KR900014425A - Amino acid derivatives - Google Patents

Abstract

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Description

Amino acid derivatives

Since this is an open matter, no full text was included.

Claims (39)

Compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof. Wherein R ¹ is alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl alkanoyl, 6- (dibenzylcarbamoyl) An acyl group of -4-oxohexanoyl or α-amino acid, wherein the amino group is substituted by alkoxycarbonyl, alkoxycarbonyl, diaralkylchamoyl, diaralkylalkanoyl or aralkanoyl: R ² is alkyl, cycloalkylalkyl or aralkyl; R ³ is hydrogen or alkyl; R ⁴ is alkyl; One of R ⁵ and R ⁶ is hydrogen and the other is hydrogen, alkyl, aryl, aralkyl, 1-alkoxycarbonyl-2phenylethyl, 1-alkoxycarbonyl-2- (imidazol-4-yl) ethyl, 2- (imidazol-1-yl) ethyl, indanyl, heterocyclylalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, aralkoxycarbonylalkyl or general formula -AN (Ra) (Rb) Wherein A is alkylene and Ra and Rb are each alkyl or one methylene group with Ra and Rb together is NH, N-alkyl, N-alkanoyl, N-arkoxycarbonyl, O, S, Is a pentamethylene group which may be substituted with SO or SO ₂ ): R ⁵ and R ⁶ are 1,2,3,4-tetrahydroisoquinoline rings with the nitrogen atom to which they are attached: one of W and X is Hydrogen and the other is hydroxy or amino: W and X together are hydroxyimino: Y is hydrogen: one of W and X is hydrogen and the other When is hydroxy, Y may be hydroxy. The compound of claim 1, wherein R ¹ is alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6- (di Benzylcarmoyl) -4-oxohexanoyl or an acyl group of the natural α-amino acid, wherein the amino group is substituted by aralkoxycarbonyl, diaralkylcarbamoyl, diaralkylalkylnoyl or aralkylnoyl One of R ⁵ and R ⁶ is hydrogen and the other is hydrogen, alkyl, aryl, aralkyl, 1-alkoxycarbonyl-2-phenylethyl, 1-alkoxycarbonyl-2- (imidazol-4-yl) A group of ethyl, 2- (imidazol-1-yl) ethyl, indanyl, heterocyclyl-alkyl or of the formula -AN (Ra) (Rb), where A is alkylene and Ra and Rb are each alkyl or Ra And Rb together is a pentamethylene group in which one methylene group can be substituted with NH, N-alkyl, N-alkanoyl, O, S, SO or SO ₂ ) Or; R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are 1,2,3,4-tetrahydroisoquinoline rings: one of W and X is hydrogen and the other is hydroxy: Y is hydrogen As used herein, alone or in combination, is a phenyl or naphthyl group optionally carrying one or more substituents selected from alkyl, alkoxy and halogen). 3. The acyl group of claim 1, wherein R ¹ is an alkoxycarbonyl, alkoxycarbonyl, alkanoyl or aroyl or an acyl group of an α-amino acid, wherein the amino group is an alkoxycarbonyl, alkoxycarbonyl, di Aralkylchamoyl, diaralkylalkanoyl or aralkyl). 4. A compound according to claim 3, wherein R ¹ is tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, tertiary butyl acetyl, 4-methyl valeryl, P-toluoyl, N-benzyloxycarbonyl asparaginyl or N Benzyloxycarbonyl-β-cyanoalanyl. The compound of any one of claims 1-4, wherein R ² is isobutyl, cyclohexylmethyl or benzyl. The compound of any of claims 1-5, wherein R ³ is alkyl. The compound of claim 6, wherein R ³ is methyl or isopropyl. 8. Compounds according to any one of claims 1 to 7, wherein R ⁴ is isobutyl or secondary butyl. The compound according to any one of claims 1 to 8, wherein one of R ⁵ and R ⁶ is hydrogen and the other is hydrogen, alkyl, aralkyl, 1-alkoxycarbonyl-2-phenylethyl, 1-alkoxycarbonyl- 2- (imidazol-4-yl) ethyl, 2- (imidazol-1-yl) ethyl, indanyl, heterocyclylalkyl or general formula -AN (Ra) (Rb), where A is alkylene Ra and Rb are each alkyl or Ra and Rb together are a group of methylene groups substituted with NH, N-alkyl, N-alkanoyl, N-arkoxycarbonyl, O, S, S, SO or SO ₂ Can be a pentamethylene group); And R ⁵ and R ⁶ together are 1,2,3,4-tetrahydroisoquinoline ring. ^{10. The} compound of claim 9, wherein one of R ⁵ and R ⁶ is hydrogen and the other is hydrogen, isobutyl, benzyl, 2-phenylethyl, 2- (4-hydroxyphenyl) ethyl, 1-methoxycarbonyl-2 -Phenylethyl, 1-methoxycarbonyl-2- (imidazol-4-yl) ethyl, 2- (imidazol-1-yl) ethyl, 2-indanyl, 2- (pyridyl) ethyl, 2- (Dimethylamino) ethyl, 2-morpholinoethyl or 2- [4- (benzyloxycarbonyl) -1-piperazinyl] ethyl or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached 1,2, A compound that is a 3,4-terahydrosoquinoline ring. The compound of claim 1, wherein one of W and X is hydrogen, the other is hydroxy, and Y is hydrogen or hydroxy. The compound of claim ¹ , wherein R ¹ is tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, tertiary butylacetyl, 4-methylvaleryl, P-toluoyl, N-benzyloxy Carbonylasparaginyl or N-benzyloxycarbonyl-β-cyanoalanyl, R ² is isobutyl, cyclohexylmethyl or benzyl, R ³ is methyl or isopropyl, and R ⁴ is isobutyl or 2 Tertiary butyl, one of R ⁵ and R ⁶ is hydrogen and the other is hydrogen, isobutyl, benzyl, 2-phenylethyl, 2- (4-hydroxyphenyl) ethyl, 1-methoxycarbonyl-2-phenylethyl , 1-methoxycarbonyl-2- (imidazol-4-yl) ethyl, 2- (imidazol-1-yl) ethyl, 2-indanyl, 2- (2-pyridyl) ethyl, dimethylethyl 1,2-3,4-, 2-morpholinoethyl or 2- [4- (benzyloxy-carbonyl) -1-piperazinyl] ethyl or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached A tetrahydroisoquinoline ring and one of W and X is hydrogen The other one is hydroxy and Y is hydrogen or do de hydroxy compounds. N ² [5 (S)-(tert-Butoxyformamido) -6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanoyl] N ¹ -phenethyl-N-isoleucine Amido. N- [N- [5 (S)-(tert-Butoxyformamido) -6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanoyl] -L-isoleucine] -L-phenylalanine methyl ester. N ^2- [5 (S)-(tert-butoxyformamido) -6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanoyl] -N ¹ -benzyl-L- Isoleucineamide. N ^2- [5 (S)-(tert-butoxyformamido) -6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanoyl] -N ^1- [2- ( 2-pyridyl) -ethyl] -L-isoleucineamide. N ^2- [5 (S)-(tert-butoxyformamido) -6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanoyl] -N ^1- (2-inda Nil) -L-isoleucineamide. N ^2- [5 (S)-(tert-Butoxyformamido) -6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanoyl] -N ^1- (2-mor Polynoethyl) -L-isoleucineamide. N ₂ --[5 (S)-(tert-butoxyformamido) -4 (S) -hydroxyl-2 (S) -isopropyl-6-phenylhexanoyl] -N ¹ -phenethyl-L -Isoleucine Amido. N ^2- [5 (S) -benzyloxyformamido-6-cyclohexyl-4 (S) -hydroxy-2- (S) -isopropylhexanoyl] -N ¹ -phenethyl-L-isoleucineamide . N ² [5 (S)-[[N- (Benzyloxycarbonyl) -L-asparinyl] -amino-6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanoyl ] -N ¹ -phenethyl-L-isoleucineamide. N ² [5 (S)-(tert butylacetamido) -6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanoyl] -N ¹ -phenethyl-L-isoleucine amides. N ² [5 (S)-[[N- (Benzyloxycarbonyl) -β-cyano-L-alanyl]]-6-cyclohexyl-4 (S) -hydroxy-2 (S) -iso Propyl-hexanoyl] -N ¹ -phenethyl-L-isoleucineamide. N ^1- [2- [4- (benzyloxycarbonyl) -1-pyrerazinyl] -ethyl] -N ^2- [5 (S)-(tert-butoxyformimido) -6-cyclohexyl- 4 (S) -hydroxy-2 (S) -isopropylhexanoyl] -L-isoleucine amido. N ² -5 (S)-(tert-butoxyformimido) -6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanoyl] -N ^1- [2- (4 -Hydroxy-phenyl) ethyl] -L-isoleucine amido. N ^1- [2- (4-benzyloxycarbonyl) -1-piperazinyl] -ethyl] -N ^2- [5 (S)-(tert-butoxyformimido) -6-cyclohexyl-3 (R), 4 (R) -Dihydroxy-2 (R) -isopropylhexanoyl] -L-isoleucineamide. Compounds of the following general formulas (II) to (iii). Wherein R ¹ is alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6- (dibenzylcarbamoyl ) -4-oxohexanoyl or an acyl group of α-amino acid, wherein the amino group is substituted by alkoxycarbonyl, aralkoxycarbonyl, diaralkylcarbamoyl, diaralkylalkanoyl or aralkanoyl R ^1a is alkoxycarbonyl or aralkoxycarbonyl; R ^1b is 3- (aralkoxymethyl) -N- (diaryl-carbamoyl or aralkanoyl) -histidyl: R ² is alkyl, cycloalkylalkyl or aralkyl: R ³ is hydrogen or alkyl: R ⁴ is alkyl: one of R ⁵ and R ⁶ is hydrogen and the other is hydrogen, alkyl, aryl, aralkyl, 1-alkoxy-carbonyl-2-phenylethyl, 1-alkoxycarbonyl-2 (already Dazol-4-yl) ethyl, 2- (imidazol-1-yl) ethyl, indanyl, heterocyclyl-alkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, aralkoxycarbonylalkyl or general A group of the formula -AN (R ^a ) (R ^b ) wherein A is alkylene and R ^a and R ^b are each alkyl or one methylene group together with R ^a and R ^b is NH, N-alkyl , N-alkyl, N-alkanoyl, N-aralkoxycarbonyl, or a pentamethylene group which may be replaced with O, S, SO or SO ₂ ); or R ⁵ and R ⁶ together with the nitrogen atom to which they are requested 1,2,3,4- Trad dihydro isoquinoline ring is: R ⁷ is alkanoyl, and: Y is hydrogen or hydroxy. 27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable acid addition salt thereof, for use as a therapeutically active substance. 27. A compound or pharmaceutically acceptable according to any one of claims 1 to 26 for use as a therapeutically active substance for the treatment or prevention of bacterial infections, in particular retroviral infections and more particularly HIV infection. Its acid addition salts. (a) treating a compound of formula (II) or (III) with an acid so that R ¹ is alkoxycarbonyl or alkoxycarbonyl, one of W and X is hydrogen and the other is hydroxy and Y is hydrogen or Preparing a compound of formula (I) which is oxy or (b) reacting a compound of formula (VI) with an acylating agent which introduces a group R ¹ as defined above, wherein one of W and X is hydrogen and the other Is a hydroxy and Y is hydrogen or hydroxy, or (c) cleaves the trialkylsilyl protecting group from the compound of formula (V) so that one of W and X is hydrogen and the other One is hydroxy and Y is hydrogen to produce a compound of formula (I), or (d) general formula (VI) is treated with a base so that R ¹ is alkanoyl, one of W and X is hydrogen and the other Of formula (I), wherein one is hydroxy and Y is hydrogen Preparing a compound, or (e) reacting a compound of formula (VII) with hydroxylamine to prepare a compound of formula (I) wherein W and X together are hydroxyamino and Y is hydrogen, or (f) W And reducing the compound of formula (I) wherein X is hydroxyimino and Y is hydrogen to prepare a compound of formula (I) wherein one of W and X is hydrogen, the other is amino and Y is hydrogen; (g) Hydrogen decomposing the compound of formula (i), wherein R ¹ is N- (dialkylcapmoyl or aralkanoyl) -histidyl, one of R ⁵ and R ⁶ is hydrogen and the other is hydrogen , Alkyl, aryl, aralkyl, 1-alkoxycarbonyl-2-phenylethyl, 1-alkoxycarbonyl-2- (imidazol-4-yl) ethyl, 2- (imidazol-1-yl) ethyl, Nyl, heterocyclyl-alkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonyl alkyl or a group of the formula -AN (R ^a ) (R ^b ) wherein A is alkylene, R ^a and R ^b are each alkyl or pentamethylene groups, where R ^a and R ^b together may be substituted with one methylene group NH, N-alkyl, N-alkanoyl, O, S, SO or SO ₂ Or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are 1,2,3,4-tetrahydroisoquinoline rings, one of W and X is hydrogen and the other is hydroxy and Y is hydrogen or hydroxy Or (h) a group of formula -AN (R ^a ) (R ^b ) wherein one of R ⁵ and R ⁶ is hydrogen and the other is aralkoxycarbonyl alkyl Wherein R ^a and R ^b together represent a pentamethylene group in which one methylene group is substituted with N-aralkoxycarbonyl) and hydrogenated to decompose the compound of general formula (I) so that R ¹ is alkoxycarbonyl, alka Noyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6- ( Dibenzylcarbamoyl) -4-oxohexanoyl or an acyl group of α-amino acid, wherein the amino group is substituted by alkoxycarbonyl, diaralkylcarboyl, diaralkylalkanoyl or aralkanoyl, One of R ⁵ and R ⁶ is hydrogen and the other is carboxyalkyl or a group of the formula —AN (R ^a ) (R ^b ), where R ^a and R ^b together penta where one methylene group is substituted with NH Methylene group), and (I) optionally converting the obtained compound of general formula (I) into a pharmaceutically acceptable acid addition salt. A method for preparing a compound according to any one of claims 1 to 26. Wherein R ^1a is alkoxycarbonyl or aralkoxycarbonyl, R ² , R ³ , R | ⁴ , R ⁵ , R ⁶ and Y are as defined in claim 1, R ⁷ is alkanoyl, R ^1b is 3- (arkoxymatic) -N- (dialkylcarbomoyl or aralkanoyl ) -Histidyl. 31. The compound of claim 30, wherein R ¹ is alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkyl-carbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6- ( Dibenzylcarbamoyl) -4-oxohexanoyl or a group of natural α-amino acids, wherein the amino acids are substituted by aralkoxycarbonyl, diaralkylcarbamoyl, diaralkylalkanoyl or aralkanoyl; One of R ⁵ and R ⁶ is hydrogen and the other is hydrogen, alkyl, aryl, aralkyl 1-alkoxycarbonyl-2-phenylethyl, 1-alkoxycarbonyl-2- (imidazol-4-yl) ethyl, A group of 2- (imidazol-1-yl) ethyl, indanyl, heterocyclyl-alkyl or a general formula-AN (R ^a ) (R ^b ) wherein A is R ^a and R ^b are each alkyl, or R ^a and R ^b together are a pentamethylene group in which one methylene group may be substituted with NH, N-alkyl N-alkanoyl, O, S, SO or SO ₂ ) or R ^a and R ^b and R ⁶ are A 1,2,3,4-tetrahydroisoquinoline ring to which they are attached: one of W and X is hydrogen, the other is hydroxy and Y is hydrogen: "aryl" used alone or in combination The term is a compound of formula (I) wherein the at least one selected from alkyl, alkoxy and halogen is a phenyl or naphthyl group optionally carrying substituents and pharmaceuticals thereof Method for manufacturing according to the acceptable acid addition salts in a method aspect (a), (b), (c), (d), (g) and / or (i). 27. A drug containing a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inactive excipient. 27. A drug containing a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable acid addition salt and therapeutically inactive excipient for the treatment or prevention of bacterial infections, in particular HIV infection. Use of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable acid addition salt thereof in the inhibition or prevention of a disease. Use of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable acid addition salt thereof for the treatment or prevention of bacterial infections, in particular HIV infection. Use of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment or prevention of bacterial infections, in particular HIV infection. A compound of formula (I) and a pharmaceutically acceptable acid addition salt thereof, prepared by the method as claimed in claim 30 or 31 or by a chemically clearly equivalent method thereof. Wherein R ¹ is alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6- (dibenzylcarbamoyl ) -4-oxohexanoyl or an acyl group of α-amino acid, wherein the amino group is substituted by alkoxycarbonyl, aralkoxycarbonyl, diaralkylcarbamoyl, diaralkylalkanoyl or aralkanoyl R ² is alkyl, cycloalkylalkyl or aralkyl, R ³ is hydrogen or alkyl, R ⁴ is alkyl, one of R ⁵ and R ⁶ is hydrogen and the other is hydrogen, alkyl, aryl, aralkyl, 1-alkoxycarbonyl-2-phenylethyl, 1-alkoxycarbonyl-2- (imidazol-4-yl) ethyl, 2- (imidazol-1-yl) ethyl, indanyl, heterocyclyl-alkyl, Carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, aralkoxycarbonylalkyl or general formula-AN (R ^a ) a group of (R ^b ) wherein A is alkylene and R ^a and R ^b are each alkyl or R ^a and R ^b together represent one methylene group is NH, N-alkyl N-alkanoyl, N Is an alkoxycarbonyl, pentamethylene group which may be replaced with O, S, SO or SO ₂ ) or R ⁵ and R ⁶ are 1,2,3,4-tetrahydroisoquinoline together with the nitrogen atom to which they are attached When one of W and X is hydrogen and the other is hydroxy or amino or W and X together are hydroxyimiso and Y is hydrogen; and when one of W and X is hydrogen and the other is hydroxy, May be hydroxy. The present invention as described above. A method of treating or preventing a bacterial infection, in particular an HIV infection, characterized by administering to a patient in need thereof a compound according to any one of claims 1 to 26 or an effective amount of a pharmaceutically acceptable acid addition salt thereof. . ※ Note: The disclosure is based on the initial application.