- Asymmetric hydrogenation of 3-alkylidene-2-piperidones using Noyori's catalyst. Effect of N-substituents on the enantioselectivity
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The enantioselectivity in the asymmetric hydrogenation of 3-alkylidene-2-piperidones catalyzed by BINAP-Ru(II) complex was found to be significantly effected by the internal substituents on the lactam nitrogen, affording the corresponding 3-alkyl-2-piperidones in 52-92% ee.
- Chung, John Y. L.,Zhao, Dalian,Hughes, David L.,McNamara, James M.,Grabowski, Edward J. J.,Reider, Paul J.
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Read Online
- PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
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The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
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Page/Page column 153-154
(2019/11/12)
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- With anti-platelet aggregation activity of the piperidinyl substituted 5- hydroxy color acid derivatives
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The invention relates to the field of pharmaceutical chemistry, particularly piperidyl substituted 5-hydroxytryptophane derivatives (I) with anti-platelet aggregation activity, and a preparation method and pharmaceutical application thereof, wherein R1, R2 and n are defined in the specification. The pharmacodynamical test proves that the piperidyl substituted 5-hydroxytryptophane derivatives have favorable anti-platelet aggregation activity.
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Paragraph 0095-0098
(2017/02/09)
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- Discovery of Potent, Selective, and Orally Active Carboxylic Acid Based Inhibitors of Matrix Metalloproteinase-13
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The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-α (TNF-α) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC50 value 0.5 nM and Ki of 0.19 nM) having no activity against MMP-1 or TACE (IC50 of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p 0.05) and at 10 mg/kg (40% inhibition, p 0.05).
- Monovich, Lauren G.,Tommasi, Ruben A.,Fujimoto, Roger A.,Blancuzzi, Vincent,Clark, Kirk,Cornell, Wendy D.,Doti, Robert,Doughty, John,Fang, James,Farley, David,Fitt, John,Ganu, Vishwas,Goldberg, Ronald,Goldstein, Robert,Lavoie, Stacey,Kulathila, Raviraj,Macchia, William,Parker, David T.,Melton, Richard,O'Byrne, Elizabeth,Pastor, Gary,Pellas, Theodore,Quadros, Elizabeth,Reel, Noela,Roland, Dennis M.,Sakane, Yumi,Singh, Hem,Skiles, Jerry,Somers, Joseph,Toscano, Karen,Wigg, Andrew,Zhou, Siyuan,Zhu, Lijuan,Shieh, Wen-Chung,Xue, Song,McQuire, Leslie W.
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experimental part
p. 3523 - 3538
(2010/03/30)
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- CARBONYL-PIPERAZINYL AND PIPERIDINIL COMPOUNDS WHICH INHIBIT FARNESYL PROTEIN TRANSFERASE
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Novel carbonyl piperazinyl and piperidinyl compounds of formula (1.0) or (1.1) and pharmaceutical compositions are disclosed. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel carbonyl piperazinyl or piperidinyl compound to a biological system. In particular, the method inhibits the abnormal growth cells in a mammal such as the human being. A compound of formula (1.0) and (1.1) or a pharmaceutically acceptable salt or solvate thereof, wherein Z is a group which is (i), (ii) or (iii), wherein X1 is CH or N; X2 can be the same or different and can be CH, N, or N-O; b is 0, 1, 2, 3, 4; n and nn independently represent 0, 1, 2, 3, 4 or when X2 is CH, n and nn can be 5; R20 and R21, R1, R2 and R3 are as given in the description.
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- Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides
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The present invention relates to azacycloalkylalkanoyl peptides and pseudopeptides which inhibit platelet aggregation and thrombus formation thereby being useful in the prevention and treatment of thrombosis associated with disease states such as myocardial infarction, stroke, peripheral arterial disease, and disseminated intravascular coagulation, to methods for the prevention or treatment of thrombosis in a mammal in need of such therapy comprising the administration of a therapeutically effective amount of such compounds, and to pharmaceutical compositions comprising such compounds.
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- Carboxylic acid derivatives, medicaments comprising these compounds, their use and processes for their production
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The present invention relates to carboxylic acid derivatives of the general formula STR1 in which Ra to Rc, A, B, D, E and X1 to X3 are as defined in claim 1, their tautomers, their stereoisomers including their mixtures, and their salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases, which have useful pharmacological properties, preferably aggregation-inhibiting inhibiting actions, medicaments containing these compounds, their use and processes for their preparation.
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- Tricyclic compounds
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Novel compounds of Formula STR1 are disclosed. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering a compound of the formula to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being.
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- Tricyclic amide and urea compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
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A method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells is disclosed. The method comprises the administration of a compound of Formula 1.0: STR1 to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being. Novel compounds of formulas 5.0, 5.1 and 5.2, wherein R is --C(R20)(R21)(R46), and 5.3, 5.3A and 5.3B, wherein R is --N(R25)(R48), are disclosed. Also disclosed are processes for making 3-substituted compounds of Formulas 5.0, 5.1, 5.2 and 5.3. Further disclosed are novel compounds which are intermediates in the process for making 3-substituted compounds of Formulas 5.0, 5.1, 5.2 and 5.3.
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- Development of new non-peptide GPIIb-IIIa antagnosts, NSL-95315 and NSL-95317, isosteres of NSL-95300
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The synthetic and structure-activity relationship (SAR) studies of new non-peptide GPIIb/IIIa antagonists (1a-f and 3) were conducted by replacing one amide bond of NSL-95300 (2) with an (E)-double bond or an enone group. NSL-95315 (1a) and NSL-95317 (3) showed the inhibitory activity for collagen-induced human platelet aggregation with IC50 values of 0.25 μM and 0.21 μM, respectively.
- Asari, Tohru,Ishikawa, Shigetaka,Sasaki, Toshiki,Katada, Jun,Hayashi, Yoshio,Harada, Takeo,Yano, Mako,Yasuda, Emiko,Uno, Isao,Ojima, Iwao
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p. 2099 - 2104
(2007/10/03)
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- Compounds and methods for identifying activated platelets
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The invention is directed to a series of novel compounds, and their pharmaceutically acceptable salts, of the formula STR1 wherein R is C0-6 alkyl substituted with R5 or a mono or polycyclic aromatic or heteroaromatic system comprised of 5 or 6-membered aromatic or heteroaromatic rings that are either unsubstituted or substituted with one or more of R1 and R2 ; R1 and R2 are independently C1-6 alkyl, carboxyl, hydroxyl, azido, nitro, amino, C1-6 alkylamino, C1-6 dialkylamino, arylamino, aryl C1-6 alkylamino, hydroxysulfonyl or arylazo; aryl is a phenyl or naphthyl ring which is unsubstituted or substituted with one or more of R3 and R4 ; R3 and R4 are independently C1-6 alkyl, azido, nitro, amino, C1-6 dialkylamino or hydroxysulfonyl; R5 is STR2 provided that when R is an unsubstituted monocyclic ring, the monocyclic ring is not phenyl or pyridyl. Such compounds are useful as fluorescent probes for identifying antiplatelet agents which selectively bind to activated platelets.
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- Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
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Novel compounds of Formula STR1 are disclosed. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering a compound of the Formula 1.0 to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being.
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- Tricyclic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
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Novel compounds of Formula (7.0a), (7.0b) or (7.0c): STR1 are disclosed. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering a compound of the formula (7.0a), (7.0b) or (7.0c) to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being.
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- Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp
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Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation.Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation.Compound 23m (L-700, 462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of >24000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors.Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with iv infusions 0.1-10 μg/kg/min of 23m in anesthetized dogs, with 10 μg/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol.Platelet aggregatability returned rapidly after the termination of the 23m infusions.These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.
- Egbertson, Melissa S.,Chang, Charles T.-C.,Duggan, Mark E.,Gould, Robert J.,Halczenko, Wasyl,et al.
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p. 2537 - 2551
(2007/10/02)
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