KR830000223A - Method for producing N²-arylsulfonyl-L-arginineamides and salts thereof - Google Patents

Abstract

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Method for producing N2-arylsulfonyl-L-arginineamides and salts thereof

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Claims (4)

Removing a substituent and hydrolysis of the resulting product as needed-substituted -N ² _- - arylsulfonyl -L- N ^G by acid decomposition or hydrogenolysis from arginine amides represented by the following general formula (II) represented by N ^G A method for producing N ² -arylsulfonyl-L-arginineamide or a salt thereof represented by the following general formula (I) characterized by: In the above formula, R is, (Wherein, R ₁ is a C ₂ to C ₁₀ alkyl group, a C ₃ to C ₁₀ alkenyl group, a C ₃ to C ₁₀ alkynyl group, a C ₂ to C ₁₀ alkoxyalkyl group, a C ₂ to C ₁₀ alkylthioalkyl group , C ₂ to C ₁₀ alkylsulfinylalkyl group, C ₁ to C ₁₀ hydroxyalkyl group, C ₃ to C ₁₀ alkoxycarbonylalkyl group, C ₃ to C ₁₀ alkylcarbonyl alkyl group, C ₁ to C ₁₀ Haloalkyl group, C ₇ to C ₁₅ aralkyl group, C ₈ to C ₁₅ α-carboxyaralkyl group, C ₃ to C ₁₀ cycloalkyl group, C ₄ to C ₁₀ cycloalkylalkyl group, furfuryl group, at least one A tetrahydrofurfuryl group, 3-furylmethyl group, at least one C ₁ to C ₅ alkyl group and/or C ₁ which may be substituted with a C ₁ to C ₅ alkyl group and/or a C ₁ to C ₅ alkoxy group To a tetrahydro-3-furylmethyl group which may be substituted with a C ₅ alkoxy group, at least one C ₁ to C alkyl group and/or a C ₁ to C ₅ alkoxy group which may be substituted with tetrahydro-2 (3 or 4)-pyranylmethyl group, 1,4-dioxy-2-cyclohexylmethyl group, 2-tenyl group which may be substituted with at least one C ₁ to C ₅ alkyl group and/or C ₁ to C ₅ alkoxy group , A 3-tenyl group, a tetrahydro-2-tenyl group or a tetrahydro-3-tenyl group which may be substituted with at least one C ₁ to C ₅ alkyl group and/or a C ₁ to C ₅ alkoxy group (hereinafter, These substituents are collectively referred to as a substituent group A), R ₂ represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a C ₆ to C ₁₀ aryl group, or a C ₇ to C ₁₂ aralkyl group, n represents an integer of 1,2 or 3), (In the formula, R₃Represents one substituent selected from the group consisting of a hydrogen atom, a methyl group and a substituent group A, and R₄Is C_OneTo C₁₀Alkyl group, at least one C_OneTo C₅Alkyl group and/or C_OneTo C₅Phenyl group which may be substituted with an alkoxy group of C₇To C₁₂Aralkyl group or ring of C_OneTo C₂Alkyl group or C_One To C₅Represents a benzyl number substituted with an alkoxy group of, R₅Is a hydrogen atom, C_OneTo C₁₀Alkyl group, C₆To C₁₀Aryl group of, or C₇To C₁₂Represents an aralkyl group of, m represents an integer of 0, 1 or 2), (Wherein, R ₆ represents -COOR ₈ (R ₈ represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a C ₆ to C ₁₀ aryl group or a C ₇ to C ₁₂ aralkyl group), and R ₇ is It may be the same or different, and each independently represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a phenyl group, a C ₁ to C ₅ alkoxy group, a C ₂ to C ₆ alkoxy carbonyl group or a carboxyl group, and p is 1,2, Represents an integer of 3 or 4, the substitution position of R ₆ is 2- or 3-position, and the substitution position of R ₆ may be any of the 2-, 3-, 4-, 5-, or 6-position). (Wherein, R ₉ represents a hydrogen atom C ₁ to C ₁₀ alkyl group, C ₆ to C ₁₀ aryl group, or C ₇ to C ₁₂ aralkyl group, and r represents an integer of 1, 2, 3 or 4 In addition, the alkyleneiminyl group may be substituted with at least one C ₁ to C ₅ alkyl group and/or a C ₁ to C ₅ alkyl group and/or a C ₁ to C ₅ alkoxy group). (Wherein, R ₁₀ represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a C ₆ to C ₁₀ aryl group or a C ₇ to C ₁₂ aralkyl group, and Z represents an oxy group, a thio group or a sulfinyl group, q represents an integer of 0 or 1), or (Wherein, R ₁₁ represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a C ₆ to C ₁₀ aryl group or a C ₇ to C ₁₂ aralkyl group, and i represents an integer of 0, 1 or 2. Provided that , i+j is an integer of 1 or 2), Ar is (a) a sulfoamino group, a carboamino group, a C ₃ to C ₁₀ N,N-dialkylcarbamoyl group, a C ₂ to C ₅ N-alkylcarbamoyl group, an amino group, a C ₁ to C ₁₀ alkylamino group, Mercapto group, C ₁ to C ₁₀ alkylthio group, C ₇ to C ₁₂ aralkyl group, carboxyl group, C ₂ to C ₁₀ alkoxycarbonyl group, C ₂ to C ₁₀ carboxyalkyl group, C ₁ to C ₁₀ hydrogen A group consisting of a hydroxyalkyl group, a C ₁ to C ₁₀ haloalkyl group, a C ₁ to C ₁₀ hydroxy alkoxy group, and at least one hydroxyl group and/or a phenyl group which may be substituted with a C ₁ to C ₅ alkoxy group ( A phenyl or naphthyl group substituted with at least one substituent selected from hereinafter this group is abbreviated as substituent group B); (b) at least one substituent and substituent group selected from halo group, nitro group, cyano group, hydroxy group, C ₁ to C ₁₀ alkyl group, C ₁ to C ₁₀ alkoxy group and C ₂ to C ₂₀ dialkylamino group A phenyl or naphthyl group substituted with at least one substituent selected from B; (c) an oxantrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of a halo group, a nitro group, a cyano group, a hydroxy group, a C ₂ to C ₂₀ dialkylamino group and a substituent group B; (d) C ₁ to C _10, at least one substituent selected from alkyl groups and C ₁ to an alkoxy group of C ₁₀ of the haloalkoxy group, a nitro group, a cyano group, a hydroxy group, C ₂ to a dialkylamino group, and the substituent groups of C ₂₀ An oxantrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of B; (e) tetrahydro naphthyl substituted with at least one substituent selected from the group consisting of halo group, nitro group, cyano group, hydroxy group, C ₂ to C ₂₀ dialkylamino group, oxo group and substituent group B, 1 ,2-ethylene dioxyphenyl, clomanyl 2,3-ethylenedioxynaphthyl or xanthenyl group; (g) C ₁ at least one of substituents to select from an alkoxy group of C ₁₀ alkyl group and C ₁ to C ₁₀ of the haloalkoxy group, a nitro group, a cyano group, a hydroxy group, C ₂ to a C ₂₀ dialkylamino group, an oxo group And a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, clomanyl, 2,3-ethylenedioxynaphthyl, or xanthenyl group substituted with at least one substituent selected from the group consisting of substituent group B; (g) Selected from the group consisting of halo group, nitro group, cyano group, hydroxy, C ₁ to C ₁₀ alkyl group, C ₁ to C ₁₀ alkoxy group, C ₂ to C ₂₀ dialkylamino group and substituent group B Naphthoquinolyl, anthoryl, phenanthoryl, pentarenyl, heptarenyl, azrenyl, biperenyl, as-indacenyl, s-indacenyl, acenaphthyrenyl, phenylcar, which may be substituted with one or more substituents Tonyl phenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, isobenzo thienyl, thianthorenyl, dibenzo thienyl, phenoxycynyl, indoryl, 1H-indazoryl, qui Noryl, inoquinonyl, phthaladinil, 1,8-naphthridinyl, quinoxarinyl, quinazolinyl, cinnolinyl, carbazoryl, acridinyl, phenadinyl, phenothiadinyl, phenoxadinil or Benzimidazoril; (h) a halo group, a nitro group, a cyano group, a hydroxy group, a C ₁ to C ₁₀ alkyl group, a C ₁ to C ₁₀ alkoxy group, a C ₂ to C ₂₀ dialkylamino group, an oxo group and a substituent) Group B a C ₇ to C ₁₂ which may be optionally substituted with one or more substituents selected from the group aralkyl, C ₉ to C ₁₆ cycloalkyl phenyl, C ₁₀ to C ₁₈ cycloalkyl, phenyl, C ₉ to C ₁₆ cycloalkyloxy Phenyl, C ₉ to C ₁₆ cycloalkylthiophenyl, 9,10-dihydroanthonyl, 5,6,7,8-tetrahydroanthoryl, 9,10-dihydrophenanthoryl, 1,2,3, 4,5,6,7,8-octahydrophenanthoryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isoclomanyl, 2,3-dihydrobenzofuranyl, 1, 3-dihydroisobenzoranyl, thioxanthenyl, 2H-clomenyl, 3,4-dihydro-1-isoclomanyl, 4H-clomenyl, indolinyl, isoindolinyl, 1,2,3, 4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group; or (i) C ₃ to C ₇ alkyl group, C ₃ to C ₇ alkoxy group, C ₃ to C ₇ haloalkoxy group, C ₃ to C ₇ alkoxyalkyl group, C ₃ to C ₇ alkoxyalkoxy group, C ₃ to C ₇ alkoxycarbonyl group and a C ₃ to C ₇ alkoxy-carbonyl is substituted with at least one substituent selected from the group consisting of ahrok time, and further a methyl group, an ethyl group, a methoxy group, an ethoxy group, a hydroxy group and a halogen A phenyl group which may be substituted with at least one substituent selected from an atom is represented, and R'and R" represent a hydrogen atom or a protecting group of a guanidino group, provided that at least one of R'and R" is a guanidino group It is a protector of. In the manufacturing method described in claim 1, the acid decomposition is carried out by contacting N ^G -substituted-N ² -arylsulfonyl-L-arginineamide with an excess acid at -10°C to 100°C. Manufacturing method characterized by. In the production method according to claim 5, the hydrocracking is carried out in a hydrogen atmosphere in the presence of a hydrogen activating catalyst in a solvent inert to the reaction at a temperature ranging from 0°C to the boiling point of the solvent. The following general formula (Wherein, Ar is as defined in claim 1, and X represents a halogen atom) N ² -arylsulfonyl-L-arginyl halide represented by is reacted with an amino acid derivative represented by the general formula RH (R is as defined in claim 1), and the resulting product is hydrolyzed as necessary. A method for preparing N ² -arylsulfonyl-L-arginineamide or a pharmaceutically acceptable salt thereof represented by the following general formula (I), characterized in that it decomposes. (Wherein, R and Ar are as described above). ※ Note: It is disclosed according to the contents of the initial application.