EP0670833A1 - Composes nitroxy presentant des proprietes pharmaceutiques - Google Patents

Composes nitroxy presentant des proprietes pharmaceutiques

Info

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Withdrawn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)
English (en)
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by IOVIS BIOMEDICAL AND PHARMACEUTICAL CONSULTANTS, BYK Nederland BV filed Critical IOVIS BIOMEDICAL AND PHARMACEUTICAL CONSULTANTS
Publication of EP0670833A1 publication Critical patent/EP0670833A1/fr
Withdrawn legal-status Critical Current

Links

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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de la formule (I) dans laquelle R1, R2, R3 et R4 ont les notations mentionnées dans la description et se prêtent au traitement de maladies cardiovasculaires, ainsi qu'au traitement de l'hypertension intraoculaire.
EP94901849A 1992-11-27 1993-11-23 Composes nitroxy presentant des proprietes pharmaceutiques Withdrawn EP0670833A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH3636/92 1992-11-27
CH363692 1992-11-27
PCT/EP1993/003278 WO1994012488A1 (fr) 1992-11-27 1993-11-23 Composes nitroxy presentant des proprietes pharmaceutiques

Publications (1)

Publication Number Publication Date
EP0670833A1 true EP0670833A1 (fr) 1995-09-13

Family

ID=4260247

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94901849A Withdrawn EP0670833A1 (fr) 1992-11-27 1993-11-23 Composes nitroxy presentant des proprietes pharmaceutiques

Country Status (4)

Country Link
EP (1) EP0670833A1 (fr)
JP (1) JPH08503484A (fr)
AU (1) AU5626494A (fr)
WO (1) WO1994012488A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2760235B1 (fr) * 1997-02-28 1999-04-09 Adir Nouveaux derives de benzenesulfonylamine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US7538233B2 (en) 2003-09-05 2009-05-26 Aventis Pharmaceuticals Inc. Coumarins as iNOS inhibitors
US20090291950A1 (en) 2006-07-07 2009-11-26 Kalypsys, Inc. Bicyclic heteroaryl inhibitors of pde4
RU2672062C1 (ru) * 2018-05-07 2018-11-09 Общество С Ограниченной Ответственностью "Сир" Гибридные кумарины, обладающие непрямым антикоагулянтным действием
RU2671983C9 (ru) * 2018-05-07 2019-01-24 Общество С Ограниченной Ответственностью "Сир" Антикоагулянтное средство непрямого действия на основе диуманкала

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6013788A (ja) * 1983-07-05 1985-01-24 Yamanouchi Pharmaceut Co Ltd 新規なクマリン誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9412488A1 *

Also Published As

Publication number Publication date
AU5626494A (en) 1994-06-22
JPH08503484A (ja) 1996-04-16
WO1994012488A1 (fr) 1994-06-09

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