DD298105A5 - PROCESS FOR PREPARING 4-SUBSTITUTED 2-AMINOALK-3-ENSAEURES - Google Patents

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

The invention relates to a process for the preparation of substituted г-АтіпоаІк-З-епзаигесіегіѵаіе of formula I.

wherein RI is an optionally acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally acylated and / or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxacycloaliphatischen radical substituted aliphatic or bonded via a C atom oxacycloaliphatic or optionally aliphatic N-substituted or N-acylated azacycloaliphatic hydrocarbon radical and R _{2 is} free or esterified carboxy, and their salts.

Aliphatic hydrocarbon radicals are, for example, alkyl radicals of up to and including 10, in particular to and having 8 carbon atoms, preferably lower alkyl radicals.

Hydroxy-substituted aliphatic hydrocarbon radicals are, for example, mono- or dihydroxy-lower alkyl. Acylated hydroxy is, for example, lower alkanoyloxy or benzoyloxy optionally substituted in the phenyl moiety. Accordingly, an aliphatic hydrocarbon radical substituted by acylated hydroxy is understood to mean, for example, lower alkanoyloxy-lower alkyl or benzoyl-lower alkyl optionally substituted in the phenyl moiety. Aliphatically etherified hydroxy is, for example, lower alkoxy; araliphatic etherified hydroxy optionally substituted phenyl-lower alkoxy. Accordingly, by aliphatic etherified hydroxy-substituted aliphatic hydrocarbon radical is exemplified by lower alkoxy-lower alkyl and by aliphatic hydrocarbon radical substituted by araliphatic etherified hydroxy, for example, optionally substituted phenyl-lower alkoxy-lower alkyl.

A halogen-substituted aliphatic hydrocarbon radical is, for example, halo-lower alkyl. Optionally acylated and / or aliphatically substituted amino is, for example, amino, N-mono- or N, N-di-lower alkylamino, N-lower alkanoylamino, in the phenyl moiety optionally substituted N-benzoylamino or N-lower alkanoyl-N-lower alkylamino. Accordingly, aliphatic hydrocarbon radicals which are optionally substituted by acylated and / or aliphatically substituted amino groups are, for example, lower alkylamino, lower alkylamino, lower alkanoylamino, lower, lower alkylamino, lower alkylanoyl, lower alkylamino, lower alkylamino, lower alkylamino, lower alkylamino, lower alkylamino, lower alkylamino, lower alkylamino

Aliphatic hydrocarbon radicals substituted by an azacycloaliphatic radical are, for example, 4- to 7-membered azacycloalkyl-lower alkyl radicals whose azacycloalkyl moiety is attached via the N or C atom and optionally N-lower alkylated in the latter case, N-lower alkanoylated or N-substituted by a benzoyl group which is optionally substituted in the phenyl moiety can be. 4- to 7-membered Azacycloalkylniederalkyl whose Azacycloalkylteil is attached via the N-atom, means, for example N, N-lower alkyleneamino-Ci ^ Valkyl / dh Azacycloalk-1-yl-C _l -C ₇ alkyl. 4- to 7-membered Azacycloalkylniederalkyl whose Azacycloalkylteil bound via a carbon atom and optionally N-lower alkylated, N-lower alkanoylated or N-substituted by a phenyl moiety in the optionally substituted benzoyl group, for example, 5- to 7-membered, bound via a carbon atom azacycloalkyl -Ci-cy-alkyl or N-Cr-CT-alkanoylazacycloalkyl-C ₁ -C ₇ -alkyl, furthermore N-Ci-C ^ AIkylazacycloalkyl-C! -C ₇ -alkyl or in the phenyl moiety optionally substituted N-benzoylazacycloalkyl-C ^ Cy alkyl.

Examples of aliphatic hydrocarbon radicals substituted by a diazacycloaliphatic radical are 4- to 7-membered diazacycloalkyl-lower alkyl radicals whose diazacycloalkyl moiety is bonded via an N atom and optionally lower alkylated, lower alkanoylated or substituted by a benzoyl group optionally substituted in the phenyl moiety, such as 4 to 7-membered, N-linked or N'-lower alkylated, N'-lower alkanoylated or by an optionally substituted in the phenyl moiety N'-substituted Diazacycloalkylniederalkylreste, in particular 5- to 7-membered diazacycloalk-i-yl-Cv-CT-alkyl.

Examples of aliphatic hydrocarbon radicals substituted by an azoxacycloaliphatic radical are 4- to 7-membered azoxacycloalkyl-lower alkyl radicals whose azoxacycloalkyl moiety is bonded via the N atom, such as 4- to 7-membered, N-atom-bonded azoxacycloalkyl-lower alkyl radicals, in particular 5- to 7-membered N, N-oxo-lower alkylamino radicals. Ci-CT-alkyl, d. H. Azoxacycloalk-1-yl-Cytacykyl.

Examples of aliphatic hydrocarbon radicals substituted by an oxacycloaliphatic radical are 4 to 7-membered oxacycloalkyl-lower alkyl radicals whose oxacycloalkyl moiety is bonded via a C atom, such as 5- to 7-membered oxacycloalkyl-CH 1 -alkyl bonded via a C atom.

Oxacycloaliphatic hydrocarbon radicals bonded via a C atom are, for example, 5- to 7-membered oxacycloalkyl groups bonded via a C atom.

Via a C atoms bonded, optionally aliphatic N-substituted or N-acylated azacycloaliphatic hydrocarbon radicals are bonded via a carbon atom optionally N-lower alkylated, N-lower alkanoylated or by in the phenyl moiety optionally substituted benzoyl N-substituted Azacycloalkylreste, such as 5- to 7-membered azacycloalkyl bonded via a carbon atom or N-Cr-C, alkanoylazacycloalkyl, furthermore N-Cr-Q-alkylazacycloalkyl or optionally substituted N-benzoylazacycloalkyl.

Esterified carboxy is, for example, carboxy esterified with an aliphatic, cycloaliphatic or araliphatic alcohol, such as lower alkoxycarbonyl, 4- to and 7-membered, especially 5- or 6-membered cycloalkoxycarbonyl, such as cyclopentyloxy or cyclohexyloxycarbonyl, or optionally substituted phenyl-lower alkoxycarbonyf.

In the abovementioned groups, phenyl radicals may be unsubstituted or in the usual way, for example by lower alkyl, lower alkoxy, halogen, cyano and / or trifluoromethyl, mono-, di-or trisubstituted, in particular mono- or disubstituted.

Above and below, lower radicals and compounds are, for example, those which have up to and including 7, preferably up to and including 4, carbon atoms (C atoms).

Lower alkyl is, for example, C- | -C ₇ alkyl, preferably C ₁ -C ₄ -alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, secondary butyl, tertiary butyl or a pentyl, hexyl or heptyl ,

Mono- or dihydroxy-lower alkyl is, for example, hydroxy-C 1 -C ₇ -alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl, or dihydroxy-C 2 -C ₇ -alkyl, in which the hydroxy groups are bonded to various carbon atoms, such as 1,2-dihydroxyethyl or in particular 1, S-dihydroxyprop ^ -yl.

Lower alkanoyl is, for example, C ₂ -C ₇ -alkyl, in particular Сг-Сд-АкапоуІ, such as acetyl, propionyl or butyryl. However, it may also be a C ₆ -C ₆ -alkanoyl group, such as pivaloyl. Accordingly Niederalkanoyloxyniederalkyl is in particular C ₂ -C ₇ alkanoyloxy-C, -C ₇ alkyl, such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-Acetyloxyäthyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 5-or 6-acetyloxyhexyl Acetyloxypentyl. By analogy, benzoyloxy-lower alkyl is, for example, in the phenyl part, optionally substituted, C ₁ -C ₆ -y1-cyano-C ₁ -C ₇ -alkyl, such as benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, 5-benzoyloxypentyl or 6-benzoyloxyhexyl.

Lower alkoxy is, for example, Ci-C ₇ -alkoxy, preferably C ₁ -C ₄ -alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but also isobutyloxy, Sekundärbutyloxy, Tertiärbutyloxy or a pentyloxy, hexyloxy or heptyloxy group can be. Correspondingly Niederalkoxyniederalkyl means, for example, C ₁ -C ₄ -alkoxy C ₁ -C ₇ alkyl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl or 6-methoxyhexyl.

For example, phenyl-lower alkoxy optionally represents substituted phenyl-Ci-Q-alkoxy as indicated, such as benzyloxy, 2-phenylethoxy or 3-phenylpropyloxy. Correspondingly Phenylniederalkoxyniederalkyl means, for example, optionally substituted as indicated phenyl - ^ - ^ - alkoxy-Ci-C ^ alkyl, such as benzyloxymethyl, 2-Phenyläthoxymethyl-, 2-Benzyloxyäthyl-, 3-Benzyloxypropyl-, 4-Benzyloxybutyl-, 5- Benzyloxypentyl or 6-Benzyloxyhexylrest.

Halo-lower alkyl is, for example, halo-C 1 -C 7 -alkyl, such as halomethyl, 2-haloGbnSiHybS-HaIOgCnPrOPyI, 4-halobutyl, 5-halopentyl or 6-halohexyl, where halogen is chlorine or in particular fluorine.

Amino-lower alkyl is, for example, amino-C 1 -C 4 -alkyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-aminohexyl.

Lower alkylamino is, for example, C 1 -C 4 -alkylamino, in particular C 1 -C 4 -alkylamino, such as methylamino, ethylamino, propylamino or butylamino, but may also be a C 5 -C 12 -alkylamino group, such as pentylamino or hexylamino group.

Accordingly, lower alkylamino-lower alkyl is in particular C ₁ -C ₄ -alkyl-methyl-C ₁ -C ₇ -alkyl, such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl.

Lower alkanoylamino is, for example, C 1 -C ₇ -alkanoylamino, in particular Сг-С ^ АІкапоуІатіпо, such as acetylamino, propionylamino or butyrylamino, but may also be C ₅ -C -alkanoylamino, such as pivaloylamino. Accordingly, lower alkanoyl-amino-lower alkyl is especially C ₂ -C ₇ -alkanoylamino-C ₁ -C ₇ -alkyl, such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl. By analogy, benzoylamino-lower alkyl, for example, in the phenyl moiety, is to be understood as meaning optionally substituted benzoylamino-C 1 -C -alkyl, such as benzoylaminomethyl, 2-benzoylaminoethyl, 3-benzoylaminopropyl, 4-benzoylaminobutyl, 5-benzoylaminopentyl or 6-benzoylaminohexyl.

Diniederalkylamino is, for example, di-C-i-C ^ alkylamino, in particular di-CHV-alkylamino, such as dimethylamino, diethylamino, N-ethyl-N-methyl-amino, N-methyl-N-propyl-amino, dipropylamino or dibutylamino. Accordingly, di-lower alkylamino-lower alkyl is in particular di - ^ -Q-alkylamino-Ci-C ^ alkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methyl-aminomethyl, N-methyl-N-propyl-aminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl , 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or -dimethylaminohexyl.

N-lower alkanoyl-N-lower alkyl-amino-lower alkyl is, for example, C ₂ -C ₇ -alkanoyl-N-C ₁ -C ₄ -alkyl-amino-C ₁ -C ₄ -alkyl, such as N-acetyl-N-methylaminomethyl, N-acetyl -N-ethyl-aminomethyl, N-propionyl-N-aminomethyl, N-butyryl-N-methylaminomethyl, 2- (N-acetyl-N-methyl-amino) ethyl, 2- (N-propionyl-N-methyl-amino ) ethyl, 2- (N-acetyl-N-ethyl-amino) -ethyl, 3- {N-acetyl-N-methyl-amino) -propyl, 4- (N-acetyl-N-methyl-amino) -butyl, S- fN-acetyl-N-methyl-aminolpentyl or 6- (N-acetyl-N-methyl-amino) hexyl.

4-7g (lower N-atom linked azacycloalkyl-C ₁ -C ₇ -a (kyl is preferably NN-lower acylofenamino-Cr-CT-alkyl, ie azacycloalk-1-yl-C 1 -C 4 -alkyl, for example pyrrolidinomethyl, Piperidinomethyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 3-pyrrolidinopropyl, 3-piperidinopropyl, 4-pyrrolidinobutyl, 4-piperidinobutyl, 5-pyrrolidinopentyl, 5-piperidinopentyl, 6-pyrrolidinohexyl or 6-piperidinohexyl.

4- to 7-membered, bound via a carbon atom azacycloalkyl-CHW-alkyl is preferably AZaCyClOaIk-S-4-yl-Ci-C ₇ -alkyl, eg piperidin-4-ylmethyl, 2- (piperidin-4-yl) ethyl , 3- (piperidin-4-yl) propyl or 4- (piperidin-4-yl) butyl.

5- to 7-member C-atom bonded N-Cz-Cr alkanoylazacycloalkyl-C-С-Ст-аІкуІ is preferably 1-C ₂ -C ₇ alkanoylazacycloalk-3-yl-Ci-C ^ alkyl or 4-Yl -C ₁ -C ₇ -BlkYl, for example, i-acetylpiperidin-4-ylmethyl, 2- (1-acetylpiperidin-4-yl) ethyl, 3- (1-acetylpiperidin-4-yl) propyl or 4- (1-acetylpiperidine-4 -yl) butyl.

5- to 7-membered, bonded via a carbon atom N - ^ - C ^ AIkylazacycloalkyl Ci-C ^ alkyl is preferably NC ₁ -C ₄ -Alkylazacycloalk-3-yl-C ^ ^ alkylbzw. 4-у1-С! -С ₇ -а1ку1, г.В. i-methylpiperidin-4-ylmethyl, i-ethylpiperidin-4-ylmethyl, 2- (1-methylpiperidin-4-yl) ethyl, 2- (1-ethylpiperidin-4-yl) ethyl, 3- (1-methylpiperidine-4 -yl) propyl, 3- (1-ethylpiperidin-4-yl) propyl, 4- (1-methylpiperidin-4-yl) butyl or 4- (1-ethylpiperidin-4-yl) butyl.

5- to 7-membered, bound via a carbon atom and optionally substituted in the phenyl moiety N-Benzoylazacycloalkyl-CHV alkyl is preferably N-Ci-Q-Benzoylazacycloalk-3-уІ-Ст-С ^ aІкуІ or 4-yl-Ci-C ₇ -alkyl, ζ. For example, i-benzoylpiperidin-4-ylmethyl, 2- (1-benzoylpiperidin-4-yl) ethyl, 3- (1-benzoylpiperidin-4-yl) -propyl or 4- (1-benzoyl-piperidin-4-yl) -butyl. 5- to 7-membered, N-atom-bonded and optionally N'-lower alkylated, N'-lower alkanoylated or by a benzoyl group N'-substituted in the phenyl moiety N'-substituted diazacycloalk-i-yl-Ci-cralkyl is, for example, such as NN-iAzaniederalkylenlamino-CH ^ -alkyl, ie diazacycloalk-1-yl-C ₁ -C 4 -alkyl, N'-CH 2 -alkyldiazacycloalk-1-yl-C ₁ -C 4 -alkyl or N'-C ₂ -C 4 -alkanoylazacycloalk-1-yl-C ₁ -C ₇ -alkyl, For example, piperazino or N'-methyl or N'-Acetylpiperazinomethyl, 2- (piperazino or N'-methyl or N'-acetylpiperazino) ethyl, 3- (piperazino or N'-methyl or N'-acetylpiperazino) propyl or 4- (piperazino or N'-methyl or N'-acetylpiperazino) butyl.

5- to 7-membered N, N- (oxo-lower alkylene) amino-Ct-C ₇ -alkyl, ie Azoxacycloalk-i-yl-CHValkyl is, for example, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 4-morpholinobutyl.

5- to 7-member C-atom bonded oxacycloalkyl-CHValkyl is especially 5- to 7-membered oxacycloalk-3-yl-Ci-C ₇ -alkyl or oxacycloalk-4-yl-CH ^ -alkyl, such as tetrahydropyran-4-ylmethyl , 2- (Tetrahydropyran-4-yl) ethyl, 3- (tetrahydropyran-4-yl) propyl or 4- (tetrahydropyran-4-yl) butyl.

5- to 7-membered, bound via a C atom oxacycloalkyl is in particular corresponding oxacycloalk-3-yl or 4-yl, z. For example, tetrahydropyran-4-yl.

5- to 7-membered, bonded via a C atom azacycloalkyl, N-Ci-C ^ AIkylazacycloalkyl or N-C2-C ₇ -Alkanoylazacycloalkyl is preferably Azacycloalk-3-yl or 4-yl or 1-C ₂ -C ₇ - Alkanoyl-azacycloalk-3-yl or 4-yl, for example piperidin-4-yl or 1-acetylpiperidin-4-yl, also N-Ci-C ^ Alkylazacycloalk-S-yl or -4-yl or in the phenyl moiety, if appropriate substituted N-benzoylazacycloalk-3-yl or-4-yl, eg 1-methylpiperidin-4-yl or i-benzoylpiperidin-4-yl.

Lower alkoxycarbonyl is, for example, Ci-C ₇ -alkoxycarbonyl, especially C ₁ -C ₄ alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl, but also a Cg-C ^ AIkoxycarbonyl- as pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl group may be ,

Phenyl-lower alkoxycarbonyl is, for example, phenyl-Cr-Ct-alkoxycarbonyl, such as benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phepylpropoxycarbo-phenyl or 4-phepylbutyloxycarbonyl.

The compounds of formula I are in the form of internal salts due to their amphoteric character and can form both acid addition salts and salts with bases.

Acid addition salts of compounds of the formula I are, for example, their pharmaceutically usable salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, e.g. Hydrochlorides, hydrobromides, sulfates, bisulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, e.g. Methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfaminates (cyclamates).

Salts of compounds of the formula I with bases are, for example, their salts m'rt pharmaceutically acceptable bases, such as non-toxic, derived from metals of groups la, Ib, Ma and IIb metal salts, for. Alkali metal, in particular sodium or potassium salts, alkaline earth metal, in particular calcium or magnesium salts, as well ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as optionally C-hydroxylated aliphatic amines, in particular mono-, di- or Triniederalkylaminen, e.g. Methyl, ethyl, diethyl, or triethylamine, mono-, di- or tri- (hydroxy-lower alkyl) amines, such as ethanol, diethanoic or triethanolamine, tris (hydroxymethyl) methylamine or 2-hydroxytertiärbutylamin, or N- (hydroxy lower alkyl ) -N, N-lower alkyl-amines and N- (polyhydroxy-lower alkyl) -N-lower alkylamines, such as 2- (dimethylamino) ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, for. B. tetrabutylammonium hydroxide.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred. The invention relates, for example, to compounds of the formula I in which R _{1 is} an aliphatic hydrocarbon radical which is optionally substituted by aliphatic or araliphatic etherified hydroxy, optionally aliphatically substituted amino or halogen and R _{2 is} free or esterified carboxy, and their salts. The compounds of the formula I have valuable pharmacological properties. In particular, they have a pronounced and selective antagonistic activity against N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory amino acid receptors of warm-blooded animals. This can be done in vitro, for example, in the experimental arrangement according to G. Fagg and A. Matus, Proc. Nat. Acad. Sci., USA, 81, 6876-6880 (1984). It is determined to what extent the binding of L- ³ H-glutamic acid to NMDA-sensitive receptors is inhibited. The NMDA antagonistic properties of the new compounds can also in vivo z. As in the mouse, demonstrated by the inhibitory effect on NMDA-induced convulsions.

Because of these properties, the compounds of formula I and their pharmaceutically acceptable salts are excellently suited for the treatment of pathological conditions which are responsive to blocking of NMDA-sensitive receptors, for example, ischemic disorders such as cerebral ischemia and ischemic disorders of the eye Vascular and muscle spasms, such as migraine or local or general spasticity, and especially convulsions, such as epilepsy.

The anticonvulsant properties of the compounds according to the invention can be determined, for example, in the mouse on the basis of their pronounced protective action against convulsions triggered by electroshock or audiogen caused, wherein z. B. the established electroshock mouse model or the experimental arrangement according to Chapman et al., Arzneimittel-Forsch. 34,1261 (1984). The compounds according to the invention are characterized, in particular in the electroshock mouse model, by an effect which is improved compared to structurally related compounds.

The antiperspirant properties of the compounds provided by the present invention for the treatment of migraine can be demonstrated, for example, in the rat by their anti-depressant action in the frontal cortex according to the experimental set-up of R. Maranes et al. Brain Res. 457,226 (1988). In this model, the compounds provided according to the invention reduce ip in the dose range of about 3 to 30 mg / kg. the threshold of "spreading depression" and shorten its duration.

The invention relates primarily to compounds of the formula I in which R _{1 is} mono- or dihydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, benzyloxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkoxy-lower alkyl, lower haloalkyl, lower-lower alkyl, lower-alkyl-amino-lower alkyl, lower alkanoyl-amino-lower alkyl, lower di-lower alkylamino, lower N-lower alkanoyl-lower alkyl, 5- to 7-membered Azacycloalkylniederalkyl whose Azacycloalkylsteil bound via the N or a C atom and optionally N-lower alkanoylated in the second case, N-lower alkanoylated or N-substituted by a phenyl moiety in the optionally substituted benzoyl, 5- to 7-membered Diazacycloalkylniederalkyl whose Diazacycloalkylteil on a N-atom bonded and optionally N'-lower alkylated, N'-lower alkanoylated or N'-substituted by a benzoyl group optionally substituted in the phenyl moiety, 5- to 7-membered, bound via the N-atom Azoxacycloalk lower alkyl, 5- to 7-membered oxacycloalkyl-lower alkyl bonded via a C atom, 5- to 7-membered, C-atom-bonded, optionally N-lower-alkylated, N-lower alkanoylated or N-substituted by a benzoyl group which is optionally substituted in the phenyl moiety, or to 7-membered, bonded via a C atom oxacycloalkyl and R _{2 is} carboxy, lower alkoxycarbonyl, 4- and with 7-membered cycloalkoxycarbonyl or Phenylniederalkoxycarbonyl, wherein in said groups R ₁ and / or R ₂ optionally unsubstituted phenyl or lower alkyl, lower alkoxy , Halogen, cyano and / or trifluoromethyl can be mono-, di- or trisubstituted, and their salts.

The invention relates primarily to, for example, compounds of the formula I in which R _{1 is} hydroxy lower alkyl, lower alkoxy, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkylamino, N, N- (aza- or Oxaniederalkylen) aminoloweralkyl or halo-lower alkyl and R _{2 represents} carboxy, lower alkoxycarbonyl, 4- to and 7-membered cycloalkoxycarbonyl or phenyl-lower alkoxycarbonyl, where in said groups R ₁ and / or R ₂ optionally unsubstituted phenyl or by lower alkyl, lower alkoxy, halogen, cyano and / or trifluoromethyl mono-, di - or trisubstituted, and their salts.

The invention relates in particular to compounds of the formula I in which R _{1 is} hydroxy-C ₁ -C ₄ -alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, dihydroxy-C ₂ -C ₇ -alkyl, such as 1,3 -Dihydroxyprop-2-yl, Сг-Су-АІкапоуІоху - ^ - Су-аІкуІ, such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetyloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 5-acetyloxypentyl or 6-acetyloxyhexyl, in the phenyl moiety, if necessary mono- C ₁ -C ₄ -alkyl, such as methyl, Ci-C ₄ -alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and / or trifluoromethyl or di-substituted benzoyloxy-C! _-C7 -alkyl, such as benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, 5-benzoyloxypentyl or 6-benzoyloxyhexyl, CHVAlkoxy-CHValkyl such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 3-methoxypropyl or 4-methoxybutyl, one in the phenyl moiety optionally by C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, such as methoxy, halogens n is the atomic number to and with 35, such as fluorine or chlorine, cyano and / or trifluoromethyl mono- or di-substituted phenyl-C ^ C ^ alkoxy-Ci-Cy-alkyl group, such as benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl Is halogeno-Cp-C ₇ -alkyl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, where halogen is chlorine or in particular fluorine, amino C ₁ -C ₇ -alkyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-aminohexyl, C ₁ -C ₄ -alkylCiIiIrImO-C ₁ -C 7 -alkyl, such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl, C 2 -C 7 alkanoylamino-C 1 -C 7 -alkyl, such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, NC ₂ -C ₇ -AlkBnOyI-NC ₁ -C 1 alkylamino-ci C ₇ alkyl, such as N-acetyl-N-methyl-aminomethyl, N-acetyl-N-ethylaminomethyl, N-propionyl-N-methyl-aminomethyl, N-butyryl-N-methylamino-methyl, 2- (N-acetyl -N-methyl-amino) ethyl, 2- (N-propionyl-N-methyl-amino) ethyl, 2- (N-acetyl-N-ethylamino) ethyl, S-fN-acetyl-N-methyl-aminolpropyl, 4 - (N-acetyl-N-methyl-amino) -butyl, 5- (N-acetyl-N-methyl-amino) -pentyl or e-fN-acetyl-N-methyl-amino-hexyl, di-C ₁ -C ₇ -alkylamino -C ₁ -C ₇ -alkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methyl-aminomethyl, N-methyl-N-propyl-aminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, S-dimethylaminopropyl ^ -Dimethylaminobutyl, S Dimethylaminopentylodere-dimethylaminohexyl, azacycloalk-1-yl-C ₁ -C ₇ -alkyl, such as pyrrolidinomethyl, piperidinomethyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 3-pyrrolidinopropyl, 3-piperidinopropyl, 4-pyrrolidinobutyl, 4-piperidinobutyl, 5- Pyrrolidinopentyl, 5-piperidinopentyl, 6-pyrrolidinohexyl or 6-piperidinohexyl, АгасусІоаІк-З -уІ - ^ - СѵаІкуІ or 4-Yl-C ₁ -C ₇ -BlClicy, z. Piperidin-4-ylmethyl, 2- (piperidin-4-yl) ethyl, 3- (piperidin-4-yl) -propyl or 4- (piperidin-4-yl) -butyl, С-Сг-С ^ АІкапоуІагасусІоаІк-З -уІ-Сі-С ^ аІкуІ or 4-yl-Ci-Cvalkyl, for example, i-acetylpiperidin-4-ylmethyl, 2- (1-acetylpiperidin-4-yl) ethyl, 3- (1-acetylpiperidin-4-yl ) propyl-4- (1-acetylpiperidin-4-yl) butyl, N-Ci-C ^ Alkylazacycloalk-3-Yl-C ₁ -C ₇ -SIlCyIbZW. 4-Yl-C ₁ -C ₇ -silyl, for example i-methylpiperidin-4-ylmethyl, i-ethylpiperidin-4-ylmethyl, 2- (1-methylpiperidin-4-y-ethyl, 2- (1-ethylpiperidin-4-yl ) ethyl, Sd-methylpiperidine ^ -dpropyl ^ -d-ethylpiperidine ^ -ypropyl ^ -d-methylpiperidin-1-y-butyl or 4- (1-ethylpiperidin-4-yl) -butyl, NC ₁ -C ₄ -benzoylazacycloalk-3-yl C ₁ -C ₇ alkyl or 4-Yl-C ₁ -C ₇ -symyl-BI-benzoylpiperidin-4-ylmethyl, 2- (1-benzoylpiperidin-4-yl) ethyl, 3- (1-benzoylpiperidine-4 -yl) propyl-4- (1-benzoylpiperidin-4-y-butyl, diazacycloalk-1-Yl-C ₁ -C ₇ -silyl, N'-C ₁ -C ₄ -alkyldiazacycloalk-1-yl-C _l -C ₇ -alkyl or N'-CH ^ -Alkanoylazacycloalk-i-yl-C! -C ₇ alkyl, for example piperazino or N'-methyl or N'-acetylpiperazinomethyl, 2- (piperazino or N'-methyl or N-acetylpiperazino) ethyl, 3- (piperazino or N'-methyl or N'-acetyl-piperazino) propyl or 4- (piperazino or N'-methyl)

or N'-acetylpiperazino) butyl, azoxacycloalkyl-1-yl-Cr-cralkyl, for example morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 4-morpholinobutyl, 5- to 7-membered oxy-saccharide-З-уІ-СНѴаІкуІ or -4-yl -C ₁ -C 7 -alkyl, such as tetrahydropyran-4-ylmethyl, 2- (tetrahydropyran-4-yl) ethyl, 3- (tetrahydropyran-4-yl) propyl or 4- (tetrahydropyran-4-yDbutyl, 5- to 7-membered Azocycloalk-3-yl or 4-yl or С-С-Су-АІкапоуІ-агасусІоаІк-З-уІ or 4-yl, for example piperidin-4-yl or 1-acetylpiperidin-4-yl, NC, -C4- Alkylazacycloalk-3-yl or -4-yl or in the phenyl moiety optionally substituted N-benzoylazacycloalk-3-yl or -4-yl, for example 1-methylpiperidin-4-yl or i-benzoylpiperidin-4-yl, or 5- to 7-membered oxacycloalk-3-yl or 4-yl, for example tetrahydropyran-4-yl, and R _{2 is} carboxy, Ci-C ^ alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, such as cyclopentyloxy or cyclohexyloxycarbonyl , or ge optionally C ₁ -C ₄ -alkyl, such as methyl, C ₁ -C ₄ -alkoxy, such as methoxy, halogen of the atomic number up to and including 35, such as fluorine or chlorine, cyano and / or trifluoromethyl mono- or disubstituted РгіепуМ ^ -Сд-аІкохусагЬопуІ, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.

The invention particularly relates, for example, to compounds of the formula I in which R _{1 is} hydroxy-C ₁ -C ₄ -alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₇ -BIkYl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl or 4-methoxybutyl, in the phenyl part optionally by C ₁ -C ₄ alkyl, such as methyl, C ₁ -C ₄ -alkoxy, such as methoxy , Halogen of the atomic number up to and including 35, such as fluorine or chlorine, cyano and / or trifluoromethyl mono-, di- or trisubstituted phenyl-Cr-C ^ alkoxy - ^ - alkyl, such as benzyloxymethyl, 2-Benzyloxyäthyl-, 3 Benzyloxypropyl or 4-benzyloxybutyl group, amino-Ci-Cy-alkyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-Aminopentvl or б-АтіпоЬехуІ.Ся-С ^ -АІкуІатіпо-С ^ -Ст -aceton, such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or the like r 6-methylaminohexyl, C _z -C ₇ -alkanoylamino-C ₁ -C ₇ -alkyl, such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, di- C ₁ -C ₇ -alkylamino-C ₁ -C ₇ -alkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 3 Dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or 6-dimethylaminohexyl, 5 to ₇ membered N, N-alkylene- ₁ -p-C ₁ -C ₇ -alkyl; N, N- (aza or Oxaalkylenlamino - ^ - C ^ alkyl, such as pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, piperazine or N'-methyl or N'-acetylpiperazinomethyl, 2-Pyrrolidinoäthyl, 2-Piperidinoäthyl, 2-Morpholinoäthyl , 3-pyrrolidinopropyl, 3-piperidinopropyl, 3-morpholinopropyl, 4-pyrrolidinobutyl, 4-piperidinobutyl, 5-pyrrolidinopentyl, 5-piperidinopentyl or 6-piperidinohexyl, or halo-C 1 -C 4 -alkyl such as halomethyl, 2-haloethyl, 3 Halo-propyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, where halogen is chlorine or in particular fluorine and R _{2 is} carboxy, dQ-alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5 to 7-membered cycloalkoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxycarbonyl, or optionally by C ₁ -C 6 -alkyl, such as methyl, C ₁ -C ₄ -alkoxy, _1- hexahoxy, halogen of the atomic number up to and including phenyl, C ₁ -C ₄ -alkoxycarbonyl mono- or disubstituted, such as fluorine or chlorine, cyano and / or trifluoromethyl, such as benzyloxycarbonyl or 2 Phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts. The invention preferably relates to compounds of the formula I in which R _{1 is} hydroxyC ₁ -C ₄ -alkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl, in the phenyl part, where appropriate by C ₁ -C ₄ -alkyl, such as methyl, C ₁ -C ₄ - AIkOXy, such as methoxy, halogen of atomic number to and with 35, such as fluorine or chlorine, cyano and / or trifluoromethyl mono- or di-substituted benzoyloxy-CiC ^ alkyl, such as 2-Benzoyloxyäthyl, dC ^ AIkoxy-Ci-Cy-alkyl, such as ethoxymethyl or 2-methoxyethyl, in the phenyl part optionally by C ₁ -C ₄ -A ^ yI, such as methyl, C ₁ -C ₄ -alkoxy, such as methoxy, halogen of the atomic number to and with 35, such as fluorine or chlorine, cyano and / or Trifluoromethyl mono- or disubstituted phenyl-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, such as benzyloxymethyl or 2-benzyloxyethyl, halo-d-d-alkyl, such as halomethyl, 2-haloethyl, where halogen is chlorine or in particular fluorine, amino-C ₄ - C ₇ alkyl, such as 4-aminobutyl or 6-aminohexyl, N-Cj-CrAlkanoyl-NDQ-alkyl-amino-d-Cralkyl, such as 2- (N-acetyl-N-methyl-amino) methyl, 5- to 7-membered Azacycloalk-3-yl or 4-yl or 1-C ₂ -C ₇ -AlкапоуІ-агасусІоаІк-З-уІ or 4-yl, for example piperidin-4-yl or i-Acetyl-piperidine-4 -yl, and R ₂ represents carboxy, dQ-alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or optionally substituted by Ci-C ₄ -alkyl, such as methyl, C ₁ -C ₄ -alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and / or trifluoromethyl mono- or disubstituted phenyl-C ^ C ^ alkoxycarbonyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, in particular their pharmaceutically acceptable salts. The invention relates, in particular, to compounds of the formula I in which R _{1 is} hydroxy-C ₁ -C 4 -alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, C 1 -C 4 -alkoxy-Cr-Q-alkyl, such as methoxymethyl, ethoxymethyl , 2-methoxyethyl, 3-methoxypropyl or 4-methoxybutyl, one in the phenyl moiety optionally substituted by C ₁ -C ₄ alkyl, such as methyl, C ₁ -C ₄ alkoxy, such as methoxy, halogen of atomic number to and including 35, such as fluorine or chloro, cyano and / or trifluoromethyl mono-, di- or trisubstituted phenyl-dG 1 -alkoxy-d-Ca-alkyl, such as benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl group, or halogen-d- Gralkyl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, where halogen is chlorine or especially fluorine and R _{2 is} carboxy, C 1 -C 4 alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxycarbonyl, or Gege if desired by C ₁ -C ₄ -alkyl, such as methyl, C ₁ -C ₄ -alkoxy, such as methoxy, halogen of the atomic number up to and including 35, such as fluorine or chlorine, cyano and / or trifluoromethyl mono- or disubstituted phenyl-C C ₄ alkoxycarbonyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, in particular their pharmaceutically acceptable salts.

On the other hand, the invention particularly relates to compounds of the formula I in which R _{1 is} amino-C ₁ -C 4 -cycloalkyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl or 7-aminoheptyl, C ₁ - C ₄ alkylamino-C ₁ -C ₇ alkyl, such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl, Сг-С ^ АІкапоуІатіпо-like acetylaminomethyl , Propionylaminomethyl, butyrylaminomethyl, г-АсеіуІатіпоаігіуІ.З-АсеіуІатіпоргору ^ 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, di-C ₁ -C ₄ -alkylamino-C ₁ -C ₇ -alkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methyl-aminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or 6-dimethylaminohexyl, 5-to 7-membered N, N -Alkylenamino-Ci-C ₇ -alkylbzw. N, N4Aza or oxaalkyleneamino-d-CT-alkyl, such as

Pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, piperazino or N'-methyl or N'-acetylpiperazinomethyl, pyrrolidinoethyl, piperidinoethyl, morpholinoethyl, pyrrolidinopropyl, piperidinopropyl, morpholinopropyl, pyrrolidinobutyl, piperidinobutyl, pyrrolidinopentyl, piperidinopentyl or piperidinohexyl, and R _{2 is} carboxy, C ₁ -C ₄ alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, such as cyclopentyloxy or cyclohexyloxycarbonyl, or optionally by C ₁ -C ₄ -alkyl, such as methyl, C ₁ -C ₄ -alkoxy, such as methoxy, halogen the atomic number to and with 35, such as fluorine or chlorine, cyano and / or trifluoromethyl mono- or di-substituted phenyl-CHV alkoxycarbonyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, in particular their pharmaceutically acceptable salts.

The invention particularly relates to compounds of the formula I in which R _{1 is} hydroxy-C ₁ -C ₄ -alkyl, such as hydroxyethyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, such as methoxymethyl, ethoxymethyl or 2-methoxyethyl, benzoyloxy. C ^ alkyl, such as 2-benzoyloxyethyl, phenyl-C, -C ₄ alkoxy-Ci-C ₇ -alkyl, such as benzyloxymethyl or 2-benzyloxyethyl, amino-Ci-Cy-alkyl, such as 4-aminobutyl, or 6-aminohexyl , NC ₂ -C ₇ alkanoyl-NC ₁ -C ₄ -alkyl-amino-C _z -C ₇ -alkyl, such as 2- (N-acetyl-methyl-amino) ethyl, 5- to 7-membered azacycloalk-3-yl or 4-yl or 1-S-С-АІкапоуІ-агасусІоаІк-З-уІ or 4-yl, such as piperidin-4-yl or i-acetylpiperidin-4-yl, or halo-C 1 -C ₄ -alkyl, wherein Halogen is chlorine or in particular fluorine, such as 2-haloethyl, and R _{2 is} carboxy or Ci-C ^ alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts, in particular their pharmaceutically acceptable salts.

Preferred subject matter of the invention are, on the one hand, compounds of the formula I in which R 1 is aminoC ₄ -C ₇ -alkyl, such as 4-aminobutyl or 6-aminohexyl, N-C 1 -C 6 -alkanoyl-N-C 1 -C ₄ -alkylamino Ci-Cy-alkyl, such as 2- (N-acetyl-N-methyl-amino) ethyl, 5- to 7-membered, bound via a carbon atom azacycloalkyl, such as piperidin-4-yl or 5- to 7-membered, via a C Atom-bonded (N-Cz-Cy-Alkanoylazalcycloalkyl, such as i-Cj-Cy-alkanoylpiperidine ^ -yl, for example i-acetylpiperidin-4-yl, and R _{2 is} carboxy or Ci-Q-alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, is, and their salts.

On the other hand, preferred subject matter of the invention are compounds of the formula I in which R _{1 is} C ₁ -C 4 -alkoxy-C ₁ -C 4 -alkyl, such as methoxymethyl, ethoxymethyl or 2-methoxyethyl, phenyl-C 1 -C 4 -alkoxy-QQ-alkyl, such as benzyloxymethyl or 2-Benzyloxyethyl, benzoyloxy-Ci-Q-alkyl, such as 2-benzoyloxyethyl, hydroxy-Ci-C ^ alkyl, such as hydroxymethyl or 2-hydroxyethyl, or halo-C ₂ -C ₄ -alkyl, such as 2-fluoroethyl, and R is _{2 represents} carboxy or C 1 -C 4 alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts.

The invention primarily relates on the one hand to compounds of the formula I in which R _{1 is} AmInO-C ₄ -C ₇ -alkyl, such as 4-aminobutyl, 5-aminopentyl, 6-aminohexyl or 7-aminoheptyl, and R _{2 is} carboxy, C ₁ -C ₄ -AlkOXyCaTbOnYl, such as methoxycarbonyl or ethoxycarbonyl, or optionally by Ci-Q-alkyl, such as methyl, C ₁ -C ₄ -alkoxy, such as methoxy, halogen of the atomic number to and with 35, such as fluorine or chlorine, cyano and / or Trifluoromethyl mono- or di-substituted phenyl-C 1 -C ₄ -alkoxycarbonyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, in particular their pharmaceutically acceptable salts.

On the other hand, the invention primarily relates to compounds of the formula I in which R 1 is C 1 -C 4 -alkoxy-Q 1 -Q-alkyl, such as 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl or 4-methoxybutyl, hydroxy-C 1 -C 4 -alkyl, as 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, or halo-C 1 -C 4 -alkyl, such as 2-fluoroethyl, 2-chloroethyl, 3-fluoropropyl or 4-fluorobutyl, and R _{2 is} carboxy, C 1 -C ₄ -alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, or an optionally by C ₁ -C ₄ -A ^ yI, such as methyl, Ci-C ₄ -alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and / or Trifluoromethyl mono- or di-substituted phenyl-Ci-Q-alkoxycarbonyl, such as benzyloxycarbonyl or 2-Phenyläthoxycarbonylgruppe, and their salts, in particular their pharmaceutically acceptable salts.

The invention relates in the first place to compounds of the formula I in which R, 2-hydroxyethyl, 3-hydroxypropyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-benzoyloxyethyl, benzyloxymethyl, 2-benzyloxyethyl, 4-aminobutyl, 6-aminohexyl, 2- (N-acetyl-N-methyl-amino) ethyl, piperidin-4-yl, i-acetylpiperidin-4-yl or 2-fluoroethyl and R _{2 is} carboxy or ^ -Q-alkoxycarbonyl, and their salts.

The invention relates in particular to the compounds of the formula I mentioned in the examples and their salts, in particular their pharmaceutically usable salts.

The process for the preparation of the compounds according to the invention is characterized in that in a compound of formula II

(II)

wherein Z ₁ , Z _{2 are} optionally protected hydroxy, Z _{3 is} an optionally protected or acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally protected or acylated and / or aliphatically substituted amino or by an azadiaza-, azoxa or oxacycloaliphatic radical substituted aliphatic or bonded via a C atom oxacycloaliphatic or optionally protected or aliphatic N-substituted or N-acylated azacycloaliphatic hydrocarbon radical and Z ₄ protected amino, protected amino Z ₄ and, if present, as a component of Z ₃ in amino and, if present, protected hydroxy Z ₁ , Z ₂ and / or as a component of Z _{3 converted} into hydroxy and, if present a protected azacycloaliphatic hydrocarbon radical Z ₃ liberated and, if desired, a compound obtained in another compound of formula I. transferred, an isomers mixture obtainable in accordance with the process is separated into the components and the particular isomers are separated off and / or a free compound obtainable in accordance with the process is converted into a salt or a salt obtainable according to the process into the corresponding free compound.

In starting materials of the formula II, protected hydroxy Zi and / or Z _{2 is} for example etherified, in particular aliphatically or aromatically etherified hydroxy, protected hydroxy as a component of Z ₃ for example acylated or silylated hydroxy, and protected amino Z ₄ and, if present, as a constituent of Z _3, for example, acylated amino.

Aliphatically etherified hydroxy is, for example, lower alkoxy, such as methoxy, ethoxy or especially isopropyloxy. Aromatically etherified hydroxy is, for example, optionally substituted by lower alkyl, lower alkoxy, halogen, cyano and / or nitro-substituted phenoxy.

Acylated hydroxy has as the acyl group, for example, the acyl radical of an araliphatic carboxylic acid or a carbonator of carbonic acid, and means, for example, lower alkanoyloxy, or a lower phenyl, lower alkoxy, halogen, cyano and / or trifluoromethyl substituted phenyl-lower alkanoyloxy or phenyl-lower alkoxycarbonyloxy group, e.g. B. benzyloxycarbonyloxy.

Silylated hydroxy is, for example, tri-lower alkylsilyloxy, e.g. B. trimethyl or Tributylsilyloxy.

Acylated amino has as acyl group, for example, a suitable organic acid, such as formic acid or an araliphatic or aromatic half ester of carbonic acid derived acyl. Acylated amino thus means, for example, formylamino, lower alkoxycarbonylamino, such as methoxy, ethoxy or tert-butyloxycarbonylamino, phenyl-lower alkoxy, lower-alkoxy, halogen, cyano and / or nitro-substituted phenyl-lower alkoxycarbonylamino, such as benzyloxycarbonylamino, or lower alkyl, lower alkoxy, halogen, cyano and / or nitro-substituted phenoxycarbonylamino.

The release of the protected groups from compounds of the formula II, ie hydroxyl-protected hydroxy groups Z ₁ , Z ₂ and / or protected hydroxy groups as a constituent of Z ₃ or of amino from protected amino groups Z ₄ and, if present, protected amino groups as part of Z ₃ , for example, by treatment with an acidic agent, for example with a Triniederalkylhalogensilan, such as trimethylbromosilane, tributylbromosilane or trimethyliodosilane. In this case, it is preferable to work in an inert solvent, such as a halogenated aliphatic hydrocarbon, eg. Example, in dichloromethane or secondarily tri- or tetrachloromethane, trichloroethane or tetrachloroethane, for example in the temperature range from about -25 ° C to about +50 ⁰ C, preferably from about 0 ° C to 30 ° C, eg at room temperature, ie at about 15 ° C to 25 ° C, preferably under substantially anhydrous conditions and under inert gas, such as argon or nitrogen. The workup is advantageously carried out by adding a hydrogen halide scavenger, in particular an aliphatic epoxy compound, such as an epoxy lower alkane, for example of propylene oxide in a lower alkanol, such as ethanol. In a preferred embodiment, for example, starting from compounds of formula II, wherein Z, and Z ₂ lower alkoxy, z. B. isopropoxy, and Z _{4 is} lower alkanoylamino, such as formylamino, and treating them in an aliphatic halohydrocarbon, such as dichloromethane, at about 15 ° C to about 25 ° C with a tri-lower alkyl bromosilane, such as trimethylbromosilane or tributylbromosilane, for some time, e.g. B. about 2 to 30 hours, then adds an ethanolic solution of propylene oxide and filtered from the product. Starting materials of the formula II are prepared, for example, by reacting an α, β-unsaturated aldehyde of the formula Ia a

^U (Ha)

with an α-isocyanacetic acid ester of the formula II b

in a conventional manner, for example in the presence of a copper or gold catalyst, for. As copper-l-oxide or Bislcyclohexylisocyanidlgold-l-tetrafluoroborate, to the corresponding 5-substituted 2-oxazoline-4-carboxylic acid ester of the formula Hc

R ₂

(Lic)

by hydrolysis, e.g. in aqueous tetrahydrofuran, in the corresponding open-chain esters of the formula Hd

OH

(IId)

Z ₃ NHCH = O

converted this by treatment with thionyl bromide in a conventional manner in the corresponding ω-bromoester of the formula He T ^ H ₂ ^^ ч ^ " 2

NHCH = O

and converts these in a manner known per se with a phosphorous acid triester of the formula P (Z ₁₁ ) (Zb) (Zc), where Z "Z _b and Z _c represent the same or different hydroxy groups protected in an ether form, such as a tri-lower alkyl phosphite, eg with triisopropyl phosphite , to the corresponding compound of formula ΙΓ

Il

far displaces.

Compounds obtainable by the process can be converted into other compounds of the formula I in the usual way.

So you can convert free and esterified carboxy groups R ₂ in each other usually. In particular, esterified carboxy R _{2 can be converted} by hydrolysis into carboxy or free carboxy R ₂ by reaction with an alcohol in esterified carboxy. It is also possible to transesterify esterified carboxy R ₂ to another esterified carboxy group. It works in usually under hydrolytic, alcoholic or transesterification conditions.

The hydrolysis of carboxylic acid esters (I; R ₂ = esterified carboxy) is carried out in a customary manner, if necessary in the presence of an acidic or basic agent, such as a mineral acid, e.g. Example of hydrogen chloride or sulfuric acid, or a base such as an alkali metal hydroxide, for example of sodium hydroxide.

In the transesterification of esters (I, R ₂ = esterified carboxy) with alcohols is usually carried out under acid or base catalytic conditions, for example in the presence of a catalytic amount of a mineral acid, such as hydrogen chloride or sulfuric acid, or a metal base, such as sodium hydroxide, or by reacting the alcohol component in the form of a metal alcoholate, e.g. B. an alkali metal alcoholate, is used.

Further, in aliphatic hydrocarbon radicals substituted by araliphatic etherified aliphatic hydrocarbon radicals, such as α-phenyl-lower alkoxy-lower alkyl radicals R _1, the α-phenyl-lower alkoxy group can be converted into hydroxy, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, such as palladium on carbon or Raney nickel.

Obtained salts can be converted in a conventional manner into the free compounds, for. By treating with a base such as an alkali metal hydroxide, a metal carbonate or bicarbonate, or ammonia, or any other salt-forming base mentioned above, or with an acid such as a mineral acid, e.g. with hydrogen chloride, or another salt-forming acid mentioned above.

Salts obtained can be converted in a manner known per se into other salts, acid addition salts. By treating with a suitable metal salt, such as a sodium, barium or silver salt, another acid in a suitable solvent in which a forming inorganic salt is insoluble and thus precipitating from the reaction equilibrium, and base salts by liberation of the free acid and salinisation again.

The compounds of formula I, including their salts, may also be obtained in the form of hydrates or may include the solvent used for crystallization.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, the meaningful and suitable, if appropriate, the corresponding salts or free compounds are to be understood above and below among the free compounds and their salts.

Resulting diastereomer mixtures and mixtures of racemates can be separated in a known manner in the known manner in pure white diastereomers or racemates due to the physico-chemical differences, for example by chromatography and / or fractional crystallization.

Obtained racemates can also be broken down by known methods into the optical antipodes, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reacting the resulting diastereomeric mixture or racemate with an optically active auxiliary compound, eg. B. according to the acidic, basic or functionally modifiable groups contained in compounds of formula I with an optically active acid, base or an optically active alcohol, in mixtures of diastereomeric salts or functional derivatives, such as esters, their separation into the diastereomers, from which each desired enantiomer can be released in the usual manner. Suitable bases, acids or alcohols are, for example, amino acids, in particular D- or L-lysine, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L- (1-phenyl) ethylamine, 3-pipecoline, ephedrine, Amphetamine and similar synthetically accessible bases, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluyltartaric, D- or L-malic acid, D- or L-mandelic acid, or D- or L-camphorsulfonic acid, or optically active alcohols, such as borneol or D- or L- (1-phenyl) ethanol.

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt or, in particular, forms under the reaction conditions.

The new starting materials which have been specially developed for the preparation of the compounds according to the invention, in particular the starting material selection which leads to the compounds of the formula I indicated at the outset, the processes for their preparation and their use as intermediates likewise form an object of the invention.

The novel compounds of formula I can, for. In the form of pharmaceutical preparations containing a therapeutically effective amount of the active ingredient, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are suitable for enteral, e.g. oral or parenteral administration. Thus, one uses tablets or gelatin capsules containing the active ingredient together with diluents, for. As lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or lubricants, for. B *. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol have. Tablets may also bind, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. As starches, agar, alginic acid or a salt thereof, for. As sodium alginate, and / or effervescent mixtures, or

Absorbents, dyes, flavors and sweeteners. Furthermore, the novel compounds of the formula I can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these z. As in lyophilized preparations containing the active substance alone or together with a carrier material, for. As mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, eg. As preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical compositions which, if desired, may contain other pharmacologically active substances, are prepared in a manner known per se, e.g. prepared by conventional mixing, granulating, coating, dissolving and lyophilization processes and containing from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilizates to about 100% of the active material.

The invention also relates to the use of the compounds of the formula I, preferably in the form of pharmaceutical preparations. The dosage may depend on various factors, such as route of administration, species, age and / or individual condition. The doses to be administered daily are between about 0.25 and about 10 mg / kg when administered orally and between about 20 mg and about 500 mg for warm-blooded animals having a body weight of about 70 kg. The following examples serve to illustrate the invention; Temperatures are given in degrees centigrade, pressures in mbar.

example 1

3.57 g (8.5 mmol) of e-acetoxy -di-isopropylphosphonomethyl-4-formylamino-hex-S-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane and admixed dropwise at room temperature with 4.4 ml (34 mmol) of trimethylbromosilane. It is allowed to stand for 22 hours at room temperature, added dropwise 22 ml of ethanol, left for another 22 hours, evaporated on a rotary evaporator, the residue is dissolved in 22 ml of ethanol and added dropwise a mixture of 22 ml of propylene oxide and 22 ml of ethanol. A suspension is formed which is stirred for a further 90 minutes and then filtered off with suction. Is obtained г-Атіпо-б-пугігоху · ^ - phosphonomethyl-hex-3-enoic acid ester of mp. 195 ° C (dec.)

The starting material may e.g. be prepared as follows:

13.0 g (10OmMoI) acetic acid (4-oxo) butyl 92,0g (112,6mMol) dimethylammonium chloride and 10,8ml (117mMol) of 37% formaldehyde solution are heated under stirring for 1 hour at 100 ⁰ C. It is allowed to cool and extracted 3 times with 30 ml of diethyl ether. The organic phases are combined, washed with saturated brine, dried over magnesium sulfate and evaporated to dryness. This gives acetic acid (3-formyl) but-3-enyl ester as a colorless oil, which can be further reacted without further purification.

13.5 g (95 mmol) of acetic acid (3-formyl) but-3-enyl ester and 10.4 g (95 mmol) of ethyl isocyanatoacetate are added dropwise to a suspension of 0.38 g of copper 1-oxide in 50 ml of benzene. After the exothermic reaction has subsided, the mixture is stirred for another 45 minutes at room temperature, filtered through Hyflo® and evaporated to dryness. The residue is taken up in 75 ml of tetrahydrofuran, treated with 25 ml of water and heated with stirring for 4 hours to reflux. Evaporate to dryness and chromatograph on silica gel with toluene / isopropanol (9: 1) as eluent. To obtain e-acetoxy-2-formylamino-S-hydroxy ^ -methylen-hexansäureäthylester as a brownish oil.

9.19 g (35.9 mmol) of ethyl e-acetoxy-4-formylamino-S-hydroxy-methylene-hexanoate are dissolved in 100 ml of dichloromethane and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise at room temperature. After 1 hour, 10 ml of water are added and allowed to stir for 10 minutes. The organic phase is separated, washed successively with water, saturated potassium bicarbonate solution and again with water, dried over magnesium sulfate, filtered and evaporated. This gives e-acetoxy ^ -brommethyl ^ -formylarriino-hex-S-enoic acid ethyl ester as a brownish oil.

8.7 g (25 mmol) e-Acetoxy ^ ^ bromomethyl -formylamino-hex-S-enoic acid ethyl ester and 21 mL (75mMol) of triisopropyl phosphite (90%) are heated to 80 ⁰ C to 9O ⁰ C and under a pressure of about ЮОтЬаг Stirred for 19 hours. The excess Triisopropylphosphit is distilled off and the evaporation residue chromatographed on 150 g of silica gel with first ethyl acetate and then ethyl acetate / ethanol (9: 1) as eluent. To obtain e-acetoxy-4-diisopropylphosphonomethyl ^ -formylamino-hex-S-enoic acid ethyl ester as a yellowish oil.

Example 2

0,415g (1,55 mmol) г-Атіпо-б-гіуагоху ^ -ргюбрііопотеиіуІ-гіех-З-епзаигеаігіуІезіег are refluxed in 3 ml of water for 24 hours. The reaction mixture is evaporated, purified by chromatography on 10 g of silica gel with ethanol / water (1: 1) as eluent and crystallized from ethanol. This gives 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid of mp.> 300 ⁰ C.

Example 3

0.5 g (1, OmMoI) of methyl S-fN-benzyloxycarbonylamino-diethylphosphonomethyl-4-formylamino-oct-S-enoate are refluxed in 5.0 ml of 6N hydrochloric acid for 6 hours. Evaporation to dryness gives 2,8-diamino-4-phosphonomethyl-oct-3-enoic dihydrochloride in the form of a gummy solid which is recrystallized from acetonitrile; Mp. 128 ⁰ C (Zers.)

The starting material can be prepared as follows:

To a solution of 5.52 g (47 mmol) of 6-aminohexan-1-ol and 3.95 g (47 mmol) of sodium bicarbonate in 100 ml of acetone and 50 ml of water are added dropwise 7.06 ml (47 mmol) of benzyl chloroformate. The mixture is stirred for 18 hours at room temperature, concentrated to about 70 ml, filtered from the white precipitate, washed with about 20ml of water, taken up in 250ml of methylene chloride on magnesium sulfate, filtered this and the residue is evaporated to dryness. This gives 6- (N-benzyloxycarbonylamino) hexan-1-ol as white crystals of mp. 58-60 ⁰ C.

To a stirred at -50 ° C solution of 0.19 ml (2.2OmMoI) oxalyl chloride in 10 ml of methylene chloride 0.32ml (4.4OmMoI) of dimethyl sulfoxide are added dropwise under nitrogen. The mixture is stirred for 15 minutes and then 0.5 g (2 mmol) of 6- (N-benzyloxycarbonylamino) hexan-1-ol is added. The mixture is stirred for 25 minutes at -50 ⁰ C, added dropwise 1.78 ml (1OmMoI) of N-ethyl-N, N-diisopropylamine and poured into 10 ml of ice water. The organic phase is separated and the water phase

extracted with 10 ml of methylene chloride, the organic phases are combined, washed twice with 5 ml of η-hydrochloric acid and once with 10 ml of saturated brine, dried over magnesium sulfate and evaporated to dryness. The resulting oil is on silica gel with hexane / ethyl acetate (1: 1) as Mobile phase purified by chromatography. 6- (N-benzyloxycarbonylamino) hexanal is obtained.

To a solution of 1.5 g (17 mmol) anhydrous piperazine and 2.03 g (34 mmol) acetic acid in 18.7 ml water are added 2.44 g (30 μmol) of 37% strength aqueous formaldehyde solution. The mixture is stirred for 15 minutes at 25 ° C and then adds 7.48 g (30mMoI) of 6- (N-benzyloxycarbonylamino) hexanal added. The reaction mixture is heated to reflux for 2 hours, then cooled with ice water and extracted twice with 50 ml of methylene chloride. The extracts are combined, washed twice each with 25 ml of saturated sodium bicarbonate solution and with 25 ml of saturated sodium chloride solution, dried and evaporated to dryness. 6- (N-Benzyloxycarbonylamino) -2-methylene-hexanal is obtained as a yellowish liquid.

4.0 g (15.3 mmol) of 6- (N-benzyloxycarbonylamino) -2-methylene-hexanal and 1.62 ml (16.8 mmol) of isocyanacetic acid methyl ester are dissolved in 50 ml of toluene and heated at 40 ° C. to a suspension of 0.12 g 96 , 4% copper-l-oxide in 50 ml of toluene.

The mixture is stirred for 2.5 hours at room temperature, filtered, added to a filled with 60 g of silica gel column and extracted first with hexane / ethyl acetate (1: 1) and then with ethyl acetate. This gives 5- [6- (N-Benzyloxycarbonylaminojhex-i-en ^ -yll-oxazolin ^ -carboxylic acid methyl ester, oil.

9.4 g (26.1 mmol) of S-je-IN-Benzyloxycarbonylaminoihex-i-en ^ -allyloxazoline ^ -carboxylic acid methyl ester are dissolved in 40 ml of tetrahydrofuran and 20 ml of water, treated with a few drops of triethylamine and heated to reflux for 18 hours. The solvent is removed under reduced pressure and the residual oil is taken up in a total of 125 ml of methylene chloride, dried over magnesium sulfate and evaporated to dryness. This gives 8- (N-benzyloxycarbonylamino) -2-formylamino-S-hydroxy ^ -methylene-octanoic acid methyl ester.

2.46 g (6.5 mmol) of methyl 8- (N-benzyloxycarbonylamino) -2-formylamino-3-hydroxy-4-methylene-octanoate in 25 ml of tetrahydrofuran are added with 5.5 ml (46 mmol) of hexa-1,5-diene and then -50 ⁰ C is added dropwise 2.6 ml (32,5mMol) thionyl bromide. The mixture is stirred for 2 hours at 0 ⁰ C to 5 ° C, poured into 25 ml of ice-cold saturated sodium bicarbonate solution and extracted twice with 20 ml of methylene chloride. The organic phase is washed with 10 ml of saturated brine, dried over magnesium sulfate and evaporated to dryness. The resulting oil is purified by chromatography on silica gel with hexane / ethyl acetate (3: 1). This gives 8- (N-benzyloxycarbonylamino) -4-bromomethyl-N-methyl-n-oct-S-enoate.

1.45 g (3.3 mmol) of methyl S-fN-benzyloxycarbonylaminoM-bromomethyl-formylamino-oct-S-enoic acid are mixed with 5 ml of triethyl phosphite and heated to 75 ° C. with stirring for 8 hours. The excess triethyl phosphite is distilled off under reduced pressure to give an oily residue. This is purified by chromatography on a silica gel column with first ethyl acetate and then ethyl acetate / methanol (9: 1). This gives 8- (N-benzyloxycarbonylamino) -4-diethyl-phosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester.

Example 4

1.77 g (4.5 mmol) of 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester are dissolved in 12 ml of dichloromethane and treated dropwise at room temperature with 2.32 ml of (18, OmMoI) trimethylbromosilane. It is allowed to stand for 22 hours at room temperature, added dropwise 12 ml of ethanol, allowed to stand again for 24 hours, evaporated on a rotary evaporator, the residue is dissolved in 10 ml of ethanol and adds a mixture of 2 ml of propylene oxide and 2 ml of ethanol. A suspension is formed which is stirred for a further 2 hours at room temperature and 2 hours under ice-cooling and then filtered off with suction. This gives 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester of mp. 242 ° C (dec.).

The starting material may, for. B. be prepared as follows:

19.7 g (193mMol) of 4-Methoxybutanal, 17.7 g (217mMol) dimethylammonium chloride and 17,0ml (226mMol) of 37% formaldehyde solution are heated under stirring for 3 hours at 100 ⁰ C. It is allowed to cool and extracted 3 times with diethyl ether. The organic phases are washed with saturated brine, combined, dried over sodium sulfate, filtered and evaporated to dryness. 4-Methoxy-2-methylene-butanal is obtained as a yellowish oil which can be further reacted without further purification.

16.5 g (144.5 mmol) of 4-methoxy-2-methylene-butanal and 15.8 ml (144.5 mmol) of isocyanacetic acid ethyl ester are dissolved in 145 ml of toluene and mixed with 400 mg of copper 1-oxide. After the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered through Hyflo® and evaporated to dryness. The residue is taken up in 145 ml of tetrahydrofuran, mixed with 33 ml of water and heated with stirring for 2 hours to reflux. It is evaporated to dryness, mixed with toluene and evaporated again. Chromatography on silica gel with toluene / ethanol (95: 5) as eluent gives g-РогтуІатіпо-З-Ьуагоху-б-methoxy-4-methylene-hexanoic acid ethyl ester as a red-brown oil.

19.0 g (77.5 mmol) of г-РогтуІатіпо-З-г ^ гоху-б-те ^ оху ^ -те ^ уІеп-пехапзаигеаігіуІезіег are dissolved in 190 ml of 1,2-dichloroethane and added dropwise at room temperature with 7.20 ml (93 , 0 mmol) thionyl bromide. After 45 minutes, 100 ml of water are added and allowed to stir intensively for 10 minutes. The organic phase is separated, washed successively with water, 1 N potassium bicarbonate solution and again with water, dried over sodium sulfate, filtered and evaporated. 4-Bromomethyl-2-formylamino-6-methoxy-hex-3-eic acid ethyl ester is obtained as a red-brown oil. 3.38 g (11 OmMoI) of 4-bromomethyl-2-formylamiпo-6-methoxy-hex-3-eпsäureäthylesteruпd 12.0 ml (44mMol) of triisopropyl phosphite (96%) are heated to 80 ⁰ C and about 130mbar at a pressure of Stirred for 18 hours. The excess Triisopropylphosphit is distilled off under reduced pressure and the evaporation residue on silica gel with ethyl acetate purified by chromatography. This gives 4-DiisopropylphosphoPomethyl-2-foгmylamiпo-6-methoxy-hex-3-enoic acid ethyl ester as a yellowish oil.

Example 5

0,98g (3,5mmol) of г-Атіпо-б-теіпоху ^ -рповропоте ^ уІ-Ііех-З-епваигеаігіуІевіег are refluxed in 7ml of water for 17 hours. The reaction mixture is evaporated and crystallized from a mixture of water and ethanol. This gives 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid of mp. 214 ⁰ C (dec.).

Example 6

0.52 g (1.36 mmol) of diisopropylphosphonomethyl-e-fluoro-4-formylamino-hex-S-enoic acid ethyl ester are dissolved in 3.5 ml of dichloromethane and treated dropwise at room temperature with 0.7 ml (5.45 mmol) of trimethylbromosilane. It is allowed to stand for 24 hours at room temperature, added dropwise 3.5 ml of ethanol, allowed to stand again for 24 hours, evaporated on a rotary evaporator, the residue dissolved in 2.4 ml of ethanol and adds a mixture of 0.6 ml of propylene oxide and 0.6 ml of ethanol added. It forms a suspension which is stirred for a further 2 hours at room temperature and 2 hours under ice cooling and then filtered with suction. This gives 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester of mp. 222 ° C (dec.).

The starting material may, for. B. be prepared as follows:

2.4 g (26.6 mmol) 4-fluorobutanal, 2.44 g (30, OmMoI) dimethyl ammonium chloride and 2.34 ml (31.1 mmol) of 37% strength formaldehyde solution are heated to 100 ° C. with stirring for 2 hours. It is allowed to cool and extracted 3 times with diethyl ether.

The organic phases are washed with saturated brine, combined, dried over sodium sulfate, filtered and evaporated to dryness. 4-Fluoro-2-methylene-butanal is obtained as a yellowish oil which can be reacted further without further purification.

1.43 g (14, OmMoI) 4-fluoro-2-methylene-butanal and 1.53 ml (14, OmMoI) Isocyanessigsäureäthylester be dissolved in 14 ml of toluene and treated with 40 mg of copper-l-oxide. After the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered through Hyflo® and evaporated to dryness. The residue is taken up in 14 ml of tetrahydrofuran, mixed with 3.1 ml of water and heated with stirring for 2 hours to reflux. It is evaporated to dryness, mixed with toluene and evaporated again. Chromatography on silica gel with toluene / ethyl acetate (1: 1) as eluent gives ethyl b-hydroxypropyl 4-methylene-hexanoate as a dark yellow oil.

1.40 g (6, OmMoI) of ethyl e-fluoro-4-formylamino-S-hydroxy-methylene-hexanoate are dissolved in 14 ml of 1,2-dichloroethane and treated dropwise at room temperature with 0.56 ml (7.2 mmol) of thionyl bromide. After 45 minutes, add 12 ml of water and stir for 15 minutes. The organic phase is separated, washed successively with water, 1 N potassium bicarbonate solution and again with water, dried over sodium sulfate, filtered and evaporated. 4-Bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a brown-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 ° C and under a pressure of about 130 mbar Stirred for 18 hours. The excess Triisopropylphosphit is distilled off under reduced pressure and the evaporation residue on silica gel with ethyl acetate purified by chromatography. 4-Diisopropylphospho-pomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.

Example 7

0.5 g (1.86 mmol) of 2-amino-6-fluoro-4-phospho-pentamethyl-hex-3-eic acid ethyl ester are refluxed in 4 ml of water for 17 hours. The reaction mixture is evaporated and separated on the strongly acidic ion exchanger (Dowex 50 Wx8, H® form) with water. One receives г-Атіпо-б-тіиокм-ргіовргюпотеіпуІ-пех-З-епзаиге of the m. 160-162 ⁰ C (Zers.).

Example 8

In a manner analogous to that described in Example 3, starting from S-aminooctan-i-ol, 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid dihydrochloride, mp. 126 ° C.

Example 9

8.63 g (15.2 mmol) of lO-fN-BenzyloxycarbonylaminoM-diisopropylphosphonomethyl ^ -formylamino-dec-S-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane and admixed dropwise at room temperature with 9.82 ml (75.9 mmol) of trimethylbromosilane. The mixture is stirred for 22 hours at room temperature, then added dropwise 22 ml of absolute ethanol, stirred for another 22 hours and evaporated on a rotary evaporator. The residue is poured over with 20 ml of toluene and evaporated in vacuo. This process is repeated three more times. The resulting pale yellow foam is dissolved in 150 ml of absolute ethanol and treated dropwise within 90 minutes with a solution of 7.5 ml of propylene oxide in 7.5 ml of ethanol. It forms a crystal suspension, which is stirred overnight at room temperature. The product is filtered off and washed with ethanol and ether. After drying in a high vacuum at room temperature, 4.70 g of crude product are obtained as pale yellow crystals. For further purification, it is stirred with 46 ml of water. After filtering off a little undissolved material (0.33 g), the clear pale yellow filtrate is totally evaporated in vacuo. The residue is mixed with 20 ml of ethanol and 20 ml of toluene and evaporated again to dryness. This process is repeated twice with toluene. The residue is suspended after drying under high vacuum in 150 ml of absolute ethanol and treated dropwise with stirring with a 5normalen solution of hydrogen chloride gas in ethanol until the mixture reacts kongosauer. The resulting clear solution is added dropwise within 1 hour with a mixture of 7.4 ml of propylene oxide in 7.4 ml of ethanol. It forms a crystal suspension, which is stirred for a further 15 hours and then filtered with suction. After washing with ethanol and ether, the product is dried for 48 hours under high vacuum at 50 ^0C. This gives 2.86 g of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ester, which begins to sinter at 157 ⁰ C and melts at 194 ° C with decomposition.

This product contains as impurities about 5-10% by weight of the corresponding N-benzylated in the 10-position and the N- (2hydroxy) propylated compound.

The starting material is prepared as follows:

In a manner analogous to that described in Example 3, starting from 8-aminooctan-1-ol via 8- (N-benzyloxycarbonylamino) octan-1-ol and 8- (N-benzyloxycarbonylamino) octanil, the 8- (N-benzyloxycarbonylamino) - 2-methylene-octanal.

15.30 g (52.9 mmol) of e-fN-benzyloxycarbonylamino-methylene-octanal and 7.37 ml (67.4 mmol) of isocyanacetic acid ethyl ester are dissolved in 78 ml of toluene and added to a suspension of 0.30 g of copper l-oxide in 76 ml of toluene added dropwise under argon within 75 minutes. The mixture is stirred for 90 minutes at 30 ° C, cooled to room temperature, filtered and gives the clear light red filtrate

a column filled with 250 g of silica gel (particle size 0.04-0.063 mm) and eluted with hexane / ethyl acetate (2: 1). After evaporation of the appropriate fractions, 8.15 g of ethyl 5- [8- (N-benzyloxycarbonylamino) oct-1-en-2-yl] -oxazoline-4-carboxylate are obtained as colorless honey.

8.15 g (20.25 mmol) of ethyl 5- [8- (N-benzyloxycarbonylamino) oct-1-en-2-yl] oxazoline-4-carboxylate are refluxed in 40 ml of tetrahydrofuran and 20 ml of water with stirring for 4 hours. The reaction mixture is evaporated to dryness in vacuo at 45 ° C and the honey-like residue is evaporated twice more after addition of toluene. The crude product is dissolved in dichloromethane, dried with sodium sulfate, filtered and evaporated. After drying in a high vacuum at room temperature, 9.03 g of 10-O-fN-benzyloxycarbonylamino-4-formylamino-S-hydroxy-1-methyldecanoic acid ethyl ester are obtained as yellowish honey.

13,70g (32,6OmMoI) of crude lO-fN-benzyloxycarbonylaminoJ ^ -formylamino-S-hydroxy-methyl-decanoic acid ethyl ester in 137 ml of tetrahydrofuran are added under argon with 18.5 ml (156.4 mmol) of hexa-1,5-diene and then added dropwise at 10 ⁰ C within 15 minutes with 6.1 ml (78.2 mmol) of thionyl bromide. The mixture is stirred for 1 hour at 10 ° C and 2 hours at room temperature, poured into 200 ml of ice-cold saturated sodium bicarbonate solution, the organic phase is separated and extracted 1 time with dichloromethane. The organic phases are washed with ice-cold sodium hydrogencarbonate and afterwards 0,5normaler saturated brine, dried over sodium sulfate and evaporated at 40 ⁰ C in vacuum to dryness. The resulting crude 10- (N-benzyloxycarbonylamino) -4-bromomethyl-2-formylamino-dec-3-enoic acid ethyl ester (27 g, yellow honey) is immediately mixed with 64 ml (26OmMoI) triisopropyl phosphite (96%) and under a pressure of about Stirred lOOmbar at 80 ° C for 17 hours, the resulting isopropyl bromide is trapped in a cold trap (CO2). The excess triisopropyl phosphite is then distilled off under reduced pressure and the evaporation residue (23 g) is purified by chromatography on a column with 650 g of silica gel (0.04-0.063 mm) with ethyl acetate / methanol (95: 5). This gives 8.73 g of 10- (N-benzyloxycarbonylamino) -4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester as a yellowish honey.

Example 10

2.25 g (6.98 mmol) of 2, 10-diamino ^ -phosphonomethyl-dec-S-ethylenediät are dissolved under argon in 45 ml 2normaler hydrochloric acid and stirred for 17 hours at a bath temperature of 120 ⁰ C. The clear, light brown solution is evaporated on a rotary evaporator. The residue is dissolved in 20 ml of ethanol and evaporated after addition of 30 ml of toluene in vacuo. This process is repeated three more times. The obtained, beige foam is dissolved in 75 ml of absolute ethanol and added dropwise within 35 minutes with a solution of 15 ml of propylene oxide in 15 ml of ethanol. The resulting crystal suspension, which has a pH of 3, is filtered off after stirring for 1 h 2 hours and washed well with ethanol and ether. After drying in vacuo, 1.65 g of beige crude product, which in the minimum amount of water (about 2 ml) and dissolved on a column filled with 67g reversed-phase silica gel (Opti-Up Ci ₂ , particle size 40pm), with pure water as eluant at low pressure (0.2 bar) is chromatographed. A pure fraction, Rf value on silica gel = 0.37 with n-propanol / water / pyridine / acetic acid (15: 12: 10: 3) as eluent, and several mixed fractions with a by-product of Rf value = 0, 48th Rechromatography of these mixed fractions and unification of the pure fractions followed by lyophilization from water gives 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid hemihydrochloride as an amorphous glass, which slowly sinters from 134 ° C and at 149 ⁰ C under Foaming decomposes.

Example 11

4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphosphonomethyl-2-formylaminohept-3-enoic acid ethyl ester are dissolved in 25 ml of dichloromethane and admixed dropwise at room temperature with 5.1 ml (39.5 mmol) of trimethylbromosilane. The mixture is allowed to stand at room temperature for 24 h, 25 ml of ethanol are added dropwise and the mixture is left to stand for 24 h, evaporated, 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 is formed which is stirred for 1 hour at room temperature and for 1 hour in an ice bath and then filtered off with suction. After drying, 2-amino-7-hydroxy ^ -phosphonomethyl-hept-S-enäureäthySester of mp. 210 ⁰ C (dec.).

The starting material may, for. B. be prepared as follows:

10g (69,4mMol) 5-Acetoxypentanal, 6,37g (78,2mMol) dimethylammonium chloride and 6.1 ml (81,2mMol) of 37% formaldehyde solution are kept under stirring T / 2 hours under reflux (bath temperature ~ 110 ⁰ C) , It is allowed to cool, extracted three times with ether, the organic phases combined, dried over MgSO4, filtered and evaporated. The 5-acetoxy-2-methylene-pentanal is obtained as a yellowish oil, which can be reacted without further purification. 9.6 g (61.5 mmol) of 5-acetoxy-2-methylene-pentanal and 7.38 ml (67.6 mmol) of isocyanacetic acid ethyl ester are initially charged in 70 ml of toluene at room temperature and admixed with 250 mg of copper 1-oxide. After the exothermic reaction has subsided, the mixture is stirred for a further 1 hour, filtered through Hyflo® and evaporated. The residue is taken up in 50 ml of tetrahydrofuran, mixed with 10 ml of water and refluxed for 3 hours. It is evaporated to dryness, mixed with toluene and evaporated again. Chromatography on silica gel with toluene / ethyl acetate (4: 1) gives ethyl 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoate as an orange oil.

5.9 g (20.5 mmol) of ethyl 7-acetoxy-2-formylamino-3-hydroxy-4-methylep-heptaupate are dissolved in 60 ml of dichloromethane and treated dropwise at room temperature with 1.9 ml (24.6 mmol) of thionyl bromide. After 1 hour, 40 ml of water are added and allowed to stir intensively for 10 minutes. The organic phase is separated off, washed successively with water, 1N KHCO ₃ solution and again with water, dried over MgSO ₄ , filtered and evaporated. This gives 7-acetoxy-4-bromomethyl ^ -formylamino-hept-S-enoic acid ethyl ester as a brown oil, which is further reacted crude. 6.1 g (17,4mMol) of 7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester and 19.1 ml (69,6mMol) triisopropyl phosphite (90%) are heated to 8O ⁰ C and under Stirred for 18 hours at a pressure of about 130mbar. The excess Triisopropylphosphit is distilled off and the residue on silica gel with ethyl acetate. This gives 7-acetoxy-4-diisopropylphosphoPomethyl-2-formylarpiopo-hept-3-eplsäureäthylester as a yellow oil.

Example 12

1.1 g (3.9 mmol) of Σ-ηηϊηο ^ -γγαΓΟχγ ^ -ρΙιοβρίΊοηοηΓίβΙΙιγΙ-ηβρί ^ -βηββυΓββίΐΊΙββΐβΓ stirred in 8 ml of water for 18 hours at 130 ⁰ C in a bomb tube. The dark reaction solution is treated with charcoal and filtered through Hyflo®. The colorless filtrate is concentrated to ~ 3 ml and mixed with ~ 25 ml of ethanol. The resulting suspension is filtered with suction and dried under high vacuum at 50 ^0C. One receives г-Атіпо-Т-пуагоху-Д-рЬоврпопотеШуІ-пері-З-епзаиге with the m. From 19O ⁰ C (Zers.).

Example 13

8.2 g (18.9 mmol) of e-fN-acetyl-N-methyl-amino ^ diisopropylphosphonomethyl ^ -formylamino-hex-S-enoic acid ethyl ester are dissolved in 40 ml of dichloromethane and admixed dropwise at room temperature with 9.8 ml (75.6 mmol) of trimethylbromosilane. It is allowed to stand for 24 hours at room temperature, added dropwise 40 ml of ethanol, allowed to stand again for 24 hours, evaporated, 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 is formed which is stirred for a further 1 hour at room temperature and for 1 hour at 0 ^° C. and then filtered off with suction. After drying, 6- (N-acetyl-methyl-amino) -2-amino-4-phosphonomethyl-hex-3-enaureateyl ester of mp. 222-223 ° C (dec.).

The starting material may, for. B. be prepared as follows:

35.8 g (0.2 mol) of 4-aminobutyraldehyde diäthylacetal (90%) are dissolved in 600 ml of dichloromethane, treated with 300 ml of saturated sodium bicarbonate solution and cooled to 0 ⁰ C. Is added dropwise at 0-5 ° C 17 ml (0.24 mol) of acetyl chloride and allowed to stir for 6 hours at 0-5 ⁰ C. The organic phase is separated and the aqueous phase nachextraiert twice with dichloromethane. The organic phases are combined, dried over MgSO ₄ , filtered and evaporated on a rotary evaporator. The residue is purified by chromatography on silica gel with ethyl acetate. 4- (N-acetylamino) butyraldehyde diäthylacetal is obtained as a yellowish oil.

35 g (172.2 mmol) of 4- (N-acetylamino) -butyraldehyde diethyl acetal are dissolved in 180 ml of dimethylformamide, treated portionwise with 8.3 g (206.6 mmol) of sodium hydride dispersion (60% in mineral oil) and 45 Stirred for minutes at room temperature. Then 12.9 ml (206.6 mmol) of methyl iodide in 20 ml of dimethylformamide are added and the mixture is stirred at room temperature for 4 hours. The reaction mixture is mixed with water / ice and extracted three times with ethyl acetate. The organic phases are washed with water and brine, combined, dried over MgSO ₄ , filtered and evaporated. The residue is distilled under high vacuum. 4- (N-acetyl-N-methyl-amino) -butyraldehyde-diethylacetal is obtained as a colorless oil of Kpo, i = 92-94 ° C.

30 g (138.2 mmol) of 4- (N-acetyl-N-methylamino) butyraldehyde diethyl acetal, 12.6 g (154.4 mmol) of dimethyl ammonium chloride and 12.1 ml (161.7 mmol) of 37% formaldehyde solution are added with stirring Refluxed for 45 minutes. It is allowed to cool and extracted three times with dichloromethane. The organic phases are combined, dried over MgSO ₄ , filtered and evaporated. 4- (N-acetyl-N-methylamino) -2-methylene-butyraldehyde is obtained as a yellowish oil which can be reacted without further purification.

19.9 g (128.3 mmol) of 4- (N-acetyl-N-methyl-amino) -2-methylene-butanal and 15.4 ml (141.1 mmol) of isocyanacetic acid ethyl ester are initially charged in 80 ml of toluene at room temperature and treated with 500 mg Copper l-oxide added. After the exothermic reaction has subsided, the mixture is stirred for a further hour at room temperature, filtered through Hyflo® and evaporated. The residue is taken up in 60 ml of tetrahydrofuran, mixed with 20 ml of water and refluxed for 4 hours. It is evaporated, mixed with toluene and evaporated again. Chromatography on silica gel with ethyl acetate / isopropanol (7: 1) gives 6- (N-acetyl-N-methylamino) -2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester as a yellow oil.

15.8 g (55.2 mmol) of ethyl e-fN-acetyl-N-methyl-aminol-formylamino-S-hydroxy-methyl-hexanoate are dissolved in 150 ml of dichloromethane and are added dropwise at room temperature to 5.1 ml (66.2 mmol). Thionyl bromide added. After 1 h, 100 ml of water are added and allowed to stir intensively for 10 minutes. The organic phase is separated off, washed successively with water, 1N KOH solution and again with water, dried over MgSO ₄ , filtered and evaporated. This gives 6- (N-acetyl-N-methyl-amino) -4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester as a yellow-orange oil, which is further reacted crude.

16.0 g (45,8mMol) e-fN-acetyl-N-methyl-aminoM-bromomethyl ^ -formylamino-hex-S-enoic acid ethyl ester and 50,3ml (183.3 mmol) of triisopropyl phosphite (90%) are at 80 ⁰ C heated and stirred under a pressure of about 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). There is obtained 6- (N-acetyl-N-methyl-amino) -4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester as a yellow oil.

Example 14

3.3 g (6.82 mmol) of e-Benzoyloxy ^ -Diisopropylphosphonomethyl ^ -formylamino-hex-S-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane and treated dropwise at room temperature with 3.52 ml (27.3 mmol) of trimethylbromosilane. The mixture is allowed to stand at room temperature for 22 hours, 20 ml of ethanol are added dropwise, the mixture is allowed to stand again for 22 hours, evaporated, 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 is formed which is stirred for 1 hour at room temperature and for 1 hour at 0 ° C. and then filtered off with suction. After drying, 2-amino-6-benzoyloxy-2-arniopo-4-phosphonomethylhex-3-enoic acid ethyl ester with the mp. 236-237 ° C (dec.).

The starting material may e.g. be prepared as follows:

10g (52 mmol) of 4-benzoyloxy-butanal, 4,78g (58,6mMol) dimethylammonium chloride und4,6ml (60.8 mmol) of formaldehyde solution (37% strength) are added under stirring maintained for 1 hour at reflux (bath temperature ~ 110 ⁰ C) , Allow to cool and extract three times with ether, combine the organic phases, wash with brine, dry over MgSO ₄ , filter and evaporate. 4-Benzoyloxy-2-methylenebutanal is obtained as a yellowish oil which can be reacted without further purification.

10 g (49 mmol) of 4-benzoyloxy-2-methylene-butanal and 5.3 ml (49 mmol) of isocyanacetic acid ethyl ester are initially charged in 70 ml of toluene at room temperature and treated with 200 mg of copper 1-oxide. After the exothermic reaction has subsided, it is still allowed to

Stir for 1 hour, filtered through Hyflo® and evaporated. The residue is taken up in 50 ml of tetrahydrofuran, admixed with 10 ml of water and refluxed for 3 hours. It is evaporated, treated again with toluene and evaporated again. Chromatography on silica gel with toluene / ethyl acetate (3: 2) gave ethylbenzoyloxy-4-formylamino-S-hydroxy-α-methylenehexanoate as a brown oil.

8 g (23.9 mmol) of ethyl e-benzoyl-4-formylamino-S-hydroxy-1-methylenehexanoate are dissolved in 80 ml of dichloromethane and treated dropwise at room temperature with 2.26 ml (28.6 mmol) of thionyl bromide. After 2 hours, 60 ml of water are added and allowed to stir intensively for 10 minutes. The organic phase is separated off, washed successively with water, 1N KOH solution and again with water, dried over MgSO ₄ , filtered and evaporated. Obtained б-ВепгоуІоху-ДготтеіпуІ-г-formylamino-hex-3-enoic acid ethyl ester as a brown oil, which is further reacted crude.

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. To obtain e-Benzoyloxy ^ -Diisopropylphosphonomethyl - ^ - formylamino-hex-S-enoic acid ethyl ester as a brown oil.

Example 15

4.0g (8.5ImMoI)

e-Benzyloxy ^ -Diisopropylphosphonomethyl ^ -formylamino-hex-S-enoic acid ethyl ester are dissolved in 24 ml of dichloromethane and treated dropwise at room temperature with 4.4 ml (34 mmol) of trimethylbromosilane. The mixture is allowed to stand at room temperature for 22 hours, 24 ml of ethanol are added dropwise, left to stand for 24 hours, evaporated on a rotary evaporator, the residue is dissolved in 24 ml of ethanol and added dropwise a mixture of 24 ml of propylene oxide and 24 ml of ethanol. A suspension is formed which is stirred for 1 hour at room temperature and for 1 hour at 0 ^° C. and then filtered off with suction. After drying, 2.2 g of a white, crystalline product are obtained, which is a mixture of г-Атіпо-б-ЬепгуІоху ^ -рповропотоетпппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппппп represents. To obtain a uniform product, this mixture is saponified with 20 ml of η-sodium hydroxide in 30 ml of ethanol overnight at room temperature, made acidic with n-hydrochloric acid and neutralized with propylene oxide. As the product crystallizes poorly, the mixture is evaporated on a rotary evaporator, the residue is filtered into water over 20 g of silica gel and the fractions containing the desired product are evaporated on a rotary evaporator. The residue is dissolved in 10 ml of tertiary-butanol / water (1: 1) and freeze-dried. You get

as a lyophilisate.

The starting material may, for. B. be prepared as follows:

6 g (0.2 mol) of a sodium hydride dispersion (80% in white oil) are initially charged in 120 ml of absolute dimethylformamide at room temperature and treated dropwise with 22.2 ml (0.25 mol) of 1,4-butanediol. After the addition is stirred for 30 minutes at room temperature. Now 23.1 ml (0.2 mol) of benzyl chloride are slowly added dropwise, whereby a slight exothermic is recognizable. The reaction mixture is stirred overnight at room temperature, treated with water / ice and extracted twice with ether. The organic phases are washed with water and with saturated brine, combined, dried over MgSO ₄ , filtered and evaporated. The residue is fractionally distilled in a water-jet vacuum over a 10 cm Vigreux column. This gives 4-benzyloxybutanol of Kp ₂ 2 = 161-162 ⁰ C.

36.6 g (17OmMoI) of pyridinium chlorochromate are initially charged in 120 ml of dichloromethane at room temperature under N ₂ and treated with a solution of 20.4 g (113 mmol) of 4-benzyloxybutanol in 20 ml of dichloromethane. The reaction mixture darkens rapidly and the reaction is slightly exothermic. The reaction mixture is stirred for Stunden2 hours at room temperature. The supernatant dichloromethane phase is decanted off and evaporated on a rotary evaporator. The residue is filtered through 100 g of silica gel. The product fractions are evaporated on a rotary evaporator and distilled under high vacuum through a 10 cm Vigreux column. 4-Benzyloxybutanal of Kp _o , i = 72-73 ° C is obtained.

8.0 g (44,9mMol) 4-Benzyloxybutanal, 4.12 g (50,6mMol) dimethylammonium chloride and 3,95ml (52,6mMol) of 37% formaldehyde solution are kept under stirring for 1 hour at 110 ⁰ C. bath temperature. It is allowed to cool and extracted three times with ether. The organic phases are washed with saturated brine, combined, dried over MgSO ₄ , filtered and evaporated. 4-Benzyloxy-2-methylene-butanal is obtained as a yellowish oil which can be further reacted without further purification.

8.0 g (42 mmol) of 4-benzyloxy-2-methylene-butanal and 4.57 ml (42 mmol) of ethyl isocyanatoacetate are initially charged in 60 ml of toluene and treated with 200 mg of copper 1-oxide. After the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered through Hyflo® and evaporated. The residue is taken up in 50 ml of tetrahydrofuran, mixed with 10 ml of water and refluxed for 3 hours. It is evaporated to dryness, mixed with toluene and evaporated again. Chromatography on silica gel with toluene / ethyl acetate (3: 2) as eluent gave benzyloxy-4-formylamino-S-hydroxy-methyl-hexanoate as a red-brown oil.

7.0 g (21.8 mmol) of e-benzyloxy-4-formylamino-S-hydroxy-methyl-hexanoate are dissolved in 70 ml of dichloromethane and treated dropwise at room temperature with 2.0 ml (26.1 mmol) of thionyl bromide. After 2 hours, add 40 ml of water and stir for 10 minutes. The organic phase is separated, washed successively with water, П-КНСО3 solution and again with water, dried over MgSO ₄ , filtered and evaporated. 6-Benzyloxy-4-bromomethyl-4-formylamino-hex-S-enoic acid ethyl ester is obtained as a red-brown oil, which is reacted further without purification. 7.9 g (20.5 mmol) of e-Benzyloxy ^ -brommethyl ^ -formylamino-hex-S-enoic acid ethyl ester and 22.5 ml (82.2 mmol) of triisopropyl phosphite (90%) are heated to 8O ⁰ C and under a pressure of about 130mbar stirred for 18 hours. The excess triisopropyl phosphite is distilled off on a rotary evaporator and the residue is purified by chromatography on silica gel with ethyl acetate. This gives e-BenzoyM-diisopropylphosphonomethyl ^ -forrnylamino-hex-3-enoic acid ethyl ester as a yellowish oil.

Example 16

3.15 g (6.84 mmol) of 4- (1-acetylpiperidin-4-yl) -5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 17 ml of dichloromethane and are added dropwise at room temperature to 3.54 ml (27.3 mmol). Trimethylbromsilan added. It is allowed to stand for 16 hours at room temperature, added dropwise 17 ml of ethanol, allowed to stand for a further 18 hours, evaporated on

Rotary evaporator, the residue is dissolved in 12 ml of ethanol and adds a mixture of 3 ml of propylene oxide and 3 ml of ethanol. It forms a suspension which is stirred for a further 2 hours at room temperature and 2 hours under ice cooling and then filtered with suction. This gives 2-amino-4- (1-acetylpiperidin-4-yl) -5-phosphono-pent-3-enoic acid ethyl ester, mp. 225 ° C (dec.).

The starting material may, for. B. be prepared as follows:

3.95G (23,3mMol) 2- (1-Acetyl-piperidine-4-yl) ethanol, 2,12g (26,3mMol) dimethyl ammonium chloride and 3 ml (4OmMoI) of 37% formaldehyde solution are heated under stirring for 2 hours at 110 ⁰ C. , It is allowed to cool and extracted several times with diethyl ether. The organic phases are combined, washed with saturated brine, dried over sodium sulfate, filtered and evaporated to dryness. 2- (1-Acetylpiperidin-4-yl) -propenal is obtained as a yellowish oil which can be further reacted without further purification.

2.9 g (16, OmMoI) of 2- (1-acetylpiperidin-4-yl) -propenal and 1.75 ml (16 mmol) of isocyanacetic acid ethyl ester are dissolved in 13 ml of toluene and admixed with 46 mg of copper (I) oxide. After the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered through Hyflo® and evaporated to dryness. The residue is taken up in 13 ml of tetrahydrofuran, treated with 6 ml of water and heated with stirring for 2 hours to reflux. It is evaporated to dryness, mixed with toluene and evaporated again. Chromatography on silica gel with ethyl acetate / methanol (9: 1) as eluent gives 4- (1-acetylpiperidin-4-yl) -2-fomylamino-S-hydroxy-p-pentanoic acid ethyl ester as a yellow-brown oil.

3.3 g (10.5 mmol) of 4- (1-acetylpiperidin-4-yl) -2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester are dissolved in 25 ml of 1,2-dichloroethane and are added dropwise at room temperature to 0.98 ml (12.6 mmol) of trionyl bromide. After Vh hours, 20 ml of water are added and allowed to stir for 15 minutes. The organic phase is separated, washed successively with water, n-potassium bicarbonate solution and again with water, dried over sodium sulfate, filtered and evaporated. This gives 4- (1-acetylpiperidin-4-yl) -5-bromo-2-formylamino-pent-3-enoic acid ethyl ester as a red-brown oil. 2.68g (7.14 mmol) of 4- (1-acetyl-piperidin-4-yl) -5-bromo-2-formyl-amino-pent-3-enoic acid ethyl ester and 7.5 ml (28.5 mmol) of triisopropyl phosphite (90%) are added 80 ⁰ C heated and stirred under a pressure of about 130mbar for 18 hours. The excess Triisopropylphosphit is distilled off under reduced pressure and the evaporation residue on silica gel with ethyl acetate / methanol (9: 1) purified by chromatography. 4- (1-acetylpiperidin-4-yl) -5-diisopropylphosphono-4-formylamino-pent-S-enoic acid ethyl ester is obtained as a yellowish oil.

Example 17

1 g (2.17 mmol) of 4- (1-acetylpiperidin-4-yl) -5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are refluxed in 20 ml of 6N hydrochloric acid for 8 hours. After evaporation, the residue is dissolved in 25 ml of ethanol. Now add 3 ml of propylene oxide, allowed to stir for 2 hours at room temperature and for 1 hour under ice cooling and then sucks off the suspension formed. This gives 2-amino-4- (piperidin-4-yl) -5-phosphono-pent-3-enoic acid, mp. 212 ° C (dec.).

Example 18

0.68 g (1.49 mmol) of S-benzyloxy ^ -diisopropylphosphonomethyl ^ -formylamino-pent-S-enoic acid ethyl ester are dissolved in 10 ml of dichloromethane and admixed dropwise at room temperature with 0.8 ml (6 mmol) of trimethylbromosilane. The mixture is allowed to stand at room temperature for 6 hours, 10 ml of ethanol are added dropwise, the mixture is allowed to stand again for 18 hours, evaporated, 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 for 2 hours at room temperature and then filtered with suction. After drying gives г-Атіпо-Б-ЬепгуІоху ^ - phosphonomethyl-pent-3-enoic acid ethyl ester, mp. 218-220 ⁰ C (dec.).

The starting material may, for. B. be prepared as follows:

3.0 g (62.4 mmol) of 50% sodium hydride dispersion in mineral oil are initially introduced in 50 ml of tetrahydrofuran and 40ml of dimethylformamide, at 0 ⁰ C was slowly added with a solution of 10.0 g (62,4mMol) S-hydroxy ^ methylene propionaldehyde diethyl acetal in 10ml tetrahydrofuran and stirred for 2 hours at 0 ⁰ C. It is diluted with 15 ml of tetrahydrofuran and 10 ml of dimethylformamide and stirred for a further 2 hours at room temperature. Now 7.2 ml (62.4 mmol) of benzyl chloride in 10 ml of dimethylformamide at 0 ⁰ C and stirred for 18 hours at room temperature. The reaction mixture is treated with water, extracted three times with ethyl acetate and the organic phases are washed with saturated brine. The organic phases are combined, dried over Na ₂ SO ₄ , filtered and evaporated. The residue is chromatographed on silica gel with methylene chloride to give S-benzyloxy-methylene-propionaldehyde-diethyl acetal as a slightly yellowish liquid.

4.8 g (19.1 mmol) of S-benzyloxy-methylene-propionaldehyde-diethyl acetal and 0.36 g (1.9 mmol) of p-toluenesulfonic acid monohydrate are stirred for 3 hours in 60 ml of acetone. It is diluted with 400 ml of methylene chloride, extracted with n-KHCO ₃ solution and saturated brine, dried over Na ₂ SO ₄ , filtered and evaporated. The remaining S-Benzyloxy ^ -methylenpropanal (yellow liquid) is presented without further purification together with 2.1 ml (19 mmol) Isocyanessigsäureäthylester in 25 ml of toluene at room temperature and treated with 50 mg of copper-l-oxide. After the exothermic reaction has subsided, the mixture is stirred for a further hour at room temperature, filtered through Hyflo® and evaporated. The residue is taken up in 25 ml of tetrahydrofuran, mixed with 5 ml of water and refluxed for 4 hours. It is evaporated, mixed with toluene and evaporated again. Chromatography on silica gel with toluene / Essstgsäureäthylester (1: 1) and subsequent crystallization from diethyl ether gives S-benzyloxy ^ -formylamino-S-hydroxy ^ -methylenpentansäureäthylester, mp. 112-114 ^O C.

1.0 g (3.25 mmol) of S-benzyloxy-4-formylamino-S-hydroxy-methylene-pentanoic acid ethyl ester are suspended in 30 ml of 1,2-dichloroethane and treated dropwise at room temperature with 0.38 ml (4.9 mmol) of thionyl bromide. After 45 minutes, 20 ml of water are added to the yellow solution and the mixture is allowed to stir intensively for 15 minutes. The organic phase is separated, washed with saturated brine, dried over Na ₂ SO ₄ , filtered and evaporated. There is obtained ö-benzyloxy ^ -brommethyl ^ - formylamino-pent-3-enoic acid ethyl ester as a yellowish oil, which is further reacted crude.

1.14 g (3.1 mmol) of S-benzyloxy-A-bromomethyl-4-formylamino-pent-S-enoic acid ethyl ester and 10 ml (38.5 mmol) of triisopropyl phosphite (95%) are heated to 80 ° C and under a pressure of about 130 mbar ЗѴг stirred for hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. S-Benzyloxy ^ -diisopropylphosphonomethyl ^ -formylamino-pent-S-enoic acid ethyl ester is obtained as a yellowish oil.

Example 19

1.10 g (2.8 mmol) of S-ethoxy-diisopropylphosphonomethyl-4-formyl-amino-pent-S-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane and treated dropwise at room temperature with 1.6 ml (12.3 mmol) of trimethylbromosilane. It is allowed to stand for 7 hours at room temperature, 20 ml of ethanol are added dropwise and left to stand for 15 hours, evaporated, the residue is dissolved in 10 ml of ethanol and added dropwise a mixture of 10 ml of propylene oxide and 10 ml of ethanol. A suspension forms, which is stirred for 2 hours at room temperature and then filtered with suction. After drying, 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester of mp. 217-218 ° C (dec.).

The starting material may, for. B. be prepared as follows:

50g (283mMol) of 3-ethoxy-propionaldehyde diethyl acetal, 27.3g (335mMol) dimethyl ammonium chloride and 30ml (392mMol) of 36% formaldehyde solution are heated under stirring for 2 hours at 110 ⁰ C. It is allowed to cool and extracted three times with diethyl ether. The organic phases are washed with saturated brine, combined, dried over sodium sulfate, filtered and evaporated to dryness. 2-ethoxy-propanal is obtained as a yellow liquid which can be further reacted without further purification.

4.2 g (36.1 mmol) of 2-ethoxy-propanal and 4.4 ml (4OmMoI) Isocyanessigsäureäthylester are dissolved in 50 ml of toluene and treated with 200 mg of copper-l-oxide. After the exothermic reaction has subsided, the mixture is stirred for a further 1 hour, filtered through Hyflo ¹ and evaporated to dryness. The residue is taken up in 50 ml of tetrahydrofuran, treated with 12 ml of water and heated with stirring for 1 hour to reflux. It is evaporated to dryness, mixed with toluene and evaporated again. Chromatography on silica gel with toluene / isopropanol (9: 1) as eluant gives ethyl S-ethoxy-4-formylamino-S-hydroxy-A-methylene pentanoate as a yellow oil.

3.70 g (15.1 mmol) of S-ethoxy ^ -formylamino-S-hydroxy ^ -methylen-pentanoic acid ethyl ester are dissolved in 100 ml of 1,2-dichloroethane and treated dropwise at room temperature with 1.8 ml (22.8 mmol) of thionyl bromide. After 1 hour, add 100 ml of water and stir for 15 minutes. The organic phase is separated, washed successively with 1 N potassium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. Is obtained ö-Äthoxy ^ -brommethyl ^ -formylamino-pent-S-enoic acid ethyl ester as a yellow-brown oil, which is further reacted crude. 3,12g (10.1 mmol) of S-ethoxy ^ ^ -formylamino bromomethyl-pent-S-enoic acid ethyl ester and 30ml (118mMol) triisopropyl phosphite (90%) are heated to 8O ⁰ C and stirred under a pressure of from about 130mbar 7 hours , The excess triisopropyl phosphite is distilled off and the residue is chromatographed on silica gel with methylene oxide / methanol (97: 3 to 95: 5). S-Ethoxy-diisopropylphosphonomethyl-4-formylamino-pent-S-enoic acid ethyl ester is obtained as a yellow oil.

Example 20

Tablets each containing 50 mg of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, e.g. the sodium salt thereof can be prepared as follows:

Composition (10000 tablets) 500.0 g active substance 500.0 g lactose 352.0 g potato starch 8.0 g gelatin 60.0 g talc 10.0 g magnesium stearate 20.0 g Silica (highly dispersed) q.s. ethanol

The active ingredient is mixed with the lactose and 292 g of potato starch, the mixture is moistened with an ethanolic solution of gelatin and granulated through a sieve.

After drying, the remainder of the potato starch, magnesium stearate, talc and silica are mixed and the mixture is compressed into 145.0 mg weight tablets and 50.0 mg active ingredient content, which may optionally be provided with partial scores for finer dosage adjustment.

Example 21

Lacquered tablets each containing 100 mg of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, e.g. the sodium salt thereof can be prepared as follows:

Composition (for 1000 coated tablets)

active substance 100.0 g lactose 100.0 g corn starch 70.0 g talc 8.5 g calcium stearate 1.5g hydroxypropyl methylcellulose 2.36 g shellac 0.64 g water q.s. methylene chloride q.s.

The active substance, the lactose and 40 g of corn starch are mixed and moistened with a paste made from 15 g of corn starch and water (with heating), and granulated. The granules are dried, the remainder of the corn starch, the talc and the calcium stearate added and mixed with the granules. The mixture is compressed into tablets (weight: 280 mg) and this is painted with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; Final weight of the coated tablet: 283 mg.

Example 22

Gelatin capsules containing 100mg of active ingredient, e.g. В. г-Атіпо-б-пуагоху-ФрпозрпопогпеігіуІ-гіех-З-епзаиге or a salt, eg. As the sodium salt, thereof, z. B. be prepared as follows:

Composition (for 1000 capsules) 100.0 g active substance 250.0 g lactose 30.0 g microcrystalline cellulose 2.0 g sodium lauryl sulfate 8.0 g magnesium stearate

Sodium lauryl sulfate is added to the lyophilized agent through a 0.2 mm mesh screen. Both components are intimately mixed. Then the lactose is first passed through a sieve with a mesh size of 0.6 mm and then the microcrystalline cellulose through a sieve with a mesh size of 0.9 mm. Then it is mixed again for 10 minutes. Finally, the magnesium stearate is added through a sieve with a mesh size of 0.8 mm. After further mixing for 3 minutes, each 390 mg of the formulation obtained are filled into size 0 gelatine capsules.

Example 23

A 0.2% solution for injection or infusion of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, e.g. of the sodium salt, thereof, can be prepared, for example, as follows:

Composition (for 1000 ampoules)

Active ingredient 5.0 g

Sodium chloride 22.5 g

Phosphate buffer pH = 7.4 300.0 g

demineralised water ad 2 500.0 ml

The active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a microfilter. It is mixed with the buffer solution and filled with water to 2500ml. For the preparation of dosage unit forms are each 1.0 or 2.5 ml filled into glass ampoules, which then contain 2.0 or 5.0 mg active ingredient.

Example 24

Can be described in an analogous manner as in Examples 1 to 19 also be prepared: 2-amino-8-hydroxy-4-phosphonomethyl-oct-3-ensaureathylester, mp 230-233 ⁰ C (dec.);. 2-amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester, m.p .; 177-180 ⁰ C, and 2-amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester

г, mp 243-244 ° C (decomp.).

Example 25

In a manner analogous to that described in Examples 20 to 23 above, it is also possible to prepare pharmaceutical preparations containing another compound of the formula I according to one of Preparation Examples 1 to 19 and 24.

Claims (85)

wherein Ri is an optionally acylated or aliphatically or araliphatically etherified hydroxy, substituted by halogen, by optionally acylated and / or aliphatically substituted amino or by an aza-, diazo, azoxa or oxacycloaliphatischen radical substituted aliphatic or bonded via a C atom oxacycloaliphatischen or optionally aliphatic N-substituted or N-acylated azacycloaliphatic hydrocarbon radical and R _{2 is} free or esterified carboxy, and their salts, characterized in that
in a compound of formula II wherein Z ₁ , Z _{2 are} optionally protected hydroxy, Z _{3 is} an optionally protected or acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally protected or acylated and / or aliphatically substituted amino or by an aza-, diaza , azoxa or oxacycloaliphatic radical substituted aliphatic or bonded via a C atom oxacycloaliphatische or optionally protected or aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical and Z ₄ protected amino, protected amino Z ₄ and, if present, as a part of Z ₃ in amino and, if present, protected hydroxy Z ₁ , Z ₂ and / or converted as part of Z ₃ in hydroxy and, if present a protected azacycloaliphatic hydrocarbon radical Z ₃ liberated and, if desired, a compound obtained in another compound of formula I. transferred, an isomer mixture obtainable in accordance with the process is separated into the components and the particular isomers are separated off and / or a free compound obtainable according to the process is converted into a salt or a salt obtainable according to the process into the corresponding free compound. A process as claimed in claim 1 for the preparation of compounds of the formula I in which R _{1 is an} aliphatic hydrocarbon radical which is optionally substituted by aliphatic or araliphatic etherified hydroxy, optionally aliphatically substituted amino or halogen and R _{2 is} free or esterified carboxy, and their salts, characterized in that in a compound of formula II wherein Z ₁ , Z _{2 represent} optionally protected hydroxy, Z _{3 represents} an optionally protected or aliphatically or araliphatically etherified hydroxy, optionally protected or aliphatically substituted amino or halogen-substituted aliphatic hydrocarbon radical and Z ₄ protected amino, protected amino Z ₄ and , if present, as part of Z ₃ in amino and, if present, protected hydroxy Z ₁ , Z ₂ and / or converted as a component of Z ₃ in hydroxy and, if desired, converting a compound obtained into another compound of formula I, a method according to available isomer mixture is separated into the components and the particular isomer is separated off and / or a process according to available free compound is converted into a salt or a salt according to the process in the corresponding free compound. 3. The method according to claim 1, characterized in that one compounds of formula I, wherein R ₁ mono- or Dihydroxyniederalkyl, Niederalkanoyloxyniederalkyl, Benzoyloxyniederalkyl, Niederalkoxyniederalkylk, Phenylniederalkoxyniederaikyl, Halogenniederalkyl, Aminoloweralkyl, Niederalkylaminoniederalkyl, Niederalkanoylaminoniederalkyl, Diniederalkylaminoloweralkyl, N-lower alkyl-N-lower alkanoylaminoloweralkyl 5 to 7-membered azacycloalkyl-lower alkyl whose azacycloalkyl moiety can be bonded via the N or C atom and optionally N-lower alkylated in the latter case, N-lower alkanoylated or N-substituted by a benzoyl group optionally substituted in the phenyl moiety, 5- to 7-membered diazacycloalkyl-lower alkyl whose diazacycloalkyl moiety is bonded via an N atom and optionally N'-lower alkylated, N'-lower alkanoylated or N'-substituted by a benzoyl group optionally substituted in the phenyl moiety, 5-to 7-membered, via the N atom g ebundenes Azoxacycloalkylniederalkyl, 5- to 7-member bonded via a C atom Oxacycloalkylniederalkyl, 5- to 7-membered, bonded via a carbon atom, optionally N-lower alkylated, N-lower alkanoylated or by an optionally substituted in the phenyl moiety N-substituted azacycloalkyl or 5- to 7-membered, bound via a C atom oxacycloalkyl and R _{2 is} carboxy, lower alkoxycarbonyl, 4- to and 7-membered cycloalkoxycarbonyl or PhenylniederaIkoxycarbonyl, wherein in said groups R ₁ and / or R ₂ optionally unsubstituted phenyl or lower alkyl , Lower alkoxy, halogen, cyano and / or trifluoromethyl mono-, di- or trisubstituted, or their salts. 4. The method according to claim 2, characterized in that compounds of formula I, wherein R _{1 is} hydroxy, lower alkoxy, lower phenyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkylamino, Nieder, Ν-Niederalkylenamino- or N, N- (Aza- or Oxaniederalkylen) amino-lower alkyl or halo-lower alkyl and R _{2 represents} carboxy, lower alkoxycarbonyl, 4-bis and 7-membered cycloalkoxycarbonyl or phenyl-lower alkoxycarbonyl, unsubstituted or unsubstituted phenyl radicals in said groups Ri and / or R ₂ or lower alkyl, lower alkoxy, halogen, cyano and / or trifluoromethyl may be mono-, di- or trisubstituted, or salts thereof. 5. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} hydroxy-C ^ Cy-alkyl, dihydroxy-Cy-C ₇ alkyl, C ₂ -C ₇ alkanoyloxy-C ₁ -C ₇ alkyl, in the phenyl part optionally by C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, halogen or atomic number up to and with 35, cyanoboric or trifluoromethyl mono- or disubstituted benzoyloxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ - Al koxy - ^ - Gj-a I ky I, a phenyl in the phenyl moiety, optionally mono- or disubstituted by Ci-C ₄ -AIlCyI, Ci-C ₄ -AIkOXy, halogen of the atomic number to and with 35, cyano and / or trifluoromethyl C ₁ -C ₄ -alkoxy-Ci-C ₇ alkyl, halogen-C ₁ -C ₇ alkyl, wherein halogen is chlorine or fluorine, amino - ^ - C ^ alkyl, С С ^ ^ АІкуІатіпо-Сі-Ст- аІкуІ, Cr-C ^ AIkanoylamino-C ₁ -C ₇ alkyl, NC ₂ -C _{7 alkanoyl-N-Ci-C4-alkyl-amino-Ci-C 7} alkyl, di - ^ - C ^ AIkylamino- Ci-C-ralkyl, 5- to 7-member АгасусІоаІк-і-уІ-Сі-Ст-аІкуІ, АгасусІоаІк-З-уІ - ^ - С ^ аІкуІ 4-yl-C--C _7- alkyl, і-Сг-С ^ АІкапоуІагасусІоаІк-З-уІ-Ст-Ст-аІкуІ or 4-уІ-СС-Ст-аІкуІ, N - ^ - C -alkylazacycloalkyl-3- Yl-C ₁ -C ₇ -alkyl or 4-Yl-C ₁ -C ₇ -BlkYl, Nd ^ -Benzoylazacycloalkyl-S-yl-C alkyl or 4-yl-C, -C ₇ alkyl, diazacycloalk -i-yl-C ^^ alkyl, N'-C ₁ -C ₄ -alkyldiazacycloalk-1-yl-C ₁ -C ₇ -alkyl, 14'-C ₂ -C ₇ -alkanoylazacycloalk-i-yl - ^ - C ^ alkyl, 5- to 7-membered azoxacycloalk-1-уІ-Ст-СгаІкуІ, 5- to 7-membered ОхасусІоаІк-З-уІ-С ^ С ^ аІкуІ or -4-уІ-Ст-С ^ аІкуІ, 5- to 7-membered azacycloalk 3-yl or 4-yl or і-Сг-С ^ АІкапоуІ-агасусІоаІк-З-уІ or 4-yl, N-Ci-Q-alkylazacycloalk-S-yl or -4-yl or in the phenyl moiety, if appropriate substituted N-benzoylazacycloalk-3-yl or 4-yl or 5- to 7-membered oxacycloalk-3-yl or 4-yl and R _{2 is} carboxy, C ₁ -C ₄ -alkoxyCaTbOnYl, 5- to 7-membered cycloalkoxycarbonyl or optionally C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, halogen of atomic number to and with 35, cyano and / or trifluoromethyl mono- or di-substituted phenyl-C ₁ -C ₄ -alkoxycarbonyl, or produces their salts. 6. The method according to claim 2, characterized in that compounds of the formula I wherein Ri is hydroxy-Ci-Cralkyl, C ₁ -C ₄ -alkoxy-Ci-C ₇ alkyl, one in the phenyl moiety optionally substituted by C ₁ -C ₄ -Alkyl, C ₁ -C ₄ -alkoxy, halogen of the atomic number up to and including 35, cyano and / or * trifluoromethyl mono-, di- or trisubstituted РпепуІ-Ст-Сд-аІкоху-Сі-СгаІкуІдгирре, aminole, C ₁ -C ₄ Alkylamino-C ₁ -C ₇ -alkyl, C ₁ -C ₄ -alkanoylamino-C ₁ -C ₄ -alkyl, C ₁ -C ₆ -alkylamino-I, 5 to 7-membered N, N- (aza or oxaalkylene-amino-C ₁ -C ₄ -alkyl), alkyl group, wherein halogen is chlorine or fluorine and R ₂ is carboxy, Ci-C ₄ alkoxycarbonyl, 5-to 7-membered cycloalkoxycarbonyl, optionally substituted by C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, halogen having an atomic number of up to and with 35, cyano and / or trifluoromethyl mono- or disubstituted РпепуІ-Сг-Сд-аІкохусагЬопуІ, or is prepared salts thereof. 7. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} hydroxy-Ci-Cy-alkyl, in the phenyl moiety optionally by C ₁ -C ₄ -Alkyl, C ₁ -C ₄ -alkoxy, halogen of Atomic number to and with 35, cyano and / or trifluoromethyl mono- or di-substituted benzoyloxy - ^ - Cy-alkyl, in the phenyl part optionally by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen of the atomic number up to and including 35 , Cyano and / or trifluoromethyl mono- or disubstituted phenyl-C ₁ -C ₄ -alkoxy-C ₁ -C ₇ -alkyl, halogeno-C ₁ -C ₇ -alkyl, where halogen is chlorine or fluorine, amino-C ₄ -C _7- alkyl, NC ₂ -C ₇ alkanoyl-NC ₁ -C ₄ -alkyl-amino-Ci-C ₇ -alkyl or 5- to 7-membered azacycloalk-3-yl or 4-yl or і-Ст-С ^ АІкапоуІ-агасусІоаІк-З-уІ or 4-yl and R _{2 is} carboxy, C ₁ -C ₄ -alkoxyCaTbOnYl or optionally by C ₁ -C ₄ -A ^ yI, C ₁ -C ₄ -alkoxy, halogen of the atomic number to and mono- or disubstituted with 35, cyano and / or trifluoromethyl Phenyl-Cv-Q-alkoxycarbonyl, or salts thereof. 8. The method according to claim 1, characterized in that compounds of the formula I, wherein R _{1 is} hydroxy - ^ - Cj-alkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, in the phenyl part optionally by C C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, halogen of the atomic number up to and including 35, cyano and / or trifluoromethyl mono-, di-or trisubstituted phenyl-C ₁ -C ₄ -alkoxy-C ₁ -C ₄ - alkyl group, or halo-C ₁ -C ₄ -alkyl, where halogen is chlorine or fluorine, and R _{2 is} carboxy, C ₁ -C ₄ -alkoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl or optionally by C ₁ -C ₄ -alkyl, C C ₁ -C ₄ -Alkoxy, halogen of the atomic number to and with 35, cyano and / or trifluoromethyl mono- or disubstituted phenyl-CiQ-alkoxycarbonyl, or the salts thereof. 9. The method according to claim 2, characterized in that compounds of formula I, wherein R _{1 is} C ₁ -C ₄ alkylamino-C ₁ -C ₇ alkyl, Cr-G ^ alkanoylamino-CiCf-alkyUDi - ^ - Ci Alkylamino-C ₁ -C ^ alkyl or 5- to 7-membered N, N- (aza- or oxa-alkylene-Ciino-C ₁ -C -alkyl and R _{2 is} carboxy, C ^ Cr alkoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl or optionally by C ₁ -C ₄ alkyl, C ₁ -C ₄ -alkoxy, halogen of the atomic number to and 35, cyano and / or trifluoromethyl mono- or di-substituted phenyl-CH ^ alkoxycarbonyl, or produces their salts. 10. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} hydroxy - ^ - C ^ alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₇ -BlkYl, benzoyloxy-CiC ^ alkyl, Amino-C ₄ -C ₇ -alkyl, NC ₂ -C ₇ -alkanoyl-NC ₁ -C ₄ -alkyl-amino-C ₂ -C ₇ -alkyl, 5- to 7-membered azacycloalk-3-yl or 4-yl or і-Сг-С ^ АІкапоуІ-агасусІоаІк-З-уІ or 4-yl, halo-C ₁ -C ₄ -alkyl, wherein halogen is chlorine or fluorine, and R _{2 is} carboxy or C ₁ -C ₄ -alkoxyCaTbOnYl means, or produces their salts. 11. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} 2-hydroxyethyl, 3-hydroxypropyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-Benzoyloxyäthyl, benzyloxymethyl, 2-Benzyloxyäthyl, 4- Aminobutyl, 6-aminohexyl, 2- {N-acetyl-N-methylamino) ethyl, piperidin-4-yl, 1-acetylpiperidin-4-yl or 2-fluoroethyl; and R _{2 represents} carboxy or ^ -Q-alkoxycarbonyl , or their salts. 12. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} amino-C ₄ -C ₇ alkyl, NC ₁ -C ₄ alkanoyl-NC ₁ -C ₄ alkyl-amino-C ₁ C ₇ -alkyl, piperidin-4-yl or 1-Сг-С ₇ -АІкапоуІрірегіаіп-4-уІ and R _{2 is} carboxy or C ₁ -C ₄ -alkoxyCaTbOnYl, or their salts. 13. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} hydroxy-C ^ C ^ alkyl.C ^ CrAlkoxy-C-Gt-alkyl, phenyl - ^ - Ct-alkoxy-Ci-Gralkyl, Benzoyloxy-Q-Gi-alkyl or halo - represents - d-alkyl and R _{2 is} carboxy or Ci-C ₄ alkoxycarbonyl, or the salts thereof. 14. The method according to claim 2, characterized in that one compounds of formula I, wherein Ri is amino-C ₄ -C ₇ alkyl and R _{2 is} carboxy, ^ -CrAlkoxycarbonyl or optionally by C ₁ -C ₄ -AllyiC, C ₁ -C ₄ -alkoxy, halogen of the atomic number to and with 35, cyano and / or trifluoromethyl mono- or di-substituted phenyl-Ci-Q-alkoxycarbonyl group, or the salts thereof. 15. The method according to claim 2, characterized in that compounds of formula I, wherein Ri compounds of formula I, wherein R ₁ Сі-Сд-АІкоху-Сг-Сд-аІкуІ, hydroxy-C ^ -Ci-alkyl or НаІодеп- Сг-Сд-аІкуІ and R _{2 is} carboxy, Cr-Ct-alkoxycarbonyl or an optionally by C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, halogen of the atomic number to and with 35, cyano and / or trifluoromethyl mono - or disubstituted phenyl-CrQ alkoxycarbonyl group, or produces their salts. 16. The method according to claim 2, characterized in that one prepares 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 17. The method according to claim 2, characterized in that one prepares г-Атіпо-phosphonmethyl-hex-3-enoic acid or a salt thereof. 18. The method according to claim 2, characterized in that one produces 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid or a salt thereof. 19. The method according to claim 2, characterized in that one produces 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid or a salt thereof. 20. The method according to claim 2, characterized in that one prepares г-Атіпо-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 21. The method according to claim 2, characterized in that one prepares 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 22. The method according to claim 1, characterized in that one produces 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof. 23. The method according to claim 1, characterized in that one produces г-Атіпо-б-ЬепгоуІоху ^ - phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 24. The method according to claim 1, characterized in that one prepares 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester or a salt thereof. 25. The method according to claim 1, characterized in that one produces г-Атіпо-У-пуагоху ^ - phosphonomethyl-hept-3-enoic acid or a salt thereof. 26. The method according to claim 1, characterized in that one produces г-Атіпо-б-ЬепгуІоху ^ - phosphonomethyl-hex-3-enoic acid or a salt thereof. 27. The method according to claim 1, characterized in that one produces 6- (N-acetyl-N-methyl-amino) -2-amino ^ -phosphonomethyl-hex-S-enoic acid ethyl ester or a salt thereof. 28. The method according to claim 1, characterized in that one prepares (1-acetylpiperidin-4-yl) -2-amino-ö-phosphono-pent-S-enoic acid ethyl ester or a salt thereof. 29. The method according to claim 1, characterized in that one prepares 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester or a salt thereof. 30. The method according to claim 1, characterized in that one produces 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid or a salt thereof. 31. The method according to claim 1, characterized in that one prepares 2-amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester or a salt thereof. 32. The method according to claim 1, characterized in that one produces г-Атіпо-б-гіуагоху ^ - phosphonomethyl-pent-3-enoic acid or a salt thereof. 33. The method according to claim 1, characterized in that one prepares г-Атіпо-б-ЬепгуІоху ^ - phosphonomethyl-pent-3-enoic acid ethyl ester or a salt thereof. 34. The method according to claim 1, characterized in that one produces г-Атіпо-б-ЬепгуІоху ^ - phosphonomethyl-pent-3-enoic acid or a salt thereof. 35. The method according to claim 1, characterized in that one prepares 2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester or a salt thereof. 36. The method according to claim 1, characterized in that one produces г-Атіпо-в-пуагоху ^ - phosphonomethyl-oct-3-enoic acid or a salt thereof. 37. The method according to claim 1, characterized in that one prepares 2-amino-6- (N-methylamino) -4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 38. The method according to claim 1, characterized in that one produces 2-amino-6 (N-methylamino) -4-phosphonomethyl-hex-3-enoic acid or a salt thereof. 39. The method according to claim 1, characterized in that one prepares 2-amino-4- (piperidirt-4-yl) -5-phosphono-pent-3-enoic acid ethyl ester or a salt thereof. 40. The method according to claim 1, characterized in that one prepares 2-amino-4- (piperidin-4-yl) -5-phosphono-pent-3-enoic acid or a salt thereof. 41. The method according to claim 1, characterized in that one prepares 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid or a salt thereof. 42. The method according to claim 1, characterized in that one prepares б-АИіоху-г-атіпо ^ - phosphonomethyl-pent-3-enoic acid ethyl ester or a salt thereof. 43. The method according to claim 1 for the preparation of Z-amino-e-hydroxy ^ phosphonomethyl-oct-S-enoic acid ethyl ester or a salt thereof. 44. The method according to claim 1 for the preparation of г-Атто-б-г ^гох phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof 45. The method according to claim 1 for the preparation of г-Атіпо-3-enoic acid ethyl ester or a salt thereof. 46. Substituted 2-aminoalk-3-enoic acid derivatives of the formula I (D, wherein Ri is an optionally acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally acylated and / or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxycycloaliphatic radical substituted aliphatic or bonded via a C atom oxacycloaliphatic or optionally aliphatic N-substituted or N-acylated azacycloaliphatic hydrocarbon radical and R _{2 is} free or esterified carboxy, and their salts. 47. Compounds according to claim 46 of the formula I, in which R 1 is an aliphatic or optionally aliphatically or araliphatically etherified hydroxy, optionally aliphatically substituted amino or halogen-substituted aliphatic hydrocarbon radical and R _{2 is} free or esterified carboxy, and their salts. 48. Compounds according to claim 46 of formula I, wherein Ri is mono- or dihydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, benzoyloxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkoxy-lower alkyl, halo-lower alkyl, lower-lower alkyl, lower-alkyl-amino-lower alkyl, lower alkanoyl-amino-lower alkyl, lower di-lower alkylamino, lower N-lower alkanoyl-lower alkyl, 5- to 7-membered azacycloalkyl-lower alkyl whose Azacycloalkylteil bound via the N or a C atom and in the second case, optionally N-lower alkylated, N-lower alkanoylated or N-substituted by an optionally substituted in the phenyl moiety benzoyl, 5- to 7-membered Diazacycloalkylniederalkyl whose Diazacycloalkylteil an N Atom and optionally N'-lower alkylated, N'-lower alkanoylated or N'-substituted by a benzoyl group optionally substituted in the phenyl moiety, 5- to 7-membered, bound via the N-atom Azoxacycloalkylniederalkyl , 5- to 7-membered C atom-bonded oxacycloalkyl-lower alkyl, 5- to 7-membered, bonded via a C atom, optionally N-lower alkylated, N-lower alkanoylated or by an optionally substituted in the phenyl moiety N-substituted azacycloalkyl or 5- to 7-membered, bound via a C atom oxacycloalkyl and R _{2 is} carboxy, lower alkoxycarbonyl, 4- to and 7-membered cycloalkoxycarbonyl or Phenylniederalkoxycarbonyl, wherein in the groups R ₁ and / or R ₂ optionally unsubstituted or may be mono-, di- or trisubstituted by lower alkyl, lower alkoxy, halogen, cyano and / or trifluoromethyl, and their salts. 49. Compounds according to claim 2 of formula I, wherein Ri is hydroxy lower alkyl, lower alkoxy, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkylamino, N, N-Niederalkylenamino- or N, N- (aza- or Oxaniederalkylen) aminoloweralkyl or halo-lower alkyl and R _{2 is} carboxy , Lower alkoxycarbonyl, 4- to and 7-membered cycloalkoxycarbonyl or Phenylniederalkoxycarbonyl, wherein in said groups Ri and / or «R ₂ optionally present phenyl unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy, halogen, cyano and / or trifluoromethyl and their salts. 50. Compounds according to claim 46 of formula I, wherein R _{1 is} hydroxy-C 1-6 -j-alkyl, dihydroxy-Cr-cyalkyl, Сг-Су-АІкапоуІоху-Ст-Су-аІкуІ, in the phenyl part, optionally by Ci-C ₄ -alkyl , C ₁ -C ₄ -alkoxy, halogen of the atomic number to and with 35, cyano and / or trifluoromethyl mono- or disubstituted benzyloxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₆ -alkyl, one in the phenyl part, if appropriate C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, halogen of the atomic number up to and including 35, cyano and / or trifluoromethyl mono- or disubstituted phenyl-C 1 -C -alkoxy-C 1 -C -alkyl group, halogen-C 1 -C ₄ -alkyl, alkyl, where halogen is chlorine or fluorine, amino-C 1 -C ₇ -alkyl, C 1 -C ₄ -alkyl-amino-C 1 -C 6 -alkyl, Сг-Су-АІкапоуіатіпо-Сі-Су-аІкуІ, N-Cr-Cy Alkanoyl-N-C 1 -alkyl-amino-C 1 -C ₇ -alkyl, C 1 -C ₄ -cycloalkyl-C 1 -C 4 -alkyl, 5 to 7-membered azacycloalk-1-yl-C 1 -C 6 -alkyl, АгасусІоаІк-З -уІ-Сі-Су-аІкуІ or Azacycloalk- ^ yl-Ci-Cy-alkyl, i-Cr-CrAlkanoylazacycloalk-3-y l-Ci-C ₇ -alkyI or ФуІ-Сі-Су-аІкуІ, NC ₁ -C ₄ -alkylazacycloalkyl-3-yl-Ci-C ₇ -alkyl or Ф-уІ - ^ - Су-аІкуІ, NC ₁ -C ₄ -benzoylazacycloalkyl-3-yl-C ₁ -C ₇ -alkyl or 4-уІ-Ст-С ^ аІкуІ, 5- to 7-membered diazacycloalk- ₁ -yl-C ^ C ^ alkyl, N'-C ₁ C ₄ alkyldiazacycloalk-1-yl-C ₁ -C ₇ alkyl, 14'-C ₂ -C ₇ alkanoylazacycloalk-1-уІ-СНѴаІкуІ, 5- to 7-membered azoxacycloalk-1-yl-Ci-Cy-alkyl , 5- to 7-membered хасусусІоаІк-З-уІ-Ст-Су-аІкуІ or -4-yl-Ci-C ^ alkyl, 5- to 7-membered azacycloalk-3-yl or 4-yl or і-Сг-С ^ АІкапоуІагасусІоаІк N-benzoylazacycloalk-3-yl or-4-yl or 5- to 7-membered oxacycloalk-4-yl, NC ₁ -C ₄ -AlkYiAZaCyClOaIk-S-Yl or -4-yl or in the phenyl moiety optionally substituted 3-yl or 4-yl and R _{2 is} carboxy, Ci-Q-alkoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl or optionally by Ci-C ₄ -AllCyI, C ₁ -C ₄ -alkoxy, halogen of the atomic number to and with 35, cyano and / or trifluoromethyl mono- or disubstituted phenyl-CiC ^ alkoxycarbonyl, and their salts. 51. Compounds according to claim 2 of the formula! Wherein R, hydroxy-Ci-C ^ alkyl, C ₁ -C ₄ -alkoxy-CIC ₇ alkyl, one in the phenyl moiety is optionally substituted by Ci-C ₄ alkyl, C ₄ -alkoxy, halogen of atomic number to and with 35, cyano and / or trifluoromethyl mono-, di-or trisubstituted phenyl-Qd-alkoxy-CT-Cy-alkyl group, amino-C ^ Cy-alkyl, Cid-alkylamino-Ci-C -7-alkyl, C ₇ -C ₁ - alkanoylamino- C ₁ -C 6 -alkyl, di- C ₁ -C 6 -alkylamino- C ₁ -C 6 -alkyl, 5 to 7-membered N, N- (aza or oxaalkylene) amino- C ₁ -C 6 -alkyl or halo-Ci-Cy-alkyl, wherein halogen is chlorine or fluorine and R _{2 is} carboxy, Ci-d-alkoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, optionally by C ₁ -C ₄ -AlkYl, C ₁ -C ₄ -alkoxy , Halogen of the atomic number to and with 35, cyano and / or trifluoromethyl is mono- or disubstituted phenyl - ^ - Q-alkoxycarbonyl, and their salts. 52. г-Атіпо-б-Ьугігоху ^ -ргюзргюпотеігіуІ-Ііех-З-епзаигеаігіуІезіег or a salt thereof. 53. г-Атіпо-б-пугігоху ^ -рЬозрІіопотеігіуІ-Ьех-З-епзаиге or a salt thereof. 54. 2,10-Diamino ^ -phosphonomethyl-dec-S-enoic acid or a salt thereof. 55. 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid or a salt thereof. 56. г-Атіпо-б-те ^ оху ^ -ргюзргюпогпеігіуІ-гіех-З-епзаигеаігіуІезіег or a salt thereof. 57. 2-Amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 58. г-Атіпо-б-теігіоху-ФргіозрпопотеігіуІ-гіех-З-епзаиге or a salt thereof. 59. г-Атіпо-б-ЬепгоуІоху-ФрЬозрЬопотеігіуІ-гіех-З-епзаигеаігіуІезіег or a salt thereof. 60. г-Атіпо ^ -Ьуагоху ^ -рЬозрІіопогпеігіуІ-гіері-З-епзаигеаігіуІезіег or a salt thereof. 61. 2-Amipo-7-hydroxy-4-phospho-pentomethyl-hept-3-eic acid or a salt thereof. 62. г-Атіпо-б-ЬепгуІоху ^ рпоэргіопотеігіуІ-гіех-З-епзаиге or a salt thereof. 63. e-iN-acetyl-N-methyl-amino ^ -amino ^ -phosphonomethyl-hex-S-enoic acid ethyl ester or a salt thereof. 64. (i-Acetylpiperidine) -cyD ^ -amino-ö-phosphono-pent-S-enoic acid ethyl ester or a salt thereof. 65. 2,10-Diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester or a salt thereof. 66. г-Атіпо-б-Яиог ^ -ргюзргіопотеігіуІ-пех-З-епзаиге or a salt thereof. 67. г-Атіпо-б-пуагоху ^ -рпоэрпопогпеігіуІ-репі-З-епзаигеаігіуІезіег or a salt thereof. 68. г-Атіпо-б-пуагоху ^ -ргюзргіопотеігіуІ-репі-З-епзаиге or a salt thereof. 69. г-Атіпо-б-ЬепгуІоху ^ ргюзргіопотеігіуІ-репі-З-епзаигеаігіуІезіег or a salt thereof. 70. г-Атіпо-б-ЬепгуІоху-ФргіозрЬюпотеігіуІ-репі-З-епзаиге or a salt thereof. 71. 2-Ami-p-8-hydroxy-4-phosphopyrpethyl-oct-3-eic acid ethyl ester or a salt thereof. 72. г-Атіпо-в-гіуагоху ^ -ргюзргюпотеігіуІ-осі-З-епзаиге or a salt thereof. 73. 2-Amino-6- (N-methylamino) -4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof. 74. 2-amino-6- (N-methylamino) -4-phosphonomethyl-hex-3-enoic acid or a salt thereof. 75. г-Атіпо-б-пуагоху ^ -ргюзргіопотеігіуІ-гіех-З-епзаиге or a salt thereof. 76. г-Атіпо-б-ИусІгоху- рЬозрЬопотеіИуІ-Ьех-З-епзаигеаіИуІезіег or a salt thereof. 77. 2-Amino-4- (piperidin-4-yl) -5-phosphono-pent-3-enoic acid ethyl ester or a salt thereof. 78. 2-Amino-4- (piperidin-4-yl) -5-phosphono-pent-3-enoic acid or a salt thereof. 79. ö-Äthioxy ^ -amino ^ phosphonomethyl-pent-S-enoic acid or a salt thereof. 80. S-Ethoxy ^ -amino ^ -phosphonomethyl-pent-S-enoic acid ethyl ester or a salt thereof. 81. г-Атіпо-З-Иуагоху-ФрЬозрИопоте ^ уІ-осЛ-З-епзаигеаігіуІевіег or a salt thereof. 82. г-Атіпо-б-Ьуагоху-б-ЬуагохутеіЬуІ-ФрЬоврЬопотеіЬуІ-Ьех-З-епзаигеаіЬуІезіег or a salt thereof. 83. г-Атіпо-ІО-Ьуагоху- рЬозрІіопотеіЬуІ-аес-З-епзаигеаіЬуІезіег or a salt thereof. 84. A compound according to any one of claims 46 to 83 for use in a method of therapeutic treatment of the human or animal body. 85. Pharmaceutical preparations containing a compound according to any one of claims 46 to 84 in free form or pharmaceutically acceptable salt form.