- Synthesis and pharmacological evaluation of benzamide derivatives as selective 5-HT4 receptor agonists
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It is thought that selective 5-HT4 receptor agonists-such as 4-amino-5-chloro-2-methoxy-N-[1-(6-oxo-6-phenylhexyl)piperidin-4-ylmethyl] benzamide (2)-have the ability to enhance both upper and lower gastrointestinal motility without any significant adverse effects. Modification of 2 was performed. Variation of the piperidin-4-ylmethyl moiety of 2 led to a decrease in the binding affinity for the 5-HT4 receptor. Following conversion of the carbonyl group on the benzoyl part to a hydroxyl or sulfoxide group, the binding affinity for the 5-HT4 receptor was retained although the effect on defecation was reduced. Many of the 4-amino-5-chloro-2-methoxy-N- (piperidin-4-ylmethyl)benzamides that had a ether or sulfide moiety in the side-chain part at the 1-position of the piperidine exhibited high affinity for the 5-HT4 receptor. Among these, phenylthio 41c and benzylthio derivative 44 were selective 5-HT4 receptor agonists, and had a similar effect on defecation to compound 2.
- Sonda, Shuji,Kawahara, Toshio,Katayama, Kenichi,Sato, Noriko,Asano, Kiyoshi
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p. 3295 - 3308
(2007/10/03)
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- 3-chloropropyl and 4-chlorobutyl phenyl ethers as sources of 1,3-dilithiopropane and 1,4-dilithiobutane: Sequential reaction with carbonyl compounds
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The reaction of 3-chloropropyl and 4-chlorobutyl phenyl ethers (1) with lithium powder and a catalytic amount of DTBB (5% molar) in THF at - 78 °C followed by successive treatment with a carbonyl compound [R1R2CO = ButCHO, Me2CO, (CH2)5CO, (-)-menthone] at -78 to 20 °C and, after 1.5 h at this temperature, with a second one [R3R4CO = Bu1CHO, PhCHO, Me2CO, MeCOPrn, (CH2)5CO, (-)-menthone] at -78 °C leads, after hydrolysis with water, to the corresponding 1,5-and 1,6-diols (2). Because of the competition of two different reductive cleavages, 1,4- and 1,5-diols 3 were also obtained as side-reaction products.
- Foubelo, Francisco,Saleh, Sadiq A.,Yus, Miguel
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p. 3478 - 3483
(2007/10/03)
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- Substituted 1,1,2-triphenylbutenes and their use in the treatment of cancer
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Compounds of the general formula (2) STR1 wherein n is an integer of from 3 to 10, the iodo substituent is in the 3- or 4-position and R 1 and R 2, which may be the same or different, represent C 1-3 alkyl, especially methyl or ethyl, groups or R l represents a hydrogen atom and R 2 a C 1-3 alkyl group or R 1 and R 2 together with the nitrogen atom to which they are attached represent a saturated heterocyclic group, especially a pyrrolidino group, in the form of their free bases or pharmaceutically acceptable acid addition salts are potent anti-oestrogenic compounds useful for treatment of oestrogen-dependent cancers, especially breast cancers. Compounds where the iodine atom is radioisotopic are useful in radiotherapy or gamma ray imaging of these cancers.
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- Rationally designed analogues of tamoxifen with improved calmodulin antagonism
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Computerized molecular modeling studies on the interactions of the antiestrogen tamoxifen (1) and its analogues bound to the calcium-binding protein calmodulin have guided the rational design of more potent antagonists. Compounds with either three or four methylene units in the basic side chain or slim lipophilic 4-substituents were expected to be more potent. All compounds were tested for antagonism of the calmodulin-dependent activity of cAMP phosphodiesterase and for binding affinity to the estrogen receptor from rat uteri. Some compounds were assayed for cytotoxicity against MCF-7 breast tumor cells in vitro. Introduction of lipophilic 4-substituents was accomplished by using palladium(0)-catalyzed coupling reactions with a 4- iodinated precursor. Both the 4-ethynyl (16 and 17) and 4-butyl (18 and 19) compounds were more potent calmodulin antagonists than tamoxifen. Extension of the basic aminoethoxy side chain of 4-iodotamoxifen (3) and idoxifene (2) ((E)-1-[4-[2-(N-pyrrolidino)ethoxy]phenyl]-1-(4-iodophenyl)-2-phenyl-1- butene) by one or two methylene units resulted in modest gains in calmodulin antagonism (10-13). All the compounds assayed retained estrogen receptor binding characteristics. The compound possessing the optimal combination of calmodulin antagonism and estrogen receptor binding was 12 ((E)-1-[4-[3-(N- pyrrolidino)propoxy]phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene)(IC50 = 1.1 μM, RBA= 23). Correlation between calmodulin antagonism and cytotoxicity was demonstrated for selected compounds.
- Hardcastle,Rowlands,Houghton,Parr,Potter,Jarman,Edwards,Laughton,Trent,Neidle
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p. 241 - 248
(2007/10/02)
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- Tests of a Piperidino Mask for the Protection of Functionalized Carbon Sites in Multistep Syntheses
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Primary alkyl chlorides (R-Cl) are easily isolated in excellent yield after treatment of the appropriate N-alkylpiperidines (R-NC5H10) with α-chloroethyl chloroformate.The method is exemplified by the conversion of a variety of alkylpiperidines, including systems with other sensitive functionalities, to the respective chlorides in yields varying from 90 to 97percent.The potential significance of this process in drug congener preparation and in total synthesis is outlined.Similar fragmentations of N-sec-alkylpiperidines are described.
- Olofson, R. A.,Abbott, Duain E.
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p. 2795 - 2799
(2007/10/02)
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