CA2181581A1 - 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 pressureInfo
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- CA2181581A1 CA2181581A1 CA002181581A CA2181581A CA2181581A1 CA 2181581 A1 CA2181581 A1 CA 2181581A1 CA 002181581 A CA002181581 A CA 002181581A CA 2181581 A CA2181581 A CA 2181581A CA 2181581 A1 CA2181581 A1 CA 2181581A1
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- substituted
- alkyl
- phenyl
- radical
- benzyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- 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
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A61P27/02—Ophthalmic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—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
- 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
- C07C323/25—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 the carbon skeleton being acyclic and saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
- C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
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, 17C-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, NHR4 or S-R5. One substituted pyrrolidine residue is substituted by one or two identical or different substituents selected from the group that consists of 14C-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
. ~181~1 Nitroxy group-containing bellzylamine derivativef- and their use for treatinc cardiovascular 1; -~A~q as well as increased intraocular pressure Area of a~lication o~ the inventiQ~
The invention relates to benzylamine derivativea which are used in the rh~ eu~i~Al industry for produc-ing ~~';. ts.
Known techniçal backqround Ni troxy _ ' ~ which are substituted in various ways and are aaid to be suitable, for example for the treatment of cardiovascular di3eases are described in the prior art.
DescriPtion gf the in.rention The invention relates to ,- a~ Of the formula I (see Arp~na~d sheet of ~ormulae), in which Al is l-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-'7C-cyt~ An-~, and in which Rl is 11YdL~ 1-7C-alkyl or 3-8C-cycloalkyl and R2 is 11YdL~ 1-7C-alkyl, 3-8C-cycloalkyl or A2-Y, 2 0 or in which Rl and R2 represent, together and with ;nrl~ ;nn of the nitrogen atQm tQ which both are bonded, an unsub-stituted or substituted 5-, 6- or 7- ' -~ ed hetero-cycle which is s~lected from the group consisting o~
pyrrolidine, pipl~ridine, piperazine, morpholine and homopiperazine, where A2 is 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cy.~lgAl kAn~-, Y is R3, NEI2, NEI-R4 or g-R5, - a substituted pyrrolidino radical is substituted by one or two identical or different substituents selected frQm the group Replacement sheet (Rule 26) 21~
Wo 95/19952 - 2 - PCT/EP95/00167 consisting of 1-4C-alkyl, 1-4C-alkoxy and hydroxyl, - a substituted piperidino radical is substituted by one or two identical or dif~erent sub-3tituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy and hydroxyl, - a substituted piperazino radical can be substi-tuted in po~ition 2, 3, 5 or 6 by a 1-4C-alkyl radical and i8 substituted in position 4 by a substituent seleeted from the group consisting of 1-4C-alk~rl, 1-4C-alkoxycarbonyl, 1-4C-alkyl-carbonyl, p]lenyl which is substituted by R6, R7 and R8, phe:Dyl-1-4C-alkyl which is substituted in the phenyl radical by R6, R7 and R8, benzoyl which is substituted in the phenyl radical by R6, R7 and R8, pieolinoyl, nieotinoyl, iso-nieotinoyl, benzhydryl whieh is, if required, substituted by halogen or 1-4C-alkyl, and the radieal R4, - a substitutEd morpholino radieal is substituted by one or t~o identical or different 1-4C-alkyl radicals and - a substitutEd homopiperazino radieal is substi-tuted in position 4 by a substituent selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylearbonyl, phenyl whieh is substituted by R6, R7 and R8, phenyl-1-4C-alkyl whieh is substituted in the phenyl radieal by R6, R7 and R8, and benzoyl whieh is substitutedl in the phenyl radieal by R6, R7 and R8, where fur~h~ - r~
R3 is furyl, n.aphthyl, tetrahydronaphthyl, phenyl whieh is sllbstituted by -O-Al-ONO2, or phenyl whieh is substituted by R6, R7 and R8, R4 is 1-7C-alkyl or the substituent -CH2 -CE (OH) - (CH2O) p-Ar and Rep~ t gheet (Rule 26) - 3 - PCT/E:P95/00167 R5 is phenyl which i5 substituted by R6, R7 and R8, phenyl-1-4C-alkyl which i~ substituted by R6, R7 and R8, if required halogen- or 1-4C-alkyl-lsubstituted benzhydryl, dibenzo-5-7C-cyrl~s~lk~nyl, dibenzocycloheptenyl or benzo-pyrido-5-7C-cyrl ~ 11 k:~nyl, and where in addition R6 is hydL~ l, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylci~rbonyl, halogen, amino, mono- or di- (1-4C-alkyl) amino or nitro, R7 i~s hydrogen, :L-4C-alkyl, 1-4C-alkoxy, halogen or ni tro, R8 is I~YdL~Y~j~ or trifluoromethyl, p i~ the number O or 1, and Ar is a hydrocarbon ring ~sylstem which is complete-ly or partly unsaturated, which is monocyclic (with 5 to 6) or bicyclic (with 9 to 10 ring atom~s), in which 1, 2 or 3 carbon atoms can be replaced by heteroatoms ~rom the group of nitrogen (~), oxygen (O) or sulfur (S), and which can be sub3tituted by one or two nt;r~l c~r different ~ubstituents from the group of 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alko~cy-1-4C-alkoxy, 3-4C-alkenyl, 3-4C-alk~nyloxy, 3-8C-cycloalkyl, 5-lOC-cycl,~alkylalkoxyalkyl, 1-4C-alkyl-carbonyl, :L-4C-alkylcarbonylamino, ~ r' ~.r--' yl-1-4C-alkyl, halogen, hydroxyl, oxo, nitro, cyano, 1-4C-alkyll3ulfonamido, amino, mono- or di- (1-4C-alkyl) amino, ureido, mono- or di- (1-4C-alkyl)ureido, mono- or di-(3-8C-cycloalkyl)ureido, trifluoromethyl, 1-4C-alkoxy which i~s completely or partially sub~stitutecl by fluorine, or 1-4C-alkoxy-carbonyl, tetrahydrofurfuryloxy or morpholino, and the ~salt~3 of theEse -, u--d~.
~erl~c-~_ t ~3heet (Rule 26) a ~ ~
The invention relates to benzylamine derivativea which are used in the rh~ eu~i~Al industry for produc-ing ~~';. ts.
Known techniçal backqround Ni troxy _ ' ~ which are substituted in various ways and are aaid to be suitable, for example for the treatment of cardiovascular di3eases are described in the prior art.
DescriPtion gf the in.rention The invention relates to ,- a~ Of the formula I (see Arp~na~d sheet of ~ormulae), in which Al is l-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-'7C-cyt~ An-~, and in which Rl is 11YdL~ 1-7C-alkyl or 3-8C-cycloalkyl and R2 is 11YdL~ 1-7C-alkyl, 3-8C-cycloalkyl or A2-Y, 2 0 or in which Rl and R2 represent, together and with ;nrl~ ;nn of the nitrogen atQm tQ which both are bonded, an unsub-stituted or substituted 5-, 6- or 7- ' -~ ed hetero-cycle which is s~lected from the group consisting o~
pyrrolidine, pipl~ridine, piperazine, morpholine and homopiperazine, where A2 is 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cy.~lgAl kAn~-, Y is R3, NEI2, NEI-R4 or g-R5, - a substituted pyrrolidino radical is substituted by one or two identical or different substituents selected frQm the group Replacement sheet (Rule 26) 21~
Wo 95/19952 - 2 - PCT/EP95/00167 consisting of 1-4C-alkyl, 1-4C-alkoxy and hydroxyl, - a substituted piperidino radical is substituted by one or two identical or dif~erent sub-3tituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy and hydroxyl, - a substituted piperazino radical can be substi-tuted in po~ition 2, 3, 5 or 6 by a 1-4C-alkyl radical and i8 substituted in position 4 by a substituent seleeted from the group consisting of 1-4C-alk~rl, 1-4C-alkoxycarbonyl, 1-4C-alkyl-carbonyl, p]lenyl which is substituted by R6, R7 and R8, phe:Dyl-1-4C-alkyl which is substituted in the phenyl radical by R6, R7 and R8, benzoyl which is substituted in the phenyl radical by R6, R7 and R8, pieolinoyl, nieotinoyl, iso-nieotinoyl, benzhydryl whieh is, if required, substituted by halogen or 1-4C-alkyl, and the radieal R4, - a substitutEd morpholino radieal is substituted by one or t~o identical or different 1-4C-alkyl radicals and - a substitutEd homopiperazino radieal is substi-tuted in position 4 by a substituent selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylearbonyl, phenyl whieh is substituted by R6, R7 and R8, phenyl-1-4C-alkyl whieh is substituted in the phenyl radieal by R6, R7 and R8, and benzoyl whieh is substitutedl in the phenyl radieal by R6, R7 and R8, where fur~h~ - r~
R3 is furyl, n.aphthyl, tetrahydronaphthyl, phenyl whieh is sllbstituted by -O-Al-ONO2, or phenyl whieh is substituted by R6, R7 and R8, R4 is 1-7C-alkyl or the substituent -CH2 -CE (OH) - (CH2O) p-Ar and Rep~ t gheet (Rule 26) - 3 - PCT/E:P95/00167 R5 is phenyl which i5 substituted by R6, R7 and R8, phenyl-1-4C-alkyl which i~ substituted by R6, R7 and R8, if required halogen- or 1-4C-alkyl-lsubstituted benzhydryl, dibenzo-5-7C-cyrl~s~lk~nyl, dibenzocycloheptenyl or benzo-pyrido-5-7C-cyrl ~ 11 k:~nyl, and where in addition R6 is hydL~ l, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylci~rbonyl, halogen, amino, mono- or di- (1-4C-alkyl) amino or nitro, R7 i~s hydrogen, :L-4C-alkyl, 1-4C-alkoxy, halogen or ni tro, R8 is I~YdL~Y~j~ or trifluoromethyl, p i~ the number O or 1, and Ar is a hydrocarbon ring ~sylstem which is complete-ly or partly unsaturated, which is monocyclic (with 5 to 6) or bicyclic (with 9 to 10 ring atom~s), in which 1, 2 or 3 carbon atoms can be replaced by heteroatoms ~rom the group of nitrogen (~), oxygen (O) or sulfur (S), and which can be sub3tituted by one or two nt;r~l c~r different ~ubstituents from the group of 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alko~cy-1-4C-alkoxy, 3-4C-alkenyl, 3-4C-alk~nyloxy, 3-8C-cycloalkyl, 5-lOC-cycl,~alkylalkoxyalkyl, 1-4C-alkyl-carbonyl, :L-4C-alkylcarbonylamino, ~ r' ~.r--' yl-1-4C-alkyl, halogen, hydroxyl, oxo, nitro, cyano, 1-4C-alkyll3ulfonamido, amino, mono- or di- (1-4C-alkyl) amino, ureido, mono- or di- (1-4C-alkyl)ureido, mono- or di-(3-8C-cycloalkyl)ureido, trifluoromethyl, 1-4C-alkoxy which i~s completely or partially sub~stitutecl by fluorine, or 1-4C-alkoxy-carbonyl, tetrahydrofurfuryloxy or morpholino, and the ~salt~3 of theEse -, u--d~.
~erl~c-~_ t ~3heet (Rule 26) a ~ ~
1-15C-Alkylene represents straight-chain or branched alkylene radicals with 1 to 15 carbon atoms.
Examples which may be - t; ~nF~d are the radicals methy-lene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), tetramethylene (-CH2CH2CH2CH2-), penta-methylene (-cH2cEI2cH2cH2cH2-) ~ hexamethylene ( - CH2 - ( CH2 ) 4 - CH2 ) ~ oc tame thyl ene ( - CH2 - ( CH2 ) 6 - CH2 - ), decamethylene (-CH2- (CH2) 8-CH2-) ~ tetradecamethylene (-CH2- (CH2) l2-CH2-) ~ 1, 2-dimethylethylene [-CH(CH3)-CH(CH3)-], l,,l-dimethylethylene [-C(CH3)2-CH2-], i ~opropylidene [ - C (CH3 ) 2 - ] ~ 2, 2 -dimethylpropylene [-CH2-C(CH3)z-CH2-], 2-methylpropylene [-CH2-CH(CH3)-CH2-]
- and 2-methylethylene [-CH2-CH(CH3)-].
Examples which may be - t; ~nF~d are the radicals methy-lene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), tetramethylene (-CH2CH2CH2CH2-), penta-methylene (-cH2cEI2cH2cH2cH2-) ~ hexamethylene ( - CH2 - ( CH2 ) 4 - CH2 ) ~ oc tame thyl ene ( - CH2 - ( CH2 ) 6 - CH2 - ), decamethylene (-CH2- (CH2) 8-CH2-) ~ tetradecamethylene (-CH2- (CH2) l2-CH2-) ~ 1, 2-dimethylethylene [-CH(CH3)-CH(CH3)-], l,,l-dimethylethylene [-C(CH3)2-CH2-], i ~opropylidene [ - C (CH3 ) 2 - ] ~ 2, 2 -dimethylpropylene [-CH2-C(CH3)z-CH2-], 2-methylpropylene [-CH2-CH(CH3)-CH2-]
- and 2-methylethylene [-CH2-CH(CH3)-].
5-7C-Cycloalkylene represents cycloalkylene radicals with 5 to 7 carbon atoms. Cyclohexylene r~dicals are preferred, exampl~s which may be mentioned being the 1,2- and the 1,4-cyclohexylene radical.
Di-1-4C-alkylene-5-7C-cyclo~lk~ne repreaents cyclic hydroc~rh~nQ with 5 to 7 carbon atoms which are substituted by two (i~l~nt;~l or different) alkylene r-~dicals with 1 to 4 carbon atoms. A preferred di-1-4C-alkylene-5-7C-c~cloalkane radical i9 the 1, 4-dimethylenecycloh~xane radical .
1-7C-alkyl re}~resents straight-chain and branched alkyl radicals with 1 to 7 carbon atoms. Examples which may be mentioned a~ e the heptyl, hexyl, neopentyl, iQopentyl, pentyl, butyl, i~30-butyl, sec-butyl, tert-butyl, propyl, iQopropyl, ethyl and the methyl radical.
3-8C-Cycloalkyl represents the cyclopropyl, 3 0 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl radical.
1-4C-Alkyl represents straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Example3 which may be mentioned are the butyl, iso-butyl, sec-butyl, 3 5 tert -butyl, propyl, isopropyl, ethyl and the methyl radical .
1-4C-Alkoxy represents a radical which, besides ~r~ t sheet (Rule 26) r ` 2L~
the oxygen atom, containa one of the ab.,v ~ n~d 1-4C-alkyl radicals. Examples which may be mentioned are the methoxy and the e~;hoxy radical.
~ Ialogen for t}le purpo3e of the present invention 5 i3 bromine, chlorine ,md $1uorine.
1-4C-l~lkoxycarbonyl L~:~Leae~.ts a radical which, be3ides the carbonyl group, contains one of the above-mentioned 1-4C-alkoxy radical3. Examples which may be mentioned are the metlloxycarbonyl and the ethoxycarbonyl 10 radical.
1-4C-Alkylcarbonyl I~:~Leaelltg a radical which, beEIides the carbonyl group, c~ntA;n~ one of the above-mentioned 1-4C-alkyl r~dicals. An example which may be mentioned ia the acetyl radical.
Dibenzo-5-7C-cy~loalkAnyl radicals which may be mentioned are the ~ ^n ~ocyclopentyl, the dibenzocyclo-hexyl and, in particular, the ~;hPn ~ocycloheptyl radical.
Benzo-pyrido-5-7C-cy~ 1 k~nyl radicals which may be mentioned are the benzo-pyridocyclopentyl, the benzo-20 pyridocyclohexyl andl, in particular, the benzo-pyrido-cycloheptyl radical.
Mono- or di- (1-4C-alkyl) amino repre3ent3 an amino radical which i3 subatituted by one or two identical or different ab~,v~ t;~nPd 1-4C-alkyl radical3. Example3 25 which may be mentioned are the methylamino, the ethyl-amino, the dimethylamino, the diethylamino and the dii30propylamino radi cal.
1-4C-Alkylthi o represents a radical which, beaides the 3ulfur atom, contains one of the above-30 mentioned 1-4C-alkyl radicala. The methylthio radical i~
pref erred .
1-4C-Alkoxy-1-4C-alkyl repre3ent3 one of the abovementioned 1-4C- 11kyl radical3 which i3 sub3tituted by one of the abovementioned 1-4C-alkoxy radicalr..
35 Examples which may be mentioned are the methoxymethyl, methoxyethyl radical and the butoxyethyl radical.
1-4C-~lkoxy-1-4C-alkoxy represents one of the R~pl~ t 3heet (Rule 26) ~ 5 ~ ~
Di-1-4C-alkylene-5-7C-cyclo~lk~ne repreaents cyclic hydroc~rh~nQ with 5 to 7 carbon atoms which are substituted by two (i~l~nt;~l or different) alkylene r-~dicals with 1 to 4 carbon atoms. A preferred di-1-4C-alkylene-5-7C-c~cloalkane radical i9 the 1, 4-dimethylenecycloh~xane radical .
1-7C-alkyl re}~resents straight-chain and branched alkyl radicals with 1 to 7 carbon atoms. Examples which may be mentioned a~ e the heptyl, hexyl, neopentyl, iQopentyl, pentyl, butyl, i~30-butyl, sec-butyl, tert-butyl, propyl, iQopropyl, ethyl and the methyl radical.
3-8C-Cycloalkyl represents the cyclopropyl, 3 0 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl radical.
1-4C-Alkyl represents straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Example3 which may be mentioned are the butyl, iso-butyl, sec-butyl, 3 5 tert -butyl, propyl, isopropyl, ethyl and the methyl radical .
1-4C-Alkoxy represents a radical which, besides ~r~ t sheet (Rule 26) r ` 2L~
the oxygen atom, containa one of the ab.,v ~ n~d 1-4C-alkyl radicals. Examples which may be mentioned are the methoxy and the e~;hoxy radical.
~ Ialogen for t}le purpo3e of the present invention 5 i3 bromine, chlorine ,md $1uorine.
1-4C-l~lkoxycarbonyl L~:~Leae~.ts a radical which, be3ides the carbonyl group, contains one of the above-mentioned 1-4C-alkoxy radical3. Examples which may be mentioned are the metlloxycarbonyl and the ethoxycarbonyl 10 radical.
1-4C-Alkylcarbonyl I~:~Leaelltg a radical which, beEIides the carbonyl group, c~ntA;n~ one of the above-mentioned 1-4C-alkyl r~dicals. An example which may be mentioned ia the acetyl radical.
Dibenzo-5-7C-cy~loalkAnyl radicals which may be mentioned are the ~ ^n ~ocyclopentyl, the dibenzocyclo-hexyl and, in particular, the ~;hPn ~ocycloheptyl radical.
Benzo-pyrido-5-7C-cy~ 1 k~nyl radicals which may be mentioned are the benzo-pyridocyclopentyl, the benzo-20 pyridocyclohexyl andl, in particular, the benzo-pyrido-cycloheptyl radical.
Mono- or di- (1-4C-alkyl) amino repre3ent3 an amino radical which i3 subatituted by one or two identical or different ab~,v~ t;~nPd 1-4C-alkyl radical3. Example3 25 which may be mentioned are the methylamino, the ethyl-amino, the dimethylamino, the diethylamino and the dii30propylamino radi cal.
1-4C-Alkylthi o represents a radical which, beaides the 3ulfur atom, contains one of the above-30 mentioned 1-4C-alkyl radicala. The methylthio radical i~
pref erred .
1-4C-Alkoxy-1-4C-alkyl repre3ent3 one of the abovementioned 1-4C- 11kyl radical3 which i3 sub3tituted by one of the abovementioned 1-4C-alkoxy radicalr..
35 Examples which may be mentioned are the methoxymethyl, methoxyethyl radical and the butoxyethyl radical.
1-4C-~lkoxy-1-4C-alkoxy represents one of the R~pl~ t 3heet (Rule 26) ~ 5 ~ ~
abovementioned 1-4C-alkoxy radicals which is substituted by another 1-4C-alkox~ radical. An example which may be mentioned is the meth~xyethoxy radical.
3-4C-Alkenyl is, for example, 2-butenyl a~d, in particular, allyl.
3-4C-Alkenyloxy c~nt~;nc~ besides the oxygen atom, a 3-4C-alke~yl radical. The allyloxy radical may be t;r~n~d as an example of a 3-4C-alkerLyloxy radical.
5-lOC-Cycloalkylalkoxyalkyl represeIlts an alkoxy-alkyl radical which is substituted by a cycloalkyl radical. An example which may be mentioned is the cyclo-propylmethoxyethyl radical.
An example of a 1-4C-alkylcarbonylami~o radical which may be t i ~nPd ig the acetamido radical 1 5 ( - N~I - CO - C~3 ) .
C~rh~ yl represe~ts the radical N~2-CO-.
C~ ' ~1-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by ~ 1. The ~ lmethyl radical may be men-tioned as an example of a ~ rh- ~.1-1-4C-alkyl radical.
1-4C-~lkylsulfonamido ~ ,r~ tc a 5111 e~)n:~mi ~
radical to which one of the ab~,v ti~n ~d 1-4C-alkyl radicals is bonded. An exa~ple which may be mentioned is the methylsulfonamido radical.
IJreido represents the radical -N~-CO-N~2. An example of mono-1-4C-alkylureido which may be mentioned is 3-methylureido and of di-1-4C-alkylureido i8 3,3-dimethylureido. Examples of mOAO- or di-3-8C-cyclo-alkylureido radicals which may be -- t; r~ned are, for example, the 3-cyclohexylureido and the 3,3-dicyclohexyl-ureido radical.
r 1 ~c which may be mentioned of 1-4C-alkoxy which is completely or partially substituted by fluorine are the 1,2,2-trifluoroethoxy, the 2,2,3,3,3-pentafluoro-propoxy, the perfluoroethoxy and, in particular, the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethox~r and the difluoromethoxy radical.
Repl~ t sheet (Rule 26) t~ ~3 ~
3-4C-Alkenyl is, for example, 2-butenyl a~d, in particular, allyl.
3-4C-Alkenyloxy c~nt~;nc~ besides the oxygen atom, a 3-4C-alke~yl radical. The allyloxy radical may be t;r~n~d as an example of a 3-4C-alkerLyloxy radical.
5-lOC-Cycloalkylalkoxyalkyl represeIlts an alkoxy-alkyl radical which is substituted by a cycloalkyl radical. An example which may be mentioned is the cyclo-propylmethoxyethyl radical.
An example of a 1-4C-alkylcarbonylami~o radical which may be t i ~nPd ig the acetamido radical 1 5 ( - N~I - CO - C~3 ) .
C~rh~ yl represe~ts the radical N~2-CO-.
C~ ' ~1-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by ~ 1. The ~ lmethyl radical may be men-tioned as an example of a ~ rh- ~.1-1-4C-alkyl radical.
1-4C-~lkylsulfonamido ~ ,r~ tc a 5111 e~)n:~mi ~
radical to which one of the ab~,v ti~n ~d 1-4C-alkyl radicals is bonded. An exa~ple which may be mentioned is the methylsulfonamido radical.
IJreido represents the radical -N~-CO-N~2. An example of mono-1-4C-alkylureido which may be mentioned is 3-methylureido and of di-1-4C-alkylureido i8 3,3-dimethylureido. Examples of mOAO- or di-3-8C-cyclo-alkylureido radicals which may be -- t; r~ned are, for example, the 3-cyclohexylureido and the 3,3-dicyclohexyl-ureido radical.
r 1 ~c which may be mentioned of 1-4C-alkoxy which is completely or partially substituted by fluorine are the 1,2,2-trifluoroethoxy, the 2,2,3,3,3-pentafluoro-propoxy, the perfluoroethoxy and, in particular, the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethox~r and the difluoromethoxy radical.
Repl~ t sheet (Rule 26) t~ ~3 ~
Examples o~ substituted pyrrolidino radicals which may be -- tin~n~d are the 2-methylpyrrolidino, 2, 5-dimethylpyrrolidino and the 3 _LYd1~)~LY~YL ~ ~Jlidino radical .
Examples of substituted piperidino rl~i;c~l~ which may be mentioned are the 3-Lyd. v~y~iperidino, 2-n-propyl-piperidino, 5-ethyl-2-methylpiperidino, 4-n-propyl-piperidino, 4, 4-dimethylpiperidino, 2, 6-dimethyl-piperidino, 4-l~ydl~y~iperidino~ 2-ethyl-2-methyl-piperidino, 2-methyl]?iperidino, 2, 6-dimethylpiperidino and the 2-ethylpiperidino radical.
Examples o~ substituted piperazino radicals which may be ~nn~d are the 4-methylpiperazino, 4- [2- (2-tri-~luoromethylphenyl)ethyl]piperazino, 4-phenylpiperazino, 4-(2-methylphenyl)piperl~zino, 4-(2,3-dimethylphenyl)-piperazino, 4- (2-chlorophenyl)piperazino, 4- (2-methoxy-phenyl) piper~zino, 4- (2 -ethoxyphenyl) piperazino, 4- (3 -chlorophenyl) piperazino, 4- (4- Eluorophenyl) -piperazino, 4- (4-chlorophenyl)piperazino, 4- (4-methoxy-20 phenyl)piperazino, 3-methyl-4- (4-chluL~h~yl)pir~r7 ~ ;nn, 3 -methyl-4- (4-metho~yphenyl) piperazino, 3 -methyl-4- (4-methylphenyl)piperazino, 4- (2,4-dimethylphenyl) -piperazino, 4-acetylpiperazino, 4- (3, 4-dichlorophenyl) -piperazino, 4- (3, 4-dimethylphenyl) piperazino, 25 4- (3-pyri~lin ~ll - yl)piperazino, 3-methyl-4-phenyl-piperaz ino, 3 -methyl - 4 - ( 3 - chlorophenyl ) p iperaz ino, 4-benzylpiperazino, 4-propylpiperazino, 4- (3-methyl-phenyl)piperazino, 4- (3-methoxyphenyl)piperazino, 4 - (4 -methylphenyl) piperazino, 4 - (2, 5-dimethylphenyl) -30 piperazino, 4-benzhydrylpiperazino, 4-n-butylpiperazino, 4-iso-butylpiperazino, 4-tert-butylpiperazino, 4- (3-tri-fluoromethylphenyl)piperazino, 4- (l-phenylethyl) -piperazino, 4- (2-pheaylethyl)piperazino, 4- (2-hydroxy-phenyl)piperazino, 4-(3~4-dimethoxyphenyl)pip~rlsin~"
35 4-isopropylpiperazino, 3-methyl-4- (3-methoxyphenyl) -piperazino, 4- (4-l~y~l- oxy~,henyl)piperazino, 3-methyl-4- (3-methylphenyl)piperazino, 4- (3-hydroxyphenyl) -~r~ t ~3heet (Rule 26) 2~
Examples of substituted piperidino rl~i;c~l~ which may be mentioned are the 3-Lyd. v~y~iperidino, 2-n-propyl-piperidino, 5-ethyl-2-methylpiperidino, 4-n-propyl-piperidino, 4, 4-dimethylpiperidino, 2, 6-dimethyl-piperidino, 4-l~ydl~y~iperidino~ 2-ethyl-2-methyl-piperidino, 2-methyl]?iperidino, 2, 6-dimethylpiperidino and the 2-ethylpiperidino radical.
Examples o~ substituted piperazino radicals which may be ~nn~d are the 4-methylpiperazino, 4- [2- (2-tri-~luoromethylphenyl)ethyl]piperazino, 4-phenylpiperazino, 4-(2-methylphenyl)piperl~zino, 4-(2,3-dimethylphenyl)-piperazino, 4- (2-chlorophenyl)piperazino, 4- (2-methoxy-phenyl) piper~zino, 4- (2 -ethoxyphenyl) piperazino, 4- (3 -chlorophenyl) piperazino, 4- (4- Eluorophenyl) -piperazino, 4- (4-chlorophenyl)piperazino, 4- (4-methoxy-20 phenyl)piperazino, 3-methyl-4- (4-chluL~h~yl)pir~r7 ~ ;nn, 3 -methyl-4- (4-metho~yphenyl) piperazino, 3 -methyl-4- (4-methylphenyl)piperazino, 4- (2,4-dimethylphenyl) -piperazino, 4-acetylpiperazino, 4- (3, 4-dichlorophenyl) -piperazino, 4- (3, 4-dimethylphenyl) piperazino, 25 4- (3-pyri~lin ~ll - yl)piperazino, 3-methyl-4-phenyl-piperaz ino, 3 -methyl - 4 - ( 3 - chlorophenyl ) p iperaz ino, 4-benzylpiperazino, 4-propylpiperazino, 4- (3-methyl-phenyl)piperazino, 4- (3-methoxyphenyl)piperazino, 4 - (4 -methylphenyl) piperazino, 4 - (2, 5-dimethylphenyl) -30 piperazino, 4-benzhydrylpiperazino, 4-n-butylpiperazino, 4-iso-butylpiperazino, 4-tert-butylpiperazino, 4- (3-tri-fluoromethylphenyl)piperazino, 4- (l-phenylethyl) -piperazino, 4- (2-pheaylethyl)piperazino, 4- (2-hydroxy-phenyl)piperazino, 4-(3~4-dimethoxyphenyl)pip~rlsin~"
35 4-isopropylpiperazino, 3-methyl-4- (3-methoxyphenyl) -piperazino, 4- (4-l~y~l- oxy~,henyl)piperazino, 3-methyl-4- (3-methylphenyl)piperazino, 4- (3-hydroxyphenyl) -~r~ t ~3heet (Rule 26) 2~
piperazino, 4-(2,6-dinitro-4-trifluoromethylphenyl)-piperazino, 4- (2-hydroxy-3-phen~.~y~L~ y1)piperazino, 4- (4-nitrophenyl)piperazino, 4- (4-acetylphenyl) -piperazino, 4-ethoxycarbonylpiperazino and the 5 4- (4-chlorobenzhydryl)piperazino radical.
An example of a substituted morpholino radical which may be mentiorled i~3 the 3, 5-dimethylmorpholino radical .
Examples of srLbstituted homopiperazino radicals 10 which may be ~ n~d are the 4-methyl-, the 4-ethoxy-carbonyl-, the 4-acetyl-, the 4- (2-methoxyphenyl) - and the 4 -benzoyl h~ ~, r~lrazino radical .
- Examples which may be t; ~n~3 of benzhydryl rA~ which are, if required, substituted by halogen 15 or 1-4C-alkyl are the benzhydryl, the bis-4,4'-fluorobenzhydryl, thebi~l-4,4'-chlorobenzhydryl, the 4 - chlorobenzhydryl and the 4 -methylbenzhydryl radical .
Examples which may be - t; ~ned of phenyl radi-cals which are substituted by R6, R7 and R8 are the20 radicals 3,4-dihydroxy-, 3-hydroxy-4-methoxy-, 3,4-dimethoxy-, 2-m~thoxy-, 2-ethoxy-, 3-methoxy-, 4-methoxy-, 2-hydroxy-, 3-hydroxy-, 4-hydroxy-, 3, 4 - dihydroxy-, 4 - ac e tyl -, 4 - f luoro -, 4 - chloro, 2-chloro-, 3-chloro-, 3,4-dichloro-, 3-trifluoromethyl-, 25 2-trifluoromethyl-, 2-methyl-, 3-methyl-, 4-methyl-, 2,3-dimethyl-, 2,4-dimethyl-, 3,4-dimethyl-, 2, 5-dimethyl-, 4-rLit~o-, 2, 6-dinitro-4-trifluoromethyl-and 5 -chloro-2 -methy~ ~m; n~ph~nyl .
Selected ~ of Ar substituents which may be 30 mentioned are the fol~lowing radicals:
pherlyl, 4- (2-~ethoxyethoxy) phenyl, 2-allylphenyl, 2-acetyl-4-butyr~m;c~ h-~nyl, 4-~ lmethylphenyl, 4-methylphenyl, 2-tetrahydrofurfuryloxyphenyl, 2-chloro-5-methylphenyl, 2-acetyl-4- (3,3-diethylureido)phenyl, 35 2-cyclohexylphenyl, 4-hydroxy-3-carbamoylphenyl, 4- (2-methoxyethyl) phe!nyl, 2 -methoxyphenyl, 4-niLl~,~h~ . ~yl, 2 - al lyloxyphenyl, 2 - cyclopentylphenyl, 2 - cyanophenyl, Replacement sheet (Rule 26) 4-ace~Am;-1-phPnyl, 4-l~y~L~,~yt,henyl, 2-cyclopropylphenyl, 4-methAn~ 1f~nAm;rlrlphl~nyl, 4-(3-cyclohexylureido)phenyl, 2-methylth;rphPnyl, .4_~'A 1 ~lphenyl, 4-cyclopropyl-methoxyethylphenyl, 2, 5-dichlor~J~hel~y1, 2 -butyryl-5 4-fluorophenyl, 2-tri~luoromethylphenyl, 2-chlorophenyl, 2-fluorophenyl, 2--methylphenyl, 2-acetylphenyl, 5,6,7,8-tetrahydro-2-Ilaphthyl, 4_~A~h~olyl~ 1-naphthyl, 5,8-dihydro-1-naphthyl, 5,6-dihydro-1-naphthyl, 1-inden-4-yl, 1-inden-7-yl, 2-methyl-4-indolyl, 6, 7-dihydroxy-5,6,7,8-tetrahydro-1-llaphthyl, 4-indolyl, 3,4-dihydro-2-l yd~o,.y~tuinolin-5-yl (= 3,4-dihydrocarbostyril-5-yl), 8-hydroxycarbo~styri1-5-yl, 2-naphthyl, 2-thiazolyl, - 4-morpholino-1,2,5-thiA~ 7Ol-3-yl, 7-ethyl-2-benzo-furanyl, 2-acetyl-7-benzofuranyl, 5-methyl-2~I-benzopyron-8-yl, 1,4-b~n ~Q~ An-5-yl, 4-indanyl and 5,6,7,8-tetra-hydro-5-oxo-1-naphthy:L .
Suitable saltls for the ~ ~ o~ the formula I are all acid addition salts. Particular mention may be made of the rhArr~--ologically acceptable ~salts of the 20 inorganic and organic acids customarily used in pharma-ceutical tel-hn~llogy. phA~^l ologically unacceptable salts which may, for example, be the initial products of the process for the preparation of the compounds according to the invention on the industrial scale are converted by 25 processes known to the skilled worker into rhArr-~olo~i-cally acceptable salts. Suitable as Isuch are water-soluble and water-;n~olllhle acid addition salts with acid~s such als, for example, hydrochloric acid, hydrobro-mic acid, rh~srhoric acid, nitric acid, sulfuric acid, 30 acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-l~ydL~ ybenzoyl)b~nzoic acid, butyric acid, sulfosal-icylic acid, maleic acid, lauric acid, malic acid, fumaric acid, ~succinic acid, oxalic acid, tartaric acid, embonic acid, stea~^ic acid, toll~An~ulfonic acid, 35 methAn~ l fonic acid or 3-hydroxy-2-nArh~h~ acid, the acids being employed in the preparation of the salts in a ratio of amounts which is equimolar or different Replace~ nt sheet (Rule 26) 15~:~
Wo 95/19952 - 10 - PCT/EP95/00167 therefrom, ~l~p~n~l~ng on whether the acid is mono- or polybaaic and ~ r~n~q;n~ on which salt i8 required.
Compounds of the f ormula I which arQ to be hA~i~ed are those in which 5 A1 is 2-lOC-alkylen~ or dimethylenecyt l~h~ n~, and in which R1 is hydLosle~l and R2 i8 hydL~g~- or A2-Y, or in which 10 R1 and R2 represent, together and with ;n~ ion of the nitrogen atom to which both are bonded, an unsub-stituted or subs~ituted piperazine radical, where A2 is l-lOC-al:kylene, Y i5 R3, NH2, NH-R4 or S-R5, - a substitut~d piperazino radical is substituted in positio~. 4 by a substituent selected from the group ,consisting of 1-4C-alko,-y~ -~yl, l-4C-alkylcarbonyl, pi~ol; noyl~ nicotinoyl, isonicotinoyl, benzhydryl and the radical R4 and where fur~h- e R3 is phenyl or phenyl which is substituted by - O -A1- ONO2, R4 is the subEtituent -CH2-CH(OH) - (CH20)p-Ar and R5 is if required halogen- or 1-4C-alkyl-substitute~ benzhydryl, dibenzocycloheptanyl, dibenzocycloheptenyl or benzo-pyrido-cycloheptarlyl, 30 and where in addition p is the number 1 and Ar is phenyl, 4- (2-me~hoxyethoxy)phenyl, 2-allyl-phenyl, 2-chloro-5-methylphenyl, 2-allyloxy-phenyl, 2-cyclopentylphenyl, 2-cyanophenyl or 1-naphthyl, and the salts of the~3e -C _ '~ of the formula I which are to be R-Qpl :~C t sheet (Rule 26) WO 95/19952 - ll - PCT/EP95/00167 particularly ~ R; 7~3d are those in which Al is 2 -lOC-alkylen~ or dimethylenecyrl ~h~T~n~ and in which Rl is llydL~ l and 5 R2 is hyd~ ~l or A2-Y, or in which Rl and R2 represent, together and with ;n- 3llR;~m of the nitrogen atom to which hoth are bonded, an un8ub-stituted or subs :ituted piperazine radical, 10 where A2 is l-lOC-al!cylene, Y is R3, NEI2, NEI-R4 or S-R5, - a substitut~d piperazino radical i5 substituted in position 4 by a substituent selected from the group consisting of 1-4C-alkylcarbonyl, nicotinoyl, benzhydryl and the radical R4 and where furTh- e R3 is phenyl or phenyl which i8 substituted by -O-Al -ON02, R4 is the substituent -CH2-CE(OE) - (CE20)p-Ar and R5 is benzhydryl which is substituted by 1-4C-alkyl, or benzhydryl, dibenzocyclo-heptanyl, rl;h~n7ocycloheptenyl, or benzo-pyrido-cycloheptanyl which is substituted by chlorine, and where in addition p i5 the number l and Ar is phenyl, 2-allylphenyl or l-naphthyl, and the salts of these ~ _ 'R.
The inventiorL furTh- ~ relates to a process for the preparation Oe the r ~ R of the for~Lula I and their salta. The process comprises aldehydes of the ~ormula II (see ~rp~T~ sheet of formulae) in which Al has the aboverLenti~ned meaning being reacted with 35 compounds of the formula III (see ~rp~n~3~fl sheet of ~ormulae) which are in the ~orm of ;llm galtg and in which R1 and R2 have the abovementioned meanings, in the Replacement sheet (Rule 26) presence of sodium c~ranoborohydride, and, if required, subse~uently the resulting - __ 'R being converted into the salta, or reRulting salts being converted into the free ~- ~1R, The process i3 carried out in a manner known per E~e to the skilled worker, for example a~3 described in the following general preparation method.
In the following examples, which are intended to explain the invention in detail, m.p. stands for melting point, RT for room temperature and h for hour(8).
Exam~l es General preparation m~thods Variant A
10 mmol of the aldehyde II and 10 mmol of the amino r~ "_ ' III (ill the form of an illm galt) are dissolved in a suitable solvent (such as, for example, methanol, ethanol or l:etrahydrofuran), 10 mmol of Rodium cyanoborohydride are ~dded, and the mixture is stirred at RT for one h. After addition of a further 10 mmol of sodium ~;y~ oboz~liydLide~ the mixture is stirred for a further 20 h. The solvent is stripped off, and the residue is dissolved in a mixture of water and ethyl acetate . The organic phase is separated of f, dried over magnesium sulfate a~ld concentrated. The residue is purified by chromatography and/or recrystallization.
Variant B
40 mmol are employed in place of 10 mmol of the amino ~ _ ' III (in the form of an ;ll~n salt) .
Variant C
100 mmol are ,employed in place of 10 mmol of the amino compound III (in the form of an ammonium salt).
An example of a substituted morpholino radical which may be mentiorled i~3 the 3, 5-dimethylmorpholino radical .
Examples of srLbstituted homopiperazino radicals 10 which may be ~ n~d are the 4-methyl-, the 4-ethoxy-carbonyl-, the 4-acetyl-, the 4- (2-methoxyphenyl) - and the 4 -benzoyl h~ ~, r~lrazino radical .
- Examples which may be t; ~n~3 of benzhydryl rA~ which are, if required, substituted by halogen 15 or 1-4C-alkyl are the benzhydryl, the bis-4,4'-fluorobenzhydryl, thebi~l-4,4'-chlorobenzhydryl, the 4 - chlorobenzhydryl and the 4 -methylbenzhydryl radical .
Examples which may be - t; ~ned of phenyl radi-cals which are substituted by R6, R7 and R8 are the20 radicals 3,4-dihydroxy-, 3-hydroxy-4-methoxy-, 3,4-dimethoxy-, 2-m~thoxy-, 2-ethoxy-, 3-methoxy-, 4-methoxy-, 2-hydroxy-, 3-hydroxy-, 4-hydroxy-, 3, 4 - dihydroxy-, 4 - ac e tyl -, 4 - f luoro -, 4 - chloro, 2-chloro-, 3-chloro-, 3,4-dichloro-, 3-trifluoromethyl-, 25 2-trifluoromethyl-, 2-methyl-, 3-methyl-, 4-methyl-, 2,3-dimethyl-, 2,4-dimethyl-, 3,4-dimethyl-, 2, 5-dimethyl-, 4-rLit~o-, 2, 6-dinitro-4-trifluoromethyl-and 5 -chloro-2 -methy~ ~m; n~ph~nyl .
Selected ~ of Ar substituents which may be 30 mentioned are the fol~lowing radicals:
pherlyl, 4- (2-~ethoxyethoxy) phenyl, 2-allylphenyl, 2-acetyl-4-butyr~m;c~ h-~nyl, 4-~ lmethylphenyl, 4-methylphenyl, 2-tetrahydrofurfuryloxyphenyl, 2-chloro-5-methylphenyl, 2-acetyl-4- (3,3-diethylureido)phenyl, 35 2-cyclohexylphenyl, 4-hydroxy-3-carbamoylphenyl, 4- (2-methoxyethyl) phe!nyl, 2 -methoxyphenyl, 4-niLl~,~h~ . ~yl, 2 - al lyloxyphenyl, 2 - cyclopentylphenyl, 2 - cyanophenyl, Replacement sheet (Rule 26) 4-ace~Am;-1-phPnyl, 4-l~y~L~,~yt,henyl, 2-cyclopropylphenyl, 4-methAn~ 1f~nAm;rlrlphl~nyl, 4-(3-cyclohexylureido)phenyl, 2-methylth;rphPnyl, .4_~'A 1 ~lphenyl, 4-cyclopropyl-methoxyethylphenyl, 2, 5-dichlor~J~hel~y1, 2 -butyryl-5 4-fluorophenyl, 2-tri~luoromethylphenyl, 2-chlorophenyl, 2-fluorophenyl, 2--methylphenyl, 2-acetylphenyl, 5,6,7,8-tetrahydro-2-Ilaphthyl, 4_~A~h~olyl~ 1-naphthyl, 5,8-dihydro-1-naphthyl, 5,6-dihydro-1-naphthyl, 1-inden-4-yl, 1-inden-7-yl, 2-methyl-4-indolyl, 6, 7-dihydroxy-5,6,7,8-tetrahydro-1-llaphthyl, 4-indolyl, 3,4-dihydro-2-l yd~o,.y~tuinolin-5-yl (= 3,4-dihydrocarbostyril-5-yl), 8-hydroxycarbo~styri1-5-yl, 2-naphthyl, 2-thiazolyl, - 4-morpholino-1,2,5-thiA~ 7Ol-3-yl, 7-ethyl-2-benzo-furanyl, 2-acetyl-7-benzofuranyl, 5-methyl-2~I-benzopyron-8-yl, 1,4-b~n ~Q~ An-5-yl, 4-indanyl and 5,6,7,8-tetra-hydro-5-oxo-1-naphthy:L .
Suitable saltls for the ~ ~ o~ the formula I are all acid addition salts. Particular mention may be made of the rhArr~--ologically acceptable ~salts of the 20 inorganic and organic acids customarily used in pharma-ceutical tel-hn~llogy. phA~^l ologically unacceptable salts which may, for example, be the initial products of the process for the preparation of the compounds according to the invention on the industrial scale are converted by 25 processes known to the skilled worker into rhArr-~olo~i-cally acceptable salts. Suitable as Isuch are water-soluble and water-;n~olllhle acid addition salts with acid~s such als, for example, hydrochloric acid, hydrobro-mic acid, rh~srhoric acid, nitric acid, sulfuric acid, 30 acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-l~ydL~ ybenzoyl)b~nzoic acid, butyric acid, sulfosal-icylic acid, maleic acid, lauric acid, malic acid, fumaric acid, ~succinic acid, oxalic acid, tartaric acid, embonic acid, stea~^ic acid, toll~An~ulfonic acid, 35 methAn~ l fonic acid or 3-hydroxy-2-nArh~h~ acid, the acids being employed in the preparation of the salts in a ratio of amounts which is equimolar or different Replace~ nt sheet (Rule 26) 15~:~
Wo 95/19952 - 10 - PCT/EP95/00167 therefrom, ~l~p~n~l~ng on whether the acid is mono- or polybaaic and ~ r~n~q;n~ on which salt i8 required.
Compounds of the f ormula I which arQ to be hA~i~ed are those in which 5 A1 is 2-lOC-alkylen~ or dimethylenecyt l~h~ n~, and in which R1 is hydLosle~l and R2 i8 hydL~g~- or A2-Y, or in which 10 R1 and R2 represent, together and with ;n~ ion of the nitrogen atom to which both are bonded, an unsub-stituted or subs~ituted piperazine radical, where A2 is l-lOC-al:kylene, Y i5 R3, NH2, NH-R4 or S-R5, - a substitut~d piperazino radical is substituted in positio~. 4 by a substituent selected from the group ,consisting of 1-4C-alko,-y~ -~yl, l-4C-alkylcarbonyl, pi~ol; noyl~ nicotinoyl, isonicotinoyl, benzhydryl and the radical R4 and where fur~h- e R3 is phenyl or phenyl which is substituted by - O -A1- ONO2, R4 is the subEtituent -CH2-CH(OH) - (CH20)p-Ar and R5 is if required halogen- or 1-4C-alkyl-substitute~ benzhydryl, dibenzocycloheptanyl, dibenzocycloheptenyl or benzo-pyrido-cycloheptarlyl, 30 and where in addition p is the number 1 and Ar is phenyl, 4- (2-me~hoxyethoxy)phenyl, 2-allyl-phenyl, 2-chloro-5-methylphenyl, 2-allyloxy-phenyl, 2-cyclopentylphenyl, 2-cyanophenyl or 1-naphthyl, and the salts of the~3e -C _ '~ of the formula I which are to be R-Qpl :~C t sheet (Rule 26) WO 95/19952 - ll - PCT/EP95/00167 particularly ~ R; 7~3d are those in which Al is 2 -lOC-alkylen~ or dimethylenecyrl ~h~T~n~ and in which Rl is llydL~ l and 5 R2 is hyd~ ~l or A2-Y, or in which Rl and R2 represent, together and with ;n- 3llR;~m of the nitrogen atom to which hoth are bonded, an un8ub-stituted or subs :ituted piperazine radical, 10 where A2 is l-lOC-al!cylene, Y is R3, NEI2, NEI-R4 or S-R5, - a substitut~d piperazino radical i5 substituted in position 4 by a substituent selected from the group consisting of 1-4C-alkylcarbonyl, nicotinoyl, benzhydryl and the radical R4 and where furTh- e R3 is phenyl or phenyl which i8 substituted by -O-Al -ON02, R4 is the substituent -CH2-CE(OE) - (CE20)p-Ar and R5 is benzhydryl which is substituted by 1-4C-alkyl, or benzhydryl, dibenzocyclo-heptanyl, rl;h~n7ocycloheptenyl, or benzo-pyrido-cycloheptanyl which is substituted by chlorine, and where in addition p i5 the number l and Ar is phenyl, 2-allylphenyl or l-naphthyl, and the salts of these ~ _ 'R.
The inventiorL furTh- ~ relates to a process for the preparation Oe the r ~ R of the for~Lula I and their salta. The process comprises aldehydes of the ~ormula II (see ~rp~T~ sheet of formulae) in which Al has the aboverLenti~ned meaning being reacted with 35 compounds of the formula III (see ~rp~n~3~fl sheet of ~ormulae) which are in the ~orm of ;llm galtg and in which R1 and R2 have the abovementioned meanings, in the Replacement sheet (Rule 26) presence of sodium c~ranoborohydride, and, if required, subse~uently the resulting - __ 'R being converted into the salta, or reRulting salts being converted into the free ~- ~1R, The process i3 carried out in a manner known per E~e to the skilled worker, for example a~3 described in the following general preparation method.
In the following examples, which are intended to explain the invention in detail, m.p. stands for melting point, RT for room temperature and h for hour(8).
Exam~l es General preparation m~thods Variant A
10 mmol of the aldehyde II and 10 mmol of the amino r~ "_ ' III (ill the form of an illm galt) are dissolved in a suitable solvent (such as, for example, methanol, ethanol or l:etrahydrofuran), 10 mmol of Rodium cyanoborohydride are ~dded, and the mixture is stirred at RT for one h. After addition of a further 10 mmol of sodium ~;y~ oboz~liydLide~ the mixture is stirred for a further 20 h. The solvent is stripped off, and the residue is dissolved in a mixture of water and ethyl acetate . The organic phase is separated of f, dried over magnesium sulfate a~ld concentrated. The residue is purified by chromatography and/or recrystallization.
Variant B
40 mmol are employed in place of 10 mmol of the amino ~ _ ' III (in the form of an ;ll~n salt) .
Variant C
100 mmol are ,employed in place of 10 mmol of the amino compound III (in the form of an ammonium salt).
Replace~ment sheet (Rule 26) ~ ~. 8 1 3 ~ ~
Wo 95/19952 - 13 - PCT/EP95/00167 1. 2- (2-NitroxYethoxY) -N- (2-PhenYlethYl)benzYlamine Prepared from 2- (2-nitroxyethoxy)b~n7Al~hyde and 2-phenylethyla~Dmonium chloride by process variant A.
Purified by chromatography on silica gel (ethyl acetate) .
5 The title ,_ ' was isola~ed as tosylate and recrys-tallized from diethyl ether. M.p. of the tosylate:
147-149C.
2. N-{2- [ (4-MethYl -alPha-PhenYlbenzyl) thio] -ethYl~-4- (2-nitroxYethoxY) -benzYlamine Prepared from 4 - (2 -nitroxyethoxy) b~n7Al ~hyde and 2- [ (4-methyl-alpha--phenylbenzyl) thio] ethylammonium chloride in tetrahydro~uran by process variant A. Puri-~ied by chromatography on silica gel (diChlc,L, - thAn~) .
M.p. of the hydrochloride: 98-103C.
3 . N- [2- (7-Chloro-10 ,11-dihYdro-5H-benzo [4, 5] cYclo-hepta [1, 2b] ~Yridine- 5 - thio) -ethYl] -4 - (2 -nitroxY-ethoxy) benzYlamine Prepared from 4- (2-nitroxyethoxy)bc~n7~ hyde and N-[2-(7-chloro-lO,ll-dihydro-5~-benzo[4,5]cyclohepta-20 [1,2b]pyridine-5-thio)ethyl]amine x 2 }ICl in tetrahydro-furan by process variant A. Purified by chromatography on ~ilica gel (ethyl acetate/methanol 7:1). Recrystallized as dihydrochloride from ethyl acetate. M.p. of the dihydrochloride: 148--151C.
25 4. N-{2-[(5~-Dibenzo~a, d~cYclohePten-5-yl)thiol-eth-yl}-2- (2,2-dime~hYl-3-niLL~"~y"~",u..y)benzYlamine Prepared froDI 2-(2,2-dimethyl-3-niLL~,-y~L~ y)-bc~n7Al d~hyde and N- {2 - [ (5~-dibenzo [a, d] cyclohepten-5-yl) thio] ethyl}amine in tetrahydrofuran by process 30 variant A. Purified by chromatography on silica gel (ethyl acetate/petro~ eum ether 60-80/1:2) . M.p.: 97-99C.
Wo 95/19952 - 13 - PCT/EP95/00167 1. 2- (2-NitroxYethoxY) -N- (2-PhenYlethYl)benzYlamine Prepared from 2- (2-nitroxyethoxy)b~n7Al~hyde and 2-phenylethyla~Dmonium chloride by process variant A.
Purified by chromatography on silica gel (ethyl acetate) .
5 The title ,_ ' was isola~ed as tosylate and recrys-tallized from diethyl ether. M.p. of the tosylate:
147-149C.
2. N-{2- [ (4-MethYl -alPha-PhenYlbenzyl) thio] -ethYl~-4- (2-nitroxYethoxY) -benzYlamine Prepared from 4 - (2 -nitroxyethoxy) b~n7Al ~hyde and 2- [ (4-methyl-alpha--phenylbenzyl) thio] ethylammonium chloride in tetrahydro~uran by process variant A. Puri-~ied by chromatography on silica gel (diChlc,L, - thAn~) .
M.p. of the hydrochloride: 98-103C.
3 . N- [2- (7-Chloro-10 ,11-dihYdro-5H-benzo [4, 5] cYclo-hepta [1, 2b] ~Yridine- 5 - thio) -ethYl] -4 - (2 -nitroxY-ethoxy) benzYlamine Prepared from 4- (2-nitroxyethoxy)bc~n7~ hyde and N-[2-(7-chloro-lO,ll-dihydro-5~-benzo[4,5]cyclohepta-20 [1,2b]pyridine-5-thio)ethyl]amine x 2 }ICl in tetrahydro-furan by process variant A. Purified by chromatography on ~ilica gel (ethyl acetate/methanol 7:1). Recrystallized as dihydrochloride from ethyl acetate. M.p. of the dihydrochloride: 148--151C.
25 4. N-{2-[(5~-Dibenzo~a, d~cYclohePten-5-yl)thiol-eth-yl}-2- (2,2-dime~hYl-3-niLL~"~y"~",u..y)benzYlamine Prepared froDI 2-(2,2-dimethyl-3-niLL~,-y~L~ y)-bc~n7Al d~hyde and N- {2 - [ (5~-dibenzo [a, d] cyclohepten-5-yl) thio] ethyl}amine in tetrahydrofuran by process 30 variant A. Purified by chromatography on silica gel (ethyl acetate/petro~ eum ether 60-80/1:2) . M.p.: 97-99C.
R^rlAc~ t sheet (Rule 26) 5. N- [2 - (2, 2 -Dimel:hyl -3 -nitroxypropoxy) benzYl] -piPerazine Prepared from 2- (2,2-dimethyl-3-~iLl~"Ly~L~u~y)-b~n~ hyde and piE)erazine x 2 HC1 in methanol by process variant B . Af ter the reaction solution has been cr~n<~-.n~rated, the residue was taken up in aqueous sodium carbonate solution am~ extracted with ethyl acetate. The organic phase was dried over potas3ium carbonate. The title ~ __ ' was l?recipitated as hydrochloride and recrys~ ecl from methanol/diethyl ether. M.p. of the hydrochloride: 200C (rl~ itior.).
6 . 3 - ( 2 -Nitroxyethoxy) benzYlamine Prepared from 3- (2-nitroxyethoxy)b~n~ hyde and ~llm acetate ir. ethanol by process variant C. The title _ __ ' was precipitated as hydrochloride Erom diethyl ether. N.p. oE the hydrochloride: 131.8-132.5C.
7 . N-AcetYl-N' - [2 - (2, 2 -dimethyl-3 -nitroxYProPoxY) -benzyl] PiPeraZine Prepared from N-acetylpiperazine x HC1 and 2-(2,2-dimethyl-3-~itroxy)b~n7~ Phyde in methanol by process variant A. Recrystallized as tosylate from ethyl acetate. M.p. of the tosylate: 123-126C.
8 . 2 - ( 2 -Ni troxYe thoxY ) benzYl amine Prepared from 2- (2-ni~roxyethoxy)b~n~ hyde and ;llm acetate in methanol by process variant C.
Purified by chromatography on silica gel (methanol/ethyl acetate 1:1) . The hydrochloride of the title - _~vulld was precipitated from diethyl ether. M.p. of the hydrochlo-ride: 124.1-125.7C.
9 . N- [2 - ( 2, 2 -Dimethyl - 3 -ni troxYProPoxY) benzYl ] -N'- (3-pYri~l;ner:~rh~nyl)piperazine Prepared from 2-(2,2-dimethyl-3-nit~."y~L~,yo~y)-bDn~ hydeandN- (3-pyri~1;nF~ rh~nyl)piperazine x 2 HCl R~pl~c~ t sheet (Rule 26) 2~
Wo 95/19952 - 15 - PCT/3P95/00167 in methanol by procesç~ variant A . Purif ied by chromatog-raphy on silica gel (ethyl acetate/methanol 5 :1) . The dihydrochloride of th~ title compound was recrystallized from methanol/diethyl ether. M.p. of the dihydrochloride:
127-129C.
10. N- [3- (2-NitroxYe'~hoxY)benzY1]Piperazine Prepared from 3- (2-nitroxyethoxy)b~n~ld~hyde and piperazine diacetate in methanol by process variant s.
The dihydrochloride o the title cl _ ' was recrystal-lized from methanol/diethyl ether. M.p. of the dihydro-chloride: 165-167C.
11. 1- (2-~ydroxy-3-pl.e~ .Y~ JYl) -4- [3- (2-nitroxvethYl) -- benzYl] PiPerazine Prepared from 3- (2-nitroxyethoxy)bQrl7~ hyde and N- (2-hydroxy-3-phenoxypropyl)piperazine x 2 llCl by process vari nt A. The dihydrochloride of the title c , _ ' wa3 recrystS~ l 1; ''9d from is~ ,y~ Ol. M.p. of the dihydrochloride: 167-169C.
12 . D i - ~ 2 - [ ( 4 - ni troxYme thYl [ trans ] cYclohexYl ) me thoxY] -benzYl}amine Prepared f rom 2 - [ ( 4 - ni troxymethyl [ trans] cyclo-hexyl)methoxy]~n~ hyde and ammonium acetate by process vari~nt C . Purif ied by chromatography on silica gel (ethyl acetate/'petroleum ether 60-80/1:1). M.p.
92-97C.
13 . N-DiPhenYlmethYl -N ' - [4 - ( 2 -nitroxYethoxY) benzYl] -piPerazine Prepared fro~l N-diphenylmethylpiperazine x 2 ~Cl and 4- (2-nitroxyethoxy)b~n~ hyde in methanol by 30 process variant A. Purified by chromatography on silica gel (ethyl acetate,lpetroleum ether 60-80/1:2). M.p.
127 -129C .
Replacement sheet (Rule 26) ~18~
WO 95/19952 - 16 - PCT/~3P95/00167 14 . N- [4- (2 -NitroxYethoxY) benzYl] homopiperazine Prepared from ~ - (2-nitroxyethoxy)b~n7~ hyde and homopiperazine diacetate in methanol by process variant B. The oxalate of the title c~ ,_ 1 was recrystallized 5 from methanol. M.p. ~f the oxalate: 179C (decomposi-tion) .
6 . 3 - ( 2 -Nitroxyethoxy) benzYlamine Prepared from 3- (2-nitroxyethoxy)b~n~ hyde and ~llm acetate ir. ethanol by process variant C. The title _ __ ' was precipitated as hydrochloride Erom diethyl ether. N.p. oE the hydrochloride: 131.8-132.5C.
7 . N-AcetYl-N' - [2 - (2, 2 -dimethyl-3 -nitroxYProPoxY) -benzyl] PiPeraZine Prepared from N-acetylpiperazine x HC1 and 2-(2,2-dimethyl-3-~itroxy)b~n7~ Phyde in methanol by process variant A. Recrystallized as tosylate from ethyl acetate. M.p. of the tosylate: 123-126C.
8 . 2 - ( 2 -Ni troxYe thoxY ) benzYl amine Prepared from 2- (2-ni~roxyethoxy)b~n~ hyde and ;llm acetate in methanol by process variant C.
Purified by chromatography on silica gel (methanol/ethyl acetate 1:1) . The hydrochloride of the title - _~vulld was precipitated from diethyl ether. M.p. of the hydrochlo-ride: 124.1-125.7C.
9 . N- [2 - ( 2, 2 -Dimethyl - 3 -ni troxYProPoxY) benzYl ] -N'- (3-pYri~l;ner:~rh~nyl)piperazine Prepared from 2-(2,2-dimethyl-3-nit~."y~L~,yo~y)-bDn~ hydeandN- (3-pyri~1;nF~ rh~nyl)piperazine x 2 HCl R~pl~c~ t sheet (Rule 26) 2~
Wo 95/19952 - 15 - PCT/3P95/00167 in methanol by procesç~ variant A . Purif ied by chromatog-raphy on silica gel (ethyl acetate/methanol 5 :1) . The dihydrochloride of th~ title compound was recrystallized from methanol/diethyl ether. M.p. of the dihydrochloride:
127-129C.
10. N- [3- (2-NitroxYe'~hoxY)benzY1]Piperazine Prepared from 3- (2-nitroxyethoxy)b~n~ld~hyde and piperazine diacetate in methanol by process variant s.
The dihydrochloride o the title cl _ ' was recrystal-lized from methanol/diethyl ether. M.p. of the dihydro-chloride: 165-167C.
11. 1- (2-~ydroxy-3-pl.e~ .Y~ JYl) -4- [3- (2-nitroxvethYl) -- benzYl] PiPerazine Prepared from 3- (2-nitroxyethoxy)bQrl7~ hyde and N- (2-hydroxy-3-phenoxypropyl)piperazine x 2 llCl by process vari nt A. The dihydrochloride of the title c , _ ' wa3 recrystS~ l 1; ''9d from is~ ,y~ Ol. M.p. of the dihydrochloride: 167-169C.
12 . D i - ~ 2 - [ ( 4 - ni troxYme thYl [ trans ] cYclohexYl ) me thoxY] -benzYl}amine Prepared f rom 2 - [ ( 4 - ni troxymethyl [ trans] cyclo-hexyl)methoxy]~n~ hyde and ammonium acetate by process vari~nt C . Purif ied by chromatography on silica gel (ethyl acetate/'petroleum ether 60-80/1:1). M.p.
92-97C.
13 . N-DiPhenYlmethYl -N ' - [4 - ( 2 -nitroxYethoxY) benzYl] -piPerazine Prepared fro~l N-diphenylmethylpiperazine x 2 ~Cl and 4- (2-nitroxyethoxy)b~n~ hyde in methanol by 30 process variant A. Purified by chromatography on silica gel (ethyl acetate,lpetroleum ether 60-80/1:2). M.p.
127 -129C .
Replacement sheet (Rule 26) ~18~
WO 95/19952 - 16 - PCT/~3P95/00167 14 . N- [4- (2 -NitroxYethoxY) benzYl] homopiperazine Prepared from ~ - (2-nitroxyethoxy)b~n7~ hyde and homopiperazine diacetate in methanol by process variant B. The oxalate of the title c~ ,_ 1 was recrystallized 5 from methanol. M.p. ~f the oxalate: 179C (decomposi-tion) .
15. N- [4- (2-Nitrox~rethoxY)benzYl] -N' - (2-hYdroxY-3-Ph=~ LY~ yl) -1,6-hexyl~n~ m;n~
Prepared from N- (2-hydroxy-3-phenc"~y~L~yl) -1,6-hexyl~neA;~m;n~ x 2 ~Cl and 4-(2-nitroxyethoxy)-b~n 7~ hyde in methanol by process variant A . The dihydrochloride of th~ title _ _ ' was ~ y~ ~11 i 7ed from methanol. M.p. o~ the dihydrochloride: 193-196C.
Prepared from N- (2-hydroxy-3-phenc"~y~L~yl) -1,6-hexyl~neA;~m;n~ x 2 ~Cl and 4-(2-nitroxyethoxy)-b~n 7~ hyde in methanol by process variant A . The dihydrochloride of th~ title _ _ ' was ~ y~ ~11 i 7ed from methanol. M.p. o~ the dihydrochloride: 193-196C.
16. N- [3- (2-AllYlPhenoxY) -2-hYdroxYProPyl] -N'- [4- (2-nitroxy,~thoxy)benzyl-1,8-octyl~n~ m1n~-Prepared from N- [3- (2-allylphenoxy) -2-hydroxy-propyl] -1, 8-octyl~n~ m;n and 4- (2-nitroxyethoxy) -~r n 7 ~ Phyde in methanol by process variant A. The hydrochloride of the title ~ 3 waa recrystallized from methanol/ethanol/diethyl ether m.p. of the hydro-chloride: 151.1-151. 7 C .
17. N- [3- (2-AllYlT~henoxY) -2-hydroxYpropYl] -N' - [2- (2-nitroxYethoxy)benzyl] -1, 8-octYl~ne~ m;n~-Prepared from N- [3- (2-allylphenoxy) -2-hydroxy-propyl]-1,8-octyl~nr~rl;~m;nP x 2 BCl and 2-(2-nitroxy-ethoxy) ~-~n7~ hyde in methanol by process variant A.
Purified by chromatc,graphy on silica gel (ethyl ace-tate/methanol/triethylamine 16:4:1). The oxalate of the title c _~o~n~ was recrystallized from ethanol/diethyl ether. M.p. of the oxalate: 157-158C.
Purified by chromatc,graphy on silica gel (ethyl ace-tate/methanol/triethylamine 16:4:1). The oxalate of the title c _~o~n~ was recrystallized from ethanol/diethyl ether. M.p. of the oxalate: 157-158C.
18. N- [3- (2-AllYlPhenoxY) -2-hYdroxYpropYl] -N ' - [3 - (2 -nitroxY ethoxy) benzyl] -1, 8 -octYlene~ m; ne Prepared from 3- (2-nitroxyethoxy)b~n7r~ hyde and Replacement sheet (Rule 26) -~lg~ 58~
N- [3- (2-allylphenoxy) -2-hydroxYpropyl] -1, 8-octylene-diamine x 2 ~ICl in me thanol by process variant A . The oxalate of the title c _ _ ' was recrystsl l; 7Pr~ from ethanol/diethyl ether. M.p. of the oxalate: 148-149C.
N- [3- (2-allylphenoxy) -2-hydroxYpropyl] -1, 8-octylene-diamine x 2 ~ICl in me thanol by process variant A . The oxalate of the title c _ _ ' was recrystsl l; 7Pr~ from ethanol/diethyl ether. M.p. of the oxalate: 148-149C.
19. N- (2-~Ydroxy-3-naPhthylv~y~rrvvyl) -N' - [4- (2-nitroxy-ethoxy)benzyl] -1, 4-butYlenPr~ m;n~s Prepared fro~ N- [2-hydroxy-3- (l-naphthyloxy) -propyl]-1,4-butylPn,9,ii9m;nP and 4-(2-nitroxyethoxy)-benzaldehyde in -~h 9nr1 by process Yariant A. The dihydrochloride of th~a title r _ ' was ~_Lyr~LdlliZed by is~crplv~r~l~ol. M.p. ~f the dihydrochloride 150-152C.
20. N- [3- (1-Na~hthyloxy) -2-hYdroxY~ro-vYl] -N' - [3- (2-nitroxY~thoxY)benzyl] -1,4-butYlPn~ m;ne Prepared from N- [2-hydroxy-3- (l-naphthyloxy) -propyl]-1,4-butylPns~;s~m;n~ and 3-(2-nitroxyethoxy)-bPn~ Phyde in methanol by process variant A. The dihydrochloride of thr5~ title - _ ' was ~ yDtallized from isopropanol. M.p. of the dihydrochloride: 145-147C.
21. N- [2- (10-NitroxYdecyloxY)benzYl] -1, 6-hexYl~9nPr~; 9m;n~
Prepared from 2- (lO-nitroxydecyloxy)bPn~ Phyde and 1,6-hexylPner~;~m;ne diacetate in methanol by process variant B. The dioxalate of the title - _ ~ was recrystallized from ethanol. M.p. of the dioxalate:
122 -127 C .
, t sheet (Rule 26) 8 ~
Industrial aPPlicatio3l The compounds of the ~ormula I have valuable properties which malce them capable of industrial exploi-tation. They are, in particular, highly effective 5 substances for treat:ing cardiovascular diaeases and diseases of the eye based on an increased intraocular pressure .
The ~ ~,ou--dEl of the f ormula I represent a desired enric_ment of the prior art in their excellent 10 efficacy, which is cl inF~ with a low toxicity and the absence of substantial side effects. Because of the nitrate groups in the molecule, the ~ of the - formula I are aultable in principle for preventing and treating those pathological states in humans which are known to be treatable by organic nitrates (such as, for example, glycerol tri3l~itrate, isosorbide 5-mononitrate or isosorbide dinitrate) or by ~ able to eliminate nitrogen 3i nY;~ (such as, for example, - lc~ n~).
In particular, the c __ ~c of the formula I can be u8ed to prevent and treat ; ~rhe~Tn; C heart diseases (angina pectoris, myocardial infarct), cardiac ~
sation, (pulmonary) hypertension, (c~rebral) thl ~08~R
and atheroscleroses, narrowing of (peripheral) vessels, arrhythmias, certain disorders of the gastrointestinal tract (such as, for example, ?"h~l lC;a, irritable colon) and of increased intraocular presaure. The _ ___ '~ of the ~ormula I are furth~- e distinguished by throm-boxane-~nt~nn; ~tic and antiviral activity and by ~rnn~hnap~ lytic properties.
The invention there~ore furthr ~d relates to a method for the treatment of mammals, in particular humans, suffering from one of the abovementioned disor-ders. The method is characterized in that a therapeuti-cally effective and rh~ Ql~gically acceptable amount of one or more c _ ,lc of the ~ormula I is administered to the individual with the di80rder.
The inventio3l additionally relate8 to the com-Replacement sheet (Rule 26) ~81~t Wo 95/19952 - 19 - PCT/EP95/00167 pounds of the formula I for use for treating said disor-ders .
The inventioll likewise embr~ces the use of c~ ~lq of the formllla I for producing rhArr-~eut;cals employed to control 3~id disorders.
The invention furth~ ~ relates to pharma-ceuticals which comp~i3e one or more - _ .,u--ds of the f ormula I .
The pharmaceuticals are produced by processes which are known per ~e and are fA~; l; Ar to the skilled worker. As rhA~-~eut;rAl~, the rhAr~ ol~ically active r. __ ~ oE the fol-mula I (= active substances) are employed either as s1lch or, preferably, in combination with suitable phAr~ P~tir~l AnrillAry aubstances in the ~orm of tablets, coat~d tablets, capsules, suppositories, plasters (for exampl~ as TTS), 1 ~ nCl~ 5ll~pAn~inn~, aProsol~, sprays, oiILtments, creamg, gelg or g~ t;onl~, with the active substance content advantageoualy being between 0.1 and 95%.
2 0 The An r; 1 1 A r~ substances sui table f or the re-~uired rhArrA-~eutica~ formulations are fA-n; l; Ar to the skilled worker on tlle basis of his expert knowledge.
Besides solvents, gel-formers, suppository bases, tablet-ting aids and other active substance vehicles, it is possible to use, for example, antinY; ~An~, dipersants, 1 ~; f; ers, An~; f onT~ masking flavors, preservatives, solubili~ers, colorants or, in particular, permeation promoters and - _ 1~Y; nrJ agents (for example cyclo-dextrins ) .
The active substances can be administered orally, rectally or parente~-ally (in particular perlingually, buccally, inLLc.v~ u~ly or percutAn~ol-~ly).
In general, it has proven advantageous in human medicine to administer the active substance or substances in the case of oral administration in a daily dose of about 0.01 to about 10, preferably 0.05 to 5, mg/kg of body weight, if required in the form of several, prefer-Repl Ar ~ sheet (Rule 26) ably from 1 to 4, individual doses to achieve the desired result. For parenteral treatment it is possible to use similar or (especiall~ in the case of intravenous admin-istration of the active substances) as a rule lower 5 dosages. If the dosa~e ia gradually increa3ed, a lower dose i~3 administered at the start of the treatment and then slowly changed to a higher dose . Af ter the desired result o~ treatment has been achieved, the dose is returned to a lower one.
Establ i~ t of the optimal dosage and mode of administration of th~ active aubstances which are re-guired in each case can easily be carried out by every skilled worker on the basis of his expert knowledge.
If the c _ ~q of the formula I are to be 15 employed to treat said disorders, it is also poEIsible for the rh~r~ eu~; cal preparations to comprise one or re other pharmacologically active ingr~dients from other rhAr~--~e~;cal groups, such a5 other antihypertensives, vasodilators, alpha-1 receptor blockers, alpha-2 receptor 20 stimulator~, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, diuretics, saluretics, A~ l oi~, analgesics, lipid-lowering agents, anticoagu-lants, anti~ hr~l ;n~rgics~ methylxanthineEI, anti-arrhythmics, antihi~tamines, dopamine stimulators, 25 serotonin receptor blockers etc. such as nifedipine, dihydralazine, prazosin, t~ n;rl;n~ atenolol, labetalol, fenoterol, captopril, digoxin, milrinone, mefruside, clops~m;d~, spironolactone, chlor~h ~ n~, furosemide, poly~h;~l~id~, hydroc]lloroth;~ 7; de, reserpine, dihydro-30 ergocristine, r~;nn~m;n~" rauwolfia total ~lk5.1~acetylsalicylic acid,, b~- If ~hrate~ warfarin, atropine, theophylline, 1 ;~ r~;nF~ astemizole, bL. - yyti ketanserin etc.
Replaq t sheet (Rule 26) . ~ 2~$:~5~l PharmacoloA~Y
The phArm-Aol,~gical effect of the compounds of the formula I was d~t~rmined in vivo on anesthetized rabbits and in vitro :in the so-called rat aorta test.
The percentage decrease in the arterial blood preasure and the effect on heart rate (percentage change) after infusion of th~ compounds to be investigated was det~rm;n~d on anesthel:ized rabbits.
In the rat aorta test, the relaxing effect of the 0 AI _ _ ~R to be inveRtigated wag det~; n~d on spiral strips o~ the rat p~ ry artery. By cumulative addi-tion, the do3e which i nhibits the contraction on average by 50% (= ECso) was det~rm;n~d from the Ar~nAAntration ef f ect plot .
The i~vestiga~:ed _ ~ are identified in the following tables by numbers which co~ ~ e~v~d to the numbers of the examples.
Determination of the blood pressure and of the heart rate in anesthetized rabbi ts The test wa~ carried out in analogy to the procedure described i~l the international patent applica-tion W092/04337. The result o~ the investigation is shown in Table 1.
Table 1 Percentage reduction in the arterial blood pressure (BP) and percentage change in the heart rate (~IR) in N anes-thetized rabbits (wit]l N ~ 1 averages) by administration of compounds of the formula I
~"rlA~ t sheet (Rule 26) ~ ~$~
Prepared from 2- (lO-nitroxydecyloxy)bPn~ Phyde and 1,6-hexylPner~;~m;ne diacetate in methanol by process variant B. The dioxalate of the title - _ ~ was recrystallized from ethanol. M.p. of the dioxalate:
122 -127 C .
, t sheet (Rule 26) 8 ~
Industrial aPPlicatio3l The compounds of the ~ormula I have valuable properties which malce them capable of industrial exploi-tation. They are, in particular, highly effective 5 substances for treat:ing cardiovascular diaeases and diseases of the eye based on an increased intraocular pressure .
The ~ ~,ou--dEl of the f ormula I represent a desired enric_ment of the prior art in their excellent 10 efficacy, which is cl inF~ with a low toxicity and the absence of substantial side effects. Because of the nitrate groups in the molecule, the ~ of the - formula I are aultable in principle for preventing and treating those pathological states in humans which are known to be treatable by organic nitrates (such as, for example, glycerol tri3l~itrate, isosorbide 5-mononitrate or isosorbide dinitrate) or by ~ able to eliminate nitrogen 3i nY;~ (such as, for example, - lc~ n~).
In particular, the c __ ~c of the formula I can be u8ed to prevent and treat ; ~rhe~Tn; C heart diseases (angina pectoris, myocardial infarct), cardiac ~
sation, (pulmonary) hypertension, (c~rebral) thl ~08~R
and atheroscleroses, narrowing of (peripheral) vessels, arrhythmias, certain disorders of the gastrointestinal tract (such as, for example, ?"h~l lC;a, irritable colon) and of increased intraocular presaure. The _ ___ '~ of the ~ormula I are furth~- e distinguished by throm-boxane-~nt~nn; ~tic and antiviral activity and by ~rnn~hnap~ lytic properties.
The invention there~ore furthr ~d relates to a method for the treatment of mammals, in particular humans, suffering from one of the abovementioned disor-ders. The method is characterized in that a therapeuti-cally effective and rh~ Ql~gically acceptable amount of one or more c _ ,lc of the ~ormula I is administered to the individual with the di80rder.
The inventio3l additionally relate8 to the com-Replacement sheet (Rule 26) ~81~t Wo 95/19952 - 19 - PCT/EP95/00167 pounds of the formula I for use for treating said disor-ders .
The inventioll likewise embr~ces the use of c~ ~lq of the formllla I for producing rhArr-~eut;cals employed to control 3~id disorders.
The invention furth~ ~ relates to pharma-ceuticals which comp~i3e one or more - _ .,u--ds of the f ormula I .
The pharmaceuticals are produced by processes which are known per ~e and are fA~; l; Ar to the skilled worker. As rhA~-~eut;rAl~, the rhAr~ ol~ically active r. __ ~ oE the fol-mula I (= active substances) are employed either as s1lch or, preferably, in combination with suitable phAr~ P~tir~l AnrillAry aubstances in the ~orm of tablets, coat~d tablets, capsules, suppositories, plasters (for exampl~ as TTS), 1 ~ nCl~ 5ll~pAn~inn~, aProsol~, sprays, oiILtments, creamg, gelg or g~ t;onl~, with the active substance content advantageoualy being between 0.1 and 95%.
2 0 The An r; 1 1 A r~ substances sui table f or the re-~uired rhArrA-~eutica~ formulations are fA-n; l; Ar to the skilled worker on tlle basis of his expert knowledge.
Besides solvents, gel-formers, suppository bases, tablet-ting aids and other active substance vehicles, it is possible to use, for example, antinY; ~An~, dipersants, 1 ~; f; ers, An~; f onT~ masking flavors, preservatives, solubili~ers, colorants or, in particular, permeation promoters and - _ 1~Y; nrJ agents (for example cyclo-dextrins ) .
The active substances can be administered orally, rectally or parente~-ally (in particular perlingually, buccally, inLLc.v~ u~ly or percutAn~ol-~ly).
In general, it has proven advantageous in human medicine to administer the active substance or substances in the case of oral administration in a daily dose of about 0.01 to about 10, preferably 0.05 to 5, mg/kg of body weight, if required in the form of several, prefer-Repl Ar ~ sheet (Rule 26) ably from 1 to 4, individual doses to achieve the desired result. For parenteral treatment it is possible to use similar or (especiall~ in the case of intravenous admin-istration of the active substances) as a rule lower 5 dosages. If the dosa~e ia gradually increa3ed, a lower dose i~3 administered at the start of the treatment and then slowly changed to a higher dose . Af ter the desired result o~ treatment has been achieved, the dose is returned to a lower one.
Establ i~ t of the optimal dosage and mode of administration of th~ active aubstances which are re-guired in each case can easily be carried out by every skilled worker on the basis of his expert knowledge.
If the c _ ~q of the formula I are to be 15 employed to treat said disorders, it is also poEIsible for the rh~r~ eu~; cal preparations to comprise one or re other pharmacologically active ingr~dients from other rhAr~--~e~;cal groups, such a5 other antihypertensives, vasodilators, alpha-1 receptor blockers, alpha-2 receptor 20 stimulator~, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, diuretics, saluretics, A~ l oi~, analgesics, lipid-lowering agents, anticoagu-lants, anti~ hr~l ;n~rgics~ methylxanthineEI, anti-arrhythmics, antihi~tamines, dopamine stimulators, 25 serotonin receptor blockers etc. such as nifedipine, dihydralazine, prazosin, t~ n;rl;n~ atenolol, labetalol, fenoterol, captopril, digoxin, milrinone, mefruside, clops~m;d~, spironolactone, chlor~h ~ n~, furosemide, poly~h;~l~id~, hydroc]lloroth;~ 7; de, reserpine, dihydro-30 ergocristine, r~;nn~m;n~" rauwolfia total ~lk5.1~acetylsalicylic acid,, b~- If ~hrate~ warfarin, atropine, theophylline, 1 ;~ r~;nF~ astemizole, bL. - yyti ketanserin etc.
Replaq t sheet (Rule 26) . ~ 2~$:~5~l PharmacoloA~Y
The phArm-Aol,~gical effect of the compounds of the formula I was d~t~rmined in vivo on anesthetized rabbits and in vitro :in the so-called rat aorta test.
The percentage decrease in the arterial blood preasure and the effect on heart rate (percentage change) after infusion of th~ compounds to be investigated was det~rm;n~d on anesthel:ized rabbits.
In the rat aorta test, the relaxing effect of the 0 AI _ _ ~R to be inveRtigated wag det~; n~d on spiral strips o~ the rat p~ ry artery. By cumulative addi-tion, the do3e which i nhibits the contraction on average by 50% (= ECso) was det~rm;n~d from the Ar~nAAntration ef f ect plot .
The i~vestiga~:ed _ ~ are identified in the following tables by numbers which co~ ~ e~v~d to the numbers of the examples.
Determination of the blood pressure and of the heart rate in anesthetized rabbi ts The test wa~ carried out in analogy to the procedure described i~l the international patent applica-tion W092/04337. The result o~ the investigation is shown in Table 1.
Table 1 Percentage reduction in the arterial blood pressure (BP) and percentage change in the heart rate (~IR) in N anes-thetized rabbits (wit]l N ~ 1 averages) by administration of compounds of the formula I
~"rlA~ t sheet (Rule 26) ~ ~$~
Compound % decrease 96 change N
No. BP ~IR
3 39.8 - 6.2 2 7 17.9 - 0.3 2 511 17.8 - 5.2 13 54.6 -18.4 2 Rat aorta test The test was carried out in analogy to the procedure described in the international patent applica-tion W092/04337. The result of the investigation i3 shown in Table 2.
Table 2 Y~n~ effect of compounds of the formula I on the rat aorta 15 C , ,.lld ECso Standard Variation N
No. [~M] de~riation 3 0.0055 0.0068 0.001 -0.02 6 6 0.0015 0.0012 0.0002-0.003 6 10 0 . 0067 0 . 0017 0 . 004 -0 . 009 6 20 11 0.0045 0.0026 0.0004-0.01 9 EC50 = concentration which i~hibit3 contraction by 50%
N ~ =u~b-r ~f ~t~lp~ of t ore~ te~t-d R~pl~q t sheet (Rule 26) 2~ 81 S~ T OF FORMULAE
O--At--ONO2 (I) N~
Rl O--A ~ N02 ( I I ) CHO
N~ (Rl) R2 (III) Replacement ~heet (Rule 26)
No. BP ~IR
3 39.8 - 6.2 2 7 17.9 - 0.3 2 511 17.8 - 5.2 13 54.6 -18.4 2 Rat aorta test The test was carried out in analogy to the procedure described in the international patent applica-tion W092/04337. The result of the investigation i3 shown in Table 2.
Table 2 Y~n~ effect of compounds of the formula I on the rat aorta 15 C , ,.lld ECso Standard Variation N
No. [~M] de~riation 3 0.0055 0.0068 0.001 -0.02 6 6 0.0015 0.0012 0.0002-0.003 6 10 0 . 0067 0 . 0017 0 . 004 -0 . 009 6 20 11 0.0045 0.0026 0.0004-0.01 9 EC50 = concentration which i~hibit3 contraction by 50%
N ~ =u~b-r ~f ~t~lp~ of t ore~ te~t-d R~pl~q t sheet (Rule 26) 2~ 81 S~ T OF FORMULAE
O--At--ONO2 (I) N~
Rl O--A ~ N02 ( I I ) CHO
N~ (Rl) R2 (III) Replacement ~heet (Rule 26)
Claims (8)
1. A compound of the formula I
(I) in which A1 is 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cycloalkane, and in which R1 is hydrogen, 1-7C-alkyl or 3-8C-cycloalkyl and R2 is hydrogen, 1-7C-alkyl, 3-8C-cycloalkyl or A2-Y, or in which R1 and R2 represent, together and with inclusion of the nitrogen atom to which both are bonded, an unsub-stituted or substituted 5-, 6- or 7-membered hetero-cycle which is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine and homopiperazine, where A2 is 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cycloalkane, Y is R3, NH2, 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 hydroxyl, - a substituted piperidino radical is substituted by one or two identical or different sub-stituents selected from the group consisting of Replacement sheet (Rule 26) 1-4C-alkyl, 1-4C-alkoxy and hydroxyl, - a substituted piperazino radical can be substi-tuted in position 2, 3, 5 or 6 by a 1-4C-alkyl radical and is substituted in position 4 by a substituent selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkyl-carbonyl, phenyl which is substituted by R6, R7 and R8, phenyl-1-4C-alkyl which is substituted in the phenyl radical by R6, R7 and R8, benzoyl which is substituted in the phenyl radical by R6, R7 and R8, picolinoyl, nicotinoyl, iso-nicotinoyl, benzhydryl which is, if required, substituted by halogen or 1-4C-alkyl, and the radical R4, - a substituted morpholino radical is substituted by one or two identical or different 1-4C-alkyl radicals and - a substituteld homopiperazino radical is substi-tuted in position 4 by a substituent selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, phenyl which is substituted by R6, R7 and R8, phenyl-1-4C-alkyl which is substituted in the phenyl radical by R6, R7 and R8, and benzoyl which is substituted in the phenyl radical by R6, R7 and R8, where furthermore R3 is furyl, naphthyl, tetrahydronaphthyl, phenyl which is substituted by -O-Al-ONO2, or phenyl which is substituted by R6, R7 and R8, R4 is 1-7C-alkyl or the substituent -CH2 -CH (OH) - (CH2O) p-Ar and R5 is phenyl which is substituted by R6, R7 and R8, phenyl-1-4C-alkyl which is substituted by R6, R7 and R8, if required halogen- or 1-4C-alkyl-substituted benzhydryl, dibenzo-5-7C-cycloalkanyl, dibenzocycloheptenyl or Replacement sheet (Rule 26) benzo-pyrido-5-7C-cycloalkanyl, and where in addition R6 is 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 is hydrogen or trifluoromethyl, p is the number 0 or 1, and Ar is a hydrocarbon ring system which is complete-ly or partly unsaturated, which is monocyclic (with 5 to 6) or bicyclic (with 9 to 10 ring atoms), in which 1, 2 or 3 carbon atoms can be replaced by heteroatoms from the group of nitrogen (N), oxygen (O) or sulfur (S), and which can be substituted by one or two identical or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy, 3-4C-alkenyl, 3-4C-alkenyloxy, 3-8C-cycloalkyl, 5 - 10 C - cycloalkylalkoxyalkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonylamino, carbamoyl, carbamoyl-1-4C-alkyl, halogen, hydroxyl, oxo, nitro, cyano, 1-4C-alkyl-sulfonamido, amino, mono- or di- (1-4C-alkyl) -amino, ureido, mono- or di- (1-4C-alkyl) ureido, mono- or di- (3-8C-cycloalkyl) ureido, trifluoro-methyl, 1-4C-alkoxy which is completely or partially substituted by fluorine, or 1-4C-alkoxycarbonyl, tetrahydrofurfuryloxy or morpholino, and the salts of these compounds.
(I) in which A1 is 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cycloalkane, and in which R1 is hydrogen, 1-7C-alkyl or 3-8C-cycloalkyl and R2 is hydrogen, 1-7C-alkyl, 3-8C-cycloalkyl or A2-Y, or in which R1 and R2 represent, together and with inclusion of the nitrogen atom to which both are bonded, an unsub-stituted or substituted 5-, 6- or 7-membered hetero-cycle which is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine and homopiperazine, where A2 is 1-15C-alkylene, 5-7C-cycloalkylene or di-1-4C-alkylene-5-7C-cycloalkane, Y is R3, NH2, 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 hydroxyl, - a substituted piperidino radical is substituted by one or two identical or different sub-stituents selected from the group consisting of Replacement sheet (Rule 26) 1-4C-alkyl, 1-4C-alkoxy and hydroxyl, - a substituted piperazino radical can be substi-tuted in position 2, 3, 5 or 6 by a 1-4C-alkyl radical and is substituted in position 4 by a substituent selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkyl-carbonyl, phenyl which is substituted by R6, R7 and R8, phenyl-1-4C-alkyl which is substituted in the phenyl radical by R6, R7 and R8, benzoyl which is substituted in the phenyl radical by R6, R7 and R8, picolinoyl, nicotinoyl, iso-nicotinoyl, benzhydryl which is, if required, substituted by halogen or 1-4C-alkyl, and the radical R4, - a substituted morpholino radical is substituted by one or two identical or different 1-4C-alkyl radicals and - a substituteld homopiperazino radical is substi-tuted in position 4 by a substituent selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, phenyl which is substituted by R6, R7 and R8, phenyl-1-4C-alkyl which is substituted in the phenyl radical by R6, R7 and R8, and benzoyl which is substituted in the phenyl radical by R6, R7 and R8, where furthermore R3 is furyl, naphthyl, tetrahydronaphthyl, phenyl which is substituted by -O-Al-ONO2, or phenyl which is substituted by R6, R7 and R8, R4 is 1-7C-alkyl or the substituent -CH2 -CH (OH) - (CH2O) p-Ar and R5 is phenyl which is substituted by R6, R7 and R8, phenyl-1-4C-alkyl which is substituted by R6, R7 and R8, if required halogen- or 1-4C-alkyl-substituted benzhydryl, dibenzo-5-7C-cycloalkanyl, dibenzocycloheptenyl or Replacement sheet (Rule 26) benzo-pyrido-5-7C-cycloalkanyl, and where in addition R6 is 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 is hydrogen or trifluoromethyl, p is the number 0 or 1, and Ar is a hydrocarbon ring system which is complete-ly or partly unsaturated, which is monocyclic (with 5 to 6) or bicyclic (with 9 to 10 ring atoms), in which 1, 2 or 3 carbon atoms can be replaced by heteroatoms from the group of nitrogen (N), oxygen (O) or sulfur (S), and which can be substituted by one or two identical or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy, 3-4C-alkenyl, 3-4C-alkenyloxy, 3-8C-cycloalkyl, 5 - 10 C - cycloalkylalkoxyalkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonylamino, carbamoyl, carbamoyl-1-4C-alkyl, halogen, hydroxyl, oxo, nitro, cyano, 1-4C-alkyl-sulfonamido, amino, mono- or di- (1-4C-alkyl) -amino, ureido, mono- or di- (1-4C-alkyl) ureido, mono- or di- (3-8C-cycloalkyl) ureido, trifluoro-methyl, 1-4C-alkoxy which is completely or partially substituted by fluorine, or 1-4C-alkoxycarbonyl, tetrahydrofurfuryloxy or morpholino, and the salts of these compounds.
2. A compound of the formula I as claimed in claim 1, in which A1 is 2-10C-alkylene or dimethylenecyclohexane and in which Replacement sheet (Rule 26) R1 is hydrogen and R2 is hydrogen or A2-Y, or in which R1 and R2 represent, together and with inclusion of the nitrogen atom to which both are bonded, an unsub-stituted or substituted piperazine radical, where A2 is 1-10C-alkylene, Y is R3, NH2, NH-R4 or S-R5, - a substituted piperazino radical is substituted in position 4 by a substituent selected from the group consisting oi 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, picolinoyl, nicotinoyl, isonicotinoyl, benzhydryl and the radical R4 and where furthermore R3 is phenyl or phenyl which is substituted by -O -A1 -ONO2, R4 is the substituent -CH2-CH(OH) - (CH2O)p-Ar and R5 is if required halogen- or 1-4C-alkyl-substituted benzhydryl, dibenzocycloheptanyl, dibenzocycloheptenyl or benzo-pyrido-cycloheptanyl, and where in addition p is the number 1 and Ar is phenyl, 4-(2-methoxyethoxy)phenyl, 2-allyl-phenyl, 2-chloro-5-methylphenyl, 2-allyloxy-phenyl, 2-cyclopentylphenyl, 2-cyanophenyl or 1-naphthyl, and the salts of these compounds.
3. A compound of the formula I as claimed in claim 1, in which A1 is 2-10C-alkylene or dimethylenecyclohexane, and in which R1 is hydrogen and R2 is hydrogen or A2-Y, or in which Replacement sheet (Rule 26) R1 and R2 represent, together and with inclusion of the nitrogen atom to which both are bonded, an unsub-stituted or substituted piperazine radical, where A2 is 1-10-alkylene, Y is R3, NH2, NH-R4 or S-R5, - a substituted piperazino radical is substituted in position 4 by a substituent selected from the group consisting of 1-4C-alkylcarbonyl, nicotinoyl, benzhydryl and the radical R4 and where furthermore R3 is phenyl or phenyl which is substituted by -O-A1 -ONO2, R4 is the substituent -CE2-CH(OH) - (CH2O)p-Ar and R5 is benzhydryl which is substituted by 1-4C-alkyl, or benzhydryl, dibenzocyclohep-tanyl, dibenzocycloheptenyl, or benzo-pyrido-cycloheptanyl which is substituted by chlorine, and where in addition p is the number 1 and Ar is phenyl, 2-allylphenyl, or 1-naphthyl, and the salts of these compounds.
4. A compound as claimed in claim 1, selected from the group consisting of 2- (2-nitroxyethoxy) -N- (2-phenyl-ethyl) benzylamine, N- {2- [(4-methyl-alpha-phenylbenzyl)-thio] -ethyl}-4- (2-nitroxyethoxy) -benzylamine, N- [2- (7-chloro-10, 11-dihydro-5E-benzo [4, 5] cyclohepta-[1,2b]pyridine-5-thio) -ethyl] -4- (2-nitroxyethoxy)benzyl-amine, N-{2- [(5H-dibenzo [a, d] cyclohepten-5-yl) thio] -eth-yl}-2- (2,2-dimethyl-3-nitroxypropoxy)benzylamine, N- [2 - (2, 2 -dimethyl-3-nitroxypropoxy) benzyl] piperazine, 3- (2-nitroxyethoxy)benzylamine, N-acetyl-N' - [2- (2,2-dimethyl-3-nitroxypropoxy)benzyl]piperazine, 2- (2-nitroxyethoxy)benzylamine, N- [2- (2,2-dimethyl-3 - nitroxypropoxy) bsnzyl]-N'- (3-pyridinecarbonyl)-piperazine, N- [3- (2 -nitroxyethoxy) benzyl] piperazine, 1- (2-hydroxy-3-phenoxypropyl) -4- [3- (2-nitroxyethyl) -Replacement sheet (Rule 26) benzyl] piperazine, di-{2- [(4-nitroxymethyl [trans] cyclo-hexyl) methoxy] benzyl } amine, N - diphenyl -methyl-N'- [4- (2-nitroxyethoxy) benzyl] piperazine, N- [4- (2 -nitroxyethoxy) benzyl] homopiperazine, N- [4- (2-nitroxyethoxy)benzyl] -N' - (2-hydroxy-3-phenoxy-propyl) -1,6-hexylenediamine, N- [3- (2-allylphenoxy) -2-hydroxypropyl] -N'- [4- (2-nitroxyethoxy)benzyl-1,8-octylenediamine, N- [3- (2-allylphenoxy) -2-hydroxy-propyl] -N' - [2- (2-nitroxyethoxy) benzyl] -1, 8 -octylene-diamine, N- [3- (2-allylphenoxy) -2-hydroxypropyl] -N' - [3 - (2-nitroxyethoxy) benzyl] -1, 8-octylenediamine, N- (2-hydroxy-3-naphthyloxypropyl) -N'- [4- (2-nitroxy-ethoxy)benzyl] -1,4-butylenediamine, N- [3- (1-naphthyloxy) -2-hydroxypropyl] -N' - [3- (2-nitroxyethoxy)benzyl] -1,4-butylenediamine, N- [2- (10-nitroxydecyloxy)benzyl] -1, 6 -hexylenediamine or a salt thereof.
5. A process for the preparation of the compounds of the formula I and their salts, which comprises aldehydes of the formula II
(II) in which A1 has the meaning stated in claim 1, being reacted with compounds of the formula III
NH (R1) R2 (III) which are in the form, of ammonium salts and in which R1 and R2 have the meanings stated in claim 1, in the pres-ence of sodium cyanoborohydride, and, if required, subsequently the resulting compounds being converted into the salts, or resulting salts being converted into the free compounds.
Replacement sheet (Rule 26)
(II) in which A1 has the meaning stated in claim 1, being reacted with compounds of the formula III
NH (R1) R2 (III) which are in the form, of ammonium salts and in which R1 and R2 have the meanings stated in claim 1, in the pres-ence of sodium cyanoborohydride, and, if required, subsequently the resulting compounds being converted into the salts, or resulting salts being converted into the free compounds.
Replacement sheet (Rule 26)
6. A pharmaceutical comprising one or more compounds as claimed in claim 1 together with conventional pharma-ceutical ancillary substances.
7. The use of a compounds as claimed in claim 1 for producing pharmaceuticals for preventing and/or treating cardiovascular diseases.
8. The use of a compound as claimed in claim 1 for producing pharmaceuticals for preventing and/or treating diseases of the eye based on an increased intraocular pressure.
Replacement sheet (Rule 26)
Replacement sheet (Rule 26)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH15794 | 1994-01-19 | ||
| CH157/94-2 | 1994-01-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2181581A1 true CA2181581A1 (en) | 1995-07-20 |
Family
ID=4180558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002181581A Abandoned CA2181581A1 (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 |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0740649A1 (en) |
| JP (1) | JPH09507672A (en) |
| KR (1) | KR970700646A (en) |
| CN (1) | CN1143950A (en) |
| AU (1) | AU679834B2 (en) |
| BR (1) | BR9506549A (en) |
| CA (1) | CA2181581A1 (en) |
| WO (1) | WO1995019952A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8067464B2 (en) | 2004-10-04 | 2011-11-29 | Nitromed, Inc. | Compositions and methods using apocynin compounds and nitric oxide donors |
| NZ584599A (en) | 2007-10-05 | 2012-07-27 | Acucela Inc | Alkoxy compounds for disease treatment |
| GB2455176A (en) | 2007-11-01 | 2009-06-03 | Acucela Inc | Amine derivatives useful for treating ophthalmic diseases and disorders |
| WO2011003103A2 (en) | 2009-07-02 | 2011-01-06 | Acucela, Inc. | Pharmacology of visual cycle modulators |
| CA2782248A1 (en) * | 2009-12-07 | 2011-06-16 | Cardioxyl Pharmaceuticals, Inc. | Bis-acylated hydroxylamine derivatives |
| US9447078B2 (en) | 2012-01-20 | 2016-09-20 | Acucela Inc. | Substituted heterocyclic compounds for disease treatment |
| JP6405312B2 (en) * | 2012-10-23 | 2018-10-17 | ニコックス サイエンス アイルランド | Quinone-based nitric oxide donor compounds for ophthalmology |
| LT2945621T (en) * | 2013-01-18 | 2019-01-10 | Cardioxyl Pharmaceuticals, Inc. | Pharmaceutical compositions comprising nitroxyl donors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56113748A (en) * | 1980-02-13 | 1981-09-07 | Kowa Co | Aminoethanol derivative and its preparation |
| NL8802276A (en) * | 1988-09-15 | 1990-04-02 | Cedona Pharm Bv | MEDICINAL PRODUCT WITH RELAXING EFFECT, CONTAINING A NITRATE ESTER AS ACTIVE SUBSTANCE. |
| NL9001955A (en) * | 1990-09-05 | 1992-04-01 | Cedona Pharm Bv | NEW THIAZOLIDINE DERIVATIVES. |
-
1995
- 1995-01-18 AU AU15350/95A patent/AU679834B2/en not_active Expired - Fee Related
- 1995-01-18 CA CA002181581A patent/CA2181581A1/en not_active Abandoned
- 1995-01-18 EP EP95906963A patent/EP0740649A1/en not_active Withdrawn
- 1995-01-18 JP JP7519335A patent/JPH09507672A/en active Pending
- 1995-01-18 CN CN95192048A patent/CN1143950A/en active Pending
- 1995-01-18 WO PCT/EP1995/000167 patent/WO1995019952A1/en not_active Application Discontinuation
- 1995-01-18 BR BR9506549A patent/BR9506549A/en not_active Application Discontinuation
- 1995-01-18 KR KR1019960703871A patent/KR970700646A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0740649A1 (en) | 1996-11-06 |
| KR970700646A (en) | 1997-02-12 |
| CN1143950A (en) | 1997-02-26 |
| JPH09507672A (en) | 1997-08-05 |
| AU1535095A (en) | 1995-08-08 |
| BR9506549A (en) | 1997-10-14 |
| MX9602847A (en) | 1997-12-31 |
| WO1995019952A1 (en) | 1995-07-27 |
| AU679834B2 (en) | 1997-07-10 |
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