- MEDICINE CONTAINING ANTIBODY DRUG CONJUGATE CONTAINING HEMIASTERLIN DERIVATIVE
-
PROBLEM TO BE SOLVED: To provide medicines containing an antibody drug conjugate containing a hemiasterlin derivative, in which specific cytotoxicity to target cells is given, while cytotoxicity to normal cells is suppressed. SOLUTION: Provided is a medicine represented by formula (2-1), and containing an antibody drug conjugate or a pharmaceutically acceptable salt thereof [where, mAb represents an antibody, q represents an integer from 1 to 8, b represents an integer from 1 to 5, Z is a group represented by formula (Z-1), formula (Z-2), formula (Z-3), formula (Za-1), formula (Za-2), formula (Za-3), formula (Za-4), or formula (Za-5)]. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
- -
-
Paragraph 0246-0427
(2020/12/01)
-
- MORPHINAN DERIVATIVE
-
A compound represented by the following general formula (I), wherein R1 represents hydrogen, C1-10 alkyl, cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms, or the like, R2 represents a 4- to 7-membered saturated heterocycle containing one or two heteroatoms which may be the same or different and are selected from N, O, and S, and two or more carbon atoms as ring-constituting atoms, the heterocycle may be substituted with a substituent such as an oxo group, R2 binds to Y via a carbon atom as a ring-constituting atom of R2, R3, R4, and R5, which are the same or different, represent hydrogen; hydroxy; or the like, R6a and R6b, which are the same or different, represent hydrogen or the like, R7 and R8, which are the same or different, represent hydrogen or the like, R9 and R10, which are the same or different, represent hydrogen or the like, X represents O or CH2, and Y represents C(= O) or the like), a tautomer of the compound, a stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof is used as an anxiolytic, an antidepressant, or the like.
- -
-
Paragraph 0113-0114; 0119-0120
(2019/06/27)
-
- Synthesis and biological evaluation of (-)-6-O-desmethylcryptopleurine and analogs
-
(-)-Cryptopleurine 1 is one of the most potent anti-proliferative member of the phenanthroquinolizidine class of alkaloids. We report here the synthesis of (-)-6-O-desmethylcryptopleurine (-)-2 and (-)-6-O-desmethyl-(15R)-hydroxycryptopleurine (-)-4 in th
- Liéby-Muller, Frédéric,Marion, Frédéric,Schmitt, Philippe,Annereau, Jean-Philippe,Kruczynski, Anna,Guilbaud, Nicolas,Bailly, Christian
-
p. 184 - 187
(2015/04/13)
-
- PIPERAZINYL PYRIMIDINE DERIVATIVES, PREPARATION METHOD AND USE THEREOF
-
Provided are piperazinyl pyrimidine derivatives of formula I having CCR4 antagonism, and the preparation method, pharmaceutical composition and use thereof in the preparation of a medicament. The medicament is useful for the treatment and preve
- -
-
Paragraph 0127; 0128
(2015/05/13)
-
- PIPERAZINYL PYRIMIDINE DERIVATIVES, PREPARATION METHOD AND USE THEREOF
-
Provided are piperazinyl pyrimidine derivatives of formula I having CCR4 antagonism, and the preparation method, pharmaceutical composition and use thereof in the preparation of a medicament. The medicament is useful for the treatment and preve
- -
-
Paragraph 0074-0075
(2014/12/09)
-
- SWEET FLAVOR MODIFIER
-
The present invention includes compounds having structural formula (I), or salts or solvates thereof. These compounds are useful as sweet flavor modifiers. The present invention also includes compositions comprising the present compounds and methods of modulating the sweet taste of compositions.
- -
-
Page/Page column 73
(2014/03/21)
-
- Design and Synthesis of (R)-1-Arylsulfonylpiperidine-2-carboxamides as 11β-Hydroxysteroid Dehydrogenase Type1 Inhibitors
-
R adamantly beats S: 11β-HSD1 is a target for treating metabolic syndrome. The Risomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11β-HSD1. It also displays a good DMPK profile invitro, and was advanced to PK/PD evaluations invivo. The results confirmed its dose-dependent activity in mice.
- Xia, Guangxin,Liu, Lin,Liu, Haiyan,Yu, Jianxin,Xu, Zhenmin,Chen, Qian,Ma, Chen,Li, Ping,Xiong, Bing,Liu, Xuejun,Shen, Jingkang
-
supporting information
p. 577 - 581
(2013/08/22)
-
- Organocatalytic one-pot oxidative cleavage of terminal diols to dehomologated carboxylic acids
-
The organocatalytic one-pot oxidative cleavage of terminal 1,2-diols to one-carbon-unit-shorter carboxylic acids is described. The combination of 1-Me-AZADO (cat.), NaOCl (cat.), and NaClO2 caused smooth one-pot oxidative cleavage under mild conditions. A broad range of substrates including carbohydrates and N-protected amino diols were converted without epimerization. Terminal triols and tetraols respectively underwent cleavage of their C-2 and C-3 moieties to afford their corresponding two- and three-carbon-unit-shorter carboxylic acids.
- Shibuya, Masatoshi,Doi, Ryusuke,Shibuta, Takuro,Uesugi, Shun-Ichiro,Iwabuchi, Yoshiharu
-
supporting information
p. 5006 - 5009
(2013/01/15)
-
- Nitroxyl radical/PhI(OAc)2: One-pot oxidative cleavage of vicinal diols to (di)carboxylic acids
-
A mild and user-friendly one-pot oxidative cleavage of vicinal diols to their corresponding (di)carboxylic acids using AZADOs and PhI(OAc)2 is described. 1,2-Diols and 2,3-diols as well as 1,2,3-triol gave one- or two-carbon-unit-shorter carboxylic acids. Internal vicinal diols also smoothly underwent one-pot oxidative cleavage to afford the corresponding dicarboxylic acids. Cyclic vicinal diols are converted to their corresponding open-form dicarboxylic acids.
- Shibuya, Masatoshi,Shibuta, Takuro,Fukuda, Hayato,Iwabuchi, Yoshiharu
-
supporting information
p. 5010 - 5013
(2013/01/15)
-
- PHARMACEUTICALLY ACTIVE DISUBSTITUTED TRIAZINE DERIVATIVES
-
The present invention relates to disubstituted triazine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, immunological diseases, autoimmune diseases, cardiovascular diseases, cell proliferative diseases, inflammation, erectile dysfunction and stroke, and pharmaceutical compositions containing at least one of said disubstituted triazine derivatives and/or pharmaceutically acceptable salts thereof. Furthermore, the present invention relates to the use of said disubstituted triazine derivatives as inhibitors for a protein kinase.
- -
-
Page/Page column 52-53
(2012/09/21)
-
- Discovery of 23 Natural Tubulysins from Angiococcus disciformis An d48 and Cystobacter SBCb004
-
The tubulysins are a family of complex peptides with promising cytotoxic activity against multi-drug-resistant tumors. To date, ten tubulysins have been described from the myxobacterial strains Angiococcus disciformis An d48 and Archangium gephyra Ar 315. We report here a third producing strain, Cystobacter sp. SBCb004. Comparison of the tubulysin biosynthetic gene clusters in SBCb004 and An d48 reveals a conserved architecture, allowing the assignment of cluster boundaries. A SBCb004 strain containing a mutant in the putative cyclodeaminase gene tubZ accumulates pretubulysin A, the proposed first enzyme-free intermediate in the pathway, whose structure we confirm by NMR. We further show, using a combination of feeding studies and structure elucidation by NMR and high-resolution tandem mass spectrometry, that SBCb004 and An d48 together biosynthesize 22 additional tubulysin derivatives. These data reveal the inherently diversity-oriented nature of the tubulysin biosynthetic pathway.
- Chai, Yi,Pistorius, Dominik,Ullrich, Angelika,Weissman, Kira J.,Kazmaier, Uli,Mueller, Rolf
-
experimental part
p. 296 - 309
(2010/06/19)
-
- Highly enantioselective catalytic dynamic resolution of N-boc-2-lithiopiperidine: Synthesis of (R)-(+)- N-boc-pipecolic acid, (S)-(-)-coniine, (S)-(+)-pelletierine, (+)-β-conhydrine, and (S)-(-)-ropivacaine and formal synthesis of (-)-lasubine II and (+)-cermizine C
-
The catalytic dynamic resolution (CDR) of rac-2-lithio-N-Boc-piperidine using chiral ligand 8 or its diastereomer 9 in the presence of TMEDA has led to the highly enantioselective syntheses of both enantiomers of 2-substituted piperidines using a wide range of electrophiles. The CDR has been applied to the synthesis of (R)- and (S)-pipecolic acid derivatives, (+)-β-conhydrine, (S)-(+)-pelletierine, and (S)-(-)-ropivacaine and the formal synthesis of ()-lasubine II and (+)-cermizine C.
- Beng, Timothy K.,Gawley, Robert E.
-
supporting information; experimental part
p. 12216 - 12217
(2010/12/25)
-
- Asymmetrie substitutions of 2-lithiated N-boc-piperidine and N-boc-azepine by dynamic resolution
-
Proton abstraction of N-tertbutoxycarbonyl-piperidine (N-Boc-piperidine) with sBuLi and TMEDA provides a racemic organolithium that can be resolved using a chiral ligand. The enantiomeric organolithiums can interconvert so that a dynamic resolution occurs. Two mechanisms for promoting enantioselectivity in the products are possible. Slow addition of an electrophile such as trimethylsilyl chloride allows dynamic resolution under kinetic control (DKR). This process occurs with high enantioselectivity and is successful by catalysis with substoichiometric chiral ligand (catalytic dynamic kinetic resolution). Alternatively, the two enantiomers of this organolithium can be resolved under thermodynamic control with good enantioselectivity (dynamic thermodynamic resolution, DTR). The best ligands found are based on chiral diamino-alkoxides. Using DTR, a variety of electrophiles can be used to provide an asymmetric synthesis of enantiomerically enriched 2-substituted piperidines, including (after Boc deprotection) the alkaloid (+)-ss-conhydrine. The chemistry was extended, albeit with lower yields, to the corresponding 2-substituted sevenmembered azepine ring derivatives.
- Coldham, Iain,Raimbault, Sophie,Whittaker, David T. E.,Chovatia, Praful T.,Leonori, Daniele,Patel, Jignesh J.,Sheikh, Nadeem S.
-
supporting information; experimental part
p. 4082 - 4090
(2010/07/10)
-
- Asymmetric deprotonation of N -boc piperidine: React IR monitoring and mechanistic aspects
-
The high yielding asymmetric deprotonation trapping of N-Boc piperidine is successfully realized using s-BuLi and a (+)-sparteine surrogate. Monitoring of the lithiation by in situ React IR allowed the direct observation of a prelithiation complex.
- Stead, Darren,Carbone, Giorgio,O'Brien, Peter,Campos, Kevin R.,Coldham, Iain,Sanderson, Adam
-
supporting information; experimental part
p. 7260 - 7261
(2010/07/13)
-
- Complementary routes to both enantiomers of pipecolic acid and 4,5-dihydroxypipecolic acid derivatives
-
Complementary new routes to both enantiomers of N-protected pipecolic acid and the corresponding 4,5-dihydroxylated derivatives are developed, which involve stereo-divergent allylation of a chiral N-allylimine and ring-closing metathesis as key steps.
- Chattopadhyay, Shital K.,Biswas, Titas,Biswas, Tanmoy
-
p. 1365 - 1369
(2008/09/18)
-
- EP4 receptor agonist, compositions and methods thereof
-
This invention relates to potent selective agonists of the EP4 subtype of prostaglandin E2 receptors, their use or a formulation thereof in the treatment of glaucoma and other conditions, which are related to elevated intraocular pressure in the eye of a patient. This invention further relates to the use of the compounds of this invention for mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.
- -
-
Page/Page column 10
(2010/02/14)
-
- EP4 receptor agonist, compositions and methods thereof
-
This invention relates to potent selective agonists of the EP4 subtype of prostaglandin E2 receptors, their use or a formulation thereof in the treatment of glaucoma and other conditions, which are related to elevated intraocular pressure in the eye of a patient. This invention further relates to the use of the compounds of this invention for mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.
- -
-
Page/Page column 10
(2010/02/08)
-
- Diastereoselective esterification of (±)-N-trifluoroacetyl pipecolic acid using (S)-α-methyl pantolactone: Synthesis of (S)-N-Boc pipecolic acid and (S)-N-Boc-2-piperidinemethanol
-
Racemic N-trifluoroacetyl pipecolic acid has been converted into (S)-N-Boc-pipecolic acid or (S)-N-Boc-2-piperidinemethanol by DCC/DMAP-induced diastereoselective esterification with (S)-α-methyl pantolactone, followed by a saponification or a reduction reaction and N-Boc protection.
- Calmes, Monique,Escale, Francoise,Rolland, Marc,Martinez, Jean
-
p. 1685 - 1689
(2007/10/03)
-
- Asymmetric synthesis and pharmacology of methylphenidate and its para- substituted derivatives
-
We report the first asymmetric synthesis of the individual enantiomers of methylphenidate (1). From d-pipecolic acid, the (2R,2'R) and (2S,2'R) enantiomers of 1 were obtained in >99% optical purity while the (2S,2'S) and (2R,2'S) enantiomers of 1 were der
- Thai, Dung L.,Sapko, Michael T.,Reiter, Clara T.,Bierer, Donald E.,Perel, James M.
-
p. 591 - 601
(2007/10/03)
-
- Synthesis of 2-piperidinecarboxylic acid derivatives as potential anticonvulsants
-
A variety of 2-piperidinecarboxamides were synthesized and evaluated for anticonvulsant activity using the MES and sc PTZ tests in mice and rats. Neurotoxicity was determined by the rotorod test. Several N-(benzyl)-2- piperidinecarboxamides exhibited potent MES activity in mice [2-CF3 14, ED50 = 29 mg/kg; 3-F 16, ED50 = 31 mg/kg; and 3-CF3 17, ED50 = 24 mg/kg]. The most active compounds in the MES test in mice were the 2,6- dimethylanilides [(R,S)-34, ED50 = 5.8 mg/kg; (R)-35, ED50 = 5.7 mg/kg; and (S)-36, ED50 = 14.8 mg/kg]. The enantiomer (S)-36 was about two-fold less potent in the MES test than (R)-35 and also was less neurotoxic. Acylation of the piperidine ring nitrogen of 12 anal 34 led to a decrease in the MES activity. In the N-(α-methylbenzyl)-2-piperidine-carboxamides, the stereochemistry at either the 2-position of the piperidine ring or at the α- position of the N-(α-methylbenzyl) group does not significantly affect MES activity.
- Ho, Bin,Venkatarangan, Prabha M.,Cruse, Sharon F.,Hinko, Christine N.,Andersen, Peter H.,Crider, Albert M.,Adloo, Ahmad A.,Roane, David S.,Stables, James P.
-
-
- Highly practical methodology for the synthesis of D- and L-α-amino acids, N-protected α-amino acids, and N-methyl-α-amino acids
-
Full details are provided for an exceedingly practical method to synthesize D- and L-α-amino acids, N-protected α-amino acids, and N-methyl-α-amino acids, employing as a key step the asymmetric alkylation of pseudoephedrine glycinamide (1) or pseudoephedrine sarcosinamide (2). Practical procedures for the synthesis of 1 and 2 from pseudoephedrine and glycine methyl ester or sarcosine methyl ester, respectively, are presented. Optimum protocols for the enolization and subsequent alkylation of 1 and 2 are described. Alkylation reactions of 1 and 2 are found to be quite efficient with a wide range of alkyl halide substrates, and the products are formed with high diastereoselectivity. The products of these alkylation reactions are hydrolyzed efficiently and with little to no racemization simply by heating in water or water-dioxane mixtures. This protocol provides an exceedingly practical method for the preparation of salt-free α-amino acids of high enantiomeric purity. Alternatively, the alkylation products may be hydrolyzed in high yield and with little to no racemization by heating with aqueous sodium hydroxide. The alkaline hydrolyzate can then be treated with an acylating reagent to provide directly highly enantiomerically enriched N-protected derivatives such as N-Boc and N-Fmoc. Key features necessary for the successful execution of these experimental procedures are identified.
- Myers, Andrew G.,Gleason, James L.,Yoon, Taeyoung,Kung, Daniel W.
-
p. 656 - 673
(2007/10/03)
-
- A Versatile Method for the Synthesis of (S)- or (R)-Cycloalkylglycines, (S)- or (R)-N-Heterocyclic and α,β-Unsaturated N-Heterocyclic α-Amino Acids
-
Two different types of cyclic α-amino acids, cycloalkylglycines and N-heterocyclic α-amino acids, were prepared in optically pure form from the same chiral synthon 1-(R) (or 1-(S)) simply by altering the quantity or type of base required for anion formation.Elaboration of the heterocyclic intermediate 3 provided α,β-unsaturated N-heterocyclic α-amino acids.
- Pauly, Regine,Sasaki, N. Andre,Potier, Pierre
-
p. 237 - 240
(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)
-
