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COMPOUNDS FOR INHIBITING THE INTERACTION OF BCL2 WITH BINDING PARTNERS

The present invention relates to compounds of formula I: in which R1, R2, R3 and R4 are as defined in the Summary of the Invention. Compounds of formula I are capable of disrupting the BCL-2 interations with proteins containing a BH3 domain. Disrupting this interaction can restore the anti-apoptotic function of BCL-2 in cancer cells and tumor tissue expressing BCL-2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds in the treatment of cancerous diseases.

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Enantioselective deprotonation of 4-tert-butylcyclohexanone by conformationally constrained chiral lithium amide bases

Conformationally rigid chiral lithium amides based on a tetrahydroisoquinoline motif have been prepared bearing a range of substituents at C1 and C3. These bases were tested in the asymmetric deprotonation reaction of 4-tert-butylcyclohexanone. Although the 1-substituted tetrahydroisoquinolines gave low enantioselectivity, the chiral bases containing a nitrogen heterocycle at C3 were found to induce high enantioselectivity (81% ee) in the presence of HMPA. The Royal Society of Chemistry 1999.

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Anticancer activity of ruthenium(II) arene complexes bearing 1,2,3,4-tetrahydroisoquinoline amino alcohol ligands

Ruthenium complexes offer potential reduced toxicity compared to current platinum anticancer drugs. 1,2,3,4-tetrahydrisoquinoline amino alcohol ligands were synthesised, characterised and coordinated to an organometallic Ru(II) centre. These complexes were evaluated for activity against the cancer cell lines MCF-7, A549 and MDA-MB-231 as well as for toxicity in the normal cell line MDBK. They were observed to be moderately active against only the MCF-7 cells with the best IC50 value of 34 muM for the cis-dia-stereomeric complex C4. They also displayed excellent selectivity by being relatively inactive against the normal MDBK cell line with SI values ranging from 2.3 to 7.4.

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The discovery of avanafil for the treatment of erectile dysfunction: A novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor

Novel pyrimidine-5-carboxamide derivatives bearing a 3-chloro-4-methoxybenzylamino group at the 4-position were identified as potent and highly selective phosphodiesterase 5 inhibitors. Among them, we successfully found 10j (avanafil) which exhibited a potent relaxant effect on isolated rabbit cavernosum (EC30 = 2.1 nM) and a high isozyme selectivity.

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Oxazolidines as Intermediates in the Asymmetric Synthesis of 3-Substituted and 1,3-Disubstituted Tetrahydroisoquinolines

A diastereoselective mercury(II)-promoted intramolecular cyclization of unsaturated aldehyde via an oxazolidine to prepare C-3-substituted tetrahydroisoquinoline is disclosed. The C-3 stereogenic center is subsequently exploited to create the C-1 stereocenter by coordination of the nucleophilic reagent to the oxygen atom of oxazolidine. Both cis- and trans-1,3-disubstituted tetrahydroisoquinolines can be readily prepared. In addition, when a cationic rhodium complex was used, intramolecular hydroamination was effected, thus avoiding mercury(II) salts and demercuration. The reaction is general and works well using aliphatic and aromatic aldehydes.

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Towards a total synthesis of quinocarcin: Diastereoselective synthesis of functionalized azepino[1,2-b]isoquinolines

1,3-Disubstituted tetrahydro-oxazolo-isoquinolinones 19a,b were obtained from phenylalanine in seven steps and 42% overall yield by Katritzky’s benzotriazole method. The tricyclic oxazolidinone 19a was further converted into amino alcohol 10 by employing a chemoselective reduction of the ester group with LiBH4/MeOH. Compound 10 and the corresponding 1-unsubstituted tetrahydroisoquinoline alcohol 11 were converted into aldehydes 27 and 33, which cyclized in the presence of different Lewis acids to give the substituted azepino[1,2-b]isoquinolines 34 and 35, respectively, which are key structural features of the alkaloid quinocarcin. The stereoselectivities of the Lewis-acid-catalyzed heteroene reaction are highly dependent on the substitution pattern and the type of Lewis acid. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

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Electric Literature of 63006-93-9, Catalysts function by providing an alternate reaction mechanism that has a lower activation energy than would be found in the absence of the catalyst. In some cases, the catalyzed mechanism may include additional steps.In a article, 63006-93-9, molcular formula is C10H13NO, introducing its new discovery.

Macrocyclizations for medicinal chemistry: Synthesis of druglike macrocycles by high-concentration ullmann coupling

Conditions have been identified for the efficient Ullmann macrocyclization of phenol and imidazole nucleophiles with aryl iodides at high reaction concentrations of up to 100 mM and using 5-10 mol % loading of an inexpensive copper catalyst. A range of substitution patterns and ring sizes are tolerated, and the method has been exemplified by the synthesis of a set of druglike macrocycles.

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Comparative molecular field analysis (CoMFA) models of phenylethanolamine N-methyltransferase (PNMT) and the alpha2-adrenoceptor: The development of new, highly selective inhibitors of PNMT

As a guide to the development of new and more selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) vs the alpha2-adrenoceptor, we have performed a comparative molecular field analysis (CoMFA) on a series of 80 benzylamine analogues. Using the models obtained, we have proposed a series of 3-trifluoromethyl-1,2,3,4-tetrahydroisoquinolines and predicted the activity of other analogues.

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INDOLE AND PYRROLE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Compounds of formula (I): wherein Ra, Rb, Rc, Rd, R3, R4, R5, A1, A2, T and W are as defined in the description. Medicinal products containing the same which are useful in treating pathologies involving a deficit in apoptosis, such as cancer, auto-immune diseases, and diseases of the immune system.

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Design, synthesis and evaluation of novel, potent DNA alkylating agents and their antibody-drug conjugates (ADCs)

Antibody-drug conjugates (ADCs) incorporating potent indolinobenzodiazepine (IGN) DNA alkylators as the cytotoxic payload are currently undergoing clinical evaluation. The optimized design of these payloads consists of an unsymmetrical dimer possessing both an imine and an amine effectively eliminating DNA crosslinking and demonstrating improved tolerability in mice. Here we present an alternate approach to generating DNA alkylating ADCs by linking the IGN monomer with a biaryl system which has a high DNA binding affinity to potentially enhance tolerability. These BIA ADCs were found to be highly cytotoxic in vitro and demonstrated potent antitumor activity in vivo.

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