WO1996031466A1 - Nouveaux derives d'ethanolamine - Google Patents

Nouveaux derives d'ethanolamine Download PDF

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Publication number
WO1996031466A1
WO1996031466A1 PCT/EP1996/001305 EP9601305W WO9631466A1 WO 1996031466 A1 WO1996031466 A1 WO 1996031466A1 EP 9601305 W EP9601305 W EP 9601305W WO 9631466 A1 WO9631466 A1 WO 9631466A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
group
derivative
acceptable salt
Prior art date
Application number
PCT/EP1996/001305
Other languages
English (en)
Inventor
Carles Puig Duran
Ferrán PUJOL NOGUERA
Maria Isabel Crespo Crespo
Jacinto Moragues Mauri
Original Assignee
Laboratorios Almirall, S.A.
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 Laboratorios Almirall, S.A. filed Critical Laboratorios Almirall, S.A.
Priority to AU51487/96A priority Critical patent/AU5148796A/en
Publication of WO1996031466A1 publication Critical patent/WO1996031466A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/04—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms

Definitions

  • This invention relates to new therapeutically useful ethanolamine derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
  • ethanolamine derivatives are compounds in which the most important characteristic is to possess a selective agonist activity on the adrenergic /6 2 -receptors of the bronchus. Such compounds are useful as bronchodilator agents.
  • the present invention provides a compound which is an ethanolamine derivative of formula (I) :
  • R 1 is a pyridyl or NR 2 R 3 group, wherein R 2 is hydrogen or a
  • R 3 is a C 2 -C 4 alkanoyl group, an unsubstituted phenyl group or a phenyl group substituted by a carbamoyl group; m is from 4 to 8; and n is 2 or 3; or a pharmacologically acceptable salt thereof.
  • the present invention also provides a process for preparing a compound as defined above which comprises reducing an i ino derivative of formula (V) :
  • R 1 , m and n are as defined above with a reducing agent and, if desired, converting the thus-formed derivative of formula (I) into a pharmacologically acceptable salt thereof.
  • the present invention additionally provides a process for preparing a compound as defined above which comprises reacting a 2-bromoethanol derivative of formula (VI) :
  • R 4 is a protecting group with an amine of formula (IV) :
  • R 1 , R 4 , m and n are as defined above, followed by deprotection of the hydroxy group and, if desired, converting the thus-formed derivative of formula (I) into a pharmacological acceptable salt thereof.
  • the present invention further provides a compound as defined above for use in a method of treatment of the human or animal body by therapy, especially for use as an agonist on the adrenergic /8-receptors of the bronchus.
  • the present invention also provides use of a compound as defined above in the manufacture of a composition for use as an agonist on the adrenergic j3 2 -receptors of the bronchus.
  • Ethanolamine derivatives of formula (I) exhibit optical isomerism and the isomers are within the scope of the invention.
  • Preferred compounds of general formula (I) are those wherein R 1 is a pyridyl group, R 1 is a NR 2 R 3 group wherein R 2 is hydrogen and R 3 is a phenyl group substituted in the 4-position by a carbamoyl group (i.e. R 1 is a
  • the compounds of the invention may, for example, be prepared from 4-amino-3-chloro-5-cyanoacetophenone of formula (II) :
  • the aldehyde of formula (III) is first formed in the reaction mixture:
  • R 1 , m and n are as defined above, preferably at a temperature of 15°C to 35°C, to give the imino derivative of formula (V) :
  • the compounds of the invention may, for example, also be prepared by reacting a 2-bromoethanol derivative of formula (VI) :
  • R* is a protecting group, preferably a t-butyldimethylsilyl group, with an amine of formula (IV) to give the intermediate compound of formula (VII) :
  • R 1 , R 4 , m and n are as defined above, and further deprotection of the hydroxy group.
  • the reaction between the 2-bromoethanol derivative of formula (VI) and the amine of formula (IV) is preferably carried out in an organic solvent as dioxane, tetrahydrofuran, acetonitrile, methyl isobutyl ketone or N,N-dimethylformamide, at a temperature of from 70°C to
  • the deprotection reaction of the compound of formula (VII) to obtain the ethanolamine derivative of formula (I) is preferably carried out in a solvent such as tetrahydrofuran, dioxane or N,N-dimethylformamide in the presence of an alkaline or tetraalkylammonium fluoride, preferably tetrabutylammonium fluoride, at a temperature of from 10°C to 40°C.
  • the -CHOH- group in the derivative of formula (I) is a chiral centre and, for this reason, the ethanolamine derivatives of the present invention have (R) - and (S) - isomers. These isomers can be prepared from the corresponding (R) - or (S) -bromethanol derivative of formula (VI) , by reaction with an amine of formula (IV) and deprotection as mentioned above. This process is carried out under the same conditions that are described for the preparation of ethanolamine derivatives of formula (I) in their racemic form.
  • the ethanolamine derivatives of formula (I) may be converted by known methods into pharmacologically acceptable salts such as acid addition salts with acids by appropriate methods with acids in appropriate solvents, for example alcohols, tetrahydrofuran or acetone.
  • Suitable acid addition salts are those derived from organic acids, for example, fumarates, acetates, malates or benzenesulphonates.
  • the new ethanolamine derivatives of the present invention are more potent than known compounds, with rapid and long duration of action, and an advantageous profile.
  • the compounds of the present invention exhibit pharmacological properties useful in the treatment of reversible airways obstruction such as asthma and chronic bronchitis. They are also indicated in the treatment of allergic and inflammatory diseases, depression, glaucoma, congestive heart failure, premature labour and in disturbances in which it is an advantage to decrease the gastric acidity.
  • compositions of the present invention comprise, as active ingredient, at least one compound of formula (I) , in association with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent Preferably the compositions are in a form suitable for inhalation, oral, rectal, transdermal, bucal, nasal or parenteral administration.
  • the pharmaceutically-acceptable carriers or diluents which are admixed with the active compound or compounds to form the compositions of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administration of the compositions.
  • Compositions of this invention are preferably adapted for administration per inhalation.
  • Compositions for inhalation administration may be in the form of solutions, suspensions or micronized powder, contained in an appropriate inhaler.
  • compositions for oral administration may take the form of tablets, capsules, lozenges or effervescent granules or liquid preparations such as elixirs, syrups or suspensions, all containing one or more compounds of the invention.
  • Such preparations may be made by methods well known in the art, for instance by mixing the derivative of formula (I) or salt thereof with the pharmaceutically acceptable carrier or diluent.
  • the liquid compositions adapted for oral use may be in the form of solutions, suspensions or aerosols.
  • the solutions may be aqueous or aqueous-alcoholic solutions of a soluble compound in association with, for example, sucrose or sorbitol to form a syrup.
  • the suspensions may comprise an insoluble or microencapsulated form of an active compound of the invention in association with water and other acceptable solvents together with a suspending agent or flavouring agent.
  • compositions for parenteral injection may be prepared from the soluble compound, which may or may not be freeze-dried and which may be dissolved in water or an appropriate parenteral injection fluid.
  • the doses of the ethanolamine derivative of formula (I) or salt thereof depend on the desired effect and duration of the treatment; adult doses are generally between 0.005 mg and 100 mg per day.
  • the physician will decide the posology taking into account the age and weight of the patient being treated.
  • the present invention also provides a method of treatment of reversible airways obstruction, allergic and inflammatory diseases, depression, glaucoma, congestive heart failure, premature labour and disturbances in which it is an advantage to decrease the gastric acidity, which method comprises administering to a subject in need of such treatment an effective amount of a derivative of formula (I) or a pharmacologically acceptable salt thereof.
  • a derivative of formula (I) or a pharmacologically acceptable salt thereof comprising to a subject in need of such treatment an effective amount of a derivative of formula (I) or a pharmacologically acceptable salt thereof.
  • the resulting mixture was stirred for 15 hours at room temperature, the solvent removed under reduced pressure, the residue treated with a mixture of diethyl ether-water and decanted.
  • the organic solution was washed with water, dried (Na 2 S0 4 ) and the solvent removed in vacuo.
  • the obtained residue was purified by silica gel column chromatography with methylene chloride-methanol- ammonium hydroxide 40:2.5:0.1 as eluent.
  • Procedure A macrocrystalline suspension prepared with these ingredients was introduced in the inhalation flasks at a volume of 20 ml per flask with a filling machine.
  • the flasks were furnished with an appropriate valve which releases 0.1 ml of suspension for each activation (0.125 mg active compound) .
  • the above ingredients were sieved through a 60 mesh sieve, then mixed in a suitable mixer and filled into 50,000 gelatine capsules.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention décrit un composé qui est un dérivé d'éthanolamine de formule (I), dans laquelle R1 est un pyridyle ou un groupe NR2R3, dans lequel R2 représente un hydrogène ou un alkyle C¿1?-C4 ou un groupe méthanesulphuryle et R?3¿ représente un groupe alkanoyle C¿2?-C4, un groupe phényle non substitué ou un groupe phényle substitué par un groupe carbamoyle; m est compris entre 4 et 8; et n vaut 2 ou 3; ou un de ses sels pharmaceutiquement acceptables, comporte une activité agoniste sur les récepteurs β adrénergiques des bronches.
PCT/EP1996/001305 1995-04-03 1996-03-25 Nouveaux derives d'ethanolamine WO1996031466A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51487/96A AU5148796A (en) 1995-04-03 1996-03-25 New ethanolamine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP9500660 1995-04-03
ES9500660 1995-04-03

Publications (1)

Publication Number Publication Date
WO1996031466A1 true WO1996031466A1 (fr) 1996-10-10

Family

ID=8289987

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/001305 WO1996031466A1 (fr) 1995-04-03 1996-03-25 Nouveaux derives d'ethanolamine

Country Status (5)

Country Link
AU (1) AU5148796A (fr)
IL (1) IL117784A0 (fr)
UY (1) UY24199A1 (fr)
WO (1) WO1996031466A1 (fr)
ZA (1) ZA962597B (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2351281A1 (de) * 1973-10-12 1975-04-24 Thomae Gmbh Dr K Neue amino-phenyl-aethanolamine und deren oxazolidine
DE4028398A1 (de) * 1990-09-07 1992-03-12 Thomae Gmbh Dr K Phenylethanolamine, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
WO1994008945A1 (fr) * 1992-10-16 1994-04-28 Byk Nederland Bv Esters d'ethanolamine substitues

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2351281A1 (de) * 1973-10-12 1975-04-24 Thomae Gmbh Dr K Neue amino-phenyl-aethanolamine und deren oxazolidine
DE4028398A1 (de) * 1990-09-07 1992-03-12 Thomae Gmbh Dr K Phenylethanolamine, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
WO1994008945A1 (fr) * 1992-10-16 1994-04-28 Byk Nederland Bv Esters d'ethanolamine substitues

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
G. KRÜGER ET AL.: "Synthesis of further Animo-Halogen-Substituted Phenyl-aminoethanols", ARZNEIMITTEL FORSCHUNG DRUG RESEARCH., vol. 34(II), no. 11a, 1984, AULENDORF DE, pages 1612 - 1624, XP002008984 *

Also Published As

Publication number Publication date
UY24199A1 (es) 1996-04-11
ZA962597B (en) 1996-07-25
AU5148796A (en) 1996-10-23
IL117784A0 (en) 1996-08-04

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