SK11594A3 - (+) 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 Download PDFInfo
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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
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- 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
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- 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
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- 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
Abstract
Description
Oblasť technikyTechnical field
Tento vynález sa týka pravotočivých (+) a ľavotočivých (-) enantiomérov kvartérnych amóniových derivátov 10(azabicyklo[2.2.2. ] okt-3-yl-metyl)-10 H-fenotiazínu.The present invention relates to the dextrorotatory (+) and levorotatory (-) enantiomers of quaternary ammonium derivatives 10 (azabicyclo [2.2.2.] Oct-3-ylmethyl) -10H-phenothiazine.
Súčasný stav technikyThe state of the art
10-(azabicyklo[2.2.2.]okt-3-yl-mety1)-10 H-fenotiazín (všeobecne známy ako mequitazín) daný všeobecným vzorcom (A)10- (azabicyclo [2.2.2.] Oct-3-ylmethyl) -10H-phenothiazine (commonly known as mequitazine) given by the general formula (A)
je známy z literatúry (pozri napríklad FR-A-2 034 605), ktorá opisuje jeho antihistaminické vlastnosti.is known from the literature (see for example FR-A-2 034 605), which describes its antihistaminic properties.
V patente EP-A-159 059 opisuje jeho prihlasovateľ racemické modifikácie kvartérnych derivátov zlúčeniny danej vzorcom (A), ktoré majú významnú antibronchospasmatickú aktivitu .In EP-A-159 059, the applicant discloses racemic modifications of the quaternary derivatives of the compound of formula (A) having significant antibronchospasmatic activity.
Podstata vynálezuSUMMARY OF THE INVENTION
Kvartérne deriváty mequitazínu obsahujú podobne ako samotný mequitazín asymetrický atóm uhlíka (pozícia 3 1azabicyklo[2.2.2.]oktánu. Každý racemický kvartérny derivát preto pozostáva z dvoch (+) a (-) enantiomérov, ktoré sa v ňom nachádzajú v pomere 50:50. Prekvapujúco bolo zistené, že enantioméry kvartérnych derivátov mequitazínu všeobecného (I) vzorca (I) β·Like mequitazine alone, the quaternary derivatives of mequitazine contain an asymmetric carbon atom (position 3 1-azabicyclo [2.2.2] octane). Therefore, each racemic quaternary derivative consists of two (+) and (-) enantiomers which are present in a ratio of 50:50 Surprisingly, it has been found that the enantiomers of the quaternary mequitazine derivatives of formula (I) of formula (I) β ·
<10'a<10 'and
10'10 '
1'1 '
9'9 '
II
CHCH
kdewhere
R = C^_4 alkyl, alebo cyklopropylR = C 1-4 alkyl, or cyclopropyl
X = halogén, dimetylsulfát,. alebo p-toluénsulfónová kyselina, majú celkom rozdielne vlastnosti, na základe ktorých sa jednotlivé deriváty hodia mimoriadne dobre na liečenie rozličných ochorení.X = halogen, dimethyl sulfate. or p-toluenesulfonic acid, have quite different properties which make the individual derivatives particularly suitable for the treatment of various diseases.
Podľa predloženého vynálezu znamená C^_4 alkyl: metyl, etyl, propyl, izopropyl, butyl, izobutyl a t-butyl a halogén znamená jód, bróm a chlór.According to the present invention, C 1-4 alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl and halogen means iodine, bromine and chlorine.
Zistila sa najmä skutočnosť, že zatiaľ čo oba enantioméry dané všeobecným vzorcom (I) sú rovnako účinné v prípade acetylcholínu (čo je zaujímavá vlastnosť sama o sebe), je pravotočivý (+) enantiomér v porovnaní s ľavotočivým (-) podstatne účinnejší v prípade histamínu. Navyše sa zistilo, že pravotočivý enantiomér je v porovnaní s ľavotočivým i menej toxický.In particular, it has been found that while both enantiomers given by formula (I) are equally effective for acetylcholine (an intrinsic property in itself), the dextrorotatory (+) enantiomer is substantially more potent for histamine compared to the levorotatory (-) . In addition, the dextrorotatory enantiomer was found to be less toxic than the dextrorotatory enantiomer.
Pravotočivý enantiomér je zlúčenina mimoriadne vhodná na liečenie bronchokonstriktívnych a alergických ochorení (najmä astmy rhinitidy) ako i všetkých patologických stavov, na ktorých sa zúčastňuje histamín. Histamín je jedným z hlavných sprostredkovateľov astmatickej bronchokonstrikcie a abnormálnej reakcie nosovej membrány v prípade alergickej rhinitidy. Je vhodný i na liečenie patologických stavov, na ktorých sa zúčastňuje acetylcholín, ktorý kontroluje tonus respiračného systému ako i sekréciu z nosnej sliznice. Ako je známe, mediátorov zúčastňujúcich sa na bronchokonstrikcii a na rhinitíde je viacero, v závislosti od typu a štádia ochorenia i od jednotlivého pacienta. Skutočnosť, že pravotočivé enantioméry sa vyznačujú oboma typmi aktivít v zhruba rovnakej koncentrácii znamená, že ich možno použiť ako obzvlášť zaujímavé preparáty na liečenie takýchto ochorení.The dextrorotatory enantiomer is a compound particularly suitable for the treatment of bronchoconstrictive and allergic diseases (especially asthma rhinitis) as well as all pathological conditions in which histamine is involved. Histamine is one of the major mediators of asthmatic bronchoconstriction and abnormal nasal membrane reactions in allergic rhinitis. It is also suitable for the treatment of pathologies involving acetylcholine, which controls the tone of the respiratory system as well as secretion from the nasal mucosa. As is known, there are several mediators involved in bronchoconstriction and rhinitis, depending on the type and stage of the disease, and the individual patient. The fact that the dextrorotatory enantiomers are characterized by both types of activities at roughly the same concentration means that they can be used as particularly interesting preparations for the treatment of such diseases.
Pri príprave jednotlivých enantiomérov opisovaných týmto vynálezom sa racemická zmes mequitazínu rozdelí na obe svoje zložky (t. j. pravo- a ľavotočivú) pomocou bežných chromatografických postupov založených na použití chirálnych fáz. Konkrétne možno použiť preparatívnu chromatografiu na kolónach s náplňou celulózy, ako elučné činidlo je možné použiť nasledujúce zmesi rozpúšťadiel: hexán / etylalkohol (94/6), hexán / metylalkohol (98/2), alebo hexán / etylalkohol / TEA (98/0.8/1.2). Takto získané enantioméry je potom možné kvarternalizovať pomocou reakčných činidiel postupom ktorý je uvedený v ďalšom texte.In the preparation of the individual enantiomers described by this invention, the racemic mixture of mequitazine is separated into its two components (i.e., right and left-handed) by conventional chromatography techniques based on the use of chiral phases. In particular, preparative chromatography on cellulose packed columns can be used, as eluent, the following solvent mixtures can be used: hexane / ethyl alcohol (94/6), hexane / methanol (98/2), or hexane / ethyl alcohol / TEA (98 / 0.8 /) 1.2). The enantiomers thus obtained can then be quaternized with reagents as described below.
Enantioméry opisované predkladaným vynálezom sa ukázali byť vhodné najmä na prípravu farmaceutických preparátov na topické použitie, najmä formou inhalácie alebo intranasálnej aplikácie alebo i na perorálne použitie. Typ farmaceutického preparátu vhodného pre podanie aktívnej zlúčeniny opisovanej vynálezom je uvedený v príklade 3 v ďalšom texte.The enantiomers described by the present invention have proven to be particularly suitable for the preparation of pharmaceutical preparations for topical use, in particular by inhalation or intranasal administration, or even for oral use. A type of pharmaceutical preparation suitable for the administration of the active compound described by the invention is shown in Example 3 below.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1 ( - ) -l-metyl-3-(10-H-fenotiazín-10-yl-metyl)-1-azoniabicyklo [2.2.2.] oktán jodid [(I) R = CH3; X = I“] g (0,1 mólu) ľavotočivého (-) enantioméru mequitazínu, získaného pomocou preparatívnej chromatografie na kolóne s chirálnou fázou z racemickej zmesi, sa rozšuspendovalo v 200 ml acetonitrilu. Suspenzia sa zhomogenizovala miešaním trvajúcim 10 minút. Pridalo sa 50 ml (0,2 mólu) metyljodídu a výsledná zmes sa zahrievala 16 hodín pri teplote 50 °C. Potom sa zmes ochladila najprv na 20 °C, potom na 0 až 4 °C a nechala na tejto teplote 48 hodín. Tuhé kryštály sa sfiltrovali pomocou vákua, premyli sa na filtri etyléterom a nakoniec sa pri 50 °C vákuovo vysušili do konštantnej hmotnosti. V podobe krémovo zafarbených kryštálov sa získalo 42 g (90% výťažok) požadovaného produktu s nasledujúcimi fyzikálnochemickými vlastnosťami:Example 1 (-) -1-methyl-3- (10-H-phenothiazin-10-ylmethyl) -1-azoniabicyclo [2.2.2.] Octane iodide [(I) R = CH 3 ; X = 1 '] g (0.1 mol) of the levorotatory (-) enantiomer of mequitazine, obtained by preparative chromatography on a chiral phase column from a racemic mixture, was suspended in 200 ml of acetonitrile. The suspension was homogenized by stirring for 10 minutes. Methyl iodide (50 mL, 0.2 mol) was added and the resulting mixture was heated at 50 ° C for 16 h. Then the mixture was cooled first to 20 ° C, then to 0 to 4 ° C and left at this temperature for 48 hours. The solid crystals were filtered under vacuum, washed on the filter with ethyl ether and finally vacuum dried to constant weight at 50 ° C. 42 g (90% yield) of the desired product with the following physicochemical properties were obtained in the form of cream-colored crystals:
HPLC na kolóne s rozmermi 150x4,6, náplň Nucleosil C^g elučné činidlo: MeOH/CH3N/NH4H2PO4 0,425% = 43/25/32 prietok: 0,5 ml/min lambda = 254 nm nástrek: 4 τ v metylalkohole jednotkový pík pri lab. teplote : 6,4 bod topenia: 142 až 144 ’C [a]D20: -21.3° (1% kone. CH3OH) elementárna analýza látky so sumárnym vzorcom C21H26IN2S 150x4.6 column HPLC, Nucleosil C ^ g cartridge eluent: MeOH / CH 3 N / NH 4 H 2 PO 4 0.425% = 43/25/32 flow rate: 0.5 ml / min lambda = 254 nm feed : 4 τ in methyl alcohol unit peak at lab. temperature: 6,4 mp: 142-144 ° C, [a] D 20: -21.3 ° (1% conc. CH3 OH) Elemental analysis of compound of molecular formula C 21 H 26 IN 2 S
4.27-3.93 (m,2H,[9]); 9.93-3.46 (m,6H,[2,6,7]) ; 3.21 (s,3H,[10]);2.71 (m,lH,[3]); 2.30 (d,lH,[4j); 1.99-1.77 (2m,4H,[5,8]) 13C NMR (CDC13): 144.62 (C-9’a, C-lO’a); 127.77 (C-ľ,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, [4j]); 1.99-1.77 (2m, 4H, [5.8]) 13 C NMR (CDCl 3 ): 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-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);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); 24.84 (C-8); 20.90 (C-4); 19.57 (C-5).57.21 (C-7); 52.54 (C-3); 48.30 (C-2); 32.06 (C-10); 24.84 (C-8); 20.90 (C-4); 19.57 (C-5).
Optická čistota produktu bola stanovená na voľnej báze pomocou HPLC na kolóne s chirálnou fázou kolóna CHIRACEL O.D.The optical purity of the product was determined on the free base by HPLC on a chiral phase column CHIRACEL O.D.
eluent : hexán/etanol = 94/6 prietok 0,5 ml/mín lambda = 254 nm nástrek 4 τ v zmesi hexán/etylalkohol pík 98 % pri lab. teplote 15,03eluent: hexane / ethanol = 94/6 flow rate 0.5 ml / min lambda = 254 nm injection of 4 τ in hexane / ethyl alcohol peak 98% at rt. temperature 15.03
Príklad2 ( + ) -l-metyl-3-(10-H-fenotiazin-10-yl-metyl)-1 azóniobicyklo [2.2.2.] oktánjodid [(I) R = CHj; X = ľ] g (0.08 mólu) (+) enantioméru mequitazínu získaného pomocou preparatívnej chromatografie na HPLC kolóne s chirálnou fázou z racemickej zmesi mequitazínu sa rozsuspendovalo v 160 ml acetonitrilu. Suspenzia sa miešala 10 minút, aby sa zhomogenizovala. Pridalo sa 40 ml (0,64 mólu) metyljodídu a výsledná reakčná zmes sa ohrievala na teplote 50 °C počas 16 hodín. Potom sa zmes ochladila najprv na 20 “C, potom na 0 až 4 “C a nechala na tejto teplote 48 hodín. Tuhé kryštály sa sfiltrovali pomocou vákua, premyli sa na filtri etyléterom a nakoniec sa pri 50 C vákuovo vysušili do konštantnej hmotnosti. V podobe krémovo zafarbených kryštálov sa získalo 35 g (94 % výťažok) požadovaného produktu s nasledujúcimi fyzikálnochemickými vlastnosťami:EXAMPLE 2 (+) -1-Methyl-3- (10-H-phenothiazin-10-ylmethyl) -1-azonobicyclo [2.2.2] octane iodide [(I) R = CH3; X = 1 µg (0.08 mol) of the (+) enantiomer of mequitazine obtained by preparative chromatography on a chiral phase HPLC column from a racemic mixture of mequitazine was suspended in 160 ml of acetonitrile. The suspension was stirred for 10 minutes to homogenize. Methyl iodide (40 mL, 0.64 mol) was added and the resulting reaction mixture was heated at 50 ° C for 16 hours. Then the mixture was cooled first to 20 ° C, then to 0 to 4 ° C and left at this temperature for 48 hours. The solid crystals were filtered under vacuum, washed on the filter with ethyl ether and finally dried to constant weight at 50 ° C. 35 g (94% yield) of the desired product with the following physicochemical properties were obtained in the form of cream-colored crystals:
NMR, 1¾} NMR: ako v príklade 1NMR, as in Example 1
HPLC ako v príklade 1HPLC as in Example 1
HPLC na kolóne s chirálnou fázou: pík pri lab. tepl. 16.73 (97%) bod topenia: 142 až 145 °C [a]D20 + 21° (1% CH3OH)HPLC on a chiral phase column: peak at room temperature. temp. 16.73 (97%) melting point: 142-145 ° C [α] D 20 + 21 ° (1% CH 3 OH)
Testy in vitroIn vitro tests
Príklad 3Example 3
Farmaceutický preparát pozostávajúci z: aktívnej látky [(+) alebo (-) zlúčenina vzorca (I)] 100 mg trioleát sorbitanu (Arlacel 85^) 20 mgPharmaceutical preparation consisting of: active substance [(+) or (-) compound of formula (I)] 100 mg sorbitan trioleate (Arlacel 85 ^) 20 mg
Freón 11R 3,380 mgFreon 11R 3,380 mg
Freón 12-114R (65:35) 10,500 mg sa umiestnil do malého valca s dávkovacím ventilom. Takýmto spôsobom možno podávať jednu presne vymeranú dávku 50 až 200 gg aktívnej zložky preparátu.Freon 12-114R (65:35) 10.500 mg was placed in a small dispensing valve cylinder. In this way, one accurately measured dose of 50 to 200 gg of the active ingredient of the preparation can be administered.
Testy na aktivituActivity tests
Vykonala sa komparatívna štúdia enantiomérov uvedených v príkladoch 1 a 2, ktor^ sa zamerala na ich farmokologické vlastnosti, najmä čo sa týka nasledujúcich aspektov: antihistaminický a antiacetylcholínový účinok v izolovanej trachei morského prasaťa, inhibicia histamínom a acetylcholínom indukovanej bronchokonstrikcie v morskom prasati (Konzett-Roesslerova metóda), akútna toxicita u myší.A comparative study of the enantiomers shown in Examples 1 and 2 was conducted, focusing on their pharmacological properties, in particular regarding the following aspects: antihistaminic and antiacetylcholine effect in isolated trachea of the swine, inhibition by histamine and acetylcholine-induced bronchoconstriction in swine Roessler method), acute toxicity in mice.
Z výsledkov vyplýva, že oba enantioméry sa v prípade trachey z morského prasaťa správajú ako kompetitívni antagonisti acetylcholínu i histamínu. Ukázalo sa, že zatiaľ čo vzhľadom na acetylcholín sú oba enantioméry rovnako účinné (pA2 = 7.96 pre ľavotočivý a 7.81 pre pravotočivý enantiomér), vzhľadom na histamín je je pravotočivý (+) enantiomér signifikantne účinnejší než ľavotočivý (-) (pA2 8,05 vs. 7,09). Výsledky z pokusov in vitro sa potvrdili i v pokusoch in vivo, kde sa ukázalo, že oba enantioméry mali rovnakú schopnosť inhibovať acetylcholínom indukovanú bronchokonstrikciu, zatiaľ čo pravotočivý (+) enantiomér bol porovnaní s ľavotočivým (-) výrazne účinnejší pri inhibovaní histamínom spôsobenej bronchokonstrikcie (ED50: 63 nmol/kg vs. 239 nmol/kg).The results show that both enantiomers behave as competitive antagonists of both acetylcholine and histamine in the case of sea pig trachea. It has been shown that while with respect to acetylcholine, both enantiomers are equally effective (pA2 = 7.96 for the levorotatory and 7.81 for the dextrorotatory enantiomer), with respect to histamine the dextrorotatory (+) enantiomer is significantly more potent than the levorotatory (-) (pA2 8.05 vs 7.09). Results from in vitro experiments were confirmed in in vivo experiments where both enantiomers showed the same ability to inhibit acetylcholine-induced bronchoconstriction, while the dextrorotatory (+) enantiomer was significantly more potent in inhibiting histamine-induced bronchoconstriction compared to the left-handed (-) : 63 nmol / kg vs. 239 nmol / kg).
Toxikologický testToxicological test
Test na akútnu toxicitu pozostával z i.v. podania aktívnych látok myšiam. Ukázalo sa, že pravotočivý enantiomér (+) je podstatne menej toxický [LD50 a limit spoľahlivostiThe acute toxicity test consisted of i.v. administration of the active ingredients to mice. The dextrorotatory enantiomer (+) has been shown to be substantially less toxic [LD50 and confidence limit
Testy in vitroIn vitro tests
Acetylcholínový a histamínový antagonizmus v izolovanej priedušnici morského prasaťa.Acetylcholine and histamine antagonism in the isolated trachea of swine.
Acetylcholinacetylcholine
Histamínhistamine
Ľavotoč. enantiomér (-) (Príklad 1) 7,96 pA2 Ľavotoč. enantiomer (-) (Example 1) 7.96 pA 2
7,097.09
Pravotočivý enant. (+) (Príklad 2)Right-handed enant. (+) (Example 2)
7,817.81
8,058.05
In vivo testyIn vivo tests
Inhibícia acetylcholínom a histamínom indukovaných bronchospasmov u morského prasaťaInhibition of acetylcholine and histamine-induced bronchospasms in swine
LD50 (mg/kg a limit spoľahlivosti pri 95 %) Ľavotočivý enantiomér (-) (Príklad 1) 2,68 (2,61 - 2,74)LD50 (mg / kg and 95% confidence limit) Left-handed enantiomer (-) (Example 1) 2.68 (2.61 - 2.74)
Pravotočivý enantiomér (+) (Príklad 2) 3,65 (3,45 -3,86)Dextrorotatory enantiomer (+) (Example 2) 3.65 (3.45 -3.86)
Claims (13)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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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 |
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 |
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SK11594A3 true SK11594A3 (en) | 1994-12-07 |
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SK115-94A SK11594A3 (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 |
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IT (1) | IT1251161B (en) |
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WO2003105811A2 (en) * | 2002-01-31 | 2003-12-24 | Southwest Research Institute | 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. |
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---|---|---|---|---|
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 |
-
1991
- 1991-08-07 IT ITMI912225A patent/IT1251161B/en active IP Right Grant
-
1992
- 1992-08-03 HU HU9400273A patent/HUT66570A/en unknown
- 1992-08-03 SK SK115-94A patent/SK11594A3/en unknown
- 1992-08-03 EP EP92916942A patent/EP0599896A1/en not_active Ceased
- 1992-08-03 CA CA002114844A patent/CA2114844A1/en not_active Abandoned
- 1992-08-03 AU AU24173/92A patent/AU2417392A/en not_active Abandoned
- 1992-08-03 BR BR9206339A patent/BR9206339A/en not_active Application Discontinuation
- 1992-08-03 CZ CS94248A patent/CZ24894A3/en unknown
- 1992-08-03 JP JP5503276A patent/JPH06509570A/en active Pending
- 1992-08-03 MA MA22900A patent/MA22611A1/en unknown
- 1992-08-03 WO PCT/EP1992/001759 patent/WO1993003029A1/en not_active Application Discontinuation
- 1992-08-04 ZA ZA925852A patent/ZA925852B/en unknown
- 1992-08-04 EC EC1992000859A patent/ECSP920859A/en unknown
- 1992-08-05 MX MX9204539A patent/MX9204539A/en unknown
- 1992-08-05 TN TNTNSN92073A patent/TNSN92073A1/en unknown
- 1992-08-06 CN CN92109021A patent/CN1071667A/en active Pending
- 1992-08-07 PT PT100765A patent/PT100765A/en not_active Application Discontinuation
-
1994
- 1994-02-04 FI FI940530A patent/FI940530A/en not_active Application Discontinuation
- 1994-02-07 BG BG98439A patent/BG98439A/en unknown
Also Published As
Publication number | Publication date |
---|---|
ITMI912225A1 (en) | 1993-02-08 |
IT1251161B (en) | 1995-05-04 |
CZ24894A3 (en) | 1994-07-13 |
TNSN92073A1 (en) | 1993-06-08 |
CA2114844A1 (en) | 1993-02-18 |
FI940530A0 (en) | 1994-02-04 |
ZA925852B (en) | 1993-03-05 |
HUT66570A (en) | 1994-12-28 |
WO1993003029A1 (en) | 1993-02-18 |
BG98439A (en) | 1994-09-30 |
FI940530A (en) | 1994-02-04 |
ITMI912225A0 (en) | 1991-08-07 |
CN1071667A (en) | 1993-05-05 |
BR9206339A (en) | 1994-11-08 |
JPH06509570A (en) | 1994-10-27 |
AU2417392A (en) | 1993-03-02 |
HU9400273D0 (en) | 1994-05-30 |
EP0599896A1 (en) | 1994-06-08 |
MA22611A1 (en) | 1993-04-01 |
MX9204539A (en) | 1993-02-01 |
ECSP920859A (en) | 1993-08-03 |
PT100765A (en) | 1993-10-29 |
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