KR840007568A - Method for preparing substituted dipeptides - Google Patents

Abstract

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Description

Method for preparing substituted dipeptides

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Claims (9)

a) reducing the C = N double bond of the compound of formula (XX) b) condensing a keto acid or ester of formula (II) with a compound of formula (III) in a reactive medium containing a reducing agent, or c) combining the amino acid of the general formula (VIII) with the amino acid of the general formula (V) d) reducing the C = N double bond of the compound of formula (XXi) e) condensing the keto acid or ester of formula (X) with an amino acid of formula (XXIII) in a reactive medium containing a reducing agent, or f) after alkylating a compound of the general formula (III) with a compound of the general formula (XXII), removing the protecting group and, if necessary, the compound formed by the above reaction with another general formula (I) as defined above. A compound of formula (I) or an enantiomer or diastereo isomer containing the same, characterized in that the desired isomer is isolated after conversion to a compound of A process for preparing the mixture and its pharmacologically acceptable salts. Said general formula, R ₁ is C 1 -C 6, alkyl, Ada maentil methyl, cycloalkyl having 4 to 8 carbon atoms or methyl AX _m -C _n H _2n -, and - wherein X is oxygen or sulfur, A is substituted with a group Y Phenyl which may be selected from Y, halogenhydroxy, prefluoromethyl, alkoxy having 1 to 6 carbon atoms, alkyl having 1 to 6 carbon atoms, 2- or 3-furanyl, 2- or 3-thienyl or phenyl Phenyl may be substituted with halogen, hydroxy, trifluoromethyl, alkoxy having 1 to 6 carbon atoms or alkyl having 1 to 6 carbon atoms], benzyl (its phenyl ring may be substituted with group Y as defined above) ), 1- or 2-naphthyl, 2- or 3-furanyl, or 2- or 3-thienyl, m is 0 or 1, n is 1, 2, 3 or 4], and R ₂ And R ₆ may be the same or different from each other and may be selected from the group consisting of hydroxy, alkoxy having 1 to 8 carbon atoms, BX _m -C _n H _2n -O- (where B Phenyl which may be substituted, or 1- or 2-naphthyl, X, m and n are as defined above, provided that m is also 0 when n = 0, -OCH ₂ OCO-alkyl, wherein Alkyl is alkyl having 1 to 6 carbon atoms, -OCH ₂ CO-phenyl, wherein the phenyl ring may be substituted by group Y as defined above, 1-glyceryl, or Wherein R ₇ is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl which may be substituted by group Y as defined above and R ₈ is hydrogen or alkyl of 1 to 6 carbon atoms, R ₂ is also -NR ₆ R ₈ (where R ₇ and R ₈ are as defined above), R ₃ is alkyl having 1 to 6 carbons, cycloalkylmethyl having 4 to 8 carbons, 2- or 3-thienylmethyl, 2- Or 3-furanylmethyl, 1- or 2-naphthylmethyl or benzyl, whose phenyl ring may be substituted by group Y as defined above, where R ₄ is DC _n H _2n -O _m-, where D is Phenyl which may be substituted by hydrogen, alkyl of 1 to 4 carbon atoms or group Z (wherein Z is halogen, hydroxy, trifluoromethyl, alkoxy of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms) and m and n Is as defined above, R ₅ is hydrogen or alkyl of 1 to 6 carbon atoms, p is 0, 1 or 2, X in formula (XXII) is halogen, and the reactive group in the reactant is protected, provided that R ₁ is alkyl of 1 to 6 carbon atoms, cycloalkylmethyl of 4 to 8 carbon atoms or AX _m -C _n H _2n- [Wherein (i) A is a phenyl residue in a phenyl group or a benzyl group is a group Y '(this Y' is halogen, hydroxy, trifluoromethyl, alkoxy having 1 to 6 carbon atoms or alkyl having 1 to 6 carbon atoms) Is as defined above except for phenyl or benzyl, optionally substituted by 1 to 4 and m is 0 or 1 and X is oxygen or (ii) A is phenyl or benzyl optionally substituted by group Y 'as defined above, n is 1 to 4 and m is 1 and X is sulfur ] And R ₃ is alkyl having 1 to 6 carbon atoms, cycloalkylmethyl having 4 to 8 carbon atoms, 2- or 3-thienylmethyl, 2- or 3-furanylmethyl, 1- or 2-naphthylmethyl, or Benzyl (its phenyl ring may be substituted by group Y 'as defined above) and R ₄ is DC _n H _2n -O _m- [wherein (i) D is hydrogen, alkyl of 1 to 4 carbon atoms or Phenyl which may be substituted by defined group Y ', m is 0 and n is 1-4, or (ii) D is hydrogen or phenyl optionally substituted by group Y' and m and n are both 0] , R ₅ and p are the same as defined in the case, at least one of R ₂ and R ₆ are the same as the BX _m -C _n X _2n -O- [wherein (i) B and X as defined above m is 1 and n is 1 to 4, or (ii) B is 1- or 3-furanyl, 2- or 3-thienyl or phenyl (which is halogen, hydroxy, trifluoromethyl, of 1 to 6 carbon atoms) Phenyl substituted with alkoxy or alkyl having 1 to 6 carbon atoms, m is 0 (silver or 1 to 4), pivaloyloxymethyl, (This phenyl group may be substituted by group Y as defined above), 1-glyceryl, And Wherein R ₇ and R ₈ are as defined above, or R ₂ is —NR ₇ R ₈ where R ₇ is phenyl substituted by Y ′ as defined above and R ₈ is As defined), The compound of claim 1, wherein R ₄ is a group DC _n H _2n -O _m -wherein D is hydrogen, alkyl of 1 to 4 carbon atoms or group Z, wherein Z is halogen, hydroxy, trifluoromethyl, 1 to C Alkoxy of 6 or alkyl of 1 to 6 carbon atoms), m is 0 or 1 and n is 0, 1, 2, 3 or 4, provided that n + m ≧ 1) A process characterized by preparing the compound of (I). The compound of claim 1 or 2, wherein any one of R ₂ and R ⁸ is 2-phenoxyethoxy, 1-glyceryl, , Or (2,2-dimenyl-1-oxopropoxy) methoxy, the remainder of which is selected from the group defined in claim 1 or is hydroxy, methoxy, ethoxy or benzyloxy Process for the preparation of a compound. 3. The compound of claim 1, wherein R ₁ is benzyl, 2-phenylethyl or 1- or 2-naphthylmethyl optionally para substituted by chlorine, methoxy, methyl, or phenyl, and R ₂ and R _6. Are the same or different from each other, and are hydroxy, methoxy, ethoxy, benzyloxy, 2-phenyloxyethoxy, 1-glyceryl, , , Or (2-2-dimethyl-1-oxopropoxy) methoxy and R ₃ is benzyl, p-methylbenzyl, p-phenylbenzyl, 1-naphthylmethyl or 3-thienylmethyl Characterized by the above. 5. A process according to claim 4, wherein R ₄ is methyl or benzyl and R ₅ is hydrogen. 4. A process according to claim 3, wherein R ₁ and R ₃ are as defined in claim 4, wherein R ₃ is hydrogen, methyl or benzyl and R ₅ is hydrogen. The method of claim 6, wherein R ₄ is hydrogen. 8. Process according to any one of the preceding claims, characterized in that a compound is prepared wherein p is 1. The method of claim 1, wherein the following compound or pharmacologically acceptable salt is prepared. N- [N- [L-1-[(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine, (2 , 2-dimethyl-1-oxopropoxy) methyl ester, N- [N- [L- [1- [phenylmethoxy] carbonyl] -2-phenylmethyl] -L-phenylalanyl] -β-alanine , (2,2-dimenyl-1-oxopropoxy) methyl ester, N- [N- [L-1-carboxy-2- (4-phenyl) phenylethyl] -L-phenylalanyl] -β- Alanine; N- [N- [L- [1-[(2,2-dimethyl-1oxopropoxy) methoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanyl] -β -Alanine, (2,2-dimethyl-1-oxopropoxy) methyl ester, N- [N- [L-1-carboxy-2-phenylethyl] -L- (4-phenyl) phenylalanyl] -β Alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2- (4-phenyl) phenylethyl] -L- (4-phenyl ) Phenylalanyl-β-alanine, (2,2-dimetal-1-oxopropoxy) methyl ester; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2-phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine, (2,2-dimethyl-1-oxopropoxy) methyl ester; N- [L-1-carboxy-2-phenylethyl] -1-phenylalanyl-β-alanine, 2,2-dimethyl-1,3-dioxolan-4-yl-methyl ester, melting point 153 to 158 ° C ; N- [N- [L- [1- (2,2-dimethyl-1,3-dioxolin-4-yl) methoxy] -carbonyl] -2-phenylethyl] -L-phenylalanyl, Rate salts; N- [N- [L-1-carboxy-2-phenylethyl] -L-phenylalanyl] -L- (α-methyl) -β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2-phenylethyl] -L-phenylalanyl] -L- (α -Methyl) -β alanine, (2,2-dimethyl-1-oxopropoxy) methyl, ester; -N- [N-[(L-1-carboxy-2-phenylethyl)]-L-phenylalanyl] -β-alanine, 2-phenoxyethyl, ester; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine; N- [N- [L- [1-[(2-phenoxy) ethoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl-β-alanine N- [N- [L- [1 -[(1-oxo-3-isobenzofuranyloxy) carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine N- [N- [L- [1-[(2, 3-dihydroxy) -1-propoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine; N- [N- [1-[(2,2-dimethyl-1,3-dioxolin-4-yl) methoxy] -carbonyl] -2-phenylethyl] -L-phenyl alanyl] -β- Alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] 2- (4-phenyl) phenylethyl] -L-phenylalanyl]- β-alanine; N- [N- [L- [1-[(2-phenoxy) ethoxy] carbonyl] -2- (4-phenyl) -phenylethyl] -L-phenylalanyl-β-alanine; N- [N- [L- [1-[(1-oxo-3-isobenzofuranyloxy)] carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanine] -β-alanine; N- [N- [L- [1-[(2,3-dihydroxy) -1-propoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanyl] -β Alanine; N- [N- [L- [1-[(2,2-dimethyl-1,3-dioxolan-4-yl] -2- (4-methoxy] -carbonyl] -2- (4-phenyl ) Phenylethyl] -L-phenylalanyl] -β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2 -Phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine; N- [N- [L- [1-[(2-phenoxy) ethoxy] carbonyl] -2-phenylethyl ] -L- (4-phenyl) phenylalanyl] -β-alanine; N- [N- [L- [1-[(1-oxo-3-isobenzofuranyloxy)] carbonyl] -2- Phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanyl; N- [N- [L- [1-[(2,3-dihydroxy-1 propoxy] carbonyl]- 2-phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine; N- [N- [L- [1-[(2,2-dimethyl) -1,3-dioxolane-4 -Yl) methoxy] -carbonyl] -2-phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine; N- [N- [L- [1-[(2,2- Dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2- (4-phenyl) phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine; N- [N- [L -[1-[(2-phenoxy) ethoxy] carbonyl] -2- (4-phenyl) -phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine; N- [N- [L- [1-[(1-oxo-3-isobenzofuranyloxy)] carbonyl] -2- (4-phenyl) phenylethyl-L- (4-phenyl) phenylalanyl ] -β-alanyl; N- [N- [L- [1-[(2,3-dihydroxy) -1-propoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L -(4-phenyl) phenylalanyl] -β-alanine; N- [N- [L-1 [2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] -carbonyl]- 2- (4-phenyl) phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopro) Foxy) methoxy] -2-carbonyl] -2-phenylethyl] -L-phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[( 2-phenoxy) ethoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[( 1-oxo-3-isobenzofuranyloxy)] carbonyl] -2-phenylethyl] -L-phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2,3-dihydroxy) -1-propoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] -carbonyl] -2-phenylethyl] -L-phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2-phenoxy) ethoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanyl] -E, L-α-methyl -β-alanine; N- [N- [L- [1-[(1-oxo-3-isobenzofuranyloxy)] carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2,3-dihydroxy) -1-propoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanyl] -D , L-α-methyl-β-alanine: N- [N- [L- [1-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] -2- (4- Carbonyl] -2-phenyl) phenylethyl] -L-phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2-phenylethyl] -L- (4-phenyl) phenylalanyl] -D, L-methyl-α-alanine; N- [N- [L- [1- [2-phenoxy) ethoxy] carbonyl] -2-phenylethyl] -L- (4-phenyl) phenylalanyl] -D, L-α-methyl- β-alanine; N- [N- [L- [1-[(1-oxo-3-isobenzofuranyloxy)] carbonyl] -2-phenylethyl] -L- (4-phenyl) phenylalanine] -D, L- α-methyl-β-alanine; N- [N- [L- [1-[(2,3-dihydroxy) -1-propoxy] carbonyl] -2-phenylethyl] -L- (4-phenyl) phenylalanyl] -D , L-α-methyl-β-alanine; N- [N- [L- [1- [(2,2-Dimethyl-1,3-dioxolan-4-yl) methoxy-carbonyl] -2-phenylethyl] -L- (4-phenyl) Phenylalanyl] -D, L-α-phenyl-β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2- (4-phenyl) phenylethyl] -L- (4-phenyl ) Phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2-phenoxy) ethoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L- (4-phenyl) phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-oxo-3-isobenzofuranyloxy)] carbonyl] -2- (4-phenyl) phenylethyl] -L- (4-phenyl) phenylalanyl-D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2,3-dihydroxy) -1-propoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L- (4-phenyl) phenyl Alanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] -carbonyl] -2- (4-phenyl) phenylethyl] -L -(4-phenyl) phenylalanyl] -D, L-α-methyl-β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] -carbonyl] -2-phenylethyl] -2-thienylalanyl] -β-alanine ; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-3-thiethylalanyl] -β- Alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl-L-2-furoalanyl] -β-alanine; N- [N- [L- [1- [1- (2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -α-methyl Alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] α-methylalanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy] methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -L-α-hydrate Roxy-β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -D-α-hydroxy-β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylenyl] -L-phenylalanyl] -L-α-mepoxy-β-alanine; N- [N- [L- [1-[(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] 2-phenylethyl] -L-phenylalanyl] -D-α-methoxy-β-alanine; N- [N- [L- [I-[(2,2-dimethyl-1-oxopropoxy) Methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl-D, L-α-methyl-β-alanine benzyl ester; N- [N- [N- [L- [1- (2, 2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2- (4-methoxy) phenylethyl] -L-phenylalanyl-β-alanine; N-[(L) -1-carboxy- 2-phenylethyl] -L-phenylalanyl-L-phenylalanine N-[(L) -1-carboxy-2-phenylethyl] -L-leusil-L-phenylalanine; ※ Note: The disclosure is based on the initial application.