- SUBSTITUTED GUANIDINE DERIVATIVE
-
The present invention provides a compound of general formula (I) (wherein, R1, X, p and q are as described in the present description and claims), or a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing that compound.
- -
-
Paragraph 11407; 1408
(2018/06/23)
-
- HYDROXYMETHYL PIPERIDINE OREXIN RECEPTOR ANTAGONISTS
-
The present invention is directed to hydroxymethyl piperidine compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
- -
-
Page/Page column 34
(2016/06/28)
-
- C-H FLUORINATION OF HETEROCYCLES WITH SILVER (II) FLUORIDE
-
The present invention provides compositions and methods for the selective C-H fluorination of nitrogen-containing heteroarenes with AgF2, which has previously been considered too reactive for practical, selective C-H fluorination. Fluorinated heteroarenes are prevalent in numerous pharmaceuticals, agrochemicals and materials. However, the reactions used to introduce fluorine into these molecules require pre-functionalized substrates or the use of F2 gas. The present invention provides a mild and general method for the C-H fluorination of nitrogen-containing heteroarene compounds to 2-fluoro-heteroarenes with commercially available AgF2. In various embodiments, these reactions occur at ambient temperature within one hour and occur with exclusive selectivity for fluorination at the 2-position. Exemplary reaction conditions are effective for fluorinating diazine heteroarenes to form a single fluorinated isomer.
- -
-
Paragraph 00123
(2015/02/19)
-
- Novel synthetic approach to fluoro- and amido-disubstituted 3-hydroxypyridin-4-ones
-
Starting from fluoropyridines as a building block, with chelating functional groups being introduced, several fluoro- and amido-disubstituted 3-hydroxypyridin-4-ones have been synthesized with the intention of improving the pharmaceutical profile of 3-hydroxypyridin-4-ones.
- Ma, Yongmin,Hider, Robert C.
-
-
- Selective C-H fluorination of pyridines and diazines inspired by a classic amination reaction
-
Fluorinated heterocycles are prevalent in pharmaceuticals, agrochemicals, and materials. However, reactions that incorporate fluorine into heteroarenes are limited in scope and can be hazardous. We present a broadly applicable and safe method for the site-selective fluorination of a single carbon-hydrogen bond in pyridines and diazines using commercially available silver(II) fluoride. The reactions occur at ambient temperature within 1 hour with exclusive selectivity for fluorination adjacent to nitrogen. The mild conditions allow access to fluorinated derivatives of medicinally important compounds, as well as a range of 2-substituted pyridines prepared by subsequent nucleophilic displacement of fluoride. Mechanistic studies demonstrate that the pathway of a classic pyridine amination can be adapted for selective fluorination of a broad range of nitrogen heterocycles.
- Fier, Patrick S.,Hartwig, John F.
-
p. 956 - 960
(2013/12/04)
-
- Design and synthesis of fluorinated iron chelators for metabolic study and brain uptake
-
A range of fluorinated 3-hydroxypyridin-4-ones has been synthesized where fluorine or fluorinated substituent was attached at 2- or 5- position of the pyridine ring in order to improve chemical and biological properties of 3-hydroxypyridin-4-ones. The synthetic route is different from conventional counterparts where a functional group is introduced to a preformed 3-hydroxypyridin-4-one ring. Herein, we introduce a novel method which starts with a fluorine containing precursor and the two hydroxyl groups at 3- and 4- positions of the pyridine ring are introduced at a later stage. The pK a values of the free ligands and the affinity constants of their iron complexes demonstrate that the presence of fluorine dramatically alters the values. The distribution coefficient values of the free ligands and corresponding iron(III) complexes between 1-octanol and MOPS buffer (pH 7.4) are also influenced. Glucuronidation and oxidation studies of selected fluorinated 3-hydroxypyridin-4-ones demonstrate that some such fluorinated compounds have clear advantage over deferiprone in that they are metabolized more slowly. Blood-brain barrier permeability studies indicated that although lipophilicity influences the permeability it is not the only factor. Two of the selected seven fluorinated 3-hydroxypyridin-4-ones have improved brain distribution when compared with deferiprone.
- Ma, Yongmin,Roy, Sourav,Kong, Xiaole,Chen, Yulin,Liu, Dingyong,Hider, Robert C.
-
p. 2185 - 2195
(2012/05/04)
-
- Homogeneous nucleophilic radiofluorination and fluorination with phosphazene hydrofluorides
-
A series of phosphazenium hydrofluorides, P1 tBu·[18/19F]HF, P1 tOct·[18/19F]HF, P2Et· [18/19F]HF, and P4tBu·[ 18/19F]HF, was synthesized. The radioactive phosphazenium [ 18F]hydrofluorides were obtained by the one-step formation and trapping of gaseous [18F]HF with the respective phosphazene bases. The [19F] isotopomers were prepared from the corresponding phosphazene bases and Et3N·3HF. Under the design of experiment (DoE)-optimized conditions, P2Et·HF and P 4tBu·HF fluorinated alkyl chlorides, bromides, and pseudohalides in 76-98 % yield, but gave lower yields with iodides and electron-deficient arenes. DoE models showed that fluorination can be performed in glass vessels, and that the reactivity of P2Et· HF and P4tBu·HF is dominated by solvent polarity but is insensitive to water to at least 2 equiv. In contrast, P1 tBu·HF and P1tOct·HF were unstable towards autofluorolysis. DFT calculations were performed to rationalize this finding in terms of diminished steric bulk, higher Parr's electrophilicity, and chemical hardness of P1RH +. The corresponding radiofluorination reaction gave no valid DoE model but displayed similar substrate scope. High specific activity and excellent radiochemical yields with various pseudohalides (81-91 %) suggest that the proposed radiofluorination methodology can complement the current [ 18F]KF/Kryptofix methods, particularly in the areas for which nonpolar reaction conditions are required. A tale of fluoride: Up to 82 % of [18F]fluoride can be recovered from aqueous solution as [ 18F]HF gas in just one step (see scheme; Tf: trifluoromethanesulfonyl, Ms: methanesulfonyl, Ts=p-toluenesulfonyl). Trapped as phosphazenium hydrofluorides, 18F- and 19F- isotopomers attain high nucleophilicity and solubility in nonpolar solvents. Excelling in fluorination and radiofluorination of various pseudohalides, their substrate scope also extends to halides and nitroarenes. Copyright
- Mathiessen, Bente,Jensen, Andreas T. I.,Zhuravlev, Fedor
-
scheme or table
p. 7796 - 7805
(2011/08/22)
-
- Microwave-accelerated fluorodenitrations and nitrodehalogenations: expeditious routes to labeled PET ligands and fluoropharmaceuticals
-
Methods for the expeditious fluorination of arenes have been investigated, using readily available fluoride sources. An optimized procedure for microwave-accelerated fluorodenitration has been developed, giving good to excellent yields in less than 10 min, rendering it practical for use in the preparation of F18 labeled ligands for PET imaging. Application of the method in the synthesis of CNS agents is demonstrated, and a practical method for the preparation of substrates is also presented.
- LaBeaume, Paul,Placzek, Michael,Daniels, Mathew,Kendrick, Ian,Ng, Patrick,McNeel, Melissa,Afroze, Roushan,Alexander, Abigail,Thomas, Rhiannon,Kallmerten, Amy E.,Jones, Graham B.
-
experimental part
p. 1906 - 1909
(2010/09/07)
-
- FLUORINATED PYRIDIN-4-0NES
-
Metal chelating compounds of formula (I) are provided: or tautomers thereof or a pharmaceutically acceptable salt of either characterised in that R1 is selected from the group H and C1-6 alkyl R2, R4 and R5 are independently selected from the group H, C1-6 alkyl, Cl, F, -CHF2, CF3, -C(O)CF3, -CH(OH)CF3 and R6 R3 is selected from the group H, C1-6 alkyl and C1-6 acyl R6 is a group -C(O)-N(R7)(R8) R7 is selected from H and C1-6 alkyl and R8 is selected from H, C1-6 alkyl and a group -CH(R9CO)-N(R10XR11 ). R9 and R10 are independently selected from H, C1-6 alkyl and C1-10 aralkyl and R11 is selected from H and C1-6 alkyl, or R10 and R11 together with the nitrogen to which they are bonded form a 3-8 membered heterocyclic ring wherein at least one of R2, R4 and R5 is F. The compounds of the invention have reduced susceptibility to glucuronidation and microsomal oxidation as compared to current clinical compounds of the same class but in preferred forms have lower molecular weight and have blood brain barrier permeability.
- -
-
Page/Page column 15; 16
(2009/10/18)
-
