-benzo [4,5] cyclohepta [1,2b] pyridine-5-thio) ethyl ] amine x 2 HC1 in tetrahydrofuran according to process variant A. Purified by chromatography on silica gel (ethyl acetate / methanol 7: 1). Recrystallized as dihydrochloride from ethyl acetate. Mp of the dihydrochloride: 148-151 β C.
4. N-(2-r(5H-Dibenzora.dlcyclohepten-5-yl)thiol-ethyl)-2-f .2-dimethyl- 3-nitroχypropoχy.benzylamin4. N- (2-r (5H-Dibenzora.dlcyclohepten-5-yl) thiol-ethyl) -2-f .2-dimethyl-3-nitroχypropoχy.benzylamine
Hergestellt aus 2-(2,2-Dimethyl-3-nitroxypropoxy)benzaldehyd und N-{2-[(5H- Dibenzo[a,d]cyclohepten-5-yl)thio]ethyl)amin in Tetrahydrofuran nach Ver¬ fahrensvariante A. Gereinigt durch Chromatografie an Kieselgel (Ethylace- tat/Petrolether 60-80/1:2). Fp.: 97-99°C.Prepared from 2- (2,2-dimethyl-3-nitroxypropoxy) benzaldehyde and N- {2 - [(5H-dibenzo [a, d] cyclohepten-5-yl) thio] ethyl) amine in tetrahydrofuran according to process variant A Purified by chromatography on silica gel (ethyl acetate / petroleum ether 60-80 / 1: 2). Mp .: 97-99 ° C.
5. N-T2-(2,2-Dimethyl-3-nitroχypropoχy)benzyllpiperazin5. N-T2- (2,2-dimethyl-3-nitroχypropoχy) benzyllpiperazine
Hergestellt aus 2-(2,2-Dimethyl-3-nitroxypropoxy)benzaldehyd und Piperazin x 2 HC1 in Methanol nach Verfahrensvariante B. Nach Einengen der Reaktions¬ lösung wurde der Rückstand in wäßriger Natriu carbonatlösung aufgenommen und mit Ethylacetat extrahiert. Die organische Phase wurde über Kaliumcar- bonat getrocknet. Die Titelverbindung wurde als Hydrochlorid gefällt und aus Methanol/Diethylether umkristallisiert. Fp. des Hydrochlorids: 200°C (Zers.) .Prepared from 2- (2,2-dimethyl-3-nitroxypropoxy) benzaldehyde and piperazine x 2 HC1 in methanol according to process variant B. After concentration of the reaction solution, the residue was taken up in aqueous sodium carbonate solution and extracted with ethyl acetate. The organic phase was dried over potassium carbonate. The title compound was precipitated as the hydrochloride and recrystallized from methanol / diethyl ether. Mp of the hydrochloride: 200 ° C (dec.).
12.12th
ERSATZBUTT(REGEL26) 6. 3- (2-Nitroχyethoxy)benzyl aminREPLACEMENT BUTT (RULE 26) 6. 3- (2-Nitroχyethoxy) benzyl amine
Hergestellt aus 3-(2-Nitroxyethoxy)benzaldehyd und Ammoniumacetat in Etha- nol nach Verfahrensvariante C. Die Titelverbindung wurde als Hydrochlorid aus Diethylether gefällt. Fp. des Hydrochlorids: 131,8-132,5βC.Prepared from 3- (2-nitroxyethoxy) benzaldehyde and ammonium acetate in ethanol according to process variant C. The title compound was precipitated as hydrochloride from diethyl ether. Mp of the hydrochloride: 131.8-132.5 β C.
7. N-Acetv1 -N/ - r2- (2.2-dimethyl -3-nitroχypropoxy)benzynpiperazin7. N-Acetv1 -N / - r2- (2,2-dimethyl -3-nitroχypropoxy) benzynpiperazine
Hergestellt aus N-Acetylpiperazin x HCl und 2-(2,2-Dimethyl-3-nitroxy)benz- aldehyd in Methanol nach Verfahrensvariante A. Als Tosylat aus Ethylacetat u kristall isiert. Fp. des Tosylats: 123-126°C.Made from N-acetylpiperazine x HCl and 2- (2,2-dimethyl-3-nitroxy) benzaldehyde in methanol according to process variant A. crystallized as tosylate from ethyl acetate. Mp of tosylate: 123-126 ° C.
8. 2-(2-Nitroχyethoxy,benzylamin8. 2- (2-Nitroχyethoxy, benzylamine
Hergestellt aus 2-(2-Nitroxyethoxy)benzaldehyd und Ammoniumacetat in Metha¬ nol nach Verfahrensvariante C. Gereinigt durch Chromatografie an Kieselgel (Methanol/Ethylacetat 1:1). Das Hydrochlorid der Titelverbindung wurde aus Diethylether gefällt. Fp. des Hydrochlorids: 124,1-125,7βC.Prepared from 2- (2-nitroxyethoxy) benzaldehyde and ammonium acetate in methanol according to process variant C. Purified by chromatography on silica gel (methanol / ethyl acetate 1: 1). The hydrochloride of the title compound was precipitated from diethyl ether. Mp of the hydrochloride: 124.1-125.7 β C.
9. N-r2-(2,2-Dimethyl-3-nitroχypropoχv.benzyn-N,-(3-pyridincarbonyl .pi¬ perazin9. N-r2- (2,2-dimethyl-3-nitroχypropoχv.benzyn-N , - (3-pyridinecarbonyl .pi¬ perazin
Hergestellt aus 2-(2,2-Dimethyl-3-nitroxypropoxy)benzaldehyd und N-(3-Pyri- dincarbonyl)piperazin x 2 HCl in Methanol nach Verfahrensvariante A. Gerei¬ nigt durch Chromatografie an Kieselgel (Ethylacetat/Methanol 5:1). Das Di¬ hydrochlorid der Titelverbindung wurde aus Methanol/Diethylether umkristal¬ lisiert. Fp. des Dihydrochlorids: 127-129°C.Prepared from 2- (2,2-dimethyl-3-nitroxypropoxy) benzaldehyde and N- (3-pyridinecarbonyl) piperazine x 2 HCl in methanol according to process variant A. Purified by chromatography on silica gel (ethyl acetate / methanol 5: 1 ). The dihydrochloride of the title compound was recrystallized from methanol / diethyl ether. Mp of dihydrochloride: 127-129 ° C.
10. N-r3-(2-Nitroxyethoχy)benzy11pi erazin10. N-r3- (2-nitroxyetho χ y) benzy11pi erazin
Hergestellt aus 3-(2-Nitroxyethoxy)benzaldehyd und Piperazin-Diacetat in Methanol nach Verfahrensvariante B. Das Dihydrochlorid der Titelverbindung wurde aus Methanol/Diethylether umkristallisiert. Fp. des Dihydrochlorids: 165-167°C.Prepared from 3- (2-nitroxyethoxy) benzaldehyde and piperazine diacetate in methanol according to process variant B. The dihydrochloride of the title compound was recrystallized from methanol / diethyl ether. Mp of the dihydrochloride: 165-167 ° C.
4343
ERSATZBUTT(REGEL26) 11. l - (2-Hydroxy-3-phenoχypropy1 ) -4- f3- (2-nitroχyethy1 . benzyl l i perazi nREPLACEMENT BUTT (RULE 26) 11. l - (2-Hydroxy-3-phenoχypropy1) -4- f3- (2-nitroχyethy1. Benzyl li perazi n
Hergestellt aus 3-(2-Nitroxyethoxy)benzaldehyd und N-(2-Hydroxy-3-phenoxy- propyl)-piperazin x 2 HCl nach Verfahrensvariante A. Das Dihydrochlorid der TitelVerbindung wurde aus Isopropanol umkristallisiert. Fp. des Dihydro¬ chlorids: 167-169βC.Prepared from 3- (2-nitroxyethoxy) benzaldehyde and N- (2-hydroxy-3-phenoxypropyl) piperazine x 2 HCl according to process variant A. The dihydrochloride of the title compound was recrystallized from isopropanol. Mp of the dihydrochloride: 167-169 β C.
12. Di-(2-r(4-nitroχymethyl rtranslcvclohexyl )methoxylbenzyl)amin12. Di- (2-r (4-nitroχymethyl rtranslcvclohexyl) methoxylbenzyl) amine
Hergestellt aus 2-[(4-Nitroxymethyl [trans]cyclohexyl)methoxy]benzaldehyd und Ammoniumacetat nach Verfahrensvariante C. Gereinigt durch Chromatogra¬ fie an Kieselgel (Ethylacetat/Petrolether 60-80/1:1). Fp. 92-97βC.Prepared from 2 - [(4-nitroxymethyl [trans] cyclohexyl) methoxy] benzaldehyde and ammonium acetate according to process variant C. Purified by chromatography on silica gel (ethyl acetate / petroleum ether 60-80 / 1: 1). Mp. 92-97 β C.
13. N-Diphenylmethyl-N -r4-(2-nitroxyethoχy)benzyll iperazin13. N-Diphenylmethyl-N -r4- (2-nitroxyethoχy) benzyll iperazine
Hergestellt aus N-Diphenylmethylpiperazin x 2 HCl und 4-(2-Nitroxyethoxy)- benzaldehyd in Methanol nach Verfahrensvariante A. Gereinigt durch Chroma¬ tografie an Kieselgel (Ethylacetat/Petrolether 60-80/1:2). Fp. 127-129°C.Manufactured from N-diphenylmethylpiperazine x 2 HCl and 4- (2-nitroxyethoxy) benzaldehyde in methanol according to process variant A. Purified by chromatography on silica gel (ethyl acetate / petroleum ether 60-80 / 1: 2). Mp 127-129 ° C.
14. N-r4-(2-Nitroxyethoxy)benzyllhomopiperazin14. N-r4- (2-nitroxyethoxy) benzyl homopiperazine
Hergestellt aus 4-(2-Nitroxyethoxy)benzaldehyd und Homopiperazin-Diacetat in Methanol nach Verfahrensvariante B. Das Oxalat der Titelverbindung wurde aus Methanol u kristallisiert. Fp. des Oxalats: 179°C (Zers.).Prepared from 4- (2-nitroxyethoxy) benzaldehyde and homopiperazine diacetate in methanol according to process variant B. The oxalate of the title compound was crystallized from methanol. Mp of the oxalate: 179 ° C (dec.).
15. N-r4-(2-Nitroχyethoxy)benzyll-N,-(2-hydroχy-3-phenoχypropyl )-l,6- hexylendia in15.N-r4- (2-nitroχyethoxy) benzyl-N , - (2-hydroχy-3-phenoχypropyl) -l, 6-hexylenedia in
Hergestellt aus N-(2-Hydroxy-3-phenoxypropyl)-l,6-hexylendiamin x 2 HCl und 4-(2-Nitroxyethoxy)benzaldehyd in Methanol nach Verfahrensvariante A. Das Dihydrochlorid der Titelverbindung wurde aus Methanol umkristallisiert. Fp. des Dihydrochlorids: 193-196°C.Prepared from N- (2-hydroxy-3-phenoxypropyl) -1, 6-hexylenediamine x 2 HCl and 4- (2-nitroxyethoxy) benzaldehyde in methanol according to process variant A. The dihydrochloride of the title compound was recrystallized from methanol. Mp of the dihydrochloride: 193-196 ° C.
ERSATZBUTT(REGEL26) 16. N-r3-(2-Anylphenoxy)-2-hydroχypropy11-N/-r4-f2-nitroxyethoχy)benzy1- 1.8-octylendiaminREPLACEMENT BUTT (RULE 26) 16. N-r3- (2-anylphenoxy) -2-hydroχypropy11-N / -r4-f2-nitroxyethoχy) benzy1-1,8-octylenediamine
Hergestel11 aus N-[3-(2-A1lylphenoxy)-2-hydroxypropyl]-1,8-octylendiamin und 4-(2-Nitroxyethoxy)benzaldehyd in Methanol nach Verfahrensvariante A. Das Hydrochlorid der TitelVerbindung wurde aus Methanol/Ethanol/Diethyl- ether umkristallisiert Fp. des Hydrochlorids: 151,1-151,7βC.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 β C.
17. N-T3-(2-Allylphenoxy)-2-hydroχypropyll-N -r2-(2-nitroxyethoxy)benzy11- 1,8-octylendiamin17. N-T3- (2-allylphenoxy) -2-hydroχypropyll-N -r2- (2-nitroxyethoxy) benzy11- 1,8-octylenediamine
» Hergestellt aus N-[3-(2-Allylphenoxy)-2-hydroxypropyl]-l,8-octylendiamin x 2 HCl und 2-(2-Nitroxyethoxy)benzaldehyd in Methanol nach Verfahrensva¬ riante A. Gereinigt durch Chromatografie an Kieselgel (Ethylacetat/Metha- nol/Triethylamin 16:4:1). Das Oxalat der Titelverbindung wurde aus Etha- nol/Diethylether umkristallisiert. Fp. des Oxalats: 157-158°C.»Made from N- [3- (2-allylphenoxy) -2-hydroxypropyl] -l, 8-octylenediamine x 2 HCl and 2- (2-nitroxyethoxy) benzaldehyde in methanol according to process variant A. Purified by chromatography on silica gel ( Ethyl acetate / methanol / triethylamine 16: 4: 1). The oxalate of the title compound was recrystallized from ethanol / diethyl ether. Mp of the oxalate: 157-158 ° C.
18. N-r3-(2-Al Iyl phenoxy) -2-hvdroχypropyn-N,-r3-(2-nitroχyethoxy)benzvn- 1,8-octylendiamin18. N-r3- (2-Allylphenoxy) -2-hvdroχypropyn-N , -r3- (2-nitroχyethoxy) benzvn-1,8-octylenediamine
Hergestellt aus 3-(2-Nitroxyethoxy)benzaldehyd und N-[3-(2-Allylphenoxy)-2- hydroxypropyl]-l,8-octylendiamin x 2 HCl in Methanol nach Verfahrensvarian¬ te A. Das Oxalat der Titelverbindung wurde aus Ethanol/Diethylether umkri- stallisiert. Fp. des Oxalats: 148-149βC.Prepared from 3- (2-nitroxyethoxy) benzaldehyde and N- [3- (2-allylphenoxy) -2-hydroxypropyl] -1,8-octylenediamine x 2 HCl in methanol according to process variant A. The oxalate of the title compound was obtained from ethanol / Recrystallized diethyl ether. Mp of the oxalate: 148-149 β C.
19. N- (2-Hydroχy-3-naphthv1oχypropyl)-N -r4-(2-nitroχyethoχy.benzyl 1-1,4- butylendia in19.N- (2-Hydroχy-3-naphthv1oχy p ropyl) -N -r4- (2-nitroχyethoχy.benzyl 1-1,4-butylenedia in
Hergestellt aus N-[2-Hydroxy-3-(l-naphthyloxy)propyl]-l,4-butylendiamin und 4-(2-Nitroxyethoxy)benzaldehyd in Methanol nach Verfahrensvariante A. Das Dihydrochlorid der Titelverbindung wurde aus Isopropanol umkristallisiert. Fp. des Dihydrochlorids 150-152°C.Prepared from N- [2-hydroxy-3- (l-naphthyloxy) propyl] -1, 4-butylenediamine and 4- (2-nitroxyethoxy) benzaldehyde in methanol according to process variant A. The dihydrochloride of the title compound was recrystallized from isopropanol. Mp of dihydrochloride 150-152 ° C.
45 20. N- T3-(l -Naphthyl oxy) -2-hydroxypropyn-N -r3-(2-nitroχyethoxy)benzyll- 1,4-butylendiamin45 20. N- T3- (l -naphthyloxy) -2-hydroxypropyn-N -r3- (2-nitroχyethoxy) benzyl-1,4-butylene diamine
Hergestellt aus N-[2-Hydroxy-3-(l-naphthyloxy)propyl]-l,4-butylendiamin und 3-(2-Nitroxyethoxy)benzaldehyd in Methanol nach Verfahrensvariante A. Das Dihydrochlorid der Titelverbindung wurde aus Isopropanol umkristallisiert. Fp. des Dihydrochlorids: 145-147°C.Prepared from N- [2-hydroxy-3- (l-naphthyloxy) propyl] -1, 4-butylenediamine and 3- (2-nitroxyethoxy) benzaldehyde in methanol according to process variant A. The dihydrochloride of the title compound was recrystallized from isopropanol. Mp of the dihydrochloride: 145-147 ° C.
21. N-r2-(10-Nitroχydecy1oχy)benzyn-1.6-heχyl endi ami n21. N-r2- (10-nitroχydecy1oχy) benzyn-1.6-heχyl endi ami n
Hergestellt aus 2-(10-Nitroxydecyloxy)benzaldehyd und 1,6-Hexylendiamin- Diacetat in Methanol nach Verfahrensvariante B. Das Dioxalat der Titelver¬ bindung wurde aus Ethanol umkristallisiert. Fp. des Dioxalats: 122-127°C.Prepared from 2- (10-nitroxydecyloxy) benzaldehyde and 1,6-hexylenediamine diacetate in methanol according to process variant B. The dioxalate of the title compound was recrystallized from ethanol. Mp of the dioxalate: 122-127 ° C.
,Z Gewerbliche Anwendbarkeit, Z Industrial applicability
Die Verbindungen der Formel I besitzen wertvolle Eigenschaften, die sie ge¬ werblich verwertbar machen. Sie stellen insbesondere hochwirksame Wirkstof¬ fe zur Behandlung von cardiovasculären Erkrankungen und Erkrankungen des Auges dar, die auf einem erhöhten Augeninnendruck beruhen.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.
In ihrer ausgezeichneten Wirksamkeit, die gepaart ist mit einer geringen Toxizität und dem Fehlen wesentlicher Nebenwirkungen, stellen die Verbin¬ dungen der Formel I eine erwünschte Bereicherung des Standes der Technik dar. Aufgrund der Nitratgruppen im Molekül eignen sich die Verbindungen der Formel I prinzipiell zur Verhütung und Behandlung solcher Krankheitszustän- de beim Menschen, für die bekannt ist, daß sie durch organische Nitrate (wie z.B. Glyceroltrinitrat, Isosorbid-5-mononitrat oder Isosorbiddinitrat) bzw. durch Verbindungen, die Stickstoffmonoxid abspalten können (wie z.B. Molsido in), therapiert werden können.In their excellent effectiveness, which is paired with a low toxicity and the absence of significant side effects, 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.
Insbesondere können die Verbindungen der Formel I angewandt werden zur Ver¬ hütung und Behandlung von ischämischen Herzerkrankungen (Angina pectoris, Herzinfarkt), cardialen Kompensationsstörungen, (pul onaler) Hypertonie, (cerebralen) Thrombosen und Atherosclerosen, (peripheren) Gefäßverengungen, Arrhythmien, bestimmten Störungen des Gastrointestinaltraktes (wie z.B. Achalasie, Reizkolon) und von erhöhtem Augeninnendruck. Darüberhinaus zeichnen sich die Verbindungen der Formel I durch thromboxanantagonistische und antivirale Wirksamkeit sowie durch bronchospasmolytische Eigenschaften aus.In particular, 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. In addition, the compounds of the formula I are notable for thromboxane-antagonistic and antiviral activity and for bronchospasmolytic properties.
Ein weiterer Gegenstand der Erfindung ist daher ein Verfahren zur Behand¬ lung von Säugetieren, insbesondere Menschen, die an einer der obengenannten Krankheiten erkrankt sind. Das Verfahren ist dadurch gekennzeichnet, daß man dem erkrankten Individuum eine therapeutisch wirksame und pharmakolo¬ gisch verträgliche Menge einer oder mehrerer Verbindungen der Formel I ver¬ abreicht.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.
Gegenstand der Erfindung sind außerdem die Verbindungen der Formel I zur Anwendung bei der Behandlung der genannten Krankheiten.The invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.
ERSATZBUTT(REGEL26) Ebenso umfaßt die Erfindung die Verwendung von Verbindungen der Formel I bei der Herstellung von Arzneimitteln, die zur Bekämpfung der genannten Krankheiten eingesetzt werden.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.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die eine oder meh¬ rere Verbindungen der Formel I enthalten.The invention further relates to medicaments which contain one or more compounds of the formula I.
Die Arzneimittel werden nach an sich bekannten, dem Fachmann geläufigen Verfahren hergestellt. Als Arzneimittel werden die pharmakologisch wirksa¬ men Verbindungen der Formel I (= Wirkstoffe) entweder als solche, oder vor¬ zugsweise in Kombination mit geeigneten pharmazeutischen Hilfsstoffen in Form von Tabletten, Dragees, Kapseln, Suppositorien, Pflastern (z.B. als TTS), Emulsionen, Suspensionen, Aerosolen, Sprays, Salben, Cremes, Gelen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwi¬ schen 0,1 und 95 % beträgt.The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The pharmacologically active compounds of the formula I (= active ingredients) are used as medicinal products either as such or preferably in combination with suitable pharmaceutical auxiliaries in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions, Suspensions, aerosols, sprays, ointments, creams, gels or solutions are used, the active substance content advantageously being between 0.1 and 95%.
Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemit¬ teln, Gelbildnern, Suppositoriengrundlagen, Tablettenhilfsstoffen und ande¬ ren Wirkstoffträgem können beispielsweise Antioxidantien, Dispergiermit¬ tel, Emulgatoren, Entschäumer, Geschmackskorrigentien, Konservierungsmit¬ tel, Lösungsvermittler, Farbstoffe oder insbesondere Permeationspromotoren und Komplexbildner (z.B. Cyclodextrine) verwendet werden.The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active ingredient carriers, it is possible, for example, to use antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).
Die Wirkstoffe können oral, rektal oder parenteral (insbesondere perlin- gual , bukkal , intravenös oder percutan) appliziert werden.The active substances can be administered orally, rectally or parenterally (in particular perlingual, buccal, intravenously or percutaneously).
Im allgemeinen hat es sich in der Humanmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe bei oraler Gabe in einer Tagesdosis von etwa 0,01 bis etwa 10, vorzugsweise 0,05 bis 5 mg/kg Körpergewicht, gewünschtenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Erzielung des ge¬ wünschten Ergebnisses zu verabreichen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verabreichung der Wirkstoffe) in der Regel niedrigere Dosierungen zur Anwendung kommen. Bei einschleichender Dosierung wird zu Beginn der Behandlung eine geringere Do¬ sis verabreicht, dann langsam auf eine höhere Dosis übergegangen. Nach Er-In general, it has proven to be advantageous in human medicine to give 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. In the case of parenteral treatment, 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. After
1S> reichen des gewünschten Therapieerfolgs wird wieder auf eine niedrigere Do¬ sis zurückgegangen.1S> If the desired therapeutic success is achieved, the dose is reduced again.
Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applika¬ tionsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwis¬ sens leicht erfolgen.The optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.
Sollen die Verbindungen der Formel I zur Behandlung der genannten Krank¬ heiten eingesetzt erden, so können die pharmazeutischen Zubereitungen auch einen oder mehrere andere pharmakologisch aktive Bestandteile anderer Arz¬ neimittelgruppen, wie andere Antihypertensiva, Vasodilatoren, alpha-1-Re- zeptorenblocker, alpha-2-Rezeptorstimulatoren, beta-1-Rezeptorenblocker, beta-2-Rezeptorstimulatoren, ACE-Hemmstoffe, Diuretika, Saluretika, Alka- loide, Analgetika, Lipidsenker, Antikoagulantien, Anticholinergika, Methyl- xanthine, Antiarrhythmika, Antihistaminika, Dopaminstimulatoren, Serotonin- -Rezeptorenblocker etc. wie Nifedipin, Dihydralazin, Prazosin, Clonidin, Atenolol, Labetalol, Fenoterol , Captopril, Digoxin, Milrinon, Mefrusid, Clopamid, Spironolacton, Chlorthalidon, Furosemid, Polythiazid, Hydrochlo- rothiazid, Resperpin, Dihydroergocristin, Rescinnamin, Rauwolfia-Gesamtal- kaloide, Acetylsal icylsäure, Bezafibrat, Warfarin, Atropin, Theophyl1in, Lidocain, Astemizol, Bromocryptin, Ketanserin etc. enthalten.If the compounds of the formula I are to be used for the treatment of the diseases mentioned, 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. such as nifedipine, dihydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, digoxin, milrinone, mefrusid, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothothiazide, resperaline rinpine, rinhydroalaminopin, rehydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinhydroalaminopin, rinphalininoxin, rinphalininoxaline, rinphaline, rinhydroalcine, rinhydroalcine, rinhydroalcine, rinhydroalcine, rinhydroalcinoin , Acetylsal icylic acid, bezafibrate, warfarin, atropine, theophyl1in, lidocaine, astemizole, bromocryp tin, ketanserin etc. included.
' *>'*>
ERSATZBUTT (REGEL 26) PharmakologieREPLACEMENT BUTT (RULE 26) pharmacology
Die pharmakologische Wirkung der Verbindungen der Formel I wurde in vivo am narkotisierten Kaninchen und in vitro im sogenannten Rattenaortatest ermit¬ telt.The pharmacological action of the compounds of formula I was telt in vivo in anesthetized rabbits and in vitro in the so-called rat aorta Test ermit ¬.
Am narkotisierten Kaninchen wurde die prozentuale Abnahme des arteriellen Blutdruckes und der Einfluß auf die Herzfrequenz (prozentuale Änderung) nach Infusion der zu untersuchenden Verbindungen bestimmt.In the anesthetized rabbit, the percentage decrease in arterial blood pressure and the influence on the heart rate (percentage change) after infusion of the compounds to be examined were determined.
Im Rattenaortatest wurde die relaxierende Wirkung der zu untersuchenden Verbindungen an Spiralstreifen der Arteria pul onalis der Ratte bestimmt. Durch kumulative Zugabe wurde aus der Konzentrationswirkungskurve diejenige Dosis ermittelt, die die Kontraktion im Mittelwert um 50 % hemmt (= EC5Q).In the rat aortic test, the relaxing effect of the compounds to be tested on spiral strips of the pulmonary artery of the rat was determined. The dose that inhibits the contraction by 50% on average (= EC 5Q ) was determined from the concentration- effect curve by cumulative addition.
In den folgenden Tabellen werden die untersuchten Verbindungen durch Num¬ mern gekennzeichnet, die den Nummern der Beispiele entsprechen.In the following tables the examined compounds are identified by numbers which correspond to the numbers of the examples.
Bestimmung des Blutdrucks und der Herzfrequenz beim narkotisierten KaninchenDetermination of blood pressure and heart rate in anesthetized rabbits
Die Versuchsdurchführung erfolgte. in Analogie zu der in der internationalen Patentanmeldung W092/04337 beschriebenen Verfahrensweise. Das Untersu¬ chungsergebnis ist in Tabelle 1 dargestellt.The experiment was carried out. in analogy to the procedure described in international patent application W092 / 04337. The result of the investigation is shown in Table 1.
Tabelle 1Table 1
Prozentuale Senkung des arteriellen Blutdrucks (BP) und prozentuale Ände¬ rung der Herzfrequenz (HR) bei N narkotisierten Kaninchen (bei N > 1 Mit¬ telwerte) durch Gabe von Verbindungen der Formel IPercentage reduction in arterial blood pressure (BP) and percentage change in heart rate (HR) in N anesthetized rabbits (with N> 1 mean values) by administration of compounds of the formula I.
Verbindung % Abnahme % Änderung N Nr. BP HRConnection% decrease% change N No. BP HR
3 39 , 8 - 6, 2 23 39, 8 - 6, 2 2
7 17 , 9 - 0 , 3 27 17, 9 - 0, 3 2
11 17 , 8 - 5 , 2 111 17, 8 - 5, 2 1
13 54 , 6 - 18 , 4 213 54, 6 - 18, 4 2
- 20 -- 20 -
ERSATZBUTT(REGEL26) RattenaortatestREPLACEMENT BUTT (RULE 26) Rat aortic test
Die Versuchsdurchführung erfolgte in Analogie zu der in der internationalen Patentanmeldung W092/04337 beschriebenen Verfahrensweise. Das Untersu¬ chungsergebnis ist in Tabelle 2 dargestellt.The test was carried out in analogy to the procedure described in international patent application W092 / 04337. The result of the investigation is shown in Table 2.
Tabelle 2Table 2
Relaxierende Wirkung von Verbindungen der Formel I an der RattenaortaRelaxing effect of compounds of the formula I on the rat aorta
Verbindung EC5Q Standard- Streubreite N Nr. lOMl abweichungConnection EC 5Q standard spread width N No. lOMl deviation
3 0,0055 0,0068 0,001 -0,02 63 0.0055 0.0068 0.001 -0.02 6
6 0,0015 0,0012 0,0002-0,003 66 0.0015 0.0012 0.0002-0.003 6
10 0,0067 0,0017 0,004 -0,009 610 0.0067 0.0017 0.004 -0.009 6
11 0,0045 0,0026 0,0004-0,01 911 0.0045 0.0026 0.0004-0.01 9
EC5Q = Konzentration, die die Kontraktion um 50 % hemmt N = Zahl der geprüften RattenaortastreifenEC 5Q = concentration that inhibits contraction by 50% N = number of rat aorta strips tested
-21--21-
ERSATZBUTT (REGEL 26) FORMELBUTTREPLACEMENT BUTT (RULE 26) FORMULA BUTT
Figure imgf000024_0001
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000024_0002
CHOCHO
NH ( R1 )R2 (III)NH (R1) R2 (III)
2.2-2.2-
ERSÄΓZBUTT (REGEL 26) ERSÄΓZBUTT (RULE 26)

Claims

Patentansprüche claims
1. Verbindungen der Formel I,1. Compounds of the formula I
Figure imgf000025_0001
Figure imgf000025_0001
worinwherein
AI l-15C-Alkylen, 5-7C-Cycloalkylen oder Di -l-4C-alkylen-5-7C-cycloalkan bedeutet, und worinAI 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cycloalkane means, and wherein
Rl Wasserstoff, 1-7C-A1 kyl oder 3-8C-Cycloal kyl undR1 hydrogen, 1-7C-A1 kyl or 3-8C-cycloal kyl and
R2 Wasserstoff, 1-7C-Alkyl, 3-8C-Cycloalkyl oder A2-Y bedeutet, oder worinR2 is hydrogen, 1-7C-alkyl, 3-8C-cycloalkyl or A2-Y, or wherein
Rl und R2 gemeinsam und unter Einschluß des Stickstoffatoms, an das beide gebunden sind, einen unsubstituierten oder substituierten 5-, 6- oder 7-Ring Heterocyclus darstellen, der ausgewählt ist aus der Gruppe be¬ stehend aus Pyrrolidin, Piperidin, Piperazin, Morpholin und Homopipera¬ zin, wobei A2 l-15C-Alkylen, 5-7C-Cycloalkylen oderR1 and R2 together and including the nitrogen atom to which both are attached 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 A2 1-15C-alkylene, 5-7C-cycloalkylene or
Di-l-4C-alkylen-5-7C-cycloalkan bedeutet,Means di-1-4C-alkylene-5-7C-cycloalkane,
R3, NH2, NH-R4 oder S-R5 bedeutet, ein substituierter Pyrrol idinorest substituiert ist mit einem oder zwei gleichen oder verschiedenen Substituenten ausgewählt aus derR3, NH 2 , NH-R4 or S-R5 means a substituted pyrrole idino residue is substituted with one or two identical or different substituents selected from the group
Gruppe bestehend aus 1-4C-A1kyl , l-4C-Alkoxy und Hydroxy, ein substituierter Piperidinorest substituiert ist mit einem oder zwei gleichen oder verschiedenen Substituenten ausgewählt aus derGroup consisting of 1-4C-A1kyl, 1-4C-alkoxy and hydroxy, a substituted piperidino radical is substituted with one or two identical or different substituents selected from the group
Gruppe bestehend aus 1-4C-A1kyl , l-4C-Alkoxy und Hydroxy,Group consisting of 1-4C-alkyl, 1-4C-alkoxy and hydroxy,
2323
ERSATZBUTT (REGEL 26) ein substituierter Piperazinorest in 2-, 3-, 5- oder 6-Position substituiert sein kann mit einem 1-4C-Alkylrest und in 4-Position substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus 1-4C-A1kyl , l-4C-Alkoxycarbonyl , l-4C-Alkylcarbonyl , durch R6, R7 und R8 substituiertem Phenyl, durch R6, R7 und R8 im Phenylrest substituiertem Phenyl -l-4C-al kyl , durch R6, R7 und R8 im Phenylrest substituiertem Benzoyl, Picolinoyl, Nicotinoyl, Iso- nicotinoyl, gewünschtenfalls durch Halogen oder 1-4C-A1kyl sub¬ stituiertem Benzhydryl und dem Rest R4, ein substituierter Morphol inorest substituiert ist mit einem oder zwei gleichen oder verschiedenen 1-4C-Alkylresten und ein substituierter Homopiperazinorest in 4-Position substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus 1-4C-A1 kyl , l-4C-Alkoxycarbonyl , l-4C-Alkylcarbonyl , durch R6, R7 und R8 substituiertem Phenyl, durch R6, R7 und R8 im Phenylrest substituiertem Phenyl -l-4C-alkyl und durch R6, R7 und R8 im Phe¬ nylrest substituiertem Benzoyl, wobei weiterhinREPLACEMENT BUTT (RULE 26) a substituted piperazino radical in the 2-, 3-, 5- or 6-position can be substituted with a 1-4C-alkyl radical and in the 4-position substituted 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 R6, R7 and R8 in the phenyl radical, benzoyl, picolinoyl substituted by R6, R7 and R8 in the phenyl radical, Nicotinoyl, iso-nicotinoyl, optionally substituted by halogen or 1-4C-alkyl substituted benzhydryl and the radical R4, a substituted morphol is substituted inorest with one or two identical or different 1-4C-alkyl radicals and a substituted homopiperazinorest in the 4-position is substituted with a substituent selected from the group consisting of 1-4C-A1 alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, phenyl substituted by R6, R7 and R8, phenyl substituted by R6, R7 and R8 in the phenyl radical - 1-4C-alkyl and d by R6, R7 and R8 in Phe ¬ nylrest substituted benzoyl, wherein further
R3 Furyl, Naphthyl, Tetrahydronaphthyl, durch -0-A1-0NC substituier¬ tes Phenyl oder durch R6, R7 und R8 substituiertes Phenyl bedeu¬ tet,R3 means furyl, naphthyl, tetrahydronaphthyl, phenyl substituted by -0-A1-0NC or phenyl substituted by R6, R7 and R8,
R4 1-7C-A1 kyl oder den Substituenten -CH2-CH(OH)-(CH20) -Ar bedeutet undR4 1-7C-A1 kyl or the substituents -CH 2 -CH (OH) - (CH 2 0) -Ar means and
R5 durch R6, R7 und R8 substituiertes Phenyl, durch R6, R7 und R8 substituiertes Phenyl -1-4C-alkyl , gewünschtenfalls durch Halogen oder 1-4C-A1 kyl substituiertes Benzhydryl, Dibenzo-5-7C-cycloal- kanyl , Dibenzocycloheptenyl oder Benzo-pyrido-5-7C-cycloalkanyl bedeutet, und wobei außerdemR5 substituted by R6, R7 and R8 phenyl, substituted by R6, R7 and R8 phenyl -1-4C-alkyl, optionally substituted by halogen or 1-4C-A1 kyl benzhydryl, dibenzo-5-7C-cycloalkanyl, dibenzocycloheptenyl or Benzo-pyrido-5-7C-cycloalkanyl means, and in addition
R6 Wasserstoff, 1-4C-A1kyl , l-4C-Alkoxy, l-4C-Alkylcarbonyl , Halogen, Amino, Mono- oder Di - (1-4C-alkyl )amino oder Nitro bedeutet,R6 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylcarbonyl, halogen, amino, mono- or di- (1-4C-alkyl) amino or nitro,
R7 Wasserstoff, 1-4C-A1 kyl , l-4C-Alkoxy, Halogen oder Nitro bedeutet,R7 is hydrogen, 1-4C-A1kyl, 1-4C-alkoxy, halogen or nitro,
R8 Wasserstoff oder Trifluormethyl bedeutet, p die Zahl 0 oder 1 bedeutet undR8 represents hydrogen or trifluoromethyl, p represents the number 0 or 1 and
ERSATZBUTT(REGEL26) Ar ein ganz oder teilweise ungesättigtes Kohlenwasserstoffringsystem bedeutet, das monocyclisch (mit 5 bis 6) oder bicyclisch (mit 9 bis 10 Ringatomen) ist, in dem 1, 2 oder 3 Kohlenstoffatome durch Heteroatome aus der Gruppe Stickstoff (N), Sauerstoff (0) oder Schwefel (S) ersetzt sein können und das durch einen oder zwei gleiche oder verschiedene Substituenten aus der Gruppe 1-4C-A1 y , l-4C-Alkoxy, 1-4C-A1 kylthio, l-4C-Alkoxy-l-4C-alkyl , l-4C-Alkoxy- l-4C-alkoxy, 3-4C-Alkenyl , 3-4C-Alkenyloxy, 3-8C-Cycloalkyl , 5-10C-Cycloalkylalkoxyalkyl, l-4C-Alkylcarbonyl , 1-4C-A1 kylcar- bonylamino, Carbamoyl, Carbamoyl -l-4C-al kyl , Halogen, Hydroxy, Oxo, Nitro, Cyan, l-4C-Alkylsufonamido, Amino, Mono- oder Di -(1- 4C-alkyl )amino, Ureido, Mono- oder Di - (1-4C-al kyl )ureido, Mono- oder Di-(3-8C-cycloalkyl)ureido, Trifluormethyl, ganz oder teil¬ weise durch Fluor substituiertes l-4C-Alkoxy, l-4C-Alkoxycarbonyl , Tetrahydrofurfuryloxy oder Morpholino substituiert sein kann, und die Salze dieser Verbindungen.REPLACEMENT BUTT (RULE 26) 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-A1 y, 1-4C-alkoxy, 1-4C-A1 kylthio, 1-4C-alkoxy-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-A1 kylcarbonylamino, carbamoyl, carbamoyl-1-4C-alkyl, halogen, hydroxy, oxo, nitro, cyano, 1-4C-alkylsufonamido, amino, mono- or di- (1-4C-alkyl) amino, ureido, mono - or di - (1-4C-alkyl) ureido, mono- or di- (3-8C-cycloalkyl) ureido, trifluoromethyl, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, Tetrahydrofurfuryloxy or Morpholino can be substituted, and the salt e of these connections.
2. Verbindungen der Formel I nach Anspruch 1, worin AI 2-10C-A1kylen oder Di ethylencyclohexan bedeutet, und worin Rl Wasserstoff und R2 Wasserstoff oder A2-Y bedeutet, oder worin2. Compounds of formula I according to claim 1, wherein AI is 2-10C-A1kylene or diethylcyclohexane, and wherein Rl is hydrogen and R2 is hydrogen or A2-Y, or wherein
Rl und R2 gemeinsam und unter Einschluß des Stickstoffatoms, an das beide gebunden sind, einen unsubstituierten oder substituierten Piperazinrest darstellen, wobeiRl and R2 together and including the nitrogen atom to which both are attached represent an unsubstituted or substituted piperazine radical, where
A2 1-10C-A1kylen bedeutet,A2 1-10C-A1kylene means
Y R3, NH2, NH-R4 oder S-R5 bedeutet, ein substituierter Piperazinorest in 4-Position substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus l-4C-Alkoxycarbonyl , l-4C-Alkylcarbonyl , Picolinoyl, Nicotinoyl, Isonicotinoyl , Benzhydryl und dem Rest R4 und wobei weiterhinY 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 Phenyl oder durch -0-A1-0NC substituiertes Phenyl bedeutet, R4 den Substituenten -CH2-CH(OH)-(CH20) -Ar bedeutet undR3 is phenyl or phenyl substituted by -0-A1-0NC, R4 is the substituent -CH 2 -CH (OH) - (CH 2 0) -Ar and
ERSATZBUTT(REGEL26) R5 gewünschtenfalls durch Halogen oder 1-4C-A1kyl substituiertes Benzhydryl, Dibenzocycloheptanyl , Dibenzocycloheptenyl oder Benzo-pyrido-cycloheptanyl bedeutet, und wobei außerdem p die Zahl 1 bedeutet undREPLACEMENT BUTT (RULE 26) R5 is benzhydryl, dibenzocycloheptanyl, dibenzocycloheptenyl or benzopyridocycloheptanyl, optionally substituted by halogen or 1-4C-alkyl, and where p is the number 1 and
Ar Phenyl, 4-(2-Methoxyethoxy)-phenyl , 2-A1lylphenyl , 2-Chlor-5- methylphenyl, 2-Allyloxyphenyl , 2-Cyclopentylphenyl , 2-Cyanphenyl oder 1-Naphthyl bedeutet, und die Salze dieser Verbindungen.Ar is phenyl, 4- (2-methoxyethoxy) phenyl, 2-A1lylphenyl, 2-chloro-5-methylphenyl, 2-allyloxyphenyl, 2-cyclopentylphenyl, 2-cyanophenyl or 1-naphthyl, and the salts of these compounds.
3. Verbindungen der Formel I nach Anspruch 1, worin AI 2-10C-Alkylen oder Dimethylencyclohexan bedeutet, und worin Rl Wasserstoff und R2 Wasserstoff oder A2-Y bedeutet, oder worin3. Compounds of formula I according to claim 1, wherein AI is 2-10C-alkylene or dimethylenecyclohexane, and wherein Rl is hydrogen and R2 is hydrogen or A2-Y, or wherein
Rl und R2 gemeinsam und unter Einschluß des Stickstoffatoms, an das beide gebunden sind, einen unsubstituierten oder substituierten Piperazinrest darstellen, wobeiRl and R2 together and including the nitrogen atom to which both are attached represent an unsubstituted or substituted piperazine radical, where
A2 1-10C-A1 kylen bedeutet,A2 1-10C-A1 means kylen,
Y R3, NH2, NH-R4 oder S-R5 bedeutet, ein substituierter Piperazinorest in 4-Position substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus l-4C-Alkylcarbonyl, Nicotinoyl, Benzhydryl und dem Rest R4 und wobei weiterhinY 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 Phenyl oder durch -0-A1-0NQ substituiertes Phenyl bedeutet, R4 den Substituenten -CH2-CH(OH)-(CH20) -Ar bedeutet und R5 durch 1-4C-A1kyl substituiertes Benzhydryl, Benzhydryl,R3 denotes phenyl or phenyl substituted by -0-A1-0NQ, R4 denotes the substituent -CH 2 -CH (OH) - (CH 2 0) -Ar and R5 denotes benzhydryl, benzhydryl substituted by 1-4C-A1kyl,
Dibenzocycloheptanyl, Dibenzocycloheptenyl oder durch Chlor - substituiertes Benzo-pyrido-cycloheptanyl bedeutet, und wobei außerdem p die Zahl 1 bedeutet undDibenzocycloheptanyl, Dibenzocycloheptenyl or chloro - substituted benzo-pyrido-cycloheptanyl, and where p also means the number 1 and
Ar Phenyl, 2-Allylphenyl oder 1-Naphthyl bedeutet, und die Salze dieser Verbindungen. 4. Verbindung nach Anspruch 1, ausgewählt aus der Gruppe bestehend aus 2-(2-Nitroxyethoxy)-N-(2-phenylethyl)benzylaminAr means phenyl, 2-allylphenyl or 1-naphthyl, and the salts of these compounds. 4. A compound according to claim 1 selected from the group consisting of 2- (2-nitroxyethoxy) -N- (2-phenylethyl) benzylamine
N-{2-[(4-Methyl-alpha-phenylbenzyl)thio]-ethyl}-4-(2-nitroxyethoxy)-benzyl- aminN- {2 - [(4-methyl-alpha-phenylbenzyl) thio] ethyl} -4- (2-nitroxyethoxy) benzylamine
N- [2- (7-Chlor- 10,11 -dihydro-5H-benzo[4,5]cyclohepta[ 1,2b] pyridin-5-thio) - ethyl]-4-(2-nitroxyethoxy)benzylaminN- [2- (7-chloro-10,11-dihydro-5H-benzo [4,5] cyclohepta [1,2b] pyridine-5-thio) ethyl] -4- (2-nitroxyethoxy) benzylamine
N-{2-[(5H-Dibenzo[a,d]cyclohepten-5-yl)thio]-ethyl}-2-(2,2-dimethyl-3-ni- troxypropoxy)benzylaminN- {2 - [(5H-Dibenzo [a, d] cyclohepten-5-yl) thio] ethyl} -2- (2,2-dimethyl-3-nitro-propoxy) benzylamine
N- [2 -(2, 2 -Dimethyl -3 -nitroxypropoxy)benzyl] piperazin 3-(2-Nitroxyethoxy)benzylaminN- [2 - (2, 2-Dimethyl -3-nitroxypropoxy) benzyl] piperazine 3- (2-nitroxyethoxy) benzylamine
N-Acetyl-N'-[2-(2,2-dimethyl-3-nitroxypropoxy)benzyl]piperazin 2-(2-Nitroxyethoxy)benzylaminN-Acetyl-N '- [2- (2,2-dimethyl-3-nitroxypropoxy) benzyl] piperazine 2- (2-nitroxyethoxy) benzylamine
N- [2- (2, 2-Dimethyl-3-nitroxypropoxy)benzyl]-N'-(3-pyridincarbonyl) piperazin N- [3- (2-Nitroxyethoxy)benzyl] piperazin l-(2-Hydroxy-3-phenoxypropyl) -4- [3- (2-nitroxyethyl)benzyl ] piperazin Di-{2-[(4-nitroxymethyl[trans]cyclohexyl)methoxy]benzyl}amin N -Di phenyl methyl -N '- [4- ( 2 -nitroxyethoxy)benzyl] piperazin N- [4- (2-Nitroxyethoxy)benzyl] homopiperazinN- [2- (2, 2-dimethyl-3-nitroxypropoxy) benzyl] -N '- (3-pyridinecarbonyl) piperazine N- [3- (2-nitroxyethoxy) benzyl] piperazine 1- (2-hydroxy-3- phenoxypropyl) -4- [3- (2-nitroxyethyl) benzyl] piperazine di- {2 - [(4-nitroxymethyl [trans] cyclohexyl) methoxy] benzyl} amine N -Di phenyl methyl -N '- [4- (2 -nitroxyethoxy) benzyl] piperazine N- [4- (2-nitroxyethoxy) benzyl] homopiperazine
N- [4- (2-Nitroxyethoxy)benzyl]-N'-(2-hydroxy-3-phenoxypropyl)-l,6-hexyl en¬ di ami nN- [4- (2-nitroxyethoxy) benzyl] -N '- (2-hydroxy-3-phenoxypropyl) -l, 6-hexyl en¬ di ami n
N-[3-(2-Allylphenoxy)-2-hydroxypropyl]-N'-[4-(2-nitroxyethoxy)benzyl-l,8- octylendiaminN- [3- (2-Allylphenoxy) -2-hydroxypropyl] -N '- [4- (2-nitroxyethoxy) benzyl-1,8-octylenediamine
N-[3-(2-Allylphenoxy)-2-hydroxypropyl]-N'-[2-(2-nitroxyethoxy)benzyl]-l,8- octylendiaminN- [3- (2-Allylphenoxy) -2-hydroxypropyl] -N '- [2- (2-nitroxyethoxy) benzyl] -1, 8-octylenediamine
N-[3-(2-Allylphenoxy)-2-hydroxypropyl]-N'-[3-(2-nitroxyethoxy)benzyl]-l,8- octylendiaminN- [3- (2-Allylphenoxy) -2-hydroxypropyl] -N '- [3- (2-nitroxyethoxy) benzyl] -1, 8-octylenediamine
N-(2-Hydroxy-3-naphthyloxypropyl)-N'-[4-(2-nitroxyethoxy)benzyl]-l,4-buty- 1endiaminN- (2-Hydroxy-3-naphthyloxypropyl) -N '- [4- (2-nitroxyethoxy) benzyl] -1, 4-buty-1-diamine
N-[3-(1-Naphthyloxy)-2-hydroxypropyl]-N'-[3-(2-nitroxyethoxy)benzyl]-1,4- butylendiaminN- [3- (1-Naphthyloxy) -2-hydroxypropyl] -N '- [3- (2-nitroxyethoxy) benzyl] -1,4-butylenediamine
N-[2-(10-Nitroxydecyloxy)benzyl]-l,6-hexylendiamin oder ein Salz davon.N- [2- (10-nitroxydecyloxy) benzyl] -1, 6-hexylenediamine or a salt thereof.
5. Verfahren zur Herstellung der Verbindungen der Formel I und ihrer Salze, dadurch gekennzeichnet, daß man Aldehyde der Formel II,5. A process for the preparation of the compounds of formula I and their salts, characterized in that aldehydes of formula II,
ERSATZBUTT(REGEL26)
Figure imgf000030_0001
REPLACEMENT BUTT (RULE 26)
Figure imgf000030_0001
CHOCHO
worin AI die in Anspruch 1 angegebene Bedeutung hat, mit den in Form von Ammoniumsalzen vorliegenden Verbindungen der Formel III,wherein AI has the meaning given in claim 1, with the compounds of the formula III present in the form of ammonium salts,
NH(R1)R2 (III)NH (R1) R2 (III)
worin Rl und R2 die in Anspruch 1 angegebenen Bedeutungen haben, in Gegen¬ wart von Natriumcyanoborhydrid umsetzt, und gewünschtenfalls anschließend erhaltene Verbindungen in die Salze oder erhaltene Salze in die freien Ver¬ bindungen überführt.in which R 1 and R 2 have the meanings given in claim 1, in the presence of sodium cyanoborohydride, and, if desired, subsequently obtained compounds are converted into the salts or salts obtained into the free compounds.
6. Arzneimittel enthaltend eine oder mehrere Verbindungen nach Anspruch 1 zusammen mit üblichen pharmazeutischen Hilfsstoffen.6. Medicament containing one or more compounds according to claim 1 together with conventional pharmaceutical auxiliaries.
7. Verwendung von Verbindungen nach Anspruch 1 zur Herstellung von Arznei¬ mitteln zur Verhütung und/oder Behandlung cardiovasculärer Erkrankungen.7. Use of compounds according to claim 1 for the manufacture of medicaments for the prevention and / or treatment of cardiovascular diseases.
8. Verwendung von Verbindungen nach Anspruch 1 zur Herstellung von Arznei¬ mitteln zur Verhütung und/oder Behandlung von Erkrankungen des Auges, die auf erhöhtem Augeninnendruck beruhen.8. Use of compounds according to claim 1 for the manufacture of medicaments for the prevention and / or treatment of diseases of the eye which are based on increased intraocular pressure.
2.Θ ERSATZBUTT(REGEL26) 2.Θ REPLACEMENT BUTT (RULE 26)
PCT/EP1995/000167 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 WO1995019952A1 (en)

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KR1019960703871A KR970700646A (en) 1994-01-19 1995-01-18 Benzylamine Derivatives Including Nitrooxy Groups, And Their Uses For The Treatment Of Cardiovascular Diseases And Intraocular Pressure Elevation
EP95906963A EP0740649A1 (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
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
BR9506549A BR9506549A (en) 1994-01-19 1995-01-18 Benzylamine derivatives containing nitroxy groups and its application for the treatment of cardiovascular diseases as well as high internal eye pressure
JP7519335A JPH09507672A (en) 1994-01-19 1995-01-18 Nitroxy-group-containing benzylamine derivatives and their use for the treatment of cardiovascular diseases and increased intraocular pressure
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

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CN105130855B (en) * 2009-12-07 2018-05-25 约翰斯霍普金斯大学 Succinylated hydroxy amine derivatives and application thereof
CA2888837C (en) * 2012-10-23 2021-02-16 Nicox Science Ireland Quinone based nitric oxide donating compounds for ophthalmic use
AU2014207408C1 (en) * 2013-01-18 2018-09-06 Cardioxyl Pharmaceuticals, Inc. Pharmaceutical compositions comprising nitroxyl donors

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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
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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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AU679834B2 (en) 1997-07-10

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