- Large-Scale Synthesis and Modifications of Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (BCP)
-
In flow photochemical addition of propellane to diacetyl allowed construction of the bicyclo[1.1.1]pentane (BCP) core in a 1 kg scale within 1 day. Haloform reaction of the formed diketone in batch afforded bicyclo[1.1.1]pentane-1,3-dicarboxylic acid in a
- Ripenko, Vasyl,Vysochyn, Daniil,Klymov, Ivan,Zhersh, Serhii,Mykhailiuk, Pavel K.
-
-
Read Online
- Cubane, Bicyclo[1.1.1]pentane and Bicyclo[2.2.2]octane: Impact and Thermal Sensitiveness of Carboxyl-, Hydroxymethyl- and Iodo-substituents
-
With the burgeoning interest in cage motifs for bioactive molecule discovery, and the recent disclosure of 1,4-cubane-dicarboxylic acid impact sensitivity, more research into the safety profiles of cage scaffolds is required. Therefore, the impact sensitivity and thermal decomposition behavior of judiciously selected starting materials and synthetic intermediates of cubane, bicyclo[1.1.1]pentane (BCP), and bicyclo[2.2.2]octane (BCO) were evaluated via hammer test and sealed cell differential scanning calorimetry, respectively. Iodo-substituted systems were found to be more impact sensitive, whereas hydroxymethyl substitution led to more rapid thermodecomposition. Cubane was more likely to be impact sensitive with these substituents, followed by BCP, whereas all BCOs were unresponsive. The majority of derivatives were placed substantially above Yoshida thresholds—a computational indicator of sensitivity.
- Dallaston, Madeleine A.,Houston, Sevan D.,Williams, Craig M.
-
supporting information
p. 11966 - 11970
(2020/08/25)
-
- SUBSTITUTED BICYCLIC COMPOUNDS AS FARNESOID X RECEPTOR MODULATORS
-
Disclosed are compounds of Formula (I): or a stereoisomer, a tautomer, or a salt or solvate thereof, wherein Q is C2-6 alkenyl or C2-6 alkynyl, each substituted with zero to 2 R1; and the other variables are as defined herein. These compounds modulate the activity of farnesoid X receptor (FXR), for example, as agonists. Also disclosed are pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
- -
-
Page/Page column 220-221
(2020/08/28)
-
- Bicyclo[1.1.1]pentane-Derived Building Blocks for Click Chemistry
-
Syntheses of bicyclo[1.1.1]pentane-derived azides and terminal alkynes – interesting substrates for click reactions – are described. With a few exceptions, these compounds were prepared in two or three steps starting from common synthetic intermediates – the corresponding carboxylic acids. The key step in the synthesis of 1-azidobicyclo[1.1.1]pentanes is a copper-catalysed diazo-transfer reaction with imidazole-1-sulfonyl azide. The preparation of bicyclo[1.1.1]pentyl-substituted alkynes relies on a Seyferth–Gilbert homologation with dimethyl 1-diazo-2-oxopropylphosphonate (Ohira–Bestmann reagent). Both types of target compounds were found to be suitable substrates for click reactions, and thus they are promising building blocks for medicinal, combinatorial and bioconjugate chemistry. A practically important side result of this study was a multigram preparation of Boc-monoprotected 1,3-diaminobicyclo[1.1.1]pentane – a representative bicyclic conformationally restricted diamine derivative.
- Kokhan, Serhii O.,Valter, Yevheniia B.,Tymtsunik, Andriy V.,Komarov, Igor V.,Grygorenko, Oleksandr O.
-
p. 6450 - 6456
(2017/12/01)
-
- HETEROARYL DERIVATIVES AS SEPIAPTERIN REDUCTASE INHIBITORS
-
Inhibitors of sepiapterin reductase of formula (I) or (I'), wherein the substituents are defined as in the claims, and uses of sepiapterin reductase inhibitors in analgesia, treatment of acute and chronic pain, anti-inflammation, and immune cell regulation are disclosed.
- -
-
Paragraph 001001-001003
(2017/05/31)
-
- Preparation method for bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethylester
-
The invention relates to a preparation method for bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethylester, and mainly solves the technical problem that a method suitable for industrial synthesis does not exist at present. The preparation method comprises the following six steps: firstly, reacting a compound (1) and bromoform under an alkaline condition to obtain a compound (2); secondly, reacting the compound (2) and lithium methide to obtain a compound (3); thirdly, illuminating the compound (3) and diacetyl by a high-pressure mercury lamp to obtain a compound (4); fourthly, treating with sodium hypochlorite to obtain a compound (5); fifthly, reacting the compound (5) and thionyl chloride to obtain a compound (6); and finally, treating the compound (6) under the effect of methanol to obtain a compound (7) which is a final product. A reaction formula is as shown in the specification, and the acquired bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethylester is a useful midbody or product for synthesis of many drugs.
- -
-
-
- Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor
-
Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) withthe bicyclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (~4-fold Cmax and AUC values relative to 1) in a mouse model of γ-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., γ-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere spacer unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.
- Stepan, Antonia F.,Subramanyam, Chakrapani,Efremov, Ivan V.,Dutra, Jason K.,O'Sullivan, Theresa J.,Dirico, Kenneth J.,McDonald, W. Scott,Won, Annie,Dorff, Peter H.,Nolan, Charles E.,Becker, Stacey L.,Pustilnik, Leslie R.,Riddell, David R.,Kauffman, Gregory W.,Kormos, Bethany L.,Zhang, Liming,Lu, Yasong,Capetta, Steven H.,Green, Michael E.,Karki, Kapil,Sibley, Evelyn,Atchison, Kevin P.,Hallgren, Andrew J.,Oborski, Christine E.,Robshaw, Ashley E.,Sneed, Blossom,O'Donnell, Christopher J.
-
p. 3414 - 3424
(2012/06/01)
-
- Synthesis and biological evaluation of 2-(3′-(1H-tetrazol-5-yl)bicyclo[1.1.1]pent-1-yl)glycine (S-TBPG), a novel mGlu1 receptor antagonist
-
The design and synthesis of 2-(3′-(1H-tetrazol-5-yl)bicyclo[1.1.1]pent-1-yl)glycine (S-TBPG), a novel mGluR1 antagonist is reported. S-TBPG is characterized by the bioisosteric replacement of the distal carboxy group of 2-(3′-carboxybicyclo[1.1.1]pent-1-yl)glycine (S-CBPG) by a tetrazolyl moiety. Despite a moderate reduction in potency, S-TBPG is a selective mGluR1 antagonist (69 μM), with no activity at other mGluR subtypes. The interesting biological profile of S-TBPG, coupled with its peculiar chemical structure, is discussed in terms of the structure-activity relationship (SAR) of mGluR1 antagonists.
- Costantino, Gabriele,Maltoni, Katiuscia,Marinozzi, Maura,Camaioni, Emidio,Prezeau, Laurent,Pin, Jean-Philippe,Pellicciari, Roberto
-
p. 221 - 227
(2007/10/03)
-
- Compounds and methods based on [1.1.1]propellane
-
Molecular bulding beams, liquid crystals, and surfactants in the form of compounds based on [1.1.1]propellane, including poly[1.1.1]propellanes. Molecular building beams having a telomeric or polymeric chain staff, and linking groups functionalized on one or both ends of the staff. A system for linking the beams to connecting units to construct molecular structures of various forms, such as whips, combs, scaffoldings, nets, or stars. Other broad aspects of the invention provide liquid crystals and surfactants. The liquid crystals include telomeric or polymeric compounds functionalized with flexible end groups, while the surfactant compounds are functionalized with surface active end groups. Methods of synthesizing the various compounds ar also provided.
- -
-
-