CA1331625C

CA1331625C - Unsaturated amino acids

Info

Publication number: CA1331625C
Application number: CA000529448A
Authority: CA
Inventors: John Grey Dingwall; Derek Edward Brundish; Graham Eric Fagg; Christof Angst
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1986-02-13
Filing date: 1987-02-11
Publication date: 1994-08-23
Anticipated expiration: 2011-08-23
Also published as: NO170938B; HU204532B; KR870007942A; DK169341B1; PH23762A; JPH07206683A; JPH0717665B2; IE59417B1; EP0233154B1; FI870558A; FI870558A0; KR900003533B1; DK70787D0; PT84270B; HUT43863A; HK95594A; NO870577L; NO170938C; NZ219255A; EP0233154A2

Abstract

Unsaturated amino acids Abstract The invention relates to unsaturated amino acids of the formula I

Description

.
- l - 21489-7094 E-2-Amino-S-phosphono-3-alkenolc acid derivatives, their pre-paratlon and pharmaceutical_compositions containin~ them _ _ The invention relates to novel E-2-amino-5-phosphono-3-alkenoic acid derivatives, to processes ~or the manufacture of these novel substances and to pharmaceutical compositions containing these substances.
The E-2-amino-$-phosphono-3-alkenoic acid derivatives according to the invention are compounds of the formula I

~.~
R4 RS .

Rl P_ A -- ~ R7 R6 (I) l2 R3 in which Rl represents hydroxy or lower alkoxy, R represents hydrogen, Cl-Cl2alkyl, hydroxy or lower alkoxy, R represents hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxyalkyl, phenyl-lower alkyl, phenyl-lower alkyl substituted by one, two or three substituents selected from -~:
lower alkyl, hydroxy,j,lower alkoxy, halogen, amino, halo~
lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and ~
nitro, lower alkenyl, halogen, phenyl or phenyl substituted : : :
by one, two or three substituents selected from lower alkyl, ;
hydroxy, lower alkoXy, halogen, amino, halo-lower alkyl, : -~
hydroxy-lower alkyl, amino-lower alkyl and nitro, R4 re-presents hydrogen, Cl-012alkyl, phenyl or phenyl substituted by one, two or three substituents selected from lower alkyl, ~. .
hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, ~ ;
D ~-~ 33 1 6~5 hydroxy-lower alkyl, amino-lower alkyl and nitro, RS re-presents hydrogen or C1-C12alkyl, R6 represents carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, phenyl-lower al~oxycarbonyl substituted by one, two or three sub-stituents selected from lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro, carbamoyl or N-mono- orN,N-di-lower alkylcarbamoyl, R7 represents amino or amino substituted by lower alkyl, lower alkanoyl or benzoyl and A
represents a methylene, ethylene or l,3-propylidene group which is unsubstituted or C1-C12alkyl-substituted or a salt thereof.
The compounds of the formula I contain at least one chiral centre and may be in the form cf enantiomers or enantiomeric mixtures, such as racemates, and if they contain more than one chiral centre, they may also be in the form of diastereoisomers or diastereoisomeric mixtures.
The carbon-carbon double bond of the compounds according to the invention is in the trans-configuration `
in relation to R3 and R4, or in relation to A and B, that is to say the compounds of the formula I are compounds of the E-series.
Compounds of the formula I in which R2 represents hydrogen are phosphonous acids, those in which R2 represents al:kyl are /phdsphinic acids, and those in which R2 represents hydroxy are phosphonic acids. In the names of the compounds of the formula I that are to be regarded as substituted carboxylic acids the D

' 21489-7094 prefixes "phosphino" (R2 represents hydrogen), "phosphonyl" (R2 represents alkyl) and "phosphono"
2 represents hydroxy) are used.
Within t~e scope of this invention, alkyl represents a saturated aliphatic hydrocarbon radical having, for example, up to 12 carbon atoms, but especially having, for example, up to 8 carbon atoms, the latter range also being represented by the term lower alkyl.

Methylene, 1,2-ethylene or 1,3-propylene substituted by alkyl is substituted at any position.
Thus, methylene substituted by alkyl is, for example, 1,1-ethylene, 1,1-butylene or 1,1-octylene, 1,2-ethylene substituted by alkyl is, for example, 1,2-propylene, 1,2-butylene, 2,3-butylene, 1,2-pentylene or 1,2-nonylene, and t,3-propylene substituted by alkyl is, for example, 1,3-butylene, 1,3-pentylene or 1,3-decylene.
Salts of compounds according to the invention are especially pharmaceutically acceptable non-toxic salts '~-of compounds of the formula I. Such salts are formed, for example, from the carboxy group present in compounds of the formula I, and are especially metal or ammonium ~ ' salts, such as alkali metal and alk21ine earth metal salts, for example sodium, potassium, magnesium or calcium salts, and alsolammonium salts with ammonia or suitable organic amines, such as lower alkyl2mines, for example methylamine, diethylamine or triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethyl-amine, bis-~2-hydroxyethyl)-amine, tris-(hydroxymethyl)-methylamine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2-diethylaminoethyl ester, lower D

alkyleneamines, for example l-ethylpiperidine, lower alkylenediamines, for example ethylenediamine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzylethylenediamine, benzyltrimethylammonium hydroxide, dibenzyl~mine or N-benzyl-~-phenylethylamine. Compounds of the form~la I
having a primary or secondary amino group may also form acid addition salts, for example with preferably pharmaceutically acceptable inorganic acids, such as hydrohalic acids, for example hydrochloric ~cid or hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, .
citric acid, pyruvic acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, pamoa acid, nicotinic acid, methanesulphonic acid, ethanesulphonic acid, hydroxy-ethanesulphonic acid, benzenesulphonic acid, 4-toluene-sulphonic acid or naphthalenesulphonic acid.
It is possible to use also pharmaceutically unsuitable salts for isolation or purification. Only the pharmaceutically acceptable non-toxic salts are used therapeutically, and these are therefore preferred.
Phenyl, also ln definitions such as benzoyl or phenyl-lower alkoxycarbonyl, may be unsubstituted or substituted by lower alkyl,. hydroxy, lower alkoxy, halogen, amino,.halo-lower alkyl hydroxy-lower alkyl, amino-lower alkyl or by nitro, and is, for example phenyl, lower alkylphenyl, for example methyl-phenyl, hydroxyphenyl, halophenyl, for example 4-halophenyl, such as 4-chlorophenyl, benzyloxyphenyl, lower alkoxyphenyl, for example.methoxyphenyl, hydroxymethylphenyl, aminomethyl-phenyl or nitrophenyl.

.LJ' .. . . . ... . .. ., ., .. , . " .. ~ .. .. . . .. . ... .

133~625 naphthyl, but preferably unsubstituted or correspond-ingly substituted phenyl, such as phenyl, lower alkylphenyl, for example methylphenyl, hydroxyphenyl, halophenyl, for example 4-halophenyl, such as 4-chloro-phenyl, benzyloxyphenyl, lower alkoxyphenyl, for example methoxyphenyl, hydroxymethylphenyl, amino-methylphenyl or nitrophenyl.
The general terms used hereinbefore and herein-after, unless defined otherwise, have the followings meanings:
The term "lower" inàicates that correspondingly defined groups or compounds contain up to and including 8, preferably up to and including 4, carbon atoms.
Alkyl represents, for example, lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, and also n-pentyl, n-hexyl, n-heptyl or n-octyl, preferably methyl, but may also represent, for example, nonyl, decyl, undecyl or dodecyl.
Phenylalkyl represents, for example, phenyl-lower alkyl in which aryl has the meanings given hereinbefore, and is especially, for example, unsubstituted phenyl-lower alkyl, such as benzyl or l- or 2-phenylethy~
Lower alkenyl contains preferably up to 6 carbon atoms and is bonded by way of an sp3-hybridised ~-carbon atom, and may be, for example, 2-propenyl, 2- or 3-butenyl or 3-pentenyl,~but may also be vinyl.
Lower alkoxy represents especially methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy.
~ alogen preferably has an atomic number of up to 35 and is especially chlorine, also fluorine or bromine, but may also be iodine.

. ~ .- - .

~ alo-lower alkyl is, for example, halomethyl, such as fluoromethyl, trifluoromethyl or 1- or 2-chloroethyl.
~ ydroxy-lower alkyl is, for example, mono- or di-hydroxy-lower alkyl, carries the hydroxy group(s), for example, especially in a position higher than the ~-position and represents, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxy- or 2,3-dihydroxy-propyl, 4-hydroxy- or 2,4-dihydroxy-butyl, or S-hydroxy-, 2,5-dihydroxy- or 3,5-dihydroxy-pentyl.
Lower alkoxy-lower alkyl is, for example, mono- or di-lower alkoxy-lower alkyl, carries the lower alkoxy group(s), for example, especially in a position higher than the ~-position and is, for example, 2-methoxy~, 2-ethoxy-, 2-propoxy- or 2-isopropoxy-ethyl, 3-methoxy-or 3-ethoxy-propyl or 3,3-dimethoxy-, 3,3-diethoxy, 2,3-dimethoxy- or 2,3-diethoxy-propyl or 4,4-dimethoxy-butyl, and also methoxy-, ethoxy-, dimethoxy-, or propoxy- or isopropoxy-methyl.
Amino-lower alkyl is, for example, aminomethyl or 1- or 2-aminoethyl.
Lower alkanoyloxy is, for example, acetoxy, propionyloxy or butyryloxy, or also formyloxy or pivaloyloxy.
Lower alkoxycarbonyl is, for example, methoxy-carbonyl or ethoxycarbonyl.
Phenyl-lower alkoxycarbonyl is preferably benzyloxycar-bonyl or l- orj2-phenylethoxycarbonyl.
Mono- or di-lower alkylamino is, for example methylamino, dimethylamino, ethylamino, propylamino, isopropylamino or butylamino.

.

r.

The compounds of the present invention have valuable pharmacological properties. For example, they are active and selective antagonists of N-methyl-D-aspartic acid (NMDA)-sensitive excitatory amino acid receptors in mammals. They are therefore suitable for the treatment of diseases that respond to a blocking of NMDA-sensitive receptors, such as, for example, cerebral ischaemia, muscular spasms (spasticity), convulsions (epilepsy), conditions of anxiety or manic conditions.
These advantageous effects may be demonstrated in in vitro or in in vivo test arrangements. For these, preferably mammals are used, for example mice, rats or monkeys, or tissue or enzyme preparations of such mammals. The compounds may be administered enterally or parenterally, preferably orally; or subcutaneously, intravenously or intraperitoneally, for example in gelatin capsules or in the form of aqueous suspensions or solutions. The dosage to be used in vivo may range from 0.1 to 600 mg/kg, preferably from 1 to ~;
300 mg/kg. In vitro, the compounds may be used in the form of aqueous solutions, the concentrations ranging from 10-4 to 10-8 molar solutions.
The inhibiting action on the NMDA-sensitive excitatory amino acid receptors may be determined in vitro by measuring, in accordance with G. Fagg and A.
Matus, Proc. Nat. Acad'. ~ici., USA, 81, 6876-80 (1984), to what-extent the bonding of L-3~-glutamic acid to NMDA-sensitive receptors is inhibited. In vivo, the inhibiting action on NMDA-sensitive excitatory amino acid receptors may be demonstrated by the inhibition in mice of NMDA-induced convulsions. -The anti-convulsive properties of the compounds according to the invention may furthermore be shown by their effectiveness in preventing audiogenically induced ~ 9 ' :`.
`::

^ 21489-7094 attacks in DBA/2 mice (Chapman et al., Arzneimittel-Forsch. 34, 1261, 1984).
The anti-convulsive properties may furthermore be shown by the effectiveness of the compounds according to the invention as electric shock antagonists in mice or in rats.
An indication of the anxiolytic activity of the compounds of the present invention is given by their pronounced effectiveness in the conflict model according to Cook/Davidson (Psychopharmacologia 15, 159-168 (1968)).
The pronounced effectiveness of the compounds of the formula I depends to a surprisingly high extent on the configuration at the double bond. For example, the racemate of D-2-amino-S-phosphono-3-cis-pentenoic acid known from Agric, Biol. Chem. 41, 573-579 (1979?, ~.K..Park et al., proves, for example in its ability to bond to the NMDA-sensitive receptor, to be far inferior to the racemate of the.2-amino-5-phosphono-3-trans-pentenoic acid according to the invention (in the Examples these compounds are referred to as compound of the "E-series").
Preferred are compounds of the formula I in which R represents hydrogen, alkyl or aryl.
Also preferred are the compounds of the formula I
in which Rl represents hydroxy or :lower alkoxy, R2!
represents hydrogen, Cl-C12alkyl, lower alkoxy or hydroxy, R represents hydrogen, Iower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl that is unsubstituted or substituted in the phenyl moiety.as indicated hereinbefore, lower alkenyl, halogen, phenyl or phenyl substituted as indicated hereinbefore, 4 - . ..
R represents hydrogen, lower alkyl, phenyl or phenyl sub-D

~33~5 _ g stituted as indicated hereinbefore, R5 represents hydrogen or lower alkyl, R represents carboxy or alkoxycarbonyl, R7 represents amino, mono-lower alkylamino, lower alkanoylamino or benzoylamino, A represents unsubstituted or lower alkyl-substituted a,~- alkylene having from l to 3 carbon atoms, or represents a bond, and B represents methylene or a bond, with the proviso that A is other than a bond when B
represents a bond, wherein the substituents of phenyl are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy- :
lower alkyl, amino-lower alkyl and nitro, and pharma-ceutically acceptable salts thereof.
Likewise preferred are compounds of the formula I
in whi~h R , R , R to R and A and B are as defined immediately above and in which R and R , independently of one another, each represents hydrogen, lower alkyl, phenyl, or phenyl substituted by lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl or by nitro, and pharmaceutically acceptable salts thereof. ~-Especially preferred are compounds of the formula I
in which Rl represents hydroxy or lower alkoxy, R
represents hydrogen, alkyl, hydroxy or lower alkoxy, R represents hydrogen, lower alkyl, phenyl or phenyl-lower alkyl, R4,and R5.represent!hydrogen or . .~
lower alkyl, R6 represents carboxy or alkoxycarbonyl, i -R represents amino, mono-lower alkylamino, lower alkanoyl- ~ ~ -amino or benzoylamino, A represents a methylene, ethylene or 1,3-propylidene group which is unsubstituted or lower alkyl-substituted and B represents a bond, and pharma-ceutically acceptable salts thereof.

.
:
D

Especially preferred are compounds of the formula I
ln which Rl is hydroxy, R2 represents hydrogen, Cl-Cl2-alkyl or hydroxy, R represents hydrogen or lower alkyl, R4 represents hydrogen or halophenyl and R5 represents hydrogen, R represents carboxy or lower alkoxycarbonyl, R represents amino, mono-lower alkylamino, lower alkanoylamino or benzoylamino, A represents methylene, ethylene or 1,3-propylene and B represents a bond, and pharmaceutically acceptable salts thereof. :~
Most especially preferred are compounds of the formula I in which Rl is hydroxy, R represents hydrogen, lower alkyl or hydroxy, R3 represents hydrogen or lower alkyl, R and RS represent hydrogen, R represents carboxy or.lower alkoxycarbonyl, R
represents amino or mono-lower alkylamino, A represents methylene, ethylene or L,3-propylene and B represents a bond, and pharmaceutically acceptable salts thereof.
Outstanding are the compounds of the formula I in which Rl and R2 represent hydroxy, R3 represents ; I ~

D

133t625 hydrogen or lower alkyl, R4 and RS represent hydrogen, R6 represents carboxy, R7 represents amino, A
represents methylene and 8 represents a bond, and the carboxylic acid lower alkyl esters and pharmaceutically acceptable salts thereof, especially the R-enantiomers thereof with reference to the atom carrying the amino group.
The compounds of the present invention may be manufactured in a manner known per se, for example as follows^
: - .
aj a compound of the formula II

. R4 R5 ! C _z6 (II) X- A -. ~ z7 in which R3, R4, R5 and A are as defined for formula I, z6 has the meaning of R6 or represents protected carboxy, Z7 has the meaning of R7 or represents ~ :
protected amino and X represents reactive esterified ~ .:
hydroxy, is reacted with a compound of the formula III

OR
2 (III) ' I ' ' ' .
in which z1 has the meaning of R1 or represents protected hydroxy, z2 has the meaning of R2 or represents protected hydrogen or protected hydroxy, and R represents an etherifying group, or : .

~ D :

.

b) in order to obtain a compound of the formula I in which RS represents hydrogen, in a compound of the formula IV

! I - z6 Z~ A - ~ Z7 (IV) l2 R3 in which R30 R4 and A are as defined for formula I, zl has the meaning of R1 or represents protected hydroxy, z2 has the meaning of R2 or represents protected hydroxy or protected hydrogen, z6 has the meaning of R6 or represents protected carboxy, Z7 has thei meaning of R7 or represents protected amino, and Y represents an optionally esterified carboxy group that can be replaced by hydrogen, the group Y is replaced by hydrogen, or and any protected functional groups that may be present in a compound resulting from one of the preceding g ..... . . .

133l625 21~89-7094 processes is freed and, if required, a resulting compound of the formulaI, wherein R7 represents amino, is N-lower alkylated or N-substituted by lowe~ alkanoyl or benzoyl, and if required, a resulting compound of the formulaI, wherein R6 denotes esterified corboxy as specified hereinbefore, is converted into the corresponding acid, wherein R6 denotes carboxy, and if required, a resulting compound of the formulaI, wherein R6 denotes carboxy, is esterified or amidated so as to produce a compound of the formulaI,whrein R6 denotes esterified or amidated carboxy asspecified ~ :
hereinbefore, and if an optical isomer isrequired, a resulting mixture of stereoisomers is separatedinto its components and the required optical isomer isisolated, and if a salt is required, a resulting freecompound is converted into a salt, or if a free compound isrequired, a resulting salt is converted into thecorresponding free compound.
In the above-defined processes, protected hydroxy and protected amino have, for example, the meanings for protected hydroxy and for acyl-substituted amino given -hereinbefore; here, protected hydroxy represents :
especially lower alkoxy and a protected amino represents especially lower alkanoylamino. Another preferred example of protected hydroxy is trisubstitute~ silyl, .
such 2S tri-lower alkiylsilyl,~ for example trimethyl-silyl or tert.-butyldimethylsilyl.
- : Furthermore, protected amino may also be amino substituted by substituted lower alkoxycarbonyl, such as amino substituted by 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloro- :

.
D

ethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxy-carbonyl, or by 2-(tris-substituted silyl)-ethoxy-carbonyl, such as 2-tri-lower alkylsilylethoxyczrbonyl, or example 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycar~onyl, or by 2-triaryl-silylethoxycarbonyl, such as 2-triphenylsilylethoxy-carbonyl, or etherified mercaptoamino or silylamino, or may be in the form of an enamino, nitro or azido group.
~ n etherified mercaptoamino group is especially a phenylthioamino group optionally substituted by lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or bromine, and/or by nitro, or a pyridylthioamino group. Corres-ponding groups are, for exam?le, 2- or ~-nitrophenyl-thioamino or 2-pyridylthioamino.
A silylamino group is especially an organic silyl-amino group. In such groups the silicon atom contains as substituent(s) preferably lower alkyl, for example methyl, ethyl, n-butyl or tert.-butyl, also aryl, for example phenyl. Suitable silyl groups are especially tri-lower alkylsilyl, especially trimethylsilyl or d~methyl-tert.-butylsilyl.
Enamino groups contain at the double bond in the 2-position an electron-attracting substituent, for example a carbonyl group. Protecting groups of this kind are, for example, 1-acyl-lower alk-1-en-2-yl - --radicals in which acyljis, flor example, the correspond-ing radical of a lower alkanecarboxylic acid, for example acetic acid, of a benzoic acid optionally substituted, for example, by lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or especially of a carbonic acid semlester, s~ch as a carbonic acid lower alkyl semiester, for example methyl semiester or ethyl semiester, and lower alk-1-ene is especially 1-propene.

Corresponding protecting groups are especially l-lower alkanoyl-prop-1-en-2-yl, ~or example 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, for example 1-ethoxycarbonyl-prop-1-en-2-yl~
Protected carboxy is customarily protected in esterified form, it being possible for the ester gro~p to be removed under reductive, such as hydrogenolytic, or solvolytic, such as acidolytic or hydrolytic, such as aciZ-hydrolytic, basic-hydrolytic or neutral-hydrolytic, conditions. A protected carboxy group may furthermore be an esterified carboxy group that can be cleaved under physiological conditions or that can readily be converted into a different functionally modified carboxy group, such as into a different esterified carboxy group.
Such esterified carboxy groups contain as esterifying groups especially lower alkyl groups that are branched in the l-position or suitably substituted in the l- or 2-position. Preferred carboxy groups in esterified form are, inter alia, lower alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl, 2-propoxy-carbonyl or tert.-butoxycarbonyl, and (hetero)aryl-methoxycarbonyl having from 1 to 3 aryl radicals or having one monocyclic heteroaryl radical, these optionally being mono- or poly-substituted, for example, by lower alkyl, such as tert.-lower alkyl, for example tert.-butyl, halogen, for example chlorine, and/or by nitro. Examples of such groups are benzyl-oxycarbonyl that is optionally substituted, ~or example in the manner mentioned above, for example 4-nitro-benzyloxycarbonyl, diphenylmethoxycarbonyl that is optionally substituted, for example in the manner mentioned above, for example diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or picolyloxycarbonyl that is optionally substituted, for example in the manner D~

mentioned above, for example 4-picolyloxycarbonyl, or furfuryloxycarbonyl, such as 2-furfuryloxycarbonyl.
Protected hydro~en zl is protected in a manner known per._ , such as is described, for example, in EP-A-0 009 348~ Corresponding protecting groups are preferably groups of the formula -C(Cl_4-alkyl)~ORa)ORb, preferably groups of the formula -CH(ORa)ORb in which Ra and Rb each represents Cl_4-alkyl. Especially suitable is the group -CH(OC2H5)2.
A reactive esterified hydroxy group, such as X, is a hydroxy group esterified by a strong organic acid, for example a hydroxy group esterified by an aliphatic or aromatic sulphonic acid ~such as a lower 21kane-sulphonic acid, especially methanesulphonic acid, trifluoromethanesulphonic acid, especially benzene-sulphonic acid, -toluenesulphonic acid, p-bromo-benzenesulphonic acid and P-nitrobenzenesulphonic acid) or by a strong inorganic acid, such as, especially, sulphuric acid, or a hydrohalic acid, such as hydrochloric acid or, most preferably, hydriodic acid or hydrobromic acid.
In process a), the etherifying group R is, for example, phenyl-lower alkyl, trisubstituted silyl, such as tri-lower alkylsilyl or, preferably, alkyl. The reaction is carried out in a manner known per se, especially under the known conditions of the Michaelis-Arbuzov reaction.
According to one variant of this process the reaction, for ex2mple, of a trialkyl phosphite of the formula III, such as t{iethyl phosphite, especially with compounds of the.formula II in which A represents a bond, can be catalysed in a suitable manner, such as by a halid~e of a metal of sub-group VIII, preferably a nickel, pall2~ium or plctinum halide, especially nickel chloride.
D

133~625 In this process, if several of the groups zl, z2, 26 and Z7 represent protected groups, these are advantageously so selected that they can be freed in a single step. The conditions in question under which the protected groups can be freed are preferably hydrolytic conditions, such as those.of an acidic hydrolysis, for example with hydrohalic acids, such as hydrochloric acid, preferably with heating.
Working up is carried out in a manner known E~
se, especially two purification operations proving advantageous. Either the crude product can be converted into a readily volatile derivative, for example by silylation, and obtained as such by distillation, and can then be desilylated, or the crude product may have added to it an agent that reacts with excess acid, such as hydrohalic acid, and thus removes the acid. There come into consideration, for example, compounds to which a corresponding acid may be added, for example lower alkylene oxides (epoxides), such as pr.opylene oxide.
It is preferable to carry out this process with :
compounds of the formulae II and III in which R3, R4, R5, A and B are as defined for formula I, z1 represents protected hydroxy, z2 represents lower alkyl, protected hydrogen or protecteà hydroxy, R
represents lower alkyl, z6 represents protected carboxy, Z7 represents protected amino and X
represents reactive esterified hydroxy and, following the reaction in which the compo~nd RX becomes free, to free the protected groups. In this case preferably z1 represents lower alkoxy, z2 represents lower alkyl, di-lower alkoxy-lower alkyl or lower alkoxy, R
represents lower zlky~, z6 represents lower alkoxy-carbonyl, z7 represents formylamino and X represents halogen.
D
., .

The compounds o~ the formula I I may be manu-factured, for example, by reacting N-protected amïno-malonic acid esters in a manner known per se with compounds of the formula VII

! _ B -X' (VII) X- A _ .D
~3 in which X and X', independently of one another, each represents reactive esterified hydroxy. The resulting compounds II' may be converted into compounds of the ~ -formula II by being decarboxylated, for example in the manner described in process b).
The starting compoundc of the formula III are preferably trialkyl phosphites (Z1 = alkoxy, z2 =
alkoxy, R = alkyl) or alkylphosphonous acid dialkyl esters (Zl = alkoxy, z2 = alkyl, R = alkyl). They are known or can be manufactured in a manner anzlogous to known processes.
Compounds of the formula II in which A represents methylene optionally substituted by alkyl, B represents a bond, X represents halogen and Z7 represents formylamino may be manufactured, for example, by reacting an ~,B-unsaturatea aldehyde, for example acrolein or methacrolein, with an ~-isocyanoacetic acid derivative,;such as' for example, an ~-cyanoacetic acid lower alkyl ester. By suitable catalysis, such as with low-valency metal salts, for example metal oxides or metal halides, such as zinc chloride, cadmium chloride, silver oxide or, preferably, copper oxide, S-vinyl-2-oxazoline-4-carboxylic acid derivatives, for example esters, are thus obtained in a manner known per se and may be converted in.o the open-chained compounds of ~ -D

the formula IX

~ z6 D / R4 Z7 ~IX) in which D represents methylidene optionally substituted by alkyl. These compounds may in turn be converted by selective halogenation, such as bromination or chlorin-ation, preferably while cooling, and with displacement -of the double bond in the manner of an allylic rearrangement, into compounds of the formula II.
In process b), the group Y represents carboxy or esterified carboxy as defined hereinbefore, especially lower aikoxycarbonyl. Replacement of the group Y by hydrogen can be carried out, for example, under conditions under which first esterified carboxy is hydrolysed and then carboxy is replaced by hydrogen ~decarboxylation), such as under hydrolytic conditions, such as those of an acidic hydrolysis, for example with hydrohalic acid, such as with hydrochloric acid, preferably while hezting. In this process, if several z1 z2 z6 and Z7 represent protected groups, these may advantageously be so selected that they can be freed together in the step in which the hydrolysis and the decarboxylation is effected.
The replacement of the group Y by hydrogen can also be carried out without previous hydrolysis, as a dealkoxycarbonylation, for example according to A.P.
Krapcho, Tetrahedron Letters 957 (1973), such as by heating in an aqueous aprotic solvent, such as dimethyl sulphoxide, in the presence of an alkali halide, such as sodium chloride.
It is preferable to carry out this process with D

1 3 3 1 6 2 5 2l489-7094 compounds of the formula IV in which R3, R4, A and B
are as defined for formula I, z1 represents protected ~ydroxy, ~2 represents lower alkyl, protected hydrogen or protected hydroxy, z6 represents protected carboxy, Z7 represents protected amino and Y represents an optionally esterified carboxy group that can be replaced by hydrogen, and for the protected groups to be freed together in the step in which the group Y is replaced by hydrogen. In this case preferably z1 represents lower alkoxy, z2 represents lower alkyl, di-lower alkoxy-lower alkyl or lower alkoxy, z6 and Y
represent lower alkoxycarbonyl and Z7 represents lower alkanoylamino.
The compounds of the formula IV may be manufactured, for example, analogously to process a) by reacting a compound of the formula II' ! _ B _ C _z6 (II') X _ A- . ~ z7 with a compouna of the formula III

OR
Z1-P (III) 2~
:, in which all radicals have the meanings given herein-before. The compounds of the formula II' may in turn be manufactured from a compound of the formula VII and an N-protected aminomalonic acid ester, as described in process a~.
D

~ ~ 3 1 6 ~ ~ 21489-7094 ~ .

To convert a resulting compound of the formula I
into a different compound of the formula I conversions such as the following may be carried out:
An amino group may be alkylated, and/or free carboxy may be freed from its esterified form by hydrol~cis or hydrogenolysis and/or an amino group may be acylated and/or free carboxy may be esterified or amidated and/or hydroxy bonded to phosphorus may be esterified.
To convert an amino group into an alkylamino group the amino group may be alkylated by substitution, for example with a reactive esterified alkanol, such as an alkyl halide, or by reduction, such as with an aldehyde or ketone, and also catalytically activated hydrogen or, in the case of formaldehyde, advantageously with formic acid as reducing agent.
Free carboxylic acids of the formula I or salts thereof may be converte~ according to known processes into the corresponding esters by suitable alcohols or :
corresponding derivatives thereof, that is to say, into compounds of the formula I that are, for example, in the form of lower alkyl, aryl-lower alkyl, lower alkanoyloxymethyl, or lower alkoxycarbonyl-lower alkyl esters.
For the esterification, a c2rboxylic acid may be reacted directly with a diazoalkane, especially diazomethane, or with a corresponding alcohol in the presence of a strongly acidic catalyst (for example a hydrohalic acid, sulphuric acid or an organic sulphonic acid~ and/or of a dehydrating agent (for example dicyclohexyl carbodiimide) Alternatively, the carboxylic acid may be converted into a reactive derivative, such as into a reactive ester, or into a mixed anhydride, for example with an acid halide (for example, especially an acid chloride), and this activated intermediate is reacted with the desired alcohol. Esterific2tion of hydroxy bonded to phosphorus may be carried out in the manner described hereinbefore or in another manner that is known per se.
Compounds of the formula I in which R7 represents amino may be converted into compounds in which R7 represents acylamino, for example using a corresponding acid anhydride or halide, or vice versa, by processes ~ .
belonging to the State of the Art and described herein in connection with protecting groups.
The above reactions are carried out according to ;-standard methods in the presence or absence of diluents, preferably those that are inert towards the reagents and are solvents therefor, in the presence of catalysts, condensation aaents and the other agents and/or in inert atmosphere, at low temperature, room temperature or elevated temperature, prefer2bly at the boiling point of the solvents used, 2t atmos~heric or superatmospheric pressure.
The invention includes furthermore those variants of the present process in which an intermeciate obtainable at any sta~e of that process is used as starting material and the remaining steps are carrieà

` D

133~625 out, or the process is interrupted at any stage, or in which the starting materials are formed under the reaction conditions or in which the reactants are used in the form of their salts or optically p~re antipodes.
There should especially be used in these reactions those starting ma'erials that result in the formation of the compounds mentioned hereinbefore as being especially valuable.
The invention relates also to novel starting materials and processes for their manufacture.
Depending on the choice of starting materials and methods, the novel compounds may be in the form of one of the possible optical isomers or mixtures thereof, for example depending on the number of asymmetric carbon atoms they may be in the form of pure optical isomers, such as antipodes, or mixtures of Opticâl isomers, such as racemates, or mixtures of diastereo-isomers from which one antipode, if desired, may be isolated.
Resulting mixtures of dizstereoisomers and mixtures of racemates may be separated in known manner on the basis of the physico-chemical differences between the constituents into the pure isomers, diastereoisomers or racemates, for example by chroma-tography and/or fractional crystallisation.
The resulting racemates (racemic diastereoisomers) may furthermore be sepa~ated into the optical antipo~es according to methods known per se, for example by recrystallisation from an optically active solvent, with the aid of microorganisms or by reaction of an acidic end product with an optically active base that forms salts with the racemic acid, and separation of the salts obtained in this manner, for example on the basis of their different solu~ilities, into the diastereoisomers, from which the antipodes can be freed D
.

by the action of suitable agents. Basic racemic products can also be separated into the antipodes, for example by separation of the diastereoisomeric salts thereof, for example by fractional crystallisation of the d- or l-tartrates thereof. Any racemic intermediate or starting material can be separated in a similar manner.
Finally, the compounds according to the invention are obtained either in free form or in the form of their salts. Any resulting base can be converted into a corresponding acid addition salt, pre'erably using a pharmaceutically tolerable acid or an anion-exchange preparation, or resulting salts can be converted into the correspondins free bases, for example using a stronger base, such as a metal or ammonium hydroxide or a basic salt, for example an alkali metal hydroxide or carbonate, or a cation-exchange preparation. A
compound of the formula I can also be converted into the corresponding metal sr ammonium salts. These or ot~er salts, for example the picrates, can also be used for the purification of the resulting bases. The bases ar~e converted into the salts, the salts are separated and the bases are freed from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is mentioned in this Application, a corres-ponding salt of that compound is also included,,iprovided that this is possible or appropriate under the given conditions.
The compounds, including their salts, can also be obtained in the form of their hydrates or contain other solvents used for the crystallisation.
The pharmaceutical preparations according to the invention are those that are suitable for enteral, such as oral or rectal, and parenteral administration to D :

t33t625 mammals, including man, for the treatment or prevention of diseases that respond to the blocking of NMDA-recept:ors, such as, for example, cerebral ischaemia, musc~lar spasms (spasticity), convu~sions (epilepsy), conditions of anxiety or manic conditions. They comprise an effective amount of a pharmacologically active compound of the formula I or a pharmaceutically acceptable salt thereof, on its own or in combination .
with one or more pharmaceutically acceptable carriers.
The pharmacologically active compounds of the invention can be used in the manufacture of pharma-ceutical compositions that comprise an effective amount of the same on i.s own or in conjunction or admixtrue with excipients or carriers that are suitable for enteral or parenteral administration. Preferred are tablets and gelatin capsules that comprise the active constituent together with a) diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, b) glidants, for example silica, talc, stearic acid, the magnesium or calcium salt thereof and/or polyethylene glycol, for tablets also c) binders, for example magnesium aluminium silicate, starch paste, gelatin, tragacanth, methyl-cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired d) dispersing or disintegrating agents, for example starches, agar, .
alginic acidior the soàium salt thereof, or foaming mixtures and/or e) absorbents, colouring agents, flavourings and sweeteners. Injectable preparations are preferably aqueous isotonic solutions or suspen-sions, and suppositories are advantageously produced from fatty emulsions or suspensions. These compositions may be sterilised and/or contain adjuvants, such as preservatives, stabilisers, wetting agents or emulsi-fiers, solubilisers, salts for regul2ting the osmotic D

.. . . . . .

t 33 1 625 pressure and/or buffers. In addition they may also contain other therapeutically valuable substances.
These preparations are manufactured according to conventional mixins, granulating or coating methods and contain approximately from O.l to 100 %, preferably approximately fro~ 1 to 50 ~, of the active constituent.
A unit dose for a mammal weighing approximately from 50 to 70 kg may contain between approximately l and 500 mg, preferably between approximately 10 and 500 mg, of active constituent.
The following Examples are intended to illustrate the invention and do not represent limitations. The temperatures are in degrees Celsius and all parts are suoted in the form of parts by weight. ~nless mentioned otherwise, all evaporation is carried out under reduced pressure, preferably between approximately 2 and 13 Kilopascal (kPa).

:

D

Example 1:
8.22 g of E-2-formylamino-5-diethylphosphono-3-pentenoic acid ethyl ester are dissolved in 170 ml of 6N hydrochloric acid and the whole is heated under reflux for 22 hours. After concentration in vacuo, the oily residue is taken up in a small amount of ethanol and the mixture is again concentrated by evapo~ation in vacuo. This procedure is repeated a further twice. The resulting residue is dissolved in 15 ml of ethanol and 20 ml of ethanol/propylene oxide (1:l) are added dropwise. The resulting brownish-coloured precipitate is filtered off and purified by ion exchange chromatography (Dowex SOW x 8/H2O).
After concentration and lyophilisation, E-2-amino-5-phosphono-3-pentenoic acid is obtained in the form of a white amorphous powder, 1H-NMR (D2O~: 2.39 (dd, 2H, C(S)-H); 4.27 (d, 1H, C(2)-H~; 5.53 (m, lH, C(3)-H);

5.87 (m, lH, C(4)-H), m.p. after recrystallisation from ethanol/water 19l-192.
The starting material is manufactured as follows:
1.6 g of red copper(I) oxide are added to 200 ml of benzene. With intensive stirring, a solution of 140 g of isocyanoacetic acid ethyl ester and 84 g of freshly distilled acrolein in 200 ml of benzene are added dropwise to this suspension within a period of 10 minutes. During the course of this addition the reaction temperature is maintained between 30 and 32 by cooling with ice. When the addition is complete the mixture is maintained at 30-32 until the exothermic reaction has subsided, and then the whole is stirred for 1 hour at room temperature. ~fter excess copper(I) oxide has been removed by filtration, the filtrate is concentrated by evaporatiOn in vacuo at 30.

D

- 28 ~

600 ml of ether are added to the residue, and the whole is ~iltered over celite and concentrated to dryness by evaporation in vacuo. In this manner 5-vinyl-2-oxa-zoline-4-carboxylic acid ethyl ester is obtained in the form of a pale yellow oil, b.p. 100-110 t5.3 Pa).
128 g of the 5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester are dissolved in 70 ml of tetrahydrofuran, and 27.4 g of water and 3.5 g of triethylamine are added. The reaction mixture is stirred for 62 hours at 65-70 and, having been cooled, is taken up in 200 ml of dichloromethane. The solution is dried over 200 g of magnesium sulphate, filtered and concentrated by evaporation in vacuo. Purification by column chromatography (silica gel;hexane/ethyl acetate 3:2) of the viscous oil that remains yields 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in the form of a diastereoisomeric mixture, m.p. 50-51.
2.0 g of 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in 80 ml of dry tetrahydrofuran are cooled to ~78. 2.5 ml of thionyl bromide are slowly added ;
dropwise thereto in such a manner that the reaction temperature does not exceed -75. When the addition is complete, the reaction solution is warmed within a period of approximately 3 hours to 0 and is stirred at that temperature for 2.5 hours. The orange-yellow solution is then poured onto 300 ml of a cold (5-10) saturated aqueous sodium hydrogen carbonate $olution ~ -and extracted with dichloromethane. The organic extracts are dried over magnesium sulphate and concentrated by evaporation in vacuo at room temperature. The oil that remains is dissolved in 20 m~ of triethyl phosphite and heated for 2 hours in ~-vacuo ~10 kPa) under reflux (S5). Excess triethyl phosphite is then distilled off under a high vacuum.
Purification by column chromatography (silica gel, ` D
.

-- 2q ethyl acetate/hexane (2:1), then ethyl acetate) yields E-2-formylamino-5-diethylphosphono-3-pentenoic acid ethyl ester in the form of a pale yellow oil~ IH-NMR-(CDC:13): 2.62 (m~ 2H, C(S)-H); S.l9 (m, lH, C(2)-H);
5.7S (m, 21~,Ct3)-H and C(4)-H).

Example 2:
.
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid is obtained by hydrolysis of E-2-formylamino-4-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester in a manner analogous to that described in Example 1, 7H-NMR (D2O): 1.73 (s, 3H, CH3); 4.55 (s, lH,C(2)-H)-The starting material is manufactured as follows:
By reaction of isocyanoacetic acid ethyl esterwith methacrolein in a manner analogous to that des-cribed in Example 1, and after subsequent fractional distillation, 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester is obtained in the form of a colour-less oil, b.p. 110-130 (5.3 Pa).
2-Formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester, m.p. 67, is obtained by hydrolysis of S-t2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 1.
By reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1, E-2-formylamino-4-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a pale yellow oil.

Example 3 By hydrolysis of E-2-formylamino-5-(O-ethyl-methylphosphonyl)-3-pentenoic acid ethyl ester in a D

manner analogous to that described in Example 1, af~er precipitation with propylene oxide E-2-amino-S-methyl-phosphonyl-3-pentenoic acid is obtained in the focm of an amorphous white powder, lH-NMR (D2O): 2.S5 (dd, 2H, C(5)-H); 4.38 (d, 1H, C(2)-H); 5.64 (m, lH, C~3)-H); 5.91 (m, 1H, C(4)-H).
The starting material is manufactured as follows:
By reaction of E-2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with methylphosphonous acid diethyl ester instead of triethyl phosphite in a manner analogous to that described in Example 1, E-2-formyl-amino-5-(O-ethyl-methylphosphonyl)-3-pentenoic acid ethyl ester is obtained in the form of a colourless oil, ~H-N~R (CDCl3): 2.63 (dd, 2~, C(5)-H); 5.1 (m, lH, C(2)-H); 5.75 (m, 2H, C(3)-H) and C(~)-H).

Example 4:
25 g of E-2-formylamino-5-0-ethyl-diethoxymethyl- ~ ~ -phosphonyl-3-pentenoic acid ethyl ester are stirred ~
under reflux for 16 hours with 500 ml of 6N hydro- ~ -chloric acid and the whole is then concentrated in vacuo at 70. The residue is suspended in lO0 ml of 95~ ethanol/water, 20 ml of propylene oxide are added and the product is filtered off. Recrystallisation from water yields E-2-amino-5-phosphino-3-pentenoic acid, m.p. 139-140. ! ' : :
The starting material is manufactured as follows:
10 g of 2-formylamino-3-hydroxy-4-pentenoic acid -ethyl ester in 50 ml of dry tetrahydrofuran are cooled to -78. 12.7 g of thionyl chloride are added drop-wise in such a manner that the reaction temperature does not exceed -75. Subsequently, the reaction solution is warmed to -20 within a period of 3 hours and stirred at that temperature for 3 hours. The D

1 3~1 6~5 21489-7094 yellow solution is then poured onto 300 ml of a cold (5~ saturated a~ueous sodium hydrogen carbonate solution and extracted with dichloromethane. The orgclnic extrac~s are dried over sodium sulphate and concentrated by evaporation in vacuo at 30. The residue is pre-purified by column chro~atography ~silica gel, ethyl acetate), and the light-yellow oil that remains is dissolved in 10 ml of tetrahydrofuran.
After the aadition of 17.0 g of diethoxymethylphos-phonous acid ethyl trimethylsilyl ester, the whole is stirred for 24 hours at 35. The dark-yellow solution is then poured onto 100 ml of a cold (5) saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo at 30. After purification of the residue by column chromatography (silica gel, ethyl acetate/methanol), E-2-~ormylamino-5-0-ethyl-diethoxy-methylphosphonyl-3-pentenoic acid ethyl ester is obtained in the form of a light-yellow oil, 1H-NMR
(CDCl3): 2.70 (m, 2H, C(5)-~); 4.68 ~q, 1H, C(2)-H);
5.20 (m, 1H, (C-P)-H); 5.80 (m, 2H, C(3)-H and C(4)-H).

Example 5:
a) l.0 g of E-2-amino-5-phosphino-3-pentenoic acid is suspended in 20 ml of ethanol and the suspension is saturated with hydrogen chloride gas for 2 hours at 65. After concentration, the residue is dissolved in 10 ml of ethanol, 10 ml of propylene oxide are added and the precipitate is filtere~ off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphino-3-pentenoic acid ethyl ester, m.p. ~72-173.

b~ 1.0 g of E-2-amino-s-phosphino-3-pentenoic acid - --is suspended in 20 ml of n-butanol and the suspension ` ~
D ~ ~-~ 331 625 is saturated with hydrogen chloride gas for 3 hours at 60~ After concentration, the residue is dissolved in 15 ml of n-butanol, 10 ml of propylene oxide are added and the precipitate is filtered off. Recrystal-lisation from water/acetone 1:1 yields E-2-amino-5-phosphino-3-pentenoic acid butyl ester, m.p. 160-161.

Example 6:
_ _ .
a) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are placed in 50 ml of ethanol and the whole is saturated with hydrogen chloride gas for 2 1/2 hours at 50. After concentration, the residue is dissolved in 18 ml of ethanol, 18 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/ethanol 1:3 yields 2-amino-5-phosphono-3-pentenoic acid ethyl ester, m.p. 167-168.

b) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 40 ml of n-butanol and the suspension is saturated with hydrogen chloride gas for 3 hours at 90. After concentration, the residue is dissolved in 30 ml of n-butanol, 15 ml of propylene oxiae are added and the precipitate is filtered off. Recrysta-llisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid butyl ester, m.p. 160-161.

c) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-octanol and the suspension is saturated with hydrogen chloride gas for 4 hours at 70. The mixture is concentrated in vacuo at 70 to half its volume, 50 ml of diethyl ether and 15 ml of propylene oxide are added and the whole is filtered.
Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid octyl ester, m.p.
161-162.
D

~ 33 1 625 21489-7094 d) 2.0 g of 2-amino-5-phosphono-3-pentenoic acid are suspended in 15 ml of l-dodecanol and 25 ml of tetra-hydrofuran and the suspension is saturated with hydrogen chloride gas for 4 hours at 50. The mixture is freed of tetrahydrofuran in vacuo at 50, 40 ml of acetone and 20 ml of propylene oxide are added and the whole is filtered. There is obtained from water/acetone 1:1, after stirring, E-2-amino-5-phosphono-3-pentenoic acid dodecyl ester, m.p. 158-e) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended i~ 30 ml of n-propanol and the suspension is saturated with hydrogen chloride gas for 2 1/2 hours at 50. After concentration, the residue is diss-olved in 15 ml of n-propanol, 15 ml of propylene oxide are added and the precipitate is filtered off. Recry-stallisation from water/acetone 1:3 yields E-2-amino-5-phosphono-3-pentenoic acid propyl ester, m.p. 161-162.

f) 1.5 g of 2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-pentanol and the suspension is saturated with hydrogen chloride gas for 3 hours at 50. After concentration, the residue is dissolved in 15 ml of n-pentanol, 15 ml of propylene oxide are added and the precipitate is filtered off. Recrysta-llisation from water/ace~tonei 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid pentyl ester, m.p. 160-161 -g) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid ~ -are suspended in 30 ml of isobutanol and the suspension is saturated with hydrogen chloride gas for 3 lj2 hours at 70. After concentratin, the residue is dissolved in 10 ml of isobutanol, 10 ml of propylene oxide are added and the precipitate is filtered off. Recrysta-D

, ` 1 33 1 625 21489-7094 llisation from water/acetone 1:1 yields E-2-aminO-S-phosphono-3-pentenoic acid isobutyl ester, m.p. 163-164.

h) l.S g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of sec.-butanol and the suspension is saturated with hydrogen chloride gas for 4 hours at 75. After concentration, the residue is dissolved in 10 ml of 2-butanol, 10 ml of propylene oxide are added and the precipitate is filtered off.
Recrystallisation from water/acetone 1:1 yields E-2- -amino-5-phosphono-3-pentenoic acid sec.-butyl ester, m.p. 169-170.

Example 7:
E-2-amino-4-methyl-S-phosphono-3-pentenoic acid is obtained by hydrolysis of E-2-formylamino-4-methyl-5-dimethyl-phosphono-~-pentenoic acid ethyl ester in a manner analogous to that described in Example 1. For H-~MR see Example 18. E-2-amino-4-methyl-5-methylDhosphono-3-pentenoic acid, m.p. 149-~50, is obtainea as a by-product in preliminary fractions.
The starting material is manufactured as follows:
By reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to th!at,described in Example 1, E-2 formylamino-4-methyl-S-dimethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a pale yellow oil.

' : 9 ~ 331 625 21489-7094 Example_8:
a) 2.0 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid are placed in 50 ml of ethanol and the whole is saturated with hydrogen chloride gas for 2 1/2 hours at S0. After concentration, the residue is dissolved in 20 ml of ethanol, 20 ml of propylene oxide are added and the precipitate is filtered off.
Recrystallisation from water/ethanol (1:3) yields E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl èster, m.p. 193-194.
The following esters are obtained in an analogous manner:

b~ E-2-amino-4-methyl-S-phosphono-3-pentenoic acid methyl ester, m.p. 193-194 [water/acetone ( 9 :. 1 ) ] ;

c) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-propyl ester, m.p. 184-185, (water), d) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-butyl ester, m.p. 186-187, [water/acetone (2:1~];
:
e) E-2-amino-4-methyl-5-phosphonO-3-pentenoiC acid isobutyl ester, m.p. 181-182, ~water/acetone (9:1)];
i f) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-pentyl ester, m.p 207-208;

g) E-2-amino-4-methyl-S-phosphOnO-3-pentenoic acid n-hexyl ester, m.p. 207-208.

.

D
` ; "`" ~ ~ ~ ~

^ 21489-7094 Example 9:
_ 21 g of E-2-formylamino-4.-methyl-5-O-ethyl-diethoxymethylphosphonyl-3-pentenoic acid ethyl ester are stirred for 16 hours at 80 with 400 ml of 4.35N
hydrochloric acid and the whole is subsequently concen~
~rated in vacuo at 45. The residue is dissolved in lO0 ml of ethanol and 30 ml of propylene oxide are added, and the product is filtered off. Recrystalli-sation from water yields E-2-amino-4-methyl-5-phos-phino-3-pentenoic acid, m.p. 176-177.
The starting material is manufactured as follows:
50 g of 2-formylamino-3-hydroxy-4-methyl-4-penten-oic acid ethyl ester.in 500 ml of dry tetrahydrofuran are cooled to -78. 89 9 of thionyl chloride are ~.
added dropwise thereto in such a manner that the reaction temperature does not exceed -70. Subse-quently, the reaction solution is warmed to -10 within a period of 3 hours and is stirred for 3 hours at that temperature and then concentrated under a high vacu~m at 20.
The residue is taken up in 400 ml of dichloro-methane and neutralised with saturated aqueous sodium hydrogen carbonate solution. The organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo at 30. The residue is pre-purified by column chromatography (silica gel, ethyl acetate) and the light-yellow oil that remains is dissolved in.30 ml of~ toluene. After.the addition of 94-g of diethoxymethylphosphonous acid ethyl trimethyl-silyl ester, the whole is stirred for 16 hours at 90. The dark-yellow solution is poured onto ice/-water, neutralised with sodium hydrogen carbonate and extracted with dichloromethane. The organic extracts are dried over sodium sulphate and concentrated by evaporation in vacuo at 30. Purification of the .

D

1 ~ 3 ~ 5 residue by column chromatography (silica gel, ethyl acetate, then ethyl acetate/methanol 9:1) yields E-2-formylamino-4-methyl-5-o-ethyl-diethoxymethylphos-phonyl-3-pentenoic acid ethyl ester in the form of a light-yellow oil, lH-N~1R (CDC13): 2.64 (dd, 2H, C(5)-H); 4.60 (d, 1H, P-CH); 5.26 (m, 2H, C(2)-H and c(3)-H)-ExamPle lO:
-Racemate separation of E-2-amino-4-methyl-S-phosphono-3-pentenoic acid.
A solution of 1.5 ml of phenylacetyl chloride in 25 ml of 1,4-dioxan is added at 20, within a period of 20 minutes, to 209 mg of E-2-amino-4-methyl-5-phos-phono-3-pentenoic acid in 21 ml of 2N sodium hydroxide solution while stirring vigorously, and the whole is stirred for 4 hours at room temperature. The reaction solution is poured onto 250 ml of water and repeatedly extracted with dichloromethane. The aqueous phase is concentrated to 20 ml in vacuo at 40, pre-purified by ion exchange chromatography (DOWEX 50 Wx8/water/1,4-dioxan 3:1) and concentrated in vacuo at 40. The resulting E-2-phenylacetylamino-4-methyl-5-phosphono-3-pentenoic acid is adjusted to pH 7.5 in 150 ml of water with 2N sodium hydroxide solution and stirred for 16 hours at 37 with 250 mg of EUPERGIT-ACYLASE. After filtering in vacuo at 40, the mixture is concen-trated to 10 ml and separated by ion exchange chroma-tography (DOWEX 50 Wx8/water) into (D)-E-2-phenyl-acetylamino-4-methyl-5-phosphono-3-pentenoic acid and into (L)-E-2-amino-4-methyl-S-phosphono-3-pentenoic acid.

D`

~ 331 625 ~ 21489-7094 - 3~ -a) The aqueous phases of (L~-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid are concentrated in vacuo and the residue is purified by recrystallisation from water, m.p. 196, ~]D0 = +97.1 + 1.9(c = 0.5;
water).

b) The aqueous phases of (D)~E-2-phenylacetylamino-4-methyl-5-phosphono-3-pentenoic acid are concentrated _ vacuo and the residue is stirred for 3.5 hours at 85 with 2S ml of 4.35N hydrochloric acid and then repeatedly extracted with dichloromethane. Concen-tration of the aqueous phases in vacuo and purifi-cation of the residue by ion exchange chromatography yield (D)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 194, [~]D0 = -96.7 + 1.2(c = 0.8;
water).

Example 11:
2.5 g of E-2-formylamino-5-O-ethyl-methylphos-phonyl-4-methyl-3-pentenoic acid ethyl ester are heated for 26 hours under nitrogen at 80 in 200 ml of 4.35N
hydrochloric acid. The whole is concentrated by evapo- ~-ration in vacuo and the residue is dissolved, in each case twice, in 200 ml each of water, tetrahydrofuran and ethanol, the solutions each time being concentrated by evaporation in vacuo.l Dissolving in 150 ml of ethanol, the addition of S ml of p~opylene oxide in ,~ :

D

100 ml of tetrahydrofuran/ethanol (1:1) at 0 within a period of 20 minutes, filtration of the precipitate and drying for 12 hours at 50 in vacuo yield crude E-2--amino-4-methyl-S-methylphosphonyl-3-pentenoic acid, which is purified by chromatography on 20 g of Dowex S0 Wx8 (H2O) (amorphous white powder), ~H-NMR (D2O):
l.20 (d, 3H, CH3-P); 1.75 (d, 3H, CH3); 2.4S (d, 2H, C(S)-H); 4.50 (d, lH, C(2)-H); 5.15 (m, lH, C(3)-H).
The starting material is manufactured by reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide in the manner described in Example 2 and subsequent treatment with methylphosphonous acid diethyl ester instead of triethyl phosphite.

Example 12:
14.5 g of E-2-formylamino-2-methyl-S-diethyl-phosphono-3-pentenoic acid methyl ester are heated for 32 hours under nitrogen at lO0-105 in S00 ml of 4.35N hydrochloric acid. Working up as in Example ll yields E-2-amino-2-methyl-S-phosphono-3-pentenoic acid, m.p. 225-226 (from water).
The starting material is manufactured as follows:
A solution of 14.1 g of 2-isocyanopropionic acid methyl ester and 8.5 g of freshly distilled acrolein in 50 ml of tetrahydrofurlan isjadded within a period of 20 minutes at 0-5 under nitrogen to a solution of 17 g of anhydrous zinc chloride in 75 ml of tetrahydrofuran, and the whole is stirred for 45 hours at 0-5. The whole is poured onto 500 ml of ~0~ sodium hydrogen carbonate solution and extracted with 200 ml of dichloromethane. The organic phase is dried over sodium sulphate and concentrated by evaporation.
Filtration of the residue over silica gel (ethyl D

acetate as eluant) yields 4-methyl-S-vinyl-2-oxa-zoline-4-carboxylic acid methyl ester. By hydrolysis o~ the 4-methyl-S-vinyl-2-oxazoline-4-carboxylic acid methyl ester in a manner analogous to that described in Example 1, 2-formylamino-2-methyl-3-hydroxy-4-pentenoic acid methyl ester is obtained. By reaction of the 2-formylamino-3-hydrOxy-2-methyl-4-pentenoic acid methyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in the manner described in Example 1, E-2-formylamino-2-methyl-5-diethylphosphono-3-pentenoic acid methyl ester is obtained in the form of a yellow oil:

Calculated C 46.91 ~ H 7.22 % N 4.56 % P 10.08 Found C 46.1 % H 7.3 % N 4.1 ~ P 10.6 %

Example 13:

6.3 g of E-2-formylamino-3-methyl-5-diethyl-phosphono-3-pentenoic acid ethyl ester are heated for 30 hours at 100-100 under nitrogen in 400 ml of 4.35N hydrochloric acid. Working up as in Example 11 yields E-2-amino-3-methyl-5-phOsphOnO-3-pentenoic acid in the form of a white powder, m.p. 168, lH-~MR
(D2O): 1.50 (d, 3H, CH3~; 2.4 (m, 2H, CH2); 4.30 (s, IH, C(2)-H~; 5.60 (m, 1H, C(4)-H).
The starting material is manufactured as follows:
5-Methy1-5-vinyl-2~oxlazo1ine-4-carboxylic acid ethyl ester, b.p 65-75 (13 Pa) is obtained by reaction of isocyanoacetic acid ethyl ester with methyl vinyl ketone in a manner analogous to that described in Example 30. By hydrolysis of the 5-methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 1, 2-formyl-amino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-3-D

~ 33 ~ 6~5 21489-7094 methyl-4-pentenoic acid ethyl ester with thionyi bromide and subsequent treatment with triethyl phosphite in a manner analogous to that describe~ in Example l yields E-2-formylamino-3-methyl-5-diethyl-phosphono-3-pentenoic acid ethyl ester in the form of a colourless liquid.

Example l4:
E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester ~s hydrolysed with 4.35N
hydrochloric acid in the manner described in Example ll. E-2-amino-5-methyl 5-phosphono-3-pentenoic acid is isolated in the form of an amorphous white solid mass.
1H-NMR (D2O): 1.05 (dd, 3H, CH3); 2.45 (m, 1H, C(5)-~); 4.33 (d, 2H, C(2)-H); 5.5 and 5.9 (2m, 2H, C(3)-H and C(4)-E~).
The starting material is manufactured as follows:
Reaction of crotonaldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example l yields 5-(propen-l-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(propen-t-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to Example 1, 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite inja~manner analogous to that described in Example l (12 hours) yields E-2-formyl-amino-5-diethylphosphono-S-methyl-3-pentenoic acid ethyl ester.

Example 15:
Hydrolysis of E-2-formylamino-4-ethyl-5-dimethyl-phosphono-3-pentenoic acid ethyl ester in a manner analogous to that described in Example ll yields : ~ 33 ~ 6~5 21489-7094 - ~2 -E-2-amino-4-ethyl-5-phosphono-3-pentenoic acid, m.p,.
176 (H2O).
The starting material is manufactured as follows:
Reaction of 2-methylene-butyraldehyde with isocyano-acetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. A solution of 16 g of 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in 100 ml of ethanol/water (1:1) is heated at the boil, under reflux, for 15 hours. The whole is concentrated by evaporation in vacuo, the residue is taken up in 200 ml of dichloromethane, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation to yield 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester.
Reaction of the 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogo~s to that described in Example 1 yields E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.

Exam~le 16:
--Hydrolysis of E-2-formylamino-4-propyl-5-dimethyl-phosphono-3-pentenoic acid ethyl ester in a manner analogous to that described in Example 11 yielas E-2-amino-4-propyl-5 phosphono-3-pentenoic acid, m.p. 193 !
(H20) .
The starting material is manufactured as follows:
Reaction of 2-~ethylene-pentanal with isocyanoacetic acid ethyl ester analogously to Example 1 yielas 5-(penten-2-yl)-2-oxazoline-4-carbox~ilic acid ethyl ester. By hydrolysis of the S-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 15~ 2-formyl- -~
D

~ 33 ~ 6~5 amino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-propyl-S-dimethyl-phosphono-3-pentenoic acid ethyl ester.

_xample 17:
Hydrolysis of E-2-formylamino-4-butyl-5-dimethyl-phosphono-3-pentenoic acid ethyl ester in a manner analogous to that described in Example ll yields E-2-amino-4-butyl-5-phosphono-3-pentenoic acid, m.p.
186-187. (H2O).
The starting material is manufactured as follows:
Reaction of 2-methylene-hexanal with isocyanoacetic acid ethyl ester analogously to Example l yields 5-(hexen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed in a manner analogous to that described in Example 15 to 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester. Reaction of the 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite analogously to Example l yields E-2-formylamino-4-butyl-S-dimethylphosphono-3- -pentenoic acid ethyl ester.
~ ~ "
Example 18:
Hydrolysis of E-2-formylamino-4-isopropyl-S-dimethylphosphono-3-pentenoic acid ethyl ester analogously to Example ll yields E-2-amino-4-isopropyl-5-phosphono-3-pentenoic acid, m.p. 201 (H2O).
The starting material is manufactured as follows:
Reaction of 3-methyl-2-methylene-butanal with isocyano-acetic acid ethyl ester analogously to Example l .
` D
.

~ 33 t 625 21489-7094 yields S-(3-methyl-buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 15 to 2-formylamino-3-hydroxy-4-isopropyl-4-pentenoic acid ethyl ester. Subsequent treatment with thionyl bromide followed by reaction with trimethyl phosphite analogously to Example 1 yields E-2-formyl-amino-4-isopropyl-S-dimethylphosphono-3-pentenoic acid ethyl ester.

Example 19:
3.9 g of E-2-formylamino-4-tert.-butyl-5-dimethyl-phosphono-3-pentenoic acid ethyl ester are hydrolysed analogously to Example 12. Separation by ion exchange chromatography (Dowex W 50, H2O~ yields 1.8 g of E-2-amino-4-tert.-butyl-5-phosphono-3-pentenoic acid and 0.075 g of Z-2-amino-4-tert.-butyl-5-phosphono-3-pentenoic acid.
E-isomer: M.p. 252-253 (H2O); lH-~MR (D20):
o.g5 (s, 9H, ~CH3)3C); 2.65 (m~ 2~, CH2); approx-imately 4.7 (d, lH, C(2)-H); 5.33 (m, lH, C(3)-H).
Z-isomer: 1H-N:`IR (D2O): I.08 (s, 9H, (CH3)3C);
2.45 (m, 2H, CH2); 4.95 (d, lH, C(2)-H); 5.20 (m, lH, C(3)-H).
The starting material is manufactured as follows:
Reaction of 3,3-dimethyl-2-methylene-butanal with isocyanoacetic acid ethyl ester in a manner analogous to that-described~in Ex~mplè 1 yields 5-(3~,3-dimethyl-buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 17 to 2- -formylamino-3-hydroxy-4-tert.-butyl-4-pentenoic acid ethyl ester. Subsequent reaction with thionyl bromide followed by treatment with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-tert.-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
D

Example 20:
0.44 g of E-2-formylamino-4-benzyl-5-diethyl-pho~;phono-3-pentenoic acid ethyl ester are dissolved in 8 ml of 4.SN hydrochloric acid and heated at 8S for 48 hours. After concentration in vacuo, the residue is dissolved in a small amount of ethanol and 1 ml of ethanol/propylene oxide (1:1 ) is added dropwise thereto.
The resulting white precipitate is filtered off and, after recrystallisation from water, E-2-amino-4-benzyl-S-phosphono-3-pentenoic acid is obtained in the form of colourless needles, m.p. 196-198.
The starting material is manufactured as follows:
By reaction of isocyanoacetic acid ethyl ester with 2-benzyl-propenal in a manner analogous to that described in Example 1 and after purification by column chromatography (silica gel; dichloromethane/ethyl acet~te 98:2), 5-(3-phenyl-propen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester is obtained in the form of a colourless oil, lH-NMR (CDC13): 3.33 (s, 2H, CH2); 4.37 (dd, IH, C(4)-H); 4.87 (s, lH); 5.07 (dd, 1H, C(5)-H); 5.16 (s, lH). -By hydrolysis of the 5-(3-phenyl-propen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 1, 2-formyl-amino-3-hydroxy-4-benzyl-4-pentenoic acid ethyl ester is obtained, m.p. 87-89.
By reaction of 2-formylamino-3-hydroxy-4-benzyl-3-pentenoic acid ethyl ester with thionyl bromide and subseguent treatment with triethyl phosphite at 100 in a manner analogous to that described in Example 1, and after chromatography (silica gel; ethyl acetate), E-2-formylamino-4-benzyl-S-diethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a colouc-less oil, 1H-NMR (CDC13): 2.45 (d, 2H, C(S)-H);
3.80 (s, IH, CH2); S.~1 (m, lH, C(3)-H). ~-9 : ~

1 33 1 6252l489-7094 Example 21:
0.15 g of E-2-formylamino-4-phenyl-5-diethyl-phospllono-3-pentenoic acid methyl ester are dissolved in 10 ml of 4.5N hydrochloric acid and heated at 75 for 192 hours. After concentration in vacuo, the foamy residue is dissolved in a small amount of ethanol and 1 ml of ethanol/propylene oxide (1:1) is added dropwise thereto. The resulting white precipitate is filtered off and recrystallised from water/acetone (1:2). E-2-amino-4-phenyl-5-phosphono-3-pentenoic acid is thus obtained in the form of colourless needles, m.p. 230-233.
The starting material is manufactured as follows:
By reaction of isocyanoacetic acid methyl ester with 2 phenylacrolein in a manner analogous to that described in Example 1, and after purification by column chromatography (silica gel; dichloromethane/-methanol 97.5:2.5), 5-(1-phenyl-vinyl)-2-oxazoline-4-carboxylic acid methyl ester is obtained in the form of a pale yellow oil. lH-NMR tCDC13): 3.80 (s, 3H, CH3); ~-4.45 (dd, 1H, C(4)-H); 5.76 (d, lH, C(5)-H).
By hydrolysis of the 5-(1-phenyl-vinyl)-2-oxazoline-4-carboxylic acid methyl ester in a manner analogous to that described in Example 1, 2-formyl-amino-3-hydroxy-4-phenyl-4-pentenoic acid methyl ester is obtained, m.p. 173-174.
sy reaction of the 2-formylamino-3-hydroxy-4-phenyl-4-pentenoic acid methyl ester with thionyl bromide and subsequentltreatment with triethyl phosphite in a manner analogous to that described in Example 1, and after chromatography (silica gel; ethyl acetàte/hexane 4:1), E-2-formylamino-4-phenyl-5-dieth phosphono-3-pentenoic acid methyl ester is obtained in the form of a colourless oil. lH-NMR (CDC13): 2.98 (d, 2H,C(5)-H); 5.03 (dd, 1H, C(2)-H); 5.77 (dd, 1H, C(31-H).
D

~ . ...... . . . . .... . . . .... . . . .. . . .

~ 33 1 625 21489-7094 Example 22:
At 0, 170 mg of sodium hydrogen carbonate and, within a period of S minutes, 50 microlitres of acetic anhydride are added to a solution of 100 mg of E-2-amino-5-phosphono-3-pentenoic acid in 6 ml of dioxan/-water (1:1), The whole is stirred for 30 minutes at 0, approximately 2 ml of Dowex 50 H+ are added and filtration is carried out. The filtrate is concentrated by evaporation and purified by ion exchange chroma-tography (Dowex S0 H+). Lyophilisation of the pure fractions yields 110 mg of E-2-acetamino-5-phosphono-3-pentenoic acid, m.p. 155.
Unless this is expressly excluded, each of the above-described compounds of the formula I can also be manufactured in accordance with any of the other processes described.

Example 23:
Manufacture of 1000 capsules, each containing 10 mg of the active substance of Example 6, with the following composition:
: :-E-2-amino-6-phosphono-4-hexenoic acid 10.0 g lactose 207.0 g modified starch 80.0 g -magnesium stearate 3.0 g , , ~
Method: All the pulverulent constituents are sieved using a sieve having a mesh width of 0.6 mm.
The active ingredient is then introduced into a suitable mixer and mixed until homogeneous first with magnesium stearate, then with lactose and starch.

D ~

1 33~ 625 - 21489-70g4 No. 2 gelatine capsules are each filled with 300 mg Q.f this mixture using a capsule-filling machine.
Capsules each containing from 10 to 200 mg of one of the other disclosed compounds mentioned in the Examples are manufactured in an analogous manner.

i ' : ' i .` i D`

Claims

1. A compound of the formula I

(I) in which R1 represents hydroxy or lower alkoxy, R2 represents hydrogen, C1-C12alkyl, hydroxy or lower alkoxy, R3 represents hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxyalkyl, phenyl-lower alkyl, phenyl-lower alkyl substituted by one, two or three substituents selected from lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro, lower alkenyl, halogen, phenyl or phenyl substituted by one, two or three substituents selected from lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro, R4 re-presents hydrogen, C1-C12alkyl, phenyl or phenyl substituted by one, two or three substituents selected from lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro, R5 re-presents hydrogen or C1-C12alkyl, R6 represents carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl substituted by one, two or three sub-stituents selected from lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro, carbamoyl or N-mono- or N,N-di-lower alkylcarbamoyl, R7 represents amino or amino substituted by lower alkyl, lower alkanoyl or benzoyl and A
represents a methylene, ethylene or 1,3-propylidene group which is unsubstituted or C1-C12alkyl-substituted or a salt thereof.

2. A compound of the formula I according to claim 1 in which R1, R2, R3, R4, R5, R6 and R7 have the meaning given in claim 1 and A represents .alpha.,.omega.-alkylene having from 1 to 3 carbon atoms, or a salt thereof.

3. A compound of the formula I according to claim 2 in which R3 represents hydrogen, lower alkyl or phenyl.

4. A compound of the formula I according to claim 1 in which R6 represents carboxy or alkoxycarbonyl, R7 represents amino, mono-lower alkylamino, lower alkanoylamino or benzoylamino, or a pharmaceutically acceptable salt thereof.

5. A compound of the formula I according to claim 4 in which R3 and R4, independently of one another, each represents hydrogen, lower alkyl, phenyl, or phenyl substituted by lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl or by nitro, or a pharmaceutically acceptable salt thereof.

6. A compound of the formula I according to claim 1 in which R1 represents hydroxy or lower alkoxy, R2 represents hydrogen, C1-C12alkyl, hydroxy or lower alkoxy, R3 represents hydrogen, lower alkyl, phenyl, or phenyl-lower alkyl, R4 and R5 represents hydrogen or lower alkyl, R6 represents carboxy or alkoxycarbonyl, R7 represents amino, mono-lower alkylamino, lower alkanoylamino or benzoyl-amino and A represents a methylene, ethylene or 1,3-propyl-idene group which is unsubstituted or lower alkyl-substi-tuted, or a pharmaceutically acceptable salt thereof.

7. A compound of the formula I according to claim 1 in which R1 is hydroxy, R2 represents hydrogen, C1-C12alkyl or hydroxy, R3 represents hydrogen, R5 represents hydrogen, R6 represents carboxy or lower alkoxycarbonyl, R7 represents amino, mono-lower alkylamino, lower alkanoylamino or benzoyl-amino and A represents methylene, ethylene or 1,3-propylene, or a pharmaceutically acceptable salt thereof.

8. A compound of the formula I according to claim 1 in which R1 is hydroxy, R2 represents hydrogen, lower alkyl or hydroxy, R3 represents hydogen or lower alkyl, R4 and R5 represent hydrogen, R6 represents carboxy, or lower alkoxycarbonyl, R7 represents amino or mono-lower alkylamino and A represents methylene, ethylene or 1,3-prop-ylene, or a pharmaceutically acceptable salt thereof.

9. A compound of the formula I according to claim 1 in which R1 and R2 represents hydroxy, R3 represents hydrogen or lower alkyl, R4 and R5 represent hydrogen, R6 represents carboxy, R7 represents amino and A represents methylene, or a carboxylic acid lower alkyl ester or a pharmaceutically acceptable salt thereof.

10. E-2-amino-5-phosphono-3-pentenoic acid or a pharmaceuti-cally acceptable salt thereof.

11. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceuticallly acceptable salt thereof.

12. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester.

13. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester.

14. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-propyl ester.

15. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-butyl ester.

16. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid isobutyl ester.

17. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-pentyl ester.

18. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-hexyl ester.

19. (D)-E-2-amino-5-phosphono-3-pentenoic acid or a pharma-ceutically acceptable salt thereof.

20. E-2-amino-2-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

21. E-2-amino-3-methyl-5-phosphono-3-pentenoic acid and its pharmaceutically acceptable salts.

22. E-2-acetylamino-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

23. E-2-amino-5-phosphono-3-pentenoic acid dodecyl ester and its pharmaceutically acceptable salts.

24. E-2-amino-5-phosphono-3-pentenoic acid ethyl ester.

25. E-2-amino-4-methyl-5-phosphono-3-pentenoic acid octyl ester.

26. E-2-amino-5-phosphono-3-pentenoic acid n-propyl ester.

27. E-2-amino-5-phosphono-3-pentenoic acid n-butyl ester.

28. E-2-amino-5-phosphono-3-pentenoic acid isobutyl ester.

29. E-2-amino-5-phosphono-3-pentenoic acid n-pentyl ester.

30. E-2-amino-5-phosphono-3-pentenoic acid sec.-butyl ester.

31. E-2-amino-5-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

32. E-2-amino-4-ethyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

33. E-2-amino-4-propyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

34. E-2-amino-4-butyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

35. E-2-amino-4-isopropyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

36. E-2-amino-4-tert.-butyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

37. E-2-amino-4-benzyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

38. E-2-amino-4-phenyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical preparation containing compounds of any one of claims 3, 5, 7, 10, 11 and 23 to 30 together with a pharmaceutically suitable carrier material.

40. A pharmaceutical preparation containing compounds of any one of claims 1, 2, 4, 6, 9, 12 to 23 and 31 to 38 together with a pharmaceutically suitable carrier material.

41. Process for the manufacture of the compounds of the formula I claimed in claim 1, in which all the symbols have the meanings given in claim 1, and salts thereof, characterised in that a) a compound of the formula II

(II) in which R3, R4, R5 and A are as defined for formula I, Z6 has the meaning of R6 or represents protected carboxy, Z7 has the meaning of R7 or represents protected amino and X represents reactive esterified hydroxy, is reacted with a compound of the formula III

(III) in which Z1 has the meaning of R1 or represents protected hydroxy, Z2 has the meaning of R2 or represents protected hydrogen or protected hydroxy, and R represents an etherifying group, or b) in order to obtain a compound of the formula I in which R5 represents hydrogen, in a compound of the formula IV

(IV) in which R3, R4 and A are as defined for formula I, Z1 has the meaning of R1 or represents protected hydroxy, Z2 has the meaning of R2 or represents protected hydroxy or protected hydrogen, Z6 has the meaning of R6 or represents protected carboxy, Z7 has the meaning of R7 or represents protected amino, and Y represents an optionally esterified carboxy group that can be replaced by hydrogen, the group Y is replaced by hydrogen, and any protected functional groups that may be present in a compound resulting from one of the preceding processes is freed and, if required, a resulting compound of the formula I, wherein R7 represents amino, is N-lower alkylated or N-substituted by lower alkanoyl or benzoyl, and if required, a resulting compound of the formula I, wherein R6 denotes esterified corboxy as specified hereinbefore, is converted into the corresponding acid, wherein R6 denotes carboxy, and if required, a resulting compound of the formula I, wherein R6 denotes carboxy, is esterified or amidated so as to produce a compound of the formula I, whrein R6 denotes esterified or amidated carboxy as specified hereinbefore, and if an optical isomer is required, a resulting mixture of stereoisomers is separated into its components and the required optical isomer is isolated, and if a salt is required, a resulting free compound is converted into a salt, or if a free compound is required, a resulting salt is converted into the corresponding free compound.

42. Process according to claim 41, characterised in that a compound of the formula II

(II) in which R3, R4, R5 and A are as defined for formula I, Z6 represents protected carboxy, Z7 represents protected amino and X represents reactive esterified hydroxy, is reacted with a compound of the formula III

(III) in which Z1 represents protected hydroxy, Z2 represents lower alkyl, protected hydrogen or protected hydroxy and R represents lower alkyl, and following this reaction the protected groups are freed.

43. Process according to claim 42, in which Z1 represents lower alkoxy, Z2 represents lower alkyl, di-lower alkoxy-lower alkyl or lower alkoxy, R represents lower alkyl, Z6 represents lower alkoxycarbonyl, Z7 represents formyl-amino and X represents halogen.

44. Process according to claim 41, characterised in that in a compound of the formula IV

(IV) in which R3, R4 and A are as defined for formula I, Z1 represents protected hydroxy, Z2 represents lower alkyl, protected hydroxy or protected hydrogen, Z6 represents protected carboxy, Z7 represents protected amino and Y represents an optionally esterified carboxy group that can be replaced by hydrogen, the protected groups are freed together in the step in which the group Y is replaced by hydrogen.

45. Process according to claim 44 in which Z1 represents lower alkoxy, Z2 represents lower alkyl, di-lower alkoxy-lower alkyl or lower alkoxy, Z6 and Y represent lower alkoxycarbonyl and Z7 represents lower alkanoylamino.

46. Process according to claim 41 characterised in that a resulting compound of the formula I in which R6 represents carboxy, is converted into the corresponding compound of the formula I in which R6 represents lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl substituted by one, two or three substituents selected from lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro.