NATIONAL UNIVERSITY CORPORATION TOKAI NATIONAL HIGHER EDUCATION AND RESEARCH SYSTEM (Japon)
YAMASA CORPORATION (Japon)
Inventeur(s)
Ueno, Yoshihito
Abrégé
Provided is a nucleoside derivative represented by the following formula (1): (IMAGE HERE) , or a salt thereof, wherein R1 represents an alkoxy group, a hydrogen atom or a halogen atom; R2 and R4, which may be the same as or different from each other, each represents a hydrogen atom, a protective group for a hydroxyl group, a phosphate group, a protected phosphate group, or -P(=O)nR5R6 in which n represents 0 or 1, R5 and R6, which may be the same as or different from each other, each represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a mercapto group, a protected mercapto group, an alkoxy group, a cyanoalkoxy group, an amino group, or a substituted amino group, provided that when n is 1, both R5 and R6 cannot be the hydrogen atom at the same time; R3 represents ?(CH2)mNHR7 in which m represents an integer of 1 to 6, R7 represents a hydrogen atom, an alkyl group, an alkenyl group or a protective group for an amino group; and B represents a purin-9-yl group, a 2-oxo-pyrimidin-1-yl group, a substituted purin-9-yl group, or a substituted 2-oxo-pyrimidin-1-yl group.
A61K 48/00 - Préparations médicinales contenant du matériel génétique qui est introduit dans des cellules du corps vivant pour traiter des maladies génétiques; Thérapie génique
C07H 19/10 - Radicaux pyrimidine avec le radical saccharide estérifié par des acides phosphoriques ou polyphosphoriques
2.
CROSSLINKED NUCLEOSIDE INTERMEDIATE CRYSTAL AND METHOD FOR PRODUCING SAME, AND METHOD FOR PRODUCING CROSSLINKED NUCLEOSIDE AMIDITE
A lyophilized product of cyclic-di-AMP requires special production equipment and is thus not suitable for large-scale production. Crystals of cyclic-di-AMP free acid are unstable under severe conditions at 105°C. Then, the present invention addresses the problem of providing a cyclic-di-AMP (Formula I) crystal that can be easily acquired in a large amount and is very stable under the severe conditions at 105°C. Crystals of c-di-AMP sodium salt according to the present invention are extremely stable even under the severe conditions at 105°C. Further, the crystals of c-di-AMP sodium salt according to the present invention can be prepared in a large amount by a simple process including adjusting a c -di-AMP aqueous solution at pH 5.2-12.0 and then adding an organic solvent thereto. (see formula I)
C07H 21/02 - Composés contenant au moins deux unités mononucléotide comportant chacune des groupes phosphate ou polyphosphate distincts liés aux radicaux saccharide des groupes nucléoside, p.ex. acides nucléiques avec le ribosyle comme radical saccharide
Although freeze-dried products of 3',3'-cGAMP are generally known, the freeze-dried products require a freeze dryer in a production process thereof, and naturally, there is a limitation to scaling-up for mass production. Thus, there has been a demand for development of crystals that can be obtained in a large amount in a simple manner without using a special device, such as a freeze dryer. In addition, because conventionally known freeze-dried products or ethanol precipitates exhibit high hygroscopicity, the present invention addresses the problem of providing crystals having excellent handleability and preservability. Hydrate crystals of 3',3'-cGAMP according to the present invention exhibit lower hygroscopicity than existing powders, either in the form of alkali metal salt crystals or free acid crystals, and thus are easy to handle in various uses and are useful as a pharmaceutical raw material or the like.
C07H 21/02 - Composés contenant au moins deux unités mononucléotide comportant chacune des groupes phosphate ou polyphosphate distincts liés aux radicaux saccharide des groupes nucléoside, p.ex. acides nucléiques avec le ribosyle comme radical saccharide
A61K 31/7084 - Composés ayant deux nucléosides ou nucléotides, p.ex. dinucléotide de la nicotinamide-adénine, dinucléotide de la flavine-adénine
A61K 39/39 - Préparations médicinales contenant des antigènes ou des anticorps caractérisées par les additifs immunostimulants, p.ex. par les adjuvants chimiques
NATIONAL UNIVERSITY CORPORATION TOKAI NATIONAL HIGHER EDUCATION AND RESEARCH SYSTEM (Japon)
Inventeur(s)
Ueno, Yoshihito
Maeda, Yusuke
Kajino, Ryohei
Abrégé
Provided are: a nucleoside that is more suitable for practical use such as an RNA medicine or the like; and the use of the nucleoside. For this purpose, provided is a nucleoside derivative represented by formula (1) or (2) or a salt thereof. [Chem. 16] (In formula (1), R1 represents a hydrogen atom, a hydroxy group, a hydroxy group in which a hydrogen atom is substituted with an alkyl group or an alkenyl group, or a protected group, and in formula (2), X represents a halogen atom. In formula (1) and formula (2), R2 and R3 may be the same or different and each represent a hydrogen atom, a protecting group for a hydroxy group, a phosphate group, a protected phosphate group, or -P(=O)nR5R6 (n represents 0 or 1, R5 and R6 may be the same or different and each represent a hydrogen atom, a hydroxy group, a protected hydroxy group, a mercapto group, a protected mercapto group, a lower alkoxy group, a cyano lower alkoxy group, an amino group, or a substituted amino group. Note that when n is 1, R5 and R6 would not simultaneously be a hydrogen atom.), each R4 represents NHR7 having a linking group (R7 represents a hydrogen atom, an alkyl group, an alkenyl group, or a protecting group for amino group), an azide group, an amidino group, or a guanidino group, and B represents one of a purin-9-yl group, a 2-oxo-pyrimidin-1-yl group, a substituted purin-9-yl group, or a substituted 2-oxo-pyrimidin-1-yl group.)
C12N 15/113 - Acides nucléiques non codants modulant l'expression des gènes, p.ex. oligonucléotides anti-sens
A61K 31/708 - Composés ayant des radicaux saccharide et des hétérocycles ayant l'azote comme hétéro-atome d'un cycle, p.ex. nucléosides, nucléotides contenant des cycles à six chaînons avec l'azote comme hétéro-atome d'un cycle contenant des pyrimidines condensées ou non-condensées contenant des purines, p.ex. adénosine, acide adénylique ayant des groupes oxo liés directement au système cyclique purine, p.ex. guanosine, acide guanylique
C07H 19/10 - Radicaux pyrimidine avec le radical saccharide estérifié par des acides phosphoriques ou polyphosphoriques
C07H 19/20 - Radicaux purine avec le radical saccharide estérifié par des acides phosphoriques ou polyphosphoriques
C07H 21/00 - Composés contenant au moins deux unités mononucléotide comportant chacune des groupes phosphate ou polyphosphate distincts liés aux radicaux saccharide des groupes nucléoside, p.ex. acides nucléiques
C07H 21/02 - Composés contenant au moins deux unités mononucléotide comportant chacune des groupes phosphate ou polyphosphate distincts liés aux radicaux saccharide des groupes nucléoside, p.ex. acides nucléiques avec le ribosyle comme radical saccharide
C12N 15/10 - Procédés pour l'isolement, la préparation ou la purification d'ADN ou d'ARN
C12N 15/87 - Introduction de matériel génétique étranger utilisant des procédés non prévus ailleurs, p.ex. co-transformation
NATIONAL UNIVERSITY CORPORATION TOKAI NATIONAL HIGHER EDUCATION AND RESEARCH SYSTEM (Japon)
Inventeur(s)
Ueno, Yoshihito
Abrégé
[Problem] To provide a nucleoside that is more practical for RNA pharmaceuticals and other applications and a use therefor. [Solution] A nucleoside derivative indicated by formula (1) or (2) or a salt thereof. (In formula (1), R1 indicates a hydrogen atom, a hydroxyl group, a hydroxyl group having a hydrogen atom substituted by an alkyl group or an alkenyl group, or a protected group. In formula (2), X indicates a halogen atom. In formulas (1) and (2), R2 and R4 can be the same or different and indicate a hydrogen atom, a protecting group for a hydroxyl group, a phosphate group, a protected phosphate group, or P(=0)nR5R6 (n indicates 0 or 1 and R5 and R6 can be the same or different and indicate either a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, a lower alkoxy group, a cyano lower alkoxy group, an amino group, or a substituted amino group. When n is 1, however, R5 and R6 are never both hydrogen atoms.) R3 indicates NHR7 having a linking group for each (R7 indicating a hydrogen atom, an alkyl group, an alkenyl group, or a protecting group for an amino group), an azide group, an amidino group, or a guanidino group. B indicates a purine-9-yl group, a 2-oxo-pyrimidin-1-yl group, a substituted purine-9-il group, or a substituted 2-oxo-pyrimidin-1-yl group.)
A61K 47/26 - Hydrates de carbone, p.ex. polyols ou sucres alcoolisés, sucres aminés, acides nucléiques, mono-, di- ou oligosaccharides; Leurs dérivés, p.ex. polysorbates, esters d’acide gras de sorbitan ou glycyrrhizine
C07H 19/067 - Radicaux pyrimidine avec un ribosyle comme radical saccharide
C07H 21/02 - Composés contenant au moins deux unités mononucléotide comportant chacune des groupes phosphate ou polyphosphate distincts liés aux radicaux saccharide des groupes nucléoside, p.ex. acides nucléiques avec le ribosyle comme radical saccharide
C07H 21/04 - Composés contenant au moins deux unités mononucléotide comportant chacune des groupes phosphate ou polyphosphate distincts liés aux radicaux saccharide des groupes nucléoside, p.ex. acides nucléiques avec le désoxyribosyle comme radical saccharide
Provided is a simple and practical method for removing iron ions, as a method for purifying P1,P4-di(uridine 5'-)tetraphosphate from a solution that contains iron ions. This method for purifying P1,P4-di(uridine 5'-)tetraphosphate by removing iron ions from an aqueous solution or hydrophilic solvent solution containing P1,P4-di(uridine 5'-)tetraphosphate and iron ions includes: (1) a column purification step that uses a chelate resin, and (2) a step for adjusting the pH of the solution to 5.5 or less following the chelate resin column purification, and then crystallizing P1,P4-di(uridine 5'-)tetraphosphate; or a step for treating the solution with zinc chloride-activated activated carbon following the chelate resin column purification.
C07H 19/10 - Radicaux pyrimidine avec le radical saccharide estérifié par des acides phosphoriques ou polyphosphoriques
A61K 31/7105 - Acides ribonucléiques naturels, c. à d. contenant uniquement des riboses liés à l'adénine, la guanine, la cytosine ou l'uracile et ayant des liaisons 3'-5' phosphodiester
Heretofore, 3',5'-cyclicdiadenylic acid has been provided only in a lyophilized form. The present invention provides a solid form, other than a lyophilized form, of 3',5'-cyclicdiadenylic acid and a method for producing the solid form. An inclusion compound of 3',5'-cyclicdiadenylic acid can be produced by a step of adding an acid to an aqueous 3',5'-cyclicdiadenylic acid solution to decrease the pH value of the solution to 1 to 3. The production method is quite easy to carry out and does not require the use of a special machine or the like.
C07H 21/02 - Composés contenant au moins deux unités mononucléotide comportant chacune des groupes phosphate ou polyphosphate distincts liés aux radicaux saccharide des groupes nucléoside, p.ex. acides nucléiques avec le ribosyle comme radical saccharide
C07H 1/00 - Procédés de préparation des dérivés du sucre
A crystal of free acid of 3',5'-cyclic diguanylic acid containing no metal salt with cobalt, magnesium or the like is provided. A method is sought for obtaining said crystal in a large amount and with ease. By a manufacturing method comprising a step of adding acid to an aqueous solution of 3',5'-cyclic diguanylic acid so as to lower pH to 1 to 3, crystals of 3',5'-cyclic diguanylic acid can be obtained in a large amount with ease. Said crystals are free acid crystals which do not contain a metal salt with cobalt, magnesium or the like.
A method for producing P1,P4-di(uridine 5'-)tetraphosphate (UP4U) is developed, which does not require the use of free UTP and does not undergo the decrease in synthesis efficiency. A method for producing UP4U, characterized by reacting a phosphoric-acid-activating compound represented by formula [II] or [III] with a phosphoric acid compound selected from the group consisting of UMP, UDP, UTP and pyrophosphoric acid or a salt thereof (excluding free UTP) in water or a hydrophilic organic solvent in the presence of a metal ion selected from the group consisting of an iron (II) ion, an iron (III) ion, a trivalent aluminum ion, a trivalent lanthanum ion and a trivalent cerium ion. (Each of R1, X and n in formula [II] and X in formula [III] is as defined in claim 1.)
C07H 19/10 - Radicaux pyrimidine avec le radical saccharide estérifié par des acides phosphoriques ou polyphosphoriques
A61K 31/7072 - Composés ayant des radicaux saccharide et des hétérocycles ayant l'azote comme hétéro-atome d'un cycle, p.ex. nucléosides, nucléotides contenant des cycles à six chaînons avec l'azote comme hétéro-atome d'un cycle contenant des pyrimidines condensées ou non-condensées ayant des groupes oxo liés directement au cycle pyrimidine, p.ex. cytidine, acide cytidylique ayant deux groupes oxo liés directement au cycle pyrimidine, p.ex. uridine, acide uridylique, thymidine, zidovudine
A61K 31/7105 - Acides ribonucléiques naturels, c. à d. contenant uniquement des riboses liés à l'adénine, la guanine, la cytosine ou l'uracile et ayant des liaisons 3'-5' phosphodiester
A61P 11/00 - Médicaments pour le traitement des troubles du système respiratoire
A signal processing device is composed of a signal acquisition unit and a signal processing unit. The signal acquisition unit acquires a signal corresponding to a vibration propagated from a string attached to a stringed instrument from a pickup element that picks up the signal corresponding to the vibration. The signal processing unit includes a filter that performs convolution operation using a filter coefficient set in the filter, the signal processing unit applying the convolution operation to the acquired signal through the filter and outputting a processed signal. The filter is set with the filter coefficient corresponding to a transfer function which has a frequency response developing a plurality of peak waveforms corresponding to resonance of a body of another stringed instrument different from the stringed instrument within a specific frequency range and which allows components of the peak waveforms to decay more rapidly than a component of a fundamental sound in the vibration of the string in the processed signal.
G10H 3/12 - Instruments dans lesquels les sons sont produits par des moyens électromécaniques utilisant des générateurs résonnants mécaniques, p.ex. des cordes ou des instruments à percussion, dont les sons sont captés par des transducteurs électromécaniques, les signaux électriques étant alors traités ou amplifiés puis convertis en ondes son
G10L 19/02 - Techniques d'analyse ou de synthèse de la parole ou des signaux audio pour la réduction de la redondance, p.ex. dans les vocodeurs; Codage ou décodage de la parole ou des signaux audio utilisant les modèles source-filtre ou l’analyse psychoacoustique utilisant l'analyse spectrale, p.ex. vocodeurs à transformée ou vocodeurs à sous-bandes
A signal processing device is composed of an acquiring unit, a filter unit and a changing unit. The acquiring unit acquires a signal indicating vibration of a string. The filter unit performs convolution operation on the signal acquired by the acquiring unit according to a filter coefficient and outputs a resulting signal. The filter coefficient is set such that the resulting signal has a frequency response containing a plurality of peak waveforms associated with resonance of a body of a stringed instrument within a specific frequency range. The changing unit changes the filter coefficient so as to change a peak value of each of the peak waveforms while maintaining a width of each of the peak waveforms in the frequency response.
G10H 3/12 - Instruments dans lesquels les sons sont produits par des moyens électromécaniques utilisant des générateurs résonnants mécaniques, p.ex. des cordes ou des instruments à percussion, dont les sons sont captés par des transducteurs électromécaniques, les signaux électriques étant alors traités ou amplifiés puis convertis en ondes son
G10L 19/02 - Techniques d'analyse ou de synthèse de la parole ou des signaux audio pour la réduction de la redondance, p.ex. dans les vocodeurs; Codage ou décodage de la parole ou des signaux audio utilisant les modèles source-filtre ou l’analyse psychoacoustique utilisant l'analyse spectrale, p.ex. vocodeurs à transformée ou vocodeurs à sous-bandes
13.
PROCESS FOR PRODUCING DI(PYRIMIDINE NUCLEOSIDE 5'-)POLYPHOSPHATE
A di (pyrimidine nucleoside 5'-)polyphosphate of Formula I (see formula I) is synthesized by converting a pyrimidine nucleoside 5'-triphosphate into a pyrimidine nucleoside 5'-cyclic triphosphate by use of a condensing agent, and subsequently reacting the pyrimidine nucleoside 5'-cyclic triphosphate with a pyrimidine nucleotide in the presence of a salt of a metal selected from among magnesium, manganese, and iron. Through the method of the invention, a di(pyrimidine nucleoside 5'-)polyphosphate can be synthesized from an unprotected pyrimidine nucleoside 5'-phosphate serving as a starting material at a synthesis yield of 50% or higher. Therefore, the method of the invention is suitable for large-scale synthesis of a di(pyrimidine nucleoside 5')polyphosphate.
The present invention relates to a method for long-term stabilizing a pulmonary surfactant protein, to a stabilized aqueous solution containing a pulmonary surfactant protein, and to a kit for assaying a pulmonary surfactant protein which kit contains, as a component reagent, a stabilized aqueous solution containing a pulmonary surfactant protein. The invention provides a method for stabilizing a pulmonary surfactant protein, the method including causing the pulmonary surfactant protein to be present with a calcium ion and an oxidizing/reducing substance. The invention also provides an aqueous solution containing a pulmonary surfactant protein which has been stabilized by use of a calcium ion and an oxidizing/reducing substance in combination. The invention also provides a kit for assaying a pulmonary surfactant protein present in a sample through an immunological technique employing antigen-antibody reaction, the kit containing, as a standard solution of pulmonary surfactant protein, an aqueous solution containing a pulmonary surfactant protein which has been stabilized by use of a calcium ion and an oxidizing/reducing substance in combination.
The invention provides a method for producing 3'- phosphoadenosine 5'-phosphosulfate (PAPS), the method including subjecting ATP to sulfation and phosphorylation by use of adenosine 5'-triphosphate sulfurylase (ATPS) and adenosine 5'-phosphosulfate kinase (APSK), wherein an adenosine 5'-triphosphate (ATP) supply/regeneration system including adenosine 5'-monophosphate (AMP), polyphosphate, polyphosphate-driven nucleoside 5'-diphosphate kinase (PNDK), and polyphosphate:AMP phosphotransferase (PAP), or an adenosine 5'-triphosphate (ATP) supply/regeneration system including adenosine 5'-monophosphate (AMP), polyphosphate, polyphosphate-driven nucleoside 5'-diphosphate kinase (PNDK), and adenylate kinase (ADK) is employed instead of ATP.
C12P 19/32 - Nucléotides avec un système cyclique condensé, contenant un cycle à six chaînons, comportant deux atomes d'azote dans le même cycle, p.ex. nucléotides puriques, dinucléotide de la nicotinamide-adénine
16.
METHOD OF PRODUCING URIDINE 5'-DIPHOSPHO-N-ACETYLGALACTOSAMINE
The present invention provides a method for enzymatically producing uridine 5'-diphospho-N-acetylgalactosamine (UDP-GalNAc) (which is an important substrate for oligosaccharide synthesis) from uridine 5'-triphosphate (UTP) and N-acetylgalactosamine 1-phosphate (GalNAc 1-P), the method including using, as an enzyme, uridine 5'-diphospho-N-acetylglucosamine pyrophosphorylase (UDP-GlcNAc pyrophosphorylase) derived from a microorganism (exclusive of a pathogenic microorganism). The GalNAc 1-P employed can be prepared from N-acetylgalactosamine and a phosphate donor in a reaction system by use of N-acetylgalactosamine kinase. According to the present invention, uridine 5'-diphospho-N-acetylgalactosamine can be efficiently produced by use of a relatively inexpensive substrate.
The present invention provides a 4'-C-substituted-2--haloadenosine derivative represented by the following formula [I], [II], or [III]: (see formula I)(see formula II)(see formula III) (wherein X represents a halogen atom, R1 represents an ethynyl group or a cyano group, and R2 represents hydrogen, a phosphate residue, or a phosphate derivative residue). The present invention also provides a pharmaceutical composition containing the derivative and a pharmaceutically acceptable carrier therefor.
C07H 19/167 - Radicaux purine avec un ribosyle comme radical saccharide
A61K 31/7076 - Composés ayant des radicaux saccharide et des hétérocycles ayant l'azote comme hétéro-atome d'un cycle, p.ex. nucléosides, nucléotides contenant des cycles à six chaînons avec l'azote comme hétéro-atome d'un cycle contenant des pyrimidines condensées ou non-condensées contenant des purines, p.ex. adénosine, acide adénylique
brevets
