2037-99-2Relevant academic research and scientific papers
Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis
Arns, Steve,Gibe, Romelo,Moreau, Anne,Monzur Morshed,Young, Robert N.
, p. 2131 - 2140 (2012/05/05)
There is an important medical need for effective therapies to redress the general bone loss associated with advanced osteoporosis. Prostaglandin E 2 and related EP4 receptor agonists have been shown to stimulate bone regrowth but their use has been limited by systemic side effects. Herein is described the design and synthesis of novel dual-action bone-targeting conjugate pro-drugs where two classes of active agents, a bone growth stimulating prostaglandin E2 EP4 receptor subtype agonist (5 or 6) and a bone resorption inhibitor bisphosphonate, alendronic acid (1), are coupled using metabolically labile carbamate or 4-hydroxyphenylacetic acid based linkers. Radiolabelled conjugates 9, 11a/b and 25 were synthesized and evaluated in vivo in rats for uptake of the conjugate into bone and subsequent release of the EP4 agonists over time. While conjugate 11a/b was taken up (9.0% of initial dose) but not released over two weeks, conjugates 9 and 25 were absorbed at 9.4% and 5.9% uptake of the initial dose and slowly released with half-lives of approximately 2 weeks and 5 days respectively. These conjugates were well tolerated and offer potential for sustained release and dual synergistic activity through their selective bone targeting and local release of the complimentary active components.
The synthesis of cyclic and acyclic long-chain arylpiperazine derivatives of salicylamide as serotonin receptor ligands
Kowalski, Piotr,Jaskowska, Jolanta,Bojarski, Andrzej J.,Duszynska, Beata
, p. 209 - 214 (2008/09/18)
(Chemical Equation Presented) The 1-arylpiperazine series of N-substituted 1,3-benzoxazine-2,4-diones as well as O- and N-substituted salicylamides with an n-propyl chain were synthesized in order to explore the effect of cyclic and acyclic salicylamide moieties on their binding affinity for 5-HT1A, 5-HT2A and 5-HT7 receptor sites. Target compounds 1 and 2 were prepared by a two-step procedure, i.e. by alkylation of 1,3-benzoxazine-2,4-dione or salicylamide with 1,3-dibromopropane and next by condensation of 3-bromopropyl intermediates with arylpiperazines; syntheses of 3-bromopropyl intermediates were performed in solvent-free conditions. Compounds 3 were prepared by hydrolysis of 1. In respect of salicylamide moieties, binding affinities for 5-HT1A and 5-HT7 receptors increase according to the rank of derivatives 3 2A receptors, increased activity of ligands was changed in reverse order to the affinity for 5-HT1A, i.e. 2 1A and 5-HT7 receptor binding constants were the highest for the 2-methoxyphenyl ligand 2c, while the 3-chlorophenyl ligand 3b was most active for 5-HT2A receptors.
N-alkylation of imides using phase transfer catalysts under solvent-free conditions
Jaskowska, Jolanta,Kowalski, Piotr
scheme or table, p. 1371 - 1375 (2009/04/07)
(Chemical Equation Presented) N-Alkylation of imides in the reaction of imides and alkylhalides, catalyzed by PT catalysts under solvent-free conditions, has been developed. The reaction occurs in the presence of K 2CO3, and in many cases it takes place spontaneously. In the N-benzylation reaction, it has been recognized that TBAB (tetrabutylammonium bromide) and TBATFB (tetrabutylammonium tetrafluoroborate) show highest catalytic effect. Versatility and synthetic capacity of the solvent-free alkylation has been confirmed by N-benzylation and N-ethylation of various imides. The developed procedure gives easy access to N-(ω-bromoalkyl) imides.
A simple one-pot synthesis of benzoxazine-2,4-diones and benzothiazine-2,4-diones
Zhu, Xiaoxiang,Yu, Qian-sheng,Greig, Nigel H.,Flippen-Anderson, Judith L.,Brossi, Arnold
, p. 115 - 128 (2007/10/03)
A simple and efficient procedure has been developed for a one-pot synthesis of substituted benzoxazine-2,4-diones and benzothiazine-2,4-diones directly from salicylic acid (or thiosalicylic acid) and amines.
3-Benzyl-2H-1,3-benzoxazine-2,4(3H)-diones, a new group of antimycobacterial compounds against potentially pathogenic strains
Waisser, Karel,Perina, Milan,Kunes, Jiri,Klimesova, Vera,Kaustova, Jarmila
, p. 1137 - 1149 (2007/10/03)
A series of derivatives of 3-benzyl-2H-benzoxazine-2,4(3H)-dione substituted in positions 6, 7 or 8 on the benzoxazine, and in positions 3 or 4 on the benzyl moiety was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium avium and two strains of Mycobacterium kansasii. The disadvantage of the compounds is in their low solubility in water. The antimycobacterial activity of N-benzylsalicylamides correlates with that of 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones and depends on the partition coefficients and electronic indexes.
Palladium-Catalyzed Cyclocarbonylation of o-Iodophenols and 2-Hydroxy-3-iodopyridine with Heterocumulenes: Regioselective Synthesis of Benzo[e]-1,3-oxazin-4-one and Pyrido[3,2-e]-1,3-oxazin-4-one Derivatives
Larksarp, Chitchamai,Alper, Howard
, p. 9194 - 9200 (2007/10/03)
Benzo[e]-1,3-oxazin-2-imine-4-ones (3) were synthesized by cyclocarbonylation of o-iodophenols with carbodiimides in the presence of a catalytic amount of a palladium catalyst and 1,4-bis-(diphenylphosphino)butane under CO pressure. Product yields are dep
Silver(I) ion-mediated desulfurization-cyclization of isothiocyanates with several hydroxy acids and N-substituted amino acids
Shibuya, Isao,Goto, Midori,Shimizu, Masao,Yanagisawa, Masaru,Gama, Yasuo
, p. 2667 - 2673 (2007/10/03)
The title reaction of 2-hydroxy-2-methylpropionic acid with phenyl isothiocyanate gave 5,5-dimethyl-3-phenyl-2,4-oxazolidinedione. The structure was determined by X-Ray crystal analysis, and the reaction pathway was estimated. The reactions of other 2-hyd
