AU679834B2 - Nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases, as well as increased intra-ocular pressure - Google Patents
Nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases, as well as increased intra-ocular pressure Download PDFInfo
- Publication number
- AU679834B2 AU679834B2 AU15350/95A AU1535095A AU679834B2 AU 679834 B2 AU679834 B2 AU 679834B2 AU 15350/95 A AU15350/95 A AU 15350/95A AU 1535095 A AU1535095 A AU 1535095A AU 679834 B2 AU679834 B2 AU 679834B2
- Authority
- AU
- Australia
- Prior art keywords
- substituted
- alkyl
- phenyl
- radical
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- 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
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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
- C07D295/084—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
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Ophthalmology & Optometry (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
WO 95/19952 PCT/EP95/00167 Nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases as well as increased intraocular pressure Area of application of the invention The invention relates to benzylamine derivatives which are used in the pharmaceutical industry for producing medicaments.
Known technical backcround Nitroxy compounds which are substituted in various ways and are said to be suitable, for example for the treatment of cardiovascular diseases are described in the prior art.
Description of the invention The invention relates to compounds of the formula I (see appended sheet of formulae), in which Al is 1-15C-alkylene, 5-7C-cycloalkylene or dil-4C-alkylene-5-7C-cycloalkane, and in which R1 is hydrogen, l-7C-alkyl or 3-8C-cycloalkyl and R2 is hydrogen, l-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 unsubstituted or substituted 6- or 7-membered heterocycle which is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine and homopiperazine, where A2 is l-15C-alkylene, 5-7C-cycloalkylene or di- 1-4C-alkylene-5-7C-cycloalkane, Y is R3, NH2, NH-R4 or a substituted pyrrolidino radical is substituted by one or two identical or different substituents selected from the group 1 Replacement sheet (Rule 26) R v
C
r I1~3LP ~S 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 different substituents selected from the group consisting of 1-4C-alkyl, l-4C-alkoxy and hydroxyl, a substituted piperazino radical can be substituted in position 2, 3, 5 or 6 by a l-4C-alkyl radical and is substituted in position 4 by a substituent selected from the group consisting of l-4C-alkyl, l-4C-alkoxycarbonyl, l-4C-alkylcarbonyl, phenyl which is substituted by R6, R7 and R8, phenyl-l-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, isonicotinoyl, 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 l-4C-alkyl radicals and a substituted homopiperazino radical is substituted in position 4 by a substituent selected from the group consisting of 1-4C-alkyl, l-4C-alkoxycarbonyl, l-4C-alkylcarbonyl, phenyl which is substituted by R6, R7 and R8, phenyll-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-ONO,, or phenyl which is substituted by R6, R7 and R8, R4 is 1-7C-alkyl or the substituent
-CH,-CH(OH)-(CH
2 O)p-Ar and 2 Replacement sheet (Rule 26) -L I I I WO 95/19952 3 WO 951995 -3-PCT/EP95/00167 is phenyl which is substituted by R6, R7 and R8, phenyl-l-4C-alkyl which is substituted by R6, R7 and RS, if required halogen- or l-4C-alkyl-substituted benzhydryl, dibenzo- 5-7C-cycloalkanyl, dibenzocycloheptenyl or -7C-cycloalkanyl, and where in addition R6' is hydrogen, l-4C-alkyl, l-4C-alkoxy, 1-4C-alkylcarboliyl, halogen, amino, mono- or di- (l-4C-alkyl)amino or nitro, R7 is hydrogen, l-4C-alkyl, 1-4C-alkoxy, halogen or ni tro, RB is hydrogen or trifluoromethyl, p is the number 0 or I, and Ar is a hydrocarbon ring system which is completely 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 oxygen or sulfur and which can be substituted by one or two identical or different substituents from the group of l-4C-alkyl, 1-4C-alkoxy, l-4C-alkylthio, l-4C-alkoxy-l-4C-alkyl, l-4C-alkoxy-1-4C-alkoxy, 3 -4C-alkenyl, 3-4C-alkenyloxy, 3 -BC-cycloalkyl, 5-1OC-cycloalkylalkoxyalkyl, 1-4C-alkylcarbonyl, l-4C-alkylcarbonylamino, carbamoyl, carbamoyl-l-4C-alkyl, halogen, hydroxyl, oxo, nitro, cyano, l-4C-alkylsufonamido, amino, mono- or di- (l-4C-alkyl) amino, ureido, mono- or di-(1-4C-alkyl)ureido, mono- or di- (3-BC-cycloalkyl)ureido, trifluoromethyl, l-4C-alkoxy which is completely or partially substituted by fluorine, or l-4C-alkoxycarbonyl, tetrahydrofurfuryloxy or morpholino, and the salts of these compounds.
3 Replacement sheet (Rule 26) WO 95/19952 4 Wa 951995 -4-PCT/EP95 /0 0167 1-lSC-Alkylene represents straight-chain or br' hed alkylene radicals with 1 to 15 carbon atoms.
Ex._y,.es which may be mentioned are the radicals methylene (-CE 2 ethylene (CH 2
CH
2 I trimethylene
-CH
2 CH, CH 2 tetramethylene (-CH 2
CH
2
CH
2
CH
2 pentamethylene (CH 2
CH
2
CH
2
CH
2
CH
2 I hexamethylene
CH
2 -(CHO, CH 2 octamethylene (CH 2
-(CHO)
6
CH
2 decamethylene (CE 2
-CH
2 tetradecamethylene -C H 2 C H 2 1 2 -C H 2 1,2-dimethylethylene 1,1-dimethylethylene I-C(CH,) 2
-CH
2 isopropylidene [-C(CE 3 2 2,2-dimethylpropylene t-CH,-C(CH,) 2
-CHI
2 2-methylpropylene [-CH 2 -CH(CH,) -CE 2 and 2 -me thyl ethylene CH, -CH I 5-7C-Cycloalkylene represents cycloalkylene radicals with 5 to 7 carbon atoms. Cyclohexylene radicals are preferred, examples which may be mentioned being the 1,2- and the 1,4-cyclohexylene radical.
Di- 1-4C-alkylene- 5-7C- cy-,loalkane represents cyclic hydrocarbons with 5 to 7 carbon atoms which are substituted by two (identical or different) alkylene radicals with 1 to 4 carbon atoms. A preferred di- 1-4C-alkylene-5-7C-cycloalkane radical is the 1, 4-dimethylenecyclohexane radical.
1-7C-alkyl represents straight-chain and branched alkyl radicals with 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, hexyl, neopentyl, isopentyl, pentyl, butyl, iso-butyl, sec-butyl, tertbutyl, propyl, isopropyl, ethyl and the methyl radical.
3-8C-Cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl radical.
1-4C-Alkyl represents straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.
1-4C-Alkoxy represents a radical which, besides 4 Replacement sheet (Rule 26) 'Ji wo 95/19952 5 PCT/EP95/00167 the oxygen atom, contains one of the abovementioned l-4C-alkyl radicals. Examples which may be mentioned are the methoxy and the ethoxy radical.
Halogen for the purpose of the present invention is bromine, chlorine and fluorine.
1-4C-Alkoxycarbonyl represents a radical which, besides the carbonyl group, contains one of the abovementioned l-4C-alkoxy radicals. Examples which may be mentioned are the methoxycarbonyl and the ethoxycarbonyl radical.
l-4C-Alkylcarbonyl represents a radical which, besides the carbonyl group, contains one of the abovementioned l-4C-alkyl radicals. An example which may be mentioned is the acetyl radical.
Dibenzo-5-7C-cycloalkanyl radicals which may be mentioned are the dibenzocyclopentyl, the dibenzocyclohexyl and, in particular, the dibenzocycloheptyl radical.
Benzo-pyrido-5-7C-cycloalkanyl radicals which may be mentioned are the benzo-pyridocyclopentyl, the benzopyridocyclohexyl and, in particular, the benzo-pyridocycloheptyl radical.
Mono- or di-(l-4C-alkyl)amino represents an amino radical which is substituted by one or two identical or different abovementioned l-4C-alkyl radicals. Examples which may be mentioned are the methylamino, the ethylamino, the dimethylamino, the diethylamino and the diisopropylamino radical.
1-4C-Alkylthio represents a radical which, besides the sulfur atom, contains one of the abovementioned l-4C-alkyl radicals. The methylthio radical is preferred.
l-4C-Alkoxy-1-4C-alkyl represents one of the abovementioned l-4C-alkyl radicals which is substituted by one of the abovementioned l-4C-alkoxy radicals.
Examples which may be mentioned are the methoxymethyl, methoxyethyl radical and the butoxyethyl radical.
l-4C-Alkoxy-l-4C-alkoxy represents one of the p *Replacement sheet (Rule 26) L n, 7 WO 95/19952 6 PCT/EP95/00167 abovementioned l-4C-alkoxy radicals which is substituted by another l-4C-alkoxy radical. An example which may be mentioned is the methoxyethoxy radical.
3-4C-Alkenyl is, for example, 2-butenyl and, in particular, allyl.
3-4C-Alkenyloxy contains, beside the oxygen atom, a 3-4C-alkenyl radical. The allyloxy radical may be mentioned as an example of a 3-4C-alkenyloxy radical.
5-10C-Cycloalkylalkoxyalkyl represents an alkoxyalkyl radical which is substituted by a cycloalkyl radical. An example which may be mentioned is the cyclopropylmethoxyethyl radical.
An example of a l-4C-alkylcarbonylamino radical which may be mentioned is the acetylamido radical
(-NH-CO-CH
3 Carbamoyl represents the radical NH,-CO-.
Carbamoyl-l-4C-alkyl represents one of the abovementioned l-4C-alkyl radicals which is substituted by carbamoyl. The carbamoylmethyl radical may be mentioned as an example of a carbamoyl-l-4C-alkyl radical.
l-4C-Alkylsulfonamido represents a sulfonamido radical to which one of the abovementioned l-4C-alkyl radicals is bonded. An example which may be mentioned is the methylsulfonamido radical.
Ureido represents the radical -NH-CO-NH,. An example of mono-l-4C-alkylureido which may be mentioned is 3-methylureido and of di-l-4C-alkylureido is 3,3-dimethylureido. Examples of mono- or di-3-8C-cycloalkylureido radicals which may be mentioned are, for example, the 3-cyclohexylureido and the 3,3-dicyclohexylureido radical.
Examples which may be mentioned of l-4C-alkoxy which is completely or partially substituted by fluorine are the 1,2,2-trifluoroethoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and, in particular, the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and the difluoromethoxy radical.
6 Replacement sheet (Rule 26) .v- ~lsrsssls I -S~galllSS WO 95/19952 7 WO 951995 -7-PCT/EP95/00167 Examples of substituted pyrrolidino radicals which may be mentioned are the 2-methylpyrrolidino, 2, 5-dimethylpyrrolidino and the 3-hydroxypyrrolidino radical.
Examples of substituted piperidino radicals which may be mentioned are the 3-hydroxypiperidino, 2-n-propylpiperidino, 5-ethyl-2-methylpiperidino, 4-n-propylpiperidino, 4,4-dimethylpiperidino, 2, 6-dimethylpiperidino, 4-hydroxypiperidino, 2-ethyl-2-methylpiperidino, 2-methylpiperidino, 2, 6-dimethylpiperidino and the 2-ethylpiperidino radical.
Examples of substituted piperazino radicals which may be mentioned are the 4-methylpiperazino, 4- (2-trif luoromethylphenyl) ethyl] piperazino, 4-phenylpiperazino, 4- (2-methylphenyl)piperazino, 4- (2,3-dimethylphenyl) piperazino, 4- (2-chlorophenyl)piperazino, 4- (2-methoxyphenyl)piperazino, 4- (2-ethoxyphenyl)piperazino, 4- (3-chlorophenyl)piperazino, 4- (4-fluorophenyl) piperazino, 4- (4-chlorophenyl)piperazino, 4- (4-methoxyphenyl)piperazino, 3-methyl-4- (4-chlorophenyl)piperazino, 3-methyl-4- (4-methoxyphenyl)piperazino, 3-methyl- 4- (4-methylphenyl)piperazino, 4- 4-dimethylphenyl) piperazino, 4-acetylpiperazino, 4- 4-dichlorophenyl) piperazino, 4- (3,4-dimethylphenyl)piperazino, 4- (3-pyridinecarbon-yl)piperazino, 3-methyl-4-phenylpiperazino, 3-methyl-4- (3-chlorophenyl)piperazino, 4-be-zylpiperazino, 4-propylpiperazino, 4- (3-methylphenyl)piperazino, 4- (3-methoxyphenyl)piperazino, 4- (4-methylphenyl)piperazino, 4- 5-dimethylphenyl) piperazino, 4-benzhydrylpiperazino, 4-n-butylpiperazino, 4-iso-butylpiperazino, 4-tvert-butylpiperazino, 4- (3-tnifluoromethylphenyl)piperazino, 4- (1-phenylethyl) piperazino, 4- (2-phenylethyl)piperazino, 4- (2-hydroxyphenyl)piperazino, 4- 4-dimethoxtyphenyl)piperazino, 4-isopropylpiperazino, 3-methyl-4- (3-methoxyphenyl) piperazino, 4- (4-hiydroxyphenyl)piperazino, 3-methyl- 4- (3-methylphenyl)piperazino, 4- (3-hydroxyphenyl) 7 Replacement sheet (Rule 26) WO 95/19952 8 WO 951995 -8-PCT/EP95/O 0167 piperazino, 4- (2,6-dinitro-4-trifluoromethylpheny.j piperazino, 4- (2-hydroxy-3-phenoxypropyl)piperazino, 4- (4-nitrophenyl)piperazino, 4- (4-acetyiphenyl)piperazino, 4-ethoxycarbonylpiperazino and the 4- (4-chlorobenzhydryl)piperazino radical.
An example of a substituted morpholino radical which may be mentioned is the 3, 5-dime thylmorpholino radical.
Examples of substituted homopiperazino radicals which may be mentioned are the 4-methyl-, the 4-ethoxycarbonyl-, the 4-acetyl-, the 4-(2-methoxyphenyl)- and the 4 -benzoylhomopiperazino radical.
Examples which may be mentioned of benzhydryl radicals which are, if requirea, substituted by halogen or l-4C-alkyl are the benzhydryl, the bis- 4,4' -fluorobeiizhyeIryl, the bis-4,4' -chlorobenzhydryl, the 4-chlorobenzhydry! and the 4-methylbenzhydryl radical.
Examples which may be mentioned of phenyl radicals which are substituted by R6, R7 and RB are the radicals 3,4-dihydroxy-, 3-hydroxy-4-methoxy-, 3,4-dimethoxy-, 2-methoxy-, 2-ethoxy-, 3-methoxy-, 4-methoxy-, 2-hydroxy-, 3-hydroxy-, 4-hydroxy-, 3,4-dihydroxy-, 4-acetyl-, 4-fluoro-, 4-chloro, 2-chloro-, 3-chloro-, 3,4-dichloro-, 3-trifluoromethyl-, 2-trifluoromethyl-, 2-methyl-, 3-methyl-, 4-methyl-, 2,3-dimethyl-, 2,4-dimethyl-, 3,4-dimethyl-, 4-nitro-, 2,6-dinitro-4-trifluoromethyland 5-chloro-2-methylaminophenyl.
Selected examples of Ar substituents which may be mentioned are the following radicals: phenyl, 4- (2-methoxyethoxy)phenyl, 2-allylphenyl, 2-acetyl-4-butyramidophenyl, 4-carbamoylmethylphenyl, 4-methylphenyl, 2-tetrahydrofurfuryloxyphenyl, 2-chloro- 2-acetyl-4- (3,3-diethylureido)phenyl, 2-cyclohexylphenyl, 4-hydroxy-3-carbamoylphenyI, 4- (2-methoxyethyl)phenyl, 2-methoxyphenyl, 4-nitrophenyl, 2 -allyloxyphenyl, 2-cyclopentylphenyl, 2 -cyanophenyl, 8 Replacement sheet (Rule 26) WO 95/19952 9 WO 951995 -9-PCT/EP9 5/00 167 4 -acetamidophenyl, 4 -hydroxyphenyl, 2- cyclopropylphenyl,.
4-methanesulfonaridophenyl, 4- cyclohexylureido) phenyl, 2-methyithiophenyl, 4-carbaxaoylphenyl, 4-cyclopropylmethoxyethylphenyl, 2,5 -dichiorophenyl, 2 -butyryl 4- fluorophenyl, 2-tr~ fluoromethyiphenyl, 2-chlorophenyl, 2-fJluorophenyl, 2-methyiphenyl, 2-acetylphenyl, 5,6,7,8-tetrahydro-2-naphthyl, 4-carbazolyl, l-naphthyl, B-dihydro-1-naphthyl, 5, 6-dihydro-l-naphthyl, 1-inden- 4-yl, 1-inden-7-yl, 2-methyl-4-indolyl, 6,7-dihydroxy- 5,6,7,8-te~rahydro-1-naphthyl, 4-indolyl, 3,4-dihydro- 3, 2-naphthyl, 2-thiazolyl, 4-morpholino-l,2,5-thiadiazol-3-yl, 7-ethyl-2-benzofuranyl, 2-acetyl-7-benzofuranyl, 5-methyl-2H-benzopyron- 8-yl, l,4-benzodioxan-5-yl, 4-indanyl and 5,6,7,8-tetrahydro- 5-oxo- l-naphthyl.
Suitable salts for the compounds of the formula I are all acid addition salts. Pa~rticular mention may be made of the pharmacologically acceptable salts olf the inorganic and organic acids customarily used in pharmaceutical technology. Pharmacologically unacceptable salts which may, for example, :De the initial products of the process for the preparation of compounds according to the invention on the industrial scale are converted by processes known to the skilled worker into pharmacologically acceptable salts. Suitable as such are watersoluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobro- -ic acid, phosphoric acid, nitric acid, sulfuric acid, aietic acid, citric acid, D-gluconic acid, benzoic acid, 2- ;4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-nanhtoic acid, the acids being employed in the preparation of the salts in a ratio of amounts which is equimolar or different 9 Replacement sheet (Rule 26) 1 C WO 95/19952 10 PCT/EP95/00167 therefrom, depending on whether the acid is mono- or polybasic and depending on which salt is required.
Compounds of the formula I which are to be emphasized are those in which Al is 2-10C-alkylene or dimethylenecyclohexane, and in which R1 R2 or R1 is hydrogen and is hydrogen or A2-Y, in which and R2 represent, together and with inclusion of the nitrogen atom to which both are bonded, an unsubstituted or substituted piperazine radical, where A2 is 1-lOC-alkylene, Y is R3, NH 2 NH-R4 or a substituted piperazino radical is substituted in position 4 by a substituent selected from the group consisting of l-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-Al-ONO,, R4 is the substituent -CH 2 -CH(OH)-(CH0O),-Ar and is if required halogen- or l-4C-alkylsubstituted benzhydryl, dibenzocycloheptanyl, dibenzocycloheptenyl or benzo-pyridocycloheptanyl, and where in addition p is the number 1 and Ar is phenyl, 4-(2-methoxyethoxy)phenyl, 2-allylphenyl, 2-chloro-5-methylphenyl, 2-allyloxyphenyl, 2-cyclopentylphenyl, 2-cyanophenyl or 1-naphthyl, and the salts of these compounds.
Compounds of the formula I which are to be Replacement sheet (Rule 26) S 'S o 7.1" M WO 95/19952 11 PCT/EP95/00167 particularly emphasized are those in which Al is 2-10C-alkylene or dimethylenecyclohexane, and in which 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 unsubstituted or substituted piperazine radical, where A2 is 1-10C-alkylene, Y is R3, NH,, NH-R4 or a substituted piperazino radical is substituted in position 4 by a substituent selected from the group consisting of l-4C-alkylcarbonyl, nicotinoyl, benzhydryl and the radical R4 and where furthermore R3 is phenyl or phenyl which is substituted by -O-Al-ONO,, R4 is the substituent -CH 2 -CH(OH)-(CHO)p-Ar and is benzhydryl which is substituted by l-4C-alkyl, or benzhydryl, dibenzocycloheptanyl, dibenzocycloheptenyl, or benzopyrido-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.
The invention furthermore relates to a process for the preparation of the compounds of the formula I and their salts. The process is characterized in that aldehydes of the formula II (see appended sheet of formulae) in which Al his the abovementioned meaning are reacted with compounds of the formula III (see appended sheet of formulae) which are in the form of ammonium salts and in which Rl and R2 have the abovementioned meanings, in the 11 ,H Replacement sheet (Rule 26) (2§ s I WO 95/19952 12 PCT/EP95/00167 presence of sodium cyanoborohydride, and, if required, subsequently the resulting compounds are converted into the salts, or resulting salts are converted into the free compounds.
The process is carried out in a manner known per se to the skilled worker, for example as 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 b for hour(s).
Examples General preparation methods Variant A mmol of the aldehyde II and 10 mmol of the amino compound III (in the form of an ammonium salt) are dissolved in a suitable solvent (such as, for example, methanol, ethanol or tetrahydrofuran), 10 mmol of sodium cyanoborohydride are added, and the mixture is stirred at RT for one h. After addition of a further 10 mmol of sodium cyanoborohydride, 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 off, dried over magnesium sulfate and concentrated. The residue is purified by chromatography and/or recrystallization.
Variant B mmol are employed in place of 10 mmol of the amino compound III (in the form of an ammonium salt).
Variant C 100 mmol are employed in place of 10 mmol of the amino compound III (in the form of an ammonium salt).
1. 2-(2-Nitroxyethoxy)-N-(2-phenylethyl)benzylamine 12 S:i^ Replacement sheet (Rule 26) i i- 4ssBIBslIP~- IP~ ~e I s-- WO 95/19952 13 WO 9/1992 3 -PCT/EP95/0 0167 Prepared from 2 (2 -ni troxyethoxy) benzaldehyde and 2-phenylethylainmonium chlcride by process variant A.
Purified by chromatography on silica gel (ethyl acetate).
The title compound was isolated as tosylate and recrystallized from diethyl ether. M.p. of the tosylate: 147-149 0
C.
2. N-{j2 -Methyl -alpha -phenylbenzyl) thiol ethyll- 4- (2-nitroxvethoxy) -benzylamine Prepared f rom. 4 (2 -nitroxyethoxy) benzaldehyde and 2 [E(4-me thyl -alpha -phenylbenzyl) thi ole th-yl~mmonium chloride in tetrahydrofuran by process variant A. Purified by chromatography on silica gel (dichloromethane).
M.p. of the hydrochloride: 98-1031C.
3. N-[2-(7-Chloro-10,11-dihydro-5H-benzo(4,5]cyclohe-pta(1, 2b],Pyridine- 5 -thio) -ethyl I- 4 -ni troxyethoxy) benzylamine Prepared from 4 (2 -ni troxyethoxy) benzaldehyde and N- [2 -chloro- 10, 11-dihydro 5-benzo 51cyc loheptax 2 HCl in tetrahydrof uran by process variant A. Purified by chromatography on silica gel (ethyl acetate/methanol Recrystallized as dihydrochloride from ethyl acetate. M.p. of the dihydrochloride: 148-151' C.
4. N-{2-Hr5H-Dibenzofa. d~cyclohepten-5-yl)thiol -ethyl}-2- (2,2-dimethyvl-3-nit-roxvpropoxy)benzylamine Prepared from 2- 2-dimethyl-3-nitroxcypropoxy) benzaldehyde and [(5H-dibenzo Ea,d] cyclohepten- -yl) thiol ethyl) amine in tetrahydrofuran by process variant A. Purified by chromatography on silica gel (ethyl acetate/petroleum ether 60-80/1:2) M.p. 97-99'C.
N- 2-Dime thyl -3 -ni troxvpropoxy) benzvyl piperazime Prepared from 2- 2-dimethyl-3-nitroxypropoxy) 13 WI Replacement sheet (Rule 26) WO 95/19952 14 PCT/EP95/00167 benzaldehyde and piperazine x 2 HC1 in methanol by process variant B. After the reaction solution has been concentrated, the residue was taken up in aqueous sodium carbonate solution and extracted with ethyl acetate. The organic phase was dried over potassium carbonate. The title compound was precipitated as hydrochloride and recrystallized from methanol/diethyl ether. M.p. of the hydrochloride: 200 0 C (decomposition).
6. 3-(2-Nitroxyethoxy)benzylamine Prepared from 3- (2-nitroxyethoxy) benzaldehyde and ammonium acetate in ethanol by process variant C. The title compound was precipitated as hydrochloride from diethyl ether. M.p. of the hydrochloride: 131.8-132.5 0
C.
7. N-Acetyl-N'-12-(2,2-dimethyl-3-nitroxypropoxy)benzyl piperazine Prepared from N-acetylpiperazine x HC1 and 2-(2,2-dimethyl-3-nitroxy)benzaldehyde in methanol by process variant A. Recrystallized as tosylate from ethyl acetate. M.p. of the tosylate: 123-126 0
C.
8. 2-(2-Nitroxyethoxy)benzylamine Prepared from 2-(2-nitroxyethoxy)benzaldehyde and ammonium acetate in methanol by process variant C.
Purified by chromatography on silica gel (methanol/ethyl acetate The hydrochloride of the title compound was precipitated from diethyl ether. M.p. of the hydrochloride: 124.1-125.7 0
C.
9. N- (2,2-Dimethyl-3-nitroxypropoxy)benzyl_- N'-(3-pyridinecarbonyl)piperazine Prepared from 2-(2,2-dimethyl-3-nitroxypropoxy)benzaldehydeandN-(3-pyridinecarbonyl)piperazine x 2 HC1 in methanol by process variant A. Purified by chromatography on silica gel (ethyl acetate/methanol The dihydrochloride of the title compound was recrystallized 14 Replacement sheet (Rule 26)
'I,
WO 95/19952 15 WO 9/1992 5 -PCT/EP95/0 0167 from methanol /diethyl ether. M.p. of the dihydrochioride: 127-129 0
C.
N- (2-Nitroxyethoxy)benzyllpiperazine Prepared f rom 3 (2 -nitroxyethoxy) benzaldehyde and piperazine diacetate in methanol by process variant B.
The dihydrochioride of the title compound was recrystallized from methanol/diethyl ether. M.p. of the dihydrochloride: 165-167 0
C.
11. 1- (2-Hvdroxv-3-phenox-oropvl) (2-nitroxyethyl)benzvll piperazine Prepared f rom 3 (2 -nitroxyethoxy) benzaldehyde and N- (2- 1 droxy-3-phenoxcypropyl)piperazine x 2 HCl by process variant A. The di-hydrochloride of the title compound was recrystallized from isopropanol. M.p. of the dihydrochloride: 167-169'C.
12. Di-{2- (4-nitroxymethyl [trans) cyclohexyl)methoxv] benzy )amine Prepared from 2- E(4-nitroxcymethyl [trans] cyclohexyl)methoxylbenzaldehyde and ammoniumn acetate by process variant C. Purified by chromatography on silica gel (ethyl acetate/petr'jleum ether 60-80/1:1). M.p.
92-97 0
C.
13. N-Diphenylmethyl-N' (2-nitroxvethoxv)benzvlj piperazine Prepared from N-diphenylmethylpiperazine x 2 HCl and 4-(2-nitroxyethoxy)benzaldehyde in methanol by process variant A. Purified by chromatography on silica gel (ethyl acetate/petroleum ether 60-80/1:2). M.p.
127-129 0
C.
14. N- (2-NitroXyethoxy)benzvl] homopiperazine Prepared from 4- (2-nitroxyethoxy)benzaldehyde and homopiperazine diacetate in methanol by process variant Replacement sheet (Rule 26) WO Q5/19952 16 WO ~51995216 -PT/EP95/00167 B. The oxalate of the title compound was recrystallized from methanol. M.p. of the oxalate: 179*C (decomposition).
N-[4-(2-Nitroxvethoxy)benzvll -N'-(2-hydroxy- 3-phenoxypropyl) 6-hexvlenediai:ine Prepared from N- (2-hydroxy-3-phenoxypropyl) 1,6-hexylenediamine x 2 HCl and 4-(2-nitroxyethoxy)benzaldehyde Ln methanol by process variant A. The dihydrochloride of the title compound was recrystallized from methanol. M.p. of the dihydrochlorid3: 193-196'C.
16. N-13-(2-Allvl-phenoxy)-2-hydroxvpropyl]- N' (2-nitroxyethoxy)be~zyl-l. 8-octylenediamine Prepared from N- (2-allylphenoxy) -2-hydroxypropyl) 8-octylenediamine and 4- (2-.iaitroxyethoxy) benzaldehyde in methanol by process variant A. The hydrochloride of the title compound was recrystallized from methanol/ ethanol /diethyl ether m.p. of the hydrochloride: 151.1-151.7*C.
17. N-[3-(2-Allylphenoxy)-2-hydroxvpropvll- NlI2(2 -nitroxvethoxv) benzvll 8-octylenediamine Prepared from N- 13- (2-a'Llylphenoxy) -2-hydroxypropyll-l,8-octylenediamine x 2 HCl and 2- (2-nitroxyethoxy)benzaldehyde in methanol by process variant A.
Purified by chromatography on silica gel (ethyl acetate/methanol/triethylamiLne 16:4:1) The oxalate of the title compound was recrystallized from ethanol/diethyl, ether. M.p. of the oxalate: 157-158*C.
18. N- (2-Al.' 1 ylphenox) -2-hydroxypropyll N' 3- (2-nitroxyethoxv)benzyll 8-octylenediamine Prepared f rom 3 (2 -nitroxyethoxy) benzaldehyde and N- (2-allylphenoxy) -2-hydroxypropyl) -1,8-octylenediamine x 2 I{Cl in methanol by process variant A. The oxalate of the title compound was recrystallized from 16 Replacement sheet (Rule 26) WO 95/19952 17 Wa 95/9952 17 -PCT/EP95 /00 167 ethanol/diethyl ether. M.p. of the oxalate: 148-149 0
C.
19. N- (2-Hydroxyv-3-naphthvloxvpropyl) A- (2-nitroxyethoxy) benzyll 4-butylenediamine Prepared from N- t2-hydroxy-3- (l-nap~hthyloxy) prolpylj -1,4-butylenediamine an 4- (2-nitroxyethoxy) benzaldehyde in methanol by process variant A. The dihydrochioride of the title compound was recrystallized by isopropanol. M.p. of the dihydrochioride 150-1520C.
N-[3-(l-Naphthvloxv)-2-hvdroxvpropylj- N' (2-nitroxyethoxv)benzvl] -1,4-butylenediamine Prepared from N- [2-hydroxy-3- (l-naphthyloxy) propyl] 4-butylenediamine and 3- (2-nitroxyethoxy) benzaldehyde in methanol by process variant A. The dihydrochloride of the title compound was recrystallized from isopropanol. M.p. of the dihydrochloride: 145-147*C.
21. N- (1O-Nitroxvdecvloxy)benzvl] 6-hexvlenediamine Prepared f rom 2 (10 -nitroxydecyloxy) benzaldehyde and 1,6-hexylenediamine diacetate in methanol by process variant B. The dioxalate of the title compound was recrystallized from ethanol. M.p. of the dioxalate: 122-127 0
C.
17 Replacement sheet (Rule 26) WO 95/19952 18 PCT/EP95/00167 Industrial application The compounds of the formula I have valuable properties which make them capable of industrial exploitation. They are, in particular, highly effective substances for treating cardiovascular diseases and diseases of the eye based on an increased intraocular pressure.
The compounds of the formula I represent a desired enrichment of the prior art in their excellent efficacy, which is combined with a low toxicity and the absence of substantial side effects. Because of the nitrate groups in the molecule, the compounds of the formula I are suitable 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 trinitrate, isosorbide 5-mononitrate or isosorbide dinitrate) or by compounds able to eliminate nitrogen monoxide (such as, for example, molsidomine).
In particular, the compounds of the formula I can be used to prevent and treat ischemic heart diseases (angina pectoris, myocardial infarct), cardiac decompensation, (pulmonary) hypertension, (cerebral) thromboses and atheroscleroses, narrowing of (peripheral) vessels, arrhythmias, certain disorders of the gastrointestinal tract (such as, for example, achalasia, irritable colon) and of increased intraocular pressure. The compounds of the formula I are furthermore distinguished by thromboxane-antagonistic and antiviral activity and by bronchospasmolytic properties.
The invention therefore furthermore relates to a method for the treatment of mammals, in particular humans, suffering from one of the abovemenrioned disorders. The method is characterized in that therapeutically effective and pharmacologically acceptable amount of one or more compounds of the formula I is administered to the individual with the disorder.
The invention additionally ielates to the com- 18 Replacement sheet (Rule 26) i,
Y
J
s BI WO 95/19952 19 PCT/EP95/00167 pounds of the formula I for use for treating said disorders.
The invention likewise embraces the use of compounds of the formula I for producing pharmaceuticals employed to control said disorders.
The invention furthermore relates to pharmaceuticals which comprise one or more compounds of the formula I.
The pharmaceuticals are produced by processes which are known per se and are familiar to the skilled worker. As pharmaceuticals, the pharmacologically active compounds of the formula I active substances) are employed either as such or, preferably, in combination with suitable pharmaceutical ancillary substances in the form of tablets, coated tablets, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions, aerosols, sprays, ointments, creams, gels or solutions, with the active substance content advantageously being between 0.1 and The ancillary substances suitable for the required pharmaceutical formulations are familiar to the skilled worker on the basis of his expert knowledge.
Besides solvents, gel-formers, suppository bases, tabletting aids and other active substance vehicles, it is possible to use, for example, antioxidants, dipersants, emulsifiers, antifoams, masking flavors, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (for example cyclodextrins).
The active substances can be administered orally, rectally or parenterally (in particular perlingually, buccally, intravenously or percutaneously).
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, prefera- 19 Replacement sheet (Rule 26)
I
WO 95/19952 20 PCT/EP95/00167 bly from 1 to 4, individual doses to achieve the desired result. For parenteral treatment it is possible to use similar or (especially in the case of intravenous administration of the active substances) as a rule lower dosages. If the dosage is gradually increased, a lower dose is administered at the start of the treatment and then slowly changed to a higher dose. After the desired result of treatment has been achieved, the dose is returned to a lower one.
Establishment of the ptimal dosage and mode of administration of the active substances which are required in each case can easily be carried out by every skilled worker on the basis of his expert knowledge.
If the compounds of the formula I are to be employed to treat said disorders, it is also possible for the pharmaceutical preparations to comprise one or more other pharmacologically active ingredients from other pharmaceutical groups, such as other antihypertensives, vasodilators, alpha-i receptor blockers, alpha-2 receptor stimulators, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dopamine stimulators, serotonin receptor blockers etc. such as nifedipine, dihydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, resperpine, dihydroergocristine, rescinnamine, rauwolfia total alkaloids, acetylsalicylic acid, bezafibrate, warfarin, atropine, theophylline, lidocaine, astemizole, bromocryptine, ketanserin etc.
Replacement sheet (Rule 26) i 'V 11 111 WO 95/19952 21 PCT/EP95/00167 Pharmacoloqy The pharmacological effect of the compounds of the formula I was determined in vivo on anesthetized rabbits and in vitro in the so-called rat aorta test.
The percentage decrease in the arterial blood pressure and the effect on heart rate (percentage change) after infusion of the compounds to be investigated was determined on anesthetized rabbits.
In the rat aorta test, the relaxing effect of the compounds to be investigated was determined on spiral strips of the rat pulmonary artery. By cumulative addition, the dose which inhibits the contract 4 .on on average by 50% EC 0 was determined from the concentrationeffect plot.
The investigated compounds are identified in the following tables by numbers which correspond to the numbers of the examples.
Determination of the blood pressure and of the heart rate in anesthetized rabbits The test was carried out in analogy to the procedure described in the international patent application W092/04337. The result of the investigation is shown in Table i.
Table 1 Percentage reduction in the arterial blood pressure (BP) and percentage change in the heart rate (HR) in N anesthetized rabbits (with N 1 averages) by administration of compounds of the formula I 21 Replacement sheet (Rule 26)
II
WO 95/19952 22 PCT/EP95/00167 Compound decrease change N No. BP HR 39.8 17.9 17.8 54.6 6.2 0.3 5.2 -18.4 Rat aorta test The test was carried out in analogy to the procedure described in the international patent application W092/04337. The result of the investigation is shown in Table 2.
Table 2 Relaxing effect of aorta compounds of the formula I on the rat Compound No.
ECS, Standard deviation Variation
I
3 0.0055 6 0.0015 .0 0.0067 .1 0.0045 0.0068 0.0012 0.0017 0.0026 0.001 -0.02 0.0002-0.003 0.004 -0.009 0.0004-0.01
EC
50 concentration which N number of strips of inhibits contraction by rat aorta tested 22 Replacement sheet (Rule 26) WO 95/19952 23 PCT/EP9 5/00 167 SHEET OF FORMULAE 2
(I)
R 2
N
00-A II
CHO
NH (RI) R2 (III) h.
~~VTO
23 Replacement sheet (Rule 26)
Claims (5)
1. Compounds of the formula I Al -ON0 2 1 R(I) N/ R1 in which Al is l-15C-alkylene, 5-7C-cycloalkylene or di- 1-4C-alkylene-5-7C-cycloalkane, and in which R1 is hydrogen, l-7C-alkyl or 3-8C-cycloalkyl and R2 is hydrogen, l-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 6- or 7-membered hetro- cycle which is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine and homopiperazine, wnere A2 is 1-15C-alkylene, 5-7C-cycloalkylene or di- 1-4C-alkylene-5-7C-cycloalkane, Y is R3, NH 2 NH-R4 or a substituted pyrrolidino radical is substituted by or.e or two identical or different substituents selected from the group consisting of l-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 24 Replacement sheet (Rule 26) !i Y L L: L- WO 95/19952 25 PCT/EP95/00167 l-4C-alkyl, l-4C-alkoxy and hydroxyl, a substituted piperazino radical can be substi- tuted in position 2, 3, 5 or 6 by a l-4C-alkyl radical and is substituted in position 4 by a substituent selected from the group consisting of l-4C-alkyl, l-4C-alkoxycarbonyl, l-4C-alkyl- carbonyl, phenyl which is subscituted by R6, R7 and R8, phenyl-l-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 l-4C-alkyl, and the radical R4, a substituted morpholino radical is substituted by one or two identical or different l-4C-alkyl radicals and a substituted homopiperazino radical is substi- tuted in position 4 by a substituent selected from the group consisting of l-4C-alkyl, 1-4C-alkoxycarbonyl, l-4C-alkylcarbonyl, phenyl which is substituted by R6, R7 and R8, phenyl- l-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-ONO, or phenyl which is substituted by R6, R7 and R8, R4 is l-7C-alkyl or the substituent -CH 2 -CH(OH)-(CH,0)p-Ar and is phenyl which is substituted by R6, R7 and R8, phenyl-l-4C-alkyl which is substituted by R6, R7 and R8, if required halogen- or l-4C-alkyl-substituted benzhydryl, dibenzo-
5-7C-cycloalkanyl, dibenzocycloheptenyl or Replacement sheet (Rule 26) II C- II WO 95/19952 26 PCT/EP95/00167 benzo-pyrido-5-7C-cycloalkanyl, aind where in addition R6 is hydrogen, l-4C-alkyl, l-4C-alkoxy, l-4C-alkylcarbonyl, halogen, amino, mono- or di- (1-4C-alkyl)amino or nitro, R7 is hydrogen, l-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 oxygen or sulfur and which can be substituted by one or two identical or different substituents from the group of l-4C-alkyl, l-4C-alkoxy, 1-4C-alkylthio, l-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy, 3 -4C-alkenyl, 3 -4C-alkenyloxy, 3 -8C-cycloalkyl, 1-4C-alkylcarbonyl, l-4C-alkylcarbonylamino, carbamoyl, carbamoyl-l-4C-alkyl, halogen, hydroxyl, oxo, nitro, cyano, l-4C-alkyl- sufonamido, amino, mono- or di-(l-4C-alkyl)- amino, ureido, mono- or diq- (-4C-alkyl)ureido, mono- or di- (3-8C-cycloalkyl)ureido, trifluoro- methyl, l-4C-alkoxy which is completely or partially substituted by fluorine, or 1 -4C-alkoxycarbonyl, tetrahydrofurfuryloxy or morpholino, and the salts of these compounds. 2. Compounds of the formula I according to claim 1, in which Al is 2-lOC-alkylene or dimethylenecyclohexane, and in which 26 Replacement sheet (Rule 26) WO 95/19952 27 PCT/EP95/00167 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, NH,, NH-R4 or a substituted piperazino radical is substituted in position 4 by a substituent selected from the group consisting of l-4C-alkoxycarbonyl, l-4C-alkylcarbonyl, picolinoyl, nicotinoyl, isonicotinoyl, benzhydryl and the radical R4 and where furthermore R3 is phenyl or phenyl which is substituted by -O-Al-ON0 2 R4 is the substituent -CH 2 -CH(OH) -(CH 2 0)-Ar and R5 is if required halogen- or l-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. Compounds of the formula I according to claim 1, in which Al is 2-10C-alkylene or dimethylenecyclohexane, and in which R1 is hydrogen and R2 is hydrogen or A2-Y, or in which 27 Replacement sheet (Rule 26) I' WO 95/19952 28 PCT/EP95/0 0167 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-lOC-alkylene, Y is R3, NH,, NH-R4 or a substituted piperazino radical is substituted in position 4 by a substituent selected from the group consisting of l-4C-alkylcarbonyl, nicotinoyl, benzhydryl and the radical R4 and where furthermore R3 is phenyl or phenyl which is substituted by -0-Al-0N0 2 1 R4 is the substituent -CH 2 -CH(OH)-(CH 2 O),-Ar and R5 is benzhydryl which is substituted by l-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 l-naphthyl, and the salts of these compounds. 4. Compound according to claim 1, selected from the group consisting of 2- (2-nitroxyet' .kxy) (2-phenyl- ethyl)benzylamine, N-{2-[(4-methyl-alpha-phenylbenzyl) thio]-ethyl}-4-(2-nitroxyethoxy)-benzylamine, N- (7-chloro-10,ll-dihydro-5H-benzo cyclohepta- (2-nitroxyethoxy)benzyl- amine, 2 (5H-dibenzo d] cyclohepten- 5-yl) thiol eth- yl}-2- (2,2-dimethyl-3-nitroxypropoxy)benzylamine, N- (2,2-dimethyl-3-nitroxypropoxy)benzyllpiperazine, 3- (2-nitroxyethoxy) benzylarnine, N-acetyl- N'I [2 2-dimethyl -3 -nitroxypropoxy) benzyll piperazine, 2- (2-nitroxyethoxy)benzylamine, N- (2,2-dimethyl- 3-nitroxypropoxy)benzyl) -N'-(3-pyridinecarbonyl)- piperazine, N- (2-nitroxyethoxy)benzyllpiperazine, 1- (2-hydroxy-3-phenoxypropyl) t3- (2-nitroxyethyl) r-I Replacement sheet (Rule 26) WO 95/19952 29 WO 95/9952 29 -PCT/EP95 /00 167 benzyllpiperazine, di-{2- 1(4-nitroxymethyl~translcyclo- hexyl) methoxy] benzyl} amine, N-diphenyl- methyl-N'-1:4-(2-nitroxyethoxy)benzyllpiperazine, N-14-(2-nitroxyethoxy)benzyllhomopiperazine, N-[14- (2-nitroxyethoxy)benzyl] -(2-hydroxy-3-phenoxy- propyl) 6-hexylenediamine, N- 13- (2-allylphenoxy) 2-hydroxypropyl] 14- (2-nitroxyethoxy)benzyl- 1,8-octylenediamine, N-[13- (2-allyiphenoxy) -2-hydroxy- propyl) E2- (2-nitroxyethoxy)benzyl) 8-octylene- diamine, N-[13- (2-allyiphenoxy) -2-hydroxypropyl] N' (2-nitrox'rethoxy)benzyl) 8-octylenediamine, N- (2-hydroxy-3-naphthyloxypropyl) 14- (2-nitroxy- ethoxy)benzyl] 4-butylenediamine, N-[13- (l-naphthyloxy) 2-hydroxypropyl]-N'-1:3-(2-nitroxyethoxy)benzyl]- 1, 4-butylenediamine, N- 12- (1Q-nitroxydecyloxy)benzyl] 1,6 -hexylenedianine or a salt thereof. Process for the preparation of the compounds of the formula I 3.nd their salts, characterized in that aldehydes of the formula II 0-Al -Q-No 2 CHO in which Al has the meaning stated in claim 1, are reacted with compounds of the formula III NH(Rl)R2(I) which are in the form of -ammonium salts and in which Rl and R2 have the meanings stated in claim 1, in the pres- ence of sodium cyanoborohydride, and, if required, subsequently the resulting compounds are converted into the salts, or resulting salts are converted into the free compounds. 29 '&-'Replacement sheet (Rule 26) WO 95/19952 30 PCT/EP95/00167
6. Pharmaceutica'. comprising one or more compounds according to claim 1 together with conventional pharma- ceutical ancillary substances.
7. Use of compounds according tc claim 1 for produc- ing pharmaceuticals for preventing and/or treating cardiovascular diseases.
8. Use of compounds according to claim 1 for produc- ing pharmaceuticals for preventing and/or treating diseases of the eye based on an increased intraocular pressure. Replacement sheet (Rule 26) M" _I~ INTERNATIONAL SEARCH REPORT I:r al Appliction No PCT/EP 95/00167 A. CLASSIFICATION OF SUBJECT MATTER IPC 6 C07C217/58 A61K31/135 C070295/096 C070295/185 C070295/088 C07D213/82 According to International Fatent Classification or to both national clasification and (PC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC 6 C07C C07D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted dunng the iternational search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where apprornate, of the relevant passages Relevant to claim No. A WO,A,92 04337 (CEDONA PHARMACEUTICALS) 19 1,6-8 March 1992 see page 2, line 1 page 4, line claims; examples A EP,A,0 034 461 (KOWA CO.) 26 August 1981 1,6-8 see page 10, line 34 page 11, line 7; claims; examples A EP,A,O 359 335 (CEDONA PHARMACEUTICALS) 21 1,6-8 March 1990 see page 2, line 3 line 6; claims; examples Further documents are listed in the continuation of box C. M Patent family members are listed in annex. Special categories of cited documents later document published after the international filing date Sdoc entenral the art which is not or priority date and not in conflict with the application but A document dening the general state of the art whch s not cited to understand the principle or theory underyivng the considered to he of particular relevance invention earlier document but published on or after the internatonal document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on prionty claim(s) or involve an nventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the nternational filing date but in the art. later than the priority date claimed document member of "ie same patent family Date of the actual completion of the International search Date of mailing of the intemational serch report 27 April 1995 05. Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL- 2280 IIV Rilswlk Tel. 31-70) 340.2040, Tx. 31 651 epo nl, S ufert G Fax: (t 31-70) 340.3016e er Form PCT/ISA/210 (second sheet) (July 1992) ~IIP I -1 l1~e11~1 Y~aeC INTERNATIONAL SEARCH REPORT intei ial Application No .aformation on patent famiuly memberi PCT/EP 95/00167 Patent document __Publication Patent famrily Publication cited in search report d ae Tmember(s) date WO-A-9204337 19-03-92 NL-A- 9001955 01-04-92 AU-B- 656146 C-019 AU-A- 8400691 30-03-92 EP-A- 0547104 23-06-93 .JP-T- 6500318 13-01-94 NZ-A- 239649 27-04-94 US-A- 5385922 31-01-095 EP-A-0034461 26-08-81 1 JP-C- 1362893 09-02-87 JP-A- 56113748 07-09-81 JP-B- 61030652 15-07-86 AT-T- 3543 15-06-83 AU-A- 6698681 20-08-81 CA-A- 1157474 22-11-83 US-A- 4374840 22-02-83 US-A- 4482562 13-11-84 EP-A-0359335 21-03-90 NL-A- 8802276 02-04-90 AU-B- 638413 01-07-93 AU-A- 4133089 22-03-90 JP-A- 2134316 23-05-90 US-A- 5049694 17-09-91 Form PCTIISA/210 (patent family annex) (July 1992)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH15794 | 1994-01-19 | ||
| CH157/94 | 1994-01-19 | ||
| PCT/EP1995/000167 WO1995019952A1 (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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1535095A AU1535095A (en) | 1995-08-08 |
| AU679834B2 true AU679834B2 (en) | 1997-07-10 |
Family
ID=4180558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU15350/95A Expired - Fee Related AU679834B2 (en) | 1994-01-19 | 1995-01-18 | Nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases, as well as increased intra-ocular pressure |
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 |
| ES2615389T3 (en) | 2007-10-05 | 2017-06-06 | Acucela, Inc. | Alkoxyphenylpropylamines for the treatment of age-related macular degeneration |
| JP5592265B2 (en) | 2007-11-01 | 2014-09-17 | アキュセラ インコーポレイテッド | Amine derivative compounds for the treatment of eye diseases and disorders |
| WO2011003103A2 (en) | 2009-07-02 | 2011-01-06 | Acucela, Inc. | Pharmacology of visual cycle modulators |
| AU2010328230B2 (en) * | 2009-12-07 | 2016-06-02 | Cardioxyl Pharmaceuticals, Inc. | Bis-acylated hydroxylamine derivatives |
| WO2013109991A1 (en) | 2012-01-20 | 2013-07-25 | 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 |
| EP2945620B1 (en) * | 2013-01-18 | 2017-11-22 | Cardioxyl Pharmaceuticals, Inc. | Nitroxyl donors with improved therapeutic index |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0034461A1 (en) * | 1980-02-13 | 1981-08-26 | Kowa Company, Ltd. | Aromatic aminoethanol compounds and salts thereof, pharmaceutical compositions comprising them and processes for their production |
| EP0359335A2 (en) * | 1988-09-15 | 1990-03-21 | Cedona Pharmaceuticals B.V. | Pharmaceutical composition having relaxing activity which contains a nitrate ester as active substance |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 WO PCT/EP1995/000167 patent/WO1995019952A1/en not_active Application Discontinuation
- 1995-01-18 CA CA002181581A patent/CA2181581A1/en not_active Abandoned
- 1995-01-18 CN CN95192048A patent/CN1143950A/en active Pending
- 1995-01-18 BR BR9506549A patent/BR9506549A/en not_active Application Discontinuation
- 1995-01-18 KR KR1019960703871A patent/KR970700646A/en not_active Application Discontinuation
- 1995-01-18 JP JP7519335A patent/JPH09507672A/en active Pending
- 1995-01-18 EP EP95906963A patent/EP0740649A1/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0034461A1 (en) * | 1980-02-13 | 1981-08-26 | Kowa Company, Ltd. | Aromatic aminoethanol compounds and salts thereof, pharmaceutical compositions comprising them and processes for their production |
| EP0359335A2 (en) * | 1988-09-15 | 1990-03-21 | Cedona Pharmaceuticals B.V. | Pharmaceutical composition having relaxing activity which contains a nitrate ester as active substance |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9506549A (en) | 1997-10-14 |
| EP0740649A1 (en) | 1996-11-06 |
| CN1143950A (en) | 1997-02-26 |
| MX9602847A (en) | 1997-12-31 |
| KR970700646A (en) | 1997-02-12 |
| JPH09507672A (en) | 1997-08-05 |
| CA2181581A1 (en) | 1995-07-20 |
| AU1535095A (en) | 1995-08-08 |
| WO1995019952A1 (en) | 1995-07-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6391881B2 (en) | Thiourea derivatives of dihydropyridine NPY antagonists | |
| US4466972A (en) | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them | |
| Boido et al. | Synthesis and preliminary pharmacological evaluation of some cytisine derivatives | |
| US5246935A (en) | Piperazinyl derivatives and methods of treating central nervous system ailments relating to the 5-ht2 receptor system | |
| US4755512A (en) | Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinylalkyl moities | |
| US5238936A (en) | Trisubstituted triazines | |
| AU679834B2 (en) | Nitroxy group-containing benzylamine derivatives and their use for treating cardiovascular diseases, as well as increased intra-ocular pressure | |
| JP2502343B2 (en) | A pharmaceutically active substituted benzamide | |
| US4539322A (en) | Dihydropyridine derivatives and their use in treating heart conditions and hypertension | |
| Klayman et al. | 2-Acetylpyridine thiosemicarbazones. 8. Derivatives of 1-acetylisoquinoline as potential antimalarial agents | |
| IE51551B1 (en) | Isoquinoline derivatives,process for their preparation and pharmaceutical formulations containing them and their use | |
| Malawska et al. | Synthesis, antiarrhythmic, and antihypertensive effects of novel 1-substituted pyrrolidin-2-one and pyrrolidine derivatives with adrenolytic activity | |
| AU4473397A (en) | Novel terephthalamide derivatives | |
| US5543422A (en) | Heterocyclic amines | |
| JPH10501550A (en) | 2-mercaptobenzimidazole derivatives having pharmacological activity | |
| US4895846A (en) | Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinylalkyl moieties | |
| BG63336B1 (en) | New derivatives of hydrosamic acid, pharmaceutical compositions based on them and method for their preparation | |
| JP2002503724A (en) | Novel substituted pyridinoarylpiperazines useful for the treatment of benign prostatic hyperplasia | |
| US4118494A (en) | Substituted 3,4-dihydro-2H-isoquinolin-1-thiones | |
| JPS5927880A (en) | Heterocyclic derivatives, manufacture and medicinal composition | |
| KATO et al. | Novel Benzamides as Selective and Potent Gastrokinetic Agents. III. Synthesis and Structure-Activity Relationships of 4-amino-5-chloro-2-methoxy-and 2-Ethoxy-N-[(4-substituted 2-morpholinyl) methyl]-benzamides | |
| KR20000005465A (en) | N-aminoalkyl-2-anthraquinonecarboxamides; novel dopamine receptors subtype specific ligands | |
| KR100307845B1 (en) | Novel n-aminoalkyl-1-biphenylenyl-2-carboxamides; new dopamine receptor subtype specific ligands | |
| US4808603A (en) | 3,5-diacyl-2,6-dialkyl-4-aryl-1,4-dihydropyridines, their use, and pharmaceutical compositions thereof | |
| US6432946B1 (en) | 3-aminoalkylamino-2H-1,4-benzoxazines and 3-aminoalkylamino-2H-1,4-benzothiazines: dopamine receptor subtype specific ligands |