Methods are provided for manufacturing a cyclic urea adduct of an ethyleneamine compound, the ethyleneamine compound being selected from the group of ethyleneamines and hydroxyethylethyleneamines and comprising at least one —NH—CH2-CH2-NH— moiety and at least two ethylene moieties, wherein the ethyleneamine compound is reacted with CO2 in the presence of an auxiliary compound selected from ethylenediamine (EDA), monoethanolamine (MEA) and mixtures thereof, the molar ratio of auxiliary compound to amine compound being at least 0.02:1. It has been found that the presence of an auxiliary compound selected from ethylenediamine (EDA), monoethanolamine (MEA) and mixtures thereof leads to a substantial increase of the reaction rate as compared to a process wherein the auxiliary compound is not present.

A compound comprises at least one cyclic urea moiety including a head portion and a tail portion connected through an amide moiety or a cyclic amidine moiety, wherein the head portion comprises a polyalkylenepolyamine structure comprising 3 to 10 C2-C4 alkylene moieties present between nitrogen atoms, wherein the alkylene moieties may be the same or different and may be substituted with one or more C1 to C3 alkyl groups, wherein at least one of the alkylene moieties together with its adjoining nitrogen atoms is in the form of a cyclic alkylene urea moiety of the formula

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wherein A is a C2 to C4 alkylene moiety which may be substituted with one or more C1 to C3 alkyl groups and wherein the tail portion includes an alkyl or alkenyl group with 6 to 24 carbon atoms which may be substituted.

The invention provides an N-benzyl-N-arylsulfonamide derivative, which is an N-benzyl-N-arylsulfonamide compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof. The N-benzyl-N-arylsulfonamide derivative is obtained by condensing a substituted nitrobenzene with 5- or 6-membered nitrogen-containing aliphatic heterocycle (the ring B), reducing the nitro group to an amino group, and subjecting the amino group to reductive amination, sulfonamidation; or by subjecting a substituted nitrobenzene to nitro reduction, reductive amination and sulfonamidation, and condensing the resultant intermediate with 5- or 6-membered nitrogen-containing aliphatic heterocycle (the ring B). It has been experimentally demonstrated that the N-benzyl-N-arylsulfonamide derivative of the invention can specifically bind to Kv1.3 potassium channel and inhibit or decrease its activity, and is useful in the treatment of autoimmune diseases caused by abnormal activation of the Kv1.3 potassium channel in human or animals. The invention further provides a medicament or a pharmaceutical composition comprising the N-benzyl-N-arylsulfonamide derivative.

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The invention provides an N-benzyl-N-arylsulfonamide derivative, which is an N-benzyl-N-arylsulfonamide compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof. The N-benzyl-N-arylsulfonamide derivative is obtained by condensing a substituted nitrobenzene with 5- or 6-membered nitrogen-containing aliphatic heterocycle (the ring B), reducing the nitro group to an amino group, and subjecting the amino group to reductive amination, sulfonamidation; or by subjecting a substituted nitrobenzene to nitro reduction, reductive amination and sulfonamidation, and condensing the resultant intermediate with 5- or 6-membered nitrogen-containing aliphatic heterocycle (the ring B). It has been experimentally demonstrated that the N-benzyl-N-arylsulfonamide derivative of the invention can specifically bind to Kv1.3 potassium channel and inhibit or decrease its activity, and is useful in the treatment of autoimmune diseases caused by abnormal activation of the Kv1.3 potassium channel in human or animals. The invention further provides a medicament or a pharmaceutical composition comprising the N-benzyl-N-arylsulfonamide derivative.

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The present invention relates to inhibitors of histone deacetylases, in particular HDAC8, that are useful for the treatment of cancer and other diseases and disorders, as well as the synthesis and applications of said inhibitors.

The present invention relates to inhibitors of histone deacetylases, in particular HDAC8, that are useful for the treatment of cancer and other diseases and disorders, as well as the synthesis and applications of said inhibitors.

A process is provided for preparing ethyleneamines of the formula NH.sub.2—(C.sub.2H.sub.4—NH—).sub.pH wherein p is at least 3, or derivatives thereof wherein one or more units —NH—C.sub.2H.sub.4—NH— may be present as a cyclic ethylene urea unit or piperazine unit or between two units —NH—C.sub.2H.sub.4—NH— a carbonyl moiety is present. The process includes reacting an ethanolamine-functional compound OH—(C.sub.2H.sub.4—NH—).sub.qH wherein q is at least 2, an amine-functional compound NH.sub.2—(C.sub.2H.sub.4—NH—).sub.rH wherein r is at least 1, in the presence of a carbon oxide delivering agent, wherein the molar ratio of ethanolamine-functional compound to amine-functional compound is from about 0.05:1 to about 0.7:1 and the molar ratio of carbon oxide delivering agent to amine-functional compound is higher than the molar ratio of ethanolamine-functional compound to amine-functional compound, provided that the process does not comprise reacting 3 moles of ethylenediamine (EDA) and 1 mole of AEEA (aminoethylethanolamine) in the presence of 1.65 moles of urea at 280 deg C. for 2 hours.

A process is provided for preparing ethyleneamines of the formula NH.sub.2—(C.sub.2H.sub.4—NH—).sub.pH wherein p is at least 3, or derivatives thereof wherein one or more units —NH—C.sub.2H.sub.4—NH— may be present as a cyclic ethylene urea unit or piperazine unit or between two units —NH—C.sub.2H.sub.4—NH— a carbonyl moiety is present. The process includes reacting an ethanolamine-functional compound OH—(C.sub.2H.sub.4—NH—).sub.qH wherein q is at least 2, an amine-functional compound NH.sub.2—(C.sub.2H.sub.4—NH—).sub.rH wherein r is at least 1, in the presence of a carbon oxide delivering agent, wherein the molar ratio of ethanolamine-functional compound to amine-functional compound is from about 0.05:1 to about 0.7:1 and the molar ratio of carbon oxide delivering agent to amine-functional compound is higher than the molar ratio of ethanolamine-functional compound to amine-functional compound, provided that the process does not comprise reacting 3 moles of ethylenediamine (EDA) and 1 mole of AEEA (aminoethylethanolamine) in the presence of 1.65 moles of urea at 280 deg C. for 2 hours.

Methods are provided for manufacturing a cyclic urea adduct of an ethyleneamine compound, the ethyleneamine compound being selected from the group of ethyleneamines and hydroxyethylethyleneamines and comprising at least one —NH—CH2-CH2-NH— moiety and at least two ethylene moieties, wherein the ethyleneamine compound is reacted with CO2 in the presence of an auxiliary compound selected from ethylenediamine (EDA), monoethanolamine (MEA) and mixtures thereof, the molar ratio of auxiliary compound to amine compound being at least 0.02:1. It has been found that the presence of an auxiliary compound selected from ethylenediamine (EDA), monoethanolamine (MEA) and mixtures thereof leads to a substantial increase of the reaction rate as compared to a process wherein the auxiliary compound is not present.

The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and methods of making and using thereof.