EP0599896A1 - (-) and (+) 10-(1-azabicyclo 2.2.2.]oct-3-yl-methyl)-10 h-phenothiazine quaternary ammonium derivatives, pharmaceutical compositions containing them and process for their preparation - Google Patents

(-) and (+) 10-(1-azabicyclo 2.2.2.]oct-3-yl-methyl)-10 h-phenothiazine quaternary ammonium derivatives, pharmaceutical compositions containing them and process for their preparation

Info

Publication number
EP0599896A1
EP0599896A1 EP92916942A EP92916942A EP0599896A1 EP 0599896 A1 EP0599896 A1 EP 0599896A1 EP 92916942 A EP92916942 A EP 92916942A EP 92916942 A EP92916942 A EP 92916942A EP 0599896 A1 EP0599896 A1 EP 0599896A1
Authority
EP
European Patent Office
Prior art keywords
per
enantiomorphs
methyl
azabicyclo
oct
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
EP92916942A
Other languages
German (de)
English (en)
French (fr)
Inventor
Raffaello Giorgi
Alessandro Subissi
Luigi Turbanti
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.)
Laboratorio Guidotti SpA
Original Assignee
Laboratorio Guidotti SpA
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 Laboratorio Guidotti SpA filed Critical Laboratorio Guidotti SpA
Publication of EP0599896A1 publication Critical patent/EP0599896A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • This invention refers to dextrorotatory (+) and levorotatory (-) enantiomorphs of 10- (l-azabicyclo[2.2.2. ]oct-3-yl-methyl)-10 H- phenothiazine quaternary ammonium derivatives as per the following general formula (I)
  • R C 1-4 alkyl, cyclopropyl
  • X halogen, dimethyl sulphate, p-toluenesulphonic acid
  • Mequitazine quaternary derivatives (just as, on the other hand, mequitazine itself) exhibit an asymmetric carbon atom (position 3 of 1-azabicyclo[2.2.2.]octane).
  • Each racemic quaternary derivative thus consists of two (+) and (-) enantiomorphs in a 50:50 ratio. It has surprisingly been found that the enantiomorphs of the quaternary derivatives of mequitazine as per formula (I)
  • R C 1-4 alkyl, cyclopropyl
  • X halogen, dimethyl sulphate, p-toluenesulphonic acid
  • C 1-4 alkyl means: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl.
  • halogen means: iodine, bromine, chlorine.
  • the dextrorotatory enantiomorph is thus being proposed hereby as an agent particularly suitable for the treatment of bronchoconstrictive and allergic diseases (in particular bronchial asthma and rhinitis) and of all pathologies involving histamine - one of the main mediators both of asthmatic bronchoconstriction and of the abnormal response of the mucous membrane of the nose in the case of allergic rhinitis - , or acetylcholine - which controls both the tone of respiratory system and the secretion of the mucous membrane of the nose.
  • the mediators involved by asthmatic bronchoconstriction and rhinitis are many, the extent of their involvement depending on the type and progress of disease and on the patient as well.
  • the fact that the dextrorotatory enantiomorph exhibits both activities at quite superimposable concentrations makes it particularly interesting as an instrument for the treatment of such diseases.
  • the racemic mixture of mequitazine (A) is resolved into the two respective dextro- and levorotatory enantiomorphs by the usual chromatographic separation techniques based on the use of chiral phases.
  • cellulose preparative chromatographic columns can be used, eluents being hexane/ethyl alcohol (94/6) , hexane/methyl alcohol (98/2) , hexane/ethyl alcohol/TEA (98/0.8/1.2) .
  • the so obtained enantiomorphs are then quaternized with reagents, as described in the examples hereinunder given by way of indication, not of limitation.
  • Enantiomorphs as per the invention result to be particularly useful in the preparation of pharmaceutical compositions for topical use (mainly by inhalation and intranasal administration) or for oral administration.
  • a type of pharmaceutical formulations suitable for the administration of the active ingredient according to the invention is conveyed in Example 3 hereinunder by way of indication, not of limitation.
  • 35 g (0.1 mole) of the mequitazine (-) enantiomorph obtained by preparative chromatographic chiral-phase column separation from the mequitazine racemic mixture is suspended in 200 ml acetonitrile. The suspension is kept under stirring for 10 minutes to homogenization.
  • a pharmaceutical formulation consisting of
  • Freon 12-114 R (65:35) 10.500 mg was placed in a metering valve type small cylinder.
  • the above preparation allows the administration of single 50 to 200 ⁇ g active ingredient metered doses.
  • Enantiomorphs as per Examples 1 and 2 were comparatively studied to ascertain their pharmacotoxicologic properties, with special regard to the following aspects: acetylcholine and histamine antagonism on guinea pig's isolated trachea, guinea pig's broncoconstriction inhibition induced by acetylcholine and histamine (Konzett-Roessler method), acute toxicity in mice.
  • both enantiomorphs are acetylcholine and histamine competitive antagonists on guinea pig's trachea.
  • both enantiomorphs are equally effective in respect of acetylcholine (pA 2 7-96 and 7-81 for levorotatory and dextrorotatory enantiomorphs, respectively
  • the dextrorotatory enantiomorph (+) (pA 2 8.05) is significantly more effective than the levorotatory (-) (pA 2 7-09) in respect of histamine.
  • mice The acute toxicity test referred to i.v. administration to mice showed that the dextrorotatory enantiomorph (+) [LD 50 and fiducial limits at 95%: 3-65 (3-45-3-86) mg kg -1 ] is significantly less toxic than the levorotatory enantiomorph (-) [2.68 (2.61-2.74) mg kg -1 ].

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP92916942A 1991-08-07 1992-08-03 (-) and (+) 10-(1-azabicyclo 2.2.2.]oct-3-yl-methyl)-10 h-phenothiazine quaternary ammonium derivatives, pharmaceutical compositions containing them and process for their preparation Ceased EP0599896A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITMI91222 1991-08-07
ITMI912225A IT1251161B (it) 1991-08-07 1991-08-07 Derivati ammonio quaternari di (-) e (+)-3-(10 h-fenotiazin-10-ilmetil)-l-azabiciclo (2.2.2.)ottano e composizioni farmaceutiche che li contengono
PCT/EP1992/001759 WO1993003029A1 (en) 1991-08-07 1992-08-03 (-) and (+) 10-(1-azabicyclo[2.2.2.]oct-3-yl-methyl)-10 h-phenothiazine quaternary ammonium derivatives, pharmaceutical compositions containing them and process for their preparation

Publications (1)

Publication Number Publication Date
EP0599896A1 true EP0599896A1 (en) 1994-06-08

Family

ID=11360550

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92916942A Ceased EP0599896A1 (en) 1991-08-07 1992-08-03 (-) and (+) 10-(1-azabicyclo 2.2.2.]oct-3-yl-methyl)-10 h-phenothiazine quaternary ammonium derivatives, pharmaceutical compositions containing them and process for their preparation

Country Status (19)

Country Link
EP (1) EP0599896A1 (cs)
JP (1) JPH06509570A (cs)
CN (1) CN1071667A (cs)
AU (1) AU2417392A (cs)
BG (1) BG98439A (cs)
BR (1) BR9206339A (cs)
CA (1) CA2114844A1 (cs)
CZ (1) CZ24894A3 (cs)
EC (1) ECSP920859A (cs)
FI (1) FI940530A7 (cs)
HU (1) HUT66570A (cs)
IT (1) IT1251161B (cs)
MA (1) MA22611A1 (cs)
MX (1) MX9204539A (cs)
PT (1) PT100765A (cs)
SK (1) SK11594A3 (cs)
TN (1) TNSN92073A1 (cs)
WO (1) WO1993003029A1 (cs)
ZA (1) ZA925852B (cs)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6072113A (en) * 1996-10-18 2000-06-06 Yamaha Corporation Musical performance teaching system and method, and machine readable medium containing program therefor
WO2003105811A2 (en) * 2002-01-31 2003-12-24 Southwest Research Institute Controlled release compositions and methods for using same
FR2910814B1 (fr) * 2006-12-28 2011-06-17 Pf Medicament Utilisation du 10-°(r3)-1-azabicyclo°2.2.2!oct-3-ylmethyl!-10h- phenothiazine pour la preparation d'un medicament exercant une inhibition selective des recepteurs muscariniques m1,2,3
FR2911606B1 (fr) * 2007-01-18 2009-04-17 Pierre Fabre Medicament Sa Nouveau derive de la quinuclidine utile dans la preparation de la mequitazine
FR2924344B1 (fr) * 2007-12-04 2010-04-16 Pf Medicament Utilisation de la mequitazine sous la forme de racemate ou d'enantiomeres pour la preparation d'un medicament destine au traitement ou a la prevention de pathologies impliquant les recepteurs histaminiques h4.
FR2970255B1 (fr) 2011-01-10 2013-09-06 Pf Medicament Vinyl quinuclidine utile en tant qu'intermediaire de synthese dans la preparation de la (r)-mequitazine.
JP7599646B2 (ja) * 2020-10-29 2024-12-16 国立大学法人金沢大学 薬物代謝酵素活性を測定するための放射性フッ素標識画像診断薬

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2522660A1 (fr) * 1982-03-05 1983-09-09 Pharmuka Lab Isomere levogyre de la mequitazine, son procede de preparation et medicaments le contenant
FR2526433B1 (fr) * 1982-05-04 1985-10-18 Pharmuka Lab Isomeres dextrogyres de derives de l'aza-1 bicyclo (2,2,2) octane, leur procede de preparation et medicaments les contenant
IT1173445B (it) * 1984-03-16 1987-06-24 Guidotti & C Spa Labor Agenti ad attivita' antibroncospastica e composizioni farmaceutiche che li contengono

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9303029A1 *

Also Published As

Publication number Publication date
IT1251161B (it) 1995-05-04
CA2114844A1 (en) 1993-02-18
WO1993003029A1 (en) 1993-02-18
CZ24894A3 (en) 1994-07-13
FI940530L (fi) 1994-02-04
FI940530A0 (fi) 1994-02-04
ZA925852B (en) 1993-03-05
TNSN92073A1 (fr) 1993-06-08
JPH06509570A (ja) 1994-10-27
MX9204539A (es) 1993-02-01
CN1071667A (zh) 1993-05-05
ITMI912225A0 (it) 1991-08-07
PT100765A (pt) 1993-10-29
BR9206339A (pt) 1994-11-08
MA22611A1 (fr) 1993-04-01
BG98439A (bg) 1994-09-30
HUT66570A (en) 1994-12-28
AU2417392A (en) 1993-03-02
ITMI912225A1 (it) 1993-02-07
SK11594A3 (en) 1994-12-07
ECSP920859A (es) 1993-08-03
FI940530A7 (fi) 1994-02-04
HU9400273D0 (en) 1994-05-30

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Free format text: (-) AND (+) 10-(1-AZABICYCLO 2.2.2. OCT-3-YL-METHYL)-10 H-PHENOTHIAZINE QUATERNARY AMMONIUM DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR THEIR PREPARA