- Substituted 2-iminopiperidines as inhibitors of human nitric oxide synthase isoforms
-
A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exhibited IC50 values of 0.1 and 0.08 μM, respectively, for hiNOS inhibition. Substitution with cyclohexylmethyl at the 6-position (13) afforded an inhibitor that showed the best selectivity for hiNOS versus heNOS (heNOS IC50/hiNOS IC50 = 64). Following oral administration, inhibitors were found to decrease serum nitrite/nitrate levels in an in vivo rat endotoxin assay. This series of 2- iminopiperidines were prepared via the described synthetic methodologies. The effect of ring substitutions on potency and selectivity for this class of cyclic amidines as NOS inhibitors is described.
- Webber, R. Keith,Metz, Suzanne,Moore, William M.,Connor, Jane R.,Currie, Mark G.,Fok, Kam F.,Hagen, Timothy J.,Hansen Jr., Donald W.,Jerome, Gina M.,Manning, Pamela T.,Pitzele, Barnett S.,Toth, Mihaly V.,Trivedi, Mahima,Zupec, Mark E.,Siong Tjoeng
-
-
Read Online
- Nucleophilic displacement in 2-chloro(trifluoromethyl)pyridines with amines and ammonia
-
The activating effect of trifluoromethyl groups in 2-chloro(trifluoromethyl)pyridines was investigated by comparing reactions of these compounds and of 2-chloropyridine with secondary cyclic amines. The ammonolysis of 2-chloro-3-trifluoromethylpyridine and 2-chloro-4-trifluoromethylpyridine is also reported and shown to proceed, in contrast to the reported behaviour of 2-chloro-5-trifluoromethylpyridine, without hydrolysis of the trifluoromethyl function. Both 2-amino-3-trifluoromethylpyridine and 2-amino-4-trifluoromethylpyridine were converted (via the corresponding pyridones) to 3-trifluoromethylpyridin-2(1H)-thione and 4-trifluoromethylpyridin-2(1H)-thione, and a number of S-alkyl derivatives of the latter compounds were prepared.
- Dunn
-
-
Read Online
- Preparation method of 2-amino substituted six-membered nitrogen-containing heterocycle complex
-
The invention discloses a preparation method of a 2-amino substituted six-membered nitrogen-containing heterocycle complex. The preparation method comprises the following steps: mix 2-fluorine substituted six-membered nitrogen-containing heterocycle complex and amidine hydrochloride salt compound, and then react under the action of a alkaline substance to obtain a 2-amino substituted six-memberednitrogen-containing heterocycle complex. Preferably, the 2-amino substituted six-membered nitrogen-containing heterocycle complex is a 2-amino pyridine compound, a 2-aminopyrimidine compound or a 2-aminopyrazine compound. Compared with the prior art, the method has the advantages of simple synthesis conditions, less reaction steps, mild reaction conditions, low cost of the catalyst used, less waste discharge and good functional group tolerance.
- -
-
Paragraph 0025; 0026; 0095
(2019/02/08)
-
- Transition-metal-free access to 2-aminopyridine derivatives from 2-fluoropyridine and acetamidine hydrochloride
-
Under catalyst-free conditions, an efficient method for the synthesis of 2-aminopyridine derivatives through the nucleophilic substitution and hydrolysis of 2-fluoropyridine and acetamidine hydrochloride has been developed. This amination uses inexpensive acetamidine hydrochloride as the ammonia source and has the advantages of a high yield, high chemoselectivity and wide substrate adaptability. The results suggest that other N-heterocycles containing fluorine substituents can also complete the reaction via these reaction conditions and yield the target products.
- Li, Yibiao,Huang, Shuo,Liao, Chunshu,Shao, Yan,Chen, Lu
-
supporting information
p. 7564 - 7567
(2018/11/02)
-
- METHOD FOR PRODUCING 2-AMINO-4-(TRIFLUOROMETHYL)PYRIDINE
-
The present invention relates to a process for producing a 2-amino-4-trifluoromethylpyridine. Specifically, the present invention provides a process for producing a compound represented by the formula (I) or a salt thereof: (in the formula, X1 is the same as X1 in the formula (II) below), which includes allowing a compound represented by the formula (II): (in the formula, each of X1 and X2 is independently a chlorine atom or a bromine atom) to react with ammonia in the presence of a hydrophilic ether; and also a process for producing 2-amino-4-trifluoromethyl pyridine or a salt thereof, which comprises subjecting the compound of the formula (I) as produced by the foregoing process to dehalogenation,
- -
-
Page/Page column 7
(2012/12/13)
-
- METHOD OF INHIBITING HAMARTOMA TUMOR CELLS
-
Dimorpholinopyrimidines are useful for inhibiting growth or proliferation of hamartoma tumor cells. Because the Dimorpholinopyrimidines inhibit the growth and proliferation of hamartoma tumor cells they are also useful in treating PTEN hamartoma tumor syndromes. The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a patient in need thereof an amount of a compound of dimorpholinopyrimidine derivative that is effective to inhibit growth or proliferation of the hamartoma tumor cells.
- -
-
Page/Page column 20
(2012/08/28)
-
- Orally active aminopyridines as inhibitors of tetrameric fructose-1,6-bisphosphatase
-
A novel sulfonylureido pyridine series exemplified by compound 19 yielded potent inhibitors of FBPase showing significant glucose reduction and modest glycogen lowering in the acute db/db mouse model for Type-2 diabetes. Our inhibitors occupy the allosteric binding site and also extend into the dyad interface region of tetrameric FBPase.
- Hebeisen, Paul,Haap, Wolfgang,Kuhn, Bernd,Mohr, Peter,Wessel, Hans Peter,Zutter, Ulrich,Kirchner, Stephan,Ruf, Armin,Benz, J?rg,Joseph, Catherine,Alvarez-Sánchez, Rubén,Gubler, Marcel,Schott, Brigitte,Benardeau, Agnes,Tozzo, Effie,Kitas, Eric
-
scheme or table
p. 3237 - 3242
(2011/07/07)
-
- Identification of NVP-BKM120 as a potent, selective, orally bioavailable class i PI3 kinase inhibitor for treating cancer
-
Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
- Burger, Matthew T.,Pecchi, Sabina,Wagman, Allan,Ni, Zhi-Jie,Knapp, Mark,Hendrickson, Thomas,Atallah, Gordana,Pfister, Keith,Zhang, Yanchen,Bartulis, Sarah,Frazier, Kelly,Ng, Simon,Smith, Aaron,Verhagen, Joelle,Haznedar, Joshua,Huh, Kay,Iwanowicz, Ed,Xin, Xiaohua,Menezes, Daniel,Merritt, Hanne,Lee, Isabelle,Wiesmann, Marion,Kaufman, Susan,Crawford, Kenneth,Chin, Michael,Bussiere, Dirksen,Shoemaker, Kevin,Zaror, Isabel,Maira, Sauveur-Michel,Voliva, Charles F.
-
supporting information; experimental part
p. 774 - 779
(2011/12/03)
-
- Process for preparing 2-amino-4- (haloalkyl) pyridine derivatives by cyclizing suitable nitrile precursors with nitrogen compounds
-
A process in which a 2-aminopyridine derivative of the general formula II is obtained from open-chain nitrile precursor I or III by reaction with a nitrogen compound in a cyclization reaction is described.
- -
-
Page/Page column 4
(2010/09/18)
-
- PI 3-KINASE INHIBITORS AND METHODS OF THEIR USE
-
Phosphatidylinositol (PI) 3-kinase inhibitor compounds, their pharmaceutically acceptable salts, and prodrugs thereof; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases, including proliferative diseases, inflammatory and obstructive airways diseases, allergic conditions, auutoimmune and cardiovascular diseases.
- -
-
Page/Page column 62
(2008/12/08)
-
- PYRIMIDINE DERIVATIVES USED AS PI-3 KINASE INHIBITORS
-
Phosphatidylinositol (PI) 3-kinase inhibitor compounds (I), their pharmaceutically acceptable salts, and prodrugs thereof ; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases.
- -
-
Page/Page column 93-94
(2010/11/28)
-
- 5,7-DIAMINOPYRAZOLO`4,3-D!PYRIMIDINES USEFUL IN THE TREATMENT OF HYPERTENSION
-
This invention relates to compounds of formula (I).
- -
-
-
- Substituted 2-aminopyridines as inhibitors of nitric oxide synthases.
-
A series of substituted 2-aminopyridines was prepared and evaluated as inhibitors of human nitric oxide synthases (NOS). 4,6-Disubstitution enhanced both potency and specificity for the inducible NOS with the most potent compound having an IC50 of 28 nM.
- Hagmann,Caldwell,Chen,Durette,Esser,Lanza,Kopka,Guthikonda,Shah,MacCoss,Chabin,Fletcher,Grant,Green,Humes,Kelly,Luell,Meurer,Moore,Pacholok,Pavia,Williams,Wong
-
p. 1975 - 1978
(2007/10/03)
-
- Amino-trifluoromethylpyridine compound
-
A novel amino-trifluoromethylpyridine compound selected from the group consisting of 3-amino-5-trifluoromethylpyridine, 2-amino-4-trifluoromethylpyridine, and 2-amino-4,6-bis(trifluoromethyl)pyridine, and, a process for preparing the same by reacting a halogeno-trifluoromethylpyridine compound with ammonia at a temperature of 50° to 200° C. The compound is useful as an intermediate from which a compound effective in controlling various harmful organisms or an effective component compound of medicines can be easily derived.
- -
-
-
