98462-58-9Relevant articles and documents
Experimental and theoretical investigations of the stereoselective synthesis of P-stereogenic phosphine oxides
Copey, Laurent,Jean-Gérard, Ludivine,Framery, Eric,Pilet, Guillaume,Robert, Vincent,Andrioletti, Bruno
supporting information, p. 9057 - 9061 (2015/06/16)
An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides has been developed, incorporating the use of (1S,2S)-2-aminocyclohexanol as the chiral auxiliary. The method relies on three key steps: 1) Highly diastereoselective formation of PV oxazaphospholidine, rationalized by a theoretical study; 2) highly diastereoselective ring-opening of the oxazaphospholidine oxide with organometallic reagents that takes place with inversion of configuration at the P atom; 3) enantioselective synthesis of phosphine oxides by cleavage of the remaining P-O bond. Interestingly, the use of a PIII phosphine precursor afforded a P-epimer oxazaphospholidine. Hence, the two enantiomeric phosphine oxides can be synthesized starting from either a PV or a PIII phosphine precursor, which constitutes a clear advantage for the stereoselective synthesis of sterically hindered phosphine oxides. That's handy: An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides was developed, incorporating the use of (1S,2S)-2-aminocyclohexanol as a chiral auxiliary, whereby enantiomeric phosphine oxides can be synthesized starting from either a PV or a PIII phosphine precursor.
Cycloalkanediamine derivatives as novel blood coagulation factor Xa inhibitors
Nagata, Tsutomu,Yoshino, Toshiharu,Haginoya, Noriyasu,Yoshikawa, Kenji,Isobe, Yumiko,Furugohri, Taketoshi,Kanno, Hideyuki
, p. 4683 - 4688 (2008/02/12)
This paper describes the synthesis of orally available potent fXa inhibitors 2 and 3 by modification of the piperazine part of lead compound 1. Carbonyl derivative 3 showed potent fXa activity but not sulfonyl derivative 2. Among the compounds synthesized, cyclohexane derivatives 3g and 3h and cycloheptane derivative 3j had potent anticoagulant activity as well as anti-fXa activity. Synthetic study of the optical isomers of 3g demonstrated that (-)-3g had more potent activity.
Second generation 'peptoid' CCK-B receptor antagonists: Identification and development of N-(adamantyloxycarbonyl)-α-methyl(R)-tryptophan derivative (CI-1015) with an improved pharmacokinetic profile
Trivedi, Bharat K.,Padia, Janak K.,Holmes, Ann,Rose, Steven,Wright, D. Scott,Hinton, Joanna P.,Pritchard, Martyn C.,Eden, Jon M.,Kneen, Clare,Webdale, Louise,Suman-Chauhan, Nirmala,Boden, Phil,Singh, Lakhbir,Field, Mark J.,Hill, David
, p. 38 - 45 (2007/10/03)
We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was determined that CI-988 had low bioavailability in both rodent and nonrodent species. In the clinic, it was further established that CI-988 had poor bioavailability. Thus, there was a need to identify an analogue with an improved pharmacokinetic (PK) profile. The poor bioavailability was attributed to poor absorption and efficient hepatic extraction. We envisaged that reducing the molecular weight of the parent compound (5, MW = 614) would lead to better absorption. Thus, we synthesized a series of analogues in which the key α-methyltryptophan and adamantyloxycarbonyl moieties, required for receptor binding, were kept intact and the C-terminus was extensively modified. This SAR study led to the identification of tricyclo[3.3.1.13,7]dec-2-yl [1S-[1α(S*)2β]-[2-[(2- hydroxycyclohexyl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2- oxoethyl]carbamate (CI-1015, 31) with binding affinities of 3.0 and 2900 nM for the CCK-B and CCK-A receptors, respectively. The compound showed CCK-B antagonist profile in the rat ventromedial hypothalamus assay with a K(e) of 34 nM. It also showed an anxiolytic like profile orally in a standard anxiety paradigm (X-maze) with a minimum effective dose (MED) of 0.1 μg/kg. Although the compound is less water soluble than CI-988, oral bioavailability in rat was improved nearly 10 times relative to CI-988 when dosed in HPβCD. The blood-brain permeability of CI-1015 (31) was also enhanced relative to CI- 988 (5). On the basis of the overall improved pharmacokinetic profile as well as enhanced brain penetration, CI-1015 (31) was chosen as a development candidate.
