- Electrochemical: N -demethylation of tropane alkaloids
-
A practical, efficient, and selective electrochemical N-demethylation method of tropane alkaloids to their nortropane derivatives is described. Nortropanes, such as noratropine and norscopolamine, are important intermediates for the semi-synthesis of the medicines ipratropium or oxitropium bromide, respectively. Synthesis was performed in a simple home-made electrochemical batch cell using a porous glassy carbon electrode. The reaction proceeds at room temperature in one step in a mixture of ethanol or methanol and water. The method avoids hazardous oxidizing agents such as H2O2 or m-chloroperbenzoic acid (m-CPBA), toxic solvents such as chloroform, as well as metal-based catalysts. Various key parameters were investigated in electrochemical batch or flow cells, and the optimized conditions were used in batch and flow-cells at gram scale to synthesize noratropine in high yield and purity using a convenient liquid-liquid extraction method without any need for chromatographic purification. Mechanistic studies showed that the electrochemical N-demethylation proceeds by the formation of an iminium intermediate which is converted by water as the nucleophile. The optimized method was further applied to scopolamine, cocaine, benzatropine, homatropine and tropacocaine, showing that this is a generic way of N-demethylating tropane alkaloids to synthesize valuable precursors for pharmaceutical products.
- Alipour Najmi, Ali,Bischoff, Rainer,Dekker, Frank J.,Permentier, Hjalmar P.,Xiao, Zhangping
-
supporting information
p. 6455 - 6463
(2020/11/09)
-
- Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment
-
Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based 1H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6 h. This interconversion process “intrinsic reversibility” was exploited by modifications of the ligand's size (length and bulkiness) to generate analogs with “tunable’ adduct residence time (τ). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by ~4.5 mmHg in a sustained manner for at least 12 h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma.
- Alapafuja, Shakiru O.,Malamas, Michael S.,Shukla, Vidyanand,Zvonok, Alexander,Miller, Sally,Daily, Laura,Rajarshi, Girija,Miyabe, Christina Yume,Chandrashekhar, Honrao,Wood, JodiAnne,Tyukhtenko, Sergiy,Straiker, Alex,Makriyannis, Alexandros
-
-
- A biocatalytic/reductive etherification approach to substituted piperidinyl ethers
-
A synthetically useful protocol has been developed for the preparation of highly functionalized piperidinyl ethers. Biocatalytic reduction of cyclhexanones 7, 10, and 14 allows for the preparation of both cis- and trans diastereomers with an extremely high degree of stereochemical control. Reductive etherification of the corresponding trimethylsilylethers with 1-(benzyloxycarbonyl)-4-piperidinone 17 in the presence of triethylsilane and catalytic TMSO-Tf provides the desired piperidinyl ethers in good to excellent yields. Finally hygrogenolysis of the nitrogen protecting group leads to piperidinyl ethers in near quantitative yields. Application of the methodology to a range of piperidinyl ethers, including the core scaffolds of diphenylpyraline and ebastine, is also described.
- Kuethe, Jeffrey T.,Janey, Jacob M.,Truppo, Matthew,Arredondo, Juan,Li, Tao,Yong, Kelvin,He, Shuwen
-
p. 4563 - 4570
(2014/06/10)
-
- HETEROCYCLIC COMPOUND AND H1 RECEPTOR ANTAGONIST
-
A heterocyclic compound useful as an antiallergic agent is provided. A compound represented by the following formula (1) or a salt thereof: wherein the ring A is a homocyclic or heterocyclic ring; the ring B is a heterocyclic ring which contains G and nitrogen atom N as constituent atoms thereof, wherein G is CH or N; R1 is a carbonyl group or an alkylene group; R2a and R2b are an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group; X is an oxygen atom or a sulfur atom; Z is a hydroxyl group, an alkoxy group, a cycloalkyloxy group, an aryloxy group, an aralkyloxy group, an amino group, or an N-substituted amino group; and n is 0 or 1; with the proviso that when the ring A is a benzene ring or when the ring B is a piperazine ring, R1 is an alkylene group which may have a substituent.
- -
-
Paragraph 0172; 0173; 0174
(2013/04/13)
-
- PROCESS FOR THE PREPARATION OF 1-[4-(1,1-DIMETHYLETHYL)PHENYL]-4-[4-(DIPHENYLMETHOXY)-1-PIPERIDINYL]-1-BUTANONE AND ACID ADDITION SALTS THEREOF
-
The present invention describes processes for the preparation of 1-[4-(11,- dimethylethyl)phenyl] -4- [4-(diphenylmethoxy)- 1 -piperidinyl] - 1 -butanone and acid addition salts thereof.
- -
-
Page/Page column 37
(2011/10/13)
-
- Process for the preparation of 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone and acid addition salts thereof
-
The present invention describes processes for the preparation of 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone and acid addition salts thereof.
- -
-
Page/Page column 25-26
(2011/10/13)
-
- Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory potency against acetylcholinesterase and Aβ1-42 aggregation for Alzheimer's disease therapeutics
-
With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Aβ) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Aβ1-42 peptide aggregation, AChE-induced Aβ1-42 aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Aβ1-42 aggregation and AChE-induced Aβ aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel π-π stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Aβ1-42 peptide aggregation.
- Kwon, Young Ee,Park, Jung Youl,No, Kyung Tai,Shin, Jae Hong,Lee, Sung Kwang,Eun, Jae Soon,Yang, Jae Heon,Shin, Tae Yong,Kim, Dae Keun,Chae, Byung Sook,Leem, Jae-Yoon,Kim, Kuk Hwan
-
p. 6596 - 6607
(2008/03/27)
-
- Treatment of CNS disorders using CNS target modulators
-
The invention is directed to compositions and methods useful for treating Central Nervous System (CNS) disorders. Furthermore, the invention provides compositions and methods of treating sleep disorders. More specifically, the invention is directed to the compositions and use of derivatized, histamine antagonists for the treatment of sleep disorders.
- -
-
-
- TREATMENT OF CNS DISORDERS USING CNS TARGET MODULATORS
-
The invention is directed to compositions used for treating Central Nervous System (CNS) disorders. In addition, the invention provides convenient methods of treatment of a CNS disorder. Furthermore, the invention provides methods of treating sleep disorders using compositions that remain active for a discrete period of time to reduce side effects. More specifically, the invention is directed to the compositions and use of derivatized, e.g., ester or carboxylic acid derivatized, antihistamine antagonists for the treatment of sleep disorders.
- -
-
-
- Triazolo and derivatives as chemokine inhibitors
-
Novel triazolo derivatives represented by the following formula and pharmaceutically acceptable salts thereof, as well as chemokine inhibitors containing the same as an effective component. These are useful as therapeutic agents for allergic diseases such
- -
-
-
- Cyanoguanidine compounds
-
A cyanoguanidine compound of the following formula: is disclosed. A cyanoguanidine compound of the present invention possess a high specificity for tumor cells. Also disclosed are methods for preparing a cyanoguanidine compound.
- -
-
-
- (Piperidinylalkoxy)chromones: Novel antihistamines with additional antagonistic activity against leukotriene D4
-
A series of novel chromone derivatives, in which the chromone moiety is connected to a (diphenylmethylene)-, (diphenylmethyl)-, or (diphenylmethoxy)piperidine via an alkyloxy spacer, were synthesized as antiallergic and antiasthmatic agents. In addition t
- Zhang,Wada,Sato,Timmerman
-
p. 2472 - 2477
(2007/10/02)
-
- Substituted or unsubstituted benzhydryl heteroalkyl-substituted aminophenol compounds and pharmaceutical compositions thereof
-
Aminophenol derivatives of the following formula (I) STR1 wherein X is hydrogen atom, lower alkyl or a protecting group for phenolic hydroxy, Y is hydrogen atom or lower alkyl, Z is hydrogen atom, lower alkyl, halogen atom or trifluoromethyl, A is hydrogen atom or lower alkyl, t is an integer of 1 to 5, l and m are respectively an integer of 2 to 4, E and W are nitrogen atoms, F is a direct bond or oxygen atom, P and Q are each hydrogen atom, halogen atom, lower alkyl or lower alkoxy, and R8 is hydrogen atom, hydroxy or a hydroxy-protecting group, and their pharmcologically acceptable salts. Since the aminophenol derivatives (I) of the present invention have excellent antioxidative action and antiinflammatory and antiallergic action in mammalian animals including human, they are extremely useful as pharmaceuticals such as an antiinflammatory or an antiallergic.
- -
-
-
- Amphoteric drugs. I. Synthesis and antiallergic activity of [4-(diphenylmethoxy)piperidino]-, [4-(diphenylmethyl)piperazinyl]- and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives
-
A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4-(diphenylmethoxy)piperidinol - (series A), [4-(diphenylmethyl)piperazinyl]- (series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a-c). N-Alkylcarboxylic acids (5a-c) showed stronger inhibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a-c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activity. (+)-3-[4-[(4-Methylphenyl)phenylmethoxy] piperidinol propionic acid ((+)-51), an optically active isomer of 51, exhibited a stronger antiallergic effect (ED50 = 0.17 mg/kg, p.o.) than ketotifen and terfenadine in the 48 h homologous passive cutaneous anaphylaxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30 mg/kg. Compound (+)-51 was thus proved to be a promising candidate as a nonsedative antiallergic agent.
- Iwasaski,Sakaguchi,Ohashi,Takahara,Ogawa,Yasuda,Koshinaka,Kato,Ito,Sawanishi
-
p. 2276 - 2284
(2007/10/02)
-
- GABA uptake inhibitors. Syntheses and structure-activity studies on GABA analogues containing diarylbutenyl and diarylmethoxyalkyl N-substituents
-
A number of analogues of GABA or β-alanine containing 4,4-diphenyl-3-butenyl (DPB), benzhydryl ethyl ether (BEE), or benzhydryl propyl ether N-substituents have been synthesized and tested as inhibitors of synaptosomal GABA uptake. Whereas the N-DPB and N
- Falch,Krogsgaard-Larsen
-
-
- New xanthine derivatives with potent and long lasting anti-bronchoconstrictive activity
-
Twenty eight new derivatives of 8-aminoalkyl substituted xanthine have been synthesized.They all have demonstrated a potent anti-bronchoconstrictive effect in the guinea pig and some of them have a very long duration of action (>48 h).Among them, one compound: 1-methyl 3-isobutyl 8-(4-benzhydryl piperazino ethyl)xanthine (57) (S 9795) has been selected for clinical trials in asthmatic patients because of its long duration of action, its lack of CNS stimulating effects and its inhibiting action on mast cell degranulation and phosphodiesterase activity.Keywords - 8-aminoalkyl substituted xanthines / benzhydryl piperazine / piperidine / ethylenediamine / anti-bronchoconstrictors / phosphodiesterase inhibitors / asthma
- Regnier, Gilbert L.,Guillonneau, Claude G.,Duhault, Jacques L.,Tisserand, Francoise P.,Saint-Romas, Guy,Holstorp, Sophie M.
-
p. 243 - 250
(2007/10/02)
-
- N-alkyleneiminoalkyl-dicarboximides as antiallergics and antiasthmatics
-
N-(diphenylmethoxy-mono- or bicyclic-alkyleneiminoalkyl)-dicarboximides, e.g. those of the formula STR1 A=aliphatic or cycloaliphatic radical R,R'=H, alkyl, halogen or CF3 R"=H or both are ethylene q=2-4 and salts thereof are antiallergics and antiasthmatics.
- -
-
-