- NOVEL COMPOUNDS AS DUAL INHIBITORS OF PHOSPHODIESTERASES AND HISTONE DEACETYLASES
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It relates to certain compounds having a polycyclic structure and a hydroxamic acid moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to a process for their preparation, as well as to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases. wherein B1 is a radical selected from the group consisting of formula (A"), formula (B"), formula (C"), and formula (D"):
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Page/Page column 53
(2014/09/16)
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- Identification of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors
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Tumor angiogenesis is mediated by KDR and other VEGFR and PDGFR kinases. Their inhibition presents an attractive approach for developing anticancer therapeutics. Here, we report a series of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted k
- Dai, Yujia,Hartandi, Kresna,Soni, Niru B.,Pease, Lori J.,Reuter, David R.,Olson, Amanda M.,Osterling, Donald J.,Doktor, Stella Z.,Albert, Daniel H.,Bouska, Jennifer J.,Glaser, Keith B.,Marcotte, Patrick A.,Stewart, Kent D.,Davidsen, Steven K.,Michaelides, Michael R.
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p. 386 - 390
(2008/04/03)
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- PHENYLALANINE ENAMIDE DERIVATIVES CONTAINING A SPIRO`3.5!NON-1-ENE RING FOR USE AS INTEGRIN INHIBITORS
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Phenylalanine enamide derivatives of formula (1) are described: wherein R1 is a -CH3, -(CH2)3CH3, -CH2CH20H, -CH2CH20CH3, -CH2CH2
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Page/Page column 15
(2010/02/06)
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- PROCESS FOR THE PREPARATION OF PHENYLALANINE ENAMIDE DERIVATIVES
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A process for the preparation of a class of phenylalanine enamide derivatives is described formula (1) wherein: Ar1 is an optionally substituted aromatic or heteroaromatic group; L2 is a linker group selected from -N(R4)- [where R4 is a hydrogen atom or an optionally substituted straight or branched C1-6alkyl group], -CON(R4)-, or -S(O)2N(R4)-; R1 is a carboxylic acid (-CO2H) or a derivative or biostere thereof; R2 is a hydrogen atom or a C1-6alkyl group; Rx, Ry and Rz which may be the same or different is each an atom or group -L1(Alk1)n(R3)v; and the salts, solvates, hydrates and N-oxides thereof; which comprises reacting a compound of formula (2): wherein: Qa is a group -N(R4)H; and the salts, solvates, hydrates and N-oxides thereof; with a compound Ar1W wherein W is a group selected from X1 (wherein X1 is a leaving atom or group), -COX2 (wherein X2 is a halogen atom or a -OH group) or -SO2 X3 (in which X3 is a halogen atom).
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- N-arylsulfonyl aza-bicyclic derivatives as potent cell adhesion inhibitors
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Compounds of Formula I are antagonists of VLA-4 and/or alpha4/beta7, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, multiple myeloma, myocarditis, organ transplantation, psoriasis, pulmonary fibrosis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, uveititis, and type I diabetes.
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- 2,3-DIPHENYLPROPIONIC ACID DERIVATIVES OR THEIR SALTS, MEDICINES OR CELL ADHESION INHIBITORS CONTAINING THE SAME, AND THEIR USAGE
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A 2,3-diphenylpropionic acid derivatives or the salts represented by general formula (1) below; and pharmaceutical compositions and cell adhesion inhibitors comprising the derivatives or the salts as the active ingredient. In the formula, A, B and C indep
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- Piperazine-based CCR5 antagonists as HIV-1 inhibitors. III: Synthesis, antiviral and pharmacokinetic profiles of symmetrical heteroaryl carboxamides
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The unsymmetrical nicotinamide-N-oxide moiety in compound 1 was replaced with symmetrical isonicotinamides as well as 4,6-dimethyl pyrimidine-5-carboxamides. Compound 16 from the latter set reduced the number of rotamers, improved potency of inhibiting UIV entry, slightly diminished the affinity for the muscarine receptors and showed very good oral absorption.
- McCombie, Stuart W.,Tagat, Jayaram R.,Vice, Susan F.,Lin, Sue-Ing,Steensma, Ruo,Palani, Anandan,Neustadt, Bernard R.,Baroudy, Bahige M.,Strizki, Julie M.,Endres, Michael,Cox, Kathleen,Dan, Niya,Chou, Chuan-Chu
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p. 567 - 571
(2007/10/03)
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- Oximino-piperidino-piperidine-based CCR5 antagonists. Part 2: Synthesis, SAR and biological evaluation of symmetrical heteroaryl carboxamides
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The synthesis, SAR and biological evaluation of symmetrical amide analogues of our clinical candidate SCH 351125 are described. A series of potent and orally bioavailable CCR5 antagonists containing symmetrical 2,6-dimethyl isonicotinamides and 2, 6-dimethyl pyrimidines amides were generated with enhanced affinity for the CCR5 receptor.
- Palani, Anandan,Shapiro, Sherry,Clader, John W.,Greenlee, William J.,Vice, Susan,McCombie, Stuart,Cox, Kathleen,Strizki, Julie,Baroudy, Bahige M.
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p. 709 - 712
(2007/10/03)
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- N-arylsulfonyl aryl aza-bicyclic derivatives as potent cell adhesion inhibitors
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Compounds of Formula I are antagonists of VLA-4 and/or alpha4/beta7, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, multiple myeloma, myocarditis, organ transplantation, psoriasis, pulmonary fibrosis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, uveititis, and type I diabetes.
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- Phenylalanine derivatives
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Phenylalanine derivatives of formula (1) are described: in which:Ar1 is an aromatic or heteroaromatic group;L1 is a linker atom or group;R is a carboxylic acid or a derivative thereof;Ar2 is an optionally substituted aromatic or heteroaromatic group;and the salts, solvates, hydrates and N-oxides thereof.The compounds are able to inhibit the binding of à4 integrins to their ligands and are of use in the prophylaxis and treatment of immune or inflammatory disorders.
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Page column 18
(2010/01/30)
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- Discovery and evaluation of N-(triazin-1,3,5-yl) phenylalanine derivatives as VLA-4 integrin antagonists.
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SAR studies aimed at improving the rate of clearance of a series of VLA-4 integrin antagonists by the introduction of a 1,3,5-triazine as an amide isostere are described.
- Porter, John R,Archibald, Sarah C,Brown, Julien A,Childs, Kirstie,Critchley, David,Head, John C,Hutchinson, Brian,Parton, Ted A H,Robinson, Martyn K,Shock, Anthony,Warrellow, Graham J,Zomaya, Alex
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p. 1591 - 1594
(2007/10/03)
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- Squaric acid derivatives as VLA-4 integrin antagonists
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SAR studies aimed at improving the rate of clearance by the incorporation of a 3,4-diamino-3-cyclobutene-1,2-dione group as an amino acid isostere in a series of VLA-4 integrin antagonists are described.
- Porter, John R.,Archibald, Sarah C.,Childs, Kirstie,Critchley, David,Head, John C.,Linsley, Janeen M.,Parton, Ted A.H.,Robinson, Martyn K.,Shock, Anthony,Taylor, Richard J.,Warrellow, Graham J.,Alexander, Rikki P.,Langham, Barry
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p. 1051 - 1054
(2007/10/03)
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- Herbicidal 1-pyridyltetrazolinones
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Herbicidal tetrazolinone derivatives of the formula: STR1 in which R1 is alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl or phenyl, and R2 is alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl or phenyl, or R1 and R2 together with the nitrogen atom to which they are bonded form an optionally benzofused heterocyclic ring, which is optionally substituted by C1-4 alkyl, n is 0, 1, 2 or 3, and R3 each independently is nitro, halogen, alkyl, haloalkyl, alkylthio or phenoxy.
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- Benzo- and pyrido-1,4-oxazepin-5-ones and -thiones: Synthesis and structure-activity relationships of a new series of H1 antihistamines
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A series of novel benzo- and pyrido-1,4-oxazepinones and -thiones which represents a new structural class of compounds possessing H1 antihistaminic acitivy was synthesized, and the SARs were evaluated. The antihistamine activity was determined by blockade of histamine-induced lethality in guinea pigs. The sedative potential was determined by comparison of the EEG profiles of the compounds with those of known sedating and nonsedating antihistamines. Several of the compounds were shown to possess potent H1 antihistaminic activity and to be free of the cortical slowing with synchronized waves and spindling activity found in the EEG of sedative antihistamines. One compound, 2-[2-(dimethylamino)ethyl]-3,4-dihydro-4-methylpyrido[3,2-f]-1,4-oxazeN pine-5(2H)-thione (rocastine) is currently undergoing clinical evaluation as a nonsedating H1 antihistamine.
- Cale Jr.,Gero,Walker,Lo,Welstead Jr.,Jaques,Johnson,Leonard,Nolan,Johnson
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p. 2178 - 2199
(2007/10/02)
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- Fused aromatic oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof
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Aromatic azepinones and thiones having the formula STR1 wherein; A is benzene, naphthalene, quinoline or pyridine; B is oxygen or sulfur; E is oxygen, sulfur or STR2 n is 1, 2 or 3; Z is an amino or a heterocyclic nitrogen-containing radical; R is hydrogen, loweralkyl, cycloalkyl or phenylloweralkyl; Y is halo, loweralkyl, loweralkoxy, diloweralkylamino, nitro, amino, loweracetylamino, trifluoromethyl, phenyl or phenyl substituted by one to three Y' radicals selected from halo, loweralkyl, loweralkoxy, diloweralkylamino, nitro, amino, loweracylamino or trifluoromethyl; and having antihistaminic utility, a process for the preparation thereof and chemical intermediates therefor are disclosed.
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- Fused aromatic oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof
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Aromatic azepinones and thiones having the formula STR1 wherein; A is benzene, naphthalene, quinoline or pyridine; B is oxygen or sulfur; E is oxygen, sulfur or STR2 n is 1, 2 or 3; Z is an amino or a heterocyclic nitrogen containing radical; R is hydrogen, loweralkyl, cycloalkyl or phenylloweralkyl; and having antihistaminic utility, a process for the preparation thereof and chemical intermediates therefor are disclosed.
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