NZ235427A

NZ235427A - Phosphonate-substituted-2-aminoalk-3-enoic acid derivatives and pharmaceutical compositions

Info

Publication number: NZ235427A
Application number: NZ235427A
Authority: NZ
Inventors: Christof Angst; Hans Allgeier; Roland Heckendorn; Daniel Wallach
Original assignee: Ciba Geigy Ag
Priority date: 1989-09-26
Filing date: 1990-09-24
Publication date: 1992-10-28
Also published as: HU906210D0; DK0420806T3; ATE124700T1; IL95729A; NO179450C; FI97231C; DD298105A5; HUT56110A; JPH03130296A; EP0420806A1; EP0420806B1; NO179450B; NO904169D0; AU638057B2; KR910006312A; IL95729A0; IE67873B1; DE59009368D1; ES2074153T3; PT95401B

Abstract

Substituted 2-aminoalk-3-enoic acid derivatives of the formula I <IMAGE> process for the preparation of unsaturated amino carboxylic acid derivatives of the formula I <IMAGE> in which R1 is an aliphatic or via a C atom bonded oxacycloaliphatic or optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical which is substituted by optionally acylated or aliphatically or araliphatically etherified hydroxyl, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxacycloaliphatic radical, and R2 is free or esterified carboxyl, and their salts have a pronounced and selective antagonistic action on N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory amino-acid receptors. They are prepared, for example, by, in a compound of the formula II <IMAGE> in which Z1, Z2 are optionally protected hydroxyl, Z3 is an aliphatic or via a C atom bonded oxacycloaliphatic or optionally protected or aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical which is substituted by optionally protected or acylated or aliphatically or araliphatically etherified hydroxyl, by halogen, by optionally protected or acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxacycloaliphatic radical, and Z4 is protected amino, converting protected amino Z4 and, where present, as component of Z3 into amino and, where present, protected hydroxyl Z1, Z2 and/or as component of Z3 into hydroxyl, and, where present, liberating a protected azacycloaliphatic hydrocarbon radical Z3 and, if required, converting a resulting compound into another compound of the formula I, fractionating a mixture of isomers obtainable according to the process into the components, and separating off the isomer which is preferred in each case, and/or converting a free compound obtainable according to the process into a salt or a salt obtainable according to the process into the corresponding free compound.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £35427 235427 ■ - - ^-.aso C.*~: flbtl^U\^klO~ P.O. Jo»« 2.8.0CI.M. f® H W?^?nS 'f is t. ■*- f Patents Form No. 5 NEW ZEALAND - •£ £.' PATENTS ACT 1953 .. "<" ' COMPLETE SPECIFICATION 4-SUBSTITUTED 2-AMINOALK-3-ENOIC ACIDS WE, CIBA-GEIGY AG, a Swiss corporation of Klybeckstrasse 141, 4002 Basle, SWITZERLAND hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) 4-17759/+ New Zealand 4-Substituted 2-aminoalk-3-enoic acids The invention relates to a process for the manufacture of substituted 2-aminoalk-3-enoic acid derivatives of formula I wherein R4 is hydroxy-Ci-Cyalkyl, dihydroxy-C2-C7alkyl, C2-C7alkanoyloxy-Ci-C7-alkyl, benzoyloxy-Ci-Cyalkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, Ci-C4alkoxy-Ci-C7alkyl, a phenyl-C][-C4alkoxy-Ci-C7alkyl group that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, halo-Ci-C7alkyl, in which halogen is chlorine or fluorine, amino-Ci-Cyalkyl, Ci-C4alkylamino-Ci-C7alkyl, C2-C7alkanoyl-amino-Ci-C7alkyl, N-C2-C7alkanoyl-N-Ci-C4alkylamino-Ci-C7-alkyl, di-Ci-C7alkyl-amino-Ci-C7alkyl, azacycloalk-l-yl-Ci-Cyalkyl, azacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, l-C2-C7alkanoylazacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, N-Ci-C4aikylazacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, N-Ci-C4benzoylaza-cycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, diazacycloalk-l-yl-Ci-C7alkyl, N' -C1 -C4alkyldiazacycloalk-1 -yl-C 1 -C7alkyl, N' -C2-C7alkanoylazacycloalk-l-yl-Ci-Cyalkyl, azoxacycloalk-l-yl-Ci-Cyalkyl, 5- to 7-membered oxacyclo-alk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, 5- to 7-membered azacycloalk-3-yl or -4-yl or l-C2-C7alkanoylazacycloalk-3-yl or -4-yl, N-Ci-C4alkylazacycloalk-3-yl or -4-yl, or N-benzoylazacycloalk-3-yl or -4-yl that is unsubstituted or substituted in the phenyl O [2 (I), (followed by page 2) moiety, or 5- to 7-membered oxacycloalk-3-yl or -4-yl, and R2 is carboxy, C1-C4-alkoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, orphenyl-Ci-C4alkoxycarbonyl that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, and to their salt, to processes for the preparation of the compounds according to the invention anf to pharmaceutical preparations containing them. In the groups mentioned above, phenyl radicals may be unsubstituted or mono-, di- or tri-substituted, especially mono- or di-substituted. Hereinbefore and hereinafter, "lower" radicals and compounds shall be understood as being, for example, radicals and compounds containing up to and including 7, preferably up to and including 4, carbon atoms (C atoms). Ci-CyAlkyl is, for example, Ci-C4alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, sec.-butyl, tert.-butyl or a pentyl, hexyl or heptyl group. Hydroxy-Ci-Cyalkyl is, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl. Dihydroxy-C2-C7alkyl is, for example, dihydroxy-C2-C7alkyl in which the hydroxy groups are bonded to different carbon atoms, such as 1,2-dihydroxyethyl or, especially, 1,3-dihydroxyprop-2-yl. C2-C7Alkanoyl is, for example, C2-C4alkanoyl, such as acetyl, propionyl or butyryl, but may also be a C5-C6alkanoyl group, such as pivaloyl. Accordingly, C2-C7-alkanoyloxy-Ci-C7alkylis especially acetoxymethyl, propionyloxymethyl, butyryl-oxymethyl, 2-acetoxyethyl, 3-acetoxypropyl, 4-acetoxybutyl, 5-acetoxypentyl or 6-acetoxyhexyl. By analogy, benzoyloxy-Ci^alkyl shall be understood as being, unsubstituted or substituted in the phenyl moiety, such as benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, 5-benzoyloxypentyl or 6-benzoyloxyhexyl. Ci-C7Alkoxy is, for example, Ci-C4alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butoxy, but may also be isobutoxy, sec.-butoxy, tert.-butoxy or a pentyloxy, hexyloxy or heptyloxy group. Accordingly, Ci-C4alkoxy-Ci-C7alkyl is, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl or 6-methoxyhexyl. Phenyl-Ci-C4alkoxy is, for example, phenyl-Ci-C4alkoxy that is unsubstituted or substituted as indicated, such as benzyloxy, 2-phenylethoxy or 3-phenylpropoxy. Accordingly, phenyl-Ci-C4alkoxy-Ci-C7alkyl is, for example, a phenyl-Ci-C4-alkoxy-Ci-Cyalkyl radical that is unsubstituted or substituted as indicated, such as a benzyloxymethyl, 2-phenylethoxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl, 4-benzyloxybutyl, 5-benzyloxypentyl or 6-benzyloxyhexyl radical. Halo-Ci-C7alkyl is, for example, halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, in which halogen is chlorine or, especially, fluorine. Amino-Ci-C7alkyl is, for example, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-aminohexyl. Ci-C7Alkylamino is, for example, Ci-C4alkylamino, such as methylamino, ethylamino, propylamino or butylamino, but may also be a C5-Cgalkylamino group, such as a pentylamino or hexylamino group. Accordingly, Ci-C4alkylamino-C][-C7alkyl is especially methylaminomethyl, ethylaminomethyl, propylaminomethyl, butyl-aminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl. C2*C7Alkanoylamino is, for example,, C2-C4alkanoylamino, such as acetylamino, propionylamino or butyTylamino, but may also be C5-C6alkanoylamino, such as pivaloylamino. Accordingly, C2-C7alkanoylamino-Ci-C7alkyl is especially acetylamino-methyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl. By analogy, benzoylamino-Ci-Cyalkyl shall be understood as being benzoylamino-Ci-C7alkyl that is unsubstituted or substituted in the phenyl moiety, such as benzoylaminomethyl, 2-benzoylaminoethyI, 3-benzoylaminopropyl, 4-benzoylaminobutyl, 5-benzoylaminopentyl or 6-benzoylaminohexyl. Di-Ci-C7alkylamino is, for example, di-Ci-C4alkylamino, such as dimethylamino, diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, dipropylamino or dibutylamino. Accordingly, di-Ci-C4alkylamino-Ci-C7alkyl, is especially dimethyl-aminomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N- propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or 6-dimethyl-aminohexyl. N-C2-C7Alkanoyl-N-Ci-C4alkylamino-Ci-C7alkyl is, for example, N-acetyl-N-methylaminomethyl, N-acetyl-N-ethylaminomethyl, N-propionyl-N-methyl-aminomethyl, N-butyryl-N-methylaminomethyl, 2-(N-acetyl-N-methylamino)ethyl, 2-(N-propionyl-N-methylamino)ethyl, 2-(N-acetyl-N-ethylamino)ethyl, 3-(N-acetyl-N-methylamino)propyl, 4-(N-acetyl-N-methylamino)butyl, 5-(N-acetyl-N-methylamino)-pentyl or 6-(N-acetyl-N-methylamino)hexyl. 4- to 7-Membered azacycloalkyI-Ci-C7alkyl is either azacycIoalk-l-yl-Ci-Cyalkyl, for example pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 3-pyrrolidinopropyl, 3-piperidinopropyl, 4-pyrrolidinobutyl, 4-piperidinobutyl, 5-pyrrolidinopentyl, 5-piperidinopentyl, 6-pyrrolidinohexyl or 6-piperi-dinohexyl, or azacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, for example piperidin- 4-ylmethyl, 2-(piperidin-4-yl)ethyI, 3-(piperidin-4-yI)propyl or 4-(piperidin-4-yl)butyI. 5- to 7-Membered N-C2-C7alkanoylazacycloalkyl-Ci-C7alkyl bonded via a carbon atom is preferably l-C2-C7alkanoylazacycloalk-3-yl-Ci-C7alkyl or-4-yl-Ci-C7alkyl, for example l-acetylpiperidin-4-ylmethyl, 2-(l-acetylpiperidin-4-yl)ethyl, 3-(l-acetylpiperidin-4-yl)propyl or 4-(l-acetylpiperidin-4-yl)butyI. N-Ci-C4Alkylazacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl is, for example, l-methylpiperidin-4-ylmethyl, l-ethylpiperidin-4-ylmethyl, 2-(l-methyl-piperidin-4-yl)ethyl, 2-(l-ethylpiperidin-4-yl)ethyl, 3-(l-methylpiperidin-4-yl)propyl, 3-(l-ethylpiperidin-4-yl)propyl, 4-(l-methylpiperidin-4-yl)butyl or 4-(l-ethylpiperidin- 4-yl)butyl. N-Ci-C4Benzoylazacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-Cyalkyl is, for example, l-benzoylpiperidin-4-ylmethyl, 2-(l-benzoylpiperidin-4-yl)ethyl, 3-(l-benzoylpiperidin- 4-yl)propyl or 4-(l-benzoylpiperidin-4-yl)butyl. 5- to 7-Membered diazacycloalk-l-yl-Ci-C7alkyl is, for example, diazacycloalk-l-yI-Ci-C7alkyl, N'-Ci-C4aIkyldiazacycIoalk-l-yl-Ci-C7alkyl or N'-C2-C7alkanoyl-azacycloalk-l-yl-Ci-C7alkyl, for example piperazino- or N'-methyl- or N'-acetyl- piperazino-methyl, 2-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-ethyl, 3-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-propyl or 4-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-butyl. 5- to 7-Membered azoxacycloalk-l-yl-Ci-Cyalkyl, is, for example, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 4-morpholinobutyl. 5- to 7-Membered oxacycloalkyl-Ci-Cyalkyl bonded via a carbon atom is especially 5- to 7-membered oxacycloalk-3-yl-Ci-C7alkyl or oxacycloalk-4-yl-Ci-C7alkyl, such as tetra-hydropyran-4-ylmethyl, 2-(tetrahydropyran-4-yl)ethyl, 3-(tetrahydropyran-4-yl)propyl or 4-(tetrahydropyran-4-yl)butyl. 5- to 7-Membered oxacycloalkyl bonded via a carbon atom is especially corresponding oxacycloalk-3-yl or -4-yl, for example tetrahydropyran-4-yl. 5- to 7-Membered azacycloalkyl, N-C}-C4alkylazacycloalkyl or N-C2-C7-alkanoylazacycloalkyl bonded via a carbon atom is preferably azacycloalk-3-yl or -4-yl or l-C2-C7alkanoylazacycloalk-3-yl or-4-yl, for example piperidin-4-yl or 1-acetyl-piperidin-4-yl, and also N-Ci-C4alkylazacycloalk-3-yl or -4-yl or N-benzoylazacycloalk-3-yl or -4-yl that is unsubstituted or substituted in the phenyl moiety, for example l-methylpiperidin-4-yl or l-benzoylpiperidin-4-yl. Ci-C7Alkoxycarbonyl is, for example, Ci-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl, but may also be a C5-C7alkoxycarbonyl group, such as a pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl group. Phenyl-Ci-C4alkoxycarbonyl is, for example, benzyloxycarbonyl, 2-phenylethoxycarbo-nyl, 3-phenylpropoxycarbonyl or 4-phenylbutoxycarbonyl. On account of their amphoteric nature, the compounds of formula I are in the form of internal salts and can form both acid addition salts and salts with bases. Acid addition salts of compounds of formula I are, for example, pharmaceutical^ acceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-sub-stituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexyl sulfamates (cyclamates). Salts of compounds of formula I with bases are, for example, salts thereof with pharmaceutically acceptable bases, such as non-toxic metal salts derived from groups la, lb, 13a and lib, for example alkali metal salts, especially sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, and also ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as unsubstituted or C-hydroxylated aliphatic amines, especially mono-, di- or tri-lower alkylamines, for example methyl-, ethyl- or diethyl-amine, mono-, di- or tri-(hydroxy-lower alkyl)amines, such as ethanol-, diethanol- or triethanol-amine, tris-(hydroxymethyl)methylamine or 2-hydroxy-tert.-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower alkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines, such as 2-(dimethylamino)ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, for example tetrabutylammonium hydroxide. For isolation or purification purposes it is also possible to use pharmaceutically unsuitable salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeutically, and these salts are therefore preferred. The invention relates especially to compounds of formula I wherein is hydroxy-Ci-Cyalkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl, benzoyloxy-Ci-Cyalkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, such as methyl, Ci-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by tri-fluoromethyl, such as 2-benzoyloxyethyl, Ci-C4alkoxy-Ci-C7alkyl, such as ethoxymethyl or 2-methoxyethyl, phenyl-Ci-C4alkoxy-Ci-C7alkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, such as methyl, Cj-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as benzyloxymethyl or 2-benzyloxyethyl, halo-C}-C7alkyl, such as halomethyl or 2-haloethyl, in which halogen is chlorine or, especially, fluorine, amino-C4-C7alkyl, such as 4-aminobutyl or 6-aminohexyl, N-C2-C7alkanoyl-N-Ci-C4alkylamino-Ci-C7alkyl, such as N-acetyl-N-methylaminomethyl, 5- to 7-membered azacycloalk-3-yl or -4-yl or I-C2-C7-alkanoylazacycloalk-3-yl or -4-yl, for example piperidin-4-yl or l-acetylpiperidin-4-yl, and R2 is carboxy, Ci-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or phenyl-Ci-C4alkoxycarbonyl that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, such as methyl, Ci-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoro-methyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts. The invention relates especially to compounds of formula I wherein Ri is amino-Ci-Cyalkyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl or 7-aminoheptyl, Ci-C4alkylamino-Ci-C7alkyl, such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl, C2-C7alkanoylamino-Ci-C7alkyl, such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, di-Ci-C4alkyl-amino-Ci-C7alkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutyl-aminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or 6-dimethylaminohexyl, 5- to 7-membered N,N-(aza- or oxa-alkylene)amino-Ci-C7alkyl, such as pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, piperazino- or N'-methyl- or N'-acetyl-piperazino-methyl, pyrrolidinoethyl, piperidinoethyl, morpholinoethyl, pyrrolidinopropyl, piperidinopropyl, morpholinopropyl, pyrrolidinobutyl, piperidinobutyl, pyrrolidinopentyl, piperidinopentyl or piperidinohexyl, and R2 is carboxy, Q^alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or phenyl-Ci-C4alkoxycarbonyl that is unsubstituted or mono-or di-substituted by Ci-C4alkyl, such as methyl, Ci-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts. The invention relates more especially to compounds of formula I wherein R^ is hydroxy-Ci-C7alkyl, such as hydroxymethyl, Ci-C4alkoxy-Ci-C7alkyl, such as methoxymethyl, ethoxymethyl or 2-methoxyethyl, benzoyloxy-C]_-C4alkyl, such as 2-benzoyloxyethyl, phenyl-Ci-C4alkoxy-Ci-C7alkyl, such as benzyloxymethyl or 2-benzyloxyethyl, amino-C4-C7alkyl, such as 4-aminobutyl or 6-aminohexyl, N-C2-C7- aIkanoyl-N-Ci-C4alkylamino-C2-C7alkyl, such as 2-(N-acetyl-N-methylamino)ethyl, 5-to 7-membered azacycloalk-3-yl or -4-yl or l-C2-C7alkanoylazacycloalk-3-yl or -4-yl, such as piperidin-4-yl or l-acetylpiperidin-4-yl, or halo-C]-C4alkyl, in which halogen is chlorine or, especially, fluorine, such as 2-haloethyl, and R2 is carboxy or Ci-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts. The invention relates preferably, on the one hand, to compounds of formula I wherein Rj is amino-C4-C7alkyl, such as 4-aminobutyl or 6-aminohexyl, N-C1-C4-alkanoyl-N-Ci-C4alkylamino-Ci-C7alkyl, piperidin-4-yl or l-C2-C7alkanoyl-piperidin-4-yl, such as l-acetylpiperidin-4-yl, and R2 is carboxy or Ci-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts. The invention relates preferably, on the other hand, to compounds of formula I wherein Rj is Ci-C4alkoxy-Ci-C4alkyl, such as methoxymethyl, ethoxymethyl or 2-methoxyethyl, phenyl-Cj-C4alkoxy-Ci-C4alkyl, such as benzyloxymethyl or 2-benzyloxyethyl, benzoyloxy-Ci-C4alkyl, such as 2-benzoyloxyethyl, hydroxy-Ci-C4alkyl, such as hydroxymethyl or 2-hydroxyethyl, or halo-C2-C4alkyl, such as 2-fluoroethyl, and R2 is carboxy or Ci-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts. The invention relates very especially, on the one hand, to compounds of formula I wherein Rj is amino-C4-C7alkyl, such as 4-aminobutyl, 5-aminopentyl, 6-aminohexyl or 7-amino-heptyl, and R2 is carboxy, Ci-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or a phenyl-Ci*C4alkoxycarbonyl group that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, such as methyl, Ci-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as a benzyloxycarbonyl or 2-phenylethoxycarbonyl group, and their salts, especially their pharmaceutically acceptable salts. The invention relates very especially, on the other hand, to compounds of formula I wherein Rj is Ci-C4alkoxy-C2-C4alkyl, such as 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl or 4-methoxybutyl, hydroxy-C2-C4alkyl, such as 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, or halo-C2-C4alkyl, such as 2-fluoroethyl, 2-chloroethyl, 3-fluoropropyl or 4-fluorobutyl, and R2 is carboxy, Ci-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or a phenyl-Ci-C4alkoxycarbonyl group that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, such as methyl, Ci-C4aikoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as a benzyloxycarbonyl or 2-phenylethoxycarbonyl group, and their salts, especially their pharmaceutically acceptable salts. The invention relates specifically to the compounds of formula I mentioned in the Examples and their salts, especially their pharmaceutically acceptable salts. The process for the preparation of the compounds according to the invention is as follows: in a compound of formula II wherein Z\, Z2 are optionally protected hydroxy, Z3 is optionally protected hydroxy-Ci-Cyalkyl, optionally protected dihydroxy-C2-C7alkyl, C2-C7alkanoyloxy-Ci-C7alkyl, benzoyloxy-Ci-C7alkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, C1-C4-alkoxy-Ci-C7alkyl, a phenyl-Ci-C4alkoxy-Ci-C7alkyl group that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, halo-Ci-C7alkyl, in which halogen is chlorine or fluorine, optionally protected amino-Ci-C7alkyl, optionally protected Ci-C4alkylamino-Ci-C7-alkyl, C2-C7alkanoylamino-Ci-C7alkyl, N-C2-C7alkanoyl-N-Ci-C4alkylamino-Ci-C7-alkyl, di-Ci-C7alkylamino-Ci-C7alkyl, azacycloalk-l-yl-Ci-C7alkyl, optionally protected azacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, I-C2-C7-alkanoyIazacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, N-C1-C4-alkylazacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, N-Ci-C4benzoylaza-cycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, diazacycloalk-l-yl-Ci-C7alkyl, - 10- N'-C]^C4alkyldiazacycloalk-l-yl-Ci-C7alkyl, N'-C2-C7alkanoylazacycloalk-l-yl-Ci-Cyalkyl, azoxacycloalk-l-yl-Cj^alkyl, 5- to 7-membered oxacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyI, optionally protected 5- to 7-membered azacycloalk-3-yl or -4-yl or l-C2-C7alkanoylazacycloalk-3-yl or -4-yl, N-Ci-C4alkylazacycloalk-3-yl or -4-yl, or N-benzoylazacycloalk-3-yl or -4-yl that is unsubstituted or substituted in the phenyl moiety, or 5- to 7-membered oxacycloalk-3-yl or -4-yl, and Z4 is protected amino, converting protected amino Z4 and, if present, protected amino as a constituent of Z3 into amino and, if present, converting protected hydroxy Z\, Z2 and/or protected hydroxy as a constituent of Z3 into hydroxy and, if present, freeing a protected azacycloaliphatic hydrocarbon radical Z3 and, if desired, converting a resulting compound into a different compound of formula I, separating an isomeric mixture obtainable in accordance with the process into its components and separating the preferred isomer, and/or converting a free compound obtainable in accordance with the process into a salt or converting a salt obtainable in accordance with the process into the corresponding free compound. In starting materials of formula n, protected hydroxy Z\ and/or Z2 is, for example, etherified, especially aliphatically or aromatically etherified, hydroxy, protected hydroxy Z3 is, for example, acylated or silylated hydroxy, and protected amino Z4 and, if present, protected amino as a constituent of Z3 is, for example, acylated amino. Aliphatically etherified hydroxy is, for example, lower alkoxy, such as methoxy, ethoxy or, especially, isopropoxy. Aromatically etherified hydroxy is, for example, phenoxy that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, cyano and/or by nitro. Acylated hydroxy contains as the acyl group, for example, the acyl radical of an araliphatic carboxylic acid or of a semi-ester of carbonic acid and is, for example, lower alkanoyloxy or a phenyl-lower alkanoyloxy or phenyl-lower alkoxycarbonyloxy group that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen, cyano and/or by trifluoromethyl, for example benzyloxycarbonyloxy. Silylated hydroxy is, for example, tri-lower alkylsilyloxy, for example trimethyl- or tributyl-silyloxy. Acylated amino contains as the acyl group, for example, acyl derived from a suitable -11 - organic acid, such as formic acid, or from an araliphatic or aromatic semi-ester of carbonic acid. Accordingly, acylated amino is, for example, formylamino, lower alkoxycarbonylamino, such as methoxy-, ethoxy- or tert.-butoxy-carbonylamino, or a phenyl-lower alkoxycarbonylamino or or phenoxycarbonylamino group that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen, cyano and/or by nitxo, such as benzyloxycarbonylamino, substituted by lower alkyl, lower alkoxy, halogen, cyano and/or by nitro. The freeing of the protected groups from compounds of formula II, i.e. of hydroxy from protected hydroxy groups Z\, Z2 and/or from protected hydroxy groups as a constituent of Z3, or of amino from protected amino groups Z4 and, if present, from protected amino groups as a constituent of Z3, is carried out, for example, by treatment with an acidic agent, for example with a tri-lower alkylhalosilane, such as trimethylbromosilane, tributylbromosilane or trimethyliodosilane. The operation is preferably carried out in an inert solvent, such as a halogenated aliphatic hydrocarbon, for example dichloromethane or, secondly, tri- or tetra-chloromethane, trichloroethane or tetrachloroethane, for example in a temperature range of from approximately -25° to approximately +50°C, preferably of approximately from 0° to 30°C, for example at room temperature, i.e. at approximately from 15° to 25°C, advantageously under substantially anhydrous conditions and under an inert gas, such as argon or nitrogen. Working up is preferably carried out with the addition of a hydrogen halide acceptor, especially an aliphatic epoxy compound, such as an epoxy-lower alkane, for example propylene oxide in a lower alkanol, such as ethanol. In a preferred form, for example compounds of formula II wherein Z\ and Z2 are lower alkoxy, for example isopropoxy, and Z4 is lower alkanoylamino, such as formylamino, are used as starting materials and are treated in an aliphatic halogenated hydrocarbon, such as dichloromethane, at from approximately 15° to approximately 25°C, with a tri-lower alkylbromosilane, such as trimethylbromosilane or tributylbromosilane; the mixture is left for a time, for example from 2 to 30 hours, to complete the reaction, and then an ethanolic solution of propylene oxide is added and the product is removed by filtration. Starting materials of formula II are prepared, for example, by reacting an a,P-unsaturated aldehyde of formula Ila Z3 0 (Da) with an a-isocyanoacetic acid ester of formula lib :C^n/R2 (lib) in a manner known per se, for example in the presence of a copper or gold catalyst, for example copper® oxide or bis(cyclohexylisocyanide)gold(I) tetrafluoroborate, to give the corresponding 5-substituted 2-oxazoline-4-carboxylic acid ester of formula lie Z3 (He) °\^N converting the ester of formula lie by hydrolysis, for example in aqueous tetrahydrofuran, into the corresponding open-chained ester of formula lid OH R2 (lid) NHCH=0 converting the ester of formula lid by treatment with thionyl bromide in a manner known Eer se into the coiresponding o>-bromic ester of formula He Z3 NHCH=0 and reacting the ester of formula lie further in a manner known per se with a phosphorous acid triester of the formula P(Za)(Zb)(Zc), wherein Za, Z5 and Zq are identical or different - 13- hydroxy groups protected in an ether form, such as a tri-lower alkyl phosphite, for example triisopropyl phosphite, to give the corresponding compound of formula II' Compounds obtainable in accordance with the process can be converted in customary manner into different compounds of formula I. For example, free and esterified carboxy groups R_2 can be converted in customary manner into one another. In particular, esterified carboxy R2 can be converted into carboxy by hydrolysis, or free carboxy R2 can be converted into esterified carboxy by reaction with an alcohol. Furthermore, esterified carboxy R2 can be transesterified to form a different esterified carboxy group. These transesterification reactions are carried out in customary manner under hydrolytic, alcoholytic or transesterifying conditions. The hydrolysis of carboxylic acid esters (I; R2 = esterified carboxy) is carried out in customary manner, if necessary in the presence of an acidic or basic agent, such as a mineral acid, for example hydrochloric acid or sulfuric acid, or a base, such as an alkali metal hydroxide, for example sodium hydroxide. The transesterification of esters (I; R2 = esterified carboxy) with alcohols is usually carried out under conditions of acid-catalysis or base-catalysis, for example in the presence of a catalytic amount of a mineral acid, such as hydrochloric acid or sulfuric acid, or of a metal base, such as sodium hydroxide, or by employing the alcohol component in the form of a metal alcoholate, for example an alkali metal alcoholate. Furthermore, in aliphatic hydrocarbon radicals substituted by araliphatically etherified hydroxy, such as a-phenyl-lower alkoxy-lower alkyl radicals R^, the a-phenyl-lower alkoxy group can be converted into hydroxy by reduction, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, such as palladium-on-carbon or Raney nickel. Resulting salts can be converted into the free compounds in a manner known per se, for O '3 (II') -14- example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate, a metal hydrogen carbonate or ammonia, or with another salt-forming base mentioned at the beginning, or with an acid, such as a mineral acid, for example hydrochloric acid, or another salt-forming acid mentioned at the beginning. Resulting salts can be converted into different salts in a manner known per se, in the case of acid addition salts, for example, by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of a different acid in a suitable solvent in which an inorganic salt being formed is insoluble and therefore is eliminated from the reaction equilibrium, and in the case of base salts, by freeing the free acid and converting it into a salt again. The compounds of formula I, including their salts, may also be obtained in the form of hydrates or include the solvent used for crystallisation. In view of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds or their salts should be understood as including also the corresponding salts or free compounds, respectively, where appropriate and expedient. Resulting diastereoisomeric mixtures and mixtures of racemates can be separated into the pure diastereoisomers and racemates in known manner on the basis of the physicochemical differences between the constituents, for example by chromatography and/or fractional crystallisation. Furthermore, resulting racemates can be separated into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, with the aid of microorganisms, or by reaction of the resulting diastereoisomeric mixture or racemate with an optically active auxiliary compound, for example, according to the acid, basic or functionally modifiable groups contained in compounds of formula I, with an optically active acid, base or an optically active alcohol, to form mixtures of diastereoisomeric salts or functional derivatives, such as esters, and separation thereof into the diastereoisomers from which the desired enantiomer can be freed in the customary manner. Suitable bases, acids and alcohols are, for example, amino acids, especially lysine, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(l-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or - 15- L-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid or D- or L-camphor-sulfonic acid, and optically active alcohols, such as borneol or D- or L-(l-phenyl)ethanol. The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out, or in which a starting material is used in the form of a salt or, especially, is formed under the reaction conditions. The invention relates also to the novel starting materials developed specifically for the preparation of the compounds according to the invention, especially to those starting materials resulting in the compounds of formula I that were described at the beginning as being preferred, to processes for the preparation thereof and to their use as intermediates. The novel compounds of formula I can be used, for example, in the form of pharmaceutical preparations that contain a therapeutically effective amount of the active ingredient, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for enteral, e.g. oral, or parenteral administration. There are used, for example, tablets or gelatin capsules that contain the active ingredient together with diluents, for example lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets can also contain binders, for example magnesium aluminium silicate, starches, such as com, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, for example sodium alginate, and/or effervescent mixtures, or absorbents, colouring agents, flavourings and sweeteners. The novel compounds of formula I can also be used in the form of parenterally administrable preparations or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions which, for example in the case of lyophilised preparations that contain the active ingredient on its own or together with a carrier, for example mannitol, can be prepared before use. The pharmaceutical preparations may be sterilised and/or may contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical preparations in question, which, if desired, may contain further pharmacologically active substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and contain r - 16- approximately from 0.1 % to 100 %, especially from approximately 1 % to approximately 50 %, in the case of lyophilisates up to approximately 100 %, active ingredient. The invention relates also to the use of the compounds of formula I, preferably in the form of pharmaceutical preparations. The dosage may depend on various factors, such as the mode of administration and the species, age and/or individual condition. The daily doses are, in the case of oral administration, from approximately 0.25 to approximately 10 mg/kg, and in the case of warm-blooded animals having a body weight of approximately 70 kg, they are preferably from approximately 20 mg to approximately 500 mg. The following Examples illustrate the invention; temperatures are given in degrees Celsius and pressures in mbar. Example 1: 3.57 g (8.5 mmol) of 6-acetoxy-4-diisopropylphosphono-methyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 22 ml of dichloro-methane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 22 ml of ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 22 ml of ethanol, and a mixture of 22 ml of propylene oxide and 22 ml of ethanol is added drop-wise. A suspension forms, which is stirred for a further 90 minutes and then filtered with suction. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 195° (decomp.) is obtained. The starting material can be prepared, for example, as follows: 13.0 g (100 mmol) of acetic acid (4-oxo)butyl ester, 92.0 g (112.6 mmol) of dimethylammonium chloride and 10.8 ml (117 mmol) of 37 % formaldehyde solution are heated at 100° for one hour with stirring. The mixture is allowed to cool and is extracted 3 times with 30 ml of diethyl ether each time. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. Acetic acid (3-formyl)but-3-enyl ester is obtained in the form of a colourless oil which can be reacted farther without further purification. 13.5 g (95 mmol) of acetic acid (3-formyl)but-3-enyl ester and 10.4 g (95 mmol) of isocyanoacetic acid ethyl ester are added dropwise to a suspension of 0.38 g of copper(I) oxide in 50 ml of benzene. When the exothermic reaction has subsided, the mixture is stirred at room temperature for a further 45 minutes, filtered over Hyflo® and concentrated to dryness by evaporation. The residue is taken up in 75 ml of tetrahydro-furan, 25 ml of water are added, and the mixture is heated under reflux for 4 hours with stirring. The mixture is concentrated to dryness by evaporation and chromatographed on silica gel with toluene/isopropanol (9:1) as eluant. 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester is obtained in the form of a brownish oil. 9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 100 ml of dichloromethane, and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 10 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, saturated potassium hydrogen carbonate solution and again with water, dried over magnesium sulfate, filtered and concentrated by evaporation. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish oil. 8.7 g (25 mmol) of 6-acetoxy-4-bromomethyl-2-formyIamino-hex-3-enoic acid ethyl ester and 21 ml (75 mmol) of triisopropyl phosphite (90 %) are heated to from 80° to 90°C and stirred for 19 hours under a pressure of approximately 100 mbar. The excess triisopropyl phosphite is distilled off and the evaporation residue is chromatographed on 150 g of silica gel with first ethyl acetate and then ethyl acetate/ethanol (9:1) as eluants. 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil. Example 2: 0.415 g (1.55 mmol) of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated under reflux in 3 ml of water for 24 hours. The reaction mixture is concentrated by evaporation, purified by chromatography on 10 g of silica gel with ethanol/water (1:1) as eluant, and crystallised from ethanol. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid having a melting point >300° is obtained. Example 3: 0.5 g (1.0 mmol) of 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is heated under 0 c -18 - reflux in 5.0 ml of 6N hydrochloric acid for 6 hours. Concentration to dryness by evaporation yields 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid dihydrochloride in the form of a rubber-like solid which is recrystallised from acetonitrile; m.p. 128° (decomp.). The starting material can be prepared as follows: 7.06 ml (47 mmol) of chloroformic acid benzyl ester are added dropwise to a solution of 5.52 g (47 mmol) of 6-aminohexan-l-ol and 3.95 g (47 mmol) of sodium hydrogen carbonate in 100 ml of acetone and 50 ml of water. The mixture is stirred at room temperature for 18 hours and concentrated to approximately 70 ml, and the white precipitate is filtered off, washed with approximately 20 ml of water, taken up in 250 ml of methylene chloride and dried over magnesium sulfate; the magnesium sulfate is filtered off and the residue is concentrated to dryness by evaporation. 6-(N-benzyloxycarbonyl-amino)hexan-l-ol is obtained in the form of white crystals having a melting point of 58-60°. 0.32 ml (4.40 mmol) of dimethyl sulfoxide is added dropwise under nitrogen to a solution of 0.19 ml (2.20 mmol) of oxalyl chloride in 10 ml of methylene chloride which is being stirred at -50°. The mixture is stirred for 15 minutes, and then 0.5 g (2 mmol) of 6-(N-benzyloxycarbonylamino)hexan-l-ol is added. Stirring is continued at -50° for 25 minutes, 1.78 ml (10 mmol) of N-ethyI-N,N-diisopropylamine are added dropwise and the mixture is poured into 10 ml of ice-water. The organic phase is separated off and the aqueous phase is extracted with 10 ml of methylene chloride. The organic phases are combined, washed twice with 5 ml of N-hydrochloric acid each time and once with 10 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. The resulting oil is purified by chromatography on silica gel with hexane/ethyl acetate (1:1) as eluant. 6-(N-benzyloxycarbonylamino)hexanal is obtained. 2.44 g (30 mmol) of 37 % aqueous formaldehyde solution are added to a solution of 1.5 g (17 mmol) of anhydrous piperazine and 2.03 g (34 mmol) of acetic acid in 18.7 ml of water. The mixture is stirred at 25° for 15 minutes, and then 7.48 g (30 mmol) of 6-(N-benzyloxycarbonylamino)hexanal are added thereto. The reaction mixture is heated under reflux for 2 hours and then cooled with ice-water and extracted twice with 50 ml of methylene chloride each time. The extracts are combined, washed twice with 25 ml of saturated sodium hydrogen carbonate solution each time and with 25 ml of saturated sodium chloride solution, dried and concentrated to dryness by evaporation. 0 - r, _ - 19- 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal is obtained in the form of a yellowish liquid. 4.0 g (15.3 mmol) of 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal and 1.62 ml (16.8 mmol) of isocyanoacetic acid methyl ester are dissolved in 50 ml of toluene and added dropwise at 40° to a suspension of 0.12 g of 96.4 % copper(I) oxide in 50 ml of toluene. The mixture is then stirred at room temperature for 2.5 hours, filtered, introduced into a column filled with 60 g of silica gel and extracted fust with hexane/ethyl acetate (1:1) and then with ethyl acetate. 5-[6-(N-benzyloxycarbonylamino)hex-l-en-2-yl]-oxazoline-4-carboxylic acid methyl ester is obtained; oil. 9.4 g (26.1 mmol) of 5-[6-(N-benzyloxycarbonylamino)hex-l-en-2-yl]-oxazoline-4-carboxylic acid methyl ester are dissolved in 40 ml of tetrahydrofuran and 20 ml of water, a few drops of triethylamine are added and the mixture is heated under reflux for 18 hours. The solvent is removed under reduced pressure and the oil that remains is taken up in a total of 125 ml of methylene chloride, dried over magnesium sulfate and concentrated to dryness by evaporation. 8-(N- benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester is obtained. To 2.46 g (6.5 mmol) of 8-(N-benzyloxycarbonylamino)-2-formyl-amino-3-hydroxy-4-methylene-octanoic acid methyl ester in 25 ml of tetrahydrofuran there are added 5.5 ml (46 mmol) of hexa-l,5-diene and then, dropwise at -50°, 2.6 ml (32.5 mmol) of thionyl bromide. The mixture is stirred at from 0° to 5° for 2 hours, poured into 25 ml of ice-cold saturated sodium hydrogen carbonate solution and extracted twice with 20 ml of methylene chloride each time. The organic phase is washed with 10 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. The resulting oil is purified by chromatography on silica gel with hexane/ethyl acetate (3:1). 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained. 5 ml of triethyl phosphite are added to 1.45 g (3.3 mmol) of 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-fomiylamino-oct-3-enoic acid methyl ester, and the mixture is heated at 75° for 8 hours with stirring. The excess triethyl phosphite is distilled off under reduced pressure to give an oily residue which is purified by chromatography on a silica gel column with first ethyl acetate and then ethyl acetate/methanol (9:1). 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained. Example 4: 1.77 g (4.5 mmol) of 4-diisopropylphosphonomethyl-2-formyIamino-6-methoxy-hex-3-enoic acid ethyl ester are dissolved in 12 ml of dichloromethane, and 2.32 ml (18.0 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 12 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 10 ml of ethanol, and a mixture of 2 ml of propylene oxide and 2 mi of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling, and is then filtered with suction. 2-amino-6-methoxy-4-phos-phonomethyl-hex-3-enoic acid ethyl ester having a melting point of 242° (decomp.) is obtained. The starting material can be prepared, for example, as follows: 19.7 g (193 mmol) of 4-methoxybutanal, 17.7 g (217 mmol) of dimethylammonium chloride and 17.0 ml (226 mmol) of 37 % formaldehyde solution are heated at 100° for 3 hours with stirring. The mixture is allowed to cool and is extracted 3 times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and concentrated to dryness by evaporation. 4-methoxy-2-methyIenebutanal is obtained in the form of a yellowish oil which can be further reacted without further purification. 16.5 g (144.5 mmol) of 4-methoxy-2-methylenebutanal and 15.8 ml (144.5 mmol) of isocyanoacetic acid ethyl ester are dissolved in 145 ml of toluene, and 400 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered over Hyflo® and concentrated to dryness by evaporation. The residue is taken up in 145 ml of tetrahydrofuran, 33 ml of water are added, and the mixture is heated under reflux for 2 hours with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with toluene/ethanol (95:5) as eluant yields 2-formyl-amino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester in the form of a reddish-brown oil. -21 - 19.0 g (77.5 mmol) of 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester are dissolved in 190 ml of 1,2-dichloroethane, and 7.20 ml (93.0 mmol) of thionyl bromide are added dropwise at room temperature. After 45 minutes, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, IN potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil. 3.38 g (11.0 mmol) of 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester and 12.0 ml (44 mmol) of triisopropyl phosphite (96 %) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil. Example 5: 0.98 g (3.5 mmol) of 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated under reflux in 7 ml of water for 17 hours. The reaction mixture is concentrated by evaporation and crystallised from a mixture of water and ethanol. 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid having a melting point of 214°C (decomp.) is obtained. Example 6: 0.52 g (1.36 mmol) of 4-diisopropylphosphono-methyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is dissolved in 3.5 ml of dichloromethane, and 0.7 ml (5.45 mmol) of trimethylbromosilane is added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 3.5 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 2.4 ml of ethanol, and a mixture of 0.6 ml of propylene oxide and 0.6 ml of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222° (decomp.) is obtained. - V ' - .. J •- <1 -22- The starting material can be prepared, for example, as follows: 2.4 g (26.6 mmol) of 4-fluorobutanal, 2.44 g (30.0 mmol) of dimethylammonium chloride and 2.34 ml (31.1 mmol) of 37 % formaldehyde solution are heated at 100° for 2 hours with stirring. The mixture is allowed to cool and is extracted 3 dmes with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and concentrated to dryness by evaporation. 4-fluoro-2-methylenebutanal is obtained in the form of a yellowish oil which can be reacted further without further purification. 1.43 g (14.0 mmol) of 4-fluoro-2-methylenebutanai and 1.53 ml (14.0 mmol) of isocyanoacetic acid ethyl ester are dissolved in 14 ml of toluene, and 40 mg of copper® oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered over Hyflo® and concentrated to dryness by evaporation. The residue is taken up in 14 ml of tetrahydrofuran, 3.1 ml of water are added, and the mixture is heated under reflux for 2 hours with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with toluene/ethyl acetate (1:1) as eluant yields 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the form of a dark-yellow oil. 1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 14 ml of 1,2-dichloroethane, and 0.56 ml (7.2 mmol) of thionyl bromide is added dropwise at room temperature. After 45 minutes, 12 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, IN potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish-yellow oil. 1.43 g (4.82 mmol) of 4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester and 5.3 ml (19 mmol) of triisopropyl phosphite (96 %) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish © -23- oil. Example 7: 0.5 g (1.86 mmol) of 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester are heated under reflux in 4 ml of water for 17 hours. The reaction mixture is concentrated by evaporation and separated with water on a strongly acidic ion-exchanger (Dowex 50Wx8; H® form). 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid having a melting point of 160-162°C (decomp.) is obtained. Example 8: In a manner analogous to that described in Example 3, 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid dihydrochloride, m.p. 126°, is obtained, starting from 8-aminooctan-l-ol. Example 9: 8.63 g (15.2 mmol) of 10-(N-benzyloxycarbonyl- amino)-4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane, and 9.82 ml (75.9 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is stirred at room temperature for 22 hours, 22 ml of absolute ethanol are then added dropwise, and the mixture is stirred for a further 22 hours and concentrated by evaporation in a rotary evaporator. 20 ml of toluene are poured over the residue, and the mixture is concentrated by evaporation in vacuo. This operation is repeated a further three times. The resulting pale yellow foam is dissolved in 150 ml of absolute ethanol, and a solution of 7.5 ml of propylene oxide in 7.5 ml of ethanol is added dropwise within a period of 90 minutes. A crystalline suspension forms, which is stirred overnight at room temperature. The product is filtered off and washed with ethanol and ether. Drying under a high vacuum at room temperature yields 4.70 g of crude product in the form of pale yellow crystals. For further purification, the product is stirred with 46 ml of water. After a small amount (0.33 g) of undissolved material has been filtered off, the clear pale yellow filtrate is completely concentrated by evaporation in vacuo. 20 ml of ethanol and 20 ml of toluene are added to the residue, and the mixture is again concentrated to dryness by evaporation. This operation is repeated twice more using toluene. After drying under a high vacuum, the residue is suspended in 150 ml of absolute ethanol, and a 5-normal solution of hydrogen chloride gas in ethanol is added dropwise, with stirring, until the mixture gives an acid reaction to Congo red. A mixture of 7.4 ml of propylene oxide in 7.4 ml of ethanol is added dropwise to the resulting clear solution within a period of one hour. A crystalline suspension forms, which is stirred for a further 15 hours and then filtered with suction. After washing with ethanol and ether, the product is dried under a high vacuum at 50° for 48 hours, yielding 2.86 g of -24- 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester, which begins to sinter at 157° and melts at 194° with decomposition. This product contains as impurities approximately from 5 to 10 % by weight of the corresponding compound that is N-benzylated in the 10-position and of the N-(2-hydroxy)propylated compound. The starting material is prepared as follows: In a manner analogous to that described in Example 3, 8-(N-benzyloxycarbonylamino)-2-methyleneoctanal is obtained, starting from 8-aminooctan-l-ol, via 8-(N-benzyIoxycarbonylamino)octan-l-ol and 8-(N-benzyloxycarbonylamino)octanal. 15.30 g (52.9 mmol) of 8-(N-benzyloxycarbonylamino)-2-methyleneoctanal and 7.37 mi (67.4 mmol) of isocyanoacetic acid ethyl ester are dissolved in 78 ml of toluene and added dropwise under argon, within a period of 75 minutes, to a suspension of 0.30 g of copper(I) oxide in 76 ml of toluene. The mixture is then stirred for 90 minutes at 30°, cooled to room temperature and filtered, and the clear, bright red filtrate is introduced into a column filled with 250 g of silica gel (particle size 0.04-0.063 mm) and eluted with hexane/ethyl acetate (2:1). Concentration of the suitable fractions by evaporation yields 8.15 g of 5-[8-(N-benzyloxycarbonylamino)oct-l-en-2-yl]-oxazoline-4-carboxylic acid ethyl ester in the form of a colourless honey. 8.15 g (20.25 mmol) of 5-[8-(N-benzyloxycarbonylamino)oct-l-en-2-yl]-oxazoline-4-carboxylic acid ethyl ester are heated under reflux in 40 ml of tetrahydrofuran and 20 ml of water for 4 hours with stirring. The reaction mixture is concentrated to dryness by evaporation in vacuo at 45°, and the honey-like residue is concentrated by evaporation twice more after the addition of toluene. The crude product is dissolved in dichloromethane, dried with sodium sulfate, filtered and concentrated by evaporation. Drying under a high vacuum at room temperature yields 9.03 g of 10-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in the form of a yellowish honey. To 13.70 g (32.60 mmol) of crude 10-(N-benzyloxycarbonyl-amino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in 137 ml of -25- tetrahydrofuran there are added, under argon, 18.5 ml (156.4 mmol) of hexa-l,5-diene and then, dropwise at 10° within a period of 15 minutes, 6.1 ml (78.2 mmol) of thionyl bromide. The mixture is stirred for one hour at 10° and for 2 hours at room temperature and is then poured into 200 ml of ice-cold saturated sodium hydrogen carbonate solution; the organic phase is separated off and re-extracted once with dichloromethane. The organic phases are washed with ice-cold 0.5-normal sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness by evaporation in vacuo at 40°. 64 ml (260 mmol) of triisopropyl phosphite (96 %) are added immediately to the resulting crude 10-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-dec-3-enoic acid ethyl ester (27 g, yellow honey), and the mixture is stirred for 17 hours at 80° under a pressure of approximately 100 mbar, the isopropyl bromide that forms being captured in a cold trap (CCb). The excess triisopropyl phosphite is then distilled off under reduced pressure and the evaporation residue (23 g) is purified by chromatography on a column filled with 650 mg of silica gel (0.04-0.063 mm) with ethyl acetate/methanol (95:5). 8.73 g of 10-(N-benzyIoxycarbonylamino)-4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester are obtained in the form of a yellowish honey. Example 10: 2.25 g (6.98 mmol) of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester are dissolved under argon in 45 ml of 2-normal hydrochloric acid and stirred for 17 hours at a bath temperature of 120°. The clear, pale brown solution is concentrated by evaporation in a rotary evaporator. The residue is dissolved in 20 ml of ethanol and, after the addition of 30 ml of toluene, concentrated by evaporation in vacuo. This operation is repeated a further three times. The resulting beige foam is dissolved in 75 ml of absolute ethanol, and a solution of 15 ml of propylene oxide in 15 ml of ethanol is added dropwise within a period of 35 minutes. The crystalline suspension that forms, which has a pH of 3, is filtered off after H hours' stirring and washed thoroughly with ethanol and ether. Drying in vacuo yields 1.65 g of beige crude product, which is dissolved in the minimum amount of water (about 2 ml) and chromatographed on a column filled with 67 g of reversed-phase silica gel (Opti-Up C12, particle size 40 Jim), using pure water as eluant, at a slight overpressure (0.2 bar). A pure fraction, Rf value on silica gel = 0.37 with n-propanol/water/pyridine/acetic acid (15:12:10:3) as eluant, and several mixed fractions containing a by-product of Rf value = 0.48 are obtained. Chromatography of those mixed fractions again and purification of the pure fractions, followed by lyophilisation from water, yield 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid hemi-hydrochloride hydrate in the form of an amorphous glass which slowly sinters at 134° and above and decomposes at 149° with foaming. Example 11: 4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphos-phonomethyl-2-formylamino-hept-3-enoic acid ethyl ester are dissolved in 25 ml of dichloromethane, and 5.1 ml (39.5 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 25 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation, the residue is dissolved in 25 ml of ethanol, and a mixture of 25 ml of propylene oxide and 25 ml of ethanol is added dropwise. A suspension forms, which is stirred for one hour at room temperature and for one hour in an ice bath and is then filtered with suction. Drying yields 2-amino-7- hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester having a melting point of 210°C (decomp.). The starting material can be prepared, for example, as follows: 10 g (69.4 mmol) of 5-acetoxypentanal, 6.37 g (78.2 mmol) of dimethylammonium chloride and 6.1 ml (81.2 mmol) of 37 % formaldehyde solution are refluxed for H hours (bath temperature ~110°C) with stirring. The mixture is allowed to cool and is extracted three times with ether; the organic phases are combined, dried over MgSC>4, filtered and concentrated by evaporation. 5-acetoxy-2-methylenepentanal is obtained in the form of a yellowish oil which can be reacted without further purification. 9.6 g (61.5 mmol) of 5-acetoxy-2-methylenepentanal and 7.38 ml (67.6 mmol) of isocyanoacetic acid ethyl ester are placed in 70 ml of toluene at room temperature, and 250 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further one hour and is filtered over Hyflo® and concentrated by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the mixture is refluxed for 3 hours. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with toluene/ethyl acetate (4:1) yields 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester in the form of an orange oil. 5.9 g (20.5 mmol) of 7-acetoxy-2-formyIamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester are dissolved in 60 ml of dichloromethane, and 1.9 ml (24.6 mmol) of thionyl -27- bromide are added dropwise at room temperature. After one hour, 40 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, IN KHCO3 solution and again with water, dried over MgSC>4, filtered and concentrated by evaporation. 7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the form of a brown oil, which is reacted further in the crude state. 6.1 g (17.4 mmol) of 7-acetoxy-4-bromomethyl-2-formylaminohept-3-enoic acid ethyl ester and 19.1 ml (69.6 mmol) of triisopropyl phosphite (90 %) are heated to 80°C and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified on silica gel with ethyl acetate. 7-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the form of a yellow oil. Example 12: 1.1 g (3.9 mmol) of 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester in 8 ml of water are stirred at 130°C for 18 hours in a bomb tube. The dark reaction solution is treated with activated carbon and filtered over Hyflo®. The colourless filtrate is concentrated to -3 ml, and -25 ml of ethanol are added. The resulting suspension is filtered with suction and dried under a high vacuum at 50°C. 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid having a melting point from 190°C and above (decomp.) is obtained. Example 13: 8.2 g (18.9 mmol) of 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 40 ml of dichloromethane, and 9.8 ml (75.6 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 40 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation, the residue is dissolved in 40 ml of ethanol, and a mixture of 40 ml of propylene oxide and 40 ml of ethanol is added dropwise. A suspension forms, which is stirred for a further one hour at room temperature and for one hour at 0° and is then filtered with suction. Drying yields 6-(N-acetyl-N-methylamino)-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222-223°C (decomp.). The starting material can be prepared, for example, as follows: 7 C -28- 35.8 g (0.2 mol) of 4-aminobutyraldehyde-diethylacetal (90 %) are dissolved in 600 ml of dichloromethane, 300 ml of saturated sodium hydrogen carbonate solution are added, and the mixture is cooled to 0°C. 17 ml (0.24 mol) of acetyl chloride are added dropwise at 0-5°C, and the mixture is stirred for a further 6 hours at 0-5°C. The organic phase is separated off and the aqueous phase is extracted twice more with dichloromethane. The organic phases are combined, dried over MgS04, filtered and concentrated by evaporation in a rotary evaporator. The residue is purified by chromatography on silica gel with ethyl acetate. 4-(N-acetylamino)butyraldehyde-diethylacetal is obtained in the form of a yellowish oil. 35 g (172.2 mmol) of 4-(N-acetylamino)butyraldehyde-diethylacetal are dissolved in 180 ml of dimethylformamide, 8.3 g (206.6 mmol) of sodium hydride dispersion (60 % in mineral oil) are added in portions, and the mixture is stirred at room temperature for 45 minutes. 12.9 ml (206.6 mmol) of methyl iodide in 20 ml of dimethylformamide are then added, and the mixture is subsequently stirred at room temperature for 4 hours. Water/ice is added to the reaction mixture, and the batch is extracted three times with ethyl acetate. The organic phases are washed with water and saturated sodium chloride solution, combined, dried over MgS04, filtered and concentrated by evaporation. The residue is distilled under a high vacuum. 4-(N-acetyl-N-methylamino)butyraldehyde-diethylacetal is obtained in the form of a colourless oil, b.p.0.i = 92-94°. 30 g (138.2 mmol) of 4-(N-acetyl-N-methylamino)butyraldehydediethylacetal, 12.6 g (154.4 mmol) of dimethylammonium chloride and 12.1 ml (161.7 mmol) of 37 % formaldehyde solution are refluxed for 45 minutes with stirring. The mixture is allowed to cool and is extracted three times with dichloromethane. The organic phases are combined, dried over MgSC>4, filtered and concentrated by evaporation. 4-(N-acetyI-N-methylamino)-2-methylene-butyraldehyde is obtained in the form of a yellowish oil which can be reacted without further purification. 19.9 g (128.3 mmol) of 4-(N-acetyl-N-methylamino)-2-methylene-butanal and 15.4 ml (141.1 mmol) of isocyanoacetic acid ethyl ester are placed at room temperature in 80 ml of toluene, and 500 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further one hour at room temperature, filtered over Hyflo® and concentrated by evaporation. The residue is taken up in 60 ml of tetrahydrofuran, 20 ml of water are added, and the mixture is refluxed for 4 hours. The mixture is concentrated by evaporation, toluene is added, and the mixture is again -7 cr -29- concentrated by evaporation. Chromatography on silica gel with ethyl acetate/isopropanol (7:1) yields 6-(N-acetyl-N-methylamino)-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the form of a yellowish oil. 15.8 g (55.2 mmol) of 6-(N-acetyl-N-methylamino)-2-formyl-amino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 150 ml of dichloromethane, and 5.1 ml (66.2 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, IN KHCO3 solution and again with water, dried over MgSC>4, filtered and concentrated by evaporation. 6-(N- acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish-orange oil which is reacted further in the crude state. 16.0 g (45.8 mmol) of 6-(N-acetyl-N-methylamino)-4-bromo-methyl-2-formylamino-hex-3-enoic acid ethyl ester and 50.3 ml (183.3 mmol) of triisopropyl phosphite (90 %) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate/isopropanol (7:2). 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellow oil. Example 14: 3.3 g (6.82 mmol) of 6-benzoyloxy-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane, and 3.52 ml (27.3 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 20 ml of ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is concentrated by evaporation, the residue is dissolved in 20 ml of ethanol, and a mixture of 20 ml of propylene oxide and 20 ml of ethanol is added dropwise. A suspension forms, which is stirred for one hour at room temperature and for one hour at 0°C and is then filtered with suction. Drying yields 2-amino-6-benzoyloxy-2-amino-4-phos-phonomethyl-hex-3-enoic acid ethyl ester having a melting point of 236-237°C (decomp.). The starting material can be prepared, for example, as follows: 10 g (52 mmol) of 4-benzoyloxybutanal, 4.78 g (58.6 mmol) of dimethylammonium -30- chloride and 4.6 ml (60.8 mmol) of formaldehyde solution (37 %) are refluxed for one hour with stirring (bath temperature ~110°C). The mixture is allowed to cool and is extracted three times with ether; the organic phases are combined, washed with saturated sodium chloride solution, dried over MgSO/}, filtered and concentrated by evaporation. 4-benzoyloxy-2-methylenebutanal is obtained in the form of a yellowish oil which can be reacted without further purification. 10 g (49 mmol) of 4-benzoyloxy-2-methylenebutanal and 5.3 ml (49 mmol) of isocyanoaceric acid ethyl ester are placed at room temperature in 70 ml of toluene, and 200 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further one hour, filtered over Hyflo® and concentrated by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the mixture is refluxed for 3 hours. The mixture is concentrated by evaporation, toluene is again added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with toluene/ethyl acetate (3:2) yields 6-benzoyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the form of a brown oil. 8 g (23.9 mmol) of 6-benzoyl-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 80 ml of dichloromethane, and 2.22 ml (28.6 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours, 60 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, IN KHCO3 solution and again with water, dried over MgSC>4, filtered and concentrated by evaporation. 6-benzoyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brown oil which is reacted further in the crude state. 8.4 g (21 mmol) of 6-benzoyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 23 ml (84 mmol) of triisopropyl phosphite (90 %) are heated to 80°C and stirred under a pressure of ~130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 6-benzoyloxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brown oil. Example 15: 4.0 g (8.51 mmol) of 6-benzyloxy-4-diisopropyl- phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 24 ml of -31 - dichloromethane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 24 ml of ethanol are added dropwise and the mixture is left to stand for a further 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 24 ml of ethanol, and a mixture of 24 ml of propylene oxide and 24 ml of ethanol is added drop-wise. A suspension forms, which is stirred for a further one hour at room temperature and for one hour at 0° and is then filtered with suction. Drying yields 2.2 g of a white crystalline product which is a mixture of 2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester and 2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid. To obtain a uniform product, that mixture is hydrolysed overnight at room temperature with 20 ml of N-sodium hydroxide solution in 30 ml of ethanol, acidified with N-hydrochloric acid and neutralised with propylene oxide. Since the product crystallises poorly, it is concentrated by evaporation in a rotary evaporator, the residue is filtered in water over 20 g of silica gel, and the fractions containing the desired product are concentrated by evaporation in a rotary evaporator. The residue is dissolved with 10 ml of tert.-butanol/water (1:1) and freeze-dried. 2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid is obtained in the form of a lyophilisate. The starting material can be prepared, for example, as follows: 6 g (0.2 mol) of a sodium hydride dispersion (80 % in white oil) are placed at room temperature in 120 ml of absolute dimethylformamide, and 22.2 ml (0:25 mol) of 1,4-butanediol are added dropwise. When the addition is complete, the mixture is stirred for a further 30 minutes at room temperature. 23.1 ml (0.2 mol) of benzyl chloride are then slowly added dropwise, a slight exothermic reaction being observed. The reaction mixture is stirred overnight at room temperature, water/ice is added, and the mixture is extracted twice with ether. The organic phases are washed with water and with saturated sodium chloride solution, combined, dried over MgS04, filtered and concentrated by evaporation. The residue is subjected to fractional distillation under a water-jet vacuum over a 10 cm Vigreux column. 4-benzyloxybutanol is obtained, b.p.22 = 161-162°. 36.6 g (170 mmol) of pyridinium chlorochromate are placed at room temperature in 120 ml of dichloromethane under N2, and a solution of 20.4 g (113 mmol) of 4-benzyloxybutanol in 20 ml of dichloromethane is added. The reaction mixture rapidly becomes dark and the reaction is slightly exothermic. The reaction mixture is stirred at room temperature for 3 k hours. The supernatant dichloromethane phase is decanted off and concentrated by evaporation in a rotary evaporator. The residue is filtered over 100 g of silica gel. The product fractions are concentrated by evaporation in a rotary evaporator and distilled under a high vacuum over a 10 cm Vigreux column. 4-benzyloxybutanal is obtained, b.p.0.[ = 72-73°. 8.0 g (44.9 mmol) of 4-benzyloxybutanal, 4.12 g (50.6 mmol) of dimethylammonium chloride and 3.95 ml (52.6 mmol) of 37 % formaldehyde solution are kept at a bath temperature of 110° for one hour with stirring. The mixture is allowed to cool and is extracted three times with ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over MgSC>4, filtered and concentrated by evaporation. 4-benzyloxy-2-methylenebutanal is obtained in the form of a yellowish oil which can be reacted further without further purification. 8.0 g (42 mmol) of 4-benzyloxy-2-methylenebutanal and 4.57 ml (42 mmol) of isocyanoacetic acid ethyl ester are placed in 60 ml of toluene, and 200 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered over Hyflo® and concentrated by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the mixture is refluxed for 3 hours. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with toluene/ethyl acetate (3:2) as eluant yields 6-benzyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the form of a reddish-brown oiL 7.0 g (21.8 mmol) of 6-benzyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 70 ml of dichloromethane, and 2.0 ml (26.1 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours, 40 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, N-KHCO3 solution and again with water, dried over MgSC>4, filtered and concentrated by evaporation. 6-benzyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil which can be reacted further without purification. 7.9 g (20.5 mmol) of 6-benzyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 22.5 ml (82.2 mmol) of triisopropyl phosphite (90 %) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl -33 - phosphite is distilled off in a rotary evaporator and the residue is purified by chromatography on silica gel with ethyl acetate. 6-benzoyl-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil. Example 16: 3.15 g (6.84 mmol) of 4-(l-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 17 ml of dichloromethane, and 3.54 ml (27.3 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 16 hours, 17 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 12 ml of ethanol, and a mixture of 3 ml of propylene oxide and 3 ml of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-4-(l-acetyI-piperidin-4-yl)-5-phosphono-pent-3-enoic acid ethyl ester having a melting point of 225° (decomp.) is obtained. The starting material can be prepared, for example, as follows: 3.95 g (23.3 mmol) of 2-(l-acetylpiperidin-4-yl)ethanol, 2.12 g (26.3 mmol) of dimethylammonium chloride and 3 ml (40 mmol) of 37 % formaldehyde solution are heated at 110°C for 2 hours with stirring. The mixture is allowed to cool and is extracted several times with diethyl ether. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness by evaporation. 2-(l-acetylpiperidin-4-yl)propenal is obtained in the form of a yellowish oil which can be further reacted without further purification. 2.9 g (16.0 mmol) of 2-(l-acetylpiperidin-4-yl)propenal and 1.75 ml (16 mmol) of isocyanoacetic acid ethyl ester are dissolved in 13 ml of toluene, and 46 mg of copper(l) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered over Hyflo® and concentrated to dryness by evaporation. The residue is taken up in 13 ml of tetrahydrofuran, 6 ml of water are added, and the mixture is heated under reflux for 2 hours with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with ethyl acetate/methanol (9:1) as eluant yields 4-(l-acetyIpiperidin-4-yl)-2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester in the form -34- of a yellowish-brown oil. 3.3 g (10.5 mmol) of 4-(l-acetylpiperidin-4-yl)-2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester are dissolved in 25 ml of 1,2-dichloroethane, and 0.98 ml (12.6 mmol) of thionyl bromide are added dropwise at room temperature. After li hours, 20 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, N-potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-(l-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil. 2.68 g (7.14 mmol) of 4-(l-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester and 7.5 ml (28.5 mmol) of triisopropyl phosphite (90 %) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate/methanol (9:1). 4-(l-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil. Example 17: 1 g (2.17 mmol) of 4-(l-acetylpiperidin-4-yl)-5- diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester is heated under reflux in 20 ml of 6N hydrochloric acid for 8 hours. After concentration by evaporation, the residue is dissolved in 25 ml of ethanol. 3 ml of propylene oxide are then added, the mixture is stirred for 2 hours at room temperature and for one hour with ice cooling, and then the suspension that has formed is filtered off with suction. 2-amino-4-(piperidin-4-yl)-5-phosphono-pent-3-enoic acid having a melting point of 212° (decomp.) is obtained. Example 18: 0.68 g (1.49 mmol) of 5-benzyloxy-4-diisopropyl-phosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is dissolved in 10 ml of dichloromethane, and 0.8 ml (6 mmol) of trimethylbromosilane is added dropwise at room temperature. The mixture is left to stand at room temperature for 6 hours, 10 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation, the residue is dissolved in 5 ml of ethanol, and a mixture of 5 ml of propylene oxide and 5 ml of ethanol is added dropwise. A suspension forms, which is stirred at room temperature for 2 hours and is then filtered with suction. Drying yields 2-amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting point of 218-220° (decomp.). The starting material can be prepared, for example, as follows: 3.0 g (62.4 mmol) of 50 % sodium hydride dispersion in mineral oil are placed in 50 ml of tetrahydrofuran and 40 ml of dimethylformamide, a solution of 10.0 g (62.4 mmol) of 3-hydroxy-2-methylenepropionaldehyde-diethylacetal in 10 ml of tetrahydrofuran is slowly added dropwise at 0°, and the mixture is stirred at 0° for 2 hours. The mixture is diluted with 15 ml of tetrahydrofuran and 10 ml of dimethylformamide and stirred at room temperature for a further 2 hours. 7.2 ml (62.4 mmol) of benzyl chloride in 10 ml of dimethylformamide are then added at 0°, and the mixture is stirred at room temperature for 18 hours. Water is added to the reaction mixture, which is then extracted three times with ethyl acetate, and the organic phases are washed with saturated sodium chloride solution. The organic phases are combined, dried over NajSO^ filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride, yielding 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal in the form of a pale yellowish liquid. 4.8 g (19.1 mmol) of 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal and 0.36 g (1,9 mmol) of p-toluenesulfonic acid monohydrate are stirred for 3 hours in 60 ml of acetone. The mixture is diluted with 400 ml of methylene chloride, extracted with N-KHCO3 solution and saturated sodium chloride solution, dried over Na2SC>4, filtered and concentrated by evaporation. The 3-benzyloxy-2-methylenepropanol that remains (yellow liquid) is placed at room temperature, without further purification, together with 2.1 ml (19 mmol) of isocyanoacetic acid ethyl ester, in 25 ml of toluene, and 50 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further one hour at room temperature, filtered over Hyflo® and concentrated by evaporation. The residue is taken up in 25 ml of tetrahydrofuran, 5 ml of water are added, and the mixture is refluxed for 4 hours. The mixture is concentrated by evaporation, toluene is added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with toluene/ethyl acetate (1:1) and subsequent crystallisation from diethyl ether yield 5-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester having a melting point of 112-114°C. 1.0 g (3.25 mmol) of 5-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are suspended in 30 ml of 1,2-dichloroethane, and 0.38 ml (4.9 mmol) of thionyl chloride is added dropwise at room temperature. After 45 minutes, 20 ml of water are added to the yellow solution, and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed with saturated sodium chloride solution, dried over Na2SC>4, filtered and concentrated by evaporation. 5-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil which is reacted further in the crude state. 1.14 g (3.1 mmol) of 5-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 10 ml (38.5 mmol) of triisopropyl phosphite (95 %) are heated to 80°C and stirred under a pressure of approximately 130 mbar for 3? hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 5-benzyloxy-4-diisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil. Example 19: 1.10 g (2.8 mmol) of 5-ethoxy-4-diisopropylphos-phonomethyl-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane, and 1.6 ml (12.3 mmol) of trimethylsilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 7 hours, 20 ml of ethanol are added, the mixture is left to stand for a funher 15 hours and is concentrated by evaporation, the residue is dissolved in 10 ml of ethanol, and a mixture of 10 ml of propylene oxide and 10 ml of ethanol is added dropwise. A suspension forms, which is stirred at room temperature for 2 hours and is then filtered with suction. Drying yields 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting point of 217-218°C (decomp.). The starting material can be prepared, for example, as follows: 50 g (283 mmol) of 3-ethoxypropionaldehyde-diethylacetal, 27.3 g (335 mmol) of dimethylammonium chloride and 30 ml (392 mmol) of 36 % formaldehyde solution are heated at 110°C for 2 hours with stirring. The mixture is allowed to cool and is extracted three times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and concentrated to dryness by evaporation. 2-ethoxypropanol is obtained in the form of a yellow liquid which can be reacted further without further purification. -37- 4.2 g (36.1 mmol) of 2-ethoxypropanol and 4.4 ml (40 mmol) of isocyanoacetic acid ethyl ester are dissolved in 50 ml of toluene, and 200 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a funher one hour, filtered over Hyflo® and concentrated to dryness by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 12 ml of water are added, and the mixture is heated under reflux for one hour with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with toluene/isopropanol (9:1) as eluant yields 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester in the form of a yellow oil. 3.70 g (15.1 mmol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are dissolved in 100 ml of 1,2-dichloroethane, and 1.8 ml (22.8 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with IN potassium hydrogen carbonate solution and with brine, dried over sodium sulfate, filtered and concentrated by evaporation. 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yeliowish-brown oil which is reacted further in the crude state. 3.12 g (10.1 mmol) of 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 30 ml (118 mmol) of triisopropyl phosphite (90 %) are heated to 80°C and stirred under a pressure of approximately 130 mbar for 7 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with methylene oxide/methanol (97:3 to 95:5). 5-ethoxy-4-dihydropropylphos-phonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellow oil. Example 20: Tablets, each containing 50 mg of 2-amino-6- hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt, thereof, can be prepared as follows: Composition (10,000 tablets) active ingredient lactose potato starch 500.0 g 500.0 g 352.0 g -38- gelarin 8.0 g talcum 60.0 g magnesium stearate 10.0 g silica (highly disperse) 20.0 g ethanol q.s. The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remaining potato starch, the magnesium stearate, the talcum and the silica are mixed in and the mixture is compressed to form tablets which each weigh 145.0 mg and contain 50.0 mg of active ingredient, and which may, if desired, be provided with dividing notches for finer adaptation of the dose. Example 21: Coated tablets, each containing 100 mg of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt, thereof, can be prepared as follows: Composition (for 1.000 coated tablets) active ingredient 100.0 g lactose 100.0 g corn starch 70.0 g talcum 8.5 g calcium stearate 1.5 g hydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s. methylene chloride q.s. The active ingredient, the lactose and 40 g of the com starch are mixed, and the mixture is moistened with a paste, prepared from 15 g of the corn starch and water (with heating), and granulated. The granulate is dried, the remaining corn starch, the talcum and the calcium stearate are added and mixed with the granulate. The mixture is compressed to form tablets (weight: 280 mg), which are coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride. Final weight of the coated tablet: 283 mg. -39 Example 22: Gelatin dry-filled capsules, containing 100 mg of active ingredient, for example 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt, thereof, can be prepared, for example, as follows: Composition Cfor 1.000 capsules) active ingredient 100.0 g lactose 250.0 g microcrystalline cellulose 30.0 g. sodium lauryl sulfate 2.0 g magnesium stearate 8.0 g The sodium lauryl sulfate is added to the lyophilised active ingredient through a sieve having a mesh size of 0.2 mm. The two components are intimately mixed. Then, first the lactose is added through a sieve having a mesh size of 0.6 mm and then the microcrystalline cellulose through a sieve having a mesh size of 0.9 mm. The mixture is again intimately mixed for 10 minutes. Finally, the magnesium stearate is added through a sieve having a mesh size of 0.8 mm. After further mixing for 3 minutes, size 0 gelatin dry-fill capsules are each filled with 390 mg of the resulting formulation. Example 23: A 0.2 % injection or infusion solution of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or of a salt, for example the sodium salt, thereof can be prepared, for example, as follows: Composition (for 1.000 ampoules) active ingredient 5.0 g sodium chloride 22.5 g phosphate buffer pH = 7.4 300.0 g demineralised water ad 2500.0 ml The active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a micro-filter. The buffer solution is added, and the mixture is made up to 2500 ml with water. To prepare dosage unit forms, 1.0 or 2.5 ml are introduced into each glass ampoule, which then contains 2.0 or 5.0 mg, respectively, of active ingredient. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> -40- Example 24: In a manner analogous to that described in Examples 1 to 10 also the following compound can be manufactured: 2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester, m.p. 230-233° (decomp.); 2-amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester, m.p. 177-180°, and 2-amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester, m.p. 243-244° (decomp.). Example 25: In a manner analogous to that described in Examples 20 to 23, it is also possible to prepare pharmaceutical preparations containing a different compound of formula I according to any one of Examples 1 to 19. and 24 -41 - WHAT WE CLAIM IS:~ 1. Substituted 2-aminoalk-3-enoic acid derivatives of formula I O HO II HO R nh2 (D, wherein R^ is hydroxy-Ci-Cyalkyl, dihydroxy-C2*C7alkyl, C2-C7alkanoyloxy-Ci-C7-alkyl, benzoyloxy-Ci-C7alkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, Ci-C4alkoxy-Ci-C7alkyl, a phenyl-Ci-C4alkoxy-Ci-C7alkyl group that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, halo-Ci-C7alkyl, in which halogen is chlorine or fluorine, amino-Ci-C7alkyl, Ci-C4alkylamino-Ci-C7alkyl, C2*C7alkanoyl-amino-Ci-Ojalkyl, N-C2-C7alkanoyl-N-Ci-C4alkylamino-Ci-C7-alkyl, di-Ci-C7alkyl-amino-Ci-C7alkyl, azacycloalk-l-yl-Ci-O/alkyl, azacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, l-C2-C7alkanoylazacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, N-Ci-C4alkylazacycloalk-3-yl-Ci-C7aIkyl or -4-yl-Cj-C7alkyl, N-Ci-C4benzoylaza-cycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, diazacycloalk-l-yl-Ci-C7alkyl, N'-Ci-C4alkyldiazacycloalk-l-yl-Ci-C7alkyl, N'-C2-C7alkanoylazacycloalk-l-yl-Ci-C7alkyl, azoxacycloalk-l-yl-Ci-C7alkyl, 5- to 7-membered oxacyclo-alk-3-yl-Ci-C7alkyl or-4-yl-C]-C7alkyl, 5- to 7-membered azacycloalk-3-yl or -4-yl or l-C2-C7alkanoylazacycloalk-3-yl or -4-yl, N-Ci-C4alkylazacycloalk-3-yl or -4-yl, or N-benzoylazacycloalk-3-yl or -4-yl that is unsubstituted or substituted in the phenyl moiety, or 5- to 7-membered oxacycloalk-3-yl or -4-yl, and R2 is carboxy, C1-C4-alkoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, or phenyl-Ci-C4alkoxycarbonyl that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, and their salts. 2. Compounds according to claim 1 of formula I, wherein R\ is hydroxy-Ci-C7alkyl, benzoyloxy-Ci[-C7alkyl that is unsubstituted or mono- or di-substituted in the phenyl r -42- moiety by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, phenyl-Ci^alkoxy-Ci-Cyalkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by C[-C4alkyl, Q-C4-alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, halo-Ci-Cyalkyl, in which halogen is chlorine or fluorine, amino-C4-C7alkyl, N-C2-C7alkanoyl-N-Ci-C4alkylamino-Ci-C7alkyl or 5- to 7-membered azacycloalk-3-yI or -4-yl or l-C2-C7alkanoylazacycloalk-3-yI or -4-yl, and R2 is carboxy, Ci-C4alkoxycarbonyl or phenyl-Cj-Gialkoxycarbonyl that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, Cj-C^alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, and their salts. 3. Compounds according to claim 1 of formula I, wherein Rj is Ci-C4alkylamino-Ci-C7-alkyl, C2-C7alkanoylamino-Ci"C7alkyl, di-Ci-C4alkylamino-Ci-C7alkyl or 5- to 7-membered N,N-(aza-, oxa- or thia-alkylene)amino-Ci-C7alkyl, piperidinopentyl or piperidinohexyl, and R2 is carboxy, Ci*C4alkoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl or phenyl-Ci-C4alkoxycarbonyl that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, C]-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, and their salts. 4. Compounds according to claim 1 of formula I, wherein Rj is hydroxy-Ci-C7alkyl, Ci-C4alkoxy-Ci-C7alkyl, benzoyloxy-C]-C4alkyl, amino-C4-C7alkyl, N-C2-C7-alkanoyl-N-Ci-C4alkylamino-C2-C7alkyl, 5- to 7-membered azacycloalk-3-yl or -4-yl or

1-C2-C7alkanoylazacycloalk-3-yl or -4-yl, or halo-Ci-C4alkyl, in which halogen is chlorine or fluorine, and R2 is carboxy or Ci-C4alkoxycarbonyl, and their salts. 5. Compounds according to claim 1 of formula I, wherein R\ is hydroxy methyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-benzoyloxyethyl, benzyloxymethyl,

2-benzyloxyethyl, 4-aminobutyl, 6-aminohexyl, 2-(N-acetyl-N-methylamino)ethyl, piperidin-4-yl, l-acetylpiperidin-4-yl or 2-fluoroethyl, and R2 is carboxy or Ci-C4alkoxycarbonyl, and their salts. 6. Compounds according to claim 1 of formula I, wherein Rps amino-C4-C7alkyl, N-Ci-C4alkanoyl-N-Ci-C4alkylamino-Ci-C7alkyl, piperidin-4-yl or I-C2-C7-alkanoylpiperidin-4-yl, and R2 is carboxy or Ci-C4alkoxycarbonyl, and their salts. 7. Compounds according to claim 1 of formula I, wherein R[ is hydroxy-Ci-C4alkyl, r> -4

3- Ci-C4aIkoxy-C]_-C4alkyl, phenyl-C\-C4alkoxy-C\-C4alkyl, benzoyloxy-Ci-C4alkyl or halo-C2-C4alkyl, and R2 is carboxy or Ci-C4alkoxycarbonyl, and their salts. 8. Compounds according to claim 1 of formula I, wherein Rj is amino-C

4-C7alkyI and R2 is carboxy, Ci-C4alkoxycarbonyl or a phenyl-C i-C4alkoxycarbonyl group that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, and their salts. 9. Compounds according to claim 1 of formula I, wherein Rj is Ci-C4alkoxy-C2-C4alkyI, hydroxy-C2-C4alkyl or halo-C2-C4alkyl, and R2 is carboxy, Ct-C4alkoxycarbonyl or a phenyl-Ci-C4alkoxycarbonyl group that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, and their salts. 10. 2-Amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 11. 2-Amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof. 12. 2,10-Diamino-4-phosphonomethyl-dec-3-enoic acid or a salt thereof. 13. 2,8-Diamino-4-phosphonomethyl-oct-3-enoic acid or a salt thereof. 14. 2-Amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 15. 2-Amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 16. 2-Amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof. 17. 2-Amino-6-benzoyloxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 18. 2-Amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester or a salt thereof. 19. 2-Amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid or a salt thereof. 20.2-Amino-6-benzyloxy-4-phosphonomethyI-hex-3-enoic acid or a salt thereof. -44- 21. 6-(N-Acetyl-N-methylamino)-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 22. 4- (l-Acetylpiperidin-4-yl) -2-amino-

5-pho3phono-pent-3-enoic acid ethyl ester or a salt thereof. 23.2,10-Diamino-4-phosphonomethyI-dec-3-enoic acid ethyl ester or a salt thereof. 24. 2-Amino-

6-fluoro-4-phosphonomethyl-hex-3-enoic acid or a salt thereof. 25.2-Amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester or a salt thereof. 26. 2-Amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid or a salt thereof. 27. 2-Amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester or a salt thereof. 28. 2-Amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid or a salt thereof. 29. 2-Amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester or a salt thereof. 30. 2-Amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid or a salt thereof. 31. 2-Amino-6-(N-methylamino)-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 32. 2-Amino-6-(N-methylamino)-4-phosphonomethyl-hex-3-enoic acid or a salt thereof. 33. 2-Amino-4-(piperidin-4-yl)-5-phosphono-pent-3-enoic acid ethyl ester or a salt thereof. 34. 2-Amino-4-(piperidin-4-yl)-5-phosphono-pent-3-enoic acid or a salt thereof. 35. 5-Ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid or a salt thereof. ' U .1 o'W'- ' -45- 36. 5-Ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester or a salt thereof. 37. 2-Amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester or a salt thereof. 38. 2-Amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 39. 2-Amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester or a salt thereof. 40. Pharmaceutical preparations containing a compound according to any one of claims 1, 2,4 to 7 and 16 to 35 in free form or in the form of a pharmaceutically acceptable salt 41. Pharmaceutical preparations containing a compound according to any one of claims 3, 8 to 15 and 36 to 39 in free form or in the form of a pharmaceutically acceptable salt 42. A process for the preparation of unsaturated aminocarboxylic acid derivatives of formula I as claimed in claim 1 and of their salts, which comprises in a compound of formula II optionally protected hydroxy-Ci-Cyalkyl, optionally protected dihydroxy-C2-C7alkyl, C2-C7alkanoyloxy-Ci-C7alkyl, benzoyloxy-Ci-C7alkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by C1-C4alkyl, Ci*C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, C1-C4-alkoxy-C;[-C7alkyl, a phenyl-Ci-C4alkoxy-Ci-C7alkyl group that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, Ci-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, halo-Ci-C7alkyl, in which halogen is chlorine or fluorine, wherein Zj and 2^ are optionally protected hydroxy, is r 10 SEP 1992 r -46- optionally protected amino-Ci-Cyalkyl, optionally protected Ci-C4alkylamino-Ci-C

7-alkyl, C2-C7alkanoylamino-C]i-C7alkyl, N-C2-C7alkanoyl-N-Ci-C4alkylamino-Ci-C7-alkyl, di-Ci-C7alkylamino-Ci-C7alkyl, azacycloalk-l-yl-Ci-C7alkyl, optionally protected azacycloalk-3-yl-Q-C7alkyl or -4-yl-Ci-C7alkyl, I-C2-C7-alkanoylazacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, N-C1-C4-alkylazacycloalk-3-yI-Ci-C7alkyl or -4-yl-Ci-C7alkyl, N-Ci-C4benzoylaza-cycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, diazacycloalk-l-yl-Ci-C7alkyl, N'-Ci-C4alkyldiazacycloalk-l-yl-Ci-C7alkyl, N'-C2-C7alkanoylazacycloalk-l-yl-Ci-C7alkyl, azoxacycloalk-l-yl-Ci-C7alkyl, 5- to 7-membered oxacycloalk-3-yl-Ci-C7alkyl or -4-yl-Ci-C7alkyl, optionally protected 5- to 7-membered azacycloalk-3-yl or-4-yl or l-C2-C7alkanoylazacycloalk-3-yl or-4-yl, N-Ci-C4alkylazacycloalk-3-yl or -4-yl, or N-benzoylazacycloalk-3-yl or -4-yl that is unsubstituted or substituted in the phenyl moiety, or 5- to 7-membered oxacycloalk-3-yl or -4-yl, and Z4 is protected amino, converting protected amino Z4 and, if present, protected amino as a constituent of Z3 into amino and, if present, converting protected hydroxy Z\ and Z2 and/or protected hydroxy as a constituent of Z3 into hydroxy and, if present, freeing a protected azacycloaliphatic hydrocarbon radical Z3 and, if desired, converting a resulting compound into a different compound of formula I, separating an isomeric mixture obtainable in accordance with the process into its components and separating the preferred isomer, and/or converting a free compound obtainable in accordance with the process into a salt or converting a salt obtainable in accordance with the process into the corresponding free compound. CIBA GEIGY AG toy Attorneys raBDWIN, SON & CAREY Attorneys </div>