5278 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
Sterling et al.
(20) Gulinnaz, A.; Girgin, F. K.; Ozgonul, M.; Mentes, G.; Ersoz, B.
MAO Inhibitors and Oxidant Stress in Aging Brain Tissue. Eur.
Neuropsychopharmacology 1999, 9, 247-252.
(21) Dostert, P.; O’Brien, E. M.; Tipton, K. F.; Meroni, M.; Melloni,
P.; Strolin, M.; Benedetti, M. Inhibition of Monoamine Oxidase
by the R and S Enantiomers of N[3-(2,4-Dichlorophenoxy)-
propyl]-N-Methyl-3-Butyn-2-Amine. Eur. J . Med. Chem. 1992,
27, 45-52.
(46) Harel, M.; Sussman, J . L.; Krejci, E.; Bon, S.; Chanal, P.;
Massoulie, J .; Silman, I. Conversion of Acetylcholinesterase to
Butyrylcholinesterase: Modeling and Mutagenesis. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 10827-10831.
(47) Lieske, C. N.; Gepp, R. T.; Clark, J . H.; Meyer, H. G.; Blumberg,
P.; Tseng, C. C. Anticholinesterase Activity of Potential Thera-
peutic 5-(1,3,3-Trimethylindolinyl) Carbamates. J . Enzyme In-
hib. 1991, 5, 215-223.
(22) Kawasaki, I.; Matsuda, K.; Kaneko, T. Preparation of 1,7-Bis-
(p-hydroxyphenyl) heptane. Bull. Chem. Soc. J pn. 1971, 44,
1986-7.
(23) Oshiro, Y.; Sakurai, Y.; Tanaka, T.; Ueda, H.; Kikuchi, T.;
Tottori, K. Novel Cerebroprotective Agents with CNS Stimulat-
ing Activity. 1. Synthesis and Pharmacology of the 1-Amino-7-
Hydroxyindan Derivatives. J . Med. Chem. 1991, 34, 2004-13.
(24) Borch, R. F.; Bernstein, M. D.; Durst, H. D. The Cyanohydri-
doborate Anion as a Selective Reducing Agent. J . Am. Chem.
Soc. 1971, 93, 2897-2904.
(25) Cannon, J . G.; Dushin, R. G.; Long, J . P.; Ilhan, M.; J ones, N.
D.; Swartzendruber, J . K. Synthesis and Dopaminergic Activity
of (R) and (S)-4-Hydroxy-2-(Di-n-propylamino)indan. J . Med.
Chem. 1985, 28, 515-18.
(26) Singh, T.; Stein, R. G.; Hoops, J . F.; Biel, J . H.; Hoya, W. K.;
Cruz, D. R. Antimalarials. 7-Chloro-4-(Substituted amino)-
quinolines. J . Med. Chem. 1971, 14, 283-286.
(48) Iyo, M.; Namba, H.; Fukushi, K.;. Measurement of Acetylcho-
linesterase by Positron Emission Tomography in the Brains of
Healthy Controls and Patients with Alzheimer’s Disease. Lancet
1997, 349, 1805-1809.
(49) Arendt, T.; Bruckner, M.; Lange, M.; Bigl, V. Changes in
Acetylcholinesterase and Butyrylcholinesterase in Alzheimer’s
Disease Resemble Embryonic Development - a Study of Molec-
ular Forms. J . Neurochem. 1992, 21, 231-244.
(50) Bolognesi, M. L.; Andrisano, V.; Bartolini, M.; Minarini, A.;
Rosini, M.; Tumiatti, V.; Melchiorre, C. Hexahydrochromeno-
[4,3-b]pyrrole Derivatives as AChE Inhibitors. J . Med. Chem.
2001, 44, 105-9.
(51) Bar-On, P.; Millard, C. B.; Harel, M.; Dvir, H.; Enz, A.; Sussman,
J . L.; Silman, I. Kinetic and Structural Studies on the Interaction
of Cholinesterases with the Anti-Alzheimer Drug Rivastigmine.
Biochemistry, 2002, 41, 3555-64, was published while this
manuscript was in the final stages of submission. In their crystal
structure, the rivastigmine carbamoyl bond has already been
cleaved and the two fragments (NAP and carbamoyl) are bound
by the enzyme some distance from one another. Thus, it is
impossible to reconstruct the conformation of rivastigmine at
the time of initial binding. Although the 4-hydroxy dimeth-
ylaminoindan resulting from 32a superimposes more success-
fully on their NAP, there is no apparent reason that 6-hydroxy
aminoindan from 31a will not also fit in the site. We are
continuing to investigate this issue.
(52) Hazelhoff, B.; De Vries, J . B.; Dijkstra, D.; de J ong, W.; Horn,
A. S. The Neuropharmacological Profile of N-Methyl-N-Propar-
gyl-2-Aminotetralin: a Potent Monoamine Oxidase Inhibitor.
Naunyn-Schmiedeberg’s Arch. Pharmacol. 1985, 330, 50-58.
(53) Sterling, J .; Veinberg, A.; Lerner, D.; Goldenberg, W.; Levy, R.;
Youdim, M.; Finberg, J . (R) (+)-N-Propargyl-1-Aminoindan
(Rasagiline) and Derivatives: Highly Selective and Potent
Inhibitors of Monoamine Oxidase B. J . Neural Transm. [Suppl]
1998, 52, 301-305.
(27) Huebner, C. F.; Donoghue, E. M.; Plummer, A. J .; Furness, P.
A. N-Methyl-N-2-Propynyl-1-indanamine, a Potent MAO Inhibi-
tor. J . Med. Chem. 1966, 9, 830-832.
(28) Toth, G., unpublished results.
(29) Lidor, R.; Bahar, E. Method for Preparing Optically Active
1-Aminoindan Derivatives. US 5639913, 1997.
(30) Teranishi, K.; Nakatsuka, S.; Goto, T. Facile synthesis of
6-Hydroxyindole and 6-Methoxyindole via Regioselective Friedel-
Crafts Acylation and Baeyer-Villiger Oxidation. Synthesis 1994,
1018-20.
(31) (a) Riggs, R. M.; Nichols, D. E.; Foreman, M. M.; Truex, L. L.
Evaluation of Isomeric 4-(Chlorohydroxyphenyl)-1,2,3,4-tet-
rahydroisoquinolines as Dopamine D-1 Antagonists. J . Med.
Chem. 1987, 30, 1887-1889. (b) Ginsburg D. The Action of tert-
Butyl Hypochlorite on Organic Compounds. II. Aromatic Alde-
hydes. J . Am. Chem. Soc. 1951, 73, 702-704.
(32) Toth, G.; Kover, K. E. Simple, Safe, Large Scale synthesis of
5-Arylmethyl-2,2-dimethyl-1,3-dioxane-4,6-diones and 3-Aryl-
Propanoic Acids. Synth. Commun. 1995, 25, 3067-3074.
(33) Meldrum, A. N. A â-Lactonic Acid from Acetone and Malonic
Acid. J . Chem. Soc. 1908, 93, 598-601. Davidson, D; Bernhard,
S. A. The Structure of Meldrum’s supposed â-Lactonic Acid. J .
Am. Chem. Soc. 1948, 70, 3426-8.
(54) Binda, C.; Newton-Ginson, P.; Hubalek, F.; Edmondson, D. E.;
Mattevi, A. Structure of Human Monoamine Oxidase B, a Drug
Target for the Treatment of Neurological Disorders. Nature
Struct. Biol. 2002, 9, 22, was published while this manuscript
was in the final stages of submission.
(34) Demir, A. S.; Tanyeli, C.; Sesenoglu, O.; Demic, S.; Evin, O. O.
A Simple Synthesis of 1-Aminophosphonic Acids from 1-Hy-
droxy-iminophosphonates with NaBH4 in the Presence of Tran-
sition Metal Compounds. Tetrahedron Lett. 1996, 37, 407-410.
(35) Copinga, S.; Tepper, P.; Grol, C. J .; Horn, A. S.; Dubocovich, M.
L. 2-Amino-8-Methoxytetralins: A Series of Nonindolic Mela-
tonin-like Agents. J . Med. Chem. 1993, 36, 2891-98.
(36) Ellenstein, A.; Ringel, I. (School of Pharmacy, the Hebrew
University, J erusalem, Israel), unpublished results, personal
communication.
(37) Weinstock, M.; Razin, M.; Ringel, I.; Tashma, Z.; Chorev, M.
Acetylcholinesterase Inhibition by Novel Carbamates: A Kinetic
and NMR Study. In Multidiscipinary Approaches to Choline-
sterase Functions, 36th; Shafferman, A., Velan, B., Eds.; Ple-
num: New York, NY, 1992; pp 251-9.
(38) Buck, J . S.; Baltzly, R.; Ide, W. S. â-Phenylethylamine Deriva-
tives. Tertiary and Quaternary salts. J . Am. Chem. Soc. 1938,
60, 1789-92.
(39) Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, pp
573-6.
(40) Carlsson, A.; Lindquist, M.; Wysokowski, J . Substituted Meta-
tyramines as Brain Monoamine Depletors. Acta Pharm. Suecica
1970, 7, 293-302.
(41) Acid addition Salts of D-(+)-1-(3-Hydroxyphenyl)-2-Aminopro-
pane and their Manufacture and Use. GB 1527479, 1977.
(42) Saari, W. S.; Raab, A. W.; Engelhardt, E. L. The Stereoisomers
of Alpha-(1-Aminoethyl)-m-Hydroxybenzyl Alcohol. J . Med. Chem.
1968, 11, 1115-7.
(55) Kalir, A.; Sabbagh, A.; Youdim, M. B. H. Selective Acetylenic
‘Suicide’ and Reversible Inhibitors of MAO Types A and B. Br.
J . Pharmacol. 1981, 73, 55-64.
(56) Riederer, P.; Reynolds, G. P.; Youdim, M. B. H.; J ellinger, K. In
Vitro Tests of MAO Inhibitors in Human Brain Tissue: Chemi-
cal Structure and Pharmacological Action. Int. Congr. Ser.-
Excerpta Med. 1982, 564 (MAO), 345-350.
(57) Polymeropoulos, P. l-Deprenyl: A Unique MAO-B Inhibitor. In
Inhibitors of MAO B, Pharmacology and Clinical Use in Neu-
rodegenerative Disorders; Szelenyi, I. Ed.; Birkhauser Verlag:
Basel, 1993.
(58) Moron, J . A.; Campillo, M; Perez, V.; Unzeta, M.; Pardo, L.
Molecular Determinants of MAO Selectivity in
a Series of
Indolylmethylamine Derivatives: Biological Activities, 3D-QSAR/
CoMFA Analysis, and Computational Simulation of Ligand
Recognition. J . Med. Chem. 2000, 43, 1684-1691.
(59) For the parent compounds (R ) H), the N-methyl derivative
showed about 3 orders of magnitude more MAOI activity than
the secondary amine for both A and B, whereas in the hydroxy
derivative (R ) OH) solely A was enhanced by this factor and B
by only 1 order of magnitude. On the other hand, N-methylation
of the methoxy analogue (R ) OCH3) decreased A activity by a
factor of 2 and B by a factor of 10. All of these compounds are A
selective by factors ranging from 2 to 200.
(60) Swett, L. R.; Martin, W. B.; Taylor, J . D.; Everett, G. M.; Wykes,
A. A.; Gladish, Y. C. Structure-Activity Relations in the
Pargyline Series. Ann. N.Y. Acad. Sci. 1963, 891-898.
(61) Borbe, H.; Niebch, G.; Nickel, B. Kinetic Evaluation of MAO-B
Activity Following Oral Administration of Selegiline and Des-
methyl Selegiline in Rat. J . Neural Transm. 1990, 32 (suppl)
131-7.
(43) Buckley, T. F., III; Rapoport, H. R-Amino Acids as Chiral Educts
for Asymmetric Products. Amino Acylation with N-Acylamino
Acids. J . Am. Chem. Soc. 1981, 103, 6157-63.
(44) Marco, J . L.; Royer, J .; Husson, H.-P. Asymmetric Synthesis
IX: Preparation of Chiral R-Substituted Phenethylamines.
Synth. Commun. 1987, 17, 669-76.
(45) Weinstock, M.; Razin, M.; Chorev, M.; Tashma, Z. Pharmacologi-
cal Activity of Novel Anticholinesterase Agents of Potential Use
in Treatment of Alzheimer’s Disease. J . Neural Transm. 1994,
s43, 219-225.
(62) Maycock, A. L.; Abeles, R. H.; Salch, J . I.; Singer, T. P. The Action
of Acetylenic Inhibitors on Mitochondrial Monoamine Oxidase:
Structure of the Flavin Site in the Inhibited Enzyme. In
Monoamine Oxidase and its Inhibition; Wolstenholme, G. E. W.,
Knight, J ., Eds.; Elsevier: Amsterdam, 1976; pp 33-47.
(63) Rudenko, V. A.; Yakubovitsch, A. Y.; Nikiforova, T. Y. J . Gen.
Chem. USSR (Engl. Transl.) 1947, 17, 2256.