- MACROCYCLIC FUSED PYRRAZOLES AS MCL-1 INHIBITORS
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Provided are compounds represented by Formula IA: (IA), and the pharmaceutically acceptable salts and solvates thereof, wherein R, R 1a, R 1b, L 1, L 2, L 3, X, A, B and C are as defined as set forth
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Paragraph 0881
(2020/08/13)
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- MACROCYCLIC INDOLES AS MCL-1 INHIBITORS
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Disclosed is compound of formula I and the pharmaceutically acceptable salts and solvates thereof, wherein R, R1a, R1b, R1h, L1, L2, L3, ?, ?, ? are as defined as set forth in the specification. Disclosed is compound of formula I for use to treat a condition or disorder responsive to Mcl-1 inhibition such as cancer.
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Paragraph 1284-1285
(2020/06/10)
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- BENZOTRIAZOLE-DERIVED AND UNSATURATED AMIDE COMPOUND USED AS TGF- R1 INHIBITOR
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A benzotriazole-derived α and β-unsaturated amide compound used as TGF-βR1 inhibitor or a pharmaceutically acceptable salt thereof, the structure of the compound being as shown in formula (I).
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Paragraph 0145; 0146
(2019/04/29)
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- Focal adhesion kinase inhibitor and use
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The invention belongs to the field of medicines, relates to a focal adhesion kinase inhibitor and use, in particular relates to a novel focal adhesion kinase inhibitor compound, or stereoisomers, geometric isomers, tautomers, oxynitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, further relates to the use of the compound and pharmaceutical compositions as medicines, in particular the use of the compound and pharmaceutical compositions in manufacture of medicines for treatment or prevention of cancer, pulmonary hypertension, and pathological angiogenesis-related diseases.
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Paragraph 0372; 0378; 0379
(2019/01/08)
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- Prolinimines: N-Amino- l -Pro-methyl Ester (Hydrazine) Schiff Bases from a Fish Gastrointestinal Tract-Derived Fungus, Trichoderma sp. CMB-F563
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A rice cultivation of a fish gastrointestinal tract-derived fungus, Trichoderma sp. CMB-F563, yielded natural products incorporating a rare hydrazine moiety, embedded within a Schiff base. Structures inclusive of absolute configurations were assigned to prolinimines A-D (1-4) on the basis of detailed spectroscopic and C3 Marfey's analysis, as well as biosynthetic considerations, biomimetic total synthesis, and chemical transformations. Of note, monomeric 1 proved to be acid labile and, during isolation, underwent quantitative transformation to dimeric 3 and trimeric 4. Prolinimines are only the second reported natural products incorporating an N-amino-Pro residue, the first to include l-Pro, the first to occur as Schiff bases, and the first to be isolated from a microorganism.
- Mohamed, Osama G.,Khalil, Zeinab G.,Capon, Robert J.
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supporting information
p. 377 - 380
(2018/01/27)
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- FACTOR IXA INHIBITORS
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The present invention provides a compound of Formula (I) (structurally represented) wherein R1 is H or C1-6 alkyl, R2 is H or C1-6 alkyl or CH20H, R3 is H or C1-6 alkyl, and R4 is H or C1-6 alkyl, provided that when R1, R2, and R3 are H, R4 is C1-6 alkyl, and when R1, R2, and R4 are H, then R3 is C1-6 alkyl, and when R1, R3, and R4 are H, R2 is C1-6 alkyl or-CH20H, and when R2, R3, and R4 are H, then R1 is C 1-6 alkyl; A is 1 ) a 9-10 membered bicyclic heterocycle having 1-3 heteroatoms independently selected from N, S and 0, which 9-10 membered bicyclic heterocycle is unsubstituted or substituted with R5 and unsubstituted or substituted with R6 and unsubstituted or substituted with NH2, or 2) a 6-9 membered monocyclic or bicyclic carbocyclic ring system unsubstituted or substituted with R5, unsubstituted or substituted with R6, and unsubstituted or substituted with -CH2NH2; and B is 1) a 5- or 6-membered monocyclic heterocycle having 1 or 2 heteroatoms independently selected from N, S or 0, which is unsubstituted or substituted on a carbon or nitrogen atom with R7, unsubstituted or substituted on a carbon or nitrogen atom with R8, and unsubstituted or substituted on a carbon or nitrogen atom with R9, or 2) an 8- or 9-membered fused bicyclic heterocycle having 1, 2 or 3 nitrogen atoms which is unsubstituted or substituted on a carbon or nitrogen atom with R7, and unsubstituted or substituted on a carbon or nitrogen atom with R8; and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses.
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Page/Page column 78-79
(2014/08/19)
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- N-nitrosation of secondary amines using p-TSA-NaNO2 as a novel nitrosating agent under mild conditions
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A combination of p-toluenesulfonic acid (p-TSA) and sodium nitrite was used as a novel effective nitrosating agent for the N-nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.
- Borikar, Sanjay P.,Paul, Vincent
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experimental part
p. 654 - 660
(2011/02/27)
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- A divergent strategy to the withasomnines
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A concise synthesis of three members of the withasomnine family of natural products is reported. The synthesis features a regioselective sydnone-alkynylboronate cycloaddition followed by Suzuki cross coupling and silyl group removal, and marks the first d
- Foster, Robert S.,Huang, Jianhui,Vivat, Jerome F.,Browne, Duncan L.,Harrity, Joseph P. A.
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experimental part
p. 4052 - 4056
(2009/12/06)
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- Stabilisation of peptide foldamers in an aqueous medium by incorporation of azapeptide building blocks
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Stable foldamers in water: Helical peptidic foldamers including H12 and H10/12 helices were constructed and stabilised in water. The foldamers' extra rigidity stems from the strong hydrogen bonding network of the azapeptide groups (see graphic).
- Hetenyi, Anasztazia,Toth, Gabor K.,Somlai, Csaba,Vass, Elemer,Martinek, Tamas A.,Fueloep, Ferenc
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experimental part
p. 10736 - 10741
(2010/04/30)
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- Efficient procedure for chemoselective N-nitrosation of secondary amines with trichloromelamine-NaNO2
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A combination of trichloromelamine and sodium nitrite in the presence of wet silica gel was used as an effective nitrosating agent for the transformation of secondary amines into the corresponding N-nitroso derivatives under mild and heterogeneous conditions in good to excellent yields.
- Bamoniri,Zolfigol,Mirjalili,Fallah
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p. 1393 - 1396
(2008/03/27)
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- V-PROU/NO, a prodrug of the nitric oxide donor, PROLI/NO
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The sensitivity to decomposition of the nitric oxide (NO) donor ion, 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), complicates direct electrophilic substitution to form useful prodrug derivatives. A modified general synthetic approach involving 1-[2-(hydroxymethyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate ion (structure A, above) was used to prepare several PROLI/NO prodrugs including the previously Inaccessible O2vinyl derivative, V-PROLl/NO. Metabolism of V-PROLI/NO by liver microsomes enriched in human cytochrome P450 isoforms was demonstrated.
- Chakrapani, Harinath,Showalter, Brett M.,Kong, Li,Keefer, Larry K.,Saavedra, Joseph E.
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p. 3409 - 3412
(2008/02/12)
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- Alumina-methanesulfonic acid (AMA)/NaNO2 as an efficient procedure for the chemoselectivite N-nitrosation of secondary amines
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A combination of alumina/methanesulfonic acid (AMA) and sodium nitrite was used as an effective nitrosating agent for the nitrosation of secondary amines under mild and heterogeneous conditions in good to excellent yields. Copyright Taylor & Francis Group, LLC.
- Niknam, Khodabakhsh,Zolfigol, Mohammad Ali
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p. 2311 - 2319
(2007/10/03)
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- Tin(IV) chloride-sodium nitrite as a new nitrosating agent for N-nitrosation of amines, amides and ureas under mild and heterogeneous conditions
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We have developed a new method of N-nitrosation of various secondary and tertiary amines, amides and ureas using a mixture of tin(IV) chloride and sodium nitrate. This method leads to a selective, high-yielding and mild heterogeneous N-nitrosation by in situ generation of nitrosyl chloride (NOCl). The reaction can be carried out in several different solvents such as chloroform, dichloromethane, ethers, ethyl acetate and alcohols, at room temperature. Georg Thieme Verlag Stuttgart.
- Celaries, Benoit,Parkanyi, Cyril
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p. 2371 - 2375
(2008/02/03)
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- Selective hydrolysis of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- carboxylate and ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate as a key step in the large-scale synthesis of bicyclic heteroaryl carboxyaldehydes
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The isomeric mixture of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazole-2- and -3-carboxylates (14 and 15), derived from a proline meso-ionic synthon, demonstrated remarkably different stabilities towards alkaline hydrolysis. On that basis, a non-chromatographic, highly efficient method for their large-scale separation was developed. The desired isomer 14 was converted into 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbaldehyde, a key intermediate in the synthesis of bicyclic heteroaryl-substituted 6-alkylidene penems.
- Nikitenko,Winkley,Zeldis,Kremer,Chan,Strong,Jennings,Jirkovsky,Blum,Khafizova,Grosu,Venkatesan
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p. 712 - 716
(2012/12/22)
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- Process for synthesizing beta-lactamase inhibitor intermediates
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There is provided a process for the preparation of bicyclicheteroaryl carboxaldehydes having the structural Formula I where X and Y are defined in the specification The bicyclic heteroaryl carboxaldehydes are useful as intermediates in the preparation of β-lactamase inhibitors.
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- Selective N-nitrosation of amines, N-alkylamides and N-alkylureas by N2O4 supported on cross-linked polyvinylpyrrolidone (PVP-N2O4)
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N2O4 was supported on the cross-linked polyvinylpyrrolidone (PVP) to afford a solid, stable and recyclable nitrosating agent. This reagent shows excellent selectivity for N-nitrosation of dialkyl amines in the presence of diaryl-, arylalkyl-, trialkylamines and also for secondary amides in dichloromethane at room temperature under mild and heterogeneous conditions. Also N-nitroso-N-alkyl amides can be selectively prepared in the presence of primary amides and N-phenylamides under similar reaction conditions. Selective N-nitrosation or dealkylation and N-nitrosation of tertiary amines can also be performed by this reagent.
- Iranpoor, Nasser,Firouzabadi, Habib,Pourali, Ali-Reza
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p. 1591 - 1597
(2007/10/03)
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- The use of Nafion-H/NaNO2 as an efficient procedure for the chemoselective N-nitrosation of secondary amines under mild and heterogeneous conditions
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A combination of Nafion-H and sodium nitrite in the presence of wet SiO2 was used as an effective agent for the N-nitrosation of secondary amines under mild and heterogeneous conditions in good to excellent yields.
- Zolfigol, Mohammad Ali,Habibi, Davood,Mirjalili, BiBi Fatemeh,Bamoniri, Abdolhamid
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p. 3345 - 3349
(2007/10/03)
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- Silica sulfuric acid/NaNO2 as a novel heterogeneous system for the chemoselective N-nitrosation of secondary amines under mild conditions
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Neat chlorosulfonic acid reacts with silica gel to give silica sulfuric acid in which sulfuric acid is immobilized on the surface of silica gel via a covalent bond. A combination of silica sulfuric acid and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in excellent yields.
- Zolfigol, Mohammad Ali,Bamoniri, Abdolhamid
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p. 1621 - 1624
(2007/10/03)
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- Trichloroisocyanuric acid/NaNo2 as a novel heterogeneous system for the N-nitrosation of N,N-dialkylamines under mild conditions
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A combination of trichloroisocyanuric acid and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of N,N-dialkyl amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.
- Zolfigol, Mohammad Ali,Choghamarani, Arash Ghorbani,Hazarkhani, Hassan
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p. 1002 - 1004
(2007/10/03)
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- Chemoselective N-nitrosation of secondary amines under mild and heterogeneous conditions
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A combination of iodic or periodic acids and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in excellent yields.
- Zolfigol,Choghamarani,Shirini,Keypour,Salehzadeh
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p. 359 - 365
(2007/10/03)
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- N-nitrosation of secondary amines under mild and heterogeneous conditions
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A combination of potassium monopersulfate and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in excellent yields.
- Zolfigol,Bagherzadeh,Choghamarani,Keypour,Salehzadeh
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p. 1161 - 1166
(2007/10/03)
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- Chemoselective N-nitrosation of secondary amines under mild and heterogeneous conditions via in situ generation of NOCI
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A combination of inorganic chloride salts [e.g. WCl6, AlCl3 and ZnCl2] and sodium nitrite in the presence of wet SiO2 were used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.
- Zolfigol,Shirini,Choghamarani,Taqian-Nasab,Keypour,Salehzadeh
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p. 420 - 422
(2007/10/03)
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- ORALLY EFFECTIVE ANTI-HYPERTENSIVE AGENTS
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Novel thiolester compounds are disclosed which are orally effective angiotensin converting enzyme inhibitors useful in the treatment of mammalian hypertension. They have the formula, EQU1 wherein Z denotes-B-A 2, R 1 is H or an acyl group, A 1 is a carboxylic acid containing at least one amino or imino-N-, A 2 is a carboxylic acid containing at least one amino or imino-N-or a lower alkyl ester or amide thereof, B is a 2-4 carbon backbone chain in mercapto linkage to S which includes a carbonyl or sulfonyl group joined in carboxamido or sulfonamido linkage, respectively, to A 2. Preferably A 2 includes a 4-6 membered C-N ring or a 5 membered ring of one N, one S and 3 C atoms.
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- Nucleophilic Catalysis in the Nitrosation of Sarcosine and Proline
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The formation of nitrosoamino acids from both sarcosine (Sar) and proline (Pro) and nitrous acid is very strongly accelerated by thiourea (TU) and tetramethylthiourea (TMTU), and to a lesser extent by thiocyanate ion.The effects of TU and TMTU are very similar and are greater than that of SCN(1-) by a factor of 17 for Sar and 30 for Pro.Thus these amino acids behave like amines and not like amides (where there is no nucleophilic catalysis).The second-order rate constants (k2) for XNO attack were obtained (a) from the variation of the observed rate constant (k0) with or and (b) from the variation with .The agreement is excellent.This analysis assumes that reaction occurs as N-nitrosation of the free -NH- function.The variation of k0 with acidity, however, shows that there is another (small) component to the reaction, and the results are consistent with an earlier idea involving initial O-nitrosation at the -CO2(1-) function.The k2 values are discussed with reference to the reaction of other substrates with these (and other) nitrosating reagent, particularly with reference to encounter-controlled processes.The extent of the alternative pathway for ONSC(NH2)2(1+) decomposition is assessed in relation to the ability of this species to act as a nitrosating agent.
- Meyer, Thomas A.,Williams, D. Lyn H.
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p. 517 - 522
(2007/10/02)
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- Anti-hypertensive agents
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Novel inhibitors of angiotensin converting enzyme having the general formula R--A--S--Z are disclosed as potent inhibitors of angiotensin converting enzyme and are useful anti-hypertensive agents.
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- The mechanism of the nitrosation of α-amino acids: Evidence for an intramolecular Pathway
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The results of a kinetic study of the nitrosation of sarcosine, proline, cysteine, and the ethyl ester of sarcosine are reported.Under the conditions in which sarcosine and proline were studied, both first- and second-order terms were found for nitrite dependence.The experimental results are interpreted by a mechanism which involves NO(1+) and N2O3 as direct nitrosating agents, while the effect of acidity changes on the firts-oredr term for nitrite shows that the N-nitroso compound is also formed in a parallel reaction in which a slow intramolecular rearrangement follows the attack of NO(1+) on the carboxylate group of the amino acid.This pathway is confirmed by the absence of sucy a parallel reaction in the nitrosation of the ethyl ester of sarcosine.The influence of acidity on the nitrosation of cysteine shows that S-nitrosation is brought about by the reaction of NO(1+) with both the N-protonated, HSCH2-CH(NH3(1+))-COOH, and zwitterion, HSCH2-CH(NH3(1+))-COO(1-), forms of the amino acid.The values obtained for the bimolecular rate constants are compatible with diffusion control, the difference between the values for both forms of the amino acid explicable in terms of charges of the reagents.
- Casado, Julio,Castro, Albino,Leis, J. Ramon,Mosquera, Manuel,Pena, M. Elena
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p. 1859 - 1864
(2007/10/02)
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- (S)-(-)-1-Amino-2-(siloxymethyl)pyrrolidines: Novel and Efficient Reagents for Chromatographic Resolution of α-Substituted Aldehydes
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A new aldehyde resolution technique based on the chromatographic seperation (preparative h.p.l.c.) of their epimeric (S)-1-amino-2-(siloxymethyl)pyrrolidine (SASP)-hydrazones is described.
- Enders, Dieter,Mies, Wolfgang
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p. 1221 - 1223
(2007/10/02)
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- Synthesis of α-acetoxy-N-nitroso-4[3H]-pyrrolidine
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Tritium labeled α-acetoxy-N-nitroso-4[3H]-pyrrolidine 3, an important model compound used in the study of the metabolism of nitrosopyrrolidine, has been prepared from commercially available 4[3H]-l-proline. The synthesis involves two steps; first the nitrosation of the aminoacid to N-nitroso-4[3H]-l-proline 2, followed by the oxidative decarboxylation with lead tetraacetate in dichloromethane with 1.2 equivalents of pyridine to α-acetoxy-N-nitroso-4[3H]-pyrrolidine in 23% overall yield. The compound was further purified by HPLC.
- Saavedra,Hecker,Farrelly
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p. 415 - 420
(2007/10/07)
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- MERCAPTOACYLAMINO DERIVATIVES OF HETROCYCLIC CARBOXYLIC ACIDS
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New mercaptoacyl derivatives of heterocyclic carboxylic acids which have the general formula STR1 are useful as angiotensin converting enzyme inhibitors.
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