cas 101469-92-5, N-(tert-Butoxycarbonyl)-(S)-(+)-3-pyrrolidinol

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Synthesis of piperidinyl and pyrrolidinyl butyrates for potential in vivo measurement of cerebral butyrylcholinesterase activity
Biochemical changes in postmortem brains of Alzheimer's disease patients include decreased acetylcholinesterase and choline acetyl transferase activity, indicating reduced activity of the central cholinergic system, while butyrylcholinesterase (BChE) activity increases. A method that can measure regional BChE activity in the brain in vivo may be useful for investigating the relationship between BChE and Alzheimer's disease. Seven compounds, either piperidinyl or pyrrolidinyl butyrates, were synthesized as BChE substrate radiotracers to map central BChE activity in vivo by positron emission tomography (PET). 14C-labeled compounds were assayed to determine their hydrolysis rates by BChE and the partition coefficient. The five esters of secondary alcohols had lipophilic properties sufficient to pass readily through the blood-brain barrier while the metabolites were sufficiently hydrophilic to be retained in the brain. The esters showed moderate hydrolysis rates by BChE and high specificity for BChE relative to acetylcholinesterase, while two esters of primary alcohols were hydrolyzed too rapidly to estimate reliably the local cerebral BChE activity. From these results, we conclude that one or more of these five esters, when labeled with 11C, would be a useful tracer for quantification of BChE activity by PET.
Kikuchi, Tatsuya,Fukushi, Kiyoshi,Ikota, Nobuo,Ueda, Takao,Nagatsuka, Shin-Ichiro,Arano, Yasushi,Irie, Toshiaki
p. 31 - 41
(2001)
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Selection of microbial biocatalysts for the reduction of cyclic and heterocyclic ketones
The reduction of carbonyl compounds plays an important role in the synthesis of complex chiral molecules. In particular, enantiopure substituted cyclic and heterocyclic compounds are useful intermediates for the synthesis of several antiviral, antitumor, and antibiotic agents, and recently, they have also been used as organocatalysts for C-C addition. Alcohol dehydrogenases (ADH) are enzymes involved in the transformation of prochiral ketones to chiral hydroxyl compounds. While significant scientific effort has been paid to the use of aliphatic and exocyclic ketones as ADH substrates, reports on (hetero)cyclic carbonyl compounds as substrates of these enzymes are scarce. In the present study, 109 bacteria and 36 fungi were screened, resulting in 10 organisms belonging to both kingdoms capable of transforming cyclic and heterocyclic ketones into the corresponding alcohols. Among them, Erwinia chrysanthemi could quantitatively reduce cyclododecanone and Geotrichum candidum could stereoselectively reduce N-Boc-3-piperidone and N-Boc-3-pyrrolidinone to their corresponding (S)-alcohols; however, the anti-Prelog isomer was obtained when acetophenone was the substrate.
Bianchi, Paola,Varela, Romina Fernández,Bianchi, Dario A.,Kemppainen, Minna,Iribarren, Adolfo M.,Lewkowicz, Elizabeth
p. 137 - 144
(2017)
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Enantioselective reduction of heterocyclic ketones with low level of asymmetry using carrots
A whole spectrum of biocatalysts for asymmetric reduction of prochiral ketones is well known including the Daucus carota root. However, this type of reaction is still challenging when pro-chiral ketones present low level of asymmetry, like heterocyclic ketones. In this work, 4,5-dihydro-3(2H)-thiophenone (1), 2-methyltetrahydrofuran-3-one (2), N-Boc-3-pyrrolidinone (3), 1-Z-3-pyrrolidinone (4) and 1-benzyl-3-pyrrolidinone (5) were studied in order to obtain the respective enantioselective heterocyclic secondary alcohols. Except for 5, the corresponding alcohols were obtained in high values of conversion and with high selectivity. In order to circumvent the low isolated yield of the corresponding chiral alcohol from 2, we observed that the use of carrots in the absence of water is feasible. Addition of co-solvents was needed to the water-insoluble ketones 3 and 4. Comparatively, baker’s yeast was used for bio reductions of 1, 3 and 4. And in terms of conversion, selectivity and work-up, the use of carrots were a more efficient biocatalyst, as well as a viable method for obtaining 5-member heterocyclic secondary alcohols.
Machado, Naira Vieira,Omori, álvaro Takeo
p. 475 - 480
(2021/09/27)

NOVEL OXADIAZOLES
The present invention relates to novel compound of Formula I, wherein, R1, A1, A2, A3, A4, A5, L1, A, L2 and R2 are as defined in the detailed description. The present invention also relates to a combination or a composition comprising the compound of Formula I.
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Page/Page column 62-63

(2020/05/15)

PDE9 inhibitor and application thereof
The invention belongs to the technical field of medicine and particularly relates to a PDE9 inhibitor compound shown as formula (I) or its pharmaceutically acceptable salts and stereoisomers, as wellas pharmaceutical preparations and pharmaceutical compositions of these compounds, and their application. The compounds herein are applicable to the preparation of drugs to treat or prevent PDE9-mediated related diseases.
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Paragraph 0256-0258

(2019/04/17)

SUBSTITUTED 2-HYDROGEN-PYRAZOLE DERIVATIVE SERVING AS ANTICANCER DRUG
Disclosed is a substituted 2H-pyrazole derivative serving as a selective CDK4/6 inhibitor. Specifically, disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof which serves as a selective CDK4/6 inhibitor.
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Paragraph 0061; 0172; 0173

(2018/02/04)

Methodology Development in Directed Evolution: Exploring Options when Applying Triple-Code Saturation Mutagenesis
Directed evolution of stereo- or regioselective enzymes as catalysts in asymmetric transformations is of particular interest in organic synthesis. Upon evolving these biocatalysts, screening is the bottleneck. To beat the numbers problem most effectively, methods and strategies for building “small but smart” mutant libraries have been developed. Herein, we compared two different strategies regarding the application of triple-code saturation mutagenesis (TCSM) at multiresidue sites of the Thermoanaerobacter brockii alcohol dehydrogenase by using distinct reduced amino-acid alphabets. By using the synthetically difficult-to-reduce prochiral ketone tetrahydrofuran-3-one as a substrate, highly R- and S-selective variants were obtained (92–99 % ee) with minimal screening. The origin of stereoselectivity was provided by molecular dynamics analyses, which is discussed in terms of the Bürgi–Dunitz trajectory.
Qu, Ge,Lonsdale, Richard,Yao, Peiyuan,Li, Guangyue,Liu, Beibei,Reetz, Manfred T.,Sun, Zhoutong
p. 239 - 246
(2018/02/09)

C-3 NOVEL TRITERPENONE WITH C-28 AMIDE DERIVATIVES AS HIV INHIBITORS
The invention relates to C-3 novel triterpenone with C-28 amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases (formula 1).
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Paragraph 0140; 0141

(2018/09/12)

Stereo-complementary bioreduction of saturated N-heterocyclic ketones
The asymmetric bioreduction of several saturated N-heterocyclic ketones is demonstrated in a stereo-complementary fashion using the ketoreductases READH and ChKRED20 for the production of (S)- and (R)-alcohols, respectively. The reaction accepts substrates with a five-, six- or seven-membered ring, and exhibits excellent stereoselectivity when using 2-propanol as both the ultimate reducing agent and cosolvent, achieve >99% ee in the majority of cases for both enantiomers.
Li, Chao,Liu, Yan,Pei, Xiao-Qiong,Wu, Zhong-Liu
p. 90 - 97
(2017/04/28)

AMINOPYRIMIDINE HETEROCYCLIC COMPOUND WITH ADENOSINE RECEPTOR ANTAGONISTIC ACTIVITY
Disclosed hereinis an aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity, comprising a compound of the general formula (I), or a pharmaceutically acceptable salt thereof. The aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activitydisclosed herein can be used as an effective adenosine receptor antagonist, and can be used for the treatment or prevention of disorders caused by abnormal level of adenosine.
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Paragraph 00052; 00053; 00054

(2017/06/23)

Preparation method of (S)-3-hydroxypyrrolidine hydrochloride
The invention relates to the field of chemistry, particularly a preparation method of a key intermediate (S)-3-hydroxypyrrolidine hydrochloride of darifenacin for treating overactive bladder syndrome and an antihypertensive drug barnidipine. The preparation method comprises the following steps: carrying out Mitsunobu reaction on (R)-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine so as to be condensed with acid to obtain an upturned-structure ester, hydrolyzing ester bond under alkaline conditions to obtain (S)-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine, and removing Boc protecting groups under acidic conditions, thereby finally obtaining the key intermediate. The method is simple and easy to implement, has the advantages of cheap and accessible raw materials, lower cost and high yield, and has potential production value.
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Paragraph 0029; 0030

(2016/11/09)

4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a Novel P2Y12 Receptor Antagonist with a Wider Therapeutic Window in the Rat Than Clopidogrel
Recent post hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.
Caroff, Eva,Hubler, Francis,Meyer, Emmanuel,Renneberg, Dorte,Gnerre, Carmela,Treiber, Alexander,Rey, Markus,Hess, Patrick,Steiner, Beat,Hilpert, Kurt,Riederer, Markus A.
p. 9133 - 9153
(2015/12/23)

AZACYCLIC CONSTRAINED ANALOGS OF FTY720
Small molecules comprised of azacyclic constrained analogs of FTY720 are provided. Formulations and medicaments are also provided that are directed to the treatment of disease, such as, for example, leukemia, and other diseases. Therapeutics are also provided containing a therapeutically effective dose of one or more small molecule compounds, present either as pharmaceutically effective salt or in pure form, including, but not limited to, formulations for oral, intravenous, or intramuscular administration.
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Paragraph 00107

(2015/02/02)

Fluorine-containing 6,7-dialkoxybiaryl-based inhibitors for phosphodiesterase 10 A: Synthesis and in vitro evaluation of inhibitory potency, selectivity, and metabolism
Based on the potent phosphodiesterase 10 A (PDE10A) inhibitor PQ-10, we synthesized 32 derivatives to determine relationships between their molecular structure and binding properties. Their roles as potential positron emission tomography (PET) ligands were evaluated, as well as their inhibitory potency toward PDE10A and other PDEs, and their metabolic stability was determined in vitro. According to our findings, halo-alkyl substituents at position 2 of the quinazoline moiety and/or halo-alkyloxy substituents at positions 6 or 7 affect not only the compounds′ affinity, but also their selectivity toward PDE10A. As a result of substituting the methoxy group for a monofluoroethoxy or difluoroethoxy group at position 6 of the quinazoline ring, the selectivity for PDE10A over PDE3A increased. The same result was obtained by 6,7-difluoride substitution on the quinoxaline moiety. Finally, fluorinated compounds (R)-7-(fluoromethoxy)-6-methoxy-4-(3-(quinoxaline-2-yloxy)pyrrolidine-1-yl) quinazoline (16 a), 19 a-d, (R)-tert-butyl-3-(6-fluoroquinoxalin-2-yloxy) pyrrolidine-1-carboxylate (29), and 35 (IC50 PDE10A 11-65 nM) showed the highest inhibitory potential. Further, fluoroethoxy substitution at position 7 of the quinazoline ring improved metabolic stability over that of the lead structure PQ-10. Fluor your health: Phosphodiesterase 10 A (PDE10A) has emerged as an attractive target for the development of 18F-labelled brain imaging agents for positron emission tomography. A series of fluorinated dialkoxybiaryl compounds were synthesized and evaluated as PDE10A inhibitors, assisted by QSAR docking studies. The 7-fluoromethoxy derivative appears to be a promising candidate for further development.
Schwan, Gregor,Barbar Asskar, Ghadir,Hoefgen, Norbert,Kubicova, Lenka,Funke, Uta,Egerland, Ute,Zahn, Michael,Nieber, Karen,Scheunemann, Matthias,Straeter, Norbert,Brust, Peter,Briel, Detlef
supporting information
p. 1476 - 1487
(2014/07/21)

A practical procedure for reduction of primary, secondary and tertiary amides to amines
A mild and general procedure for reduction of primary, secondary, and tertiary amides using catalytic triruthenium dodecacarbonyl and 1,1,3,3-tetramethyldisiloxane as reductant is described. The reaction is tolerant of numerous functional groups, and the amine products can often be isolated by direct crystallization as hydrochloride salts. The catalyst and silane are commercially available, air stable, and inexpensive, making the procedure accessible for both laboratory and large-scale applications. Copyright
Reeves, Jonathan T.,Tan, Zhulin,Marsini, Maurice A.,Han, Zhengxu S.,Xu, Yibo,Reeves, Diana C.,Lee, Heewon,Lu, Bruce Z.,Senanayake, Chris H.
supporting information
p. 47 - 52
(2013/03/13)

Design, synthesis, and antileukemic activity of stereochemically defined constrained analogues of FTY720 (Gilenya)
FTY720 functions as an immunosuppressant due to its effect on sphingosine-1-phosphate receptors. At doses well above those needed for immunosuppression, FTY720 also has antineoplastic actions. Our published work suggests that at least some of FTY720's anticancer activity is independent of its effects on S1P receptors and due instead to its ability to induce nutrient transporter down-regulation. Compounds that trigger nutrient transporter loss but lack FTY720's S1P receptor-related, dose-limiting toxicity have the potential to be effective and selective antitumor agents. In this study, a series of enantiomerically pure and stereochemically diverse O-substituted benzyl ethers of pyrrolidines was generated and tested for the ability to kill human leukemia cells. The stereochemistry of the hydroxymethyl was found to be a key determinant of compound activity. Moreover, phosphorylation of this group was not required for antileukemic activity.
Fransson, Rebecca,McCracken, Alison N.,Chen, Bin,McMonigle, Ryan J.,Edinger, Aimee L.,Hanessian, Stephen
supporting information
p. 969 - 973
(2013/10/22)

A new solvent system (Cyclopentyl methyl ether-water) in process development of darifenacin HBr
Darifenacin is a potent and competitive M3 selective receptor antagonist (M3SRA), and its hydrobromide salt (1) is the active ingredient of pharmaceutical formulations for oral treatment of urinary incontinence. The present work demonstrates an efficient, commercial manufacturing process for darifenacin hydrobromide (1).
Pramanik, Chinmoy,Bapat, Kiran,Chaudhari, Ashok,Tripathy, Narendra K.,Gurjar, Mukund K.
p. 1591 - 1597
(2013/02/23)

SUBSTITUTED 2-PHENYL-PYRIDINE DERIVATIVES
The present invention relates to compounds of formula I wherein R1, R2, R4, R5, Ra, Rb, n, W and Z are as defined in the application, their preparation and their use as P2Y12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals.
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Page/Page column 18

(2011/04/14)

COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
The present disclosure relates to pyrazine compounds of formula (I) wherein L, n, R1, and R2 are as described in the specification. These compounds are useful as inhibitors of ATR protein kinase. The disclosure also relates to pharmaceutically acceptable compositions comprising the compounds of the disclosure; methods of treating of various diseases, disorders, and conditions using the compounds of the disclosure; processes for preparing the compounds of the disclosure; intermediates for the preparation of the compounds of the disclosure; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.
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Page/Page column 190

(2010/06/11)

N-SUBSTITUTED SATURATED HETEROCYCLIC SULFONE COMPOUNDS WITH CB2 RECEPTOR AGONISTIC ACTIVITY
This invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein X, R1, R2,R3, R4, R5, R6, R7, k, m, n, p, q, r and s are each as described herein, and compositions containing such compounds, and the use of such compounds in the treatment of a condition mediated by CB2 receptor activity.
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Page/Page column 79-80

(2010/08/08)

METHOD OF PRODUCING (S)-3-(1-CYANO-1,1-DIPHENYLMETHYL)-PYRROLIDINE
The present application relates to a method of (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine by reacting an (S)-1-protected-3-(sulfonyloxy)-pyrrolidine having an easily deprotectable protecting group with diphenylacetonitrile in the presence of a base to obtain an (S)-1-protected-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine and then deprotecting the obtained compound under a mild condition. According to the method of the present invention, it is possible to efficiently produce (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine, which is an important intermediate in the process of producing a muscarinic receptor antagonist such as darifenacin.
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Page/Page column 13

(2010/12/30)

Daucus carota mediated-reduction of cyclic 3-oxo-amines
Carrots (Daucus carota) were used to reduce cyclic amino-ketones in high yields and enantiomeric excesses. This cheap, eco-compatible, and efficient reducing reagent allows the easy access to precursors of biologically active products.
Lacheretz, Romain,Pardo, Domingo Gomez,Cossy, Janine
supporting information; experimental part
p. 1245 - 1248
(2009/08/08)

Pleuromutilin derivatives having a purine ring. Part 2: Influence of the central spacer on the antibacterial activity against Gram-positive pathogens
Structural modification of the 4-piperidinethio moiety, as a spacer of the first pleuromutilin analogues 2A and 2B having a purine ring, led to discovery of the novel pleuromutilin derivatives 14B and 17B. These compounds with good solubility in water showed promising in vitro antibacterial activity against various Gram-positive bacteria including MRSA, PRSP, and VRE and have potent in vivo efficacy.
Hirokawa, Yoshimi,Kinoshita, Hironori,Tanaka, Tomoyuki,Nakamura, Takanori,Fujimoto, Koichi,Kashimoto, Shigeki,Kojima, Tsuyoshi,Kato, Shiro
scheme or table
p. 170 - 174
(2009/05/07)

PHOSPHONIC ACID DERIVATES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
The invention relates to 2-phenyl-pyrimidine derivatives containing a phosphonic acid motif and their use as P2Y12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. (I).
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Page/Page column 63

(2009/07/03)

SUBSTITUTED 2-PHENYL-PYRIDINE DERIVATIVES
The present invention relates to compounds of formula (I) wherein R1, R2, R4, R5, Ra, Rb, n, W and Z are as defined in the application, their preparation and their use as P2Y12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals.
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Page/Page column 42

(2009/11/29)

AMINOOXIME DERIVATIVES OF 2- AND/OR 4-SUBSTITUTED ANDROSTANES AND ANDROSTENES AS MEDICAMENTS FOR CARDIOVASCULAR DISORDERS
New aminooxime derivatives at position 3 of 2-and/or 4-substituted androstanes and androstenes, processes for their preparation, and to pharmaceutical compositions containing them for the treatment of cardiovascular disorders, such as heart failure and hypertension. In particular compounds having the general formula (I) are described,where the radicals have the meanings described in detail in the application.
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Page/Page column 86

(2009/05/30)

2-AMINOCARBONYL-PYRIDINE DERIVATIVES
The present invention relates to 2-aminocarbonyl-pyridine derivatives and their use as P2Yi2 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals.
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Page/Page column 116

(2008/06/13)

Novel analogues of istaroxime, a potent inhibitor of Na+,K +-ATPase: Synthesis and structure-activity relationship
We report the synthesis and biological properties of novel inhibitors of the Na+,K+-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5α,14α-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the (E)-3-[(R)-3- pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the E isomers of the oxime are more potent than the Z form. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na +,K+-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5α,14α-androstane.
Gobbini, Mauro,Armaroli, Silvia,Banfi, Leonardo,Benicchio, Alessandra,Carzana, Giulio,Fedrizzi, Giorgio,Ferrari, Patrizia,Giacalone, Giuseppe,Giubileo, Michele,Marazzi, Giuseppe,Micheletti, Rosella,Moro, Barbara,Pozzi, Marco,Scotti, Piero Enrico,Torri, Marco,Cerri, Alberto
supporting information; experimental part
p. 4601 - 4608
(2009/06/06)

METHOD AND COMPOSITIONS FOR TREATING HIV INFECTIONS
Described herein are compounds and compositions that are useful in the treatment of HIV, AIDS, and AIDS-related diseases. In addition, compounds are described herein that are capable of inhibiting the dimerization of HIV proteases.
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Page/Page column 40-41

(2008/12/08)

AZAHETEROCYCLYL DERIVATIVES OF ANDROSTANES AND ANDROSTENES AS MEDICAMENTS FOR CARDIOVASCULAR DISORDERS
Compounds of formula (I) wherein: the groups are as defined in the description, are useful for the preparation of medicaments for the treatment of cardiovascular disorders, in particular heart failure and hypertension. The compounds are inhibitors of the enzymatic activity of the Na+,K+-ATPase. They are useful for the preparation of a medicament for the treatment of a disease caused by the hypertensive effects of endogenous ouabain, such as renal failure progression in autosomal dominant polycystic renal disease (ADPKD), preeclamptic hypertension and proteinuria and renal failure progression in patients with adducin polymorphisms.
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Page/Page column 94

(2008/06/13)

PROCESS FOR THE PREPARATION OF CHIRAL 3-HYDROXY PYRROLIDINE COMPOUND AND DERIVATIVES THEREOF HAVING HIGH OPTICAL PURITY
The present invention relates to an effective process for the preparation of optically pure chiral 3-hydroxypyrrolidine or derivatives thereof. More particularly, the present invention relates to an efficient process for the preparation of chiral 3-hydroxypyrrolidine or derivatives thereof, comprised of introducing a suitable protecting group to the starting material 4-chloro-3-hydroxybutyronitrile. Introduction of the hydroxy-protecting group provides advantages: efficient prevention of formation of side products, enhanced performance of the reduction of the nitrile group of the starting material, and enhanced performance of in-situ in? tramolecular cyclization. The chiral 3-hydroxypyrrolidine compound is produced in high yield and with high purity.
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Page/Page column 20

(2010/11/26)

2-(CYCLIC AMINO)-PYRIMIDONE DERIVATIVES AS TPK1 INHIBITORS
A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof (I) wherein R2 represents a hydrogen or the like; R3 represents methyl group or the like; R20 represents a halogen atom or the like; q represents an integer of 0 to 3; Z represent nitrogen atom, CH, or the like; R4 represents hydrogen or the like; R5 represents hydrogen or the like; R6 represents a substituted alkyloxy and the like; p represents an integer of 0 to 3; X represents bond, CH2, oxygen atom, NH, or the like; any one or more of R5 and R6, R5 and R4, R6 and R4, X and R5, X and R4, X and R6, and R6 and R6 may combine to each other to form a ring, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).
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Page/Page column 207-208

(2008/06/13)

THERAPEUTIC AGENTS
Compounds of formula (I), processes for preparing such compounds, their use in the treatment of obesity, psychiatric disorders, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related conditions, and neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Huntington's chorea and Alzheimer's disease and pain related disorders and to pharmaceutical compositions containing them.
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Page/Page column 28

(2010/11/25)

DERIVATIVES FOR MODULATION OF ION CHANNELS
Sulfonamide derivatives act as ion channel antagonists. These compounds have the general Formula (I): Formula (I) compositions are useful for treating or relieving pain-related conditions.
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Page/Page column 56-57

(2010/11/27)

Synthesis of racemic and enantiomeric 3-pyrrolidinyl derivatives of nucleobases
The synthesis of novel 3-pyrrolidinyl derivatives of nucleobases is described. Starting from malic acid, we improved the synthesis of both racemic and optically active N-benzyl-3-hydroxypyrrolidine-2,5-diones, which were transformed in four steps into N-tert-butyloxycarbonyl-3-mesyloxypyrrolidines, the key synthons for the alkylation of purine and pyrimidine nucleobases. Alkylations of cesium salts of purines and sodium salts of pyrimidines with N-tert-butyloxycarbonyl-3-mesyloxypyrrolidines proceeded smoothly, giving high yields of 9-substituted purine derivatives and moderate yields of 1-substituted pyrimidine derivatives. Using (S)-N-tert-butyloxycarbonyl-3-mesyloxypyrrolidine as the same intermediate for the synthesis of both enantiomeric N-Boc-3-pyrrolidinyladenines, and considering the results obtained on chiral HPLC analysis of the products, we proved that nucleophilic displacement of the mesyloxy group proceeded with inversion and not with retention of the configuration. Prepared compounds were tested for cytostatic and antiviral properties, but no significant activity was found.
Ko?alka, Petr,Pohl, Radek,Rejman, Dominik,Rosenberg, Ivan
p. 5763 - 5774
(2007/10/03)

NEW DIPEPTIDYL PEPTIDASE IN INHIBITORS; PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM
The present invention relates to new dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula (I), and their analogs, isomers, pharmaceutical compositions and therapeutic uses, methods of making the same.
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Page/Page column 39

(2010/02/12)

ANTITHROMBOTIC ETHERS
This application relates to a compound of formula I (or a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa and/or thrombin, as well as a process for its preparation and intermediates therefor (I).
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Page 78

(2008/06/13)

NOVEL TRICYCLIC SPIROPIPERIDINES OR SPIROPYRROLIDINES
The invention provides compounds of formula (I) wherein m, R1, n, R2, q, X, Y, Z, R3, R4, R5, R6, R7, R8, t and R9 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page 141-142

(2008/06/13)

NEW COMPOUNDS USEFUL FOR THE TREATMENT OF OBESITY, TYPE II DIABETES AND CNS DISORDERS
The present invention relates to compounds of the general formula (I), wherein P is sulfone or sulfonamide; and A, B, W, X, Y and R3 are as defined in the description;to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the prophylaxis and treatment of medical conditions relating to obesity, type II diabetes, and/or CNS disorders, to achieve reduction of body weight and of body weight gain.
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(2008/06/13)

Azetidine, pyrrolidine and piperidine derivatives as 5-HT receptor agonists
PCT No. PCT/GB97/01137 Sec. 371 Date Oct. 14, 1998 Sec. 102(e) Date Oct. 14, 1998 PCT Filed Apr. 24, 1997 PCT Pub. No. WO97/42189 PCT Pub. Date Nov. 13, 1997A class of compounds of formula (I) wherein Z, E, Q, T, U, V, W, M, R1, R7 and R8 are as defined herein; are selective agonists of 5-HT1-like receptors, being potent agonists of the human 5-HT1D alpha receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT1D alpha receptor subtype relative to the 5-HT1D beta subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT1D receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT1D receptor agonists.
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(2008/06/13)

Synthesis of (3R)-carboxy pyrrolidine (a β-proline analogue) and its oligomer
A decamer of a β-amino acid analogue of L-proline, (3R)-carboxy pyrrolidine (β-proline), was synthesized from a readily available (R)-glycidol. It was found to possess a rigid secondary structure, as evidenced by its CD spectrum. The β-proline decamer, however, failed to bind to profilin, whereas the corresponding α-L-proline decamer bound tightly to this protein. (C) 2000 Published by Elsevier Science Ltd.
Kim, Yong Jip,Kaiser, Donald A.,Pollard, Thomas D.,Ichikawa, Yoshitaka
p. 2417 - 2419
(2007/10/03)

Process for making 3-amino-pyrolidine derivatives
The invention is concerned with a process for making a compound of formula STR1 wherein R1 is hydrogen, alkyl, cyclo-alkyl, alkenyl, aryl or an amino protecting group; and R2, R3 each independently is hydrogen, alkyl, cyclo-alkyl, alkenyl or aryl; by reacting a compound of the formula STR2 wherein X is a protected hydroxy group; with R1 NH2 to form a compound of formula STR3 wherein X and R1 are described herein above; and then reacting the compound of formula III with R2 R3 NH under pressure to form the compound of formula I. These compounds are valuable intermediates useful in making cephalosporin derivatives.
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(2008/06/13)

Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1- yl)ethyl]indoles: Potent agonists for the h5-HT(1D) receptor with high selectivity over the h5-HT(1B) receptor
The design, synthesis, and biological evaluation of a novel series of 3- [2-(pyrrolidin-1-yl)ethyl]-indoles with excellent selectivity for h5-HT(1D) (formerly 5-HT(1Dα)) receptors over h5-HT(1B) (formerly 5-HT(1Dβ)) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT(1D) and h5-HT(1B) receptors. The differential expression of h5-HT(1D) and h5-HT(1B) receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT(1D) subtype would have the same clinical efficacy but with reduced side effects. The pyrrolidine 3b was initially identified as having 9-fold selectivity for h5-HT(1D) over h5-HT(1B) receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT(1D) receptor and 100-fold selectivity with respect to h5-HT(1B) receptors. Modification of the indole 5-substituent led to the oxazolidinones 24a,b with up to 163-fold selectivity for the h5-HT(1D) subtype and improved selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [35S]GTPγS binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT(1D) and h5-HT(1B) receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT(1D) receptor domain which is absent for the h5-HT(1B) receptor. The compounds described herein will be important tools to delineate the role of h5-HT(1D) receptors in migraine.
Sternfeld, Francine,Guiblin, Alexander R.,Jelley, Richard A.,Matassa, Victor G.,Reeve, Austin J.,Hunt, Peter A.,Beer, Margaret S.,Heald, Anne,Stanton, Josephine A.,Sohal, Bindi,Watt, Alan P.,Street, Leslie J.
p. 677 - 690
(2007/10/03)

Asymmetric synthesis of 1-Boc-3- and 4-hydroxypyrrolidines
Lewis Acid-mediated coupling reactions of (5R, 6S)-2-acetoxy-4- (benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazine (2a) with allylsilanes (3a-d) proceeded to give the coupling products (4a-b) with moderate to good stereoselectivity. The coupling products (4a-b) were effectively converted into 1-Boc-3- and 4-hydroxypyrrolidines (8a, syn-b, and c).
Aoyagi, Yutaka,Williams, Robert M.
p. 13045 - 13058
(2007/10/03)

3-[2-(Pyrrolidin-1-yl)ethyl]indoles and 3-[3-(Piperidin-1- yl)propyl]indoles: Agonists for the h5-HT(1D) receptor with high selectivity over the h5-HT(1B) subtype
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Castro,Street,Guiblin,Jelley,Russell,Sternfeld,Beer,Stanton,Matassa
p. 3497 - 3500
(2007/10/03)

Preparative and structural chemistry of chiral 3-(diphenylphosphanyl)pyrrolidines and their palladium(II) complexes
The preparation of both enantiomers of 3-diphenylphosphanylpyrrolidine (2) and several N-substituted derivatives together with two Pd complexes of this ligand is reported. From L-malic acid and L-hydroxyproline both enantiomers of 3-hydroxypyrrolidine are prepared without any problems due to epimerization. KPPh2 in the presence of LiCl is shown to be the most effective reagent for the synthesis of 2. The reported X-ray structure determinations of PdI2 complexes show a rather rigid bicyclic hetero-norbornane skeleton. The flexibility of the other parts of the molecules is obvious in several polymorphs revealed by this method. This polymorphism is additionally investigated by a 31P-CP-MAS study. From solution 'H-, 13C- and 31P-NMR studies it is concluded that the bicyclic hetero-norbornane skeleton is retained in solution. VCH Verlagsgesellschaft mbH.
Nagel, Ulrich,Nedden, Hans Guenter
p. 385 - 397
(2007/10/03)

1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds
1-Azabicyclo[3.2.0]hept-2-ene-2-carboxyic acids having antimicrobial activity have been prepared.
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(2008/06/13)

SYNTHETIC ROUTES TO CHIRAL 3-PYRROLIDINOLS
Short convenient syntheses of chiral 3-pyrrolidinols and related compounds are described.
Bhat, Krishna L.,Flanagan, Denise M.,Joullie, Madeleine M.
p. 587 - 598
(2007/10/02)