AU2417392A - (-) 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

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Publication number
AU2417392A
AU2417392A AU24173/92A AU2417392A AU2417392A AU 2417392 A AU2417392 A AU 2417392A AU 24173/92 A AU24173/92 A AU 24173/92A AU 2417392 A AU2417392 A AU 2417392A AU 2417392 A AU2417392 A AU 2417392A
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AU
Australia
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.)
Abandoned
Application number
AU24173/92A
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 AU2417392A publication Critical patent/AU2417392A/en
Abandoned legal-status Critical Current

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    • 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

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

(-) 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
Field of the Invention
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)
where x
R = C1-4 alkyl, cyclopropyl
X = halogen, dimethyl sulphate, p-toluenesulphonic acid
as well as to the pharmaceutical compositions containing them.
State of the Art
The 10- (1-azabicyclo[2.2.2]oct-3-yl-methyl) -10 H-phenothiazine compound (internationally known as mequitazine) as per the following formula (A)
is acknowledged by literature (see, e.g., FR-A-203^ 605 and its antihistaminic properties are described herein.
In patent EP-A-159 059, the applicant described quaternary derivatives of the compound as per formula (A), in the form of racemic modifications, endowed with a significant anti- bronchospastic activity.
Detailed Description of the Invention
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)
where
R = C1-4 alkyl, cyclopropyl
X = halogen, dimethyl sulphate, p-toluenesulphonic acid
exhibit differing properties that make each of them particularly fit for respectively different treatments.
According to the present invention, C1-4 alkyl means: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl.
According to the present invention, halogen means: iodine, bromine, chlorine.
In particular, it has been found that while both enantiomorphs as per general formula (I) are equally effective in respect of acetylcholine - a quite surprising property in itself - , the dextrorotatory (+) enantiomorph is significantly more effective in respect of histamine than the respective levorotatory ( - ) enantiomorph. Moreover, the dextrorotatory enantiomorph was found to be less toxic than the levorotatory.
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. As is known, in fact, 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.
In the preparation of enantiomorphs as per the invention, 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. In particular 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.
EXAMPLE 1
(-)-1-Methyl-3-(10-H-phenothiazine-10-yl-methyl)-1-azoniabicyclo
[2.2.2. ] octane iodide [(I) R = CH3; X = I-]
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.
50 ml (0.2 mole) methyl iodide is added; the solution thus obtained is heated to 50ºC and is kept at this temperature for 16 hours. The reaction mixture is allowed to cool to 20ºC, then to 0-4ºC and kept at this temperature for 48 hours. Solid crystals are vacuum filtered, washed on filter with ethyl ether, then vacuum dried at
50ºC to constant weight.
42 g of the desired product is obtained (90% yield) as cream- coloured solid crystals having the following chemo-physical properties:
HPLC Nucleosil C18®150x4.6 column
eluent: MeOH/CH3CN/NH4PO4 0.425% = 43/25/32
flow rate: 0.5 ml/min λ = 254 nm
injection: 4 γ in methyl alcohol unit peak at r.t.: 6.4
m.p.: 142-144ºC
[α]D20: -21.3º (1% CH3OH concentr.)
Elementary analysis for C21H26IN2S
C H I N S
calculated 54.31 5-59 27-35 6.03 6.89 found 54.06 5-60 27.20 5.94 6.80
1H NMR (CDCl3): 7-21-6.84 (2m, 8H, [1',2',3',4',6',7',8',9']);
4.27-3-93 (m, 2H. [9]); 9-93-3-46 (m, 6H [2,6,7]);
3-21 (s, 3H, [10]); 2.71 (m. 1H, [3]); 2.30 (d, 1H [4]);
1-99-1-77 (2m, 4H, [5.8])
13C NMR (CDCl3): 144.62 (C-9'a, C-10'a); 127-77 (C-1', C-4',C-6', c-9');
126.97 (C-4'a. C-5'a); 123.26 (C-2', C-8'); 116.25 (C-3', C-7'); 60.49 (C-9); 57-38 (C-6); 57-21 (C-7); 52-54 (C-3); 48.30 (C-2); 32.06 (C-10); 24.87 (C-8); 20.90 (C-4); 19-57 (C-5).
The product optical purity was assayed on free basis by HPLC with chiral-phase column
column CHIRACEL O.D.®
eluent hexane/ethyl alcohol = 94/6
flow rate 0.5 ml/min. λ = 254 nm
injection 4 γ in hexane/ethyl alcohol
peak 98% at r.t. 15-03
EXAMPLE 2
(+)-1-methyl-3-(10-H-phenothiazine-10-yl-methyl)-1 azoniabicyclo [2.2.2.] octane iodide [(I) R = CH3; X = I-]
28 g (0.08 mole) of the mequitazine (+) enantiomorph obtained by preparative chromatographic chiral-phase column separation from the mequitazine racemic mixture is suspended in 160 ml acetonitrlle. The suspension is kept under stirring for 10 minutes to homogenization. 40 ml (0.64 mole) methyl iodide is added; the solution thus obtained is heated to 50ºC and is kept at this temperature for 16 hours. The reaction mixture is allowed to cool to 20ºC, then to 0-4ºC and kept at this temperature for 48 hours. Solid crystals are vacuum filtered, washed on filter with ethyl ether, then vacuum dried at 50ºC to constant weight.
35 g of the desired product is obtained (94? yield) as cream- coloured solid crystals having the following chemo-physical properties:
1H NMR; 13C NMR: as per Example 1
HPLC as per Example 1
chiral-phase HPLC: peak at r.t. 16.73 (97%)
m.p.: 142-145ºC
[α]D 20 + 21º (1% CH3OH concentr.)
Elementary analysis for C21H26IN2S
C H I N S
calculated 54.31 5-59 27-35 6.03 6.89
found 54-00 5-62 27-18 5-96 6.82 In vitro tests
EXAMPLE 3
A pharmaceutical formulation consisting of
active ingredient [(+) or (-) compound as
per formula (I)] 100 mg sorbitan trioleate (Arlacel 85R) 20 mg
Freon 11R 3.380 mg
Freon 12-114R (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 μg active ingredient metered doses.
Activity Tests
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.
Results demonstrated that both enantiomorphs are acetylcholine and histamine competitive antagonists on guinea pig's trachea. Anyway, while both enantiomorphs are equally effective in respect of acetylcholine (pA27-96 and 7-81 for levorotatory and dextrorotatory enantiomorphs, respectively, the dextrorotatory enantiomorph (+) (pA28.05) is significantly more effective than the levorotatory (-) (pA2 7-09) in respect of histamine. The in vitro results were confirmed by the in vivo tests, which demonstrated that the two enantiomorphs are equally effective in inhibiting bronchocostriction from acetylcholine, while the dextrorotatory (+) enantiomorph is significantly more effective than the levorotatory (-) in inhibiting bronchoconstriction from histamine (ED50: 63 and 239 nmole kg-1, respectively).
Tαxicologic Tests
The acute toxicity test referred to i.v. administration to mice showed that the dextrorotatory enantiomorph (+) [LD50 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].
TABLE 1
In Vitro Tests
Acetylcholine and histamine antagonism, on guinea pig's isolated trachea
Acetylcholine Histamine pA2
Levorotatory enantiomorph (-)
[Example 1] 7-96 7-09
Dextrorotatory enantiomorph (+)
[Example 2] 7.8l 8.05
In Vivo Tests
Inhibition of guinea pig' s bronchospasm from acetylcholine and histamine
Acetylcholine Histamine
ED50 (nmole kg-1)
Levorotatory enantiomorph (-)
[Example 1] 65 239 Dextrorotatory enantiomorph (+)
[Example 2] 71 63
Acute Toxicity in Mice
LD50 (mg kg-1 and fiducial limits at 95?)
Levorotatory enantiomorph (-)
[Example 1] 2.68 (2.61-2.74)
Dextrorotatory enantiomorph (+)
[Example 2] 3-65 (3-45-3-86)

Claims (13)

1. (-) 10-(1-azabicyclo[2.2.2.]oct-3-yl-methyl)-10 H-phenothiazine quaternary ammonium derivatives as per the following general formula
(I)
(I)
where
R = C1-4 alkyl, cyclopropyl
X = halogen, dimethyl sulphate, p-toluenesulphonic acid.
2. (+) 10-(1-azabicyclo[2.2.2.]oct-3-yl-methyl)-10 H-phenothiazine quaternary ammonium derivativvs as per the following general formula
(I)
(I)
where R and X are as per claim 1.
3. Enantiomorphs as per claims 1 and 2, where R = CH3 and X = I.
4. Enantiomorphs as per claims 1 and 2, where R = CH3 and X = Cl.
5. Enantiomorphs as per claims 1 and 2, where R = CH3 and X = Br.
6. Enantiomorphs as per claims 1 and 2, where R = CH3 and X = dimethyl sulphate.
7. Enantiomorphs as per claims 1 and 2, where R = CH3 and X = p- toluenesulphonic acid.
8. Process for the preparation of (-) and ( + ) 10 - (1- azabicyclo[2.2.2.]oct-3-yl-methyl)-10 H-phenotiazine quaternary ammonium derivatives of formula (I)
where
R = C1-4 alkyl, cyclopropyl
X = halogen, dimethyl sulphate, p-toluenesulphonic acid
wherein the racemicic mixture of mequitazine (A)
is resolved into the two respective dextro- and levorotatory enantiomorphs through chromatoghrapic separation techniques using chiral phases, and the so obtained enantiomorphs are quaternized with the suitable reagents.
9. Pharmaceutical compositions containing a dextrorotatory (+) enantiomorph as active ingredient, as per claims 2-7.
10. Pharmaceutical compositions containing a levorotatory (-) enantiomorph as active ingredient, as per claims 1, 3-7.
11. Process for preparing a pharmaceutical composition according to claims 9 and 10 wherein a pharmaceutical effective amount of a (+) or (-) 10 -(1-azabicyclo[2.2.2.]oct-3-yl-methyl)-10 H-phenotiazine quaternary ammonium derivatives of formula (I)
where
R = C1-4 alkyl, cyclopropyl
X = halogen, dimethyl sulphate, p-toluenesulphonic acid
is mixed with the suitable carriers for the preparation of compositions useful for topical use or oral administration.
12. Use of compositions as per claim 9. for bronchial asthma and rhinitis treatment.
13. Use of compositions as per claim 10, for bronchial asthma and rhinitis treatment.
AU24173/92A 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 Abandoned AU2417392A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI91A2225 1991-08-07
ITMI912225A IT1251161B (en) 1991-08-07 1991-08-07 QUATERNARY AMMONIUM DERIVATIVES OF (-) AND (+) - 3- (10 H-PHENOTHIAZIN-10-ILMETHYL) -L-AZABICYCLE (2.2.2.) OCT AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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AU2417392A true AU2417392A (en) 1993-03-02

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EP (1) EP0599896A1 (en)
JP (1) JPH06509570A (en)
CN (1) CN1071667A (en)
AU (1) AU2417392A (en)
BG (1) BG98439A (en)
BR (1) BR9206339A (en)
CA (1) CA2114844A1 (en)
CZ (1) CZ24894A3 (en)
EC (1) ECSP920859A (en)
FI (1) FI940530A (en)
HU (1) HUT66570A (en)
IT (1) IT1251161B (en)
MA (1) MA22611A1 (en)
MX (1) MX9204539A (en)
PT (1) PT100765A (en)
SK (1) SK11594A3 (en)
TN (1) TNSN92073A1 (en)
WO (1) WO1993003029A1 (en)
ZA (1) ZA925852B (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1216353C (en) * 1996-10-18 2005-08-24 雅马哈株式会社 Music teaching system, method and storing media for performing programme
US20050220888A1 (en) * 2002-01-31 2005-10-06 Lakahmi Putcha Controlled release compositions and methods for using same
FR2910814B1 (en) * 2006-12-28 2011-06-17 Pf Medicament USE OF 10- (R3) -1-AZABICYCLO2.2.2-OCT-3-YLMETHYL-10H-PHENOTHIAZINE FOR THE PREPARATION OF A MEDICAMENT EXERCISING SELECTIVE INHIBITION OF M1,2,3 MUSCARINIC RECEPTORS
FR2911606B1 (en) * 2007-01-18 2009-04-17 Pierre Fabre Medicament Sa NEW QUINUCLIDINE DERIVATIVE USEFUL IN THE PREPARATION OF MEQUITAZINE
FR2924344B1 (en) * 2007-12-04 2010-04-16 Pf Medicament USE OF MEQUITAZINE IN THE FORM OF RACEMATE OR ENANTIOMERS FOR THE PREPARATION OF A MEDICAMENT FOR THE TREATMENT OR PREVENTION OF PATHOLOGIES INVOLVING HISTAMIC RECEPTORS H4.
FR2970255B1 (en) 2011-01-10 2013-09-06 Pf Medicament VINYL QUINUCLIDINE USEFUL AS A SYNTHETIC INTERMEDIARY IN THE PREPARATION OF (R) -MEQUITAZINE

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2522660A1 (en) * 1982-03-05 1983-09-09 Pharmuka Lab MEQUITAZINE LEVOGYER ISOMER, PROCESS FOR PREPARING THE SAME AND MEDICAMENTS CONTAINING THE SAME
FR2526433B1 (en) * 1982-05-04 1985-10-18 Pharmuka Lab DEXTROGYRIC ISOMERS OF AZA-1 BICYCLO (2,2,2) OCTANE DERIVATIVES, THEIR PREPARATION METHOD AND MEDICAMENTS CONTAINING THEM
IT1173445B (en) * 1984-03-16 1987-06-24 Guidotti & C Spa Labor AGENTS WITH ANTIBRONCOSPASTIC ACTIVITY AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM

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ECSP920859A (en) 1993-08-03
BR9206339A (en) 1994-11-08
CN1071667A (en) 1993-05-05
HU9400273D0 (en) 1994-05-30
JPH06509570A (en) 1994-10-27
IT1251161B (en) 1995-05-04
FI940530A0 (en) 1994-02-04
CZ24894A3 (en) 1994-07-13
ITMI912225A0 (en) 1991-08-07
PT100765A (en) 1993-10-29
EP0599896A1 (en) 1994-06-08
TNSN92073A1 (en) 1993-06-08
BG98439A (en) 1994-09-30
ZA925852B (en) 1993-03-05
MX9204539A (en) 1993-02-01
HUT66570A (en) 1994-12-28
SK11594A3 (en) 1994-12-07
MA22611A1 (en) 1993-04-01
WO1993003029A1 (en) 1993-02-18
FI940530A (en) 1994-02-04
ITMI912225A1 (en) 1993-02-08
CA2114844A1 (en) 1993-02-18

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