- Palladium-catalyzed diastereoselective synthesis of β,β-diarylpropionic acid derivatives and its application to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718
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Palladium-catalyzed diastereoselective synthesis of optically active β,β-diarylpropionic acid derivatives employing 4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary under an air atmosphere in excellent yields with high diastereoselectivity is reported. The catalytic system is applied to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718.
- Zhi, Wubin,Li, Jingya,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
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Read Online
- Chiral Inductive Diastereoconvergent Allylation Reactions of Allyltrimethylsilane and Diastereomixtures of Diarylmethanols Catalyzed by FeCl3
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We report the chiral-auxiliary-controlled diastereoconvergent allylation reactions of allyltrimethylsilane with diastereomeric mixtures of diarylmethanols in the presence of FeCl3 as a Lewis acid catalyst. This reaction was successfully applied to a variety of substrates; it proceeded irrespective of the substituent on the aromatic ring of the substrate. The present method was used as the key step in synthesizing (R)-tolterodine.
- Fujihara, Rina,Nakata, Kenya
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Read Online
- Enantioselective synthesis of (S)- and (R)-tolterodine by asymmetric hydrogenation of a coumarin derivative obtained by a Heck reaction
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(Chemical Equation Presented) An efficient and short enantioselective synthesis of (S)- and (R)-tolterodine was performed by asymmetric hydrogenation of a coumarin intermediate, easily obtained by a Heck reaction from inexpensive and commercially available starting materials.
- Ulgheri, Fausta,Marchetti, Mauro,Piccolo, Oreste
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Read Online
- Asymmetric Hydroesterification of Diarylmethyl Carbinols
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An efficient asymmetric hydroesterfication of diarylmethyl carbinols is developed for the first time with a Pd-WingPhos catalyst, resulting in a series of chiral 4-aryl-3,4-dihydrocoumarins in excellent enantioselectivities and good yields. The method features mild reaction conditions, a broad substrate scope, use of easily accessible starting materials, and low palladium loadings. A plausible stereochemical model is also proposed with the Pd-WingPhos catalyst. This method has enabled a 4-step asymmetric synthesis of (R)-tolterodine from readily available starting materials.
- Tian, Duanshuai,Xu, Ronghua,Zhu, Jinbin,Huang, Jianxun,Dong, Wei,Claverie, Jerome,Tang, Wenjun
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p. 6305 - 6309
(2021/02/09)
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- Chiral Fe(ii) complex catalyzed enantioselective [1,3] O-to-C rearrangement of alkyl vinyl ethers and synthesis of chromanols and beyond
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A highly efficient enantioselective [1,3] O-to-C rearrangement of racemic vinyl ethers that operates under mild conditions was developed. This method with chiral ferrous complex catalyst provided an efficient access to a wide range of chromanols with high yields and excellent enantioselectivities. In addition, an important urological drug (R)-tolterodine and others were easily obtained after simple transformations.
- Dong, Shunxi,Feng, Xiaoming,Lin, Qianchi,Liu, Xiaohua,Wang, Lifeng,Zhou, Pengfei
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p. 10101 - 10106
(2020/10/19)
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- Rh-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to 3-Arylpropenoates: Enantioselective Synthesis of (R)-Tolterodine
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A highly enantioselective conjugate addition of arylboronic acids to 3-arylpropenoates is presented. The rhodium complexes obtained from deoxycholic acid derived binaphthyl phosphites showed good activity as well as very high enantioselectivity (ee up to 99 %) in the conjugate addition to different ethyl-3-arylpropenoates, allowing to obtain useful chiral building blocks for the synthesis of active pharmaceutical ingredients. The method was applied to the enantioselective synthesis of the antimuscarinic drug (R)-tolterodine.
- Zullo, Valerio,Iuliano, Anna
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p. 1377 - 1384
(2019/01/04)
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- Synthesis method of tolterodine and enantiomers thereof
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Belonging to the field of chemical synthesis, the invention discloses a synthesis method of tolterodine and enantiomers thereof. The method includes: taking cinnamaldehyde as the raw material for asymmetric arylation reaction with (2-hydroxy-5-methylphenyl)boric acid under the action of a rhodium catalyst to obtain a hemiacetal intermediate, and subjecting the hemiacetal intermediate directly to reductive amination reaction without purification, thus obtaining high optically pure tolterodine. 2-hydroxyl-5-methyl cinnamaldehyde and phenylboronic acid are taken as the starting raw materials, andthe same synthesis method and operation steps are employed to prepare high optically pure tolterodine enantiomers. The method reported by the invention has the characteristics of short route, high total yield, good stereoselectivity and the like, and the ee values of the two synthesized configuration products are both greater than 99%.
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- Catalytic asymmetric synthesis of chiral phenols in ethanol with recyclable rhodium catalyst
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A general method to access diverse chiral phenols by rhodium-catalyzed asymmetric conjugate arylation using hydroxylated arylboronic acids in ethanol was developed. Recycling of the rhodium catalyst by flash chromatography on silica gel was feasible in this system. The synthetic utility of the strategy was demonstrated by efficient synthesis of chiral drug tolterodine.
- Yao, Jian,Liu, Na,Yin, Long,Xing, Junhao,Lu, Tao,Dou, Xiaowei
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supporting information
p. 4946 - 4950
(2019/09/30)
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- Computationally-Led Ligand Modification using Interplay between Theory and Experiments: Highly Active Chiral Rhodium Catalyst Controlled by Electronic Effects and CH–π Interactions
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A chiral ligand for the rhodium-catalyzed asymmetric 1,4-addition of an arylboronic acid to a coumarin substrate that could markedly reduce catalyst loading was developed using interplay between theoretical and experimental approaches. Evaluation of the transition states for insertion and for hydrolysis of intermediate complexes (which were emphasized in response to the experimental results) using DFT calculations at the B97D/6-31G(d) level with the LANL2DZ basis set for rhodium revealed that: (i) the electron-poor nature of the ligands and (ii) CH–π interactions between the ligand and coumarin substrates played significant roles in both acceleration of insertion and inhibition of ArB(OH)2 decomposition (protodeboronation). The computationally-designed ligand, incorporating the above information, enabled a decrease in the catalyst loading to 0.025 mol% (S/C=4,000), which is less than one one-hundredth relative to past catalyst loadings of typically 3 mol%, with almost complete enantioselectivity. Furthermore, the gram-scale synthesis of the urological drug, (R)-tolterodine (l)-tartrate, was demonstrated without the need of intermediate purification. (Figure presented.).
- Korenaga, Toshinobu,Sasaki, Ryo,Takemoto, Toshihide,Yasuda, Toshihisa,Watanabe, Masahito
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supporting information
p. 322 - 333
(2018/01/22)
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- NOVEL (R) AND RAC 3-(2-(ALLYLOXY)-5-METHYLPHENYL)-N,N-DIISOPROPYL-3- PHENYLPROPAN-1-AMINE AND ITS USE FOR SYNTHESIS OF (R) AND RAC-2-(3- (DIISOPROPYLAMINO)-1-PHENYLPROPYL)-4-(HYDROXYMETHYL)PHENOL
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The present invention relates to novel chiral 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) and racemic 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine () and its use in improved and industrially advantageous process for preparation of chiral and racemic form of 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol. Further, present invention relates to preparation of the same.
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(2017/09/05)
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- PHOSPHOLIPID CONJUGATE
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PROBLEM TO BE SOLVED: To provide a compound that suitably interacts with a receptor existing on a cell surface to regulate its activity, to provide a pharmaceutical composition containing the compound, and to provide a method for treating a disease using the compound, and the like. SOLUTION: The above mentioned object is achieved by providing a compound represented by general formula: P-S-L (where, P is a phospholipid moiety; S is a spacer moiety which includes a structure represented by -(PEG)n- wherein n is an integer equal or greater than 5; L is a ligand moiety of a cytoplasmic membrane receptor). SELECTED DRAWING: Figure 3 COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0056
(2017/02/28)
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- Coumarins from free ortho -hydroxy cinnamates by Heck-Matsuda arylations: A scalable total synthesis of (R)-tolterodine
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Free ortho-hydroxy cinnamate ester derivatives are evaluated in the synthesis of structurally diverse 4-aryl-coumarins via a tandem Heck-Matsuda cyclization reaction. Free phenolic groups were considered incompatible with such a reaction, which usually provide the corresponding diazo dyes. A concise and scalable route employing a ligand-free, Pd-catalyzed Heck-Matsuda arylation under aerobic conditions for the preparation of (R)-Tolterodine in high overall yield and ee is also presented.
- Barancelli, Daniela A.,Salles, Airton G.,Taylor, Jason G.,Correia, Carlos Roque D.
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p. 6036 - 6039
(2013/02/23)
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- Enantioselective synthesis of (R)-tolterodine using lithiation/borylation- protodeboronation methodology
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The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation-protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee.
- Roesner, Stefan,Aggarwal, Varinder K.
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p. 965 - 974
(2013/02/22)
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- Highly enantioselective hydrogenation of styrenes directed by 2′-hydroxyl groups
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A new synthetic strategy that turns styrene-type olefins into excellent substrates for Rh-catalyzed asymmetric hydrogenation by installing a 2′-hydroxyl substituent is described. This methodology accommodates trisubstituted olefinic substrates in various E/Z mixtures, leading to valuable benzylic chiral compounds including (R)-tolterodine. It is also demonstrated that the 2′-hydroxyl groups could be readily removed in high yield without loss of ee from the products. Thus, this technology represents an attractive alternative to the Ir(P-N) catalyst system for the asymmetric hydrogenation of unfunctionalized olefins.
- Wang, Xiang,Guram, Anil,Caille, Seb,Hu, Jack,Preston,Ronk, Michael,Walker, Shawn
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p. 1881 - 1883
(2011/05/15)
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- A process for the rapid removal of dialkylamino-substituents from aromatic rings. Application to the expedient synthesis of (R)-tolterodine
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A range of N,N-dialkylanilines have been successfully converted to the parent substituted benzenes by a novel two-step pathway. The products are obtained in good yields and optical purity of adjacent stereocenters is maintained. This technology has been applied toward the synthesis of (R)-tolterodine.
- Paras, Nick A.,Simmons, Bryon,MacMillan, David W.C.
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experimental part
p. 3232 - 3238
(2009/08/15)
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- Asymmetrie Conjugate reductions of coumarins. A new route to tolterodine and related coumarin derivatives
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"Chemical Equation Presented" The combination of catalytic amounts of [(R)-DTBM-SEGPHOS]CUH In the presence of stoichiometric DEMS (dlethoxymethylsllane) In toluene at room temperature leads to asymmetric reductions of 4-substituted coumarins. Several targets or their known precursors can be prepared In high yields and ee's, Including the muscarine receptor antagonist (R)-tolterodine.
- Gallagher, Brian D.,Taft, Benjamin R.,Lipshutz, Bruce H.
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supporting information; experimental part
p. 5374 - 5377
(2010/02/28)
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- Enantioselective synthesis of (R)-tolterodine via CuH-catalyzed asymmetric conjugate reduction
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(Chemical Equation Presented) An efficient and highly enantioselective method for the preparation of (R)-tolterodine is described. The synthesis was performed by CuH-catalyzed asymmetric conjugate reduction of a β,β-diaryl-substituted unsaturated nitrile
- Yoo, Kihyun,Kim, Hyohyun,Yun, Jaesook
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supporting information; experimental part
p. 4232 - 4235
(2009/09/25)
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- Co-catalyzed mild and chemoselective reduction of phenyl esters with NaBH4: a practical synthesis of (R)-tolterodine
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CoCl2 catalyzes effectively the chemoselective reduction of phenyl carboxylic esters to the corresponding saturated alcohols in high yields using NaBH4 at ambient conditions. By employing this methodology, the synthesis of (R)-tolterodine, a muscarinic receptor antagonist, has been achieved in high yield and optical purity.
- Jagdale, Arun R.,Sudalai, Arumugam
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p. 3790 - 3793
(2008/09/21)
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- Rhodium/chiral diene-catalyzed asymmetric 1,4-addition of arylboronic acids to arylmethylene cyanoacetates
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Asymmetric 1,4-addition of arylboronic acids to (£)-methyl 2-cyano-3-arylpropenoates proceeded in the presence of a rhodium catalyst (3 mol %) coordinated with a chiral diene ligand, (R,R)-Ph-bod*, to give high yields of the corresponding methyl 3,3-diaryl-2-cyanopropanoates with high enantioselectivity (up to 99% ee). This catalytic asymmetric transformation was applied to the asymmetric synthesis of (R)-tolterodine. American Chemical Society.
- Soegel, Sebastian,Tokunaga, Norihito,Sasaki, Keigo,Okamoto, Kazuhiro,Hayashi, Tamio
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p. 589 - 592
(2008/04/12)
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- PROCESS FOR PREPARATION OF 3-(2-HYDROXY-5-SUBSTITUTED PHENYL)-N-ALKYL-3-PHENYLPROPYLAMINES
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A new process for preparation of 3-(2-hydroxy-5-substituted phenyl)-N,alkyl-3- phenylpropylamiηes from cinamoyl chloride via N-alky-3-phenylprop-2-en-1 -amine has been developed.
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- A process for the preparation of tolterodine
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A novel process for the preparation of tolterodine (I), i.e. (R)-N,N-diisopropyI-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, in the racemic form, as well as intermediates useful for its preparation.
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- ENANTIOSELECTIVE SYNTHESIS OF ENANTIOMERICALLY ENRICHED COMPOUNDS
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Method of preparing an enantiomerically enriched compound of formula (II) comprising enantioselective hydrogenation of a compound of general formula (I): where W, X and Z have the meanings indicated in the description, to give a compound of general formula (II): where W, Y, T and C* have the meanings indicated in the description, in the presence of a catalyst or its suitable precursor based on Rh, Ru or Ir, having an oxidation state of 0, +1 or +2, and containing at least one enantiomerically enriched chiral ligand.
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- 4 against the first quaternary ammonium compounds and their use as muscarine
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The compound 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(trifluoromethyl) phenol may be used to prepare the compound (3R)-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium bromide by reaction with methyl bromide.
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- Catalytic asymmetric total synthesis of the muscarinic receptor antagonist (R)-tolterodine
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A convenient and high yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantioenriched (A)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)-tolterodine in a four-step procedure. The configuration of the crucial stereocenter was preserved during the synthesis and the obtained product was identified by chiral HPLC to be the (R)-tolterodine enantiomer.
- Hedberg, Christian,Andersson, Pher G.
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p. 662 - 666
(2007/10/03)
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- Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins: Asymmetric synthesis of (R)-tolterodine
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(Chemical Equation Presented) Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins proceeded with high enantioselectivity in the presence of a rhodium catalyst (3 mol %) generated from Rh(acac)(C 2H4)2 and (R)-Segphos to give the corresponding (R)-4-arylchroman-2-ones in over 99% ee. This asymmetric reaction was applied to the synthesis of (R)-tolterodine.
- Chen, Gang,Tokunaga, Norihito,Hayashi, Tamio
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p. 2285 - 2288
(2007/10/03)
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- Combination therapies
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The invention is directed to methods of treating asthma, COPD, allergic rhinitis, and infectious rhinitis by administering a first pharmaceutical agent including one or more compounds selected from the quarternary ammonium compounds of formulae I-V and a second pharmaceutical agent including one or more pharmaceutical agents selected from Adenosine A2a Receptor Agonists, D2-Dopamine Receptor Agonists, Phosphodiesterase Inhibitors (PDE's), corticosteroids, norepinephrine reuptake inhibitors, 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]-propylsulphonyl]ethylamino]ethyl]-1,3-benzothiazol-2(3H)-one, and pharmaceutically acceptable salts thereof, and non-quarternized antimuscarinic compounds.
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- Quaternary ammonium compounds
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Novel quaternary ammonium compounds of the formula and any stereoisomers thereof, wherein R1, R2 and R3 independently represent C1-C6 alkyl, optionally substituted with phenyl or hydroxyl, or both, and wherein any two of R1, R2 and R3 may form a ring together with the quaternary ammonium nitrogen; R4 represents —H, —CH3, or —CO—R4-1,wherein R4-1 represents —(C1-C4 alkyl), —(C1-C4 alkoxy), or —NR4-2R4-3, wherein R4-2 and R4-3 independently represent —H or —(C1-C4 alkyl); R5, R6 and R7 independently represent —H, —OCH3, —OH, —CONH2, —SO2NH2, —F, —Cl, —Br, —I, —CF3, or —(C1-C4 alkyl), optionally substituted with one or two —OH, —(C1-C4 alkoxy), —COOH, or —CO—O—(C1-C3 alkyl); and X? represents an anion of a pharmaceutically acceptable acid, the compounds for use as medicaments, use of the compounds for the manufacture of specific medicaments, and pharmaceutical compositions comprising the compounds. The present invention also concerns a method of treatment involving administration of the compounds.
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