Darstellung und Charakterisierung neuartiger, chiraler, basischer Benzilsäureester mit anticholinerger WirkungJana Selent1.171819226#14351#4685#20102#2251#3162#4442#4443#1243#1244#1252#392.202.1.453#431212.2.222.2.1.614#116388#23223254#1522.2.2.24491#812.2.3.25587#154478#9026127#2812.2.4.27473#3572.2.5.28286#114455#34229587#1032.2.6.211#14130264#1512.2.7.615#2183189#2432.2.8.3.323.1.3.1.1.3.1.2.33471#4353.1.2.1.34478#17951#4551#1183#20103#2251#3162#4335332#21636150#12951#4551#1183#20101#22587#92373.1.2.2.169#24138359#17039109#103143#138141#141121#13940154#15951#4651#1283#2091#2051#3162#4442#4442#1142#1243#12413.1.2.3.42576#140433.1.2.4.443.1.2.5.45463.1.3.3.1.3.1.4748182#9850513.1.3.2.336#206525354182#983.1.3.3.555657583.1.4.3.1.4.1.5960132#140130#135137#13397#97126#12261196#4762182#9863643.1.4.2.128#10865164#113212#147663.1.4.3.673.1.5.68430#144693.1.5.1.70575#768#858#153574#399713.1.5.2.182#9872170#473.1.5.3.7374246#1353.2.753.2.1.31#2595#417631#25182#9832#2532#253.2.2.77251#22878273#2023.2.3.7980122#12781123#12482313#3403.2.4.83264#1923.2.5.395#10884575#140182#9885451#337477#32386518#366518#36687518#366518#3833.2.6.88893.3.3.3.1.903.3.2.91923.3.3.587#14993616#255943.4.953.4.1.96181#98100#67100#6497585#36098280#28499275#2723.4.2.100177#245101156#2741023.5.1033.5.1.551#392104480#3221053.5.2.1063.5.2.1.3.5.2.2.1073.5.2.3.3.5.3.1083.5.3.1.237#284109420#277110418#2641111123.5.3.2.113114182#98110#67115264#702116538#2553.5.4.1174.1184.1.4.1.1.586#1154.1.2.1194.2.1201214.3.1224.3.1.4.3.1.1.58#76147#9245#2678#4795#4645#6345#261231241251264.3.1.2.127245#22258#7847#2681#4696#461281294.3.1.3.13013158#76202#22248#2678#4795#4649#6353#2639#2844#2543#2644#2848#3913213313413513613758#76202#22248#2678#4795#4648#391381394.3.1.4.14058#76134#16178#4795#4649#6353#2639#2843#2543#2643#2748#391411421434.3.1.5.14458#76138#16178#4795#4649#6353#2639#2843#2543#2643#2548#391451464.3.1.6.14714858#76214#18578#4795#4649#6353#2639#2844#2542#2544#2548#3940#2514940#2540#2515040#2540#2540#2515140#2515240#2540#2515340#2540#2540#2515440#2540#2540#2515540#254.3.2.4.3.2.1.15658#76138#16178#4795#4649#6353#2639#2844#2548#2648#391571581591604.3.2.2.16158#76214#18578#4795#4649#6353#2639#2844#2543#2644#2548#3953#261621631641651664.3.2.3.16745#29201#21245#1037#1037#1037#1045#3654#471684.3.3.4.3.3.1.1694.3.3.2.4.4.4.4.1.92#224.4.2.1704.4.3.4.4.4.4.4.4.1.4.4.4.2.1714.4.4.3.1724.4.4.4.4.4.5.17325#244.4.6.4.4.7.4.5.174175151#1554.6.1765.177178179 Literaturverzeichnis180181182183184185186187188Verzeichnis der verwendeten Substanzbezeichnungen (Teil 1)Verzeichnis der verwendeten Substanzbezeichnungen (Teil 2)Verzeichnis der verwendeten AbkürzungendeInhaltsverzeichnisHilfe Literaturverzeichnis 1 Roth, H., J.: Dex-, Lev-, Es-, eine Bilanz der letzten fünf Jahre; Deutsche Apothekerzeitung; 2004 , 144 (20) , S. 57-64 2 Auterhoff, H., Knabe, J., Höltje, H.-D.: Lehrbuch der Pharmazeutischen Chemie; 13. Auflage, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1994 3 Vorwerk, Th., Fröhlich, L., Göber, B.: Benzilates - A Review of Their Actions, Synthesis and Properties; Die Pharmazie; 2001, 56 (8), S. 595-609 4 Morgenstern, E.: Forschungsbericht (Entwicklung neuer Arzneimittel zur Behandlung des Parkinson-Syndroms), Berlin 1991, über Pharmakologische Forschungsgesellschaft Biopharm GmbH Berlin 5 Vorwerk, Th.: Dissertation: Untersuchungen zu Synthese, Analytik, Stabilität und Pharmakologie neuer substituierter Piperidylbenzilate;

Humboldt-Universität zu Berlin

, 2000 6 Kiesewetter, D., O., Silverton, J.,V., Eckelman, W., C.: Syntheses and Biological Properties of Chiral Fluoroalkyl Quinuclidinyl Benzilates; J. Med. Chem.; 1995, 38, S. 1711-1719 7 Mutschler, E., Geisslinger, G., Kroemer, H., K., Schäfer-Korting, M.: Arzneimittelwirkungen-Lehrbuch der Pharmakologie und Toxikokolgie; 8. Auflage, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 2001 8 Battock, T., M., Castelden, C., M.: Pharmacological Treatment of Urinary Incontinence; Brit. Med. Bull.; 1990, 46 (1), S. 147-155 9 a) Chapple, C.: Muscarinic Receptor Antagonist in the Treatment of Overactive Bladder; Urology; 2000, 55 , S. 33-46 b) Eglen, R., Watson, N.: Selective Muscarinic Agonists and Antagonists; Pharmacology & Toxicology, 1996, 78 , S. 59-68 10 Bierwisch, Michael: Dissertation: Synthese und Charakterisierung neuer potentieller M 3 -selektiver Anticholinergika mit Diphenylessigsäurestruktur zur Therapie der Harninkontinenz;

Humboldt-Universität zu Berlin

, 2002 11 Adam, O., Dörfler, H., Forth, W.: Ulzera im oberen Magen-Darm-Trakt- Pharmakologische Grundlagen der Behandlung; Deutsches Ärzteblatt, 2001, 98 (13) , S. A840 12 Müller, C., E., Hubert, M., A., Mayer, R.: Parkinson-Therapeutika; Deutsche Apothekerzeitung; 2002 , 142 (38) , S. 53-64 13 Franke, S.: Lehrbuch der Militärchemie; Band 1, 2. Auflage, Berlin, Militärverlag der Deutschen Demokratischen Republik, 1977, S. 207-214 14 McKenzie, A.: Studies in Asymmetric Synthesis. I. Reduction of Menthyl Benzoylformate. II. Action of Magnesium Alkyl Haloids on Menthyl Benzoylformate; J. Chem. Soc.; 1904, 85, S. 1249 15 Prelog, V.: Untersuchungen über asymmetrische Synthesen I. Über den sterischen Verlauf der Reaktion von α-Ketosäureestern optisch aktiver Alkohole mit Grignard´schen Verbindungen; Helv. Chim. Acta; 1953, 36, S. 308 16 Fiaud, J., C.: Prelog´s Methods in Kagan, H., B.: Fundamentals and Methods of Stereochemistry; Band 3,

Stuttgart

, Georg Thieme Verlag, 1977, S. 19 17 Meyers, A., I., Slade, J.: Asymmetric Addition of Organometallics to Chiral Ketooxazolines. Preparation of Enantiomerically Enriched α-Hydroxy Acids; J. Org. Chem.; 1980, 45, S. 2785-2791 18 Ashby, E., C. and Reed, R.: A Method for the Preparation of Grignard Compounds in Hydrocarbon Solution; J. Org. Chem.; 1966, 31, S. 971 19 Senanayake, C., H., Fang, K., Grover, P., Bakale, R., P., Vandenbossche, C., P., Wald, S., A.: Rigid Aminoalcohol Backbone as a Highly Defined Chiral Template for the Preparation of Optically Active Tertiary Hydroxyl Acids; Tetrahedron Lett.; 1999, 40, S. 819-822 20 Boireau, G., Deberly, D., A.: Synthese D´ α -Hydroxyacides Optiquement Actifs par Addition D´Organozinciques sur le Phenylglyoxylat de (-) Menthyle; Tetrahedron; 1989, 45 (18), S. 5837-5844 21 Whitesell, J., K.: New Perspectives in Asymmetric Induction; Acc. Chem. Res.; 1985, 18, S. 280-284 22 Corey, E., J., Ensley, H., E.: Preparation of an Optically Active Prostaglandin Intermediate via Asymmetric Induction; J. Am. Chem. Soc.; 1975, 97, S. 6908 23 Oppolzer, W., Kurth, M., Reichlin, D., Chapuis, C., Mohnhaupt, M., Moffat, F.: Asymmetric Induction in Diels-Alder Reactions to Acrylates Derived from Chiral sec-Alcohols; Helv. Chim. Acta; 1981, 64, S. 2802 24 Whitesell, J., K., Bhattacharya, A., Henke, K.: Asymmetric Induction. Nucleophilic Addition to a chiral Glyoxylate Ester; J. Chem. Soc. Chem. Commun.; 1982, S. 988-989 25 Whitesell, J., K., Lawrence, R., M., Huang-Hsing Chen: Auxiliary Structure and Asymmetric Induction in the Ene Reactions of Chiral Glyoxylates; J. Org. Chem.; 1986, 51, S.4779-4784 26 Kiesewetter, D., O.: Asymmetric Synthesis of Benzilic Acid Analoques Using 8-Phenylmenthyl as a Chiral Auxiliary; Tetrahedron Asymmetry; 1993, 4 (10), S. 2183-2198 27 Olah, G., A., Yamato, T., Hashimoto, T., Shih, J., G., Trivedi, N., Singh, B., P., Piteau, M., Olah, J., A.: Electrophilic Nitration, Halogenation, Acylation, and Alkylation of α,α,α -Trifluormethoxybenzene; J. Am. Chem. Soc.; 1987, 109, S. 3708-3713 28 Sheppard, W., A.: Aryl fluoroalkyl Ethers and Sulfides: Evidence for Sulfur d-Orbital Interaction; J. Am. Chem. Soc.; 1961, 83, S. 4860-4861 29 Pelzer, R., Scharf, H.-D., Buschmann, H., Runsink, J.: Derivate der (+)-Menthyl-glyoxylate in der Paternó-Büchi-Reaktion. Einfluß von Substituenten im Glyoxylsäurerest auf die Diastereoselektivität; Chem. Ber.; 1989, 122, S. 1187-1192 30 Ottenheijm, H., C., J., De Man, J., H., M.: Syntheses of α-Keto Acid Chlorides; Synthesis; 1975, S. 163-164 31 Ying K., Y., Tebbe, A., L., Linebarger, J., H., Beight, D., B., Craft, T., J., Gifford-Moore, D., Goodson, Th., Herron, D., K., Klimkowski, V., J., Kyle, J., A., Sawyer, J., S., Smith, G., F., Tinsley, J., M., Towner, R., D., Weir, L., Wiley, M., R.: N2-Aroylanthranilamide Inhibitors of Human Factor Xa; J. Med. Chem.; 2000, 43, S. 873-882 32 Pailer, M., Bergthaller, P.: O-Alkylierung von Phenolen und Carbonsäuren mit Dialkylsulfaten und Alkyltosylaten in Dimethylformamid; Monatsh. Chem.; 1968, 99, S. 103-111 33 Scheithauer, S.: Synthese einiger Metabolite des Blasenspasmolytikums Propiverinhydrochlorid; Pharmazie; 1988, 43, S. 86 34 Ashby, E., C., Al-Fekri, D., M. : The Reaction of Benzotrihalides and Benzal Halides with Magnesium. Synthetic and Mechanistic Studies; J. Organomet. Chem.; 1990, 390, S. 275-292 35 Collet, A.: Separation and purification of enantiomers by crystallisation methods; Enantiomer; 1999, 4, S. 157 36 Eliel, E., L., Samuel, H., W.: Basic Organic Stereochemistry; New York, Wiley-Interscience, 2001 37 Collet, A., Brienne M.-J., Jacques J.: Optical Resolution by Direct Crystallization of Enantiomer Mixtures; Chemical Reviews; 1980, 3, S. 215-230 38 Meyer, H.: Di-anisoyl-d-weinsäure in: Rabe, P.: Über die Reduktion der China-Ketone zu China-Alkoholen und über die sterische Umlagerung der China-Alkaloide; Justus Liebigs Ann. Chem.; 1932, 492, S. 265-266 39 Vries, T., Wynberg, H., van Echten, E., Koek, J., ten Hoeve, W., Kellogg, R., M., Broxterman, Q., B., Minnaard, A., Kaptein, B., van der Sluis, S., Hulshof, L., Kooistra, J.: Racematspaltung mit Substanzfamilien; Angew. Chem.; 1998, 110 (17), S. 2491-2496 40 Cohen, V., I., Rzeszotarski, W., J., Gibson, R., E., Fan, L., H., Reba, R., C.: Preparation and Properties of (R)-(-)-Azabicyclo[2.2.2]oct-3yl-(R)-(+)-α-hydroxy-α-(4-[ 125 I]iodophenyl)-α-phenyl Acetat and (R)-(-)-1-Azabicyclo[2.2.2]oct-3-yl-(S)-(-)-α-hydroxy-α-(4-[ 125 I]iodophenyl)-α-phenyl Acetate as Potential Radiopharmaceuticals]; J. Pharm. Science; 1989, 78, S. 833-836 41 Pasteur, L.: Ann. Chim. Phys.; 1848, 24, S. 442 42 Jacques, J., Collet, A.: Enantiomers, Racemates and Resolutions;

New York

, Wiley, 1981 43 Li, J., Z., Grant, D., J., W.: Effects of excess enantiomer on the crystal properties of a racemic compound: ephedrinium 2-naphthalenesulfonate; Int. J. Pharm.; 1996, 137, S. 21-31 44 Jacques, J., Leclercq, M., Brienne, M.-J.: La Formation de Sels Augmente-T-Elle La Fréquence des Déboublements Spontanés?; Tetrahedron; 1981, 37, S. 1727 45 van der Haest, A., D., Wynberg, H.: Towards a rational design of resolving agents. Part IV. Crystal packing analyses and molecular mechanics calculations for five pairs of diastereomeric salts of ephedrine and a cyclic phosphoric acid; Recl. Trav. Chim. Pays-Bas; 1992, 111, S. 111-118 46 Gould, R., O., Gray, A., M., Taylor, P., Walkinshaw, M., D. : Crystal Environments and Geometries of Leucine, Isoleucine, Valine, and Phenylalanine Provide Estimates of Minimum Nonbonded Contact and Preferred van der Waals Interaction Distances; J. Am. Chem. Soc.; 1985, 107, S. 5921-5927 47 Okamoto, Y., Yashima, E.: Chromatographische Enantiomerentrennung an Polysaccharidderivaten; Angew. Chem.; 1998, 110, S. 1072-1095 48 Yashima, E., Okamoto, Y.: Chiral Discrimination on Polysaccharides Derivatives; Bull. Chem. Soc. Jpn.; 1995, 68, S. 3289-3307 49 Wainer I., W., Stifflin, R., M., Ya-Quin Chu: Drug Analysis using High-Performance Liquid Chromatographic (HPLC) - Chiral Stationary Phases: Where to Begin and which to use, in: Stevenson, D., Wilson, I., D.: Chiral Separations,

London,

Plenum Press, 1988, S. 11-21 50 Okamoto, Y., Kawashima, M., Hatada, K.: Chromatographic Resolution: XI: Controlled Chiral Recognition of Cellulose Triphenylcarbamate derivatives Supported on Silica Gel; J. Chrom. A; 1986, 363, S. 173-186 51 Daicel Chemical Industries, LTD.: Application Guide for chiral column selection; Second Edition, Tokyo 52 Okamoto, Y., Aburatani, R., Kaida, Y.: Chem. Lett.; 1988, S. 1125 53 Blaschke, G.: Substituted Polyacrylamides as Chiral Phases for the Resolution of Drugs in Zief, M., Crane, L., J.: Chromatographic Chiral Separations, Chapt. 7,

New York,

Dekker, 1988 54 Han, S., M., Armstrong, D., W.: HPLC-separation of enantiomers and other isomers with cyclodextrin-bonded phases: rules for chiral recognition in Krstulovic, A., M.: Chiral Separations by HPLC-applications to pharmaceutical compounds;

Chichester

, Ellis Horwood Limited, 1989, S. 208 55 Wainer, I., W. (Hrsg.): Drug Stereochemistry; 2. Auflage,

New York, Basel, Hong Kong

, Dekker, 1993, S. 154 56 Feitsma, K., G., Drenth, B., F., H.: A Note on Separation of Enantiomers of Oxyphenonium Bromide by High-Performance Liquid Chromatography, in: Stevenson, D., Wilson, I., D.: Chiral Separations, London, Plenum Press, 1988, S. 38, 39 57 Feitsma, K., G., Drenth, B., F., H., De Zeeuw, R., A.: Comparison of two β-cyclodextrin bonded stationary phases for high-performance liquid chromatography: Elution order and optical purity of enantiomers of cyclohexylphenylglycolic acid; J. Chromatogr., 1987, 387, S. 447-452  58 Rücker, G., Neugebauer, M., Willems, G., G.: Instrumentelle pharmazeutische Analytik; 3. Auflage, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 2001 59 Meyers, A., I., Slade, J.: Resolution of α-Substituted Mandelic Acids via Chiral Oxazolines Using Pressurized Chromatography; J. Org. Chem.; 1980, 45, S. 2912-2914 60 Eyrich, B.: Dissertation: Untersuchungen zur Biotransformation neuer substituierter Piperidyl benzilate; Humboldt-Universität zu Berlin, 2001 61 Dreßler, K.: Dissertation: Analytik, Stabilität und Biotransformation (Ratte) von Propiverinhydrochlorid (Mictonorm®) und Benzilsäure[1-methylpiperidinyl-(4)]ester; Humboldt-Universität zu Berlin, 1987 62 Göber, B., Dressler, K., Franke, P.: Zur Biotransformation von Propiverinhydrochlorid (Mictonorm®) bei der Ratte; Die Pharmazie, 1988, 43, S. 96-98 63 Persichetti, R., A., Lalonde, J., J., Govardhan, C., P., Khalaf, N., K., Margolin, A., L.: Candida Rugosa Lipase: Enantioselectivity Enhancements in Organic Solvents; Tetrahedron Letters; 1996, 37 (36), S. 6507-6510 64 Colton, I., J., Ahmed, S., N., Kazlauskas, R., J.: A 2-Propanol Treatment Increases the Enantioselectivity of Candida rugosa Lipase towards Esters of Chiral Carboxylic Acids; J. Org. Chem.; 1995, 60, S. 212-217 65 Gupta, A., K., Kaslauskas, J.: Substrate Modification to Increase the Enantioselectivity of Hydrolases. A Route to Optically-Active Cyclic Allylic Alcohols; Tetrahedron Asymmetry; 1993, 4 (5), S. 879-888 66 Lefker, B., A., Hada, W., A.: An efficient synthesis of enantiomerically enriched aryllactic esters; Tetrahedron Lett.; 1994, 35, S. 5205-5208 67 Basavaiah, D., Krishna, P., R.: Synthesis of Chiral α -Aryl- α -Hydroxyacetic Acids: Substituent Effects in Pig Liver Acetone Powder (PLAP) Induced Enantioselective Hydrolysis; Tetrahedron; 1995, 51, S. 2403-2416 68 Drioli, S., Felluga, F.: Synthesis of (+)- and (-)-trans-tetrahydro-5-oxo-2-pentylfuran-3-carboxylic acid, precursors of (+)- and (-)-methylenolactocin; J. Chem. Soc. Chem. Commun.; 1996, S. 1289-1290 69 Bornscheuer, U., T., Kazlauskas, R., J.: Hydrolases in Organic Synthesis;

Weinheim, New York

, Wiley-VCH Verlag GmbH, 1999 70 Li-Ming Zhu, Tedford, M., C.: Application of Pig Liver Esterase (PLE) in Asymmetric Synthesis; Tetrahedron; 1990, 46 (19), S. 6587-6611 71 Frey, P., A.: Mechanisms of Enzymatic Reactions: Stereochemistry;

New York

, Elsevier, 1986, S. 3 72 Moorlag, H., Kellogg, R., M.: PLE catalyzed hydrolyses of α -substituted α -hydroxy ester: The influence of the substituents; Tetrahedron Asymmetry; 2 (7), 1991, S. 705-720 73 Davis, B., G., Boyer, V.: Biocatalysis and enzymes in organic synthesis; Nat. Prod. Rep.; 2001, 18, S. 618-640 74 Davies, A., G., Ebeid, F., M.: The Resolution and Reactions of Tertiary Alcohols: Two Disubstituted Glycollic Acids and the Corresponding Disubstituted Glycols; J. Chem. Soc.; 1957, S. 3154-3155 75 Berova, N., Nakanishi, K., Woody, R., W.: Circular Dichroismus – Principles and Applications; 2. Auflage,

New York,

Wiley-VCH, 2000 76 Purdie, N., Brittain, H., G.: Analytical Applications of Circular Dichroism,

Amsterdam,

Elsvier, 1994 77 Pickard, S., T., Smith, H., E.: Optically Active Amines. 34. Application of the Benzene Chirality Rule to Ring-Substituted Phenylcarbinamines and Carbinols; J. Am. Chem. Soc.; 1990, 112, S. 5741-5747 78 Stanchev, St., Rakovska, R., Berova, N., Snatzke, G.: Synthesis, Absolute Configuration and Circular Dichroism of Some Diarylmethane Derivatives; Tetrahedron Asymmetry; 1995, 6 (1), S. 183-198 79 Harada, N., Watanabe, M., Kuwahara, S., Sugio, A., Kasai, Y., Ichikawa, A.: 2-Methoxy-2-(naphthyl)propionic acid, a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1 H-NMR anisotropy method; Tetrahedron Asymmetry; 2000, 11, S. 1249-1253 80 Kosaka, M., Sugito, T., Kasai, Y., Kuwahara, S., Watanabe, M., Harada, N., Job, G., E., Shvet, A., Pirkle, W.: Enantioresolution and Absolute Configuration of Chiral meta-Substituted Diphenylmethanols as Determined by X-Ray Crystallographic and 1H NMR Anisotropy Methods; Chirality; 2003, 15, S. 324-328 81 Engelhardt, H., Beck, W., Schmitt, Th.: Kapillarelektrophorese-Methoden und Möglichkeiten,

Braunschweig/Wiesbaden,

Vieweg & Sohn Verlagsgesellschaft mbH, 1994, S. 134 82 Rogan, M., M., Altria, K., D., Goodall, D., M.: Enantioselective separations using capillary electrophoresis; Chirality, 1994, 6, S. 25-40 83 Nishi, H., Terabe, S.: Optical Resolution of drugs by capillary electrophoretic techniques; J. Chromatogr. A, 1995, 694, S. 245-276 84 Rickard, E., C., Bopp, R., J., Skancy, D., J., Chetwyn, K., L., Pahlen, B., Stobaugh, J., F.: Role of capillary electrophoresis methods in the drug development process: Chirality, 1996, 8, S. 108-121 85 Heuermann, M., Blaschke, G.: Chiral separation of basic drugs using cyclodextrins as chiral pseudo-stationary phases in capillary electrophoresis; J. Chromatogr., 1993, 648, S. 267-274  86 Fanali, S.: Separation of optical isomers by capillary zone electrophoresis based on host-guest complexation with cyclodextrins;  J. Chromatogr., 1989, 464, S. 441-446  87 Snopek, J., Soini, H., Novotny, N., Smolkova-Keulemansova, E., Jelinek, I.: Selected applications of cyclodextrin selectors in capillary electrophoresis; J. Chromatogr., 1991, 559, S. 215-222 88 Terabe, S., Ozaki, H., Otsuka, K., Ando, T.: Electrokinetic chromatography with 2-O-carboxymethyl- β -cyclodextrin as a moving "stationary" phase: J. Chromatogr., 1985, 332, S. 211-217 89 Eliel, E., L., Samuel, H., W.: Stereochemistry of Organic Compounds;

New York

, Wiley, 1994 90 Reist, M., Testa, B., Carrupt, P.-A., Jung, M., Schurig, V.: Racemization, Enantiomerization, Diastereomerization, and Epimerization: Their Meaning and Pharmacological Significance; Chirality; 1995, 7, S. 396-400 91 Dao, L., H., Maleki, M., Hopkins, C., Lee-Ruff, E.: α -Carbonyl Carbocations. 4. NMR Detection and Reactivities of Diaryl α -Carbonyl Cations; J. Am. Chem. Soc.; 1986, 108, S. 5237-5242 92 Murr, B., L., Feller, L., M.: Stereochemistry of Trityl Compounds. IV. The Optical Rotation of an Asymmetric Carbonium Ion and Microscopic Reversibility in Carbonium Ion Reactions; J. Am. Chem. Soc.; 1968, 90, S. 2966 93 Cheng, Y.-C., Prusoff, W.: Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction; Biochem. Pharmacol., 1973, 22, S. 3099-3108 94 Karlson, P.; Kurzes Lehrbuch der Biochemie für Mediziner und Naturwissenschaflter, 13. Auflage,

Stuttgart, New York,

Georg Thieme Verlag, 1988 95 Höltje, H.-D., Folkers, G.: Molecular Modeling; Band 5,

Weinheim

, VCH, 1997 96 Böhm, H.-J., Klebe, G., Kubinyi, H.: Wirkstoffdesign, 1. Auflage,

Heidelberg, Berlin, Oxford,

Spektrum Akademischer Verlag GmbH, Nachdruck 2002 97 Gether, U.: Uncovering Molecular Mechanisms Involved in Activation of G-Protein-Coupled Receptors; Endocrine Review, 2000, 21 (1) S. 90-113 98 Campagne, F. and Maigret, B (Laboratoire de Chimie Théorique de Nancy, U.A. CNRS 510, B.P. 239 - 54506 Vandoeuvre-les-Nancy CEDEX, France) and Bernassau, J., M. (Sanofi Recherche, 371, Rue du Pr. Blayac, 34184 Montpellier CEDEX 4, France): Snake-like Diagram of M1-Receptor 99 Palczewski, K., Kumasaka, T., Hori, T., Behnke, C., A., Motoshima, H., Fox, B., A., Le Trong, I., Teller, D., C., Okada, T., Stenkamp, R., E., Yamamoto, M., Miyano, M.: Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor; Science; 2000, 289, S. 739-745 100 Hulme, E., C., Lu, Z., L.: Structure and activation of muscarinic acetylcholine receptors; Biochem. Soc. Trans.; 2003, 31,S. 29-34 101 Schwartz, T.,W., Gether, U.: Molecular mechanism of action of non-peptide ligands for peptide receptors; Curr. Pharm. Design; 1995, 1, S. 325-342 102 Schwartz, T.: Vortrag: Structure-based drug discovery in 7TM receptors based on knowledge on molecular mechanism of activation; 15. März, 2004 (Erlangen) 103 Hulme, E., C., Curtis, C., A., M.: The Role of Charge Interactions in Muscarinic Agonist Binding, and Receptor-Response Coupling; Life Science; 1995, 56 (11/12), S. 891-898 104 Hulme, E., C., Lu, Z., L.: Scanning Mutagenesis Studies of the M 1 Muscarinic Acetylcholine Receptor; Receptors and Channels; 2003, 9, S. 215-228 105 MOE (Molecular operating environment), Chemical Computing Group Inc., Montreal, Canada 106 Lu, Z.,L., Curtis, C., A., M., Jones, Ph., G., Pavia, J., Hulme E., C. : The Role of the Aspartate-Arginine-Tyrosine Triad in the M 1 Muscarinic Receptor: Mutations of Aspartate 122 and Tyrosine 124 Decrease Receptor Expression but Do Not Abolish Signaling; Mol. Pharmacol.; 1997, 51, S. 234-241 107 Clark, M., Cramer III, R., D., van Opdenbosch, N., J.: J. Comput. Chem.; 1989, 10, S. 982-1012 108 Gasteiger, J., Marsili, M.: Iterative Partial Equalization of Orbital Electronegativity - A Rapid Access to Atomic Charges; Tetrahedron; 1980, 36, S. 3219-3228 109 SYBYL© Tripos Associates Inc., S. L., MO; U.S.A. 110 Laskowski, R., A., MacArthur, M., W., Moss, D., S., Thornton, J., M.: PROCHECK: a program to check the stereochemical quality of protein structures; J. Appl. Cryst.; 1993, 26, S. 283-291 111 GOLD-Copyright-Cambridge Crystallographic Data Centre-1998-located in Cambridge, UK 112 Wang, R., Liang, L.: SCORE: A New Empirical Method for estimating the Binding Affinity of a Protein-Ligand Complex; J. Mol. Model.; 1998, 4, S. 379-394 113 Flavin, M., T., Lu, M., C., Thompson, E., B., Bhargava, H., N.: Molecular modification of anticholinergics as probes for muscarinic receptors. 3. Conformationally restricted analogs of benactyzine; J. Med. Chem.; 1987, 30, S. 278-285 114 Forth, H., Henschler, D., Rummel, W., Förstermann, U., Starke, K.: Allgemeine und Spezielle Pharmakologie und Toxikologie; 8. Auflage, München, Urban & Fischer, 2001 115 Wittke, K.: Dissertation: Untersuchungen zur Synthese, Analytik und biopharmazeutischer Charakterisierung neuer basischer substituierter Benzilsäureester, Humboldt-Universität zu Berlin, 1993 116 Barnish, Ian, T.; Cross, Peter, E., Danilewicz, J., C., Dickonson, R., P., Stopher, D., A.: Promotion of Carbohydrate Oxidation in the Heart by Some Phenylglyoxylic Acids; J. Med. Chem.; 1981, 24, S. 399-404 117 Vogel, Ch.; Matter, M.: syn-anti Isomerie bei Arylhydrazonen und Arylglyoxylsäuren; Helvetica Chimica Acta; 1959, 59, S. 528-533 118 Becker, H., G., O.: Organikum; 21. Auflage,

Weinheim

, Wiley-VCH, 2001 119 Oehme, G., Fischer, G., Schellenberger, A.: IR-Spektroskopische Untersuchungen der Stereochemie und Energieübertragung in intramolekularen Wasserstoffbrücken substituierter Phenylglyoxylsäuren; Chem. Ber.; 1967, 100, S. 425-435 120 Budesinsky, Z., Sluka, J., Bydzovsky, V.: Antituberkulosni Latky. Isonikotinoylhydrazony nekterych fenylglyoxylovych kyselin; Cesk. Farm.; 1964, 13, S. 345, 347 121 Staudinger, H.; Stockmann, H.: Über Einwirkung von Oxalylchlorid auf Dimethylanilin; Chem. Ber.; 1909, 42, S. 3485 122 Tumiatti, V., Recanatini, M., Minarini, A., Melchiorre, C., Chiarini, A., Budriesi, R., Bolognesi, M., L.: Affinity and Selectivity at M 2 and M 3 , Muscarinic Receptor Subtypes of Cyclic and Open Oxygenated Analogues of 4-DAMP; IL Farmaco; 1992, 47 (9), S. 1133-1147 123 Bockstahler, W.: Some Ethers Derived from Diethylaminoethyl Benzilate; J. Am. Chem. Soc.; 1949, 71, S. 3760, 3761 124 Singh, D.: p-Dimethylaminodiphenylacetic Acid; J. Chem. Soc.; 1925, 127, S. 2447 125 Auterhoff, H., Kovar, K.-A.: Identifizierung von Arzneistoffen; 6. Auflage, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1998 126 Jork, H., Funk, W., Fischer, W.: Dünnschichtchromatographie, Reagenzien und Nachweismethoden; Band 1a,

Weinheim

, VCH Verlagsgesellschaft mbH, 1990 127 Cheney, L., C., Bywater, W., G.: 4-Morpholinealkyl Esters and Amides Possessing Antispasmodic Activity; J. Am. Chem. Soc.; 1942, 64, S. 973