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WO1991009834A1 - DERIVES D'o-HYDROXY-β-(1-NAPHTYL)-PROPIOPHENONE, LEUR PROCEDE DE PRODUCTION ET MEDICAMENTS CONTENANT CES COMPOSES - Google Patents

DERIVES D'o-HYDROXY-β-(1-NAPHTYL)-PROPIOPHENONE, LEUR PROCEDE DE PRODUCTION ET MEDICAMENTS CONTENANT CES COMPOSES Download PDF

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Publication number
WO1991009834A1
WO1991009834A1 PCT/EP1991/000007 EP9100007W WO9109834A1 WO 1991009834 A1 WO1991009834 A1 WO 1991009834A1 EP 9100007 W EP9100007 W EP 9100007W WO 9109834 A1 WO9109834 A1 WO 9109834A1
Authority
WO
WIPO (PCT)
Prior art keywords
naphthyl
phenyl
hydroxy
carbon atoms
propoxy
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.)
Ceased
Application number
PCT/EP1991/000007
Other languages
German (de)
English (en)
Inventor
Gerd Petrik
Klemens Schubert
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.)
Helopharm W Petrik and Co KG
Original Assignee
Helopharm W Petrik and Co KG
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 Helopharm W Petrik and Co KG filed Critical Helopharm W Petrik and Co KG
Publication of WO1991009834A1 publication Critical patent/WO1991009834A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/36—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms

Definitions

  • the invention relates to new o-hydroxy-3- (1-naphthyl) propiophenone derivatives and their physiologically tolerable salts with acids, processes for their preparation and pharmaceutical compositions containing these compounds.
  • n-propylamino compound, R n - C 3 H 7 (propafenone) has an antiarrhythmic activity.
  • R 1 - R 4 are hydrogen atoms or alkyl radicals; n has a value of 1, 2 or 3.
  • These compounds are drugs that are used as antiarrhythmics. When tested on the isolated atrium of the guinea pig heart, many of these compounds are as potent as the standard compound propafenone.
  • the object of the present invention is new o-hydroxy-jß- (1-naphthyl) propiophenone derivatives of the general formula I.
  • R 1 and R 2 are identical or different and denote hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl or hydroxyalkyl radicals each having up to 6 carbon atoms, alkoxyalkyl, alkylthioalkyl or dialkylami- noalkyl radicals with up to 9 carbon atoms each, or phenylalkyl or phenoxyalkyl radicals with up to 6 carbon atoms in the alkyl part, where the phenyl radical is optionally substituted by an alkyl or alkoxy radical with up to 3 carbon atoms each, or,
  • R 1 and R 2 together with the nitrogen atom connecting them form a 5- to 7-membered saturated, heterocyclic ring which may be substituted by one or two phenyl and / or hydroxyl radicals and an oxygen atom or Nitrogen atom as a further hetero atom in the ring can contain, where an additional nitrogen atom can be substituted by an alkyl radical with 1 to 3 carbon atoms or a phenyl radical, R 3 is a hydrogen atom, an alkyl radical with up to 3 carbon atoms.
  • Ato en a fluorine, chlorine or bromine atom, a hydroxy group or an alkoxy group with up to 6 carbon atoms.
  • NR ⁇ -R 2 is a tert-pentylamino, n-propylamino, isopropyl ino, tert-butylamino, morpholino or piperidino group and R 3 is a hydrogen atom or represents methyl group.
  • the invention further relates to a process for the preparation of the compounds of the general formula I and their acid addition salts, which is characterized in that a phenol ether of the general formula II
  • R 1 , R 2 and R 3 have the meaning given above.
  • the compound of general formula I obtained is converted into an acid addition salt using an acid.
  • the reaction can be carried out, for example, using the process described in EP-B 0 074 014.
  • the reaction is carried out at temperatures from 10 to 120 ° C., ie at room temperature or at higher temperatures, advantageously at temperatures from 50 to 120 ° C., under atmospheric pressure or in a closed vessel under elevated pressure.
  • the starting compounds of the formulas II and III can be reacted without diluents or solvents.
  • the reactions are expediently carried out in the presence of an inert diluent or solvent, for example a lower alcohol having 1 to 4 carbon atoms, such as methanol, ethanol or propanol, preferably isopropanol or ethanol, or a lower saturated one Dialkyl ether, dialkyl glycol ether or cyclic ether, such as
  • a benzene hydrocarbon such as benzene itself or an alkylbenzene, in particular toluene or xylene
  • an aliphatic hydrocarbon such as hexane, heptane or octane, dimethyl sulfoxide or in the presence of water or mixtures of the mentioned solvents.
  • the amine of the general formula III used in excess is optionally suitable as a diluent or solvent.
  • the complete reaction depends on the reaction temperature and is generally completed within 2 to 15 hours.
  • the reaction product can be obtained in a conventional manner, for example by filtering or distilling off the diluent from the reaction mixture.
  • the compound obtained is purified in a customary manner, for example by recrystallization from a solvent, transfer to an acid addition salt or by column chromatography.
  • the phenol ether of the general formula II can by alkylation of a 3- (l-naphthyl) -l (2 * -hydroxyphenyl) -1-propanone of the general formula IV
  • R 3 has the meaning given above.
  • Epichlorohydrin, epibromohydrin and epiiodohydrin are suitable as epihalohydrins.
  • the reaction of the compounds IV for the preparation of the starting compounds of the general formula II is expediently carried out at temperatures from 0 to 120 ° C. and under normal pressure or in a closed vessel under increased pressure.
  • a lower aliphatic ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a lower alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol or butanol, a lower aliphatic or cyclic ether, such as diethyl ether, are expediently used as solvents or diluents , Tetrahydrofuran or dioxane, a dialkyl formate, such as dimethylformamide or diethylformamide, or dimethyl sulfoxide or hexamethylphosphoric acid triamide or excess alkylating agent.
  • the reactions are preferably carried out in the presence of a base as an acid-binding agent.
  • Suitable bases are alkali metal carbonates, bicarbonates, hydroxides, hydrides or alcoholates, in particular of sodium and potassium, basic oxides such as aluminum oxide or calcium oxide, see organic tertiary bases such as pyridine, lower trialkylamines such as trimethyl or triethylamine, or piperidine.
  • the bases can be in relation to the alkylating agent used be used in a catalytic amount or in a stoichiometric amount or in a slight excess.
  • the compound of general formula IV with epichlorohydrin or epibromohydrin in a polar, aprotic solvent, in particular diethyl sulfoxide, is preferred in the presence of at least one molar equivalent of base, in particular sodium hydride, based on the alkylating agent, at temperatures from 0 to 50 ° C implemented.
  • the compound of the general formula I obtained according to the invention is converted into an acid addition salt, preferably into a salt of a physiologically tolerable acid
  • customary physiologically tolerable inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid , Fumaric acid, lactic acid, tartaric acid, ⁇ pp ⁇ rock acid, citric acid, salicylic acid, adipic acid and benzoic acid.
  • Further usable acids are described e.g. in Progress in Pharmaceutical Research, vol. 10, pages 224-225, Birkhäuser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pages 1-5 (1977). Hydrochloric acid is preferred.
  • the acid addition salts are generally prepared in a manner known per se by mixing the free base or its solutions with the corresponding acid or their solutions in an organic solvent, for example a lower alcohol, such as methanol, ethanol, n-propanol or isopropanol, or a lower ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether, such as
  • solvents can be used.
  • pharmaceutically acceptable aqueous solutions of acid addition salts of the compound of the formula I can be prepared in an aqueous acid solution.
  • the acid addition salts of the compound of formula I can be used in a manner known per se, e.g. with alkalis or ion exchangers, are converted into the free base. Additional salts can be obtained from the free base by reaction with inorganic or organic acids, in particular those which are suitable for forming therapeutically usable salts. These or other salts of the new compound, e.g. the picrate can also be used to clean the free base by converting the free base into a salt, separating it and releasing the base from the salt.
  • the present invention also relates to pharmaceuticals for oral, rectal, intravenous or intramuscular application which, in addition to conventional carriers and diluents, contain a compound of the formula I or its acid addition salt as active ingredient, and the use of the new compound and its physiologically tolerable Salts in the treatment of heart rhythm disorders.
  • the medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage.
  • the preferred preparations consist of a dosage form which is suitable for oral administration.
  • dosage forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot forms.
  • parenteral preparations such as injection solutions, can also be used.
  • Suppositories may also be mentioned as preparations.
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve one Depot effects such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained.
  • auxiliaries for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve one Depot effects such as carboxypoly
  • coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in coated tablets, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Solutions or suspensions with the active ingredient according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and e.g. Flavors such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates.
  • Capsules containing active substances can be produced, for example, by mixing the active substance with an inert carrier, such as milk sugar or sorbitol, and encapsulating it in gelatin capsules.
  • Suitable suppositories can be found, for example
  • the individual dose for humans for oral use is between 0.5 - 5 mg / kg for i.v. Use between 0.05 - 2 mg / kg for the i.m. Use between 0.1 - 3 mg / kg for rectal use between 0.5 - 10 mg / kg.
  • the compounds according to the invention and their physiologically tolerated acid addition salts are strongly antiarrhythmic. They also have antidepressant activity. They are therefore particularly suitable for the pharmacotherapy of cardiac arrhythmias, for the treatment of coronary heart disease and for the prophylaxis of sudden cardiac death. Since patients with heart problems often suffer from depression, the combination of antiarrhythmic and antidepressant properties is particularly desirable.
  • the antiarrhythmic effectiveness of the compounds according to the invention was determined both on the basis of electrophysiological studies on Purkinje fibers from dog hearts and with the aid of ouabain-induced ventricular tachycardias in dogs.
  • SF safety factor
  • prematurity index (prematurity factor), which characterizes the desired activity of the compounds according to the invention in premature extrasystoles, was determined as an additional criterion.
  • Example 1 The compound of Example 1 is sieved if necessary, then all raw materials except magnesium stearate are mixed in a mixer and also moistened in the mixer with a suitable amount of a granulating liquid (e.g. water or isopropanol-dichloromethane 1: 1).
  • a suitable amount of a granulating liquid e.g. water or isopropanol-dichloromethane 1: 1).
  • the moist mixture is sieved using a suitable sieve, dried in a drying cabinet and sieved again.
  • the dry granulate is mixed with the magnesium stearate in the mixer.
  • Tablets with a weight between 40 and 400 mg are pressed from the mixture prepared according to a) in a tablet press.
  • the pressing force and the tablet diameter are chosen so that the disintegration time in the test device according to Ph. Eur. Is less than 15 minutes and the tablets are mechanically sufficiently stable.
  • the components of the film coating are dissolved in a suitable solvent (eg water or ethanol / water 70:30).
  • a suitable solvent eg water or ethanol / water 70:30.
  • the tablets are sprayed with the solution of the film former and the plasticizer in a film coating system and dried in a hot air stream.
  • the film-coated tablets are dried in the drying cabinet.
  • Titanium (IV) oxide 1.6%
  • composition of the coating solution, cover mix and coating suspension used
  • the dragee cores are first moistened with the coating solution in the rotating kettle and then powdered with sufficient cover mixture until they roll freely again. After the cores have dried, this process is repeated. Then the cores are dried in the drying cabinet. The cores are then coated with the coating suspension in layers until the desired final weight is reached. The cores must be dried after each application of a layer.
  • the granules are filled into size 3, 2, 1 or 0 hard gelatin capsules using a capsule filling machine.
  • the filling quantity per capsule depends on the desired dosage of the active ingredient.
  • the total weight of active substance and microcrystalline cellulose should always be 91.25 g.
  • the amount of active ingredient is a thousand times the individual dose.
  • 100 mg granules are filled into size 3 or 2 hard gelatin capsules using a capsule filling machine.
  • the finished solution is filled into glass ampoules, the filling quantity of which depends on the desired dosage. Then the glass ampoules are sealed.
  • the amount of hard fat required for a certain number of suppositories is melted at 40 ° C in a water bath.
  • the active ingredient is pressed through a 0.8 mm sieve and stirred into the melt, so that a suspension is formed.
  • the melt is allowed to cool to 37-38 ° C. and filled into suppository forms with constant stirring in such a way that the weight of a suppository is 2000 mg.
  • the suppository shape is closed after the melt solidifies.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Dérivés d'o-hydroxy-beta-(1-naphtyl)-propiophénone ayant la formule générale (I), leurs sels d'addition d'acide, leur procédé de produciton et médicaments contenant ces composés.
PCT/EP1991/000007 1990-01-05 1991-01-04 DERIVES D'o-HYDROXY-β-(1-NAPHTYL)-PROPIOPHENONE, LEUR PROCEDE DE PRODUCTION ET MEDICAMENTS CONTENANT CES COMPOSES Ceased WO1991009834A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4000213.6 1990-01-05
DE19904000213 DE4000213A1 (de) 1990-01-05 1990-01-05 O-hydroxy-ss-(1-naphthyl)-propiophenonderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel

Publications (1)

Publication Number Publication Date
WO1991009834A1 true WO1991009834A1 (fr) 1991-07-11

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PCT/EP1991/000007 Ceased WO1991009834A1 (fr) 1990-01-05 1991-01-04 DERIVES D'o-HYDROXY-β-(1-NAPHTYL)-PROPIOPHENONE, LEUR PROCEDE DE PRODUCTION ET MEDICAMENTS CONTENANT CES COMPOSES

Country Status (3)

Country Link
AU (1) AU7070391A (fr)
DE (1) DE4000213A1 (fr)
WO (1) WO1991009834A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0462150B1 (fr) * 1989-03-08 1994-09-07 Laevosan-Gesellschaft m.b.H. Nouvelles aryloxy-alkylamines, leur fabrication et medicaments les contenant
AT401726B (de) * 1993-05-17 1996-11-25 Gerhard Dr Ecker O-acylaryloxypropanolamine mit tertiärem oder quartärem stickstoff als reversionsmodulatoren für p-glykoprotein mediierte multidrug-resistenz

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102372643A (zh) * 2010-08-13 2012-03-14 天津市科林化工有限公司 盐酸沙格雷酯的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2001431B2 (de) * 1970-01-06 1974-05-09 Helopharm W. Petrik & Co Kg, 1000 Berlin 2-(2'-Hydroxy-3'-alkylaminopropoxy)-Omega-phenyl-propiophenone und Verfahren zur Herstellung derselben
EP0074014A1 (fr) * 1981-08-25 1983-03-16 Helopharm W. Petrik GmbH & Co.KG. 2-(2'-hydroxy-3'-(1,1-diméthylpropylamino)-propoxy)-bêta-propiophénone, ses sels d'addition, procédé de sa préparation et médicament
EP0075207A2 (fr) * 1981-09-18 1983-03-30 BASF Aktiengesellschaft Derivés propanolamines de 2-hydroxy-béta-phényl-propiophénones, procédés pour leur préparation et agents thérapeutiques les contenant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2001431B2 (de) * 1970-01-06 1974-05-09 Helopharm W. Petrik & Co Kg, 1000 Berlin 2-(2'-Hydroxy-3'-alkylaminopropoxy)-Omega-phenyl-propiophenone und Verfahren zur Herstellung derselben
EP0074014A1 (fr) * 1981-08-25 1983-03-16 Helopharm W. Petrik GmbH & Co.KG. 2-(2'-hydroxy-3'-(1,1-diméthylpropylamino)-propoxy)-bêta-propiophénone, ses sels d'addition, procédé de sa préparation et médicament
EP0075207A2 (fr) * 1981-09-18 1983-03-30 BASF Aktiengesellschaft Derivés propanolamines de 2-hydroxy-béta-phényl-propiophénones, procédés pour leur préparation et agents thérapeutiques les contenant

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0462150B1 (fr) * 1989-03-08 1994-09-07 Laevosan-Gesellschaft m.b.H. Nouvelles aryloxy-alkylamines, leur fabrication et medicaments les contenant
AT401726B (de) * 1993-05-17 1996-11-25 Gerhard Dr Ecker O-acylaryloxypropanolamine mit tertiärem oder quartärem stickstoff als reversionsmodulatoren für p-glykoprotein mediierte multidrug-resistenz

Also Published As

Publication number Publication date
AU7070391A (en) 1991-07-24
DE4000213A1 (de) 1991-07-11

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