- General synthetic strategies towards N-alkyl sulfoximine building blocks for medicinal chemistry and the use of dimethylsulfoximine as a versatile precursor
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The sulfoximine group has great potential as a substituent in drug discovery, as evidenced by two new clinical candidates, and can be viewed as an isosteric alternative to the commonly used sulfone. Our aim was to improve the accessibility of this group by synthesising a diverse range of S-alkyl and N-alkyl sulfoximine building blocks with procedures that are applicable on a practical scale (>10 g). In particular, synthesis of the less well exploited N-alkyl sulfoximines and the use of dimethylsulfoximine as a versatile, commercially available precursor is discussed.
- Goldberg, Frederick W.,Kettle, Jason G.,Xiong, Jian,Lin, Daoguang
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p. 6613 - 6622
(2015/03/30)
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- Novel pseudopeptides incorporating a benzodiazepine-based turn mimetic - Targeting Mycobacterium tuberculosis ribonucleotide reductase
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Peptides mimicking the C-terminus of the small subunit (R2) of Mycobacterium tuberculosis ribonucleotide reductase (RNR) can compete for binding to the large subunit (R1) and thus inhibit RNR activity. Moreover, it has been suggested that the binding of t
- Nurbo, Johanna,Ericsson, Daniel J.,Rosenstr?m, Ulrika,Muthas, Daniel,Jansson, Anna M.,Lindeberg, Gunnar,Unge, Torsten,Karlén, Anders
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p. 1992 - 2000
(2013/05/08)
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- Carbazole inhibitors of histamine receptors for the treatment of disease
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The present invention relates to carbazole compounds, pharmaceutical compositions comprising them, and methods which may be useful as inhibitors of H1R and/or H4R for the treatment or prevention of inflammatory, autoimmune, allergic, and ocular diseases.
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Page/Page column 72
(2012/01/04)
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- COMPOUNDS
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The invention provides an optically active form of the compound of formula (I), or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt; uses of the
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Page/Page column 34
(2010/11/26)
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- New selective AT2 receptor ligands encompassing a γ-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists
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New benzodiazepine-based γ-turn mimetics with one or two amino acid side chains were synthesized. The γ-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val3-Tyr4-Ile 5 or Tyr4-Ile
- Rosenstr?m, Ulrika,Sk?ld, Christian,Plouffe, Bianca,Beaudry, Hélène,Lindeberg, Gunnar,Botros, Milad,Nyberg, Fred,Wolf, Gunter,Karlén, Anders,Gallo-Payet, Nicole,Hallberg, Anders
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p. 4009 - 4024
(2007/10/03)
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- Aniline derivatives possessing an inhibitory effect of nitric oxide synthase
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Compounds represented by the general formula (1): ? (where R1is SR6or NR7R8, where R6is typically an alkyl group having 1-6 carbon atoms, R7is a hydrogen atom, an alkyl group having 1-6 carbon atoms or a nitro group, and R8is a hydrogen atom or an alkyl group having 1-6 carbon atoms; R2and R3are each typically a hydrogen atom or an alkyl group having 1-6 carbon atoms; R4is a hydrogen atom, an alkyl group having 1-6 carbon atoms or an amidino group of which the amine portion may be substituted by an alkyl or nitro group; R5is a hydrogen atom or an alkyl group having 1-6 carbon atoms; Y1, Y2, Y3and Y4which may be the same or different are each typically a hydrogen atom, a halogen atom or an alkoxy group having 1-6 carbon atoms; n and m are each an integer of 0 or 1), or possible stereoisomers or optically active forms of the compounds or pharmaceutically acceptable salts thereof. The compounds possess a potent nitric oxide synthase inhibiting activity and are useful as therapeutics of cerebrovascular diseases.
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- Compounds useful in treating cytokine mediated diseases
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Disclosed are amide compounds of formula(I): wherein Ar1, Q, Y and R3-R6 of formula(I) are defined herein. The compounds inhibit production of cytokines involved in inflammatory processes and are thus useful for treating d
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- Preparation and NMR analysis of 2,6-heterodifunctional halobenzenes as precursors for substituted biphenyls
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Preparation and complete characterization of 16 2,6-disubstituted halobenzenes, including nine new compounds, from two common starting materials is described. Seven of the new compounds contain one or two propylthio groups, which have been introduced in two ways. Direct reaction of arenediazonium salts with 1-propanethiolate gives yields comparable to those obtained in a three-step method through sulfonyl chlorides. The 1H- and 13C NMR chemical shifts of 17 1,2,3-trisubstituted benzenes have been correlated with the predicted values and the observed trends explained using commonly available modeling packages.
- Sienkowska, Monika,Benin, Vladimir,Kaszynski, Piotr
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p. 165 - 173
(2007/10/03)
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- Dihydropyrimidine macrocyclic lactones useful as calcium antagonists and agonists
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A compound of the formula STR1 (symbols defined in the specification), its 3,4-dihydropyrimidine tautomer form and pharmaceutically acceptable salts thereof have calcium entry blocking activity. A process of preparation, pharmaceutical composition and met
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- NOVEL FENAMIC ACID METHYL HYDROXAMATE DERIVATIVES HAVING CYCLOOXYGENASE AND 5-LIPOXYGENASE INHIBITION
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The present invention is novel selected hydroxamic acid derivatives of fenamic acids having 5-lipoxygenase and cyclooxygenase inhibiting properties, pharmaceutical compositions for treating conditions advantageously affected by the inhibition and methods
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- Studies directed toward ascertaining the active conformation of 1,4-dihydropyridine calcium entry blockers
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A series of unsymmetrically substituted 4-phenyl-1,4-dihydropyridine calcium entry blockers were investigated for their ability to relax potassium-contracted rabbit aortic smooth muscle and to competitively displace [3H][nitrendipine from its specific binding sites on guinea pig myocardial membranes in order to delineate the pharmacologically active conformer with respect to the position of the aromatic substituents (synperiplanar or antiperiplanar). The data show that the 1,4-dihydropyridine receptor distinguishes between 2',3'-disubstituted phenyldihydropyridines and 2',5'-disubstituted analogues as measured by changes of vasodilation and receptor affinity in vitro. The IC50 values for vasorelaxation by the analogues presented here correlate best with the K(d) values for binding to the predominant receptor of two coexisting dihydropyridine binding sites in the guinea pig myocardium. We report the first observation of an antiperiplaner orientation of an o-phenyl substituent in the X-ray structure of 2-chlorophenyl analogue 3. Using nuclear Overhauser enhancement, we have developed a method that also demonstrates that an ortho (chloro or nitro) substituent on the phenyl ring does not preclude the presence of either synperiplanar or antiperiplanar phenyl rotamer in solution. These experimental findings contrast with the accepted belief that o-phenyl substituents essentially force these 1,4-dihydropyridines into the synperiplanar conformation exclusively.
- Rovnyak,Andersen,Gougoutas,Hedberg,Kimball,Malley,Moreland,Porubcan,Pudzianowski
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p. 936 - 944
(2007/10/02)
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- Synthesis and Evaluation of Non-Catechol D-1 and D-2 Dopamine Receptor Agonists: Benzimidazol-2-one, Benzoxazol-2-one, and the Highly Potent Benzothiazol-2-one 7-Ethylamines
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Our interest in identifying D-1 and D-2 dopamine receptor agonists that are not catechols led us to extend previous studies with oxindoles by investigating analogues of dopamine, N,N-dipropyldopamine, m-tyramine, N,N-dipropyl-m-tyramine, and epinine in which the m-hydroxyl is replaced by the NH portion of a thiazol-2-one, oxazol-2-one, or imidazol-2-one group fused to the 2,3-position.These compounds were evaluated for their affinity and agonist activity at D-1 and D-2 receptors by using in vitro assays.Replacement of the m-hydroxy in N,N-dipropyldopamine with the thiazol-2-one group resulted in a dramatic increase in D-2 receptor affinity and activity compared to that of N,N-dipropyldopamine itself or that of the corresponding oxindole, 1.The resulting compound, 7-hydroxy-4-benzothiazol-2(3H)-one (4), is the most potent D-2 receptor agonist reported to date in the field-stimulated rabbit ear artery (ED50=0.028 nM).The benzoxazol-2-one (6), benzimidazol-2-one (5), and isatin (51) analogues showed D-2 receptor agonist potency similar to that of 1.The des-7-hydroxy analogues of 4 (21) also has enhanced D-2 receptor activity compared to that of the corresponding oxindole, 8. 7-Hydroxy-4-(2-aminoethyl)benzothiazol-2(3H)-one, 27, a non-catechol, has enhanced D-1 and D-2 receptor activity in vitro compared to that of the corresponding oxindole, 7.In vivo, 27 increased renal blood flow and decreased blood in the dog.However, these effects were mediated primarily by D-2 receptor agonist activity.This may be a result of the D-1 partial agonist activity of 27 coupled with its potent D-2 receptor activity.
- Weinstock, Joseph,Gaitanopoulos, Dimitri E.,Stringer, Orum D.,Franz, Robert G.,Hieble, J. Paul,et al.
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p. 1166 - 1176
(2007/10/02)
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