cas 166815-96-9, N-TERT-BUTOXYCARBONYL-4-(4-TOLUENESULFONYLOXYMETHYL)PIPERIDINE

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Synthesis and evaluation of amide, sulfonamide and urea-benzisoxazole derivatives as potential atypical antipsychotics
In this paper, we report the optimization of a series of novel, potential antipsychotic derivatives combining potent dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptor affinities. The pharmacological features of compound 27 are a high affinity for dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptors. Moreover it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). Furthermore, compound 27 inhibited apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitch without observable catalepsy at the highest dose tested in mice. Taken together, among the amide derivatives, we identified compound 27 as a potential antipsychotic lead candidate.
Chen, Yin,Lan, Yu,Cao, Xudong,Xu, Xiangqing,Zhang, Juecheng,Yu, Minquan,Liu, Xin,Liu, Bi-Feng,Zhang, Guisen
p. 831 - 838
(2015)
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Substituted-3H-imidazo[4,5-c]pyridine and 1H-pyrrolo[2,3-c]pyridine series of novel Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) and Stimulator for Interferon Genes (STING) modulators as cancer immunotherapeutics
Substituted -3H-imidazo[4,5-c]pyridine and 1H-pyrrolo[2,3-c]pyridine series of novel Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) and related compounds, which are useful as inhibitors of ENPP1; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds and compositions to treat disorders associated with dysfunction of the ENPP1.
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Paragraph 0380-0381

(2020/02/19)

Method for synthesizing 1-azabicyclo[2, 2, 1]heptane and derivatives thereof
The invention relates to the technical field of organic chemical synthesis, and particularly relates to a method for synthesizing 1-azabicyclo[2, 2, 1]pyridine and derivatives thereof. A hydroxyl group in 4-(1-hydroxymethyl)piperidine derivatives reacts with p-toluenesulfonyl chloride (TsCl) to be converted into an OTs group which is easy to leave, a tert-butyloxycarbonyl (-boc) protecting group on an N atom is removed under an acidic condition, a nucleophilic substitution ring closing reaction is performed under an alkaline condition, and extraction, solvent removal and concentration are carried out on a final reaction mixture to obtain the pure product 1-azabicyclo[2, 2, 1]heptane and derivatives thereof. The 1-azabicyclo[2, 2, 1]heptane and the derivatives thereof are obtained through three-step synthesis by reacting the 4-(1-hydroxymethyl)piperidine derivative with cheap and easily available common chemical reagents, and the method is discovered for the first time. The N-boc-4-(1-hydroxymethyl)piperidine used in the method is a cheap and easily available raw material, the synthesis method is simple, few in synthesis steps and easy to separate, and a large amount of target products can be synthesized.
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Paragraph 0019-0020

(2020/10/14)

Palladium-Catalyzed Atom-Transfer Radical Cyclization at Remote Unactivated C(sp3)?H Sites: Hydrogen-Atom Transfer of Hybrid Vinyl Palladium Radical Intermediates
A novel mild, visible-light-induced palladium-catalyzed hydrogen atom translocation/atom-transfer radical cyclization (HAT/ATRC) cascade has been developed. This protocol involves a 1,5-HAT process of previously unknown hybrid vinyl palladium radical intermediates, thus leading to iodomethyl carbo- and heterocyclic structures.
Ratushnyy, Maxim,Parasram, Marvin,Wang, Yang,Gevorgyan, Vladimir
p. 2712 - 2715
(2018/03/02)

Design, synthesis and evaluation of new classes of nonquaternary reactivators for acetylcholinesterase inhibited by organophosphates
A new series of nonquaternary conjugates for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. It was found that substituted salicylaldehydes conjugated to aminobenzamide through piperidine would produce efficient reactivators for sarin, VX and tabun inhibited hAChE, such as L6M1R3, L6M1R5 to L6M1R7, L4M1R3 and L4M1R5 to L4M1R7. The in vitro reactivation experiment for pesticides inhibited hAChE of these new synthesized oximes were conducted for the first time. Despite they were less efficient than obidoxime, some of them were highlighted as equal or more efficient reactivators in comparison to 2-PAM. It was found that introduction of peripheral site ligands could increase oximes’ binding affinity for inhibited hAChE in most cases, which resulted in greater reactivation ability.
Wei, Zhao,Bi, Huanglei,Liu, Yan-qin,Nie, Hui-fang,Yao, Lin,Wang, Sheng-zheng,Yang, Jun,Wang, Yong-an,Liu, Xueying,Zheng, Zhi-bing
p. 681 - 688
(2018/09/29)

Conjugates of salicylaldoximes and peripheral site ligands: Novel efficient nonquaternary reactivators for nerve agent-inhibited acetylcholinesterase
A new family of nonquaternary reactivators for nerve agent-inhibited human acetylcholinesterase (hAChE) were designed, synthesized and tested in this paper. It was found that salicylaldoximes were able to quickly cleave the P–S bond of organophosphate and avoid the reinhibition phenomenon in the reactivation process, but they lacked reactivating ability due to poor affinity for AChE. Based on a dual site binding strategy, different peripheral site ligands of AChE were introduced to achieve extra affinity. The in vitro reactivation experiments demonstrated that some of the yielding conjugates exhibited similar or even superior ability to reactivate sarin-, VX- or tabun-inhibited hAChE in comparison with the mono- and bis-pyridinium aldoximes currently used. Moreover, due to greatly improved lipophilicity, these nonquaternary conjugates hold promise for the development of efficient centrally activating reactivators.
Wei, Zhao,Liu, Yan-qin,Wang, Sheng-zheng,Yao, Lin,Nie, Hui-fang,Wang, Yong-an,Liu, Xue-Ying,Zheng, Zhi-bing,Li, Song
p. 4497 - 4505
(2017/07/22)

ANALOGUES OF 4H-PYRAZOLO[1,5-a] BENZIMIDAZOLE COMPOUND AS PARP INHIBITORS
Disclosed is a series of analogues of 4H-pyrazolo[1,5-α]benzimidazole compound as PARP inhibitors. In particular, disclosed in the invention is a compound as shown by formula (I) or a pharmaceutically acceptable salt thereof as a PARP inhibitor.
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Paragraph 0255

(2017/02/28)

An alternative synthesis of Vandetanib (Caprelsa) via a microwave accelerated Dimroth rearrangement
Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12–14).
Brocklesby, Kayleigh L.,Waby, Jennifer S.,Cawthorne, Chris,Smith, Graham
supporting information
p. 1467 - 1469
(2017/03/23)

A New Class of Fluorinated A2A Adenosine Receptor Agonist with Application to Last-Step Enzymatic [18F]Fluorination for PET Imaging
The A2A adenosine receptor belongs to a family of G-coupled protein receptors that have been subjected to extensive investigation over the last few decades. Due to their prominent role in the biological functions of the heart, lungs, CNS and brain, they have become a target for the treatment of illnesses ranging from cancer immunotherapy to Parkinson's disease. The imaging of such receptors by using positron emission tomography (PET) has also been of interest, potentially providing a valuable tool for analysing and diagnosing various myocardial and neurodegenerative disorders, as well as offering support to drug discovery trials. Reported herein are the design, synthesis and evaluation of two new 5′-fluorodeoxy-adenosine (FDA)-based receptor agonists (FDA-PP1 and FDA-PP2), each substituted at the C-2 position with a terminally functionalised ethynyl unit. The structures enable a synthesis of 18F-labelled analogues by direct, last-step radiosynthesis from chlorinated precursors using the fluorinase enzyme (5′-fluoro-5′-deoxyadenosine synthase), which catalyses a transhalogenation reaction. This delivers a new class of A2A adenosine receptor agonist that can be directly radiolabelled for exploration in PET studies.
Lowe, Phillip T.,Dall'Angelo, Sergio,Mulder-Krieger, Thea,IJzerman, Adriaan P.,Zanda, Matteo,O'Hagan, David
p. 2156 - 2164
(2017/10/07)

PYRROLOPYRIDINE RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR MODULATORS AND USES THEREOF
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of Retinoic Acid Receptor-Related Orphan Receptor regulated diseases and disorders.
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Paragraph 0085; 0086

(2017/11/06)

Design and synthesis of vandetanib derivatives containing nitroimidazole groups as tyrosine kinase inhibitors in normoxia and hypoxia
Sixteen novel epidermal growth factor receptor (EGFR)/vascular endothelial growth factor (VEGF)-2 inhibitors (nitroimidazole-substituted 4-anilinoquinazoline derivatives (16a-p)) were designed and prepared via the introduction of a nitroimidazole group in the piperidine side chain and modification on the aniline moiety of vandetanib. Preliminary biological tests showed that comparing with vandetanib, some target compounds exhibited excellent EGFR inhibitory activities and anti-proliferative over A549/H446 cells in hypoxia. Meanwhile, several of the above compounds demonstrated better bioactivity than vandetanib in VEGF gene expression inhibition. Owing to the excellent IC50 value (1.64 μmol/L), the inhibition ratios of 16f over A549 and H446 cells were 62.01% and 59.86% at the concentration of 0.5 μM in hypoxia, respectively. All of these results indicated that 16f was a potential cancer therapeutic agent in hypoxia and was worthy of further development.
Wei, Huiqiang,Li, Deguan,Yang, Xiangbo,Shang, Haihua,Fan, Saijun,Li, Yiliang,Song, Dan
(2016/12/30)

Amide derivative and application thereof
The invention belongs to the field of medicinal chemistry, and particularly relates to an amide derivative and an application thereof. The amide derivative has a structure represented by a formula (I). Experiments verify that the compounds can be applied to preparing drugs for treating nervous and mental diseases.
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Paragraph 0033; 0049

(2016/10/08)

COMPOUNDS HAVING MUSCARINIC RECEPTOR ANTAGONIST AND BETA2 ADRENERGIC RECEPTOR AGONIST ACTIVITY
Compounds of formula I, defined herein, act both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists and are useful for treating broncho-obstructive and inflammatory diseases.
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Paragraph 0370; 0384; 0385; 0386

(2016/09/12)

4-Methylsulfonyl-Substituted Piperidine Urea Compounds
The present invention provides novel 4-methylsulphone-substituted piperidine urea compounds that are useful for the treatment of dilated cardiomyopathy (DCM) and conditions associated with left and/or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the compounds is described, as well as methods for treating DCM and other forms of heart disease.
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Paragraph 0075-0076

(2016/09/26)

Two Routes to 4-Fluorobenzisoxazol-3-one in the Synthesis of a 5-HT4 Partial Agonist
A potent 5-HT4 partial agonist, 1 (PF-04995274), targeted for the treatment of Alzheimer's disease and cognitive impairment, has been prepared on a multi-kilogram scale. The initial synthetic route, that proceeded through a 4-substituted 3-hydroxybenzisoxazole core, gave an undesired benzoxazolinone through a Lossen-type rearrangement. Route scouting led to two new robust routes to the desired 4-substituted core. Process development led to the efficient assembly of the API on a pilot plant scale under process-friendly conditions with enhanced throughput. In addition, crystallization of a hemicitrate salt of the API with pharmaceutically beneficial properties was developed to enable progression of clinical studies.
Widlicka, Daniel W.,Murray, John C.,Coffman, Karen J.,Xiao, Chunguang,Brodney, Michael A.,Rainville, Joseph P.,Samas, Brian
p. 233 - 241
(2016/03/04)

PYRIMIDINE AND TRIAZINE DERIVATIVES AND THEIR USE AS AXL INHIBITORS
Compounds of the general formula(I): (I) processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.
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Page/Page column 78

(2016/07/05)

Quinoline or quinazoline derivatives, its preparation process and its use in medicine
The invention relates to a quinoline or quinazoline derivative, its preparation method and an application in medicines, specifically to new quinoline or quinazoline derivative as shown in a general formula (I) and its medicinal salt or a pharmaceutical composition containing the derivative and a preparation method thereof. The invention further relates to an application of the quinoline or quinazoline derivative and its medicinal salt or the pharmaceutical composition containing the derivative in the preparation of a therapeutic agent, especially a protein kinase inhibitor. Each substituent group in the general formula (I) has the same definition as in the specification.
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Paragraph 0277-0281

(2018/01/19)

SULFONAMIDE RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR MODULATORS AND USES THEREOF
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of Retinoic Acid Receptor-Related Orphan Receptor regulated diseases and disorders.
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Paragraph 0260

(2016/02/16)

SERINE/THREONINE KINASE INHIBITORS
Compounds having the formula I wherein R1, R2, R3, R4, R5, Ra, Rb, Rc, Rd, Re, n, r, s and t are as defined herein and which compounds are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.
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Paragraph 0271; 0272

(2015/02/19)

RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR MODULATORS AND USES THEREOF
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of Retinoic Acid Receptor-Related Orphan Receptor regulated diseases and disorders.
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Paragraph 0211

(2015/09/28)

SUBSTITUTED 3-PHENYLPROPYLAMINE DERIVATIVES FOR THE TREATMENT OF OPHTHALMIC DISEASES AND DISORDERS
The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are substituted 3-phenylpropylamine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compositions are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease.
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Paragraph 0465; 0486

(2014/09/29)

COMPOUNDS HAVING MUSCARINIC RECEPTOR ANTAGONIST AND BETA2 ADRENERGIC RECEPTOR AGONIST ACTIVITY
Compounds of formula (I) act both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists and are useful for treating and/or preventing broncho-obstructive and inflammatory diseases.
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Paragraph 0147; 0148; 0149

(2013/03/26)

COMPOUNDS HAVING MUSCARINIC RECEPTOR ANTAGONIST AND BETA2 ADRENERGIC RECEPTOR AGONIST ACTIVITY
The present invention relates to compounds of general formula (I), acting both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists, to processes for their preparation, to compositions comprising them, to therapeutic uses and combinations with other pharmaceutical active ingredients.
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Page/Page column 37

(2013/02/27)

Quinoline- and isoquinoline-sulfonamide derivatives of LCAP as potent CNS multi-receptor - 5-HT1A/5-HT2A/5-HT7 and D 2/D3/D4 - Agents: The synthesis and pharmacological evaluation
Two series of arylpiperazinyl-alkyl quinoline-, isoquinoline-, naphthalene-sulfonamides with flexible (13-26) and semi-rigid (33-36) alkylene spacer were synthesized and evaluated for 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and selected compounds for D2, D3, D4 receptors. The compounds with a mixed 5-HT and D receptors profile 16 (N-{4-[4-(3-chlorophenyl)-piperazin-1-yl]-butyl}-3- quinolinesulfonamide) and 36 (4-(4-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]- ethyl}-piperidine-1-sulfonyl)-isoquinoline), displaying antagonistic activity at 5-HT7, 5-HT2A, D2 postsynaptic sites, produced antidepressant-like effects in the forced swim test in mice and showed significant anxiolytic activity in the plus-maze test in rats. The lead compound 36, a multi-receptor 5-HT2A/5-HT7/D2/D 3/D4 agent, also displayed significant antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.
Zajdel, Pawe?,Marciniec, Krzysztof,Ma?lankiewicz, Andrzej,Sata?a, Grzegorz,Duszyńska, Beata,Bojarski, Andrzej J.,Partyka, Anna,Jastrzbska-Wisek, Magdalena,Wróbel, Dagmara,Weso?owska, Anna,Paw?owski, MacIej
experimental part
p. 1545 - 1556
(2012/04/17)

DERIVATIVES OF N-ACYL-N'-PHENYLPIPERAZINE USEFUL (INTER ALIA) FOR THE PROPHYLAXIS OR TREATMENT OF DIABETES
The present invention relates to a compound represented by the formula wherein each symbol is as defined in the present specification, which has a superior RBP4-lowering action and is useful as a pharmaceutical composition for the prophylaxis or treatment of a disease or condition mediated by an increase in RBP4.
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Page/Page column 55

(2012/04/04)

(R)-4-((4-((4-(TETRAHYDROFURAN-3-YLOXY)BENZO[D]ISOXAZOL-3-YLOXY)METHYL)PIPERIDIN-1-YL)METHYL)TETRAHYDRO-2H-PYRAN-4-OL, A PARTIAL AGONIST OF 5-HT4 RECEPTORS
(R)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3- yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol and its use in treating neurodegenerative disorders, is described herein.
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Page/Page column 27-28

(2011/09/19)

HETEROCYCLIC COMPOUND
The present invention relates to wherein each symbol is as defined in the specification. The compound of the present invention has a superior RBP4-lowering action, and is useful as a medicament for the prophylaxis or treatment of disease and condition mediated by increased RBP4.
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Page/Page column 51; 48-49

(2010/07/08)

SUBSTITUTED QUINAZOLINE INHIBITORS OF GROWTH FACTOR RECEPTOR TYROSINE KINASES
The present invention relates to new substituted quinazoline inhibitors of vascular endothelial growth factor receptor tyrosine kinase, epidermal growth factor receptor tyrosine kinase, and/or REarranged during Transfection tyrosine kinase, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 19

(2010/04/23)

CHIRAL CIS-IMIDAZOLINES
There are provided compounds of Formula (I), or the pharmaceutically acceptable salts thereof, wherein X, Y, Z, V1, V2, R1, R2, R3, R4 and R5 are as herein described, processes for obtaining said compounds and pharmaceutical preparations containing them. These compounds are useful as anticancer agents, in particular as agents in the treatment of solid tumors.
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Page/Page column 72

(2009/05/30)

JAK-2 MODULATORS AND METHODS OF USE
This invention relates to the field of protein tyrosine kinases and inhibitors thereof. In particular, the invention relates to inhibitors of JAK-2, pharmaceutical compositions of the compounds for inhibiting JAK-2, methods of inhibiting JAK-2 in a cell, comprising contacting a cell in which inhibition of JAK-2 is desired with a compound or pharmaceutical composition comprising a compound according to the invention. The also comprises methods of treating a disease or condition that involves JAK-2 comprising administering to a patient a pharmaceutical composition comprising a compound according to the invention
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Page/Page column 107-108; 168-169; 210-211

(2008/06/13)

Therapeutic quinazoline derivatives
A compound of formula (I) or a salt, ester, amide or prodrug thereof; where X is O, or S, S(O), S(O)2 or NR6 where R6 is hydrogen of C1-6alkyl; R5 is an optionally substituted 6-membered aromatic ring containing at least one nitrogen atom, and R1, R2, R3, R4 are independently selected from halogeno, cyano, nitro, C1-3alkylsulphanyl, —N(OH)R7— (wherein R7 is hydrogen, or C1-3alkyl), or R9X1— (wherein X1 represents a direct bond, —O—, —CH2—, —OC(O), —C(O)—, —S—, —SO—, —SO2—, —NR10C(O)—, —C(O)NR11—, —SO2NR12—, —NR13SO2— or NR14— (wherein R10, R11, R12, R13 and R14 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl), and R9 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy; provided that at least one of R2 or R3 is other than hydrogen. These compounds inhibit aurora 2 kinase and are useful in the preparation of medicaments for the treatment of proliferative disease such as cancer.
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(2008/06/13)

CHEMICAL PROCESS
The present invention relates to chemical processes for the manufacture of certain quinazoline derivatives, or pharmaceutically acceptable salts thereof. The invention also relates to processes for the manufacture of certain intermediates useful in the manufacture of the quinazoline derivatives and to processes for the manufacture of the quinazoline derivatives utilising said intermediates. In particular, the present invention relates to chemical processes and intermediates useful in the manufacture of the compound 4-(4- bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.
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Page/Page column 48; 49

(2008/06/13)

QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS
The invention relates to quinazoline derivatives of the formula I:- wherein: m is an integer from 1 to 3; R 1 represents halogeno or C 1-3 alkyl; X 1 represents -O-; R 2 is selected from one of the following three groups: 1) C 1-5 alkylR 3 (wherein R 3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy; 2) C 2-5 alkenylR 3 (wherein R 3 is as defined hereinbefore); 3) C 2-5 alkynylR 3 (wherein R 3 is as defined hereinbefore); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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Page/Page column 19

(2010/11/08)

An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression
We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4- cyclohexylmethanesulfonylaminobutyl)-piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs α1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.
Becker, Oren M.,Dhanoa, Dale S.,Marantz, Yael,Chen, Dongli,Shacham, Sharon,Cheruku, Srinivasa,Heifetz, Alexander,Mohanty, Pradyumna,Fichman, Merav,Sharadendu, Anurag,Nudelman, Raphael,Kauffman, Michael,Noiman, Silvia
p. 3116 - 3135
(2007/10/03)

2-polycyclic propynyl adenosine analogs having A2A agonist activity
The invention provides compounds having the following general formula (I): wherein X, R1, R2, R7 and Z are as described herein.
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Page/Page column 26

(2008/06/13)

2-PROPYNYL ADENOSINE ANALOGS WITH MODIFIED 5'-RIBOSE GROUPS HAVING A2A AGONIST ACTIVITY
The invention provides compounds having the following general formula (I): wherein X, R1, R2, R7 and Z are as described herein.
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Page/Page column 72

(2008/06/13)

QUINAZOLINE DERIVATIVES
The invention relates to the use of compounds of the formula I: wherein: ring C is a 5-6 membered heterocyclic moiety; Z is -O-, -S-, or -CH2-; R1 is hydrogen, C1-4alkyl, C1-4alkoxymethyl, di(C1-4)alkoxy)methyl, C1-4alkanoyl, trifluoromethyl, cyano, amino, C2-5alkenyl, C2-5alkynyl, carboxy, C3-7cycloalkyl, C3-7-cycloalkylC1-3alkyl, or an optionally substituted group selected from phenyl, benzyl, phenylC2-4alkyl and a 5-6 membered heterocyclic group; n is an integer from 0 to 5; m is an integer from 0 to 3; R2 represents hydrogen, hydroxy, halgeno, cyano, nitro, trifluoromethyl, C1-3alkyl, C1-3alkoxy, C1-3alkylsulphanyl, -NR3R4 (wherein R3 and R4, which may be the same or different, each represents hydrogen or C1-3alkyl), or R5X1- (wherein X1 represents a direct bond, -CH2-, or a heteroatom linker group and R5 is an alkyl, alkenyl or alkynyl chain optionally substituted by for example hydroxy, amino, nitro, alkyl, cycloalkyl, alkoxyalkyl, or an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring, which alkyl, alkenyl or alkynyl chain may have a heteroatom linker group, or R5 is an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring, and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula I. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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Page/Page column 35

(2010/02/11)

Quinazoline derivatives with anti-tumour activity
The invention concerns quinazoline derivatives of Formula I wherein each of m, R1, n, R2 and R3 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
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(2008/06/13)

QUINAZOLINE COMPOUNDS
Quinazoline derivatives of formula (I) wherein A is 5-membered heteroaryl containing a sulphur atom and optionally containing one or more nitrogen atoms; compositions containing them, processes for their preparation and their use in therapy.
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Page 140

(2010/02/07)

Quinazoline derivatives
The invention concerns quinazoline derivatives of Formula (I) wherein Q1includes a quinazoline ring optionally substituted with a group such as halogeno, trifluoromethyl and cyano, or a group of the formula: Q3—X1— wherein X1includes a direct bond and O and Q3includes aryl, aryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl; each of R2and R3is hydrogen or (1-6C)alkyl; Z includes O, S and NH; and Q2includes aryl and aryl-(1-3C)alkyl or a pharmaceutically-acceptable salt thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the prevention or treatment of T cell mediated diseases or medical conditions in a warm-blooded animal.
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Page/Page column 44;45

(2010/02/08)

Cinnoline compounds
The invention relatest to compounds of the formula (I) wherein either any one of G1, G2, G3, G4 and G5 is nitrogen and the other four are —CH—, or G1, G2, G3, G4 and G5 are all —CH—; Z is —O—, —NH—, —S—, —CH2— or a direct bond; Z is linked to any one of G1, G2, G3 and G4 which is a free carbon atom; n is an integer from 0 to 5; any of the substitutents R1 may be attached at any free carbon atom of the indole, azaindole or indazole group; m is an integer from 0 to 3; Ra represents hydrogen; Rb represents hydrogen or another value as defined herein; R1 represents hydrogen, oxo, hydroxy, halogeno, C1-4alkyl, C1-4alkoxy, C1-4alkoxy, C1-4-alkyl, aminoC1-4alkyl, C1-3alkylaminoC1-4alkyl, di(C1-3alkyl)aminoC1-4alkyl, —C1-5alkyl(ring B) wherein ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinly, N-ethylpiperazinyl, morpholino and thiomorpholino; R2 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C1-3alkyl, C1-3alkoxy, C1-3aklylsulphanyl, —NR3R4 (wherein R3 and R4, which may be the same or different, each represents hydrogen or C1-3alkyl), or R5X1— (wherein R5 and X1 are as defined herein) and salts thereof, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and the use of a compound of formula I in the manufacture of medicament for the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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(2008/06/13)

Novel cyclic amide derivatives
Novel compounds represented by the following formula (I) that act as a ligand to sigma receptor/binding cite and a medicament comprising the same as an active ingredient: wherein X represents an alkyl group, an aryl group, a heterocyclic group or the like; Q represents a group represented by —CH2—, —CO—, —O—, —CH(OR7)— or the like wherein R7 represents a hydrogen atom, an alkyl group or the like; n represents an integer of from 0 to 5; R1 and R2 each represent a hydrogen atom, an alkyl group or the like; B represents either of the following groups: wherein R3, R4, R5, and R6 each represent a hydrogen atom, a halogen atom, an alkoxyl group or the like; m represents 1 or 2; and the ring of: represents an aromatic heterocyclic ring.
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(2008/06/13)

Therapy
The invention concerns the use of a quinazoline derivative of Formula (I) wherein Q1 includes a quinazoline ring optionally substituted with a group such as halogeno, trifluoromethyl and cyano, or a group of the formula: Q3—X1— wherein X1 includes a direct bond and O and Q3includes aryl, aryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl; each of R2 and R3 is hydrogen or (1-6C)alkyl; Z includes O, S and NH; and Q2 includes aryl and aryl-(1-3C)alkyl or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human.
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Page 26, 27

(2008/06/13)

Synthesis of [18F]FA-4 and [11C]pipzA-4 as radioligands for the high affinity choline uptake system
We have prepared two radiolabelled analogues of hemicholinium-3 (HC-3) as potential in vivo tracers of the sodium dependent high affinity choline uptake (SDHAChU) system. Thus, 4-[1-hydroxy-2-(4-[18F]fluoromethylpiperidinyl)ethyl]-4'-[1-hydroxy-2-(4 -methylpiperidinyl)ethyl]biphenyl ([18F]FA-4) and 4-[1-hydroxy-2-(4-11C]methylpiperazinyl)ethyl]-4'-[1-hydroxy-2-(4 -methylpiperidinyl)]biphenyl ([11C]pipzA-4) have been synthesized. [18F]FA-4 was prepared by reaction of 4-[18F]fluoromethylpiperidine with 4-(α-bromoacetyl)-4'-(4-methylpiperidinylacetyl)biphenyl followed by reduction of the keto groups to alcohols with NaBH4. The total synthesis time was 300 minutes and [18F]FA-4 was obtained with a specific activity of 5.6 GBq/μmol (EOS) and an overall decay corrected radiochemical yield of 3.1 ± 0.6%. [11C]pipzA-4 was prepared by reaction of [11C]methyl triflate with 4-[1-hydroxy-2-piperazinyl)ethyl]-4'-[1-hydroxy-2-(4 -methylpiperidinyl)ethyl]biphenyl. The total synthesis time was 25 minutes and [11C]pipzA-4 was obtained with a specific activity of 13.7 GBq/μmol (EOS) and an overall decay corrected radiochemical yield of 19.5 ± 2.2%.
Gilissen,Bormans,De Groot,Verbruggen
p. 1289 - 1300
(2007/10/03)

1-PHENYLALKANONE 5-HT4 RECEPTOR LIGANDS
The present invention relates to novel 5-HT 4 receptor ligands which are 1-(5-halo-4-aminophenyl) (C 2-6)alkan-1-one derivatives in which the 5-halo-4-aminophenyl group is substituted at its 2-position with (C 1-4)alkyloxy or phenyl(C 1-4)alkyloxy and optionally substituted at its 3-position with (C 1-4)alkyloxy or substituted at its 2-and 3-positions together with methylenedioxy or ethylenedioxy and the highest numbered carbon of the (C 2-6)alkan-1-one is substituted with di(C 1-4)alkylamino, morpholin-1-yl or pyrrolidin-1-yl or optionally substituted piperidin-1-yl, piperidin-4-yl, azacyclohept-1-yl, azabicyclo[2.2.1]hept-3-yl, azabicylo[2.2.2]oct-3-yl or azabicylo[3.2. 2] non-3-yl; and the pharmaceutically acceptable salts, individual isomers and mixtures of isomers and methods of using and making such derivatives.
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(2008/06/13)