cas 191348-04-6, (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate

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X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
p. 8303 - 8332
(2021/06/30)

Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1 H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia
BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.
Zhang, Dongfeng,Li, Peng,Gao, Yongxin,Song, Yaoyao,Zhu, Yaqin,Su, Hong,Yang, Beibei,Li, Li,Li, Gang,Gong, Ningbo,Lu, Yang,Shao, Huanjie,Yu, Chunrong,Huang, Haihong
p. 7434 - 7452
(2021/06/25)

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.
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Paragraph 00898

(2021/02/19)

CDK9 Kinase inhibitors
The present application relates to CDK9 kinase inhibitors which provide a compound of formula (I) or a stereoisomer thereof. A solvate, a metabolite, a pharmaceutically acceptable salt or prodrug, and a pharmaceutical composition comprising the same. Also provided are the use of compounds and pharmaceutical compositions in the manufacture of a medicament for the treatment of cancer.
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Paragraph 0197-0199

(2021/11/21)

C11-CYCLIC SUBSTITUTED 13-MEMBERED MACROLIDES AND USES THEREOF
Provided are 13-membered macrolides for the treatment of infectious diseases. The 13- membered macrolides described herein are azaketolides. Also provided are methods for preparing the 13-membered macrolides, pharmaceutical compositions comprising the 13-
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Paragraph 00307; 00309; 00310

(2020/06/10)

TEAD INHIBITORS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00465; 00718

(2020/12/11)

NON-LYSOSOMAL GLUCOSYLCERAMIDASE INHIBITORS AND USES THEREOF
The invention provides compounds for inhibiting glucosylceramidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds.
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Paragraph 00487

(2020/12/01)

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner-Wadsworth-Emmons-based approach
Integrin inhibitors based on the tripeptide sequence Arg-Gly-Asp (RGD) are potential therapeutics for the treatment of idiopathic pulmonary fibrosis (IPF). Herein, we describe an expeditious three-step synthetic sequence of Horner-Wadsworth-Emmons olefination, diimide reduction, and global deprotection to synthesise cores for these compounds in high yields (63-83% over 3 steps) with no need for chromatography. Key to this transformation is the phosphoramidate protecting group, which is stable to metalation steps.
Lippa, Rhys A.,Murphy, John A.,Barrett, Tim N.
supporting information
p. 1617 - 1626
(2020/09/11)

Nickel-Catalyzed Selective Reduction of Carboxylic Acids to Aldehydes
The direct reduction of carboxylic acids to aldehydes is a fundamental transformation in organic synthesis. The combination of an air-stable Ni precatalyst, dimethyl dicarbonate as an activator, and silane reductant effects this reduction for a wide variety of substrates, including pharmaceutically relevant structures, in good yields and with no overreduction to alcohols. Moreover, this methodology is scalable, allows access to deuterated aldehydes, and is also compatible with one-pot utilization of the aldehyde products.
Iosub, Andrei V.,Morav?ík, ?tefan,Wallentin, Carl-Johan,Bergman, Joakim
supporting information
p. 7804 - 7808
(2019/10/14)

Boosting the hydrolytic stability of phosphite ligand in hydroformylation by the construction of superhydrophobic porous framework
The development of a catalyst that delivers high activities and selectivities with excellent durability is of great importance. Numerous efficient catalysts suffer from the inherent hydrolysis liabilities, plaguing their practical applications. Herein, we show that this challenge can be tackled by constructing them into superhydrophobic porous frameworks, as exemplified by a water-sensitive phosphite ligand, tris(2-tert-butylphenyl) phosphite. The efficiency and long-term stability of the developed system are remarkably high in the hydroformylation of internal olefins after metalation with Rh species, superior to the corresponding homogeneous analogues. The significantly boosted hydrolytic stability allows for catalytic transformations using water as a green solvent, which not only facilitates the isolation of the products, but also furnishes the aldehydes with higher regioselectivities for the desired linear form in comparison with that operated under benchmark conditions using toluene as a reaction medium. Given these promising results, we anticipate the strategy advanced herein will form the basis for constructive perspectives in the enhancement of the water resistance of catalysts and the development of high performance hydroformylation catalysts.
Tang, Yongquan,Dong, Ke,Wang, Sai,Sun, Qi,Meng, Xiangju,Xiao, Feng-Shou
(2019/06/05)

A process for preparing N - Boc - 3 - pyrrolidine of formaldehyde (by machine translation)
The invention discloses a method for preparing N - Boc - 3 - pyrrolidine of formaldehyde, comprising the following steps: (1) in the solvent is added in chloromethane-based [...] and triphenyl phosphate reaction, to obtain the benzyloxy methyl trityl chloride; (2) the benzyloxy methyl trityl chloride by adding solvent, under alkaline conditions, adding N - Boc - 3 - pyrrolidone reaction, to obtain compound N - Boc - 3 - benzyloxy methylene pyrrolidine; (3) high-pressure container for adding a solvent, N - Boc - 3 - benzyloxy methylene pyrrolidine and catalyst, hydrogenation reaction to obtain N - Boc - 3 - pyrrolidine methanol; (4) will be N - Boc - 3 - pyrrolidine methanol dissolved in dichloromethane solvent, adding Dess - Martin oxidizer to carry out oxidizing, get N - Boc - 3 - pyrrolidine formaldehyde. The method of the invention has the following advantages: the used raw materials low toxicity, easy, low cost, consumption, high yield, few by-products, easy large-scale production. (by machine translation)
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Paragraph 0045; 0049; 0050; 0054

(2019/02/04)

Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927
The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted
Kahraman, Mehmet,Govek, Steven P.,Nagasawa, Johnny Y.,Lai, Andiliy,Bonnefous, Celine,Douglas, Karensa,Sensintaffar, John,Liu, Nhin,Lee, Kyoungjin,Aparicio, Anna,Kaufman, Josh,Qian, Jing,Shao, Gang,Prudente, Rene,Joseph, James D.,Darimont, Beatrice,Brigham, Daniel,Heyman, Richard,Rix, Peter J.,Hager, Jeffrey H.,Smith, Nicholas D.
supporting information
p. 50 - 55
(2019/01/15)

DISUBTITUTED AZETIDINES, PYRROLIDINES, PIPERIDINES AND AZEPANES AS INHIBITORS OF MONOAMINE OXIDASE B FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
This invention relates to new inhibitors of MAO-Bwith the general formula I, where substituents are described in patent description. Compounds can be in the form of pure enantiomers or as racemic mixtures, or in the form of pharmaceutically acceptable salts. The present invention relates to the use of these inhibitors for the alleviation of symptoms and treatment of acute and chronic neurological disorders, cognitive and neurodegenerative diseases.
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Page/Page column 18; 19

(2018/04/20)

Method for synthesizing N-Boc-3-pyrrolidine formaldehyde
The invention discloses a method for synthesizing N-Boc-3-pyrrolidine formaldehyde. The method comprises that dimethyl itaconate as a raw material undergoes an intramolecular cyclization reaction to produce methyl 5-oxo-3-pyrrolidine carboxylate, then the methyl 5-oxo-3-pyrrolidine carboxylate undergoes a reduction reaction to produce pyrrolidine-3-methanol, then the pyrrolidine-3-methanol is subjected to Boc protection so that N-Boc-pyrrolidine-3-methanol is obtained, and finally, the N-Boc-pyrrolidine-3-methanol is oxidized to form a final product compound. The method is simple and convenient, has a low cost, content greater than 99%, produces small environmental pollution and is suitable for industrial production.
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(2017/06/02)

Backbone-Modified Bisdiazaphospholanes for Regioselective Rhodium-Catalyzed Hydroformylation of Alkenes
A series of tetraaryl bisdiazaphospholane (BDP) ligands were prepared varying the phosphine bridge, backbone, and substituents in the 2- and 5-positions of the diazaphospholane ring. The parent acylhydrazine backbone was transformed to an alkylhydrazine via a borane reduction procedure. These reduced ligands contained an all sp3 hybridized ring mimicking the all sp3 phospholane of (R,R)-Ph-BPE, a highly selective ligand in asymmetric hydroformylation. The reduced bisdiazaphospholane (red-BDP) ligands were shown crystallographically to have an increased C-N-N-C torsion angle - this puckering resembles the structure of (R,R)-Ph-BPE and has a dramatic influence on regioselectivity in rhodium catalyzed hydroformylation. The red-BDPs demonstrated up to a 5-fold increase in selectivity for the branched aldehyde compared to the acylhydrazine parent ligands. This work demonstrates a facile procedure for increased branched selectivity from the highly active and accessible class of BDP ligands in hydroformylation.
Wildt, Julia,Brezny, Anna C.,Landis, Clark R.
p. 3142 - 3151
(2017/09/05)

Enantioselective Fluorination of Spirocyclic β-Prolinals Using Enamine Catalysis
A series of spirocyclic carbaldehydes were successfully fluorinated using enamine catalysis, furnishing the corresponding tertiary fluorides in both high yields and enantioselectivities. The fluorinated spirocycles provide a set of novel building blocks interesting from a medicinal chemistry point of view.
Fjelbye, Kasper,Marigo, Mauro,Clausen, Rasmus Pr?torius,Juhl, Karsten
supporting information
p. 425 - 428
(2017/02/24)

Highly selective bisphosphine ligands for asymmetric hydroformylation of heterocyclic olefins
The bisphosphine ligand 1c is highly efficient and selective for the asymmetric hydroformylation (AHF) of dihydrofuran and pyrrolines. The AHF of 2,3-dihydrofuran yielded the 2-carbaldehyde in up to 93% ee. The remarkable highest regioselectivity of 2,5-dihydrofuran was obtained to date up to 499 β-isomer/α-isomer with ligand 1c. Furthermore, the highest 96% and 92% ee values were accomplished using the same catalytic system in the AHF of N-Boc pyrroline 11 and 14.
Zheng, Xin,Xu, Kun,Zhang, Xumu
p. 1149 - 1152
(2015/02/19)

Easily accessible and highly tunable bisphosphine ligands for asymmetric hydroformylation of terminal and internal alkenes
An efficient methodology for synthesizing a small library of easily tunable and sterically bulky ligands for asymmetric hydroformylation (AHF) has been reported. Five groups of alkene substrates have been tested with excellent conversions, moderate-to-excellent regio- and enantioselectivities. Among the best result of the reported literature, application of ligand 1 c in the highly selective AHF of the challenging substrate 2,5-dihydrofuran yielded almost one isomer in up to 99 % conversion along with enantiomeric excesses (ee) of up to 92 %. Highly enantioselective AHF of dihydropyrrole substrates is achieved using the same ligand, with up to 95 % ee and up to >1:50 β-isomer/α- isomer ratio. The simpler the better! An efficient method for the easy and tunable synthesis of a series of asymmetric hydroformylation (AHF) ligands from low-cost, commercially available starting materials has been reported. These ligands can give excellent conversions and moderate to excellent regio- and enantioselectivities for a broad range of mono- and disubstituted alkenes with a low catalyst loading (substrate-to-catalyst ratios (S/C) of 1000:1 to 3000:1).
Xu, Kun,Zheng, Xin,Wang, Zhiyong,Zhang, Xumu
p. 4357 - 4362
(2014/05/06)

A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: Synthesis and structure-activity relationships
A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro p
Van Orden, Lori Jean,Van Dyke, Priscilla M.,Saito, D. Roland,Church, Timothy J.,Chang, Ray,Smith, Jacqueline A.M.,Martin, William J.,Jaw-Tsai, Sarah,Stangeland, Eric L.
supporting information
p. 1456 - 1461
(2013/03/14)

CRYSTALLINE FORMS OF A 3-[2-METHANESULFONYL-1-(4-TRIFLUOROMETHYL-PHENOXY)ETHYL]PYRROLIDINE COMPOUND
The invention provides crystalline hydrochloride salts of (S)-3-[(S)-2-methanesulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine. This invention also provides pharmaceutical compositions comprising the crystalline salts, processes and intermediates for preparing the crystalline salts, and methods of using the crystalline salts to treat diseases.
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Page/Page column 35

(2013/04/13)

Highly selective asymmetric Rh-catalyzed hydroformylation of heterocyclic olefins
A small family of new chiral hybrid, diphosphorus ligands, consisting of phosphine-phosphoramidites L1 and L2 and phosphine-phosphonites L3a-c, was synthesized for the application in Rh-catalyzed asymmetric hydroformylation of heterocyclic olefins. High-pressure (HP)-NMR and HP-IR spectroscopy under 5-10 bar of syngas has been employed to characterize the corresponding catalyst resting state with each ligand. Indole-based ligands L1 and L2 led to selective ea coordination, while the xanthene derived system L3c gave predominant ee coordination. Application of the small bite-angle ligands L1 and L2 in the highly selective asymmetric hydroformylation (AHF) of the challenging substrate 2,3-dihydrofuran (1) yielded the 2-carbaldehyde (3) as the major regioisomer in up to 68% yield (with ligand L2) along with good ees of up to 62%. This is the first example in which the asymmetric hydroformylation of 1 is both regio- and enantioselective for isomer 3. Interestingly, use of ligand L3c in the same reaction completely changed the regioselectivity to 3-carbaldehyde (4) with a remarkably high enantioselectivity of 91%. Ligand L3c also performs very well in the Rh-catalyzed asymmetric hydroformylation of other heterocyclic olefins. Highly enantioselective conversion of the notoriously difficult substrate 2,5-dihydrofuran (2) is achieved using the same catalyst, with up to 91% ee, concomitant with complete regioselectivity to the 3-carbaldehyde product (4) under mild reaction conditions. Interestingly, the Rh-catalyst derived from L3c is thus able to produce both enantiomers of 3-carbaldehyde 4, simply by changing the substrate from 1 to 2. Furthermore, 85% ee was obtained in the hydroformylation of N-acetyl-3-pyrroline (5) with exceptionally high regioselectivities for 3-carbaldehyde 8Ac (>99%). Similarly, an ee of 86% for derivative 8Boc was accomplished using the same catalyst system in the AHF of N-(tert-butoxycarbonyl)-3-pyrroline (6). These results represent the highest ees reported to date in the AHF of dihydrofurans (1, 2) and 3-pyrrolines (5, 6).
Chikkali, Samir H.,Bellini, Rosalba,De Bruin, Bas,Van Der Vlugt, Jarl Ivar,Reek, Joost N. H.
experimental part
p. 6607 - 6616
(2012/06/15)

SEROTONIN REUPTAKE INHIBITORS
In one aspect, the invention relates to compounds of formula I: where X, Y, R1, R2, R3, R4, R4, and n are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula I are serotonin reuptake inhibitors. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.
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Page/Page column 22

(2012/04/18)

SEROTONIN REUPTAKE INHIBITORS
In one aspect, the invention relates to compounds of formula (I) where Y, R1, R2, n, and Q are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula I are serotonin reuptake inhibito
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Page/Page column 48

(2012/06/16)

3-PHENOXYMETHYLPYRROLIDINE COMPOUNDS
In one aspect, the invention relates to compounds of formula I: where R1-6 are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula I are serotonin and norepinephrine reuptake inhibitors. In a
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Page/Page column 19

(2011/02/15)

3-PHENOXYMETHYLPYRROLIDINE COMPOUNDS
In one aspect, the invention relates to compounds of formula I: where R1-6 are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula I are serotonin and norepinephrine reuptake inhibitors. In a
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Page/Page column 19

(2011/02/18)

Enantioselective hydroformylation of N-vinyl carboxamides, allyl carbamates, and allyl ethers using chiral diazaphospholane ligands
Rhodium complexes of diazaphospholane ligands catalyze the asymmetric hydroformylation of N-vinyl carboxamides, allyl ethers, and allyl carbamates; products include 1,2- and 1,3-aminoaldehydes and 1,3-alkoxyaldehydes. Using glass pressure bottles, short reaction times (generally less than 6 h), and low catalyst loading (commonly 0.5 mol %), 20 substrates are successfully converted to chiral aldehydes with useful regioselectivity and high enantioselectivity (up to 99% ee). Chiral Roche aldehyde is obtained with 97% ee from the hydroformylation of allyl silyl ethers. Commonly difficult substrates such as 1,1- and 1,2-disubstituted alkenes undergo effective hydroformylation with 89-97% ee and complete conversion for six examples. Palladium-catalyzed aerobic oxidative amination of allyl benzyl ether followed by enantioselective hydroformylation yields the β3-aminoaldehyde with 74% ee.
McDonald, Richard I.,Wong, Gene W.,Neupane, Ram P.,Stahl, Shannon S.,Landis, Clark R.
supporting information; experimental part
p. 14027 - 14029
(2011/01/04)

3-(PHENOXYPHENYLMETHYL)PYRROLIDINE COMPOUNDS
In one aspect, the invention relates to compounds of formula I: where a and R1-6 are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula I are serotonin and norepinephrine reuptake inhibitors
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Page/Page column 35

(2010/02/17)

3-(PHENOXYPYRROLIDIN-3-YL-METHYL)HETEROARYL, 3-(PHENYLPYRROLIDIN-3-YLMETHOXY)HETEROARYL, AND 3-(HETEROARYLPYRROLIDIN-3-YLMETHOXY)HETEROARYL COMPOUNDS
In one aspect, the invention relates to compounds of formula I: where RA and RB are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula I are serotonin and norepinephrine reuptake
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Page/Page column 25

(2010/11/03)

N-(HETERO)ARYL-PYRROLIDINE DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AND PYRROL-3-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS
The present invention relates to N-(hetero)aryl-pyrrolidine derivatives of Formula I: which are JAK inhibitors, such as selective JAK1 inhibitors, useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer.
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Page/Page column 68

(2010/12/29)

4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: Design, synthesis and structure-activity relationships
Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
Fish, Paul V.,Andrews, Mark D.,Jonathan Fray,Stobie, Alan,Wakenhut, Florian,Whitlock, Gavin A.
scheme or table
p. 2829 - 2834
(2010/03/03)

Evaluation of structurally diverse neuronal nicotinic receptor ligands for selectivity at the α6* subtype
Direct comparison of pyridine versus pyrimidine substituents on a small but diverse set of ligands indicates that the pyrimidine substitution has the potential to enhance affinity and/or functional activity at α6 subunit-containing neuronal nicotinic rece
Breining, Scott R.,Bencherif, Merouane,Grady, Sharon R.,Whiteaker, Paul,Marks, Michael J.,Wageman, Charles R.,Lester, Henry A.,Yohannes, Daniel
scheme or table
p. 4359 - 4363
(2010/04/05)

SPIRO CONDENSED PIPERIDNES AS MODULATORS OF MUSCARINIC RECEPTORS
The present invention relates to modulators of muscarnic receptors of formula (I). The present invention also provides impositions comprising such modulators, and methods therewith for treating muscarinic receptor mediated diseases.
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(2008/06/13)

Phosphabarrelenes as ligands in rhodium-catalyzed hydroformylation of internal alkenes essentially free of alkene isomerization
Despite significant research efforts in the past, one of the remaining problems to be solved in industrially important hydroformylation is the chemoselective low-pressure hydroformylation of internal alkenes. We report here on a new class of phosphabarrelene/rhodium catalysts 2 that display very high activity towards hydroformylation of internal alkenes with an unusually low tendency towards alkene isomerization. Preparation of new phosphabarrelene ligands, studies of their coordination properties, as well as results obtained in the rhodium-catalyzed hydroformylation of cyclic and acyclic internal alkenes are reported.
Fuchs, Evelyn,Keller, Manfred,Breit, Bernhard
p. 6930 - 6939
(2007/10/03)

HETEROCYCLIC COMPOUNDS AS CCR2B ANTAGONISTS
Compounds of formula (I) Q-L-W-C(=X)-Z-P wherein Q is an amine of the formula-N (R1)(R2); L is an alkyl or heterocyclyl-alkyl linker; W is a 6-or 7-membered aliphatic ring comprising ring atoms Y1 and Y2 which are linked to groups L and C(X) respectively and Y1 and Y2 are independently selected from N and C; X is O, N, N-CN or S; Z is NR 3; P is an optionally substituted monocyclic or bicyclic aryl or heteroaryl group; and pharmaceutically acceptable salts or solvates thereof, are useful in the treatment of C-C chemokine mediated conditions.
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Page/Page column 215

(2008/06/13)

QUINOLONE ANTIBACTERIAL AGENTS
Compounds of formula (I) wherein A is formula (II), formula (III) or formula (IV), and B is formula (V), formula (VI), or formula (VII), can be used in a variety of applications including use as antibacterial agents.
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Page/Page column 89; 90; 131

(2010/02/12)

ANTIBACTERIAL AMINOQUINAZOLIDINEDIONE DERIVATIVES
Compounds of formula (I) wherein: A is Formula (II), Formula (III), or Formula (IV) and B is Formula (V), Formula (VI), or Formula (VII), can be used in a variety of applications including use as antibacterial agents.
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Page/Page column 117; 118; 159

(2010/02/12)

Phosphabarrelene-rhodium complexes as highly active catalysts for isomerization free hydroformylation of internal alkenes
A new class of phosphabarrelene-rhodium catalysts is described which allows for the first time hydroformylation of internal alkenes with very high activity and which proceeds essentially free of alkene isomerization.
Breit, Bernhard,Fuchs, Evelyn
p. 694 - 695
(2007/10/03)

N-BENZYL-3-PHENYL-3-HETEROCYCLYL-PROPIONAMIDE COMPOUNDS AS TACHYKININ AND/ OR SEROTONIN REUPTAKE INHIBITORS
The present invention relates to heterocyclic derivatives of formula (1) wherein R1 represents a 5 or 6 membered heteroaryl group, in which the 5-membered heteroaryl group contains at least one heteroatom selected from oxygen, sulphur or nitrogen and the 6-membered heteroaryl group contains from 1 to 3 nitrogen atoms, or R1 represents a 4,5 or 6 membered heterocyclic group, wherein saids 5 or 6 membered heteroaryl or the 4,5 or 6 membered heterocyclic group may optionally be substituted by one to three substituents, which may be the same or different, selected from (CH2)pR6, wherein p is zero or an integer from 1 to 4 and wherein R and R2- R6 are each as defined in the description and pharmaceutically acceptable salts and solvates thereof; process for their preparation and their use in the treatment of conditions mediated by tachykinins and/or by selective inhibition of serotonin reuptake transporter protein.
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Page 48

(2010/02/06)

CCR3 antagonists: a potential new therapy for the treatment of asthma. Discovery and structure-activity relationships.
CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.
Wacker, Dean A,Santella 3rd., Joseph B,Gardner, Daniel S,Varnes, Jeffrey G,Estrella, Melissa,DeLucca, George V,Ko, Soo S,Tanabe, Keiichi,Watson, Paul S,Welch, Patricia K,Covington, Maryanne,Stowell, Nicole C,Wadman, Eric A,Davies, Paul,Solomon, Kimberly A,Newton, Robert C,Trainor, George L,Friedman, Steven M,Decicco, Carl P,Duncia, John V
p. 1785 - 1789
(2007/10/03)

Asymmetric Hydroformylation of Heterocyclic Olefins Catalyzed by Chiral Phosphine-Phosphite-Rh(I) Complexes
Asymmetric hydroformylation of heterocyclic olefins catalyzed by phosphine-phosphite-Rh(I) complexes has been investigated. Hydroformylation of symmetrical heterocyclic olefins such as 2,5-dihydrofuran, 3-pyrroline derivatives, and 4,7-dihydro-1,3-dioxepin derivatives afforded the optically active aldehydes as single products in 64-76% ee. Unsymmetrical substrates such as 2,3-dihydrofuran and N-(tert-butoxycarbonyl)-2-pyrroline gave a mixture of regioisomers. From N-(tert-butoxycarbonyl)-2-pyrroline was obtained N-(tert-butoxycarbonyl)pyrrolidine-2-carbaldehyde in 97% ee. The hydroformylation products from 2,5-dihydrofuran and N-(tert-butoxycarbonyl)-3-pyrroline have the opposite configurations to those from 2,3-dihydrofuran and N-(tert-butoxycarbonyl)-2-pyrroline, respectively, with the same catalyst. The new phosphine-phosphite ligand (R,S)-3,3′-Me2-BINAPHOS [= (A)-2-(diphenylphosphino)-1,1′-binaphthalen-2′-yl (S)-3,3′-dimethyl-1,1′-binaphthalene-2,2′-diyl phosphite] was prepared and its hydridorhodium complex was characterized by NMR spectroscopy. Using (R,S)-3,3′-Me2-BINAPHOS as a ligand, the enantioselectivity was improved for some substrates. In addition, higher catalytic activity was observed with this ligand for most of the substrates employed.
Horiuchi, Toshihide,Ohta, Tetsuo,Shirakawa, Eiji,Nozaki, Kyoko,Takaya, Hidemasa
p. 4285 - 4292
(2007/10/03)