145166-04-7Relevant articles and documents
Lipase-catalyzed Kinetic Resolution of (+/-)-trans- and cis-2-Azidocycloalkanols
Ami, Ei'ichi,Ohrui, Hiroshi
, p. 2150 - 2156 (2007/10/03)
The lipase-catalyzed kinetic resolution of trans- and cis-2-azidocycloalkanols and the preparation of enantiomerically pure trans- and cis-2-aminocycloalkanols are described. Four kinds of lipases were screened for the acetylation of trans- and cis-2-azidocycloalkanols. Among them, Pseudomonas sp. lipases (lipase PS and lipase AK, Amamo Pharmaceutical Co.) showed the highest enantioselectivity. These products were converted to the corresponding 2-aminocycloalkanols to determine their enantiomeric excess (ee) and absolute configurations by HPLC and CD analyses, using (S)-TBMB carboxylic acid [(S)-2-tert-butyl-2-methyl-1,3-benzodioxole-4-carboxylic acid] as the chiral conversion reagent. The results of the CD analysis proved N,O-bis-(S)-TBMB carboxylated cis-2-aminocycloalkanols to adopt a predominantly N-equatorial conformation. The partially resolved trans- and cis-2-aminocycloalkanols, except for trans-2-aminocyclopentanol, were recrystallized from ethyl acetate to give enantiomerically pure forms.
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.
CYCLOALKYL AMINE BIS-ARYL SQUALENE SYNTHASE INHIBITORS
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, (2008/06/13)
This invention relates to a class of novel polycyclic compounds containing a cycloalkyl ring having substituted there on a primary amine and which is further linked or bridged to two mono- and/or bicyclic rings and which reduces levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention
Synthesis of enantiopure N-tert-butoxycarbonyl-2-aminocycloalkanones
Aube,Wolfe,Yantiss,Cook,Takusagawa
, p. 3003 - 3012 (2007/10/02)
A route to enantiomerically pure N-tert-butoxycarbonyl-2-aminocycloalkanones (ring size: 5-8 membered) from the corresponding cycloalkene oxides is described. The procedure involves (1) aminolysis with (S)-α-methylbenzylamine/Me3Al and chromatographic separation of diastereomers, (2) hydrogenolysis to afford the trans-2-aminocycloalkanols, (3) tert-butoxycarbonyl (Boc) protection, and (4) PCC oxidation.
Compounds with Bridgehead Nitrogen. Part 43. The Reaction between trans-2-Aminocycloalkanethiols and Formaldehyde
Barkworth, Peter M. R.,Crabb, Trevor A.
, p. 2777 - 2782 (2007/10/02)
trans-2-Aminocyclopentanethiol condenses with formaldehyde to give rel-(3aR,6aR,9aR,12aR)-6,12-methanoperhydrodicyclopentanodithiadiazecine, whereas trans-2-aminocyclohexanethiol and trans-2-aminocycloheptanethiol give 1:1 mixture of diastereomeric bis(perhydrocycloalkanothiazol-3-yl)methanes.
The Reaction between trans-2-Alkylaminocycloalkanols and Formaldehyde
Barkworth, Peter M. R.,Crabb, Trevor A.
, p. 260 - 264 (2007/10/02)
trans-2-Alkylaminocyclohexanols and trans-2-alkylaminocycloheptanols condense with formaldehyde to give perhydrocycloalkanooxazoles, whereas trans-2-alkylaminocyclopentanols give rise to perhydrocyclopentanodioxazepines.The two types of ring systems are characterized by differing proton-proton geminal coupling constants and 13C NMR parameters.
2-Substituted-1H-benz(de)-isoquinoline-1,3-(2H)-diones
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, (2008/06/13)
Compounds of the following formula STR1 wherein R1 and R2 are independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, nitro, cyano, and trifluoromethyl, and R is selected from a triacetyl substituted pentose, pentose, a tetraacetyl substituted hexose, hexose, a hydroxy substituted cycloalkyl of 5 to 7 carbons, STR2 wherein n is 1 or 2 and R3 is hydrogen, an alkali metal or alkaline earth metal ion; are disclosed. These compounds possess useful anti-inflammatory activity.
