- X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
-
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
- Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
-
p. 8303 - 8332
(2021/06/30)
-
- Process Development and GMP Production of a Conjugate Warhead: Auristatin F-HPA-Ala/TFA (XMT-1864/TFA)
-
An efficient, large-scale manufacturing process is described for XMT-1864/TFA (1-TFA), an auristatin F derivative, used as a novel, highly potent, cytotoxic warhead in Mersana's oncology antibody-drug conjugate platforms. The process achieves high diastereomeric purity and controls the impurities with all intermediates readily isolated by crystallization or precipitation in high yield and purity. Protecting groups were selected to ensure tolerability, scalability, and stability of the intermediates under various solution-phase peptide coupling conditions. Crystallization of the final product was developed to remove specified impurities and provide a high-purity active warhead molecule for use in the bioconjugation processing. The convergent synthesis involving six non-GMP steps and five GMP steps has been carried out in multiple cGMP productions on 1-kg scale to produce 1-TFA in >98% chemical purity and 1% total diastereomeric contamination with ~50% overall yield for the GMP steps.
- Conlon, Patrick R.,Gurijala, Venu Reddy,Kaufman, Michael,Li, Dachang,Li, Jiuyuan,Li, Yuanyuan,Reddy, Bollu Satyanarayan,Wagler, Thomas,Wang, Zedong,Xu, Zhongmin,Yin, Mao,Yurkovetskiy, Aleksandr V.,Zhu, Lei
-
-
- Preparation Method for Tyrosine Kinase Inhibitor and Intermediate Thereof
-
Provided is a preparation method for a tyrosine kinase inhibitor and an intermediate thereof. Specifically, a preparation method for a cyanoquinoline compound is provided. The method has a high yield, good product purity, and mild reaction conditions.
- -
-
Paragraph 0094
(2020/08/19)
-
- NOVEL POTASSIUM CHANNEL INHIBITORS
-
The present invention relates to novel compounds, pharmaceutical compositions comprising such compounds and their use for treating, alleviating or preventing diseases or disorders relating to the activity of potassium channels.
- -
-
Page/Page column 56; 72
(2020/10/20)
-
- Compound, preparation method thereof, pharmaceutical composition and application of compound
-
The invention discloses a compound, a preparation method thereof, a pharmaceutical composition and application of the compound. The compound I, and a stereoisomer or a pharmacologically acceptable salt thereof can serve as a CDK7 kinase inhibitor, are high in inhibition activity, and can be used for treatment of various malignant tumors.
- -
-
Paragraph 0108; 0112-0114
(2020/01/03)
-
- METHOD FOR PREPARING TYROSINE KINASE INHIBITOR AND DERIVATIVE THEREOF
-
The present invention relates to a method for preparing a tyrosine kinase inhibitor and a derivative thereof. The present method has a short synthesis route, low costs, easy operation, and is suitable for large-scale production.
- -
-
Paragraph 0061-0063
(2019/05/15)
-
- MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS AND USES THEREOF
-
The present disclosure describes novel TRK kinase inhibitors and methods for preparing them. The pharmaceutical compositions comprising such TRK kinase inhibitors and methods of using them for treating cancer, infectious diseases, and other disorders are also described.
- -
-
Paragraph 173
(2019/05/30)
-
- Compound (E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride and synthetic method
-
The invention discloses a compound (E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride and a synthetic method. The compound is structurally as shown in a formula (I). The synthetic method of the compound comprises the following steps: using BOC-L-prolinol (or BOC-D-prolinol) as an initial material, and by oxidization, forming aldehyde; removing a BOC protective agent; then reacting with haloalkane; then by a Wittig reaction, synthesizing (S,E)-3-(1-methylpyrrolidine-2-yl)-ethyl acrylate; after hydrolysis, salifying to obtain (S,E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride [or (R,E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride]. The compound, as a medical intermediate, can be used for preparing quinazoline or quinolines medicine derivatives. The formula is shown in the description.
- -
-
Paragraph 0069; 0070; 0071
(2018/08/03)
-
- COMPOUNDS, COMPOSITIONS AND METHODS FOR SYNTHESIS
-
The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.
- -
-
Paragraph 001705; 001706; 001707; 001708
(2019/01/10)
-
- A base promoted multigram synthesis of aminoisoxazoles: Valuable building blocks for drug discovery and peptidomimetics
-
A practical multigram metal free synthesis of isoxazole-containing building blocks from commercially available amino acids was elaborated. The key reaction was a regioselective [3 + 2]-cycloaddition of in situ generated nitrile oxides with alkynes/enamines. The obtained building blocks were used in the preparation of bioactive compounds and peptidomimetics.
- Chalyk, Bohdan A.,Kandaurova, Inna Y.,Hrebeniuk, Kateryna V.,Manoilenko, Olga V.,Kulik, Irene B.,Iminov, Rustam T.,Kubyshkin, Vladimir,Tverdokhlebov, Anton V.,Ablialimov, Osman K.,Mykhailiuk, Pavel K.
-
p. 25713 - 25723
(2016/03/25)
-
- Benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation and use
-
The invention relates to a benzimidazole-2-piperazine derivative and a preparing method and application of the benzimidazole-2-piperazine derivative in medicine, in particular to a novel benzimidazole-2-piperazine derivative shown in the general formula (I), a preparing method of the derivative, a pharmaceutical composition containing the derivative and application of the derivative serving as a therapeutic agent, especially serving as a poly (ADP-ribose) polymerase (PARP) inhibitor. In the general formula (I), R refers to hydrogen or halogen, G refers to carbonyl or methylene, m is 1-2, n is 1-3, and Q refers to hydrogen or C1-C4 alkyl. When X is methylene and Y is NR1 or methylene, X is NR1; R1 refers to hydrogen, C1-C6 alkyl, benzyl, COR2 or SO2R2; R2 refers to the following groups which are not substituted or groups substituted by 1-3 substituent groups, including C1-C6 alkyl, C3-C8 naphthenic base, phenyl, benzyl, naphthyl and C5-C10 aromatic heterocycle base, heterocycle in the C5-C10 aromatic heterocycle base comprises 1-3 heteroatoms selected from N, O and S, and the substituent groups are selected from the following atoms or groups of C1-C6 alkyl, C1-C6 alkoxy, halogen, amidogen, nitryl, sulfydryl, hydroxyl, cyanogroup and trifluoromethyl. The general formula (I) is shown in the specification.
- -
-
Paragraph 0209; 0246; 0249; 0250
(2016/10/20)
-
- PHARMACEUTICAL COMPOUNDS
-
This invention relates to compounds that inhibit or modulate the activity of Chk-1 kinase. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds.
- -
-
Page/Page column 97; 178
(2015/09/23)
-
- BICYCLIC AZA COMPOUNDS AS MUSCARINIC M1 RECEPTOR AGONISTS.
-
This invention relates to compounds that are agonists of the muscarinic M1 receptor and/or M4 receptor and which are useful in the treatment of muscarinic M1/M4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds include those according to formula 1, or a salt thereof, wherein Q, R1 , R2, R3 and R4 are as defined herein.
- -
-
Page/Page column 94; 95
(2015/09/22)
-
- Highly selective bisphosphine ligands for asymmetric hydroformylation of heterocyclic olefins
-
The bisphosphine ligand 1c is highly efficient and selective for the asymmetric hydroformylation (AHF) of dihydrofuran and pyrrolines. The AHF of 2,3-dihydrofuran yielded the 2-carbaldehyde in up to 93% ee. The remarkable highest regioselectivity of 2,5-dihydrofuran was obtained to date up to 499 β-isomer/α-isomer with ligand 1c. Furthermore, the highest 96% and 92% ee values were accomplished using the same catalytic system in the AHF of N-Boc pyrroline 11 and 14.
- Zheng, Xin,Xu, Kun,Zhang, Xumu
-
p. 1149 - 1152
(2015/02/19)
-
- Total synthesis and isolation of citrinalin and cyclopiamine congeners
-
Many natural products that contain basic nitrogen atoms-for example alkaloids like morphine and quinine-have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalinB and cyclopiamineB. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalinB and citrinalinC (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously.
- Mercado-Marin, Eduardo V.,Garcia-Reynaga, Pablo,Romminger, Stelamar,Pimenta, Eli. F.,Romney, David K.,Lodewyk, Michael W.,Williams, David E.,Andersen, Raymond J.,Miller, Scott J.,Tantillo, Dean J.,Berlinck, Roberto G. S.,Sarpong, Richmond
-
p. 318 - 324
(2014/06/09)
-
- Easily accessible and highly tunable bisphosphine ligands for asymmetric hydroformylation of terminal and internal alkenes
-
An efficient methodology for synthesizing a small library of easily tunable and sterically bulky ligands for asymmetric hydroformylation (AHF) has been reported. Five groups of alkene substrates have been tested with excellent conversions, moderate-to-excellent regio- and enantioselectivities. Among the best result of the reported literature, application of ligand 1 c in the highly selective AHF of the challenging substrate 2,5-dihydrofuran yielded almost one isomer in up to 99 % conversion along with enantiomeric excesses (ee) of up to 92 %. Highly enantioselective AHF of dihydropyrrole substrates is achieved using the same ligand, with up to 95 % ee and up to >1:50 β-isomer/α- isomer ratio. The simpler the better! An efficient method for the easy and tunable synthesis of a series of asymmetric hydroformylation (AHF) ligands from low-cost, commercially available starting materials has been reported. These ligands can give excellent conversions and moderate to excellent regio- and enantioselectivities for a broad range of mono- and disubstituted alkenes with a low catalyst loading (substrate-to-catalyst ratios (S/C) of 1000:1 to 3000:1).
- Xu, Kun,Zheng, Xin,Wang, Zhiyong,Zhang, Xumu
-
p. 4357 - 4362
(2014/05/06)
-
- Novel pyrrolidone derivatives for use as MetAP-2 inhibitors
-
Compounds of the formula (I), in which R, X, Y, Z, R3 and R4 have the meanings indicated in claim 1, are inhibitors of methionine aminopeptidase and can be employed for the treatment of tumours.
- -
-
-
- One-Pot Bi(OTf)catalyzed oxidative deprotection of tert -butyldimethyl silyl ethers with TEMPO and co-oxidants
-
A sequential one-pot synthesis for the oxidation of primary and secondary tert-butyldimethylsilyl (TBDMS) ethers, using catalytic amounts of metal triflates and TEMPO in combination with PhIO or PhI(OAc)in THF or acetonitrile, is described. Acid-sensitive protecting groups such as methylidene, isopropylidene, acetals, and Boc are unaffected under the reaction conditions. Another feature of this procedure is its high selectivity for TBDMS ethers over tert-butyldiphenylsilyl ethers and of aliphatic TBDMS groups over phenolic TBDMS groups. Georg Thieme Verlag Stuttgart - New York.
- Barnych, Bogdan,Vatèle, Jean-Michel
-
experimental part
p. 2048 - 2052
(2011/10/19)
-
- ADENINE DERIVATIVES
-
Novel adenine derivatives of the formula (I), in which R1, R2, R3, X and Y have the meanings indicated in Claim 1, are HSP90 inhibitors and can be used for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and/or modulation of HSP90 plays a role.
- -
-
Page/Page column 16
(2010/07/04)
-
- Evaluation of retro-inverso modifications of HTLV-1 protease inhibitors containing a hydroxyethylamine isoster
-
Effects of retro-inverso (RI) modifications of HTLV-1 protease inhibitors containing a hydroxyethylamine isoster backbone were clarified. Construction of the isoster backbone was achieved by a stereoselective aldol reaction. Four diastereomers with different configurations at the isoster hydroxyl site and the scissile site substituent were synthesized. Inhibitory activities of the new inhibitors suggest that partially modified RI inhibitors would interact with HTLV-1 protease in the same manner as the parent hydroxyethylamine inhibitor.
- Tatsumi, Tadashi,Awahara, Chiyuki,Naka, Hiromi,Aimoto, Saburo,Konno, Hiroyuki,Nosaka, Kazuto,Akaji, Kenichi
-
experimental part
p. 2720 - 2727
(2010/06/16)
-
- Rhodium-catalyzed 1.4-additions to enantiopure acceptors: Asymmetric synthesis of functionalized pyrrolizidinones
-
The rhodium-catalyzed 1,4-addition of arylboronic acids to an enantiopure heterocyclic acceptor proceeds under ligand control to effect an asymmetric synthesis of functionalized pyrrolizidinones. The protocol allows convenient access to all four stereoiso
- Zoute, Ludivine,Kociok-Koehn, Gabriele,Frost, Christopher G.
-
supporting information; experimental part
p. 2491 - 2494
(2009/10/24)
-
- BETA-SECRETASE INHIBITING COMPOUNDS HAVING OXO-DIHYDRO-PYRAZOLE MOIETY
-
Disclosed are compounds represented by Formula (I) as defined in the specification, or pharmaceutically acceptable salts or isomers thereof, and a pharmaceutical composition for inhibiting beta-secretase activity comprising a therapeutically effective amo
- -
-
Page/Page column 41-42
(2009/04/25)
-
- TETRAZOLE DERIVATIVES AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS
-
The present invention relates to new compounds of formula (I) wherein Y1 and Y2 selected from the group consisting of hydrogen, halogen atom, C1-4 alkyl, C1-4 alkoxy or cyano group, X is oxygen or two hydrogen a
- -
-
Page/Page column 33
(2008/06/13)
-
- MGluR5 modulators I
-
The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.
- -
-
Page/Page column 8
(2008/06/13)
-
- MGluR5 modulators IV
-
The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.
- -
-
Page/Page column 8
(2008/06/13)
-
- β-isocupreidine-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes
-
β-Isocupreidine (β-ICD)-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes and 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) takes place without racemization and exhibits the match-mismatch relationship between the substrate and the catalyst. In the case of acyclic amino aldehydes, α,-substrates show excellent syn selectivity and high reactivity in contrast to L-substrates. On the other hand, in the case of cyclic amino aldehydes, D-substrates rather than L-substrates show excellent anti selectivity and high reactivity.
- Nakano, Ayako,Takahashi, Keisuke,Ishihara, Jun,Hatakeyama, Susumi
-
p. 5357 - 5360
(2007/10/03)
-
- FUSED BENZENE DERIVATIVE AND USE
-
The present invention provides a compound represented by the general formula: [wherein Ring A represents an optionally substituted 5- to 8-membered ring, Ring B represents a further optionally substituted 4- to 10-membered ring, Ring C represents a further optionally substituted benzene ring, X1 represents carbon atom, X2 represents a carbon atom, an oxygen atom, etc., W represents a nitrogen atom, etc., Y11 represents a group represented by the formula CR2R3' (wherein R2 represents a hydrogen atom, a cyano group, a nitro group, etc., and R3' represents a hydrogen atom, a cyano group, a nitro group, etc., respectively), Y21 represents a group represented by the formula CR4R5' (wherein R4 represents a hydrogen atom, a cyano group, a nitro group, etc., and R5' represents a hydrogen atom, a cyano group, a nitro group, etc., respectively), etc., and R1 represents an electron-withdrawing group, respectively. The formula represents a single bond or a double bond] or a salt thereof, which is useful as an androgen receptor modulator.
- -
-
Page/Page column 49-50
(2010/02/12)
-
- MELANOCORTIN RECEPTOR AGONISTS
-
The present invention relates a compound of formula 1, and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof effective as agonist of melanocortin receptor, and an agonistic composition of melanocortin receptor comprising the same as active ingredient.
- -
-
Page/Page column 46
(2010/02/11)
-
- 8-(heterocyclylmethyl)quinoline derivatives for treating urinary incontinence
-
The invention concerns compounds of formula (I) wherein: A represents either a hydrogen atom or a hydroxyl group; B represents a pyrrolidin-2-yl (D) or 2-piperidyl (E), B capable of being substituted by one or two R5groups; R1represents a hydrogen atom, a C1-C6alkyl, a C2-C6alkenyl, a C1-C2perfluoroalkyl or a C1-C6fluoroalkyl group; R2, R3or R4, independently of one another, represent a hydrogen atom, a C1-C6alkyl, group or a C2-C6alkenyl group, or R1and R2can together form a C1-C6alkylene chain, or a C3-C6alkenylene chain; R5represents a C1-C6alkyl group, and R6represents a hydrogen atom, a C1-C6alkyl group, a C2-C6alkenyl group, C3-C6cycloalkyl, C3-C6cycloalkenyl or a benzyl. Said compounds have therapeutic applications
- -
-
-
- 4-Alkenyl- and 4-alkynyloxindoles
-
Disclosed are novel 4-alkenyl- and 4-alkynyl oxindoles having the formula and the pharmaceutically acceptable salts thereof, wherein R1, R2, R3, a, b, and X are as defined herein. These compounds inhibit cyclin-dependent kinases (CDKs), in particular CDK2. These compounds and their pharmaceutically acceptable salts, and prodrugs of said compounds, are anti-proliferative agents useful in the treatment or control of cell proliferative disorders, in particular cancer, more particularly, the treatment or control of breast and colon tumors. Also disclosed are pharmaceutical compositions containing the compounds of formula I and II as well as intermediates useful in the preparation of the compounds of formula I and II.
- -
-
-
- Synthesis and activity of 3-pyridylamine ligands at central nicotinic receptors
-
A series of thirty 2-(3-pyridylaminomethyl)azetidine, pyrrolidine and piperidine analogues as nicotinic acetylcholine receptor (nAChR) ligands was explored. In general, pyrrolidinyl and many azetidinyl compounds were found to bind with enhanced affinity relative to the piperidines. In the three series, the parallel structural changes (stereochemistry, N-methylation and/or chloro substitution) do not consistently lead to parallel shifts in affinity. The more active compounds (K(i) affinity values ranging from 8.9 to 90 nM) were about as analgesic as nicotine in a tail-flick assay in mice after subcutaneous injections. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Balboni, Gianfranco,Marastoni, Mauro,Merighi, Stefania,Borea, Pier Andrea,Tomatis, Roberto
-
p. 979 - 988
(2007/10/03)
-
- Synthesis of chiral vinylogous sulfonamidopeptides (vs-peptides)
-
Chiral vinylogous amino sulfonic acids (vs-amino acids) were synthesized starting from either L- or D-α-amino acids via N-Boc-α-amino aldehydes. Wittig-Horner reaction with methyl (or ethyl) diethylphosphoryl methanesulfonate and nBuLi gave the corresponding α,β-unsaturated sulfonates in high yield and complete (E) stereoselectivity. Cleavage of the methyl (ethyl) ester was effected by treatment of the sulfonates with nBu4NI in refluxing acetone. Treatment of the nBu4N+ sulfonate salts with SO2Cl2/PPh3/CH2Cl2 gave the corresponding sulfonyl chlorides as stable chromatographable compounds. The synthetic sequence proved successful not only starting from α-amino acids carrying unfunctionalized side-chains (Ala, Val, Phe, Leu, Pro), but also with functionalized α-amino acids (Ser, Tyr, Gln) provided that the side chains were suitably protected. The sulfonyl chlorides were coupled with the amine salts to give vs-dipeptides. Amine hydrochlorides were prepared from N-Boc derivatives by treatment with HCl in methanol or ethyl acetate. The process was further iterated to give vstripeptides and vs-tetrapeptides. The above procedure was also used to synthesize "mixed" peptides, which incorporate both proteinogenic α-amino acids and vs-amino acids. Proteinogenic α-amino acids were incorporated at both the C-terminal and the N-terminal position.
- Gennari, Cesare,Longari, Chiara,Ressel, Stefano,Salom, Barbara,Mielgo, Antonia
-
p. 945 - 959
(2007/10/03)
-
- Synthesis and absolute configuration of two defensive alkaloids from the Mexican bean beetle, Epilachna varivestis
-
Syntheses of (2S,12'R)-2-(12'-aminotridecyl)-pyrrolidine (1) and (28,12'R)-1-(2'-hydroxyethyl)-2-(12'-aminotridecyl)-pyrrolidine (2), two defensive alkaloids recently isolated from the Mexican bean beetle, Epilachna varivestis, are described. By a comparison of 1H NMR data of MTPA derivatives of natural alkaloid 2 with those of the synthetic standard, we confirm the (2S,12'R) configuration previously suggested for this alkaloid. Further support of these assignments was provided by the synthesis and 1H NMR investigation of(2S,12'S)-1, (2S,12'S)-2, and their MTPA derivatives.
- Shi, Xiongwei,Attygalle, Athula B.,Meinwald, Jerrold
-
p. 6479 - 6482
(2007/10/03)
-
- Bombesin antagonists
-
The present invention provides polypeptides of the formula XX1 TrpX2 X3 X4 X5 X6 X7 NH2, methods of treatment using the polypeptides, pharmaceutical compositions comprising such polypeptides, and processes for their preparation. The polypeptides possess antagonist properties against bombesin and bombesin-like peptides and are useful in the treatment of malignant disease. M, X, X1, X2, X3, X4, X5, X6, and X7 are as defined in the specification.
- -
-
-
- Potent Gastrin-Releasing Peptide (GRP) Antagonists Derived from GRP (19-27) with a C-Terminal DProΨPhe-NH2 and N-Terminal Aromatic Residues
-
We have previously reported that octapeptides with a -DProΨPhe-NH2 C-terminus are potent GRP antagonists and have greatly enhanced in vivo stability.Now we report the detailed syntheses of such peptides and additional attempts to further increase m
- Leban, Johann J.,Landavazo, Antonio,McDermed, John D.,Diliberto, Emanuel J.,Jansen, Marilyn,et al.
-
p. 439 - 445
(2007/10/02)
-
- Synthesis and in Vitro Characterization of Novel Amino Terminally Modified Oxotremorine Derivatives for Brain Muscarinic Receptors
-
A series of novel 2-substituted acetylenic pyrrolidines and piperidines related to oxotremorine (1) were prepared and evaluated in vitro as muscarinic cholinergic agents at brain M1 and M2 receptors.One analogue, 3-(2-oxo-1-pyrrolidinyl)-1--1-propyne hydrogen oxalate (6a), was found to be a partial agonist producing a PI hydrolysis response at cortical M1 receptors approximately 3-fold larger than that produced by 1.The intrinsic activity profile of 6a at brain muscarinic receptors is similar to those of azetidine oxo analogue 2 and dimethylamino oxo analogue (3).All three compounds are partial M1 agonists and full M2 agonists; however, the profile of 6a in binding studies is significantly different.While 2 and 3 exhibit large M2 selectivities ranging between 8-fold to several hundred-fold, the binding profile of 6a shows almost no subtype selectivity.
- Garvey, David S.,Wasicak, James T.,Chung, John Y.-L.,Shue, Youe-Kong,Carrera, George M.,et al.
-
p. 1550 - 1557
(2007/10/02)
-
- Chemical and biochemical studies of 2-propynylpyrrolidine derivatives. Restricted-rotation analogues of N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM-5)
-
A series of optically pure 2-[substituted-3-aminopropynyl]pyrrolidine derivatives, which are restricted-rotation analogues of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM-5, compound 1), have been prepared from d- and l-proline. The compounds when tested in a series of in vitro muscarinic assays [[3H]CD (cortex), [3H]QNB (cortex), [3H]PZ (cortex), [3H]QNB (heart), [3H]QNB + GppNHp (heart)] were found to have weaker muscarinic properties than compound 1. The decrease in affinity was attributed to the increased size of the molecule resulting from the addition of a methylene group to form the pyrrolidine ring. The use of optically active compounds provided a more detailed examination of the complex pharmacological effects of the flexible muscarinic agent 1. The R enantiomers in the acetamide derivatives 12b, 12d, and 12f had a 5-10-fold greater affinity for the muscarinic receptor than the corresponding S enantiomers. A 5-fold difference or less found in the (R)- and (S)-carbamate derivatives 9, 15, and 16 suggested close overlap of the two enantiomers in the receptor binding domain. The affinity differences found in the enantiomeric acetamido derivatives when compared to those of the carbamate analogues may be the result of limited rotation of the acetamido group.
- Trybulski,Kramss,Mangano,Rusinko III
-
p. 3190 - 3198
(2007/10/02)
-
- Synthesis of chiral α-acetylenic cyclic amines from α-amino acids: Applications to differentially constrained oxotremorine analogues as muscarinic agents
-
Application of the Cory-Fuchs reaction on Boc-prolinal, Boc-4-hydroxyprolinal, Boc-piperidinal and Boc-serinal derivatives to give chiral 2-pyrrolidinyl-, 2-piperidinyl- and 4-oxazolidinyl-acetylene derivatives provided rapid access to a number of differentially constrained oxotremorine analogues as muscarinic agents.
- Chung,Wasicak
-
p. 3957 - 3960
(2007/10/02)
-
- A Straightforward Synthesis of Allyl Amines from α-Amino Acids without Racemization
-
An extremely simple and practical synthesis of allyl amine derivatives from α-amino acids has been developed involving aldehyde olefination pathway with AlMe3-Zn-CH2I2 reagent which has proven to be crucial for preservation of stereochemical integrity.
- Moriwake, Toshio,Hamano, Shin-ichi,Saito, Seiki,Torii, Sigeru
-
p. 2085 - 2088
(2007/10/02)
-
- Asymmetric Hydroformylation and Hydrocarboxylation of Enamides. Synthesis of Alanine and Proline
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Carbonyltris(triphenylphosphine)hydridorhodium (1) catalyzed the hydroformylation of N-vinylimides in the presence of optically active 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (DIOP) or 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(5H-dibenzophospholyl)butane (DIPHOL) to afford optically active α-amido aldehydes.Linear disubstituted N-vinylimides or -amides reacted very sluggishly, while the cyclic N-acyl-2-pyrroline (19) was very reactive.In the unsubstituted N-vinylimides moderate (20-40percent ee) asymmetric induction was observed.The optically active α-amido aldehydes were readily converted to the corresponding α-amino acids.Asymmetric hydrocarboxylation of the same substrates in the presence of bis(triphenylphosphine)palladium chloride (2) produced α-amido esters in low optical purity.
- Becker, Y.,Eisenstadt, A.,Stille, J. K.
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p. 2145 - 2151
(2007/10/02)
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