ABSTRACTS OF PAPERS
`
`Part 2
`
`213th ACS National Meeting
`
`0-8412-3500-7
`
`M
`
`American Chemical Society
`
`San Francisco, CA
`
`April 13-17, 1997
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1029 — Page 1
`SS
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1029 - Page 1
`
`

`
`MEDI
`
`pyrazines have been demostrated to bind with nM potency to muscarinic receptors without
`producing the side effects of salivation and tremor in mice usually associated with the m3
`receptors. Derivatives linking the 3.2.1 azacycie with 1,2.5~tht'adiazofes incorporating an oxygen
`link also have excellent binding aftinity to the muscarinic receptors but are non selective as
`indicated by the production of sahvation and tremor in mice. The most potent anatogs were those
`substituted in the 3 position of the pyrazine by alkylthiols with 2-5 carbons.
`
`046.
`
`l.2.3.4-Tlz‘[RAH"/DROv3~lSOL)I_lINOLlI‘J.EC'.r’tR_BOXYLA1li lJi:IRl\-'A’]'J\r'lES:A NUVJEI. (‘LASS (J5-'
`Si7.].IiCTIVl-. MUSCARINIC ANTAGONISTS. lll. M. Takeuclti . R. Noito. Y. Yonetoku. K. lkeda. Y.
`lsomuru . Institute tor Drug Discttvery‘ Research. Yamanouchi Pharrttalcetttical ('_‘o.. Ltd. 21 l’\-liyultigaoka.
`Tsukuha Cit), [baraki 3U5. Japan
`
`As ".3 part otsearcltirtg for novel bladder selective muscarinic M3 antagonists as potentiai therarpeutie agents:
`for urinatj,‘ incontinence. we have already reported two series otearbatnute derivrtzive.-;. [n order to dt:\‘elop
`more bladder selective M3 antagonists. a series ot‘ l 2.3.-l-tetrahydro-3-isoquinolinecarhoxylute derit utives
`was prepared and evaluated for the binding affittities for the musearinic receptors and for in vim ellects on
`rellexly- evoked rhydtmic contraction of bladder and oxotremurine-induced salivary secretion in rats. Among
`these compounds. t-i-J-(J 5.3'R)-3'-quinuclidinyl J-phcnyl-l
`-at-tetraltydro-2-isoquinolinecarboxylatc b_\'dro-
`chloridct YM-537115) showed high affinity for M3 receptor with a Ki value of l2rtM and 10-fold selectivity
`between rhythmic contraction t'IDflt)-——O.2]1ngfkg.i.v.) and salivary secretion (l[)SD=1.l:ttg.’lrg.i.\'.). YM-53'."ttS
`will he expected as ‘cl drug for the treatment ofurinary ll'lCm'ltll1€.'l1CE without Side—cl‘fEct such as dr_\ mouth.
`
`947‘
`
`PH/\RMA('Ol-‘HORE ll\’ll’ROVEMENT OF AI.LOSTF.RI(' MCJDULATORS OF MUSCARlNlC
`RE(“l:‘PTORS Q Holzgrabe, H M Botero Cid. li Kostenis. E Mies-Klomfafl. and K Mohr.
`Pharmaceutical institute. ljnivcrsity of Bonn. Kreuzhergweg 26, D—53l IS Bonn. Germany
`
`A variety ofdrugs has been described to retard the dissociation of antagonists. c. g. N«I'r1eth_\*lscopolamine.
`from the M_--aoetylcholine receptor This effect is attributed to an allosterit: modulation ofthe receptor protein
`which might be exploited in case oforganopltosphorus poisonings Recently we developed a pltarntacophore
`model Using neurontuscular blockers as well as compounds consisting ofa bisquaternary middle chain and
`aromatic heterocycles, such as pltthalirnido groups‘ at both lateral ends Two positive charges in the middle
`chain as well as two aromatic areas at both ends arranged in an S~shape conformation were found to be
`essential for a high allosteric potency. Herein, substituents of increasing size. e g alkoxy groups and any!
`rings, were added to the phthalimido skeletons. in order to improve the potency and to elucidate whether
`there is any sterical restriction at the allosteric binding site in this series a positive correlation was found
`between the allosteric potency and the lipophilicity of the introduced substituents. Accordingly, an additional
`hydrophobic interaction is probably the explanation to the high potency of‘ benzylidene substituted
`plttltalimido derivatives.
`
`o4g_ SYNTHESIS AND EVAl.lJA'l'lON OF S-AMINOMETHYL DERIVATIVES OF 3,3-
`DIETHYI.-2{3H)-FURANONE AS SUBTYPE-SPECIFIC MUSCARINIC LIGANDS.
`Apyyehu Ahunggna. Daniel J. Canney. Department of Phamtaceutical Sciences. School of
`Pharmacy. Temple University. Philadelphia. PA 19140.
`
`Structurally rigid lactone derivatives of the nonselective muscarinic antagonist benactyzine (1)
`exhibit subtype-specific properties. A series of 5-aminomethyl
`lactones (2b) were prepared and
`evaluated based on this report. 3.3-diethyi-5-imidazolylrnethyl-2t’3H Hitranonc (333. showed a three-
`fold selectivity for the M; receptor subtype over either M. or M1. To investigate the effect of all-;y|—
`substitution on subtype selectivity. a series of 2'-allzyl derivatives of 3a were synthesized. The binding
`properties of the novel lactone derivatives (3b) of 3:. and their thio analogs (3ct. are described here.
`
`Pr?"
`
`R 131:”
`1
`,\~/N._R
`
`RR1
`
`O
`
`R: 2! R1==Ph
`|
`2|: R1=Et
`1
`
`R
`
`3: X-O,R'H
`3|:tX=O,R‘Nky|
`J 3:!-S.R-H,AIky|
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`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1029 — Page 2
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1029 - Page 2