cas 89531-58-8, MORPHOLIN-4-YL-ACETIC ACID

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MODIFIED DRUGS FOR USE IN LIPOSOMAL NANOPARTICLES
Drag derivatives are provided herein which are suitable for loading into liposomal nanoparticle carriers. In some preferred aspects, the derivatives comprise a poorly water-soluble drag derivatized with a weak-base moiety that facilitates active loading of the drag through a LN transmembrane pH or ion gradient into the aqueous interior of the LN. The weak-base moiety can optionally comprise a lipophilic domain that facilitates active loading of the drag to the inner monolayer of the liposomal membrane. Advantageously, LN formulations of the drag derivatives exhibit improved solubility, reduced toxicity, enhanced efficacy, and/or other benefits relative to the corresponding free drags.
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Paragraph 0270; 0301-0303; 0310-0311

(2018/08/25)

FUSED IMIDAZO-PIPERIDINE JAK INHIBITOR COMPOUND
The invention provides a compound of formula 1 or a pharmaceutically-acceptable salt thereof, that is useful as a JAK inhibitor. The invention also provides crystalline forms of the compound, pharmaceutical compositions comprising the compound, methods of using the compound to treat diseases amenable to a JAK inhibitor, and processes and intermediates useful for preparing the compound.
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Paragraph 0224

(2018/11/21)

Tandem Palladium and Isothiourea Relay Catalysis: Enantioselective Synthesis of α-Amino Acid Derivatives via Allylic Amination and [2,3]-Sigmatropic Rearrangement
A tandem relay catalytic protocol using both Pd and isothiourea catalysis has been developed for the enantioselective synthesis of α-amino acid derivatives containing two stereogenic centers from readily accessible N,N-disubstituted glycine aryl esters and allylic phosphates. The optimized process uses a bench-stable succinimide-based Pd precatalyst (FurCat) to promote Pd-catalyzed allylic ammonium salt generation from the allylic phosphate and the glycine aryl ester. Subsequent in situ enantioselective [2,3]-sigmatropic rearrangement catalyzed by the isothiourea benzotetramisole forms syn-α-amino acid derivatives with high diastereo- and enantioselectivity. This methodology is most effective using 4-nitrophenylglycine esters and tolerates a variety of substituted cinnamic and styrenyl allylic ethyl phosphates. The use of challenging unsymmetrical N-allyl-N-methylglycine esters is also tolerated under the catalytic relay conditions without compromising stereoselectivity.
Spoehrle, Stéphanie S. M.,West, Thomas H.,Taylor, James E.,Slawin, Alexandra M. Z.,Smith, Andrew D.
supporting information
p. 11895 - 11902
(2017/09/07)

Fluorinated epoxyketone-based compounds and uses thereof as proteasome inhibitors
The present application relates to novel fluorinated epoxyketone-based compounds, compositions comprising these compounds and their use, in particular for the treatment of diseases, disorders or conditions mediated by proteasome inhibition, in particular, the present application includes compounds of Formula I, and compositions and uses thereof.
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(2016/09/28)

Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect
The chemotherapeutic gemcitabine was actively and stably loaded into lipid nanoparticles through the formation of a prodrug. Gemcitabine was chemically modified to increase the lipophilicity and introduce a weak base moiety for remote loading. Several derivatives were synthesized and screened for their potential to be good liposomal drug candidates for remote loading by studying their solubility, stability, cytotoxicity, and loading efficiency. Two morpholino derivatives of GEM (22 and 23) were chosen as the preferred prodrugs for this purpose as they possessed the best loading efficiencies (100% for drug-to-lipid ratio of 0.36 w/w). This is a considerable improvement over a passive loading strategy where typical loading efficiencies are on the order of ～10-20% for a drug-to-lipid ratio of ～0.01. Liposomes loaded with these two prodrugs were studied in an s.c. tumor model in vivo and showed improved therapeutic effect over free GEM (～2-fold) and saline control (8- to 10-fold). This work demonstrates how chemical modification of a known hydrophilic drug can lead to improved loading, stability, and drug delivery in vivo.
May, Jonathan P.,Undzys, Elijus,Roy, Aniruddha,Li, Shyh-Dar
p. 226 - 237
(2016/02/05)

FLUORINATED EPOXYKETONE-BASED TETRAPEPTIDE COMPOUNDS AND USES THEREOF AS PROTEASOME INHIBITORS
The present application relates to novel fluorinated epoxyketone-based tetrapeptide compounds, compositions comprising these compounds and their use, in particular for the treatment of diseases, disorders or conditions mediated by proteasome inhibition. In particular, the present application includes compounds of Formula I, and compositions and uses thereof:
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(2015/09/22)

Optimization of plasmepsin inhibitor by focusing on similar structural feature with chloroquine to avoid drug-resistant mechanism of Plasmodium falciparum
The plasmepsins are specific aspartic proteases of the malaria parasite and a potential target for developing new antimalarial agents. Our previously reported peptidomimetic plasmepsin inhibitor with modified 2-aminoethylamino substituent, KNI-10740, was tested against chloroquine sensitive Plasmodium falciparum, D6, to be highly potent, however, the inhibitor exhibited about 5 times less activity against multi-drug resistant parasite (TM91C235). We hypothesized the potency reduction resulted from structural similarity between 2-aminoethylamino substituent of KNI-10740 and chloroquine. Then, we modified the moiety and finally identified compound 15d (KNI-10823), that could avoid drug-resistant mechanism of TM91C235 strain.
Miura, Takuya,Hidaka, Koushi,Azai, Yukiko,Kashimoto, Keisuke,Kawasaki, Yuko,Chen, Shen-En,De Freitas, Renato Ferreira,Freire, Ernesto,Kiso, Yoshiaki
p. 1698 - 1701
(2014/04/17)

4-AMINO-2,6-DIMETHYLPHENOL COMPOUND, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
A 4-amino-2,6-dimethylphenol compound having the formula given in the description, acid-addition salts thereof, a process for preparing them, pharmaceutical composition comprising them and its use as anti-pyretic and anti-nociceptive agents.
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(2009/06/27)

4-AMINO-2,6-DIMETHYLPHENOL COMPOUND, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
A 4-amino-2, 6-dimethylphenol compound having the formula given in the description, acid-addition salts thereof, a process for preparing them, pharmaceutical composition comprising them and its use as anti-pyretic and anti-nociceptive agents.
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(2008/06/13)

Pyrimidine derivatives and processes for the preparation thereof
The present invention relates to novel pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts thereof which possess an excellent anti-secretory activity, pharmaceutical compositions containing the same as an active ingredient, their novel intermediates, and processes for the preparation thereof wherein: when A is piperidin-1-yl or —NH—B, wherein B is C3-C4alkyl, C3-C4alkenyl, C3-C7cycloalkyl, C1-C3alkoxyethyl, phenylethl which may be substituted or unsubstituted, 3-trifluoromethylphenylmethyl, 1-naphthylmethyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl, R1is hydrogen or methyl; and R2, R3, R4and R5are hydrogen; or when A is a group of formula (II); when R1is hydroxymethyl or C1-C3alkoxymethyl, R2, R3, R4, R5and R6are hydrogen; and R7is hydrogen or halogen; or when R1is hydrogen or methyl, R7is hydrogen or halogen; and one or two of R2, R3, R4, R5and R6is hydroxy, methoxy, or a group of formula (III) wherein Z is C1-C4alkyl, substituted or unsubstituted C1-C4alkenyl, cyloalkyl, benzyloxyalkyl, alkoxycarbonylalkyl, morpholinomethyl, piperidinomethyl, 4-substituted-piperazinomethyl, substituted or unsubstituted phenyl, naphthyl, substituted or unsubstituted benzyl, thiophen-2-yl-methyl, 1-substituted-pyrrolidin-2-yl or —CHR8NHR9, wherein R8is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl, methylthioethyl, benzyloxycarbonylmethyl, carbamolymethyl, carbamoylethyl, or 1-benzylimidazol-4-ylmethyl and R9is hydrogen or t-butoxycarbonyl; and the others are hydrogen or methyl.
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Page column 13

(2008/06/13)

13C CP MAS NMR, FTIR, X-ray diffraction and PM3 studies of some N-(ω-carboxyalkyl)morpholine hydrohalides
N-(ω-carboxyalkyl)morpholine hydrochlorides, OC4H8N(CH2)nCOOH·HCI, n = 1-5, were obtained and analyzed by 13C cross polarization (CP) magic angle spinning (MAS) NMR, FTIR and PM3 calculations. The structure of N-(3-carboxy-propyl)morpholine hydrochloride (n = 3) has been solved by X-ray diffraction method at 100 K and refined to the R = 0.031. The crystals are monoclinic, space group P21/c, a = 14.307(3), b = 9.879(2), c = 7.166(1) A?, β = 93.20(3)°, V = 1011.3(3) A?3, Z = 4. In this compound the nitrogen atom is protonated and two molecules form a centrosymmetric dimer, connected by two N+-H···Cl- (3.095(1) A?) and two O-H···Cl- (3.003(1) A?) hydrogen bonds. 13C CP MAS NMR spectra, contrary to the solution, showed non-equivalence of the ring carbon atoms. The PM3 calculations predict a molecular dimer without proton transfer for an HCl complex, while for an HBr complex an ion pairs with proton transfer, and reproduces correctly the conformation of both dimers but overestimates H-bond distances. Shielding constants calculated from the PM3 geometry of ion pairs gave a linear correlation with the 13C chemical shifts in solids.
Dega-Szafran,Ga?szczyk,Maciejewska,Szafran,Tykarska,Wawer
p. 261 - 273
(2007/10/03)