FI97231B - Process for the preparation of 4-substituted 2-aminoalk-3-enoic acids - 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

97231

Process for the preparation of 4-substituted 2-aminoalk-3-enoic acids

The invention relates to a process for the treatment of therapeutically useful, unsaturated, substituted, formula I

O D

For the preparation of 2-aminoalk-3-enoic acid derivatives according to HO 1 2, (p) (I) HO R) NH 2 and their salts, in which R 1 represents hydroxy-C 1 -C 3 alkyl, dihydroxy-C 2 -C 7 - alkyl, C2-C7-alkanoyloxy-C1-C7-alkyl, in the phenyl part optionally mono- or disubstituted benzoyloxy-C1-C4-alkyl, C1-C4-alkoxy, halogen, cyano and / or trifluoromethyl mono- or disubstituted C 1 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 7 -alkyl, phenyl mono- or disubstituted in the phenyl part optionally mono- or di-substituted by C 1 -C 4 -alkyl, C 1-4 -alkoxy, halogen, cyano and / or trifluoromethyl -C 1 -C 4 alkoxy-C 1 -C 7 alkyl, halo-C 1 -C 7 -alkyl, wherein halogen represents chlorine or fluorine, amino-C 1 -C 4 -alkyl, C 1 -C 4 -alkylamino-C 1 -C 7 -alkyl -alkyl, C2-C7-alkanoylamino-C1-C7-alkyl, N-C2-C7-alkanoyl-N-C1-C4-alkylamino-C1-C7-alkyl, di-C1-C7-alkylamino-C1 -C7-alkyl, 5- - 7-membered azacycloalk-1-yl-C1-C7-alkyl, 5- to 7-membered azacycloalk-3-yl-C1-C7-alkyl or equivalent, azacycloalk-4-yl-C1-C7-alkyl, 1-C2 -C7-alkanoyl-azacycloalk-3-yl-C1-C7-alkyl or 1-C1-C7-alkanoylazacycloalk-4-yl-C2-C7-alkyl, N-C1-C4-alkylazacycloalk-3-yl-C1-C7-alkyl or -4-yl-C1-C7-alkyl, N-C1-C4-benzoylazacycloalk-3-yl-C1-C7-alkyl or -4-yl-C1-C7-alkyl, 5- to 7-membered diazacycloalk-1-yl-C1-4-C4-alkyl, N1-C1-C4-alkyldiazacycloalk-1-yl-C1-4 -C7-alkyl, N'-C2-C7-alkanoylazacyclo-2,97231 alk-1-yl-C1-C6-alkyl, 5- to 7-membered azoxacycloalk-1-yl-C1-C6-alkyl, 5- to 7-membered oxacycloalk-5-yl-C 1 -C 3 -alkyl or oxacycloalk-4-yl-C 1 -C 6 -alkyl, 5- to 7-membered azacycloalk-3-yl or the like. -4-yl or 1-C2-C7-alkanoyl-azacycloalk-3-yl or -4-yl, N-C1-C4-alkylazacycloalk-3-yl or 4-yl or N-benzoylazacycloalk-3-yl or -4-yl or 5- to 7-membered oxacycloalk-3-yl or optionally substituted in the phenyl moiety, or the like. -4-yl, and R 2 represents carboxy, C 1 -C 4 alkoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl or, optionally, mono-C 1-4 alkyl, C 1 -C 4 -alkoxy, halogen, cyano and / or trifluoromethyl having an order of 35 or less. - or disubstituted phenyl-C1-C4-alkoxycarbonyl.

Above and below, lower radicals and compounds mean, for example, those having up to 7, in particular up to 4, carbon atoms (C atoms).

C 1 -C 4 alkyl is, for example, C 1 -C 4 alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, but it can also be isobutyl, sec-butyl, tert-butyl or a pentyl, hexyl or heptyl group.

•.

Hydroxy-C 1 -C 7 -alkyl is, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl.

Dihydroxy-C2-C7-alkyl is, for example, one in which the hydroxy groups are bonded at different C atoms, such as 1,2-dihydroxyethyl or, in particular, 1,3-dihydroxyprop-2-yl.

C2-C7-Alkanoyl is, for example, C2-C4-alkanoyl, such as acetyl, propionyl or butyryl, but it can also be a C5-C6-alkanoyl group, such as pivaloyl. Thus 97231 3 C 2 -C 7 alkanoyloxy-C 1 -C 7 alkyl is, for example, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetyloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 5-acetyloxypentyl or 6-acetyloxyhexyl. Correspondingly, benzoyloxy-C 1 -C 4 -alkyl means, for example, benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, 5-benzoyloxypentyl or 6-benzoyloxyhexyl optionally substituted in the phenyl part.

C1-C7-Alkoxy is, for example, C1-C4-alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but it can also be isobutyloxy, sec-butyloxy, tert-butyloxy or a pentyloxy, hexyloxy or heptyloxy group. Accordingly, C 1 -C 4 alkoxy-C 1 -C 7 alkyl denotes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl or 6-methoxyhexyl.

Phenyl-C1-C4-alkoxy denotes, for example, optionally substituted benzyloxy, 2-phenylethoxy or 3-phenylpropyloxy. Accordingly, phenyl-C 1 -C 4 -alkoxy-C 1 -C 7 -alkyl denotes, for example, benzyloxymethyl, 2-phenylethoxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl, 4-benzyloxybutyl, optionally substituted as indicated. -benzyloxysipentyl or 6-benzyloxyhexyl residue.

Halogen-C 1 -C 4 -alkyl is, for example, halomethyl, -2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, wherein halogen denotes chlorine or in particular fluorine.

Amino-C 1 -C 7 alkyl is, for example, aminomethyl, 2-aminoethyl, 3-aminopropyl; 4-aminobutyl, 5-aminopentyl: or 6-aminohexyl.

4,97231 C 1 -C 7 alkylamino is, for example, a C 1 -C 4 alkylamino, such as methylamino, ethylamino, propylamino or butylamino, but it can also be a C 5 -C 8 alkylamino, such as pentylamino or hexylamino. Thus, for example, C1-C4-alkylamino-C1-C7-alkyl is methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylamino.

The C 2 -C 7 alkanoylamino is, for example, a C 2 -C 4 alkanoylamino such as acetylamino, propionylamino or butyrylamino, but it can also be a C 5 -C 8 alkanoylamino such as pivaloylamino. Thus, for example, C2-C7-alkanoylamino-C1-C7-alkyl is acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylamino-6-aminophenylamino. Accordingly, benzoylamino-C 1 -C 7 -alkyl means, for example, benzoylaminomethyl, 2-benzoylaminoethyl, 3-benzoylaminopropyl, 4-benzoylaminobutyl, 5-benzoylaminophenyl or 6-benzoylamine, optionally substituted in the phenyl part.

Di-C1-C7-alkylamino is in particular di-C1-C4-alkylamino, such as dimethylamino, diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, dipropylamino or di-butylamino. Thus, lower dialkylamino lower alkyl is especially di-C1-C4-alkylamino-C1-C7-alkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methyl-; 1-aminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or 6-dimethylaminohexyl.

97231 5 N-C2-C7-alkanoyl-N-C1-C4-alkylamino-C1-C7-alkyl is, for example, N-acetyl-N-methylaminomethyl, N-acetyl-N-ethylaminomethyl, N-propionyl -N-methylaminomethyl, N-butyryl-N-methylaminomethyl, 2- (N-acetyl-N-methylamino) ethyl, 2- (N-propionyl-N-methylamino) ethyl, 2- (N-acetyl-N-ethylamino) ethyl, 3- (N-acetyl-N-methylamino) propyl, 4- (N-acetyl-N-methylamino) butyl, 5- ( N-acetyl-N-methylamino) pentyl or 6- (N-acetyl-N-methylamino) hexyl.

4- to 7-membered, N-bonded azacycloalkyl-C 1 -C 4 -alkyl is especially 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-piperidino-pentyl, 6-pyrrolidinohexyl or 6-piperidinohexyl.

The 4- to 7-membered azacycloalkyl-C 1 -C 4 -alkyl bonded via the C atom is in particular azacycloalk-5-yl-C 1 -C 4 -alkyl or the like. 4-yl-C1-C7-alkyl, e.g. piperidin-4-ylmethyl, 2- (piperidin-4-yl) ethyl, 3- (piperidin-4-yl) propyl or 4- (piperidin-4-yl) butyl.

The 5- to 7-membered N-C2-C7-alkanoylazacycloalkyl-C1-C7-alkyl, bonded via the C atom, is in particular 1-C2-C7-alkanoyl-azacycloalk-3-yl-C1-C7-alkyl or the like. . 4-yl-C 1 -C 7 -alkyl, e.g. 1-acetylpiperidin-4-ylmethyl, 2- (1-acetylpiperidin-4-yl) ethyl, 3- (1-acetylpiperidin-4-yl) propyl or 4- (1-acetylpiperidin-4-yl) butyl.

5- to 7-membered N-C1-C4-alkylazacycloalkyl-C1-C7-alkyl, bonded via a C atom, is in particular N-C1-C4-alkylazacycloalk-3-yl-C1-C7-alkyl or the like; . 4-yl-C1-C7-alkyl, e.g. 1-methylpiperidin-4-ylmethyl, 1-6,97231 ethylpiperidin-4-ylmethyl, 2- (1-methylpiperidin-4-yl) ethyl, 2- (1-ethylpiperidine 4-yl) ethyl, 3- (1-methylpiperidin-4-yl) propyl, 3- (1-ethylpiperidin-4-yl) propyl, 4- (1-methylpiperidin-4-yl) butyl or 4- (l-ethyl-piperidin-4-yl) butyl.

The 5- to 7-membered N-benzoylazacycloalkyl-C 1 -C 7 -alkyl, bonded via the C atom and optionally substituted in the phenyl moiety is in particular N-C 1 -C 4 -benzoylazacycloalk-3-yl-C C7-alkyl or resp. 4-yl-C1-C7-alkyl, e.g. 1-benzoylpiperidin-4-ylmethyl, 2- (1-benzoylpiperidin-4-yl) ethyl, 3- (1-benzoylpiperidin-4-yl) propyl or 4- (1-benzoylpiperidin-4-yl) butyl.

5- to 7-membered diazacycloalk-1-yl-C 1 -C 7 -alkyl, N 1 -C 1 -C 4 -alkyldiazacycloalk-1-yl-C 1 -C 7 -alkyl or Ν'-C 2 -C 7 -alkanoylazacycloalk-1-yl- C 1 -C 7 alkyl is, for example, piperazino or N'-methyl or resp. N'-acetylpiperazinomethyl, 2- (piperazino or

N'-methyl or resp. N'-acetylpiperazino) ethyl, 3- (piperazino or N'-methyl or N'-acetyl lipiperazino) propyl or 4- (piperazino or N'-methyl or N'-methyl) -asetyylipiperatsino) butyl.

• A 5- to 7-membered azoxacycloalk-1-yl-C 1 -C 3 alkyl is, for example, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 4-morpholinobutyl.

5- to 7-membered oxacycloalkyl-C1-C7-alkyl is in particular 5- to 7-membered oxacycloalk-3-yl-C1-C7-alkyl or oxacycloalk-4-yl-C1-C7-alkyl, such as tetrahydropyran-4- ylmethyl, 2- (tetrahydropyran-4-yl) ethyl, 3- (tetrahydropyran-4-yl) propyl or 4- (tetrahydropyran-4-yl) butyl.

5- <7-membered oxacycloalkyl is in particular the corresponding oxacycloalk-3-yl or -4-yl, e.g. tetrahydropyran-4-yl.

5- to 7-membered azacycloalkyl, N-C1-C4-alkylazacycloalkyl or N-C2-C7-alkanoylazacycloalkyl is in particular azacycloalk-3-yl or the like. -4-yl or 1-C2-C7-alkanoyl-azacycloalk-3-yl or -4-yl, e.g. piperidin-4-yl or 1-acetylpiperidin-4-yl, further N-C 1 -C 4 -alkylazacycloalk-5-yl or the like. 4-yl or N-benzoylazacycloalk-3-yl or -4-yl optionally substituted in the phenyl moiety, e.g. 1-methylpiperidin-4-yl or 1-benzoylpiperidin-4-yl.

C 1 -C 7 alkoxycarbonyl is, for example, C 1 -C 7 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butyloxycarbonyl, but may also be C 5 -C 7 alkoxycarbonyl, such as pentyloxycarbonyl, - or a heptyloxycarbonyl group.

Phenyl-C 1 -C 4 -alkoxycarbonyl is, for example, benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl or 4-phenylbutyloxycarbonyl.

• ·

According to their amphoteric nature, the compounds of formula I exist in the form of internal salts and can form both acid addition salts and salts with bases.

Acid addition salts of the compounds of formula I include, for example, their pharmaceutically acceptable salts formed with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, e.g. hydrochlorides, hydrobromides, sulphates, hydrogen sulphates or phosphates, or salts thereof, or 8 97231 with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, e.g. methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulphaminates (cyclamates).

Salts of the compounds of formula I formed with bases are, for example, those formed with pharmaceutically acceptable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, Ha and Hb, e.g. alkali metal, especially sodium or potassium salts, earth -alkali metal, especially calcium or magnesium salts, as well as ammonium salts formed with ammonia or organic amines or quaternary ammonium bases, such as optionally C-hydroxylated aliphatic amines, in particular mono-, di- or trialempalkylamines, e.g. methyl, ethyl, ethyl or triethylamine, mono-, di- or tri- (hydroxy-lower alkyl) amines, such as ethanol, diethanol or triethanolamine, tris- (hydroxymethyl) methylamine or 2-hydroxytertiarybutylamine, or N- (hydroxy-lower alkyl) -Ν, Ν -dialkylalkylamines or N- (polyhydroxy lower alkyl) -N-lower alkylamines, such as 2- (dimethylamino) ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, e.g.

.. with tetrabutylammonium hydroxide.

Pharmaceutically unsuitable salts may also be used for isolation or purification. However, only pharmaceutically acceptable, non-toxic salts are used therapeutically, which are therefore preferred. brush.

The compounds of formula I have valuable pharmacological properties. In particular, they have a clear and selective antagonistic effect on warm-blooded N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory axnino acid receptors. These can be determined in vitro, for example, in an experimental set-up described by G. Fagg and A. Matus in Proc. Nat. Acad. Sci., USA, 81, 6876-80 (1984). This determines the extent to which the binding of L-N-glutamic acid to NMDA-sensitive receptors is inhibited. However, the NMDA antagonistic properties of the new compounds can also be demonstrated in vivo, e.g. in mice, by the inhibitory effect of NMDA-induced convulsions.

Due to these properties, the compounds of formula I and their pharmaceutically usable salts can be used excellently for the treatment of pathological conditions responsive to the blockade of NMDA-sensitive receptors, for example ischemic diseases such as cerebral ischemia and ocular ischemic diseases, vascular and muscular spasms or local migraine and especially for the treatment of convulsions such as epilepsy.

The anticonvulsant properties of the compounds according to the invention can be determined, for example, by their clear protective effect against electroconvulsive or audiogenic convulsions in mice, using, for example, the established electroconvulsive mouse model or experimental set-up described by Chapman et al. in Arzneimittel-Forsch. 34, 1261 (1984). The compounds according to the invention are then characterized, especially in the electric shock-mouse model, by an improved effect compared to structurally related compounds.

The antispastic properties justifying the suitability of the compounds according to the invention for the treatment of migraine can be demonstrated, for example, in the rat by their antidepressant effect in the forebrain according to the experimental arrangement presented by R. Marannes et al. in Brain Res. 457. 226 (1988). In this model, the compounds of the invention lower the "spreading depression" threshold in the i.p. dose range of about 3 to 30 mg / kg and shorten its duration.

Finnish patent application 870558 describes compounds of the formula I which have NMDA-antagonistic properties in which R1 is replaced by an alkyl residue. Comparing the structurally closest compounds mentioned in said publication with the compounds of formula I prepared by the process according to the invention, it is found that the compounds prepared by the process according to the invention achieve a higher antiepileptic effect. Thus, when comparative experiments were performed according to the above-mentioned electroshock model, the following ED5Q values were obtained in mice:

O

Höj.

H0 R! NH2 (I)> 97231 11 R- ^ S2 Electroshock model

in the mouse ED5Q (mo / kcH

Compounds prepared according to the invention: HOCH2CH2 COOEt 2.75 8h p.o.

COOCH2Ph 2.54 4h p.o.

COOH 12.3 4h p.o.

COOH (R) 4 4h p.o.

HOCH2CH2CH2 COOEt 6.87 8h p.o.

CH 3 CH (OH) CH 2 COOEt 0.77 lh i.v.

HOCH2CH2CH2CH2 COOEt 23.4 4h p.o.

COOH 35.0 4h p.o.

HOCH2CH2CH2CH2CH2CH2 COOH 0.8 lh i.v.

HOCH2CH2CH2CH2CH2CH2 COOEt 5.4 lh i.V

CH 3 OCH 2 CH 2 COOEt 17.6 8h p.o.

COOH 23.8 4h p.o.

CH3CH2OCH2 COOEt 21 4h p.o.

CH3NHCH2CH2 COOH 7.0 lh i.v.

H2NCH2CH2CH2CH2CH2CH2 COOEt 8 lh i.v.

H2NCH2CH2CH2CH2 COOH 4.6 2h i.V.

PhCONHCH2CH2CH2CH2CH2CH2 COOH 3 lh i.v.

FCH2CH2 COOEt 30 8h p.o.

·· Compounds according to patent application FI 870558: CH3CH2CH2 COOH 34 4h p.O.

CH3CH2CH2CH2 COOH 53 4h p.o.

The invention relates in particular to the preparation of compounds of the formula I and their salts, in particular their pharmaceutically usable salts, in which R 1 denotes hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 1,3-dihydroxyprop-2-yl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetyloxyethyl, 3-acetyloxypropyl, 12,97231 4-acetyloxybutyl, 5-acetyloxypentyl or 6-acetyloxyhexyl, in the phenyl moiety optionally with methyl, niethoxy or janyl or halogen, disubstituted benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, 5-benzoyloxypentyl or 6-benzoyloxyhexyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 3-methoxypropyl, optionally, 4-methoxypropyl, or 4-methoxypropyl or 4-methoxypropyl or and / or trifluoromethyl mono- or disubstituted benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl, halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halo-halogen or 6-halopentyl chlorine or especially fluorine, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-aminohexyl, methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminomethyl, 3-methylaminoethyl, -methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl, acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylamino-propyl, 4-acetylamino-butyl, 4-acetylamino-butyl -methylaminomethyl, N-acetyl-N-ethylaminomethyl, N-propionyl-N-methylaminomethyl, N-butyl N-methyl-N-methylaminomethyl, 2- (N-acetyl-N-methylamino) ethyl, 2- (N-propionyl-N-methylamino) ethyl, 2- (N-acetyl-N-ethyl) -amino) ethyl, 3- (N-acetyl-N-methylamino) propyl, 4- (N-acetyl-N-methylamino) butyl, 5- (N-acetyl-N-methylamino) pentyl or 6- (N-acetyl-N-methylamino) hexyl, dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 3-dimethyl-97231 13 -stylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or 6-dimethylamino-hexyl, pyrrolidinomethyl, piperidinomethyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 4-pyridinino-ethyl, 3-pyrrolidinyl , 4-piperidinobutyl, 5-pyrrolidinopentyl, 5-piperidinopentyl, 6-pyrrolidinohexyl or 6-piperidinohexyl, piperidin-4-ylmethyl, 2- (piperidin-4-yl) ethyl, 3- (piperidin-4-yl) propyl or 4- (piperidin-4-yl) butyl, 1-acetylpiperidin-4-ylmethyl, 2- (1-acetylpiperidin-4-yl) ethyl, 3- (1-acetylpiperidin-4-yl) 4-yl) propyl or 4- (1-acetylpiperidin-4-yl) butyl, 1-methylpiperidin-4-ylmethyl, 1-ethylpiperidin-4-ylmethyl, 2- (1-methylpiperidin-4-yl) ethyl, 2- (1-ethylpiperidin-4-yl) ethyl, 3- (1-methylpiperidin-4-yl) propyl, 3- (1-ethylpiperidin-4-yl) propyl, 4- (1-methylpiperidin-4-yl) butyl or 4- (1-ethylpiperidin-4-yl) butyl, 1-benzoylpiperidin-4-ylmethyl, 2- (1-Benzoylpiperidin-4-yl) ethyl, 3- (1-benzoylpiperidin-4-yl) propyl or 4- (1-benzoylpiperidin-4-yl) butyl, diazacycloalk-1-yl-C 1 -C 6 alkyl, piperazino or the like. N'-methyl or resp. Ν'-acetylpiperazinomethyl, 2- (piperazino or N'-methyl or

Ν'-acetylpiperazino) ethyl, 3- (piperazino or resp.

Ν'-methyl or resp. N'-acetylpiperazino) propyl or 4- (piperazino or N'-methyl or N'-acetylpiperazino) butyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 4-morpholinobutyl, tetrahydropyran-4- ylmethyl, 2- (tetrahydropyran-4-yl) ethyl, 3- (tetrahydropyran-4-yl) propyl or 4- (tetrahydropyran-4-yl) butyl, piperidin-4-yl or 1-acetylpiperidin-4-yl , 1-methylpiperidin-4-yl or 1-benzoylpiperidin-4-yl, or tetrahydropyran-4-yl, and R 2 denotes carboxy, methoxycarbonyl or ethoxycarbonyl, cyclopentyloxy or cyclohexyloxycarbonyl, or optionally methyl, niethoxy, 35 mono- or disubstituted benzyloxycarbonyl or 2-phenylethoxycarbonyl with halogen, cyano and / or trifluoromethyl.

The invention relates in particular to the preparation of the compounds of the formula I and their salts, in particular their pharmaceutically usable salts, in which hydroxy-C1-C7-alkyl, such as hydroxyethyl, C1-C4-alkoxy-C1-C7-alkyl, such as methoxymethyl, ethoxymethyl or 2-methoxyethyl, benzoyloxy-C1-C4-alkyl, such as 2-benzoyloxyethyl, phenyl-C1-C4-alkoxy-C1-C7-alkyl, such as benzyloxymethyl or 2-benzyloxyethyl, amino-C4-C7-alkyl, such as 4-aminobutyl or 6-aminohexyl, N-C2-C7-alkanoyl-N-C1-C4-alkylamino-C2-C7-alkyl, such as 2- (N-acetyl-N-methylamino) ethyl, 5-- 7- members azacycloalk-3-yl or resp. -4-yl or 1-C2-C7-alkanoyl-azacycloalk-3-yl or -4-yl, e.g. piperidin-4-yl or 1-acetylpiperidin-4-yl, or halo-C 1 -C 4 -alkyl, wherein halogen denotes chlorine or in particular fluorine, such as 2-haloethyl, and R 2 denotes carboxyl. or C1-C4 alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl.

The invention relates in particular to compounds of the formula I and their salts, in particular their pharmaceutically usable salts, in which amino-C4-C7-alkyl, such as 4-aminobutyl, 5-aminopentyl, 6-aminohexyl or 7-aminoheptyl, and R2 . box, C 1 -C 4 alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or optionally C 1 -C 4 alkyl, such as methyl, C 1 -C 4 alkoxy, such as methoxy, halogen of the order up to 35, such as fluorine or chlorine, cyano and / or trifluoromethyl. phenyl mono- or disubstituted phenyl-C1-C4-alkoxy-! · »> * Helit I I *« · «97231 15 carbonyl groups such as benzyloxycarbonyl or 2-phenylethoxycarbonyl.

The invention relates in particular to compounds of the formula I and their salts, in particular their pharmaceutically usable salts, in which C 1 -C 4 -alkoxy-C 2 -C 4 -alkyl, such as 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, is present. or 4-methoxybutyl, hydroxy-C2-C4-alkyl, such as 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, or halo-C2-C4-alkyl, such as 2-fluoroethyl, 2-chloroethyl, 3-fluoropropyl or 4-fluorobutyl, and R 2 represents carboxy, C 1 -C 4 alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or optionally C 1 -C 4 alkyl, such as methyl, C 1 -C 4 alkoxy, such as nitro, having an order of 35 or less. a phenyl-C1-C4-alkoxycarbonyl mono- or disubstituted by a halogen, such as fluorine or chlorine, cyano and / or trifluoromethyl, such as a benzyloxycarbonyl or 2-phenylethoxycarbonyl group.

The invention relates most preferably to compounds of the formula I and their salts, in which 2-hydroxyethyl, 3-hydroxypropyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-benzoyloxyethyl, benzyloxymethyl, 2-benzyloxyethyl, 4-benzyloxyethyl, , 6-aminohexyl, 2- (N-acetyl-N-methylamino) ethyl, piperidin-4-yl, 1-acetylpiperidin-4-yl or 2-fluoroethyl and R 2 represents carboxy or C 1 -C 4 - -alkoxycarbonyl.

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

The process for the preparation of the compounds according to the invention is characterized in that 16 97231

of formula II

z, Il / K2 ^: p (Π).

Z2 Z3 In a compound according to z4, wherein z1 # Z2 represents an optionally protected hydroxy, Z3 represents an optionally protected residue and Z4 represents a protected amino, converting the protected amino Z4 and the protected amino amino which may be part of the residue Z3 to a protected amino amino and, if present, protected hydroxy Z1 # Z2 and / or the protected hydroxy present as part of the residue Z3 and, if present, releasing the protected 5- to 7-membered azacycloalkyl residue Z3 and, if desired, converting the resulting compound into another compound of the formula I, separating the isomeric mixture according to process and separating the most preferred isomer and / or converting the free compound obtained by the method into a salt or the salt obtained according to the method into the corresponding free compound.

In the starting materials of the formula II, the protected hydroxy Z1 and / or Z2 denote, for example, etherified, in particular sub-·. phosphatically or aromatically etherified hydroxy, protected hydroxy as part of residue Z3 denotes, for example, acylated or silylated hydroxy and protected amino Z4 and, if present, as part of residue Z3, denote, for example, acylated amino.

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

ii · η i tm 111 «17 97231

The acylated hydroxy acyl group has, for example, an acyl residue of an araliphatic carboxylic acid or carbonic acid half-ester and denotes, for example, lower alkanoyloxy or in the phenyl moiety optionally substituted by lower alkyl, lower alkoxy, aryloxyalkyloxyalkyloxyalkylaloxyal

Silylated hydroxy is, for example, trialkylalkylsilyloxy, e.g. trimethyl or tributylsilyloxy.

The acyl group in the acylated amino is, for example, an acyl derived from a suitable acid such as formic acid or an araliphatic or aromatic half-ester of a carbonic acid. Thus, acylated amino denotes, for example, formylamino, lower alkoxycarbonylamino, such as methoxy, ethoxy or tert-butyloxycarbonylamino, phenyl-lower alkyloxyalkoxy, allyl-alkoxy, allyl-alkoxy, allyl, halogen, cyano and / or nitro substituted phenoxycarbonylamino.

• ♦

Release of protected groups from compounds of formula II, i. release of hydroxy from protected hydroxy groups Z1, Z2 and / or protected hydroxy groups as part of residue Z3 or, correspondingly, release of amino from protected amino groups Z4 and, if present, from protected amino groups as part of residue Z3 is effected, for example, by treatment with an acidic substance, e.g. alkyl halosilane such as trimethylbromosilane, tributylbromosilane or trimethyliodosilane. In this case, work is preferably carried out in an inert solvent, such as a halogenated aliphatic hydrocarbon, e.g.

18 97231 in dichloromethane or in another position in tri- or tetrachloromethane, trichloroethane or tetrachloroethane, for example in the temperature range from about -25 ° to about + 50 ° C, preferably from about 0 ° to 30 ° C , e.g. at room temperature, i.e. at about 15 ° to 25 ° C, preferably under largely anhydrous conditions, by adding a hydrogen halide collector, especially an aliphatic epoxy compound such as an epoxy lower alkane, e.g. propylene oxide in a lower alkanol such as ethanol.

In a preferred embodiment, for example, starting from a compound of formula II wherein Ζχ and Z2 represent lower alkoxy, e.g. isopropyloxy and Z4 represents lower alkanoylamino such as formylamino, it is treated in an aliphatic halogenated hydrocarbon such as dichloromethane at about 15 ° C to about 25 ° C. -ylylbromosilane, such as trimethylbromosilane or tributylbromosilane, is allowed to react for some time, e.g. about 2 to 30 seconds, then an ethanolic solution of propylene oxide is added and the product is filtered off.

The starting materials of the formula II are prepared by reacting an α, β-unsaturated aldehyde of the formula Ha "γ> · Z3 with an α-isocyanoacetic acid ester of the formula Hb: C = * NR> (Hb) in a manner known per se, for example copper or gold catalysts - * il IM I * Hi I 'I * 1 19 97231 in the presence of a market, e.g. copper I-oxide or bis (cyclohexyl-iso-cyanide) gold I-tetrafluoroborate, corresponding to the formula Ile 7 »V- / 2 / (Ole )

° \ ^ N

5-substituted 2-oxazoline-4-carboxylic acid ester, this is converted by hydrolysis, e.g. in aqueous tetrahydrofuran, to the corresponding formula Ild

OH

Old)

Z3 NHCHO

is converted to the corresponding ω-bromoester of the formula Ile B rCHj (ne) Z3 NHCH = O by treatment with thionyl bromide in a manner known per se and is further reacted in a manner known per se with the phosphoric acid of the formula P (Za) (Z) (Zc). wherein Za, Z1 and Z_ denote the same or different ether-protected hydroxy groups, such as with a trialempkyl phosphite, e.g. triisopropyl phosphite, corresponding to the formula 11 '«* 20 97231

O

ηρ an ^ Z3 to a compound according to NHCH = 0.

The compounds obtained according to the process can be converted in a conventional manner into other compounds of the formula I.

Thus, the free and esterified carboxy groups R2 can be converted into each other in a conventional manner. In particular, esterified carboxy R2 can be converted to carboxy by hydrolysis or, conversely, free carboxy R2 can be converted to esterified carboxy by reaction with an alcohol. Further, the esterified carboxy R2 can be re-esterified to another esterified carboxy group. In this case, work is carried out in a conventional manner under hydrolytic, alcohololytic or transesterification conditions.

The hydrolysis of carboxylic acid esters (I; R 2 = esterified carboxy) takes place in a conventional manner, if necessary in the presence of an acidic or basic substance, such as a mineral acid, e.g. hydrochloric or sulfuric acid, or a base, such as an alkali metal hydroxide, e.g. sodium hydroxide.

When re-esterifying esters (I; R2 = esterified carboxy) with alcohols, the acid is usually treated. or under base-catalytic conditions, for example in the presence of a catalytic amount of a mineral acid such as hydrochloric acid or sulfuric acid or a metal base such as sodium hydroxide or in which the alcohol component is used in the form of a metal alcoholate, e.g. an alkali metal alcoholate.

97231 21

Further, in aliphatic hydrocarbon radicals substituted with araliphatically etherified hydroxy, such as α-phenyl-lower alkoxy-lower alkyl radicals, the R 1 α-phenyl-lower alkoxy group can be converted to hydroxy by reduction, e.g.

The salts obtained can be converted into the free compounds in a manner known per se, e.g. by treatment with a base such as alkali metal hydroxide, metal carbonate or bicarbonate, or ammonia, or with any other salt-forming base or acid mentioned above, such as a mineral acid, e.g. with said salt-forming acid.

The salts obtained can be converted into other salts in a manner known per se, the acid addition salts, e.g. by treating another acid with a suitable metal salt such as sodium, barium or silver in a suitable solvent in which the inorganic salt formed is insoluble and thus different from the reaction equilibrium, and the base salts salt.

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

Due to the close relationship between the compounds of the formula I in free form and in the form of salts, the above and the following free compounds or their salts are to be understood as meaning, if appropriate, the corresponding salts or the corresponding free compounds.

22 97231

The resulting diastereomeric mixtures and racemate mixtures can be separated into the pure diastereomers or racemates, for example on the basis of the physicochemical differences of the components, for example by chromatography and / or co-crystallization.

The racemates obtained can be further decomposed into optical antipodes according to known methods, for example by recrystallization from an optically active solvent, by means of microorganisms or by reacting the resulting diastereomeric mixture or the racemate with an optically active auxiliary compound, for example acidic, basic or functional. according to modified groups with an optically active acid, a base or an optically active alcohol, mixtures of diastereomeric salts or functional derivatives, such as esters, by separating them into diastereomers from which the desired enantiomer can in each case be liberated in the customary manner. Suitable bases, acids or alcohols for this purpose are, for example, amino acids, in particular D- or L-lysine, optically active alkaloid bases, such as Strykin, cinchonine or brucine, or D- or L- (1-phenyl) -ethylamine , 3-pipecoline, ephedrine, amphetamine and · corresponding synthetic bases, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluyltartaric acid, D- or L- malic acid, D- or L-mandelic acid or D- or L-camphorsulfonic acid or, respectively, optically active alcohols such as borneol or D- or L- (1-phenyl) ethanol.

The invention also relates to those embodiments of the process which start at some stage in the process with the intermediate compound and carry out the missing steps or use the starting material in the form of a salt or form it, in particular under reaction conditions.

97231 23

The novel starting materials which have been developed in particular for the preparation of the compounds according to the invention, in particular the choice of starting materials leading to the compounds of the formula I mentioned at the beginning, the processes for their preparation and their use as intermediates also form part of the present invention.

The novel compounds of the formula I can be used, for example, in the form of pharmaceutical preparations containing a therapeutically effective amount of active ingredient, optionally together with inorganic or organic, solid or liquid pharmaceutically acceptable carriers suitable for enteral, e.g. oral, or parenteral use. Thus tablets or gelatine capsules are used which contain the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or lubricants, e.g. diatomaceous earth, talc, stearic acid or its salts, such as magnesium or calcium and / or polyethylene glycol. Tablets may also contain binders, 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. starches, agar, alginic acid or a salt thereof, e.g. sodium alginate, and / or effervescent mixtures, or absorbents, colorants, flavors and sweeteners. Furthermore, the novel compounds of the formula I can be used in the form of preparations for parenteral administration or infusion solutions. Such solutions are especially isotonic aqueous solutions or suspensions, which may be prepared before use, e.g. in the case of lyophilized preparations containing the active ingredient alone or in combination with a carrier, e.g. mannitol. The pharmaceutical preparations may be sterilized and / or contain auxiliaries, e.g. preservatives, stabilizers, wetting and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. These pharmaceutical preparations, which may contain other pharmacologically active substances if desired, are prepared in a manner known per se, e.g. according to customary mixing, granulating, granulating, dissolving and lyophilizing methods, and contain from about 0.1 to 100%, in particular n. 1 to about 50% lyophilic acid to about 100% active ingredient.

The invention also relates to the use of the compounds of the formula I, in particular in the form of pharmaceutical preparations. The dosage depends on various factors, such as the route of administration, the species, the age and / or the individual condition. The daily doses for oral use are about 0.25 to about 10 mg / kg and for warm-blooded people weighing about 70 kg, especially about 20 mg to about 500 mg.

The following examples illustrate the invention. Temperatures are expressed in degrees Celsius, pressures in mbar.

Example 1: 3.57 g (8.5 mmol) of 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane and then added dropwise at room temperature 4, 4 ml (34 mmol) of trimethylbromosilane. Allow to stand for 22 hours at room temperature, add dropwise 22 ml of ethanol, allow to stand for a further 22 hours, evaporate on a rotary evaporator, dissolve the residue in 22 ml of ethanol and add 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 which is then filtered off with suction. 2-Amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained, m.p. 195 ° C (dec.).

The starting material can be prepared, for example, as follows: 13.0 g (100 mmol) of acetic acid (4-oxo) butyl ester, 92.0 g (112.6 mmol) of dimethylammonium chloride and 10.8 ml (117 mmol) of a 37% formaldehyde solution are heated with stirring for one hour. time at 100 °. Allow to cool and extract 3 times with 30 ml of diethyl ether each time. The organic phases are combined, washed with saturated brine, dried over magnesium sulfate and evaporated to dryness. Acetic acid (3-formyl) but-3-enyl ester is obtained 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 isocyanoacetic acid ethyl ester are added dropwise to a suspension of 0.38 g of copper I-oxide. ml of benzene. After completion of the exothermic reaction, the mixture is stirred for a further 45 minutes at room temperature, filtered through Hyflo * and evaporated to dryness. The residue is taken up in 75 ml of tetrahydrofuran, 25 ml of water are added and the mixture is heated under reflux with stirring for 4 hours. Evaporate to dryness and chromatograph on silica gel using toluene / isopropanol (9: 1) as eluent. 6-Acetoxy-2-formyl- Liamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester as a brownish oil.

9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 100 ml of dichloromethane and then added dropwise at room temperature to 3.34 ml (43 ml). 1 mmol) thionyl bromide.

After one hour, add 10 ml of water and mix vigorously for 10 minutes. The organic phase is separated, washed successively with water, saturated potassium hydrogen carbonate solution and once more with water, dried over magnesium sulphate, filtered and evaporated. * »26 97231 6-Acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid polyethyl ester is obtained in the form of a brownish oil.

8.7 g (25 mmol) of 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 21 ml (75 mmol) of triisopropyl phosphite (90%) are heated to 80 ° -90 °: and stirred for 19 hours at a pressure of about 100 mbar. The excess triisopropyl phosphite is distilled off and the evaporation residue is chromatographed on 150 g of silica gel, eluting first with acetic acid ethyl ester and then with acetic acid ethyl ester / ethanol (9: 1). 6-Acetoxy-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.

Example 2: 0.415 g (1.55 mmol) of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester are heated in 3 ml of water for 24 hours under reflux. The reaction mixture is evaporated, purified by chromatography on 10 g of silica gel using ethanol / water (1: 1) as eluent and crystallized from ethanol. 2-Amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid is obtained, m.p. > 300 °.

Example 3: 0.5 g (1.0 mmol) of 8- (N-benzyloxycarbonylamino) -4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is heated in 5.0 ml of 6n-hydrochloric acid for 6 hours. time to reflux. Evaporate to dryness to give 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid dihydrochloride as a gummy solid which is recrystallized from acetonitrile, m.p.

: · 128 ° (dec.).

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 100 97231 in 27 ml of acetone and 50 ml of water are added dropwise 7.06 ml ( 47 mmol) of chloroformic acid benzyl ester. Stir for 18 hours at room temperature, evaporate to about 70 ml, filter off the white precipitate, wash with about 20 ml of water, take up to 250 ml of methylene chloride, dry over magnesium sulphate, filter this off and evaporate the residue to dryness. . Obtained as 6- (N-benzyloxycarbonylamino) hexan-1-ol in the form of white crystals, m.p. 58-60 °.

To a stirred solution of 0.19 ml (2.20 mmol) of oxalyl chloride in 10 ml of methylene chloride at -50 ° is added dropwise 0.32 ml (4.40 mmol) of dimethyl sulfoxide under a nitrogen atmosphere. Stir for 15 minutes and then add 0.5 g (2 mmol) of 6- (N-benzyloxycarbonylamino) hexan-1-ol. Stir for 25 minutes at -50 °, add dropwise 1.78 ml (10 mmol) of N-ethyl-N, N-diisopropylamine and pour into 10 ml of ice water. The organic phase is separated and the aqueous phase is extracted with 10 ml of methylene chloride. The organic phases are combined, washed twice with 5 ml each of n-hydrochloric acid and once with 10 ml of saturated brine, dried over magnesium sulphate and evaporated to dryness. The oil obtained is purified by chromatography on silica gel using hexane / ethyl acetate (1: 1) as eluent. 6- (N-Benzyloxycarbonylamino) hexanal is obtained.

To a solution of 1.5 g (17 mmol) of anhydrous piperazine and 2.03 g (34 mmol) of acetic acid in 18.7 ml of water is added 2.44 g (30 mmol) of a 37% aqueous formaldehyde solution. Stir for 15 minutes at 25 ° and then add 7.48 g (30 mmol) of 6- (N-benzyloxycarbonylamino) hexanal. The reaction mixture is refluxed for 2 hours, then cooled with ice-water and extracted twice with 50 ml of methylene chloride each time. The extracts are combined, washed twice with 25 ml of saturated sodium bicarbonate solution and 25 ml of saturated brine each time, 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-methylenehexanal and 1.62 ml (16.8 mmol) of isocyanoacetic acid methyl ester are dissolved in 50 ml of toluene and added dropwise at 40 °. to a suspension of 0.12 g of 96.4% copper I-oxide in 50 ml of toluene. Stir for 2.5 hours at room temperature, filter, apply 60 g of silica gel to a packed column and extract first with a 1: 1 mixture of hexane and ethyl acetate and then with ethyl acetate. 5- [6- (N-Benzyloxycarbonylamino) hex-1-en-2-yl] -oxazole-4-carboxylic acid methyl ester is obtained as an oil.

9.4 g (26.1 mmol) of 5- [6- (N-benzyloxycarbonylamino) hex-1-en-2-yl] oxazoline-4-carboxylic acid methyl ester are dissolved in 40 ml of tetrahydrofuran and 20 ml of water. , add a few drops of triethylamine and heat 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 sulphate and evaporated to dryness. 8- (N-Benzyloxycarbonylamino) -2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester is obtained.

To 2.46 g (6.5 mmol) of 8- (N-benzyloxycarbonylamino) -2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester in 25 ml of tetrahydrofuran is added 5.5 ml ( 46 mmol) of hexa-1,5-diene and then dropwise at -50e 2.6 ml (32.5 mmol) of thionyl bromide. Stir for 2 hours at 0 ° to 5 °, pour into 25 ml of ice-cold saturated sodium hydrogen carbonate solution and extract 2 times 29 97231 times with 20 ml of methylene chloride each time. 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 a 3: 1 mixture of hexane and ethyl acetate. 8- (N-Benzyloxycarbonylamino) -4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.

To 1.45 g (3.3 mmol) of 8- (N-benzyloxycarbonylamino) -4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is added 5 ml of triethyl phosphite and heated with stirring at 75 ° for 8 hours: in. Excess triethyl phosphite is distilled off under reduced pressure to give an oily residue. This is purified by chromatography on a column of silica gel, first with ethyl acetate and then with ethyl acetate / methanol (9: 1). 8- (N-Benzyloxycarbonylamino) -4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.

Example 4: 1.77 g (4.5 mmol) of 4-diisopropylphosphono-methyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester are dissolved in 12 ml of dichloromethane and then added dropwise at room temperature 2, 32 ml (18.0; mmol) of trimethylbromosilane. Allow to stand for 22 hours at room temperature, add dropwise 12 ml of ethanol, allow to stand again for 24 hours, evaporate on a rotary evaporator, then dissolve the residue in 10 ml of ethanol and add a mixture of 2 ml of propylene oxide and 2 ml of ethanol. A suspension is formed which is stirred for 2 hours at room temperature and for 2 hours under ice-cooling and which is then filtered off with suction. 2-Amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained, m.p. 242 ° (dec.).

The starting material can be prepared, for example, as follows: • 309 P9Z231 19.7 g (193 mmol) of 4-methoxybutanal, 17.7 g (217 mmol) of dimethylammonium chloride and 17.0 ml (226 mmol) of a 37% formaldehyde solution are heated with stirring For 3 hours at 100 °. Allow to cool and extract 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 isocyanoacetic acid ethyl ester are dissolved in 145 ml of toluene and then 400 mg of copper I-oxide are added. After completion of the exothermic reaction, stir for a further 2 hours, filter through Hyflon * and evaporate to dryness. The residue is taken up in 145 ml of tetrahydrofuran, 33 ml of water are added and the mixture is heated under reflux with stirring for 2 hours. Evaporate to dryness, add toluene and re-evaporate. Chromatography on silica gel using a 95: 5 mixture of toluene and ethanol as eluent affords 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester as a red-brown oil.

19.0 g (77.5 mmol) of 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester are dissolved in 190 ml of 1,2-dichloroethane and then dropwise at room temperature, 7.20 ml ( 93.0 mmol) thionyl bromide. After 45 minutes, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed successively with water, 1N potassium hydrogen carbonate solution and once more with water, dried over sodium sulphate, filtered and evaporated. 4-Bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a red-brown oil.

I · 97231 31 3.38 g (11.0 mmol) of 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester and 12.0 ml (44 mmol) of triisopropyl phosphite (from 96% ) is heated to 80 ° and stirred at a pressure of about 130 mbar for 18 hours. Excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-Diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.

Example 5: 0.98 g (3.5 mmol) of 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester are heated in 7 ml of water under reflux for 17 hours. The reaction mixture is evaporated and crystallized from a mixture of water and ethanol. 2-Amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid is obtained, m.p. 214 ° C (dec.).

Example 6; 0.52 g (1.36 mmol) of 4-diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 3.5 ml of dichloromethane and then added dropwise at room temperature to 0.7 ml. ml (5.45 mmol) of trimethylbromosilane. Allow to stand for 24 hours at room temperature, add dropwise 3.5 ml of ethanol, allow to stand once more for 24 hours, evaporate on a rotary evaporator, then dissolve the residue in 2.4 ml of ethanol and add a mixture of 0.6 ml of propylene oxide and 0 ml. , 6 ml of ethanol. A suspension is formed which is stirred for 2 hours at room temperature and for 2 hours under ice-cooling and which is then filtered off with suction. 2-Amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained, m.p. 222 ° (dec.).

The starting material can be prepared, for example, as follows: 2.4 g (26.6 mmol) of 4-fluorobutanal, 2.44 g (30.0 mmol) of dimethylammonium chloride and 2.34 ml (31.1 mmol of 97231 32 l) of 37%: The formaldehyde solution is heated with stirring for 2 hours at 100 °. Allow to cool and extract 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 further reacted without further purification.

1.43 g (14.0 mmol) of 4-fluoro-2-methylene-butanal and 1.53 ml (14.0 mmol) of isocyanoacetic acid ethyl ester are dissolved in 14 ml of toluene and then 40 mg of copper I-oxide are added. After completion of the exothermic reaction, stir for a further 2 hours, filter through Hyflon * and evaporate to dryness. The residue is taken up in 14 ml of tetrahydrofuran, 3.1 ml of water are added and the mixture is refluxed for 2 hours. Evaporate to dryness, add toluene and re-evaporate. Chromatography on silica gel using a 1: 1 mixture of toluene and ethyl acetate as eluent affords 6-fluoro-2-formyl-amino-3-hydroxy-4-methylene-hexanoic acid ethyl ester as a dark yellow oil.

1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 14 ml of 1,2-dichloroethane and then 0.56 ml (7, 2 mmol) thionyl bromide. After 45 minutes, add 12 ml of water and stir vigorously for 15 minutes. The organic phase is separated, washed successively with water, 1N potassium bicarbonate solution and once more with water, dried over sodium sulphate, filtered and evaporated. 4-Bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of 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 97231 33 triisopropyl phosphite (96%) are heated to 80 ° and stirred at a pressure of about 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-Diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.

Example 7: 0.5 g (1.86 mmol) of 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated in 4 ml of water at reflux for 17 hours. The reaction mixture is evaporated and separated in a strongly acidic ion exchanger (Dowex 50Wx8, H + form) with water. 2-Amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid is obtained, m.p. 160-162 ° (dec.).

Example 8: Starting from 8-amino-octan-1-ol in a similar manner to that described in Example 3, 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid dihydrochloride is obtained, m.p. 126 °.

Example 9: 8.63 g (15.2 mmol) of 10- (N-benzyloxycarbonylamino) -4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane and then added at room temperature. 9.82 ml (75.9 mmol) of trimethylbromosilane. Stir for 22 hours at room temperature, add dropwise 22 ml of absolute ethanol, stir once more for 22 hours and evaporate on a rotary evaporator. 20 ml of toluene are poured onto the residue and then evaporated in vacuo. This operation is repeated: · 3 times. The resulting pale yellow foam is dissolved in 150 ml of absolute ethanol and then a solution of 7.5 ml of propylene oxide in 7.5 ml of ethanol is added dropwise over 90 minutes. A crystal suspension is formed which is stirred overnight at room temperature. The product is filtered off and washed with ethanol and ether. 97231 34 are dried under high vacuum at room temperature to give 4.70 g of crude product as pale yellow crystals. For further purification, it is mixed with 46 ml of water. After filtration of a small amount of insoluble matter (0.33 g), the clear pale yellow filtrate is completely evaporated in vacuo. To the residue are added 20 ml of ethanol and 20 ml of toluene and re-evaporated to dryness. This procedure is repeated 2 more times with toluene. After drying under high vacuum, the residue is suspended in 150 ml of absolute ethanol and then a 5N solution of hydrogen chloride gas in ethanol is added dropwise with stirring until the mixture reacts with Congo acid. To the resulting clear solution is added dropwise over 1 hour a mixture of 7.4 ml of propylene oxide in 7.4 ml of ethanol. A crystal suspension is formed which is stirred for 15 hours and then suction filtered. Wash with ethanol and ether, then dry the product for 48 hours under high vacuum at 50 °. 2.86 g of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester are thus obtained, which begins to sinter at 157 ° and melts at 194 ° with decomposition.

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

The starting material is prepared as follows:

In a similar manner, starting from 8-aminooctan-1-ol as described in Example 3, 8- (N-benzyloxycarbonylamino) octan-1-ol and 8- (N-benzyloxycarbonylamino) octanal via 8- (N- benzyloxycarbonylamino) -2-methylene octanal.

15.30 g (52.9 mmol) of 8- (N-benzyloxycarbonylamino) -2-methyleneoctanal and 7.37 ml (67.4 mmol) of isocyanoacetic acid ethyl ester are dissolved in 78 ml of toluene 97231 35 and added under argon 75 within 1 minute dropwise to a suspension of 0.30 g of copper I oxide in 76 ml of toluene. Stir for 90 minutes at 30 °, cool to room temperature, filter and then apply the clear pink filtrate to a packed column of 250 g silica gel (grain size 0.04-0.063 mm) and elute with a 2: 1 mixture of hexane and ethyl acetate. After evaporation of the appropriate fractions, 8.15 g of 5- [8- (N-benzyloxycarbonylamino) oct-1-en-2-yl] oxazoline-4-carboxylic acid ethyl ester are obtained in the form of a colorless honey-like substance.

8.15 g (20.25 mmol) of 5- [8- (N-benzyloxycarbonylamino) oct-1-en-2-yl) oxazoline-4-carboxylic acid ethyl ester are heated under reflux for 4 hours in 40 ml of tetrahydrofuran. and in 20 ml of water. The reaction mixture is evaporated to dryness in vacuo at 45 ° and the honey-like residue is evaporated a further 2 times by adding toluene. The crude product is dissolved in dichloromethane, dried over sodium sulfate, filtered and evaporated. Dry under high vacuum at room temperature to give 9.03 g of 10- (N-benzyloxycarbonylamino) -2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester as a yellowish honey-like substance.

To 13.70 g (32.60 mmol) of crude 10- (N-benzyloxycarbonylamino) -2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in 137 ml of tetrahydrofuran is added 18.5 ml of argon. (156.4 mmol) of hexa-1,5-diene and then dropwise at 10 ° over 15 minutes to 6.1 ml (78.2 mmol) of thionyl bromide. Stir for 1 hour at 10 ° and 2 hours at room temperature, pour into 200 ml of ice-cold saturated sodium hydrogen carbonate solution, separate the organic phase and extract once with dichloromethane. The organic phases are washed with ice-cold 0.5N sodium bicarbonate solution and then with saturated brine, dried over sodium sulfate and evaporated to dryness at 40 ° under vacuum. To the resulting crude 10- (N-benzyloxycarbonylamino) -4-bromomethyl-2-formylamino-dec-3-enoic acid ethyl ester (27 g, yellow honey) was immediately added 64 mL (260 mmol) of triisopropyl phosphite (96%: ista) and stirred at a pressure of about 100 mbar for 17 hours at 80 °, whereupon the formed isopropyl bromide is collected in a cold trap (CO 2). The excess triisopropyl phosphite is then distilled off under reduced pressure, and the evaporation residue (23 g) is purified by chromatography on a column of 650 g of silica gel (grain size 0.04 to 0.063 mm) with a 95: 5 mixture of ethyl acetate and methanol. 8.73 g of 10- (N-benzyloxycarbonylamino) -4-diisopropylphosphono-methyl-2-formylamino-dec-3-enoic acid ethyl ester are obtained in the form of a yellowish honey-like substance.

Example 10: 2.25 g (6.98 mmol) of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester are dissolved in 45 ml of 2N hydrochloric acid under argon and stirred for 17 hours at 120 °. bath temperature. The clear, light brown solution is evaporated on a rotary evaporator. The residue is dissolved in 20 ml of ethanol, 30 ml of to- are added. read and evaporate in vacuo. This procedure is repeated 3 times. The resulting light brown foam is dissolved in 75 ml of absolute ethanol and then a solution of 15 ml of propylene oxide in 15 ml of ethanol is added dropwise over 35 minutes. The resulting crystal suspension, pH 3, is filtered after stirring for 1.5 hours | after and wash well with ethanol and ether. Dry in vacuo to give 1.65 g of a beige crude product which is dissolved in a small amount of water (ca. 2 ml) and chromatographed on a column packed with 67 g of reversed-phase silica gel (Opti-Up C12, grain size 40). μιη), using water at low pressure (0.2 bar) as eluent. A pure fraction with an Rf of 0.37 on silica gel is obtained using a 15:12: 10: 3 mixture of n-propanol, water, pyridine and acetic acid as propellant, and several mixed fractions with a by-product with an Rf of 0.48 . New chromatography of these mixed fractions and pooling and lyophilization of the pure fractions from water yields 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid hemihydrochloride hydrate as an amorphous glass which Sint slowly decomposes from 134 ° and decomposes at 149 °. foaming-ten.

Example 11: 4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester are dissolved in 25 ml of dichloromethane and then added dropwise at room temperature. 1 ml (39.5 mmol) of trimethylbromosilane. Allow to stand for 24 hours at room temperature, add 25 ml of ethanol and allow to stand again for 24 hours, evaporate, dissolve the residue in 25 ml of ethanol and add dropwise a mixture of 25 ml of propylene oxide and 25 ml of ethanol. A suspension is formed which is stirred for one hour at room temperature and for one hour in an ice bath and which is then filtered off with suction. After drying, 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl is obtained. esters, m.p. 210 ° (dec.).

The starting material can be prepared, for example, as follows: 10 g (69.4 mmol) of 5-acetoxypentanal, 6.37 g (78.2 mmol) of dimethylammonium chloride and 6.1 ml (81.2 mmol) of 37% formaldehyde. The solution is kept under stirring for 1.5 hours at reflux (bath temperature -110 °). Allow to cool, extract 3 times with ether, combine the organic phases, dry over MgSO 4, filter and evaporate. 5-Acetoxy-2-methylene-pentanal is obtained as a yellowish oil which can be reacted without further purification.

38 97231 9.6 g (61.5 mmol) of 5-acetoxy-2-methylenepentanal and 7.38 ml (67.6 mmol) of isocyanoacetic acid ethyl ester are dissolved in 70 ml of toluene at room temperature and then 250 mg of copper-I- oxide. At the end of the exothermic reaction, stir for a further hour, filter through Hyflon * and evaporate. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added and the mixture is refluxed for 3 hours. Evaporate to dryness, add toluene and evaporate once more. Chromatography on silica gel using a 4: 1 mixture of toluene and ethyl acetate as eluent affords 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester as an orange oil.

5.9 g (20.5 mmol) of 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester are dissolved in 60 ml of dichloromethane and then 1.9 ml (24.6 mmol) are added dropwise at room temperature. ) thionyl bromide. After one hour, add 40 ml of water and stir vigorously for 10 minutes. The organic phase is separated, washed successively with water, 1N KHCO 3 solution and once more with water, dried over MgSO 4, filtered and evaporated. 7-Acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained as a brown oil which is further reacted crude.

6.1 g (17.4 mmol) of 7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester and 19.1 ml (69.6 mmol) of triisopropyl phosphite (90%) are heated To 80 ° and stirred at a pressure of about 130 mbar for 18 hours. Excess triisopropyl phosphite is distilled off under reduced pressure and the residue is purified by chromatography on silica gel with ethyl acetate. 7-Acetoxy-4-diisopropyl-phosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained as a yellow oil.

Il a ». * A.Ui I I t at. .

97231 39

Example 12: 1.1 g (3.9 mmol) of 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester are heated in 8 ml of water for 18 hours at 130 ° in a bomb tube. The dark reaction solution is treated with activated carbon and filtered through Hyflon *. The colorless filtrate is evaporated to about 3 ml and then about 25 ml of ethanol are added. The resulting suspension is filtered off with suction and dried under high vacuum at 50 °. 2-Amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid is obtained, m.p. From 190 ° (dec.).

Example 13: 8.2 g (18.9 mmol) of 6- (N-acetyl-N-methylamino) -4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 40 ml of dichloromethane. -methane and then 9.8 ml (75.6 mmol) of trimethylbromosilane are added dropwise at room temperature. Allow to stand for 24 hours at room temperature, add dropwise 40 ml of ethanol, allow to stand once more for 24 hours, evaporate, dissolve the residue in 40 ml of ethanol and add dropwise a mixture of 40 ml of propylene oxide and 40 ml of ethanol. A suspension is formed which is stirred for a further hour at room temperature and for one hour at 0 ° and which is then filtered off with suction. After drying, 6- (N-acetyl-N-methylamino) -2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained, m.p.

·. 222-223 ° C (dec.).

The starting material can be prepared, for example, as follows: 35.8 g (0.2 mol) of 4-aminobutyraldehyde diethyl acetal (90%) are dissolved in 600 ml of dichloromethane, additional | 300 ml of saturated sodium hydrogen carbonate solution and cooled to 0 °. 17 ml (0.24 mol) of acetyl chloride are added dropwise at 0-5 ° and the mixture is stirred for 6 hours at 0-5 °. The organic phase is separated off and the aqueous phase is extracted twice more 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-diethyl acetal 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, 8.3 g (206.6 mmol) of sodium hydride dispersion (60%) are added portionwise. in mineral oil) and stirred for 45 minutes at room temperature. 12.9 ml (206.6 mmol) of methyl iodide in 20 ml of dimethylformamide are then added and the mixture is stirred for 4 hours at room temperature. A mixture of water and ice is added to the reaction mixture and extracted 3 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-methylamino) -butyraldehyde diethyl acetal is obtained in the form of a colorless oil, b.p. = 92-94 °.

30 g (138.2 mmol) of 4- (N-acetyl-N-methylamino) -butyraldehyde diethyl acetal, 12.6 g (154.4 mmol) of dimethylammonium chloride and 12.1 ml (161.7 mmol) of mmol) of a 37% formaldehyde solution is kept under stirring for 45 minutes at reflux. Allow to cool and extract 3 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-methylamino) -2-raethylene butanal and 15.4 ml (141.1 mmol) of isocyanoacetic acid ethyl ester are dissolved in 80 ml of toluene at room temperature. temperature and then 500 mg of copper I oxide are added. After completion of the exothermic reaction, a further 97231 are stirred for 41 hours at room temperature, filtered through Hyflon * and evaporated. The residue is taken up in 60 ml of tetrahydrofuran, 20 ml of water are added and the mixture is refluxed for 4 hours. Evaporate, add toluene and evaporate once more. Chromatography on silica gel using a 7: 1 mixture of acetic acid ethyl ester and isopropanol as eluent affords 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 6- (N-acetyl-N-methylamino) -2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 150 ml of dichloromethane and then added dropwise at room temperature. 5.1 ml (66.2 mmol) of thionyl bromide. After one hour, add 100 ml of water and stir vigorously for 10 minutes. The organic phase is separated, washed successively with water, 1N KHCO 3 solution and once more with water, dried over MgSO 4, filtered and evaporated. 6- (N-Acetyl-N-methylamino) -4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellow-orange oil which is further reacted crude.

16.0 g (45.8 mmol) of 6- (N-acetyl-N-methylamino) -4-. bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 50.3 ml (183.3 mmol) of triisopropyl phosphite (90%) are heated to 80 ° and stirred at a pressure of about 130 mbar for 18 hours. Excess triisopropylphosphite is distilled off and the residue is purified by chromatography on silica gel with a 7: 2 mixture of ethyl acetate and isopropanol. 6- (N-Acetyl-N-methylamino) -4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellow oil.

Example 14: 3.3 g (6.82 mmol) of 6-benzoyloxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid 97231 42 poethyl ester are dissolved in 20 ml of dichloromethane and then added dropwise at room temperature 3, 52 ml (27.3 mmol) of trimethylbromosilane. Allow to stand for 22 hours at room temperature, add dropwise 20 ml of ethanol, allow to stand again for 22 hours, evaporate, then dissolve the residue in 20 ml of ethanol and add dropwise a mixture of 20 ml of propylene oxide and 20 ml of ethanol. A suspension is formed which is stirred for 1 hour at room temperature and for one hour at 0 ° and which is then filtered off with suction. 2-Amino-6-benzoyloxy-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained, m.p. 236-237 ° (dec.).

The starting material can be prepared, for example, as follows: 10 g (52 mmol) of 4-benzoyloxybutanal, 4.78 g (58.6 mmol) of dimethylammonium chloride and 4.6 ml (60.8 mmol) of a 37% formaldehyde solution are kept under stirring. for 1 hour at reflux (bath temperature -110 ° C). Allow to cool and extract 3 times with ether, combine the organic phases, wash with saturated brine, dry over MgSO 4, filter and evaporate. 4-Benzoyloxy-2-methylene-butanal is obtained as a yellowish oil which can be further reacted without further purification. 1 g (49 mmol) of 4-benzoyloxy-2-methylene-butanal and 5.3 ml (49 mmol) of isocyanoacetic acid ethyl ester are dissolved in 70 ml of toluene at room temperature and then 200 mg of copper I-oxide are added. At the end of the exothermic reaction, stir for a further hour, filter through Hyflon * and evaporate. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added and the mixture is refluxed for 3 hours. Evaporate, add more toluene and re-evaporate. Chromatography on silica gel using 97231 43 of a 3: 2 mixture of toluene and ethyl acetate as eluent affords 6-benzoyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester as a brown oil.

8 g (23.9 mmol) of 6-benzoyl-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 80 ml of dichloromethane and then 2.22 ml (28.6 mmol) of thionyl bromide are added dropwise at room temperature. . After 2 hours, add 60 ml of water and stir vigorously for 10 minutes. The organic phase is separated, washed successively with water, 1N KHCO 3 solution and once more with water, dried over MgSO 4, filtered and evaporated. 6-Benzoyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a brown oil which is further reacted crude.

8 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 ° and stirred for approx. At 130 mbar for 18 hours. the excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 6-Benzoyloxy-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid poethyl ester is obtained as a brown oil.

Example 15: 4.0 g (8.51 mmol) of 6-benzyloxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid polyethyl ester are dissolved in 24 ml of dichloromethane and then 4.4 ml are added dropwise at room temperature. (34 mmol) trimethylbromosilane. Allow to stand for 22 hours at room temperature, add dropwise 24 ml of absolute ethanol, allow to stand once more for 24 hours, evaporate on a rotary evaporator, dissolve the residue in 24 ml of ethanol and then add dropwise a mixture of 24 ml of propylene oxide and 24 ml of ethanol.

97231 44

A suspension is formed which is stirred for 1 hour at room temperature and for one hour at 0 ° and which is then filtered off with suction. After drying, 2.2 g of a white crystalline product of 2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester and 2-amino-6-benzyloxy-4-phosphonomethyl-hex-3- a mixture of enoic acid. To obtain a homogeneous product, this mixture is saponified with 20 ml of n-sodium hydroxide in 30 ml of ethanol overnight at room temperature, acidified with n-hydrochloric acid and neutralized with propylene oxide. Since the product crystallizes poorly, it is evaporated on a rotary evaporator, the residue is filtered into water through silica gel (20 g) and the fractions containing the desired product are evaporated off on a rotary evaporator. The residue is dissolved in 10 ml of a 1: 1 mixture of tert-butanol and water and freeze-dried. 2-Amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid is obtained as a lyophilisate.

The starting material can be prepared as follows: 6 g (0.2 mol) of a dispersion of sodium hydride (80% in white oil) are dissolved in 120 ml of absolute dimethylformamide at room temperature and then 22.2 ml (0.25 mol) are added dropwise. 1,4-butanediol. After the addition is complete, stir for an additional 30 minutes at room temperature. 23.1 ml (0.2 mol) of benzyl chloride are then slowly added dropwise, a slight exotherm being observed. The reaction mixture is stirred overnight at room temperature, a mixture of water and ice is added and extracted twice with ether. The organic phases are washed with water and brine, combined, dried over MgSO 4, filtered and evaporated. The residue is fractionally distilled in a water-jet vacuum through a 10 cm Vigreux column. 4-Benzyloxybutanol is obtained, b.p. 22 = 161 "162 °.

36.6 g (170 mmol) of pyridinium chlorochromate are dissolved in: 120 ml of dichloromethane at room temperature under an atmosphere of N2 at 97231 45 and then a solution of 20.4 g (113 mmol) of 4-benzyloxybutanol in 20 ml of dichloromethane is added. nia. The reaction mixture darkens rapidly and the reaction is slightly exothermic. The reaction mixture is stirred for 3.5 hours at room temperature. The upper dichloromethane phase is decanted off and evaporated on a rotary evaporator. The residue is filtered through silica gel (100 g). The product fractions are evaporated on a rotary evaporator and distilled through a 10 cm Vigreux column. 4-Benzoyloxybutanal is obtained, b.p. = 72-73 °.

8.0 g (44.9 mmol) of 4-benzyloxybutanal, 4.12 g (50.6 mmol) of dimethylammonium chloride and 3.95 ml (52.6 mmol) of a 37% formaldehyde solution are kept under stirring for one hour at a bath temperature of 110 °. . Allow to cool and extract 3 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 isocyanoacetic acid ethyl ester are dissolved in 60 ml of toluene and then 200 mg of copper I-oxide are added. At the end of the exothermic reaction, stir for a further 2 hours, filter through Hyflon * and evaporate. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added and the mixture is refluxed for 3 hours. Evaporate to dryness, add toluene and re-evaporate. Chromatography on silica gel using a 3: 2 mixture of toluene and ethyl acetate as eluent gives 6-benzyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester as a red-brown oil.

97231 46 7.0 g (21.8 mmol) of 6-benzyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 70 ml of dichloromethane and then 2.0 ml (26.1 mmol) are added dropwise at room temperature. ) thionyl bromide. After 2 hours, add 40 ml of water and stir vigorously for 10 minutes. The organic phase is separated, washed successively with water, n-KHCO 3 solution and once more with water, dried over MgSO 4, filtered and evaporated. 6-Benzyloxy-4-bromomethyl-2-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a red-brown oil, which is further reacted without further purification.

7.9 g (20.5 mmol) of 6-benzyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 22.5 ml (82.2 mmol) of triisopropyl phosphite (90%) are heated To 80 ° and stirred at a pressure of about 130 mbar 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. 6-Benzoyl-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.

Example 16: 3.15 g (6.84 mmol) of 4- (1-acetyl-piperidin-4-yl) -5-diisopropyl-phosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 17 ml of dichloromethane and then 3.54 ml (27.3 mmol) of trimethylbromosilane are added dropwise at room temperature. Allow to stand for 16 hours at room temperature, add dropwise 17 ml of ethanol, allow to stand again for 18 hours, evaporate on a rotary evaporator, then dissolve the residue in 12 ml of ethanol and add dropwise a mixture of 3 ml of propylene oxide and 3 ml of ethanol. A suspension is formed which is stirred for a further 2 hours at room temperature and for 2 hours under ice-cooling and which is then filtered off with suction. 2-Amino-4- (1-97231-7-acetyl-piperidin-4-yl) -5-phosphono-pent-3-enoic acid ethyl ester is obtained, m.p. 225 ° (dec.).

The starting material can be prepared, for example, as follows: 3.95 g (23.3 mmol) of 2- (1-acetylpiperidin-4-yl) ethanol, 2.12 g (26.3 mmol) of dimethylammonium chloride and 3 ml (40 mmol) of 37 The% formaldehyde solution is heated at 110 ° for 2 hours. Allow to cool and extract 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 (16.0 mmol) of 2- (1-acetylpiperidin-4-yl) propenal and 1.75 ml (16 mmol) of isocyanoacetic acid ethyl ester are dissolved in 13 ml of toluene and then 46 mg of copper are added. I-oxide. After completion of the exothermic reaction, stir for a further 2 hours, filter through Hyflon * and evaporate to dryness. The residue is taken up in 13 ml of tetrahydrofuran, 6 ml of water are added and the mixture is refluxed for 2 hours with stirring. Evaporate to dryness, add toluene and re-evaporate. Chromatography on silica gel using a 9: 1 mixture of acetic acid ethyl ester and methanol as eluent affords 4- (1-acetyl-piperidin-4-yl) -2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester as a tan oil.

3.3 g (10.5 mmol) of 4- (1-acetyl-piperidin-4-yl) -2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester are dissolved in 25 ml of 1,2-dichloroethane and then added. dropwise at room temperature 0.98 ml (12.6 mmol) of thionyl bromide. After 1.5 hours, add 20 ml of water and stir vigorously for 15 minutes. The organic phase is separated, washed successively with water, n-potassium hydrogen carbonate solution and once more with water, dried over sodium sulfate, filtered and evaporated. 4- (1-Acetyl-piperidin-4-yl) -5-bromo-2-formylamino-pent-3-enoic acid ethyl ester is obtained as a red-brown oil.

2.68 g (7.14 mmol) of 4- (1-acetylpiperidin-4-yl) -5-bromo-2-formylamino-pent-3-enoic acid ethyl ester and 7.5 ml (28.5 mmol) of triisopropyl phosphite ( 90%) is heated to 80 ° and stirred at a pressure of about 130 mbar for 18 hours. Excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with a 9: 1 mixture of ethyl acetate and methanol. 4- (1-Acetyl-piperidin-4-yl) -5-diisopropyl-phosphono-2-formylamino-pent-3-enoic acid ethyl ester is obtained as a yellowish oil.

Example 17: 1 g (2.17 mmol) of 4- (1-acetyl-piperidin-4-yl) -5-diisopropyl-phosphono-2-formylamino-pent-3-enoic acid ethyl ester is heated in 20 ml of 6n-hydrochloric acid for 8 hours. time to reflux. After evaporation, the residue is dissolved in 25 ml of ethanol. 3 ml of propylene oxide are added, the mixture is stirred for 2 hours at room temperature and for 1 hour under ice-cooling, and then the suspension formed is filtered off with suction. 2-Amino-4- (piperidin-4-yl) -5-phosphono-pent-3-enoic acid is obtained, m.p. 212 ° (dec.).

Example 18: 0.68 g (1.49 mmol) of 5-benzyloxy-4-diisopropyl-phosphonomethyl-2-formylamino-pent-3-enoic acid poethyl ester is dissolved in 10 ml of dichloromethane and then 0.8 ml of dichloromethane are added dropwise at room temperature. (6 mmol) trimethylbromosilane. Allow to stand for 6 hours at room temperature, add dropwise 10 ml of ethanol, allow to stand again for 18 hours, evaporate, then dissolve the residue in 5 ml of ethanol and then add dropwise a mixture of 5 ml of propylene oxide and 5 ml of ethanol. A suspension is formed which is stirred for 2 hours at room temperature and which is then filtered off with suction. After drying, 2-amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester, m.p. 218-220 ° C (dec.).

The starting material can be prepared as follows: 3.0 g (62.4 mmol) of a 50% dispersion of sodium hydride in mineral oil are added to 50 ml of tetrahydrofuran and 40 ml of dimethylformamide, a solution of 10.0 g is slowly added at 0 °. (62.4 mmol) of 3-hydroxy-2-methylene-propionaldehyde-diethyl acetal in 10 ml of tetrahydrofuran, and stirred for 2 hours at 0 °. Dilute 15 ml of tetrahydrofuran and 10 ml of dimethylformamide and stir for a further 2 hours at room temperature. Add 7.2 ml (62.4 mmol) of benzyl chloride in 10 ml of dimethylformamide at 0 ° C and stir for 18 hours at room temperature. Water is added to the reaction mixture, extracted 3 times with ethyl acetate and the organic phases are washed with saturated brine. The organic phases are combined, dried: over Na2SO4, filtered and evaporated. The residue is chromatographed on silica gel with methylene chloride to give 3-benzyloxy-2-methylene-propionaldehyde-diethylacetal as a slightly yellowish liquid.

4.8 g (19.1 mmol) of 3-benzyloxy-2-methylene-propioni-. aldehyde diethyl acetal and 0.36 g (1.9 mmol) of p-toluenesulfonic acid monohydrate are stirred for 3 hours in 60 ml of acetone. Dilute with 400 ml of methylene chloride, extract with n-KHCO 3 solution and saturated brine, dry over Na 2 SO 4, filter and evaporate. The remaining 3-benzyloxy-2-97231 methylene propanal (yellow liquid) is added without further purification together with isocyanoacetic acid ethyl ester (2.1 ml, 19 mmol) to 25 ml toluene at room temperature and then 50 mg of copper-I- oxide. After completion of the exothermic reaction, the mixture is stirred for a further hour at room temperature, filtered through Hyflon * and evaporated. The residue is taken up in 25 ml of tetrahydrofuran, 5 ml of water are added and the mixture is refluxed for 4 hours. Evaporate, add toluene and evaporate once more. Chromatography on silica gel using a 1: 1 mixture of toluene and ethyl acetate as eluent and crystallization from diethyl ether gives 5-benzyloxy-2 '* formylamino-3-hydroxy-4-methylenipentanoic acid ethyl ester, m.p. 112-114 °.

1/9 (3.25 mmol) of 5-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester is suspended in 30 ml of 1,2-dichloroethane and then added dropwise at room temperature to 0.38. ml (4.9 mmol) of thionyl bromide. After 45 minutes, add 20 ml of water to the yellow solution and stir vigorously for 15 minutes. The organic phase is separated, washed with saturated brine, dried over Na 2 SO 4, filtered and evaporated. 5-Benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained as a yellowish oil which is further reacted crude.

1.14 g (3.1 mmol) of 5-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 10 ml (38.5 mmol) of triisopropyl phosphite (95%) are heated to 80 ° and stirred at a pressure of about 130 mbar for 3.5 hours. Excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 5-Benzyloxy-4-diisopropylphosphonomethyl-2-formylamino-pentene is obtained. 3-Enoic acid ethyl ester as a yellowish oil.

97231 51

Example 19; 1.10 g (2.8 mmol) of 5-ethoxy-4-diisopropyl-phosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane and then 1.6 ml (at room temperature) are added dropwise. 12.3 mmol) of trimethylbromosilane. Allow to stand for 7 hours at room temperature, add dropwise 20 ml of ethanol, allow to stand again for 15 hours, evaporate, then dissolve the residue in 10 ml of ethanol and add dropwise a mixture of 10 ml of propylene oxide and 10 ml of ethanol. A suspension is formed which is stirred for 2 hours at room temperature and then suction filtered. After drying, 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester, m.p. 217-218 ° (dec.).

The starting material can be prepared, for example, as follows: 50 g (283 mmol) of 3-ethoxypropionaldehyde diethyl acetal, 27.3 g (335 mmol) of dimethylammonium chloride and 30 ml (392 mmol) of a 36% formaldehyde solution are heated with stirring for 2 hours. time at 110 °. Allow to cool and extract 3 times with diethyl ether. The organic phases are washed with saturated brine, combined, dried over sodium sulfate, filtered and evaporated to dryness. 2-Ethoxypropanal is obtained as a yellow liquid which can be further reacted without further purification.

4.2 g (36.1 mmol) of 2-ethoxypropanal and 4.4 ml (40 mmol) of isocyanoacetic acid ethyl ester are dissolved in 50 ml of toluene and then 200 mg of copper I-oxide are added. After completion of the exothermic reaction, the mixture is stirred for a further hour, filtered through Hyflon * and evaporated to dryness. The residue is taken up in 50 ml of tetrahydrofuran, 12 ml of water are added and the mixture is heated under reflux with stirring for 1 hour. Evaporate to dryness, add toluene 97231 52 and re-evaporate. Chromatography on silica gel using a 9: 1 mixture of toluene and isopropanol as eluent affords 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester as a yellow oil.

3.70 g (15.1 mmol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are dissolved in 1.8 ml of 1,2-dichloroethane and then 1.8 ml ( 22.8 mmol) thionyl bromide. After one hour, add 100 ml of water and stir vigorously for 15 minutes. The organic phase is separated, washed successively with 1N potassium hydrogen carbonate solution and brine, dried over sodium sulfate, filtered and evaporated. 5-Ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a tan oil, which is further reacted crude.

3.12 g (10.1 mmol) of 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 30 ml (118 mmol) of triisopropyl phosphite (90%) are heated to 80 ° and stirred at a pressure of about 130 mbar for 7 hours. Excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel: a mixture of methylene oxide and methanol (97: 3 to 95: 5).

5-Ethoxy-4-diisopropyl-phosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained as a yellow oil.

Example 20: Tablets containing 50 mg of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof, e.g. the sodium salt, can be prepared as follows:

Composition (10,000 tablets): active substance 500.0 g lactose 500.0 g potato starch 352.0 g <53 97231 gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (high disp.) 20.0 g ethanol gs

The active ingredient is mixed with lactose and potato starch (292 g), the mixture is moistened with an ethanolic solution of gelatin and granulated through a sieve. After drying, the rest of the potato starch, magnesium stearate, talc and silica are mixed and compressed into tablets weighing 145.0 mg and containing 50.0 mg of active ingredient, which may, if desired, be provided with a divider for better dosage adjustment.

Example 21: Lacquer tablets containing 100 mg of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof, e.g. the sodium salt, can be prepared as follows:

Composition (1000 lacquer tablets): active substance 100.0 g lactose 100.0 g corn starch 70.0 g: talc 8.5 g calcium stearate 1.5 g hydroxypropylmethylcellulose 2.36 g saliva 0.64 g water q.s.

. methylene chloride q.s.

The active ingredient, lactose and 40 g of corn starch are mixed together and moistened with a paste made of 15 g of corn starch and water (with heating) and granulated. The granulate is dried, t · 97231 54 the rest of the corn starch, talc and calcium stearate are added and mixed with the granulate. The mixture is compressed into tablets (weight: 280 mg) and these are lacquered with a solution of hydroxypropyl raethylcellulose and shellac in methylene chloride. Final weight of lacquer tablet: 283 mg.

Example 22: Gelatin capsules containing 100 mg of active ingredient, e.g. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof, e.g. the sodium salt, can be prepared e.g.

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

Sodium lauryl sulphate is sieved through a sieve with a mesh size of 0.2 mm into the lyophilized active substance. Both components are thoroughly mixed together. The lactose is then screened first with a sieve with a mesh size of 0.6 mm and then with microcrystalline cellulose with a sieve with a mesh size of 0.9 mm. After that, mix. again thoroughly for 10 minutes. Finally, the magnesium stearate is sieved through a sieve with a mesh size of 0.8 mm. Stirring is continued for 3 minutes, then in each case 390 mg of the preparation obtained are filled into gelatin injection capsules of size 0.

. Example 23: A 0.2% solution for injection or infusion of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof, e.g. the sodium salt, can be prepared, for example, as follows: 97231 55

Composition (1000 ampoules): active substance 5.0 g sodium chloride 22.5 g phosphate buffer, pH 1 7.4 300, o g demineralized water ad 2500.0 ml

The active substance and sodium chloride are dissolved in 1000 ml of water and filtered through a microfilter. Add the buffer solution and make up to 2500 ml with water. Dosage unit forms are prepared by filling into 1.0 or 2.5 ml glass ampoules, each containing 2.0 or 2.5 ml. 5.0 mg of active substance.

Example 24: In a similar manner to that described in Examples 1-19, the following can be further prepared: 2-Amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester, m.p. 230-233 ° (dec.), 2-amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester, m.p. 177-180 °, and 2-amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester, m.p. 243-244 ° (dec.).

Example 25: In a similar manner to that described in Examples 20 to 23, pharmaceutical preparations containing another compound of formula I according to any of Preparation Examples 1 to 19 and 24 can also be prepared.

· • ·

Claims (9)

A process for the preparation of therapeutically usable, unsaturated amino carboxylic acid derivatives of formula I And R salts thereof, in which formula R 1 represents hydroxy-C 1 -C 3 alkyl, dihydroxy-C 1 -C 8 alkyl, C 2 -C 7 alkanoyloxy-C 1 -C 7 -al -kyl, in the phenyl moiety optionally with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen having an order number of not more than 35, cyano and / or trifluoromethyl mono- or disubstituted benzoyloxy-C 1 -C 4 alkyl, C C ^-alkoxy-C--Cj alkyl, in the phenyl moiety optionally with Cj-C4 alkyl, C -alkoxy-Cj-Cj alkyl group, halo gene Cj-C alkyl alkyl, wherein halogen represents chlorine or fluoro, amino-C ^-Cy alkyl, C ^-CC alkylamino-C C-C ^ alkyl, C C7-alkanoylamino-C1-C7-alkyl, N-C2-C7-alkanoyl-N-C1-C4-alkylamino-C1-C3-alkyl, di-C1-C3-alkylamino-C1-C1-alkyl , azacyloalkyl-1-yl-C 1 -C 7 alkyl of 5-7 members, azacycloalk-3-yl-C 1 -C 4 alkyl or resp. azacycloalk-4-yl-C 1 -C 7 -alkyl with 5-7 members, 1-C 1 -C 4 -alkanoylazacycloalk-5-yl-C 1 -C 4 -alkyl or, respectively. 1-C 1 -C 2 alkanoylazacycloalkyl-C 1 -C 3 -C 3 alkyl, N-C 1 -C 4 alkylazacycloalk-3-yl-C 1 -C 7 alkyl or, respectively. -4-yl-C ^-C ^ alkyl, N-t ^-C ^-benzoyl azacycloalk-S-yl-C ^-Cy alkyl or, resp. -4-yl-C 1 -C 7 -alkyl, diazacycloalk-1-yl-C 1 -C 2 -alkyl with 5-7 members, N 1 -C 2 -C 3 -alkyldiazacycloalk-1-yl-C 2 -; -alkyl, N'-C ^-Cj-alkanoylazacycloalk-1-yl-C 1 -C 6 alkyl, azoxacycloalk-1-yl-C , -C7-alkyl or oxacycloalk-4-yl-C, -C7-alkyl of 5-7 members, azacycloalk-3-yl or resp. -4-yl with 5-7 members or 1- C2-C7 alkanoyl-azacycloalk-3-yl or 1-8 in III. irf 61 97231 clay resp. -4-yl, N-C, -C4-alkylazacycloalk-3-yl or resp. -4-yl or in the phenyl moiety optionally substituted N-benzoyl azacycloalk-3-yl or -4-yl or oxacycloalk-3-yl or resp. -4-yl of 5-7 members, and R2 represents carboxy, C1-C4 alkoxycarbonyl, cycloalkoxycarbonyl of 5-7 members or optionally C1-C4 alkyl, C1-C4 alkoxy, halogen having an order number of at most 35, cyano and / or trifluoromethyl mono- or disubstituted phenyl-C optionally protected hydroxy, Z3 represents an optionally protected residue R, and Z4 represents a protected amino, converts the protected amino Z4 and an optionally protected amino acid into amino and, if present, the protected hydroxin Z1, Z2 and / or as part of the residual Z3 present protected hydroxy to hydroxy and, as present, releases the protected azacycloalkyl residue Z3 of 5-7 members and, if desired, converts the obtained compound into another compound of formula I, dividing it according to the procedure. the obtained isomer mixture to compone and isolates the most advantageous isomer and / or converts the free compound obtained by the process into a salt or the salt obtained by the process into a corresponding free compound. 2. A process according to claim 1 for the preparation of compounds of formula I and salts thereof, wherein R is hydroxy-C 1 -C 7 alkyl, C 1 -C 2 alkoxy-C 1 -C 6 alkyl, benzoyloxy. C 1 -C 4 alkyl, amino-C 1 -C 3 alkyl, N-C 1 -C 3 alkanoyl-N-C 1 -C 4 alkyl-amino-C 1 -C 3 alkyl, azacycloalk-3-yl or resp. -4-yl with 5-7 members or 1- C2-C7 alkanoyl-azacycloalk-3-. wool or resp. -4-yl, halo-C1-C4-alkyl, wherein halogen represents chlorine or fluoro, amino-C4-C7-alkyl, N-C1-C6 -alkanoyl-N-C1-C6alkyl-amino-C3 -C 1-4 alkyl, piperidin-4-yl or 1- C2-C7 alkanoylpiperidin-4-yl and R 2 represents carboxy or C 1 -C 4 alkoxycarbonyl. A process according to claim 1 for the preparation of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or its salt. A process according to claim 1 for the preparation of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or its salt. 5. A process according to claim 1 for the preparation of 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester or its salt. A process according to claim 1 for the preparation of 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid or its salt. « A process according to claim 1 for the preparation of 2-amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester or its salt. 8. A process according to claim 1 for the preparation of; 2-amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid or its salt. A process according to claim 1 for the preparation of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid, 2-amino-6-metho-xi-4-phosphonomethyl-hex-3- 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester, 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid, 2,1-dianiino-4 phosphonomethyl-dec-3-enoic acid ethyl ester, 2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester, 2-axino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid, 2-amino-6- (N-methylamino) -4-phosphonomethyl-hex-3-enoic acid, 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid, 2-amino-8-hydroxy-4-phosphonomethyl-oct. 3-enoic acid ethyl ester, 2-amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester or 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester or its salts.