EP0670833A1 - Nitroxy compounds with pharmaceutical properties - Google Patents

Nitroxy compounds with pharmaceutical properties

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Publication number
EP0670833A1
EP0670833A1 EP94901849A EP94901849A EP0670833A1 EP 0670833 A1 EP0670833 A1 EP 0670833A1 EP 94901849 A EP94901849 A EP 94901849A EP 94901849 A EP94901849 A EP 94901849A EP 0670833 A1 EP0670833 A1 EP 0670833A1
Authority
EP
European Patent Office
Prior art keywords
coumarin
compounds
formula
alkyl
nitroxyethoxy
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.)
Withdrawn
Application number
EP94901849A
Other languages
German (de)
French (fr)
Inventor
Mark A. Broekhoven
Jan Bron
Astrid H. M. Van Loenen
Geert Jan Sterk
Hendrik Timmerman
Meta E. J. Veerman
Jan Fetze Van Der Werf
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
IOVIS BIOMEDICAL AND PHARMACEUTICAL CONSULTANTS
Original Assignee
IOVIS BIOMEDICAL AND PHARMACEUTICAL CONSULTANTS
BYK Nederland BV
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Publication of EP0670833A1 publication Critical patent/EP0670833A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
    • C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7

Definitions

  • the invention relates to nitroxy compounds used in the pharmaceutical industry for the manufacture of medicaments.
  • the invention relates to compounds of the formula I (see attached
  • Rl represents the substituent -Y- (CH 2 ) m -A- (CH 2 ) n -0-N0 2 ,
  • R2 represents hydrogen, 1-4C-alkyl or the substituents -Y- (CH,) -A- (CH) -0-N0 “Z'm Z'n Z,
  • R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl-1-4C-alkyl , Carboxyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, phenyl, phenyl-1-4C-alkyl, phenyl-1-4C-alkoxy, halogen, trifluoromethyl or cyan and
  • R4 is hydrogen or 1-4C-alkyl, where in the substituent -Y- (CH 2 ) -A- (CH 2 ) -O-NC
  • n each the number 0 and A 2-12C-alkylene, or
  • - m and n each represent the number 2 and A 0 (oxygen) or 0-CH 2 -CH 2 -0 (ethylenedioxy).
  • 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially methyl est.
  • 1-4C-alkoxy radicals contain one of the 1-4C-alkyl radicals mentioned above. The methoxy radical is preferred.
  • 1-4C-Alkoxy-1-4C-alkyl represents 1-4C-alkyl radicals which are substituted by 1-4C-alkoxy radicals.
  • the methoxymethyl (CH- j OCH «-) and the methoxyethyl (CH 3 0CH 2 CH 2 -) may be mentioned.
  • 1-4C-Alkylcarbonyl stands for a carbonyl group to which one of the 1-4C-alkyl radicals mentioned above is bound.
  • the acetyl residue (CH-.C0-) may be mentioned.
  • 1-4C-alkylcarbonyloxy radicals contain one of the 1-4C-alkylcarbonyl radicals mentioned above.
  • the acetoxy residue (CH 3 C0-0-) may be mentioned.
  • 1-4C-Alkylcarbonyl-1-4C-alkyl represents 1-4C-alkyl radicals which are substituted by 1-4C-A1-alkylcarbonyl radicals.
  • the 2-0xopropyl- (CH 3 COCH 2 -) and the 3-0xobutyl (CH.-COCH 2 CH 2 -) may be mentioned.
  • Carboxy-1-4C-alkyl represents 1-4C-alkyl radicals which are substituted by the carboxyl group.
  • the carboxymethyl radical (-CH 2 C00H) may be mentioned.
  • 1-4C-Alkoxycarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached.
  • the methoxycarbonyl (CH - 0-C0-) and the ethoxycarbonyl (CH 3 CH 2 0-C0-) are mentioned.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • 2-12C-Alkylene stands for straight-chain or branched alkylene radicals with 2 to 12 carbon atoms. Examples are ethylene (-CH ⁇ CH «-), trimethylene (-CH 2 CH 2 CH 2 -), tetramethylene (-CH 2 CH 2 CH 2 CH 2 -), pentaethylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexamethylene (-CH 2 - (CH 2 ) 4 -CH 2 -), octamethylene (-CH 2 - (CH 2 ) 6 -CH 2 -), decamethylene (-CH 2 - (CH 2 ) g-CH 2 -), dodecamethylene (-CH 2 - (CH 2 ) 10 -CH 2 -), 1,2-dimethylethylene [-CH (CH 3 ) -CH (CH 3 ) -], 1,1-dimethylethylene [-C (CH 3 ) 2 -CH 2 -], isopropylidene [-C (CH 3 ) 2
  • the 1,2- and in particular the 1,4-cyclohexylene radical may be mentioned.
  • the substituents can be in the ice or trans position to one another.
  • the invention encompasses both the ice and trans compounds and all conceivable cis / trans mixtures.
  • Rl represents the substituent -Y- (CH 2 ) m -A- (CH 2 ) n -0-N0 2 ,
  • R2 represents hydrogen or 1-4C-alkyl
  • R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, halogen or trifluoromethyl and R4 is hydrogen or 1-4C-alkyl, where in the substituent -Y- (CH 2 ) rr) -A- (CH 2 ) -0-N0 2
  • n each represent the number 2 and A 0 (oxygen) or O-Ü -Ü -O (ethylenedioxy).
  • the compounds according to the invention are prepared in a manner known per se, for example by
  • the nitration according to process variant a) is carried out in a manner known per se using nitric acid in an inert solvent (such as ethyl acetate or glacial acetic acid) or without a solvent, if desired in the presence of a water-binding or water-releasing medium (such as acetic anhydride), for example in Temperatures between -20 ° C and + 50 ° C, preferably at room temperature.
  • an inert solvent such as ethyl acetate or glacial acetic acid
  • a water-binding or water-releasing medium such as acetic anhydride
  • 4- Toluenesulfonic acid or in the presence of an auxiliary base (eg triethylamine) if Z represents a leaving group, for example a halogen atom (especially chlorine).
  • an auxiliary base eg triethylamine
  • halogenation according to process variant d which is preferably carried out as chlorination or bromination, also takes place in a manner known per se in an inert solvent, e.g. in dichloromethane.
  • R 1 and optionally R 2 represent the substituent -Y- (CH 2 ) -A- (CH 2 ) -OH are known or they can be prepared according to standard reactions known to the person skilled in the art (for example as described in the following examples are explained).
  • Example AI Analogously to Example AI, the title compound of mp. 141.3-145.2 ° C. is obtained from 7-hydroxy-4-methylcoumarin and ethylene carbonate.
  • Example AI Analogously to Example AI, the title compound of mp. 85.0-89.2 ° C. is obtained from 7-hydroxycoumarin and ethylene carbonate.
  • Example AI Analogously to Example AI, the title compound of mp 128.1-131.8 ⁇ C is obtained from 7-hydroxy-3,4,8-trimethylcoumarin and ethylene carbonate.
  • Example AI Analogously to Example AI, the title compound is obtained from 7-hydroxy-4-trifluoromethylcoumarin and ethylene carbonate. A6. 7- (2-Hydro ⁇ yetho ⁇ y) -4-methoxymethy1coumarin
  • Example AI Analogously to Example AI, the title compound is obtained from 7-hydroxy-4-methoxyethylcoumarin and ethylene carbonate.
  • Example A8 Analogously to Example A8, the title compound of mp 54-57 ⁇ C is obtained from 4-hydroxycoumarin and 2- [2- (2-chloroethoxy) ethoxy] ethanol.
  • Example A8 Analogously to Example A8 is obtained at a reaction temperature of 80 C ⁇ , Lö ⁇ solution of the residue in water, extraction with ethyl acetate and after Chroma ⁇ the title compound chromatography of 4-hydroxycoumarin and 6-bromo-l-hexanol.
  • Example A8 Analogously to Example A8, the title compound of mp 91-92'C is obtained from 7-hydroxy-4-methylcoumarin and 2- (2-chloroethoxy) ethanol.
  • Example A8 Analogously to Example A8, the title compound is obtained from 7-hydroxy-4-methyl-coumarin and 4-bromomethyl [trans] cyclohexylmethanol.
  • the compounds of the formula I have valuable properties which make them commercially viable. In particular, they represent highly effective active substances for the treatment of cardiovascular diseases and diseases of the eye which are based on increased intraocular pressure.
  • the compounds of the formula I represent a desired enrichment of the prior art. Because of the nitrate groups in the molecule, the compounds of the formula I are in principle suitable for prevention and treatment of such disease states in humans for which it is known that they can be treated by organic nitrates (such as, for example, glycerol trinitrate, isosorbide-5-mononitrate or isosorbide dinitrate) or by compounds which can release nitrogen monoxide (such as, for example, molsidomine) .
  • organic nitrates such as, for example, glycerol trinitrate, isosorbide-5-mononitrate or isosorbide dinitrate
  • nitrogen monoxide such as, for example, molsidomine
  • the compounds of formula I can be used for the prevention and treatment of ischemic heart diseases (angina pectoris, heart attack), cardiac compensation disorders, (pulmonary) hypertension, (cerebral) thrombosis and atherosclerosis, (peripheral) vasoconstrictions, arrhythmias, certain disorders of the Gastrointestinal tract (such as achalasia, irritable bowel syndrome) and increased intraocular pressure.
  • ischemic heart diseases angina pectoris, heart attack
  • cardiac compensation disorders pulmonary hypertension
  • (cerebral) thrombosis and atherosclerosis peripheral vasoconstrictions
  • arrhythmias certain disorders of the Gastrointestinal tract (such as achalasia, irritable bowel syndrome) and increased intraocular pressure.
  • the compounds of the formula I are notable for thromboxane-antagonistic and antiviral activity and for bronchospasmolytic properties.
  • Another object of the invention is therefore a method for the treatment of mammals, in particular humans, who are suffering from one of the abovementioned diseases.
  • the method is characterized in that the diseased individual is administered a therapeutically effective and pharmaceutically compatible amount of one or more compounds of the formula I.
  • the invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.
  • the invention also encompasses the use of compounds of the formula I in the production of medicaments which are used to combat the diseases mentioned.
  • the invention further relates to medicaments which contain one or more compounds of the formula I.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents gel formers, suppository bases, tablet auxiliaries and other active ingredient carriers
  • antioxidants dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).
  • the active substances can be administered orally, rectally or parenterally (in particular perlingual, buccal, intravenously or percutaneously).
  • the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 10, preferably 0.05 to 5 mg / kg body weight, if desired in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
  • similar or generally lower doses in particular when the active compounds are administered intravenously
  • the dosage creeps in, a lower dose is administered at the beginning of the treatment and then slowly switched to a higher dose. After If the desired therapeutic success is achieved, the dose is reduced again.
  • the pharmaceutical preparations can also contain one or more other pharmacologically active constituents of other groups of medicaments, such as other antihypertensives, vasodilators, alpha-1 receptor blockers, alpha- 2-receptor stimulators, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dopamine blockers etc.
  • other antihypertensives such as other antihypertensives, vasodilators, alpha-1 receptor blockers, alpha- 2-receptor stimulators, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dopamine block
  • nifedipine such as nifedipine, dihydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, resperinistin, ralphinamine-resinpin-rinpine, rinhydroinamine-dihydroerginamine-dihydroergamine-dihydroergamine-dihydroergamine-dihydroinamine-dihydroergamine-dihydroergamine-dihydroergamine-dihydroergamine-dihydroergamine-dihydroerginamine, dihydroergamine-dihydroerginamine, dihydroergamine, dihydroerginamine, di
  • the pharmacological activity of the compounds of the formula I was determined in vivo on anesthetized rabbits and in vitro in the so-called rat aortic test.

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Abstract

The invention concerns compounds of formula (I), in which R1, R2, R3 and R4 are as defined in the description. Such compounds are suitable for use in the treatment of cardiovascular conditions as well as the treatment of high eye pressure.

Description

N1troxyverb1ndungen mit pharmazeutischen EigenschaftenNitroxy compounds with pharmaceutical properties
Anwendungsgebiet der ErfindungField of application of the invention
Die Erfindung betrifft Nitroxyverbindungen, die in der pharmazeutischen Industrie für die Herstellung von Medikamenten verwendet werden.The invention relates to nitroxy compounds used in the pharmaceutical industry for the manufacture of medicaments.
Beschreibung der ErfindungDescription of the invention
Gegenstand der Erfindung sind Verbindungen der Formel I (siehe beiliegendesThe invention relates to compounds of the formula I (see attached
Formelblatt), in der für jeden der Substituenten Rl, R2, R3 und R4 gilt, daß er an jedes gewünschte Kohlenstoffatom in den Positionen 3, 4, 5, 6, 7 oder 8 im Cumarinring gebunden sein kann, und worinFormula sheet) in which each of the substituents R1, R2, R3 and R4 applies that it can be bonded to any desired carbon atom in positions 3, 4, 5, 6, 7 or 8 in the coumarin ring, and in which
Rl den Substituenten -Y-(CH2)m-A-(CH2)n-0-N02 darstellt,Rl represents the substituent -Y- (CH 2 ) m -A- (CH 2 ) n -0-N0 2 ,
R2 Wasserstoff, 1-4C-Alkyl oder den Substituenten -Y-(CH,) -A-(CH ) -0-N0„ Z'm Z'n Z darstellt,R2 represents hydrogen, 1-4C-alkyl or the substituents -Y- (CH,) -A- (CH) -0-N0 “Z'm Z'n Z,
R3 Wasserstoff, 1-4C-Alkyl, l-4C-Alkoxy, l-4C-Alkoxy-l-4C-alkyl , l-4C-Alkylcarbonyl , l-4C-Alkylcarbonyloxy, l-4C-Alkylcarbonyl-l-4C-alkyl, Carboxyl , Carboxy-l-4C-alkyl, l-4C-Alkoxycarbonyl, Phenyl , Phenyl-l-4C-alkyl , Phenyl-l-4C-alkoxy, Halogen, Trif1uormethyl oder Cyan bedeutet undR3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl-1-4C-alkyl , Carboxyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, phenyl, phenyl-1-4C-alkyl, phenyl-1-4C-alkoxy, halogen, trifluoromethyl or cyan and
R4 Wasserstoff oder 1-4C-Alkyl bedeutet, wobei im Substituenten -Y-(CH2) -A-(CH2) -O-NCR4 is hydrogen or 1-4C-alkyl, where in the substituent -Y- (CH 2 ) -A- (CH 2 ) -O-NC
- Y 0 (Sauerstoff), CO-0 (Carbonyloxy) oder CO-NH (Carbonylamino) be¬ deutet und- Y 0 (oxygen), CO-0 (carbonyloxy) or CO-NH (carbonylamino) means and
- und n jeweils die Zahl 0 und A 2-12C-Alkylen, oder- and n each the number 0 and A 2-12C-alkylene, or
- m und n jeweils die Zahl 1 und A Cyclohexylen, oder- m and n each the number 1 and A cyclohexylene, or
- m und n jeweils die Zahl 2 und A 0 (Sauerstoff) oder 0-CH2-CH2-0 (Ethylendioxy) bedeuten.- m and n each represent the number 2 and A 0 (oxygen) or 0-CH 2 -CH 2 -0 (ethylenedioxy).
1-4C-Alkyl steht für geradkettige oder verzweigte Alkylreste mit 1 bis 4 Kohlenstoffatomen. Beispielsweise seien genannt der Butyl-, iso-Butyl-, sec.-Butyl-, tert.-Butyl-, Propyl-, Isopropyl-, Ethyl- und insbesondere der Methyl est. l-4C-Alkoxyreste enthalten neben dem Sauerstoffatom einen der vorstehend genannten 1-4C-Alkylreste. Bevorzugt ist der Methoxyrest.1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially methyl est. In addition to the oxygen atom, 1-4C-alkoxy radicals contain one of the 1-4C-alkyl radicals mentioned above. The methoxy radical is preferred.
l-4C-Alkoxy-l-4C-alkyl steht für 1-4C-Alkylreste, die durch l-4C-Alkoxy- reste substituiert sind. Beispielsweise seien der Methoxymethyl- (CH-jOCH«-) und der Methoxyethylrest (CH30CH2CH2-) genannt.1-4C-Alkoxy-1-4C-alkyl represents 1-4C-alkyl radicals which are substituted by 1-4C-alkoxy radicals. For example, the methoxymethyl (CH- j OCH «-) and the methoxyethyl (CH 3 0CH 2 CH 2 -) may be mentioned.
l-4C-Alkylcarbonyl steht für eine Carbonylgruppe, an die einer der vorste¬ hend genannten 1-4C-Alkylreste gebunden ist. Beispielsweise sei der Acetyl- rest (CH-.C0-) genannt.1-4C-Alkylcarbonyl stands for a carbonyl group to which one of the 1-4C-alkyl radicals mentioned above is bound. For example, the acetyl residue (CH-.C0-) may be mentioned.
l-4C-Alkylcarbonyloxyreste enthalten neben dem Sauerstoffatom einen der vorstehend genannten l-4C-Alkylcarbonylreste. Beispielsweise sei der Acet- oxyrest (CH3C0-0-) genannt.In addition to the oxygen atom, 1-4C-alkylcarbonyloxy radicals contain one of the 1-4C-alkylcarbonyl radicals mentioned above. For example, the acetoxy residue (CH 3 C0-0-) may be mentioned.
l-4C-Alkylcarbonyl-l-4C-alkyl steht für 1-4C-Alkylreste, die durch 1-4C-A1- kylcarbonylreste substituiert sind. Beispielsweise seien der 2-0xopropyl- (CH3C0CH2-) und der 3-0xobutylrest (CH.-COCH2CH2-) genannt.1-4C-Alkylcarbonyl-1-4C-alkyl represents 1-4C-alkyl radicals which are substituted by 1-4C-A1-alkylcarbonyl radicals. For example, the 2-0xopropyl- (CH 3 COCH 2 -) and the 3-0xobutyl (CH.-COCH 2 CH 2 -) may be mentioned.
Carboxy-l-4C-alkyl steht für 1-4C-Alkylreste, die durch die Carboxylgruppe substituiert sind. Beispielsweise sei der Carboxymethylrest (-CH2C00H) ge¬ nannt.Carboxy-1-4C-alkyl represents 1-4C-alkyl radicals which are substituted by the carboxyl group. For example, the carboxymethyl radical (-CH 2 C00H) may be mentioned.
l-4C-Alkoxycarbonyl steht für eine Carbonylgruppe, an die einer der vor¬ stehend genannten l-4C-Alkoxyreste gebunden ist. Beispielsweise seien der Methoxycarbonyl- (CH--0-C0-) und der Ethoxycarbonylrest (CH3CH20-C0-) ge¬ nannt.1-4C-Alkoxycarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached. For example, the methoxycarbonyl (CH - 0-C0-) and the ethoxycarbonyl (CH 3 CH 2 0-C0-) are mentioned.
Halogen im Sinne der vorliegenden Erfindung ist Brom, Chlor und Fluor.Halogen in the sense of the present invention is bromine, chlorine and fluorine.
2-12C-Alkylen steht für geradkettige oder verzweigte Alkylenreste mit 2 bis 12 Kohlenstoffatomen. Beispielsweise seien die Reste Ethylen (-CH^CH«-), Trimethylen (-CH2CH2CH2-), Tetramethylen (-CH2CH2CH2CH2-), Penta ethylen (-CH2CH2CH2CH2CH2-), Hexamethylen (-CH2-(CH2)4-CH2-), Octamethylen (-CH2-(CH2)6-CH2-), Decamethylen (-CH2-(CH2)g-CH2-), Dodecamethylen (-CH2-(CH2)10-CH2-), 1,2-Dimethylethylen [-CH(CH3)-CH(CH3)-], 1,1-Dimethy - ethylen [-C(CH3)2-CH2-], Isopropyliden [-C(CH3)2-], 2,2-Dimethylpropylen [-CH2-C(CH3)2-CH2-], 2-Methylpropylen [-CH2-CH(CH3)-CH2-] und 2-Methyl- ethylen [-CH2-CH(CH3)-] genannt.2-12C-Alkylene stands for straight-chain or branched alkylene radicals with 2 to 12 carbon atoms. Examples are ethylene (-CH ^ CH «-), trimethylene (-CH 2 CH 2 CH 2 -), tetramethylene (-CH 2 CH 2 CH 2 CH 2 -), pentaethylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexamethylene (-CH 2 - (CH 2 ) 4 -CH 2 -), octamethylene (-CH 2 - (CH 2 ) 6 -CH 2 -), decamethylene (-CH 2 - (CH 2 ) g-CH 2 -), dodecamethylene (-CH 2 - (CH 2 ) 10 -CH 2 -), 1,2-dimethylethylene [-CH (CH 3 ) -CH (CH 3 ) -], 1,1-dimethylethylene [-C (CH 3 ) 2 -CH 2 -], isopropylidene [-C (CH 3 ) 2 -], 2,2-dimethylpropylene [-CH 2 -C (CH 3 ) 2 -CH 2 -], 2-methylpropylene [-CH 2 - CH (CH 3 ) -CH 2 -] and 2-methylethylene [-CH 2 -CH (CH 3 ) -] called.
Von den Cyclohexylenresten seien der 1,2- und insbesondere der 1,4-Cyclo- hexylenrest erwähnt. Bei den Cyclohexylenverbindungen können die Substitu¬ enten eis- oder trans-ständig zueinander stehen. Die Erfindung umfaßt so¬ wohl die eis- als auch die trans-ständigen Verbindungen sowie alle denkba¬ ren cis-/trans-Mischungen.Of the cyclohexylene radicals, the 1,2- and in particular the 1,4-cyclohexylene radical may be mentioned. In the case of the cyclohexylene compounds, the substituents can be in the ice or trans position to one another. The invention encompasses both the ice and trans compounds and all conceivable cis / trans mixtures.
Hervorzuheben sind solche Verbindungen der Formel I, in denenOf particular note are those compounds of formula I in which
Rl den Substituenten -Y-(CH2)m-A-(CH2)n-0-N02 darstellt,Rl represents the substituent -Y- (CH 2 ) m -A- (CH 2 ) n -0-N0 2 ,
R2 Wasserstoff oder 1-4C-Alkyl darstellt,R2 represents hydrogen or 1-4C-alkyl,
R3 Wasserstoff, 1-4C-Alkyl, l-4C-Alkoxy, l-4C-Alkoxy-l-4C-alkyl , Halogen oder Trifluormethyl bedeutet und R4 Wasserstoff oder 1-4C-Alkyl bedeutet, wobei im Substituenten -Y-(CH2)rr)-A-(CH2) -0-N02 R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, halogen or trifluoromethyl and R4 is hydrogen or 1-4C-alkyl, where in the substituent -Y- (CH 2 ) rr) -A- (CH 2 ) -0-N0 2
- Y 0 (Sauerstoff), CO-0 (Carbonyloxy) oder CO-NH (Carbonylamino) be¬ deutet und- Y 0 (oxygen), CO-0 (carbonyloxy) or CO-NH (carbonylamino) means and
- m und n jeweils die Zahl 0 und A 2-8C-Alkylen, oder- m and n each the number 0 and A 2-8C-alkylene, or
- m und n jeweils die Zahl 1 und A Cyclohexylen, oder- m and n each the number 1 and A cyclohexylene, or
- m und n jeweils die Zahl 2 und A 0 (Sauerstoff) oder O-Ü -Ü -O (Ethylendioxy) bedeuten.- m and n each represent the number 2 and A 0 (oxygen) or O-Ü -Ü -O (ethylenedioxy).
Besonders hervorzuheben sind solche Verbindungen der Formel I, in denen Rl [wenn Y 0 (Sauerstoff) bedeutet] in 4- oder in 7-Position im Cumarinring gebunden ist.Particularly noteworthy are those compounds of the formula I in which R1 [when Y is 0 (oxygen)] is bonded in the 4- or in the 7-position in the coumarin ring.
Besonders hervorzuheben sind weiterhin solche Verbindungen der Formel I, in denen Rl [wenn Y CO-0 (Carbonyloxy) oder CO-NH (Carbonylamino) bedeutet] in 3-Position im Cumarinring gebunden ist.Particularly noteworthy are those compounds of the formula I in which Rl [when Y is CO-0 (carbonyloxy) or CO-NH (carbonylamino)] is bonded in the 3-position in the coumarin ring.
Als beispielhafte erfindungsgemäße Verbindungen seien genannt: -Acetyl-7-(2-nitroxyethoxy)cumarin -Cyan-7-(2-nitroxyethoxy)cumarin ,4-Dimethyl-7-(2-nitroxyethoxy)cumarin -(2-Nitroxyethoxy)cumarin-4-essigsäure -Phenyl-7-(2-nitroxyethoxy)cumarin -(2-Nitroxyethoxy)cumarin-3-carbonsäue -(2-Nitroxyethoxy)cumarin-3-carbonsäueethylester -(2-Nitroxyethoxy)-4-propylcumarin -(2-Nitroxyethoxy)-3-(3-oxobutyl)cumarin -Chlor-4-methyl-7-(2-nitroxyethoxy)cumarin -(2-Nitroxyethoxy)-3-phenylcumarin -Methyl-6-(2-nitroxyethoxy)cumarin -Methyl-5,7-bis-(2-nitroxyethoxy)cumarin -Methyl-7,8-bis-(2-nitroxyethoxy)cumarin -Methoxy-6-(2-nitroxyethoxy)cumarin ,8-Bis-(2-nitroxyethoxy)cumarin -Methoxy-7-(2-nitroxyethoxy)cumarin -(2-Nitroxyethoxy)cumarin -(2-Nitroxyethoxy)cumarin-3-carbonsäure -(2-Nitroxyethoxy)cumarin-3-carbonsäureethylester -Benzyloxy-4-methyl-6-(2-nitroxyethoxy)cumarin ,8-Dimethyl-7-(2-nitroxyethoxy)cumarin -Phenyl-7-(2-nitroxyethoxy)cumarin -Methyl-6,7-bis-(2-nitroxyethoxy)cumarin -Methoxy-7-(2-nitroxyethoxy)cumarin -Benzyl-4-methyl-7-(2-nitroxyethoxy)cumarin -Hydroxy-3-(2-nitroxyethoxycarbonyl)cumarin -Brom-3-(2-nitroxyethoxycarbonyl)cumarin ,8-Dichlor-3-(2-nitroxyethoxycarbonyl)cumarin -(2-Nitroxyethoxycarbonyl )cumarin -Hydroxy-3-(2-nitroxyethoxycarbonyl )cumarin -Acetoxy-3-(2-nitroxyethoxycarbonyl)cumarin -Hydroxy-3-(2-nitroxyethylaminocarbonyl)cumarin -Brom-3-(2-nitroxyethylaminocarbonyl)cumarin ,8-Dichlor-3-(2-nitroxyethylaminocarbonyl)cumarin -Hydroxy-3-(2-nitroxyethylaminocarbonyl)cumarin -Acetoxy-3-(2-nitroxyethylaminocarbonyl)cumarin -(3-Nitroxypropoxy)-4-trif1uormethylcumarin -(3-Nitroxypropoxy)-3,4,8-trimethylcumarin -Acetyl-7-(3-nitroxypropoxy)cumarin -Cyan-7-(3-nitroxypropox )cumarin ,4-Dimethyl-7-(3-nitroxypropoxy)cumarin -(3-Nitroxypropoxy)cumarin-4-essigsäure -Phenyl-7-(3-nitroxypropoxy)cumarin -(3-Nitroxypropoxy)cumarin-3-carbonsäue -(3-Nitroxypropoxy)cumarin-3-carbonsäueethylester -Methoxymethyl-7-(3-nitroxypropoxy)cumarin -(3-Nitroxypropoxy)-4-propylcumarin -(3-Nitroxypropoxy)-3-(3-oxobutyl)cumarin -Chlor-4-methyl-7-(3-nitroxypropoxy)cumarin -(3-Nitroxypropoxy)-3-phenylcumarin -Methyl-6-(3-nitroxypropoxy)cumarin -Methyl-5,7-bis-(3-nitroxypropoxy)cumarin -Methyl-7,8-bis-(3-nitroxypropoxy)cumarin -Methoxy-6-(3-nitroxypropoxy)cumarin ,8-Bis-(3-nitroxypropoxy)cumarin -Methoxy-7-(3-nitroxypropoxy)cumarin -(3-Nitroxypropoxy)cumarin -(3-Nitroxypropox )cumarin-3-carbonsäure -(3-Nitroxypropoxy)cumarin-3-carbonsäureethylester -Benzyloxy-4-methyl-6-(3-nitroxypropoxy)cumarin ,8-Dimethyl-7-(3-nitroxypropoxy)cumarin -Phenyl-7-(3-nitroxypropoxy)cumarin -Methyl-6,7-bis-(3-nitroxypropoxy)cumarin -Methoxy-7-(3-nitroxypropoxy)cumarin -Benzyl-4-methyl-7-(3-nitroxypropoxy)cumarin -Hydroxy-3-(3-nitroxypropoxycarbonyl)cumarin -Brom-3-(3-nitroxypropoxycarbonyl)cumarin ,8-Dichlor-3-(3-nitroxypropoxycarbonyl)cumarin -(3-Nitroxypropoxycarbonyl)cumarin -Hydroxy-3-(3-nitroxypropoxycarbonyl )cumarin -Acetoxy-3-(3-nitroxypropoxycarbonyl)cumarin 4-Hydroxy-3-(3-nitroxypropylaminocarbonyl)cumarinThe following are examples of compounds according to the invention: -Acetyl-7- (2-nitroxyethoxy) coumarin -cyan-7- (2-nitroxyethoxy) coumarin, 4-dimethyl-7- (2-nitroxyethoxy) coumarin - (2-nitroxyethoxy) coumarin-4-acetic acid -phenyl-7 - (2-nitroxyethoxy) coumarin - (2-nitroxyethoxy) coumarin-3-carboxylic acid - (2-nitroxyethoxy) coumarin-3-carboxylic acid ethyl ester - (2-nitroxyethoxy) -4-propylcoumarin - (2-nitroxyethoxy) -3- (3 -oxobutyl) coumarin -chloro-4-methyl-7- (2-nitroxyethoxy) coumarin - (2-nitroxyethoxy) -3-phenylcoumarin -Methyl-6- (2-nitroxyethoxy) coumarin -Methyl-5,7-bis- ( 2-nitroxyethoxy) coumarin-methyl-7,8-bis- (2-nitroxyethoxy) coumarin-methoxy-6- (2-nitroxyethoxy) coumarin, 8-bis- (2-nitroxyethoxy) coumarin-methoxy-7- (2- nitroxyethoxy) coumarin - (2-nitroxyethoxy) coumarin - (2-nitroxyethoxy) coumarin-3-carboxylic acid - (2-nitroxyethoxy) coumarin-3-carboxylic acid ethyl ester-benzyloxy-4-methyl-6- (2-nitroxyethoxy) coumarin, 8- Dimethyl-7- (2-nitroxyethoxy) coumarin -phenyl-7- (2-nitroxyethoxy) coumarin -Methyl-6,7-bis- (2-nitroxyethoxy) coumarin -Methoxy-7- (2-nitroxyethoxy) coumarin -Benzyl- 4-methyl-7- (2-nitroxyethoxy) c umarin -hydroxy-3- (2-nitroxyethoxycarbonyl) coumarin -Brom-3- (2-nitroxyethoxycarbonyl) coumarin, 8-dichloro-3- (2-nitroxyethoxycarbonyl) coumarin - (2-nitroxyethoxycarbonyl) coumarin -hydroxy-3- (2 -nitroxyethoxycarbonyl) coumarin -acetoxy-3- (2-nitroxyethoxycarbonyl) coumarin -hydroxy-3- (2-nitroxyethylaminocarbonyl) coumarin -Brom-3- (2-nitroxyethylaminocarbonyl) coumarin, 8-dichloro-3- (2-nitroxyethylaminocarbonyl) coumarin -Hydroxy-3- (2-nitroxyethylaminocarbonyl) coumarin -Acetoxy-3- (2-nitroxyethylaminocarbonyl) coumarin - (3-nitroxypropoxy) -4-trif1uormethylcoumarin - (3-nitroxypropoxy) -3,4,8-trimethylcoumarin -acetyl-7- (3-nitroxypropoxy) coumarin-cyano-7 - (3-nitroxypropox) coumarin, 4-dimethyl-7- (3-nitroxypropoxy) coumarin - (3-nitroxypropoxy) coumarin-4-acetic acid -phenyl-7- (3-nitroxypropoxy) coumarin - (3-nitroxypropoxy) coumarin 3-carboxylic acid - (3-nitroxypropoxy) coumarin-3-carboxylic acid ethyl ester-methoxymethyl-7- (3-nitroxypropoxy) coumarin - (3-nitroxypropoxy) -4-propylcoumarin - (3-nitroxypropoxy) -3- (3-oxobutyl) coumarin - Chloro-4-methyl-7- (3-nitroxypropoxy) coumarin - (3-nitroxypropoxy) -3-phenylcoumarin -Methyl-6- (3-nitroxypropoxy) coumarin -Methyl-5,7-bis- (3-nitroxypropoxy) coumarin -methyl-7,8-bis (3-nitroxypropoxy) coumarin-methoxy-6- (3-nitroxypropoxy) coumarin, 8-bis- (3-nitroxypropoxy) coumarin -Methoxy-7- (3-nitroxypropoxy) coumarin - (3-nitroxypropoxy) coumarin - (3-nitroxypropox) coumarin-3-carboxylic acid - (3-nitroxypropoxy) coumarin-3-carboxylic acid ethyl ester-benzyloxy-4-methyl-6- (3-nitroxypropo xy) coumarin, 8-dimethyl-7- (3-nitroxypropoxy) coumarin -phenyl-7- (3-nitroxypropoxy) coumarin-methyl-6,7-bis- (3-nitroxypropoxy) coumarin-methoxy-7- (3- nitroxypropoxy) coumarin-benzyl-4-methyl-7- (3-nitroxypropoxy) coumarin -hydroxy-3- (3-nitroxypropoxycarbonyl) coumarin-bromo-3- (3-nitroxypropoxycarbonyl) coumarin, 8-dichloro-3- (3- nitroxypropoxycarbonyl) coumarin - (3-nitroxypropoxycarbonyl) coumarin -hydroxy-3- (3-nitroxypropoxycarbonyl) coumarin -acetoxy-3- (3-nitroxypropoxycarbonyl) coumarin 4-hydroxy-3- (3-nitroxypropylaminocarbonyl) coumarin
6-Brom-3-(3-nitroxypropylaminocarbonyl)cumarin6-bromo-3- (3-nitroxypropylaminocarbonyl) coumarin
6,8-Dichlor-3-(3-nitroxypropylaminocarbonyl)cumarin6,8-dichloro-3- (3-nitroxypropylaminocarbonyl) coumarin
3-(3-Nitroxypropylaminocarbonyl)cumarin3- (3-nitroxypropylaminocarbonyl) coumarin
7-Hydroxy-3-(3-nitroxypropylaminocarbonyl)cumarin und7-hydroxy-3- (3-nitroxypropylaminocarbonyl) coumarin and
7-Acetoxy-3-(3-nitroxypropylaminocarbonyl)cumarin.7-acetoxy-3- (3-nitroxypropylaminocarbonyl) coumarin.
Die Herstellung der erfindungsgemäßen Verbindungen erfolgt in an sich be¬ kannter Weise, indem man beispielsweiseThe compounds according to the invention are prepared in a manner known per se, for example by
a) Verbindungen der Formel I, in denen Rl und gegebenenfalls R2 den Sub¬ stituenten -Y-(CH2) -A-(CH2) -OH darstellt, nitriert, oder indem mana) Compounds of formula I, in which Rl and optionally R2 represents the substituent -Y- (CH 2 ) -A- (CH 2 ) -OH, nitrated, or by
b) zur Herstellung von Verbindungen der Formel I, in denen Y CO-0 (Car¬ bonyloxy) bedeutet, Verbindungen der Formel I, in denen Rl und gege¬ benenfalls R2 den Substituenten -CO-Z und Z OH (Hydroxy) oder eine geeignete Abgangsgruppe darstellt, mit Verbindungen der Formel HO-(CH2)m-A-(CH2)n-0-N02 umsetzt, oder indem manb) for the preparation of compounds of the formula I in which Y is CO-0 (carbonyloxy), compounds of the formula I in which R 1 and, if appropriate, R 2 have the substituents -CO-Z and Z OH (hydroxy) or a represents a suitable leaving group, with compounds of the formula HO- (CH 2 ) m -A- (CH 2 ) n -0 -N0 2 , or by reacting
c) zur Herstellung von Verbindungen der Formel I, in denen Y CO-NH (Car¬ bonylamino) bedeutet, Verbindungen der Formel I, in denen Rl und ge¬ gebenenfalls R2 den Substituenten -CO-Z und Z OH (Hydroxy) oder eine geeignete Abgangsgruppe darstellt, mit Verbindungen der Formel H2N-(CH2)m-A-(CH2)n-0-N02 umsetzt, oder indem manc) for the preparation of compounds of the formula I in which Y is CO-NH (carbonylamino), compounds of the formula I in which R 1 and optionally R 2 have the substituents -CO-Z and Z OH (hydroxy) or a represents a suitable leaving group, with compounds of the formula H 2 N- (CH 2 ) m -A- (CH 2 ) n -0 -N0 2 , or by reacting
d) zur Herstellung von Verbindungen der Formel I, in denen R3 Halogen be¬ deutet, Verbindungen der Formel I, in denen R3 Wasserstoff bedeutet, halogeniert.d) for the preparation of compounds of the formula I in which R3 is halogen, compounds of the formula I in which R3 is hydrogen are halogenated.
Die Nitrierung gemäß Verfahrensvariante a) erfolgt in an sich bekannter Weise mittels Salpetersäure in einem inerten Lösungsmittel (wie z.B. Ethyl acetat oder Eisessig) oder ohne Lösungsmittel, gewünschtenfalls in Gegen¬ wart eines wasserbindenden oder wasserabspaltenden Mediums (wie z.B. Acet- anhydrid), beispielsweise bei Temperaturen zwischen -20°C und + 50°C, vor¬ zugsweise bei Raumtemperatur. Die Umsetzung gemäß Verfahrensvariante b oder c erfolgt ebenfalls in an sich bekannter Weise, wie sie dem Fachmann aufgrund seines Fachwissens über Veresterungsreaktionen bekannt ist. Die Veresterung erfolgt in inerten Lö¬ sungsmitteln, wie beispielsweise Dioxan oder Tetrahydrofuran, und je nach Art der Gruppe Z entweder in Gegenwart eines wasserabspaltenden bzw. Wasser chemisch bindenden Mittels, wie beispielsweise Dicyclohexylcarbodiimid (wenn Z = OH), oder in Gegenwart von 4-Toluolsulfonsäure, oder in Gegenwart einer Hilfsbase (z.B. Triethylamin), wenn Z eine Abgangsgruppe, beispiels¬ weise ein Halogenatom (insbesondere Chlor) darstellt. Bei einer Veresterung ausgehend von der Carbonsäure (Z = OH) erfolgt die Umsetzung unter sauren Reaktionsbedingungen wie z.B. beschrieben von M. Bodanszky und A. Bodanszky in : "The Practice of Peptide Synthesis" (Springer-Verlag, Berlin, 1984, S. 37).The nitration according to process variant a) is carried out in a manner known per se using nitric acid in an inert solvent (such as ethyl acetate or glacial acetic acid) or without a solvent, if desired in the presence of a water-binding or water-releasing medium (such as acetic anhydride), for example in Temperatures between -20 ° C and + 50 ° C, preferably at room temperature. The reaction according to process variant b or c also takes place in a manner known per se, as is known to the person skilled in the art on the basis of his specialist knowledge of esterification reactions. The esterification takes place in inert solvents, such as, for example, dioxane or tetrahydrofuran, and, depending on the type of group Z, either in the presence of a water-releasing or water-chemically binding agent, such as, for example, dicyclohexylcarbodiimide (if Z = OH), or in the presence of 4- Toluenesulfonic acid, or in the presence of an auxiliary base (eg triethylamine) if Z represents a leaving group, for example a halogen atom (especially chlorine). In the case of esterification starting from the carboxylic acid (Z = OH), the reaction takes place under acidic reaction conditions, as described, for example, by M. Bodanszky and A. Bodanszky in: "The Practice of Peptide Synthesis" (Springer-Verlag, Berlin, 1984, p. 37 ).
Die Halogenierung gemäß Verfahrensvariante d), die vorzugsweise als Chlo¬ rierung oder Bromierung vorgenommen wird, erfolgt ebenfalls in an sich be¬ kannter Weise in einem inerten Lösungsmittel, z.B. in Dichlormethan.The halogenation according to process variant d), which is preferably carried out as chlorination or bromination, also takes place in a manner known per se in an inert solvent, e.g. in dichloromethane.
Verbindungen der Formel I, in denen Rl und gegebenenfalls R2 den Substitu¬ enten -Y-(CH2) -A-(CH2) -OH darstellt, sind bekannt oder sie können nach dem Fachmann bekannten Standardreaktionen (z.B. so, wie dies in den nach¬ folgenden Beispielen näher erläutert ist) hergestellt werden.Compounds of the formula I in which R 1 and optionally R 2 represent the substituent -Y- (CH 2 ) -A- (CH 2 ) -OH are known or they can be prepared according to standard reactions known to the person skilled in the art (for example as described in the following examples are explained).
Anhand der folgenden Beispiele soll die Herstellung der erfindungsgemäßen Verbindungen exemplarisch erläutert werden. Die namentlich genannten Ver¬ bindungen und ihre Anwendung sind bevorzugter Gegenstand der Erfindung. The preparation of the compounds according to the invention will be explained by way of example using the following examples. The compounds mentioned by name and their use are the preferred subject of the invention.
Beispiel eExample e
AUSGANGSVERBINDUNGENINITIAL CONNECTIONS
AI. 4-(2-Hvdroxyethoxy)cumarinAI. 4- (2-hydroxyethyloxy) coumarin
Eine Mischung aus 10 g 4-Hydroxycumarin, 5,4 g Ethylencarbonat und 4,3 g Tetraethylammoniumbromid wird für 5 h auf 160°C erhitzt. Nach dem Abkühlen löst man das Reaktionsgemisch in Wasser und Ethylacetat und extrahiert die wäßrige Phase mit Ethylacetat. Die organische Phase wird über Magnesium¬ sulfat getrocknet und eingeengt. Nach Umkristallisieren des Rückstandes aus Ethylacetat erhält man 7,4 g (60 %) der Titelverbindung vom Schmp. 137,9-141,4βC.A mixture of 10 g of 4-hydroxycoumarin, 5.4 g of ethylene carbonate and 4.3 g of tetraethylammonium bromide is heated to 160 ° C. for 5 hours. After cooling, the reaction mixture is dissolved in water and ethyl acetate and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated. After recrystallization of the residue from ethyl acetate, 7.4 g (60%) of the title compound of mp 137.9-141.4 β C.
A2. 7-(2-Hvdroxyethoxy)-4-methylcumarinA2. 7- (2-Hydroxyethoxy) -4-methylcoumarin
Analog Beispiel AI erhält man die Titelverbindung vom Schmp. 141,3-145,2°C aus 7-Hydroxy-4-methylcumarin und Ethylencarbonat.Analogously to Example AI, the title compound of mp. 141.3-145.2 ° C. is obtained from 7-hydroxy-4-methylcoumarin and ethylene carbonate.
A3. 7-(2-Hvdroxyethoxy)cumarinA3. 7- (2-Hydroxyethoxy) coumarin
Analog Beispiel AI erhält man die Titelverbindung vom Schmp. 85,0-89,2°C aus 7-Hydroxycumarin und Ethylencarbonat.Analogously to Example AI, the title compound of mp. 85.0-89.2 ° C. is obtained from 7-hydroxycoumarin and ethylene carbonate.
A4. 7-(2-Hvdroxyethoχy)-4,4,8-trimethylcumarinA4. 7- (2-Hvdroxyethoχy) -4,4,8-trimethylcoumarin
Analog Beispiel AI erhält man die Titelverbindung vom Schmp. 128,1-131,8βC aus 7-Hydroxy-3,4,8-trimethylcumarin und Ethylencarbonat.Analogously to Example AI, the title compound of mp 128.1-131.8 β C is obtained from 7-hydroxy-3,4,8-trimethylcoumarin and ethylene carbonate.
A5. 7-(2-Hvdroχyethoχy)-4-trif1uormethylcumarinA5. 7- (2-Hvdroχyethoχy) -4-trif1uormethylcoumarin
Analog Beispiel AI erhält man die Titelverbindung aus 7-Hydroxy-4-trifluor- methylcumarin und Ethylencarbonat. A6. 7-(2-Hydroχyethoχy)-4-methoxymethy1cumarinAnalogously to Example AI, the title compound is obtained from 7-hydroxy-4-trifluoromethylcoumarin and ethylene carbonate. A6. 7- (2-Hydroχyethoχy) -4-methoxymethy1coumarin
Analog Beispiel AI erhält man die Titelverbindung aus 7-Hydroxy-4-methoxy- ethylcumarin und Ethylencarbonat.Analogously to Example AI, the title compound is obtained from 7-hydroxy-4-methoxyethylcoumarin and ethylene carbonate.
A7. 4-(3-Hydroχy-2,2-dimethylpropoxy)cumarinA7. 4- (3-Hydroχy-2,2-dimethylpropoxy) coumarin
20,0 g 4-Hydroxycumarin, 20,6 g 3-Brom-2,2-dimethylpropanol und 7,0 g Kali¬ umhydroxid werden in 250 ml Di ethylsulfoxid gelöst. Die Lösung wird für 8 h auf 130°C erhitzt. Nach dem Abkühlen wird das Reaktionsgemisch in Was¬ ser gegossen und mit Ethylacetat extrahiert. Die organische Phase wird über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wird durch Chroma¬ tographie gereinigt.20.0 g of 4-hydroxycoumarin, 20.6 g of 3-bromo-2,2-dimethylpropanol and 7.0 g of potassium hydroxide are dissolved in 250 ml of diethyl sulfoxide. The solution is heated to 130 ° C for 8 h. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by chromatography.
A8. 4-(3-Hydroχypropoxy)cumarinA8. 4- (3-Hydroχypropoxy) coumarin
16,2 g 4-Hydroxycumarin, 7 g Kaliumhydroxid und 9,5 g 3-Chlor-l-propanol werden in Dimethylformamid gelöst und bei 130βC gerührt. Nach Beendigung der Reaktion (DC-Kontrolle) wird eingeengt und der Rückstand in Ethylacetat aufgenommen. Nach Reinigung durch Chromatographie erhält man die Titelver¬ bindung vom Schmp. 84-90βC.16.2 g of 4-hydroxycoumarin, 7 g of potassium hydroxide and 9.5 g of 3-chloro-l-propanol are dissolved in dimethylformamide and stirred at 130 ° C. After the reaction has ended (TLC control), the mixture is concentrated and the residue is taken up in ethyl acetate. After purification by chromatography 84-90 β C. to give the title compound are obtained of melting point.
A9. 4-(2-r2-(2-Hvdroχyethoχy)ethoχyl-ethoxy)cumarinA9. 4- (2-r2- (2-Hvdroχyethoχy) ethoχyl-ethoxy) coumarin
Analog Beispiel A8 erhält man die Titelverbindung vom Schmp. 54-57βC aus 4-Hydroxycumarin und 2-[2-(2-Chlorethoxy)ethoxy]ethanol .Analogously to Example A8, the title compound of mp 54-57 β C is obtained from 4-hydroxycoumarin and 2- [2- (2-chloroethoxy) ethoxy] ethanol.
A10. 4-(6-Hydroxyheχyloχy)cumarinA10. 4- (6-Hydroxyheχyloχy) coumarin
Analog Beispiel A8 erhält man bei einer Reaktionstemperatur von 80βC, Lö¬ sung des Rückstandes in Wasser, Extraktion mit Ethylacetat und nach Chroma¬ tographie die Titelverbindung aus 4-Hydroxycumarin und 6-Brom-l-hexanol .Analogously to Example A8 is obtained at a reaction temperature of 80 C β, Lö¬ solution of the residue in water, extraction with ethyl acetate and after Chroma¬ the title compound chromatography of 4-hydroxycoumarin and 6-bromo-l-hexanol.
All. 7-(3-Hydroχypropoχy)-4-methy1cumarinAlles. 7- (3-Hydroχypropoχy) -4-methy1coumarin
Analog Beispiel A8 erhält man die Titelverbindung vom Schmp. 95-96,5°C aus 7-Hydroxy-4-methylcumarin und 3-Chlor-l-propanol . A12. 7- \2-(2-Hvdroxyethoχy)ethoχyl-4-methylcumarinAnalogously to Example A8, the title compound of melting point 95-96.5 ° C. is obtained from 7-hydroxy-4-methylcoumarin and 3-chloro-l-propanol. A12. 7- \ 2- (2-Hvdroxyethoχy) ethoχyl-4-methylcoumarin
Analog Beispiel A8 erhält man die Titelverbindung vom Schmp. 91-92'C aus 7-Hydroxy-4-methylcumarin und 2-(2-Chlorethoxy)ethanol .Analogously to Example A8, the title compound of mp 91-92'C is obtained from 7-hydroxy-4-methylcoumarin and 2- (2-chloroethoxy) ethanol.
A13. 7-r4-(Hydroxymethyl)rtranslcvcloheχylmethoχyl-4-methylcumarinA13. 7-r4- (hydroxymethyl) rtranslcvcloheχylmethoχyl-4-methylcoumarin
Analog Beispiel A8 erhält man die TitelVerbindung aus 7-Hydroxy-4-methyl- cumarin und 4-Brommethyl[trans]cyclohexylmethanol .Analogously to Example A8, the title compound is obtained from 7-hydroxy-4-methyl-coumarin and 4-bromomethyl [trans] cyclohexylmethanol.
A14. 4-r4-(Hvdroxymethv1)rtranslcvc1ohexylmethoχylcumarinA14. 4-r4- (Hvdroxymethv1) rtranslcvc1ohexylmethoχylcoumarin
2,5 g einer Natriumhydridsuspension (60 %) werden zu einer Lösung von 10 g 4-Hydroxycumarin in Dimethylformamid gegeben und für 30 Min. bei Raumtempe¬ ratur gerührt. Nach Zugabe von 12,5 g 4-Brommethyl [trans]cyclohexylmethanol wird das Reaktionsgemisch für 2,5 h auf 120βC erhitzt. Nach dem Abkühlen und Einengen wird der Rückstand in Ethylacetat gelöst. Nach Waschen mit Wasser und Trocknen mit Magnesiumsulfat wird die organische Phase einge¬ engt. Der Rückstand wird aus Ethylacetat/Diethylether umkristallisiert.2.5 g of a sodium hydride suspension (60%) are added to a solution of 10 g of 4-hydroxycoumarin in dimethylformamide and stirred for 30 minutes at room temperature. After adding 12.5 g of 4-bromomethyl [trans] cyclohexylmethanol, the reaction mixture is heated to 120 ° C. for 2.5 h. After cooling and concentration, the residue is dissolved in ethyl acetate. After washing with water and drying with magnesium sulfate, the organic phase is concentrated. The residue is recrystallized from ethyl acetate / diethyl ether.
ENDPRODUKTEFINAL PRODUCTS
1. 4-(2-Nitroxyethoxy)cumarin1. 4- (2-nitroxyethoxy) coumarin
Eine Mischung aus 1,6 ml Salpetersäure und 5,0 ml Acetanhydrid wird zu einer Lösung von 5,5 g 4-(2-Hydroxyethoxy)cumarin in Essigsäure/Ethylacetat gegeben. Nach einigen Stunden wird Ethylacetat und Wasser zugegeben. Die wäßrige Phase wird mit Natriumcarbonatiösung alkalisch gemacht und mit Ethylacetat extrahiert. Die organische Phase wird über Magnesiumsulfat getrocknet und eingeengt. Nach Umkristallisieren aus Ethanol erhält man die Titelverbindung vom Schmp. 119,2-120,7°C. 2. 4-Methyl -7- (2-nitroxyethoxy) cumari nA mixture of 1.6 ml of nitric acid and 5.0 ml of acetic anhydride is added to a solution of 5.5 g of 4- (2-hydroxyethoxy) coumarin in acetic acid / ethyl acetate. After a few hours, ethyl acetate and water are added. The aqueous phase is made alkaline with sodium carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated. After recrystallization from ethanol, the title compound of mp 119.2-120.7 ° C. is obtained. 2. 4-methyl -7- (2-nitroxyethoxy) cumari n
Durch Nitrieren von 7-(2-Hydroxyethoxy)-4-methylcumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 97,7-98,3βC.By nitrating 7- (2-hydroxyethoxy) -4-methylcoumarin analogously to Example 1, the title compound of mp 97.7-98.3 β C is obtained.
3. 7-f2-Nitroχyethoxy)cumarin3. 7-f2-nitroχyethoxy) coumarin
Durch Nitrieren von 7-(2-Hydroxyethoxy)cumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 111,2-112,3βC [(aus Ethylacetat/Petrolether (60-80)].By nitrating 7- (2-hydroxyethoxy) coumarin analogously to Example 1, the title compound of mp 111.2-112.3 β C [(from ethyl acetate / petroleum ether (60-80)] is obtained.
4. 7-(2-Nitroxyethoχy)-3.4,8-trimethylcumarin4. 7- (2-Nitroxyethoχy) -3,4,8-trimethylcoumarin
Durch Nitrieren von 7-(2-Hydroxyethoxy)-3,4,8-trimethylcumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 160,9-161,8°C (aus Metha¬ nol).By nitrating 7- (2-hydroxyethoxy) -3,4,8-trimethylcoumarin, analogously to Example 1, the title compound of mp 160.9-161.8 ° C. (from methanol) is obtained.
5. 7-(2-Nitroxyethoχy)-4-trifluormethy1cumarin5. 7- (2-Nitroxyethoχy) -4-trifluoromethyl1coumarin
Durch Nitrieren von 7-(2-Hydroxyethoxy)-4-trifluormethylcumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 90,0-91,lβC.By nitrating 7- (2-hydroxyethoxy) -4-trifluoromethylcoumarin analogously to Example 1, the title compound of mp 90.0-91, l β C is obtained.
6. 4-Methoχymethyl-7-(2-nitroχyethoxy)cumarin6. 4-Methoχymethyl-7- (2-nitroχyethoxy) coumarin
Durch Nitrieren von 7-(2-Hydroxyethoxy)-4-methoxymethylcumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 110,7-112,3βC.By nitrating 7- (2-hydroxyethoxy) -4-methoxymethylcoumarin analogously to Example 1, the title compound of mp 110.7-112.3 β C is obtained.
7. 4-(2,2-Dimethy1 -3-nitroxypropoxy)cumarin7. 4- (2,2-Dimethy1 -3-nitroxypropoxy) coumarin
Durch Nitrieren von 4-(3-Hydroxy-2,2-dimethylpropoxy)cumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 117,8-118,3βC.By nitrating 4- (3-hydroxy-2,2-dimethylpropoxy) coumarin analogously to Example 1, the title compound of mp 117.8-118.3 β C is obtained.
8. 4-(3-Nitroχypropoχy)cumarin8. 4- (3-Nitroχypropoχy) coumarin
Durch Nitrieren von 4-(3-Hydroxypropoxy)cumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 96-98βC (aus Ethanol). 9. 4-(2- r2- (2-Nitroxyethoxy)ethoxylethoxy)cumari nBy nitrating 4- (3-hydroxypropoxy) coumarin analogously to Example 1, the title compound of mp 96-98 β C (from ethanol) is obtained. 9. 4- (2- r2- (2-nitroxyethoxy) ethoxylethoxy) cumari n
Durch Nitrieren von 4-(2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy}cumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 55.3-57,1°C (aus Etha¬ nol).By nitrating 4- (2- [2- (2-hydroxyethoxy) ethoxy] ethoxy} coumarin, analogously to Example 1, the title compound of mp 55.3-57.1 ° C. (from ethanol) is obtained.
10. 4-(6-Nitroxyhexyloχy)cumarin10. 4- (6-nitroxyhexyloχy) coumarin
Durch Nitrieren von 4-(6-Hydroxyhexyloxy)cumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 94,5-97,6°C (aus Ethanol).By nitrating 4- (6-hydroxyhexyloxy) coumarin analogously to Example 1, the title compound of mp 94.5-97.6 ° C (from ethanol) is obtained.
11. 4-Methyl-7-(3-nitroxypropoxy)cumarin11. 4-methyl-7- (3-nitroxypropoxy) coumarin
Durch Nitrieren von 7-(3-Hydroxypropoxy)-4-methylcumarin erhält man analog Beispiel 1 die TitelVerbindung vom Schmp. 80-83βC (aus Ethanol).By nitrating 7- (3-hydroxypropoxy) -4-methylcoumarin analogously to Example 1, the title compound of mp 80-83 β C (from ethanol) is obtained.
12. 4-Methv1-7-r2-(2-nitroxyethoχy)ethoχylcumarin12. 4-Methv1-7-r2- (2-nitroxyethoχy) ethoχylcoumarin
Durch Nitrieren von 7-[2-(2-Hydroxyethoxy)ethoxy]-4-methylcumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 63-64βC.By nitrating 7- [2- (2-hydroxyethoxy) ethoxy] -4-methylcoumarin, analogously to Example 1, the title compound of mp 63-64 β C is obtained.
13. 4-Methyl -7- r4- (nitroxymethyl Utranslcycl ohexylmethoxylcumarin13. 4-Methyl -7- r4- (nitroxymethyl Utranslcycl ohexylmethoxylcoumarin
Durch Nitrieren von 7-[4-(Hydroxymethyl)[trans]cyclohexylmethoxy]-4-methyl- cumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 116-120'C.By nitrating 7- [4- (hydroxymethyl) [trans] cyclohexylmethoxy] -4-methyl-coumarin, the title compound of mp 116-120'C is obtained analogously to Example 1.
14. 4-T4-fNitroxymethyl)rtranslcvclohexylmethoxylcumarin14. 4-T4-nitroxymethyl) rtranslcvclohexylmethoxylcoumarin
Durch Nitrieren von 4-[4-(Hydroxymethyl)[trans]cyclohexylmethoxy]cumarin erhält man analog Beispiel 1 die Titelverbindung vom Schmp. 110-112βC (aus Methanol ) . 15. 3-Brom-4-methyl -7- (2-ni troxyethoxy) cumari nBy nitrating 4- [4- (hydroxymethyl) [trans] cyclohexylmethoxy] coumarin, analogously to Example 1, the title compound of mp 110-112 β C (from methanol) is obtained. 15. 3-bromo-4-methyl -7- (2-ni troxyethoxy) cumari n
Eine Lösung von 3,0 g Brom in Dichlormethan wird zu einer Lösung von 5,0 g 4-Methyl-7-(2-nitroxyethoxy)cumarin in Dichlormethan unter Rühren langsam zugetropft. Nach einstündigem weiterem Rühren wird der Niederschlag abfil¬ triert und aus Methanol/Aceton umkristallisiert. Man erhält die Titelver¬ bindung vom Schmp. 127-130βC.A solution of 3.0 g of bromine in dichloromethane is slowly added dropwise to a solution of 5.0 g of 4-methyl-7- (2-nitroxyethoxy) coumarin in dichloromethane with stirring. After stirring for another hour, the precipitate is filtered off and recrystallized from methanol / acetone. The title compound of mp 127-130 β C is obtained.
16. 3-(2-Nitroχyethylaminocarbonylleumarin16. 3- (2-Nitroχyethylaminocarbonylleumarin
Zu einer Lösung von 5,0 g Cumarin-3-carbonsäure und 3,64 ml Triethylamin in Dichlormethan werden 2,9 ml Chlorameisensäureethylester zugegeben. Nach 30-minütigem Rühren der erhaltenen Lösung wird eine Lösung von 4,5 g 2-Nitroxyethylamin-nitrat und 3,64 ml Triethylamin in Dichlormethan zuge¬ fügt, und das erhaltene Reaktionsgemisch wird für weitere 30 Min. gerührt. Anschließend wird zunächst mit verdünnter Salzsäure, dann mit wäßriger Na- triumcarbonatlösung gewaschen. Nach dem Trocknen über Magnesiumsulfat wird eingeengt, der Rückstand wird aus Ethylacetat/Aceton umkristallisiert. Man erhält die Titelverbindung vom Schmp. 167-170βC. 2.9 ml of ethyl chloroformate are added to a solution of 5.0 g of coumarin-3-carboxylic acid and 3.64 ml of triethylamine in dichloromethane. After stirring the solution obtained for 30 minutes, a solution of 4.5 g of 2-nitroxyethylamine nitrate and 3.64 ml of triethylamine in dichloromethane is added, and the reaction mixture obtained is stirred for a further 30 minutes. It is then washed first with dilute hydrochloric acid and then with aqueous sodium carbonate solution. After drying over magnesium sulfate, the mixture is concentrated, the residue is recrystallized from ethyl acetate / acetone. The title compound of mp 167-170 β C. is obtained.
Gewerbliche AnwendbarkeitIndustrial applicability
Die Verbindungen der Formel I besitzen wertvolle Eigenschaften, die sie ge¬ werblich verwertbar machen. Sie stellen insbesondere hochwirksame Wirkstof¬ fe zur Behandlung von cardiovasculären Erkrankungen und Erkrankungen des Auges dar, die auf einem erhöhten Augeninnendruck beruhen.The compounds of the formula I have valuable properties which make them commercially viable. In particular, they represent highly effective active substances for the treatment of cardiovascular diseases and diseases of the eye which are based on increased intraocular pressure.
In ihrer ausgezeichneten Wirksamkeit, die gepaart ist mit einer geringen Toxizität und dem Fehlen wesentlicher Nebenwirkungen, stellen die Verbin¬ dungen der Formel I eine erwünschte Bereicherung des Standes der Technik dar. Aufgrund der Nitratgruppen im Molekül eignen sich die Verbindungen der Formel I prinzipiell zur Verhütung und Behandlung solcher Krankheitszustän- de beim Menschen, für die bekannt ist, daß sie durch organische Nitrate (wie z.B. Glyceroltrinitrat, Isosorbid-5-mononitrat oder Isosorbiddinitrat) bzw. durch Verbindungen, die Stickstoffmonoxid abspalten können (wie z.B. Molsidomin), therapiert werden können.In their excellent effectiveness, which is paired with a low toxicity and the absence of significant side effects, the compounds of the formula I represent a desired enrichment of the prior art. Because of the nitrate groups in the molecule, the compounds of the formula I are in principle suitable for prevention and treatment of such disease states in humans for which it is known that they can be treated by organic nitrates (such as, for example, glycerol trinitrate, isosorbide-5-mononitrate or isosorbide dinitrate) or by compounds which can release nitrogen monoxide (such as, for example, molsidomine) .
Insbesondere können die Verbindungen der Formel I angewandt werden zur Ver¬ hütung und Behandlung von ischämischen Herzerkrankungen (Angina pectoris, Herzinfarkt), cardialen Kompensationsstörungen, (pulmonaler) Hypertonie, (cerebralen) Thrombosen und Atherosclerosen, (peripheren) Gefäßverengungen, Arrhythmien, bestimmten Störungen des Gastrointestinaltraktes (wie z.B. Achalasie, Reizkolon) und von erhöhtem Augeninnendruck. Darüberhinaus zeichnen sich die Verbindungen der Formel I durch thromboxanantagonistische und antivirale Wirksamkeit sowie durch bronchospasmolytische Eigenschaften aus.In particular, the compounds of formula I can be used for the prevention and treatment of ischemic heart diseases (angina pectoris, heart attack), cardiac compensation disorders, (pulmonary) hypertension, (cerebral) thrombosis and atherosclerosis, (peripheral) vasoconstrictions, arrhythmias, certain disorders of the Gastrointestinal tract (such as achalasia, irritable bowel syndrome) and increased intraocular pressure. In addition, the compounds of the formula I are notable for thromboxane-antagonistic and antiviral activity and for bronchospasmolytic properties.
Ein weiterer Gegenstand der Erfindung ist daher ein Verfahren zur Behand¬ lung von Säugetieren, insbesondere Menschen, die an einer der obengenannten Krankheiten erkrankt sind. Das Verfahren ist dadurch gekennzeichnet, daß man dem erkrankten Individuum eine therapeutisch wirksame und phar akolo- gisch verträgliche Menge einer oder mehrerer Verbindungen der Formel I ver¬ abreicht.Another object of the invention is therefore a method for the treatment of mammals, in particular humans, who are suffering from one of the abovementioned diseases. The method is characterized in that the diseased individual is administered a therapeutically effective and pharmaceutically compatible amount of one or more compounds of the formula I.
Gegenstand der Erfindung sind außerdem die Verbindungen der Formel I zur Anwendung bei der Behandlung der genannten Krankheiten. Ebenso umfaßt die Erfindung die Verwendung von Verbindungen der Formel I bei der Herstellung von Arzneimitteln, die zur Bekämpfung der genannten Krankheiten eingesetzt werden.The invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned. The invention also encompasses the use of compounds of the formula I in the production of medicaments which are used to combat the diseases mentioned.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die eine oder meh¬ rere Verbindungen der Formel I enthalten.The invention further relates to medicaments which contain one or more compounds of the formula I.
Die Arzneimittel werden nach an sich bekannten, dem Fachmann geläufigen Verfahren hergestellt. Als Arzneimittel werden die pharmakologisch wirksa¬ men Verbindungen der Formel I (= Wirkstoffe) entweder als solche, oder vor¬ zugsweise in Kombination mit geeigneten pharmazeutischen Hilfsstoffen in Form von Tabletten, Dragees, Kapseln, Suppositorien, Pflastern (z.B. als TTS), Emulsionen, Suspensionen, Aerosolen, Sprays, Salben, Cremes, Gelen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwi¬ schen 0,1 und 95 % beträgt.The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The pharmacologically active compounds of the formula I (= active ingredients) are used as medicinal products either as such or preferably in combination with suitable pharmaceutical auxiliaries in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions, Suspensions, aerosols, sprays, ointments, creams, gels or solutions are used, the active substance content advantageously being between 0.1 and 95%.
Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemit¬ teln, Gelbildnern, Suppositoriengrundlagen, Tablettenhilfsstoffen und ande¬ ren Wirkstoffträgem können beispielsweise Antioxidantien, Dispergiermit¬ tel, Emulgatoren, Entschäumer, Geschmackskorrigentien, Konservierungsmit¬ tel, Lösungsvermittler, Farbstoffe oder insbesondere Permeationspromotoren und Komplexbildner (z.B. Cyclodextrine) verwendet werden.The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active ingredient carriers, it is possible, for example, to use antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).
Die Wirkstoffe können oral, rektal oder parenteral (insbesondere perlin- gual , bukkal , intravenös oder percutan) appliziert werden.The active substances can be administered orally, rectally or parenterally (in particular perlingual, buccal, intravenously or percutaneously).
Im allgemeinen hat es sich in der Humanmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe bei oraler Gabe in einer Tagesdosis von etwa 0,01 bis etwa 10, vorzugsweise 0,05 bis 5 mg/kg Körpergewicht, gewünschtenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Erzielung des ge¬ wünschten Ergebnisses zu verabreichen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verabreichung der Wirkstoffe) in der Regel niedrigere Dosierungen zur Anwendung kommen. Bei einschleichender Dosierung wird zu Beginn der Behandlung eine geringere Do¬ sis verabreicht, dann langsam auf eine höhere Dosis übergegangen. Nach Er- reichen des gewünschten Therapieerfolgs wird wieder auf eine niedrigere Do¬ sis zurückgegangen.In general, it has proven to be advantageous in human medicine to give the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 10, preferably 0.05 to 5 mg / kg body weight, if desired in the form of several, preferably 1 to 4 individual doses to achieve the desired result. In the case of parenteral treatment, similar or generally lower doses (in particular when the active compounds are administered intravenously) can be used. If the dosage creeps in, a lower dose is administered at the beginning of the treatment and then slowly switched to a higher dose. After If the desired therapeutic success is achieved, the dose is reduced again.
Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applika¬ tionsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwis¬ sens leicht erfolgen.The optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.
Sollen die Verbindungen der Formel I zur Behandlung der genannten Krank¬ heiten eingesetzt erden, so können die pharmazeutischen Zubereitungen auch einen oder mehrere andere pharmakologisch aktive Bestandteile anderer Arz¬ neimittelgruppen, wie andere Antihypertensiva, Vasodilatoren, alpha-1-Re- zeptorenblocker, alpha-2-Rezeptorstimulatoren, beta-1-Rezeptorenblocker, beta-2-Rezeptorstimulatoren, ACE-Hemmstoffe, Diuretika, Saluretika, Alka- loide, Analgetika, Lipidsenker, Antikoagulantien, Anticholinergika, Methyl- xanthine, Antiarrhythmika, Antihistaminika, Dopaminstimulatoren, Serotonin- -Rezeptorenblocker etc. wie Nifedipin, Dihydralazin, Prazosin, Clonidin, Atenolol, Labetalol, Fenoterol , Captopril, Digoxin, Milrinon, Mefrusid, Clopamid, Spironolacton, Chlorthalidon, Furosemid, Polythiazid, Hydrochlo- rothiazid, Resperpin, Dihydroergocristin, Rescinnamin, Rauwolfia-Gesa tal- kaloide, Acetylsalicylsäure, Bezafibrat, Warfarin, Atropin, Theophyllin, Lidocain, Astemizol, Bromocryptin, Ketanserin etc. enthalten. If the compounds of the formula I are to be used for the treatment of the diseases mentioned, the pharmaceutical preparations can also contain one or more other pharmacologically active constituents of other groups of medicaments, such as other antihypertensives, vasodilators, alpha-1 receptor blockers, alpha- 2-receptor stimulators, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dopamine blockers etc. such as nifedipine, dihydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, resperinistin, ralphinamine-resinpin-rinpine, rinhydroinamine-dihydroerginamine-dihydroergamine-dihydroergamine-dihydroergamine-dihydroinamine-dihydroergamine-dihydroergamine-dihydroinamine-dihydroergamine-dihydroergamine-dihydroerginamine, dihydroergamine-dihydroerginamine, dihydroerginamine, dihydroergamine, dihydroergamine, dihydroergamine, dihydroergamine, dihydroergamine, dihydroergine, kaloids, acetylsalicylic acid, bezafibrate, warfarin, atropine, theophylline, lidocaine, astemizole, bromocrypt contained in, Ketanserin etc.
Pharmakologiepharmacology
Die pharmakologische Wirkung der Verbindungen der Formel I wurde in vivo am narkotisierten Kaninchen und in vitro im sogenannten Rattenaortatest ermit¬ telt.The pharmacological activity of the compounds of the formula I was determined in vivo on anesthetized rabbits and in vitro in the so-called rat aortic test.
Am narkotisierten Kaninchen wurde die prozentuale Abnahme des arteriellen Blutdruckes und der Einfluß auf die Herzfrequenz (prozentuale Änderung) nach Infusion der zu untersuchenden Verbindungen bestimmt.In the anesthetized rabbit, the percentage decrease in arterial blood pressure and the influence on the heart rate (percentage change) after infusion of the compounds to be examined were determined.
Im Rattenaortatest wurde die relaxierende Wirkung der zu untersuchenden Verbindungen an Spiralstreifen der Arteria pulmonalis der Ratte bestimmt. Durch kumulative Zugabe wurde aus der Konzentrationswirkungskurve diejenige Dosis ermittelt, die die Kontraktion im Mittelwert um 50 % hemmt (= E 5Q).In the rat aortic test, the relaxing effect of the compounds to be investigated on spiral strips of the pulmonary artery of the rat was determined. The dose that inhibits the contraction by 50% on average (= E 5Q ) was determined from the concentration- effect curve by cumulative addition.
In den folgenden Tabellen werden die untersuchten Verbindungen durch Num¬ mern gekennzeichnet, die den Nummern der Beispiele entsprechen.In the following tables the examined compounds are identified by numbers which correspond to the numbers of the examples.
Bestimmung des Blutdrucks und der Herzfrequenz beim narkotisierten KaninchenDetermination of blood pressure and heart rate in anesthetized rabbits
Die Versuchsdurchführung erfolgte in Analogie zu der in der internationalen Patentanmeldung W092/04337 beschriebenen Verfahrensweise. Das Untersu¬ chungsergebnis ist in Tabelle 1 dargestellt. The test was carried out in analogy to the procedure described in international patent application W092 / 04337. The result of the investigation is shown in Table 1.
Tabel l e 1Table 1
Prozentuale Senkung des arteriellen Blutdrucks (BP) und prozentuale Ände¬ rung der Herzfrequenz (HR) bei N narkotisierten Kaninchen (bei N > 1 Mit¬ telwerte) durch Gabe von Verbindungen der Formel IPercentage reduction in arterial blood pressure (BP) and percentage change in heart rate (HR) in N anesthetized rabbits (with N> 1 mean values) by administration of compounds of the formula I.
Die Versuchsdurchführung erfolgte in Analogie zu der in der internationalen Patentanmeldung W092/04337 beschriebenen Verfahrensweise. Das Untersu¬ chungsergebnis ist in Tabelle 2 dargestellt.The test was carried out in analogy to the procedure described in international patent application W092 / 04337. The result of the investigation is shown in Table 2.
Tabelle 2Table 2
Relaxierende Wirkung von Verbindungen der Formel I an der RattenaortaRelaxing effect of compounds of the formula I on the rat aorta
Fortsetzung Tabelle 2 Continuation of table 2
ECJ-Q = Konzentration, die die Kontraktion um 50 % hemmt N = Zahl der geprüften Rattenaortastreifen ECJ- Q = concentration that inhibits contraction by 50% N = number of rat aorta strips tested

Claims

Patentansprüche Claims
1. Verbindungen der Formel I,1. Compounds of the formula I
in der für jeden der Substituenten Rl, R2, R3 und R4 gilt, daß er an jedes gewünschte Kohlenstoffatom in den Positionen 3, 4, 5, 6, 7 oder 8 im Cuma¬ rinring gebunden sein kann, und worin Rl den Substituenten -Y-(CH2)rr]-A-(CH2)n-0-N02 darstellt,in which applies to each of the substituents R1, R2, R3 and R4 that it can be bound to any desired carbon atom in positions 3, 4, 5, 6, 7 or 8 in the cumaine ring, and in which R1 represents the substituent -Y Represents - (CH 2 ) rr] -A- (CH 2 ) n -0-N0 2 ,
R2 Wasserstoff, 1-4C-Alkyl oder den Substituenten -Y-(CHz) -A-(CHz)yn-0-N0z darstellt,R2 represents hydrogen, 1-4C-alkyl or the substituents -Y- (CHz) -A- (CHz) y n-0-N0z,
R3 Wasserstoff, 1-4C-Alkyl, l-4C-Alkoxy, l-4C-Alkoxy-l-4C-alkyl , l-4C-Alkylcarbonyl , l-4C-Alkylcarbonyloxy, l-4C-Alkylcarbonyl-l-4C-alkyl, Carboxyl , Carboxy-l-4C-alkyl , l-4C-Alkoxycarbonyl , Phenyl , Phenyl-l-4C-alkyl , Phenyl-l-4C-alkoxy, Halogen, Trifluor ethyl oder Cyan bedeutet undR3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl-1-4C-alkyl , Carboxyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, phenyl, phenyl-1-4C-alkyl, phenyl-1-4C-alkoxy, halogen, trifluoroethyl or cyan and
R4 Wasserstoff oder 1-4C-Alkyl bedeutet, wobei im Substituenten -Y-(CH2)m-A-(CH2) -0-N02 R4 is hydrogen or 1-4C-alkyl, the substituent being -Y- (CH 2 ) m -A- (CH 2 ) -0-N0 2
- Y 0 (Sauerstoff), CO-0 (Carbonyloxy) oder CO-NH (Carbonylamino) be¬ deutet und- Y 0 (oxygen), CO-0 (carbonyloxy) or CO-NH (carbonylamino) means and
- und n jeweils die Zahl 0 und A 2-12C-Alkylen, oder- and n each the number 0 and A 2-12C-alkylene, or
- m und n jeweils die Zahl 1 und A Cyclohexylen, oder- m and n each the number 1 and A cyclohexylene, or
- m und n jeweils die Zahl 2 und A 0 (Sauerstoff) oder 0-CH2-CH?-0 (Ethylendioxy) bedeuten.- m and n each the number 2 and A 0 (oxygen) or 0-CH 2 -CH ? Mean -0 (ethylenedioxy).
2. Verbindungen der Formel I nach Anspruch 1, in denen Rl den Substituenten -Y-(CH2)m-A-(CH2)n-0-N02 darstellt, R2 Wasserstoff oder 1-4C-Alkyl darstellt,2. Compounds of formula I according to claim 1, in which Rl represents the substituent -Y- (CH 2 ) m -A- (CH 2 ) n -0-N0 2 , R2 represents hydrogen or 1-4C-alkyl,
R3 Wasserstoff, 1-4C-Alkyl, l-4C-Alkoxy, l-4C-Alkoxy-l-4C-alkyl , Halogen oder Trifluormethyl bedeutet und R4 Wasserstoff oder 1-4C-Alkyl bedeutet, wobei im Substituenten -Y-(CH2)-n-A-(CH2)n-0-N02 R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, halogen or trifluoromethyl and R4 is hydrogen or 1-4C-alkyl, where in the substituent -Y- (CH 2 ) - n -A- (CH 2 ) n -0-N0 2
- Y 0 (Sauerstoff), CO-0 (Carbonyloxy) oder CO-NH (Carbonylamino) be¬ deutet und- Y 0 (oxygen), CO-0 (carbonyloxy) or CO-NH (carbonylamino) means and
- und n jeweils die Zahl 0 und A 2-8C-Alkylen, oder- and n each the number 0 and A 2-8C-alkylene, or
- m und n jeweils die Zahl 1 und A Cyclohexylen, oder- m and n each the number 1 and A cyclohexylene, or
- m und n jeweils die Zahl 2 und A 0 (Sauerstoff) oder 0-CH2-CH2-0 (Ethylendioxy) bedeuten.- m and n each represent the number 2 and A 0 (oxygen) or 0-CH 2 -CH 2 -0 (ethylenedioxy).
3. Verbindungen der Formel I nach Anspruch 1 oder 2, in denen Y 0 (Sauer¬ stoff) bedeutet und in denen Rl in 4- oder in 7-Position im Cumarinring ge¬ bunden ist.3. Compounds of formula I according to claim 1 or 2, in which Y is 0 (oxygen) and in which Rl is bound in the 4- or in the 7-position in the coumarin ring.
4. Verbindungen der Formel I nach Anspruch 1 oder 2, in denen Y CO-0 (Car¬ bonyloxy) oder CO-NH (Carbonylamino) bedeutet und in denen Rl in 3-Position im Cumarinring gebunden ist.4. Compounds of formula I according to claim 1 or 2, in which Y is CO-0 (carbonyloxy) or CO-NH (carbonylamino) and in which Rl is bonded in the 3-position in the coumarin ring.
5. Verbindung ausgewählt aus der Gruppe bestehend aus5. Connection selected from the group consisting of
4-(2-Nitroxyethoxy)cumarin4- (2-nitroxyethoxy) coumarin
4-Methyl-7-(2-nitroxyethoxy)cumarin4-methyl-7- (2-nitroxyethoxy) coumarin
7-(2-Nitroxyethoxy)cumarin7- (2-nitroxyethoxy) coumarin
7-(2-Nitroxyethoxy)-3,4,8-trimethylcumarin7- (2-nitroxyethoxy) -3,4,8-trimethylcoumarin
7-(2-Nitroxyethoxy)-4-trifluormethylcumarin7- (2-nitroxyethoxy) -4-trifluoromethylcoumarin
4-Methoxymethyl-7-(2-nitroxyethoxy)cumarin4-methoxymethyl-7- (2-nitroxyethoxy) coumarin
4-(2,2-Dimethyl-3-nitroxypropoxy)cumarin4- (2,2-dimethyl-3-nitroxypropoxy) coumarin
4-(3-Nitroxypropoxy)cumarin4- (3-nitroxypropoxy) coumarin
4-{2-[2-(2-Nitroxyethoxy)ethoxy]ethoxy}cumarin4- {2- [2- (2-nitroxyethoxy) ethoxy] ethoxy} coumarin
4-(6-Nitroxyhexyloxy)cumarin4- (6-nitroxyhexyloxy) coumarin
4-Methyl-7-(3-nitroxypropoxy)cumarin4-methyl-7- (3-nitroxypropoxy) coumarin
4-Methyl-7-[2-(2-nitroxyethoxy)ethoxy]cumarin4-methyl-7- [2- (2-nitroxyethoxy) ethoxy] coumarin
4-Methyl-7-[4-(nitroxymethyl)[trans]cyclohexylmethoxy]cumarin4-methyl-7- [4- (nitroxymethyl) [trans] cyclohexylmethoxy] coumarin
4-[4-(Nitroxymethyl)[trans]cyclohexylmethoxy]cumarin 3-Brom-4-methyl-7-(2-nitroxyethoxy)cumarin und 3-(2-Nitroxyethylaminocarbonyl)cumarin.4- [4- (nitroxymethyl) [trans] cyclohexylmethoxy] coumarin 3-bromo-4-methyl-7- (2-nitroxyethoxy) coumarin and 3- (2-nitroxyethylaminocarbonyl) coumarin.
6. Verfahren zur Herstellung der Verbindungen der Formel I nach Anspruch 1, dadurch gekennzeichnet, daß man6. A process for the preparation of the compounds of formula I according to claim 1, characterized in that
a) Verbindungen der Formel I, in denen Rl und gegebenenfalls R2 den Sub¬ stituenten -Y-(CH2) -A-(CH2) -OH darstellt, nitriert, oder daß mana) Compounds of formula I, in which Rl and optionally R2 represents the substituent -Y- (CH 2 ) -A- (CH 2 ) -OH, or that
b) zur Herstellung von Verbindungen der Formel I, in denen Y CO-0 (Car¬ bonyloxy) bedeutet, Verbindungen der Formel I, in denen Rl und gege¬ benenfalls R2 den Substituenten -CO-Z und Z OH (Hydroxy) oder eine geeignete Abgangsgruppe darstellt, mit Verbindungen der Formel H0-(CH2)m-A-(CH2)n-0-N02 umsetzt, oder daß manb) for the preparation of compounds of the formula I in which Y is CO-0 (carbonyloxy), compounds of the formula I in which R 1 and, if appropriate, R 2 have the substituents -CO-Z and Z OH (hydroxy) or a represents a suitable leaving group, with compounds of the formula H0- (CH 2 ) m -A- (CH 2 ) n -0 -N0 2 , or in that
c) zur Herstellung von Verbindungen der Formel I, in denen Y CO-NH (Car¬ bonylamino) bedeutet, Verbindungen der Formel I, in denen Rl und ge¬ gebenenfalls R2 den Substituenten -CO-Z und Z OH (Hydroxy) oder eine geeignete Abgangsgruppe darstellt, mit Verbindungen der Formel H2N-(CH2) -A-(CH2)n-0-N02 umsetzt, oder daß manc) for the preparation of compounds of the formula I in which Y is CO-NH (carbonylamino), compounds of the formula I in which R 1 and optionally R 2 have the substituents -CO-Z and Z OH (hydroxy) or a represents a suitable leaving group, with compounds of the formula H 2 N- (CH 2 ) -A- (CH 2 ) n -0-N0 2 or that
d) zur Herstellung von Verbindungen der Formel I, in denen R3 Halogen be¬ deutet, Verbindungen der Formel I, in denen R3 Wasserstoff bedeutet, halogeniert.d) for the preparation of compounds of the formula I in which R3 is halogen, compounds of the formula I in which R3 is hydrogen are halogenated.
7. Arzneimittel enthaltend eine oder mehrere Verbindungen nach Anspruch 1 zusammen mit üblichen pharmazeutischen Hilfsstoffen.7. Medicament containing one or more compounds according to claim 1 together with conventional pharmaceutical excipients.
8. Verwendung von Verbindungen nach Anspruch 1 zur Herstellung von Arznei¬ mitteln zur Verhütung und/oder Behandlung cardiovasculärer Erkrankungen.8. Use of compounds according to claim 1 for the manufacture of medicaments for the prevention and / or treatment of cardiovascular diseases.
9. Verwendung von Verbindungen nach Anspruch 1 zur Herstellung von Arznei¬ mitteln zur Verhütung und/oder Behandlung von Erkrankungen des Auges, die auf erhöhtem Augeninnendruck beruhen. 9. Use of compounds according to claim 1 for the manufacture of medicaments for the prevention and / or treatment of diseases of the eye which are based on increased intraocular pressure.
EP94901849A 1992-11-27 1993-11-23 Nitroxy compounds with pharmaceutical properties Withdrawn EP0670833A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH363692 1992-11-27
CH3636/92 1992-11-27
PCT/EP1993/003278 WO1994012488A1 (en) 1992-11-27 1993-11-23 Nitroxy compounds with pharmaceutical properties

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FR2760235B1 (en) * 1997-02-28 1999-04-09 Adir NOVEL BENZENESULFONYLAMINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US7538233B2 (en) 2003-09-05 2009-05-26 Aventis Pharmaceuticals Inc. Coumarins as iNOS inhibitors
BRPI0713253A2 (en) 2006-07-07 2012-10-30 Steven P Govek pde4 inhibition method, method of treating a pde4-mediated disease, compound and pharmaceutical composition
RU2672062C1 (en) * 2018-05-07 2018-11-09 Общество С Ограниченной Ответственностью "Сир" Hybrid coumarins with indirect anticoagulant action
RU2671983C9 (en) * 2018-05-07 2019-01-24 Общество С Ограниченной Ответственностью "Сир" Anticoagulant agent of indirect action on basis of diumancal

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JPS6013788A (en) * 1983-07-05 1985-01-24 Yamanouchi Pharmaceut Co Ltd Novel coumarin derivative

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AU5626494A (en) 1994-06-22
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