Note: Descriptions are shown in the official language in which they were submitted.
~2~3~
- 1 -
4-17759/+
.
4-Substituted 2-ammoalk-3-enoic acids
The invention relates to substituted 2-aminoalk-3-enoic acid derivatives of formula I
HO~ P /\~ R2
wherein Rl is an aliphatic hydrocarbon radical that is substituted by optionally acyla~ed or
aliphatically or araliphatically etheri~led hydroxy, by halogen, by optionally acylated
and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic
radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an
optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical,
and R2 is free or esterifîed carboxy, and their salts, to processes for the preparation of the
compounds according to the invention, to pharmaceutical preparations containing them,
and to their use as active ingredients in medicaments.
- .
Aliphatic hydrocarbon radicals are, ~or example, aL1~yl radicals having up to and including
10, especlally up to and including 8, carbon atoms, preferably lower aL~cyl radicals.
Hydroxy-substituted aliphatic hydrocarbon radicals are, for example, mono- or
di-hydroxy-lower alkyl. ~ -
Acylated hydroxy is, for example, lower aLIcanoyloxy or benzoyloxy that is unsubstitutedor substituted in the phenyl moiety. Accordingly, an aliphatic hydrocarbon radical that is
substituted by acylated hydroxy shall be understood as being,~ for example, lower
alkanoyloxy-lower alkyl or benzoyloxy-lower aLt~yl that is unsubstituted or substituted in
the phenyl moiety.
.
.
:
2 ~ 2 ~
Aliphatically etherified hydroxy is, for example, lower alkoxy; araliphatically etherified
hydroxy is, for example, unsubstituted or substituted phenyl-lower alkoxy. Accordingly,
an aliphatic hydrocarbon radical that is substituted by aliphatically etherified hydroxy
shall be understood as being, for example, lower alkoxy-lower alkyl, and an aliphatic
hydrocarbon radical that is substituted by araliphatically etherified hydroxy shall be
understood as being, for example, unsubstituted or substituted phenyl-lower alkoxy- lower
alkyl.
A halo-substituted aliphatic hydrocarbon radical is, for example, halo-lower alkyl.
Optionally acylated andlor aliphatically substituted amino is, for example, amino,
N-mono- or N,N-di-lower alkylamino, N-lower aLI~anoylamino, N-benzoylamino that is
unsubstituted or substituted in the phenyl moiety, or N-lower aLkanoyl-N-lower alkyl-
amino. Accordingly, aliphatic hydrocarbon radicals that are substituted by optionally
acylated and/or aliphatically substituted amino are, for example, amino-lower alkyl, lower
alkylamino-lower alkyl, lower aL~anoylamino-lower aL~cyl, benzoylamino-lower aLkyl that
is unsubstituted or substituted in the phenyl moiety, di-lower aLtcylamino-lower aL1cyl or
N-lower aL~canoyl-N-lower alkylamino-lower aL~cyl.
Aliphatic hydrocarbon radicals that are substituted by an azacycloaliphatic radical are, for
example, 4- to 7-membered azacycloaLlcyl-lower aLlcyl radicals whose azacycloaLkyl
moiety may be bonded via the N atom or a carbon atom and, in ~he latter case, may be
N-lower aLIcylated, N-lower aLIcanoylated or N-substituted by a benzoyl group that is
unsubstituted or substituted in the phenyl moiety. 4- ~o 7-membered azacycloalkyl-lower
aLkyl whose azacycloaLIcyl moiety is bonded via the N atom is, for example, N,N-lower
alkyleneamino-Cl-C7allcyl, i.e. azacycloaLIc~l-yl-Cl-C7aLkyl. 4- to 7-membered
azacycloalkyl-lower alkyl whose azacycloaLlcyl moiety is bonded via a carbon atom and is
optionally N-lower aLlcylated, N-lower aLkanoylated or N-substituted by a benzoyl group
that is unsubs~ituted or substituted in the phenyl moiety is, for example, ~- to 7-membered
azacycloalkyl-Cl-qalkyl or N-C2-C7aL1canoylazacycloalkyl-Cl-C7aL~cyl, also
N-Cl-C4aLI~ylæacycloalkyl-Cl-C7alkyl or N-benzoylazacycloaL~cyl-Cl-C7alkyl that is
unsubstituted or substituted in the phenyl moiety, each of which is bonded via a carbon
atom.
Aliphatic hydrocarbon radicals that are substituted by a diazacycloaliphatic radical are, for
2 ~ 2 ~
-3-
example, 4- tO 7-membered diazacycloalkyl-lower alkyl radicals whose diazacycloalkyl
moiety is bonded via one N atom and may, at the other N atom, optionally be lower
alkylated, lower alkanoylated or substituted by a benzoyl group that is unsubstituted or
substituted in the phenyl moiety, such as 4- to 7-membered diazacycloalkyl-lower alkyl
radicals that are bonded via an N atom and are optionally N'-lower alkylated, N'-lower
alkanoylated or N'-substituted by a benzoyl group that is unsubstituted or substituted in
the phenyl moiety, especially 5- to 7-membered diazacycloalk-1-yl-Cl-C7alkyl.
Aliphatic hydrocarbon radicals that are substituted by an azoxacycloaliphatic radical are,
for example, 4- to 7-membered azoxacycloaLIcyl-lower alkyl radicals whose azoxacyclo-
al~cyl moiety is bonded via the N atom, such as 4- to 7-membered azoxacycloalkyl-lower
alkyl radicals bonded via the N atom, especially 5- to 7-membered N,N-(oxa-loweralkylene)amino-Cl-qalkyl, i.e. azoxacycloalk-l-yl-Cl-qalkyl.
Aliphatic hydrocarbon radicals that are substituted by an oxacycloaliphatic radical are, for
example, 4- to 7-membered oxacycloalkyl-lower alkyl radicals whose oxacycloalkylmoiety is bonded via a carbon atom, such as 5- to 7-membered oxacycloalkyl-Cl-C7alkyl
bonded via a carbon atom.
Oxacycloaliphatic hydrocarbon radicals that are bonded via a carbon atom are, for
example, 5- to 7-membered oxacycloalkyl groups bonded via a carbon atom.
Azacycloaliphatic hydrocarbon radicals that are bonded via a carbon atom and areoptionally aliphatically N-substituted or N-acylated are azacycloaL~cyl radicals that are
bonded via a carbon atom and are optionally N-lower alkylated, N-lower alkanoylated or
N-substituted by benzoyl that is unsubstituted or substituted in the phenyl moiety, such as
5- to 7-membered azacycloaLIcyl or N-C2-C7aL~canoylazacycloaL~yl, also N-Cl-(:~4aLIcyl-
azacycloallcyl or unsubstituted or substituted N-benzoylazacycloaLIcyl, each of which is
bonded via a carbon atom.
Esterified carboxy is, for example, carboxy esterified by an aliphatic, cycloaliphatic or
araliphatic alcohol, such as lower alkoxycarbonyl, 4- up to and including 7-membered,
especially 5- or ~membered, cycloaLkoxycarbonyl, such as cyclopentyloxy- or
cyclohexyloxy-carbonyl, or unsubstituted or substituted phenyl-lower aL~oxycarbonyl.
In the groups mentioned above, phenyl radicals may be unsubstitutFd or mono-, di- or
- 4-
tri-subs~ituted, especially mono- or di-substituted, in customary manner, for example by
lower aLlcyl, lower alkoxy, halogen, cyaDo and/or by trifluoromethyl.
Hereinbefore and hereinafter, "lower" radicals and compounds shall be understood as
being, for example, radicals and compounds containing up to and including 7, preferably
up to and including 4, carbon atoms (C atoms).
Lower alkyl is, for example, Cl-C7aLlcyl, preferably Cl-C4aL~cyl, such as methyl, ethyl,
propyl, isopropyl or butyl, but may also be isobutyl, sec.-butyl, tert.-butyl or a pentyl,
hexyl or heptyl group.
Mono- or di-hydroxy-lower alkyl is, for example, hydroxy-Cl-C7aL~cyl, such as
hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, S-hydroxypentyl or
6-hydroxyhexyl, or dihydroxy-C2-C7aLI~yl in which the hydroxy groups are bonded to
different carbon atoms, such as 1,2-dihydroxyethyl or, especially, 1,3-dihydroxyprop-2-yl.
Lower alkanoyl is, ~or example, C2-C7aL~anoyl, especially C2-C4aL~anoyl, such as acetyl,
propionyl or butyryl, but may also be a Cs-C6alkanoyl group, such as pivaloyl. Accor-
dingly, lower alkanoyloxy-lower alkyl is especially C2-C7aLtcanoyloxy-Cl-qaLlcyl, such
as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetoxyethyl, 3-acetoxy-
propyl, 4-acetoxybutyl, S-acetoxypentyl or 6-acetoxyhexyl. By analogy,
benzoyloxy-lower alkyl shall be understood as being, for exarnple, benzoyloxy-Cl-q-
aLIcyl that is unsubstituted or substituted in the phenyl moiety, such as benzoyloxymethyl,
2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, 5-benzoyloxypentyl or
6-benzoyloxyhexyl.
Lower alkoxy is, for example, Cl-C7aLlcoxy, preferably Cl-C4aL~oxy, such as methoxy,
ethoxy, propoxy, isopropoxy or butoxy, but may also be isobutoxy, sec.-butoxy,
tert.-butoxy or a pentyloxy, hexyloxy or heptyloxy group. Accordingly, lower
aL1coxy-lower aLIcyl is, for example, Cl-C4aLkoxy-Cl-C7aL~yl, such as methoxymethyl,
ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 4-methoxybutyl,
5-methoxypentyl or 6-methoxyhexyl.
Phenyl-lower aLtcoxy is, for example, phenyl-Cl-C4alkoxy that is unsubstituted or
substituted as indicated, such as benzyloxy, 2-phenylethoxy or 3-phenylpropoxy.
Accordingly, phenyl-lower alkoxy-lower alkyl is, for example, a phenyl-Cl-C4-
alkoxy-Cl-C7alkyl radical that is unsubstituted or substituted as indicated, such as a
benzyloxymethyl, 2-phenylethoxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl,
4-benzyloxybutyl, 5-benzyloxypentyl or 6-benzyloxyhexyl radical.
Halo-lower alkyl is, for example, halo-Cl-C7allcyl, such as halomethyl, 2-haloethyl,
3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, in which halogen is chlorine or,
especially, fluoline.
Amino-lower alkyl is, for example, amino-Cl-C7alkyl, such as aminomethyl,
2-aminoethyl, 3-aminopropyl7 4-aminobutyl, 5-aminopentyl or 6-aminohexyl.
Lower alkylamino is, for example, Cl-C7aLkylamino, especially Cl-C4alkylamino, such
as methylamino, ethylamino, propylamino or butylamino, but may also be a Cs-C6alkyl-
amino group, such as a pentylamino or hexylamino group. Accordingly, lower alkyl-
amino-lower alkyl is especially Cl-C4alkylamino-Cl-C7alkyl, such as
methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-
methylaminoethyl, 3-methylarninopropyl, 4-methylaminobutyl, 5-methylaminopentyl or
6-methylaminohexyl .
:
Lower alkanoylamino is, for example, C2-qaL~sanoylamino, especially C2-C4alkanoyl-
amino, such as acetylamino, propionylamino or butyrylamino, but may also be Cs-C6-
alkanoylamino, such as pivaloylamino. Accordingly, lower alkanoylamin~lower alkyl is
especially C2-qalkanoylamino-Cl-qaLIcyl, such as acetylaminomethyl,
propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl,
4-acetylaminobutyl, 5-acetylaminopentyl or ~acetylaminohexyl. By analogy,
benzoylamino-lower aLtcyl shall be unders~ood as being, for example,
benzoylamino-Cl-C?alkyl that is unsubstituted or substituted in the phenyl moiety, such
as benzoylaminomethyl, 2-benzoylaminoethyl, 3-benzoylaminopropyl,
4-benzoylaminobutyl, 5-ben~oylaminopentyl or 6-ben~oylaminohexyl.
.
Di-lower aLkylalIuno is, for example, di-Cl-C7aL~cylamino, especially di-Cl-C4-
alkylarnino, such as dimethylamino, diethylamino, N-ethyl-N-methylamino, N-methyl-
N-propylamino, dipropylamino or dibutylamino. Accordingly, di-lower aLIcylamino-lower
alkyl is especially di-Cl-C4alkylamino-Cl-qalkyl, such as dimethylaminomethyl,
diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl,
dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl,
~ ~ 2 ~ 8
- 6-
3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or 6-dimethyl-
aminohexyl.
N-lower alkanoyl-N-lower aL~cylamino-lower alkyl is, for example, N-C2-C7-
alkanoyl-N-Cl-C4alkylamino-Cl-C7aL~cyl, such as N-acetyl-N-methylaminomethyl,
N-acetyl-N-ethylaminomethyl, N-propionyl-N-methylaminomethyl, N-butyIyl-
N-methylaminomethyl, 2-(N-acetyl-N-methylamino)ethyl, 2-(N-propionyl-N-methyl-
arnino)ethyl, 2-(N-acetyl-N-ethylarnino)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 azacycloaL~cyl-C1-C7aLkyl bonded via an N atom is preferably
N,N-lower alkylenearnino-Cl-C7alkyl, i.e. azacycloalk-1-yl-Cl-C7alkyl, for example
pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, 2-pyrrolidinoethyl,
2-piperidinoethyl, 3-pyrrolidinopropyl, 3-p;peridinopropyl, 4-pyrrolidinobutyl,
4-piperidinobutyl, S-pyrrolidinopentyl, 5-piperidinopentyl, 6-pyrrolidinohexyl or 6-piperi-
dinohexyl.
4- to 7-membered azacycloaL~cyl-cl-qaLlcyl bonded via a carbon atom is preferably
azacycloaLk-3-yl-C1-qalkyl or -4-yl-cl-qaL~yl~ for example piperidin-4-ylmethyl,2-(piperidin-4-yl)ethyl, 3-(piperidin-4-yl)propyl or 4-(piperidin-4-yl)butyl.
5- to 7-membered N-c2-qaL~anoylazacycloaLl~yl-cl-qallcyl bonded via a carbon atom
is preferably 1-c2-c7alkanoylazacycloallc-3-yl-cl-qalkyl or -4-yl-C1-C7aLIcyl, for
example 1-acetylpiperidin-4-ylmethyl, 2-(1-acetylpiperidin-4-yljethyl,
3-(1-acetylpiperidin-4-yl)propyl or 4-(1-acetylpiperidin-4-yl)butyl.
5- to 7-membered N-cl-c4aL~cylazacycloaLlcyl-cl-qaLkyl bonded via a carbon atom is
preferably N-C1-C4aLIcylazacycloaLk-3-yl-Cl-C7aLlcyl or -4-yl-Cl-C7alkyl, for example
1-methylpiperidin-4-ylmethyl, 1-ethylpiperidin-4-ylmethyl, 2-(1-methyl-
piperidin-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.
5- to 7-membered N-benzoylazacycls)alkyl-C1-C7aLtcyl that is bonded via a carbon atom
and unsubstituted or substituted in the phenyl moiety is preferably N-C1-C4benzoyl-
azacycloaLlc-3-yl-Cl-C7alkyl or -4-yl-Cl-C7alkyl, for example l-benzoyl-
piperidin-4-ylmethyl, 2-(1-benzoylpiperidin-4-yl)ethyl, 3-(1-benzoylpiperi~lin-4-yl)propyl
or 4-tl-benzoylpiperidin-4-yl)butyl.
5- to 7-membered diazacycloalk-1-yl-Cl-C7alkyl that is bonded vla an N atom and is
optionally N'-lower alkylated, N'-lower alkanoylated or N'-substituted by a benzoyl
group that is unsubstituted or substituted in the phenyl moiety is, for example,N,N-(aza-lower alkylene)amino-Cl-C7alkyl, i.e. diazacycloalk-1-yl-Cl-C7alkyl,
N'-Cl-C4alkyldiazacycloalk-1-yl-Cl-C7alkyl or N'-C2-C7alkanoylazacycloaL~c-l-yl-Cl-C7alkyl, for e:carnple piperazino- or N'-methyl- or N'-acetyl-piperazino-methyl,
2-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-ethyl, 3-(piperazino- or N'-methyl-
or N'-acetyl-piyerazino)-propyl or 4-(piperazino- or N'-methyl- or N'-ace~yl-
piperazino)-butyl.
5- to 7-rnembered N,N-(oxa-lower alkylene)amino-Cl-C7alkyl, i.e. azoxacycloaL~c-l-yl-Cl-C7aLtcyl, is, for exarnple, morpholinomethyl, 2-morpholinoethyl, 3-morpholino-
propyl or 4-morpholinobutyl.
5- to 7-membered oxacycloalkyl-Cl-qalkyl bonded via a carbon atom is especially 5- to
7-membered oxacycloalk-3-yl-Cl-C7alkyl or oxacycloalk-4-yl-Cl-C7aLlcyl, such as tetra-
hydropyran-4-ylmethyl, 2-~tetrahydropyran-4-yl)ethyl, 3-(tetrahydropyran-4-yl)propyl or
4-(tetrahydropyran-4-yl)butyl.
S- to 7-membered oxacycloalkyl bonded via a carbon atorn is especially corresponding
oxacycloalk-3-yl or -4-yl, for example tetrahydropyran-4-yl.
5- to 7-membered azacycloaLIcyl, N-Cl-C4alkylazacycloalkyl or N-C2-C7-
alkanoylazacycloaLkyl bonded via a carbon atom is preferably azacycloaLlc-3-yl or -4-yl or
l-C2-C7aLIcanoylazacycloaL~c-3-yl or -4-yl, for example piperidin-4-yl or l-acetyl-
piperidin-4-yl, and also M-Cl C4aLI~ylazacycloaLlc-3-yl or -4-yl or
N-benzoylazacycloaLI~-3-yl or -4-yl that is unsubstituted or substituted in the phenyl
moiety, for example l-methylpiperidin-4-yl or 1-benzoylpiperidin-4-yl.
Lower alkoxycarbonyl is, for example, Cl-C7aL~oxycarbonyl, especially
Cl-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl or butoxycarbonyl, but may also be a Cs-C7allcoxycarbonyl group,
~2~3~
such as a pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl group.
Phenyl-lower alkoxycarbonyl is, for example, phenyl-Cl-C4alkoxycarbonyl, such asbenzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl or
4-phenylbutoxycarbonyl .
On account of their amphoteric nature, the compounds of formula I are in the form of
internal salts and can form both acid addition salts and salts with bases.
Acid addition salts of compounds of formula I are, for example, pharmaceuticallyacceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid
or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen
sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-sub-
stituted sulfamic acids, for example methanesulfonates, benzenesulfonates,
p-toluenesulfonates or N-cyclohexyl sulfamates (cyclamates).
Salts of compounds of formula I with bases are, for example, salts thereof with
pharmaceutically acceptable bases, such as non-toxic metal salts derived from groups Ia,
Ib, IIa and IIb, for example aLtcali metal salts, especially sodium or potassium salts,
alkaline earth metal salts, especially calcium or magnesium salts, and also ammonium
salts with ammonia or organic amines or quaternary amrnonium bases, such as
unsubstituted or C-hydroxylated aliphatic amines, especially mono-, di- or tri-lower
alkylamines, for example methyl-, ethyl- or diethyl-amine, mono-, di- or ~i-(hydroxy-
lower alkyl)amines, such as ethanol-, die~hanol- or ~riethanol-amine,
tris-(hydroxymethyl)methylamine or 2-hydroxy-tert.-butylamine, or N-(hydroxy-lower
alkyl)-N,N-di-lower aLkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines,
such as 2-(dimethylarnino)ethanol or D-glucamine, or quatemary aliphatic ammonium
hydroxides, for example ~etrabutylammonium hydroxide.
:'
For isolation or purification puIposes it is also possible to use phannaceutically unsuitable
salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeudcally, and
these salts are therefore preferred.
The invention relates, for example, to compounds of formula I wherein Rl is an aliphatic
hydrocarbon radical that is substituted by optionally aliphatically s~r araliphatically
etherified hydroxy, optionally aliphatically substituted amino or by halogen, and R2 is free
or esterified carboxy, and ~heir salts.
The compounds of formula I have valuable pharrnacological properties. In particular, they
have a pronounced and selective antagonistic activity towards N-methyl-D-aspartic acid-
sensitive (NMDA-sensitive) excitatory amino acid receptors in warm-blooded animals.
This can be demonstrated in vitro, for example, in the experimental procedure according
to G. Fagg and A. Matus, Proc. Nat. Acad. Sci., USA, 81, 6876-6880 (1984). This
procedure determines the extent to which the binding of L-3H-glutarnic acid to
NMDA-sensitive receptors is inhibited. The NMDA-antagonistic properties of the novel
compounds can also be demonstrated in vivo, however, for example in mice, by theinhibiting effçct on NMDA-induced convulsions.
On account of these properties, the compounds of formula I and their pharmaceutically
acceptable salts are erninently suitable for the treatment of pathological conditions respon-
sive to a blocking of NMDA-sensitive receptors, for exarnple ischaemic disorders, such as
cerebral ischaemia and ischaemic disorders of the eye, vascular and muscular spasms,
such as migraines, or local or general spasticity and, especially, convulsions, such as
epilepsy.
The anti-convulsive properties of the compounds of the invention can be demonstrated, for
example, in mice by their pronounced protective effect against convulsions triggered by
electric shock or induced audiogenically, it being possible to make use, for example, of the
established electric shock rnouse model or of the experimental procedure according to
Chapman et aL, Arzneimittel-Forsch. 34, 1251 (1984). The compounds of the invention
are distinguished, especially in the electric shock mouse model, by improved action as
compared with structurally related compounds.
The anti-spastic properties that render the compounds provided according to the invention
suitable for the treatment of migraines can be demonstrated, for example, in rats by their
depression-inhibiting action in the frontal cortex in accordance with the experimental
procedure of R. Marannes et aL, Brain Res. 457, 226 (1988). In this model9 at doses in the
range of approximately from 3 to 30 mg/kg i.p., the compounds provided according to the
invention lower the threshold value of spreading depression and shorten the duration
thereof.
The invention relates especially to compounds of forrnula I wherein Rl is mono- or
2~2~
- 10-
di-hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, benzoyloxy-lower alkyl, lower
alkoxy-lower alkyl, phenyl-lower alkoxy-lower alkyl, halo-lower alkyl, amino-lower
alkyl, lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, di-lower
alkylamino-lower alkyl, N-lower alkyl-N-lower alkanoylamino-lower alkyl, 5- to
7-mernbered azacycloalkyl-lower alkyl whose azacycloalkyl moiety is bonded via the N
atom or a carbon atom and, in the latter case, may be N-lower alkylated, N-loweralkanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the
phenyl moiety, 5- to 7-membered diazacycloaLkyl-lower alkyl whose diazacycloalkyl
moiety is bonded via an N atom and is optionally N'-lower aL~cylated, N'-lower
alkanoylated or N'-substituted by a benzoyl group that is unsubstituted or substituted in
the phenyl moiety, 5- to 7-membered azoxacycloaLkyl-lower alkyl bonded via the N atom,
5- to 7-membered oxacycloalkyl-lower alkyl bonded via a carbon atom, 5- to 7-membered
azacycloaLkyl that is bonded via a carbon atom and is optionally N-lower aLkylated,
N-lower alkanoylated or N-substituted by a benzoyl group that is unsubstituted or
substituted in the phenyl moiety, or 5- to 7-membered oxacycloalkyl bonded via a carbon
atom, and R2 is carboxy, lower aLcoxycarbonyl, 4- up to and including 7-membered cyclo-
alkoxycarbonyl or phenyl-lower aL~coxycarbonyl, any phenyl radicals ;n the mentioned
groups R1 and/or R2 being unsubstituted or mono-, di- or tri-substituted by lower aLkyl,
lower aLlcoxy, halogen, cyano and/or by trifluoromethyl, and their salts.
The invention relates especially, for example, to compounds of formula I wherein R1 is
hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkoxy-lower aL~cyL amino-
lower aL~cyl, lower aL~cylarnino-lower aLkyl, di-lower aLkylamino-lower aL~cyl, N,N-lower
alkyleneamin~ or N,N-(aza- or oxa-lower aLkylene)amin~lower aLkyl, or halo-loweraLlcyl, and R2 is carboxy, lower alkoxycarbonyl, 4- up to and including 7-membered cyclo-
alkoxycarbonyl or phenyl-lower aLlcoxycarbonyl, any phenyl radicals in the mentioned
groups R1 andlor R2 being unsubstituted or mon~, di- or tri-subs~ituted by lower aL~cyl,
lower aLkoxy, halogen, cyano andlor by ~ifluoromethyl, and their salts.
The invention relates especially to compounds of formula I wherein R1 is
hydroxy-C1-C7alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or
4-hydroxybutyl, dihydroxy-C2-C7alkyl, such as 1,3-dihydroxyprop-2-yl, C2-C7-
alkanoyloxy-C1-C7aLI~yl, such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl,
2-acetyloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 5-acetyloxypentyl or ~acetyloxy-
hexyl, benzoyloxy-C1-C7alkyl that is unsubstituted or mono- or di-substituted in the
phenyl moiety by Cl-C4altcyl, such as methyl, Cl-C~ coxy, such as methoxy, halogen
2~2~3~
having an atomic number of up to and including 35, such as fluorine or chlorine, cyano
andlor by trifluoromethyl, such as benzoyloxymethyl, 2-benzoyloxyethyl,
3-benzoyloxypropyl, 4-benzoyloxybutyl, S-benzoyloxypentyl or 6-benzoyloxyhexyl,
Cl-C4allcoxy-Cl-C7alkyl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl,
3-methoxypropyl or 4-methoxybutyl, a phenyl-Cl-C4alkoxy-Cl-C7alkyl group that isunsubstituted or mono- or di-substituted in the phenyl moiety by Cl-C4alkyl, such as
methyl, Cl-C4alkoxy, such as methoxy, halogen having an atomic number of up to and
including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as
benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl,
halo-Cl-qaLI~yl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl
or 6-halohexyl, in which halogen is chlorine or, especially, fluorine, amino-Cl-C7alkyl,
such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-
amunohexyl, Cl-C4alkylamino-CI-C7all~yl, such as methylaminomethyl, ethylamino-
methyl, propylaminomethyl, butylarninomethyl, 2-methylaminoethyl, 3-
methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl,
C2-C7alkanoylamino-Cl-~7alkyl, such as acetylaminomethyl, propionylaminomethyl,
butyrylarninomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl,
5-acetylaminopentyl or 6-acetylaminohexyl, N-C2-C7aL1canoyl-N-Cl-C4alkyl-
amino-Cl-C7alkyl, such as N-acetyl-N-methylarninomethyl, N-acetyl-N-ethyl-
aminomethyl, 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-methyl-
amino)butyl, 5-(N-acetyl-N-methylamino)pentyl or 6-(N-acetyl-N-methylamino)hexyl,
di-Cl-C7alkylamino-Cl-C7aLIcyl, such as dimethylaminomethyl, diethylaminomethyl,N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl,
dibutylaminomethyl, 2-dimethylarrunoethyl, 3-dimethylaminopropyl, 4-dimethyl-
aminobutyl, S-dimethylaminopentyl or 6-dimethylaminohexyl,
azacycloalk-l-yl-CI-C7aLlsyl, such as pyrrolidinomethyl, piperidinome~hyl,
2-pyrrolidinoethyl, 2-piperidinoethyl, 3-py~rolidinopropyl, 3-piperidinopropyl, 4-pyrroli-
dinobutyl, 4-piperidinobutyl, S-pyrrolidinopentyl, S-piperidinopentyl, ~pyIrolidinohexyl
or ~piperidinohexyl, azacycloaL~c-3-yl-Cl-C7aLkyl or -4-yl-Cl-C7aL~cyl, for exarnple
piperidin-4-ylmethyl, 2-(piperidin-4-yl~ethyl, 3-(piperidin-4-yl)propyl or
4-(piperidin-4-yl)butyl, l-C2-C7aL1canoylazacycloaLlc-3-yl-Cl-qalkyl or
-4-yl-C1-C7alkyl, for example 1-acetylpiperidin-4-ylmethyl, 2-(1-acetylpiperidin-4-yl)-
ethyl, 3-(1-acetylpiperidin-4-yl)propyl or 4-(1-acetylpiperidin-4-yl)butyl,
N-Cl-C4alkylazacycloalk-3-yl-Cl-qaLtcyl or -4-yl-Cl-qalkyl, for example
~2~3~,~
- 12-
l-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-ethyl-
piperidin-4-yl)butyl, N-Cl-C4benzoylazacycloalk-3-yl-Cl-C7alkyl or -4-yl-Cl-C7alkyl,
for example l-benzoylpiperidin-4-ylmethyl, 2-(1-benzoylpiperidin-4-yl)ethyl,
3-(1-benzoylpiperidin-4-yl)propyl or 4-(1-benzoylpiperidin-4-yl)butyl,
diazacycloalk-l-yl-Cl-C7alkyl, N'-Cl-C4aL~cyldiazacycloalk-l-yl-Cl-C7alkyl or
N'-C2-qalkanoylazacycloalk-1-yl-Cl-qalkyl, for example piperazino- or N'-methyl- or
N'-acetyl-piperazino-methyl, 2-(pipcrazino- or N'-methyl- or N'-acetyl-piperazino)-ethyl,
3-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-propyl or 4-(piperazino- or
N'-methyl- or N'-acetyl-piperazino)-butyl, azoxacycloalk- l-yl-Cl-C7aLtcyl, for example
morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 4-morpholinobutyl, 5- to
7-membered oxacycloalk-3-yl-Cl-qalkyl or -4-yl-Cl-C7aL~cyl, such as tetrahydropyran-
4-ylmethyl, 2-(tetrahydropyran-4-yl)ethyl, 3-~tetrahydropyran-4-yl)propyl or
4-(tetrahydropyran-4-yl)butyl, S- to 7-membered azacycloalk-3-yl or -4-yl or 1-C2-q-
alkanoylazacycloalk-3-yl or -4-yl, ~or exarnple piperidin-4-yl or 1-acetylpiperidin-4-yl,
N-Cl-C4aLIcylazacycloalk-3-yl or -4-yl or N-benzoylazacycloalk-3-yl or -4-yl that is
unsubstituted or substituted in the phenyl moiety, for example l-methylpipeAdin-4-yl or
l-benzoylpiperidin-4-yl, or 5- to 7-membered oxacycloalk-3-yl or -4-yl, for example tetra-
hydropyran-4-yl, and R2 is carboxy, Cl-C4alkoxycarbonyl, such as me~hoxycarbonyl or
ethoxycarbonyl, 5- to 7-membered cycloaLIcoxycarbonyl, such as cyclopentyloxy- or
cyclohexyloxy-carbonyl, or phenyl-Cl-C4aLIcoxycarbonyl that is unsubstituted or mono-
or di-substituted by Cl-C4aLlcyl, such as methyl, Cl-C4alkoxy, such as methoxy, halogen
having an atomic number of up to and including 35, such as fluorine or chlo~ne, cyano
and/or by trifluoromethyl, such ~s benzyloxycarbonyl or 2-phenylcthoxycarbonyl, and
their salts, especially their pharmaceutically acceptable salts.
~he invention relates especially, for example~ to compounds of formula I wherein Rl is
hydroxy-Cl-C7aL~cyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-
hydroxybutyl, Cl-C4aL~coxy-Cl-qalkyl, such as methoxymethyl, ethoxyme~hyl,
2-methoxyethyl, 2-ethoxye~hyl, 3-methoxypropyl or 4-methoxybutyl, a
phenyl-Cl-C4aLIcoxy-Cl-C7allcyl group that is unsubstituted or mon~, di- or
tri-substituted in the phenyl moiety by Cl-C4alkyl, such as methyl, Cl-C4aLkoxy, such as
methoxy, halogen having an atomic number of up to and including 35, such as fluoline or
chlorine, cyano andlor by trifluoromethyl, such as a benzyloxymethyl, 2-benzyloxyethyl,
3-benzyloxypropyl or 4-benzyloxybutyl group, amino-Cl-C7alkyl, such as an~inomethyl,
~ ~ 2 ;, ~
- 13-
2-arninoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-aminohexyl,
Cl-C4aL~ylamino-Cl-C7aL~cyl, such as methylaminomethyl, ethylaminomethyl,
propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl, C2-C7alkanoylamino-Cl-C7alkyl, such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-
acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-
acetylaminohexyl, di-Cl-C7alkylamino-Cl-C7alkyl, such as dimethylaminomethyl,
diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl,
dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 3-di-
methylaminopropyl, 4-dimethylaminobutyl, 5-dimethylarninopentyl or
6-dimethylaminohexyl, 5- to 7-membered N,N-(aza- or s:~xa-alkylene)amino-Cl-C7aL~yl,
such as pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, piperazino- or
N'-methyl- or N'-acetyl-piperazino-methyl, 2-pyrrolidinoethyl, 2-piperidinoethyl,
2-morpholinoethyl, 3-pyrrolidinopropyl, 3-piperidinopropyl, 3-morpholinopropyl, 4-pyrro-
lidinobutyl, 4-piperidinobutyl, 5-pyrrolidinopentyl, 5-piperidinopentyl or
6-piperidinohexyl, or halo-Cl-C7aL~cyl, such as halomethyl, 2-haloethyl, 3-halopropyl,
4-halobutyl, S-halopentyl or 6-halohexyl, in which halogerl is chlorine or, especially,
fluorine, and R2 is carboxy, Cl-C4alkoxycarbonyl, such as methoxycarbonyl or
ethoxycarbonyl, 5- to 7-membered cycloaL1coxycarbonyl, such as cyclopentyloxy- or
cyclohexyloxy-carbonyl, or phenyl-C~l-C4aLtcoxycarbonyl that is unsubstituted or mono-
or di-substituted by Cl-C4aL~cyl, such as methyl, Cl-C4aLtcoxy, such as methoxy, halogen
having an atomic number of up to and including 35, such as fluorine or chlorine, cyano
and/or by trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and
their salts, especially their pharmaceutically acceptable salts.
.
The invention relates preferably to compounds of formula I whe~ein Rl is hydroxy-
Cl-qalkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl,
benzoyloxy-Cl-qaLlcyl that is unsubstituted or mono- or di-substi~uted in the phenyl
moiety by Cl-C4alkyl, such as methyl, Cl-C~ oxy, such as methoxy, halogen having an
atomic number of up to and including 35, such as fluorine or chlorine, cyano andlor by tri-
fluoromethyl, such as 2-benzoyloxyethyl, Cl-C4alkoxy-Cl-C7alkyl, such as
ethoxymethyl or 2-methoxyethyl, phenyl-Cl-C4aLIcoxy-Cl-C7aL~yl that is unsubstituted
or mono- or di-substituted in the phenyl moiety by Cl-C4aL~yl, such as methyl,(
Cl-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including
35, such as fluorine or chlorine, cyano and/or by tri~luoromethyl, such as benzyloxymethyl
or 2-benzyloxyethyl, halo-Cl-C7alkyl, such as halomethyl or 2-haloethyl, in which
2l~2~g
- 14-
halogen is chlorine or, especially, fluorine, amino-C4-qalkyl, such as 4-aminobutyl or
6-aminohexyl, N-C2-C7aLkanoyl-N-Cl-C4aLkylarnino-Cl-C7alkyl, such as N-acetyl-
N-methylaminometllyl, 5- to 7-membered azacycloalk-3-yl or -4-yl or 1-C2-C7-
alk~moylazacycloalk-3-yl or -4-yl, for example piperidin-4-yl or 1-acetylpiperidin-4-yl,
and R2 is carboxy, Cl-C4aLkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or
phenyl-Cl-C4aLkoxycarbonyl that is unsubstituted or mono- or di-substituted by
Cl-C4aLkyl, such as methyl, Cl-C4aLkoxy, such as methoxy, halogen having an atomic
number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoro-
methyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially
their pharmaceutically acceptable salts.
The invention relates especially, on the one hand, to compounds of formula I wherein R
is hydroxy-Cl-C4alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-
hydroxybutyl, Cl-C4aLkoxy-Cl-C4alkyl, such as methoxymethyl, ethoxymethyl,
2-methoxyethyl, 3-methoxypropyl or 4-methoxybutyl, a phenyl-Cl-C4aLkoxy-Cl-C~aL~yl
group that is unsubstituted or mono-, di- or tri-substituted in the phenyl moiety by Cl-C4-
aLkyl, such as methyl, Cl-C4aLkoxy, such as methoxy, halogen having an atomic number
of up to and including 35, such as fluorine or chlorine, cyano andlor by tri~luoromethyl,
such as a benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl
group, or halo-Cl-C4aLlcyl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl,
5-halopentyl or 6-halohexyl, in which halogen is chlorine or, especially, fluorine, and R2
is carboxy, Cl-~4aLIcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to
7-membered cycloaLkoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or
phenyl-Cl-C4aL~coxycarbonyl that is unsubstituted or mono- or di-substituted by
Cl-C4alkyl, such as methyl, Cl-C4aL~coxy, such as methoxy, halogen having an atomic
number of up to and including 35, such as fluorine or chloline, cyano and/or by
trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts,
especially their pharmaceutically acceptable salts.
The invention relates especially, on the other hand, to compounds of formula I wherein R
is amino-Cl-C7aL~cyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl,
5-aminopentyl, 6-aminohexyl or 7-arninoheptyl, Cl-C4aL~ylamino-Cl-qalkyl, such as
methylarninomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl,
2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or
~methylaminohexyl, C2-c7aL~canoylamino-ci-qaLlcyl~ such as acetylaminomethyl,
propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl,
2~
- 15-
4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, di-C1-C4alkyl-
amino-C1-qalkyl, such as dimethylarninomethyl, diethylaminomethyl, N-ethyl-N-
methylaminomethyl, N-methyl-N-propylarninomethyl, dipropylaminomethyl, dibutyl-
aminomethyl, 2-dimethylaminoethyl, 3-dimethylan~inopropyl, 4-dimethylaminobutyl,5-dimethylaminopentyl or 6-dimethylaminohexyl, 5- to 7-membered N,N-(aza- or
oxa-alkylene)amino-Cl-C7alkyl, such as pyrrolidinomethyl, piperidinomethyl,
morpholinomethyl, piperazino- or N'-rnethyl- or N'-acetyl-piperazino-methyl,
pyrrolidinoethyl, piperidinoethyl, morpholinoethyl, pyrrolidinopropyl, piperidinopropyl,
morpholinopropyl, pyrrolidinobutyl, piperidinobutyl, pyrrolidinopentyl, piperidinopentyl
or piperidinohexyl, and R2 is carboxy, Cl-C4aLtcoxycarbonyl, such as methoxycarbonyl or
ethoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, such as cyclopentyloxy- orcyclohexyloxy-carbonyl, or phenyl-Cl-C4aL~coxycarbonyl that is unsubstituted or mono-
or di-substituted by C1-C4aL~yl, such as methyl, C1-C4aL~coxy, such as methoxy, halogen
having an atomic number of up to and including 35, such as fluorine or chlorine, cyano
andlor by trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and
their salts, especially their pharmaceutically acceptable salts.
The invention relates more especially to compounds of formula I wherein R1 is
hydroxy-Cl-C7aLtcyl, such as hydroxymethyl, Cl-C4alkoxy-Cl-C7alkyl, such as
methoxymethyl, ethoxymethyl or 2-methoxyethyl, benzoyloxy-Cl-C4alkyl, such as
2-benzoyloxyethyl, phenyl-C1-C4aL~coxy-C1-C7a1kyl, such as benzyloxymethyl or
2-benzyloxyethyl, amino-c4-qaLlcyl~ such as 4-aminobutyl or 6-arninohexyl, N-C2-C7-
alkanoyl-N-cl-c4allcylamino-c2-qaLkyl~ such as 2-(N-acetyl-N-methylamino)ethyl, 5-
to 7-membered azacycloaLl~-3-yl or -4-yl or 1-C2-C7aL~canoylazacycloaLIc-3-yl or -4-yl,
such as piperidin-4-yl or 1-acetylpipelidin-4-yl, or halo-C1-C4aL~cyl, in which halogen is
chlorine or, especially, ~luorine, such as 2-haloethyl, and R2 is carboxy or
Cl-C4aLIcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts,
especially their pha~maceutically acceptable salts.
The invention relates preferably, on the one hand, to compounds of formula I wherein R
is amino-C4-qaL~cyl, such as 4-arninobutyl or ~aminohexyl, N-Cl-C4-
alkanoyl-N-Cl-C4alkylamino-Cl-qaL~yl, pipe~idin-4-yl or 1-C 2-C7aLlsanoyl-
piperidin-4-yl, such as 1-acetylpiperidin-4-yl, and R2 is carboxy or C1-C4alkoxycarbonyl,
such as methoxycarbonyl or ethoxycarbonyl, and their salts.
The invention relates preferably, on the other hand, to compounds of formula I wherein R
- 16-
is Cl-C4alkoxy-Cl-C4alkyl, such as methoxymethyl, ethoxymetllyl or 2-methoxyethyl,
phenyl-Cl-C4alkoxy-Cl-C4alkyl7 such as benzyloxymethyl or 2-benzyloxyethyl,
benzoyloxy-Cl-C4alkyl, such as 2-benzoyloxyethyl, hydroxy-Cl-C4alkyl, such as
hydroxymethyl or 2-hydroxyethyl, or halo-C2-C4allcyl, such as 2-fluoroethyl, and R2 is
carboxy or Cl-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their
s~llts.
The invention relates very especially, on the one hand, to compounds of ~ormula I wherein
Rl is amino-C4-qalkyl, such as 4-aminobutyl, S-aminopentyl, ~aminohexyl or 7-amino-
heptyl, and R2 is carboxy, Cl-C4aLkoxycarbonyl, such as methoxycarbonyl or
ethoxycarbonyl, or a phenyl-Cl-C4aLkoxycarbonyl group that is unsubstituted or mono- or
di-substi~uted by Cl-C4aLkyl, such as methyl, Cl-C4aL~coxy, such as me~hoxy, halogen
having an atomic number of up to and including 35, such as fluorine or chlorine, cyano
andJor by trifluoromethyl, such as a benzyloxycarbonyl or 2-phenylethoxycarbonyl group,
and their salts, especially their pharmaceutically acceptable salts.
The invention relates very especially, on the other hand, to compounds of formula I
wherein Rl is Cl-C4aLkoxy-C2-C4aLI<yl, such as 2-methoxyethyl, 2-ethoxyethyl,
3-meehoxypropyl or 4-methoxybutyl, hydroxy-C2-C4aLkyl, such as 2-hydroxyethyl,
3-hydroxypropyl or 4-hydroxybutyl, or halo-C2-C4aLlcyl, such as 2-fluoroethyl,
2-chloroethyl, 3-fluoropropyl or 4-fluorobutyl, and R2 is carboxy, Cl-C4aLIcoxycarbonyl,
such as methoxycarbonyl or ethoxycarbonyl, or a phenyl-Cl-C4aLkoxycarbonyl group that
is unsubstituted or mono- or di-substituted by Cl-C4aLlcyl, such as methyl, Cl-C4aLlcoxy,
such as methoxy, halogen having an atomic number of up to and including 35, such as
fluorine or chlorine, cyano and/or by trifluoromethyl, such as a benzyloxycarbonyl or
2-phenylethoxycarbonyl group, and their salts, especially their pharmaceuticallyacceptable salts.
The invention relates specifically to the compounds of formula I mentioned in the
Examples and their salts, especially their pharmaceutically acceptable salts.
The process for the preparation of the compounds according to the invention is as follows:
in a compound of formula II
.
2 ~ 2 ~
- 17-
Z~ /~ R2
Z2 Z3 Z4
wherein Zl. Z2 are optionally protected hydroxy, Z3 is an aliphatic hydrocarbon radical
that is substituted by optionally protected or acylated or aliphatically or araliphatically
etherified hydroxy, by halogen, by optionally protected or acylated and/or aliphatically
substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an
oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally
protected or aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon
radical, and Z4 is protected arnino, protected amino Z4 and, if present, protected amino as
a constituent of Z3 is converted into amino and, if present, protected hydroxy Zl. Z2
and/or protected hydroxy as a constituent of :Z3 is converted into hydroxy and, if present, a
protected azacycloaliphatic hydrocarbon radical Z3 is freed and, if desired, a resulting
compound is converted into a different compound of formula I, an isomeric rnixture
obtainable in accordance with the process is separated into its components and the
preferred isomer is separated, andlor a free compound obtainable in accordance with the
process is converted into a salt or a salt obtainable in accordance with the process is
converted into the corresponding free compound.
In starting materials of formula II, protected hydroxy Zl andJor Z2 is, for example,
etheri~led, especially aliphatically or aromatically etheri~led, hydroxy, protected hydroxy
Z3 is, for exarnple, acylated or silylated hydroxy, and protected amino Z4 and, if present,
protected amino as a constituent of Z3 is, for exarnple, acylated amino.
Aliphatically etheriffed hydroxy is, for example, iower aLtcoxy, such as me~hoxy, ethoxy
or, especially, isopropoxy. Aromatically etherified hydroxy is, for example, phenoxy that
is unsubstituted or substituted by lower aLkyl, lower alkoxy, halogen, cyano andlor by
nitro.
Acylated hydroxy contains as the acyl group, for example, the acyl radical of anaraliphatic carboxylic acid or of a semi-ester of carbonic acid and is, for example, lower
alkanoyloxy or a phenyl-lower aLlcanoyloxy or phenyl-lower aLlcoxycarbonyloxy group
~hat is unsubstituted or substituted in the phenyl moiety by lower aLIcyl, lower aL~coxy,
halogen, cyano and/or by trifluoromethyl, for example benzyloxycarbonyloxy.
2 ~
- 18-
Silylated hydroxy is, for example, tri-lower alkylsilyloxy, for example trimethyl- or
tributyl-silyloxy.
Acylated amino contains as the acyl group, for example, acyl derived from a suitable
organic acid, such as forrnic acid, or from an araliphatic or aromatic semi-ester of carbonic
acid. Accordingly, acylated amino is, for exarnple, formylamino, lower
alkoxycarbonylamino, such as methoxy-, ethoxy- or tert.-butoxy-carbonylamino, or a
phenyl-lower aL'coxycarbonylamino or or phenoxycarbonylamino group that is
unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen,
cyano and/or by nitro, such as benzyloxycarbonylamino, substituted by lower aLIcyl, lower
alkoxy, halogen, cyano and/or by nitro.
The freeing of the protected groups ~rom compounds of formula II, i.e. of hydroxy from
protected hydroxy groups Zl, Z2 and/or from protected hydroxy groups as a constituent of
Z3, or of amino from protected amino groups ~4 and, if present, from protected amino
groups as a constituent of Z3, is carried out, for example, by treatment with an acidic
agent, for example with a tri-lower aLkylhalosilane, such as trimethylbromosilane,
tributylbromosilane or trimethyliodosilane. The operation is preferably carried out in an
inert solvent, such as a halogenated aliphatic hydrocarbon, for example dichloromethane
or, secondly, tri- or tetra-chloromethane, trichloroethane or tetrachloroethane, for example
in a temperature range of frorn approximately -25 ~o approximately +50C, preferably of
approximately from 0 to 30C, for example at room temperature, i.e. at approximately
from 15 to 25C, advantageously under substantially anhydrous condi~ions and under an
inert gas, such as argon or nitrogen. Working up is preferably carried out with the addition
of a hydrogen halide acceptor, especially an aliphatic epoxy compound, such as an
`epoxy-lower aLIcane, for example propylene oxide in a lower aL4anol, such as ethanol.
In a prefelred form, for example compounds of formula II wherein Zl and Z2 are lower
alkoxy, for example isopropoxy, and Z4 is lower aLkanoylamino, such as formylamino, are
used as starting materials and are treated in an aliphatic halogenated hydrocarbon, such as
dichloromethane, at from approximately 15 to approxirnately 25C, with a tri-lower
alkylbromosilane, such as ~imethylbromosilane or tributylbromosilane; the rnixture is left
for a time, for example from 2 to 30 hours, to complete the reaction, and then an ethanolic
solution of propylene oxide is added and the product is removed by filtration.
~2.~u~
- 19-
Starting materials of formula II are prepared, for example, by reacting an a,~-unsaturated
aldehyde of forrnula IIa
~0
z~ (IIa)
with an (x-isocyanoacetic acid ester of forrnula IIb
:C~ N ~- R2 (IIb)
in a manner known Per se9 for example in the presence of a copper or gold catalyst, for
example copper(I) oxide or bis(cyclohexylisocyanide)gold(I) tetrafluoroborate, to give the
corresponding S-substituted 2-oxazoline-4-carboxylic acid ester of forrnula IIc
z3
=< ~J?2
---~ (IIc)
O~N
conYerting the ester of formula IIc by hydrolysis, for example in aqueous tetrahydrofuran,
into the corresponding open-chained ester of formula IId
OH
"R2 (IId~,
NHCH=O
converting the ester of formula IId by treatment with thionyl brornide in a manner known
per se into the corresponding ~bromic ester of formula IIe
B r CH2 ~R2 (~e)
Z3 NHC~=O
~a2~?s
and reacting the ester of formula IIe further in a manner known ~ se with a phosphorous
acid triester of the formula P(Za)(Zb)(ZC), wherein Za. Zb and ~c are identical or different
hydroxy groups protected in an ether form, such as a tri-lower alkyl phosphite, for
example triisopropyl phosphite, to give the corresponding compound of formula II'
o
Z \ ~ R2
Z3 NHCH=O
Compounds obtainable in accordance with the process can be converted in customary
manner into different compounds of formula I.
For example, free and esterified carboxy groups R2 can be converted in customary manner
into one another. In particular, esterified carboxy R~ can be converted into carboxy by
hydrolysis, or free carboxy R2 can be converted into esterified carboxy by reaction with
an alcohol. Furthermore, esterified carboxy R2 can be transesterified to form a different
esterified carboxy group. These transesterification reactions are carried out in customary
manner under hydrolytic, alcoholytic or transesterifying conditions.
The hydrolysis of carboxylic acid esters (I; R2 = esterified carboxy) is carried out in
customary manner, if necessary in the presence of an acidic or basic agent, such as a
mineral acid, for example hydrochloric acid or sulfuric acid, or a base, such as an aLlcali
metal hydroxide, for example sodium hydroxide.
The transesterification of esters (I; R2 = esterified carboxy) with alcohols is usually
carried out under conditions of acid-catalysis or base-catalysis, fo} example in the
presence of a catalytic amount of a mineral acid, such as hydrochloric acid or sulfuric
acid, or of a metal base, such as sodium hydroxide, or by employing the alcohol
component in the form of a metal alcoholate, for example an aLkali metal alcoholate.
Furthermore, in aliphatic hydrocarbon radicals substituted by araliphatically etherified
hydroxy, such as a-phenyl-lower aL~coxy-lower aLIcyl radicals Rl, the a-phenyl-lower
alkoxy group can be converted into hydroxy by reduction, for example by treatment wi~
hydrogen in the presence of a hydrogenation catalyst, such as palladium-on-carbon or
Raney nickel.
-21- 202~
Resulting salts can be converted into the free compounds in a manner known Per se, for
example by treatment with a base, such as an aLkali metal hydroxide, a metal carbonate, a
metal hydrogen carbonate or ammonia, or with another salt-forming base mentioned at the
beginning, or with an acid, such as a mineral acid, for example hydrochloric acid, or
another salt-forming acid mentioned at the beginning.
Resulting salts can be converted into different salts in a manner known 1~ se, in the case
of acid addition sal~s, for example, by treatment with a suitable metal salt, such as a
sodium, barium or silver salt, of a different acid in a suitable solvent in which an inorganic
salt being formed is insoluble and therefore is eliminated from the reaction equilibrium,
and in the case of base salts, by freeing the free acid and converting it into a salt again.
The compounds of formula I, including their salts, may also be obtained in the form of
hydrates or include the solvent used for crystallisation.
In view of the close relationship between the novel compounds in free form and in the
form of their salts, hereinbefore and hereinafter any reference to the free compounds or
their salts should be understood as including also the corresponding salts or free
compounds, respectively, where appropriate and expedient.
Resulting diastereoisomeric mixtures and mibctures of racemates can be separated into the
pure diastereoisomers and racemates in known manner on the basis of the
physicochemical differences between the constituents, for example by chromatography
and/or fractional crystallisation. -
Furthermore, resulting racemates can be separated into the optical antipodes by knownmethods, for example by recrystallisation from an optically active solvent, with the aid of
microorganisms, or by reaction of the resulting diastereoisomeric mixture or racemate
with an optically active auxiliary compound, for example, according to the acid, basic or
functionally modifiable groups contained in compounds of formula I, with an optically
active ~cid, base or an optically active alcohol, ~o form mixtures of diastereoisomeric salts
or functional derivatives, such as esters, and separation thereof into the diastereoisomers
from which the desired enantiomer can be freed in the customary manner. Suitable bases,
acids and alcohols are, for example~ amino acids, especially lysine, optically active
alkaloid bases, such as strychnine, cinchonine or brucine, or ~ or L-(1-phenyl)ethylarnine,
2 ~
-22 -
3-pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases, optically
active carboxylic or sulfonic acids, such as quinic acid or ~ or L-tartaric acid, D- or
L-di-o-toluyltartaric acid, D- or L-malic acid, ~ or L-mandelic acid or D- or L-camphor-
sulfonic acid, and optically active alcohols, such as borneol or ~ or L-~l-phenyl)ethanol.
The invention relates also to those forms of the process in which a compound obtainable
as intermediate at any stage of the process is used as starting material and the remaiDing
steps are carried out, or in which a starting material is used in the form of a salt or,
especially, is formed under the reaction conditions.
The invention relates also to the novel starting materials developed specifically for the
preparation of the compounds according to the invention, especially to those starting
materials resulting in the compounds of forrnula I that were described at the beginning as
being preferred, to processes for the preparation thereof and to their use as interrnediates.
The novel compounds of folmula I can be used, for example, in the form of
pharmaceutical preparations that contain a therapeutically effective amount of the active
ingredient, optionally together with inorganic or organic, solid or liquid, pharmaceutically
acceptable carriers, which are suitable for enteral, e.g. oral, or parenteral administration.
There are used, for example, tablets or gelatin capsules that contain the active ingredient
together with diluents, for exarnple lactose, dextrose, saccharose, mannitol, sorbitol,
cellulose, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as
magnesium or calcium stearate, and/or polyethylene glycol. Tablets can also contaun
binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or
arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose
and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar,
alginic acid or a salt thereof, for example sodium alginate, and/or effervescent mixtures, or
absorbents, colouring agents, flavourings and sweeteners. The novel compounds offormula 1 can also be used in the form of parenterally administrable preparations or in the
form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or
suspensions which, for example in the case of lyophilised preparations that con~ain the
active ingredient on its own or together with a calTier, for example mannitol, can be
prepared before use. The pharmaceutical preparations may be sterilised and/or may
contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers,
solubilisers, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical
preparations in question, which, if desired, may contain further pharmacologically active
2Q2~
- 23 -
su~stances, are prepared in a manner known ~ se, for example by means of conventional
mixing, granulating, confectioning, dissolving or lyophilising processes, and contain
approximately from 0.1 % to 100 %, especially from approximately 1 % to approximately
50 %, in the case of lyophilisates up to approximately 100 %, active ingredient.
The invention relates also to the use of the compounds of formula I, preferably in the form
of pharmaceutical preparatiolls. The dosage may depend on various factors, such as the
mode of administration and the species, age and/or individual condition. The daily doses
are, in the case of oral administration, from approximately 0.25 to approximately
10 mg/kg, and in the case of warm-blooded animals having a body weight of
approximately 70 kg, they are preferably from approximately 20 mg to approximately 500
mg.
The following Exarnples illustrate the invention; temperatures are given in degrees Celsius
and pressures in mbar.
Example 1: 3.57 g (8.5 mrnol) of 6-acetoxy-4-diisopropylphosphono-
methyl-2-forrnylamino-hex-3-enoic acid ethyl ester are dissolved in 22 ml of dichloro-
methane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at roomtemperature. The mix~ure is left to stand at room temperature for 22 hours, ~2 ml of
ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is con-
centrated by evaporation in a rotary evaporator, the residue is dissolved in 22 ml of
ethanol, and a mixture of 22 ml of propylene oxide and 22 rrl of ethanol is added drop-
wise. A suspension forms, which is stirred for a fu~ther 90 rninutes and then filtered with
suction. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a
melting point of 195 (decomp.) is obtained.
The starting material can be prepared, for example, as follows:
13.0 g (100 mmol) of acetic acid (4-oxo)bu~yl ester, 92.0 g (112.6 mmol) of
dimethylammonium chloride and 10.8 ml (117 mmol) of 37 % formaldehyde solution are
heated at 100 ~or one hour with stirring. The mixture is allowed to cool and is extracted 3
times with 30 ml of diethyl ether each time. The organic phases are combined, washed
with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to
dryness by evaporation. Acetic acid (3-formyl)but-3-enyl ester is obtained in the form of
a colourless oil which can be reacted further without further purification.
2 ~ 2 ~
- 24 -
13.5 g (95 mmol) o~ acetic acid (3-formyl)but-3-enyl ester and 10.4 g (9S mmol) of
isocyanoacetic acid ethyl ester are added dropwise to a suspension of 0.38 g of copper(I)
oxide in S0 ml of benzene. When the exothermic reaction has subsided, the mixture is
stirred at room temperature for a further 45 minutes, filtered over Hyflo(~ and
concentrated to dryness by evaporation. The residue is taken up in 75 ml of tetrahydro-
furan, 25 ml of water are added, and the mixture is heated under reflux for 4 hours with
stirnng. The mixture is concentrated to dryness by evaporadon and chromatographed on
silica gel with toluene/isopropanol (9:1) as eluant.
6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester is obtained in
the form of a brownish oil.
9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoi~ acid
ethyl ester are dissolved in 100 ml of dichloromethane, and 3.34 ml (43.1 mmol) of
thionyl bromide are added dropwise at room temperature. After one hour, 10 ml of water
are added and the mixture is stirred vigorously for 10 minutes. The organic phase is
separated off, washed in succession with water, saturated potassium hydrogen carbonate
solution and again with water, dried over magnesium sulfate, filtered and concentrated by
evaporation. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is
obtained in the form of a brownish oil.
8.7 g (25 mmol) of 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester
and 21 ml (75 mmol) of triisopropyl phosphite (90 %) are heated to from 80 to 90C and
stirred for 19 hours under a pressure of approximately 100 mbar. The excess triisopropyl
phosphite is distilled off and the evaporation residue is chromatographed on 150 g of silica
gel with first ethyl acetate and then ethyl acetate/ethallol (9:1) as eluants. 6-acetoxy-4-
diisopropylphosphonomethyl-2-formylamin~hex-3-enoic acid ethyl ester is obtained in
the form of a yellowish oil.
ExamDle 2: 0.415 g (1.55 mmul) of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic
acid ethyl ester is heated under reflux in 3 ml of water for 24 hours. The reaction mixture
is concentrated by evaporation, purified by chromatography on 10 g of silica gel with
ethanoVwater (1:1) as eluant, and crystallised from e~hanol.
2-arnino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid having a melting point >300 is
obtained.
2~2~v~
-25 -
Example 3: 0.5 g (1.0 mmol) of 8-(N-benzyloxycarbonylamino)-
4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is heated under
reflux in 5.0 ml of 6N hydrochloric acid for 6 hours. Concentration to dryness by evapora-
tion yields 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid dihydrochloride in the form
of a rubber-like solid which is recrystallised from acetonitrile; m.p. 128 (decomp.).
The starting rmaterial can be prepared as follows:
7.06 ml (47 mmol) of chloroformic acid benzyl ester are added dropwise to a solution of
5.52 g (47 mmol) of 6-aminohexan-1-ol and 3.95 g (47 mrnol) of sodium hydrogen
caIbonate in 100 ml of acetone and SU ml of water. The mixture is stirred at room
temperature for 18 hours and concentrated to approximately 70 ml, and the white
precipitate is filtered off, washed with approximately 20 ml of water, taken up in 250 ml
of methylene chloride and dried over magnesium sulfate; the magnesium sulfate is filtered
off and the residue is concentrated to dryness by evaporation. 6-(N-benzyloxyca~bonyl-
amino)hexan-l-ol is obtained in the form of white crystals having a melting point of
58-60.
0.32 ml (4.40 mrnol) of dimethyl sulfoxide is added dropwise under nitrogen to a solution
of 0.19 ml (2.20 mmol) of oxalyl chloride in 10 ml of methylene chloride which is being
stirred at -50. The mixture is stirred for 15 minutes, and then 0.5 g (2 mrnol) of
6-(N-benzyloxycarbonylamino)hexan-l-ol is added. Stirring is continued at -50 for
25 minutes, 1.78 ml ~10 mmol) of N-ethyl-N,N-diisopropylamine are added dropwise and
the mixture is poured into 10 ml of ice-water. The organic phase is separated off and the
aqueous phase is extracted with 10 ml of methylene chlonde. The organic phases are
combined, washed twice with S ml of N-hydrochloric acid each time and once with 10 ml
of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to
dryness by evaporation. The resulting oil is purified by chromatography on silica gel with
hexanelethyl acetate (1:1) as eluant. 6-(N-benzyloxycarbonylamino)hexanal is obtained.
2.44 g (30 mmol) of 37 % aqueous formaldehyde solution are added to a solution of 1.5 g
(17 mmol) of anhydrous piperazine and 2.03 g (34 mmol) of acetic acid in 18.7 ml of
water. The mixture is sti~red at 25 for 15 minutes, and then 7.48 g (30 mmol) of
6-(N-benzyloxycarbonylamino)hexanal are added thereto. The reaction mixture is heated
under reflux for 2 hours and then cooled with ice-water and extracted twice with 50 ml of
methylene chloride each time. The extracts are combined, washed twice with 25 ml of
~ 3 ~J .~
- 26 -
saturated sodium hydrogen carbonate solution each eime and with 25 ml of saturated
sodium chloride solution, dried and concentrated to dryness by evaporation.
6-(N-benzyloxycarbonylarnino)-2-methylene-hexanal is obtained in the form of a
yellowish liquid.
4.0 g (15.3 mmol) of 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal and 1.62 ml
(16.8 mmol) of isocyanoacetic acid methyl ester are dissolved in 50 ml of toluene and
added dropwise at 40 to a suspension of 0.12 g of 96.4 % copper(I) oxide in 50 ml of
toluene. The mixture is then stirred at room temperature for 2.5 hours, filtered, introduced
into a column filled with 6û g of silica gel and extracted first with hexane/ethyl acetate
(1:1) and then with ethyl acetate.
5-[6-(N-benzyloxycarbonylamino)hex-l-en-2-yl]-oxazoline-4-carboxylic acid methyl ester
is obtained; oil.
9.4 g (26.1 mmol) of 5-[6-(N-benzyloxycarbonylarnino)hex-l-en-
2-yl]-oxazoline-4-carboxylic acid methyl ester are dissolved in 40 ml of tetrahydrofuran
and 20 ml of water, a few drops of triethylamine are added and the mixture is heated under
reflux for 18 hours. The solvent is removed under reduced pressure and the oil that
remains is taken up in a total of 125 ml of methylene chloride, dried ovçr magnesium
sulfate and concentrated to dryness by evaporation. 8-(N-
benzyloxycarbonylarn~no)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl
ester is obtained.
To 2.46 g (6.5 mmol) of 8-(N-benzyloxycarbonylarnino)-2-formyl-
amino-3-hydroxy-4-methylene-octanoic acid methyl ester in 25 ml of tetrahydrofuran
there are added S.S ml (46 mmol) of hexa-1,5-diene and then, dropwise at -50, 2.6 ml
(32.5 mmol) of thionyl bron~ide. The mixture is stirred at from 0 to 5 for 2 hours,
poured into 25 ml of ice-cold saturated sodium hydrogen carbonate solution and extracted
twice with 20 ml of methylene chloride each time. The organic phase is washed with
10 ~nl of saturated sodium chloride solution, dried over magnesium sulfate and concen-
trated to dryness by evaporation. The resulting oil is purified by chromatography on silica
gel with hexane/ethyl acetate (3:1). 8-(N-benzyloxycarbonylamino~-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.
5 ml of triethyl phosphite are added to 1.45 g (3.3 mmol) of
8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl
2 3 ~
- 27 -
ester, and the mixture is heated at 75 for 8 hours with stirring. The excess triethyl
phosphite is distilled off under reduced pressure to give an oily residue which is purified
by chromatography on a silica gel column with first ethyl acetate and then ethylacetate/methanol (9:1). 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-
2-formylamino-oct-3-enoic acid methyl ester is obtained.
Exarnple 4: 1.77 g (4.5 mmol) of 4-diisopropylphosphonomethyl-
2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester are dissolved in 12 ml of
dichloromethane, and 2.32 ml (18.0 mmol) of trimethylbromosilane are added dropwise at
room temperature. The mixture is left to stand at room temperature for 22 hours, 12 ml of
ethanol are added dropwise, the mixture is left to stand for a furiher 24 hours and is
concentrated by evaporation in a rotary evaporator, the residue is dissolved in 10 ml of
ethanol, and a mixture of 2 ml of propylene oxide and 2 ml of ethanol is added. A
suspension forms, which is s~irred for a fur~her 2 hours at room temperature and for
2 hours wi~h ice cooling, and is then filtered with suction. 2-amino-6-methoxy-4-phos-
phonomethyl-hex-3-enoic acid ethyl ester having a melting point of 242 (decomp.) is
obtained.
The starting material can be prepared, for exarnple, as follows:
19.7 g (193 mmol) of 4-methoxybutanal, 17.7 g (217 mmol) of dimethylammonium
chloride and 17.0 ml (226 mmol) of 37 % formaldehyde solution are heated at 100 for
3 hours with stirring. The mixture is allowed to cool and is extracted 3 times with diethyl
ether. The organic phases are washed with saturated sodium chloride solution, combined,
dried over sodium sulfate, filtered and concentrated to dryness by evaporation.
4-methoxy-2-methylenebutanal is obtained in ~he form of a yellowish oil which can be
further reacted without further purification.
16.5 g (144.5 mmol) of 4-methoxy-2-methylenebutanal and 15.8 ml (144.5 mmol) of
isocyanoacetic acid ethyl ester are dissolved in 145 ml of toluene, and 400 mg of copper(I)
oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a
further 2 hours, filtered over Hyflo~) and concentrated to dryness by evaporation. The
residue is talcen up in 145 ml of tetrahydrofuran, 33 ml of water are added, and the mixture
is heated under reflux for 2 hours with stirring. The mixture is concentrated to dryness by
evaporation, toluene is added, and the mixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethanol ~95:5) as eluant yields 2-formyl-
.
~ 3 ~ 1j v ~J ,~
- 28 -
amino-3-hydroxy-S-methoxy-4-methylene-hexanoic acid ethyl ester in the form of areddish-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, ~md 7.20 ml (93.0 mmol) of
thionyl bromide are added dropwise at room temperature. After 45 minutes, 100 ml of
water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is
separated off, washed in succession with water, lN potassium hydrogen carbonate
solution and again with water, dried over sodium sulfate, ~lltered and concentrated by
evaporation. 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is
obtained in the form of a reddish-brown oil.
3.38 g (11.0 mmol) of 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl
ester and 12.0 ml (44 mmol) of triisopropyl phosphite (96 %) are heated to 80 and stirred
under a pressure of approximately 130 m~ar ~or 18 hours. The excess triisopropylphosphite is distilled off under reduced pressure and the evaporation residue is purified by
chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a
yellowish oil.
Exam~le S: 0.98 g (3.5 rnmol) of 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoicacid ethyl ester is heated under reflux in ? ml of water for 17 hours. The Teaction mixture
is concentrated by evaporation and crystallised from a mixture of water and ethanol.
2-amino-~methoxy-4-phosphonomethyl-hex-3-enoic acid having a melting point of
214C (decomp.) is obtained.
Example 6: 0.52 g (1.36 rnmol) of 4-diisopropylphosphono-
methyl-6-fluoro-2-formylarnino-hex-3-enoic acid ethyl ester is dissolved in 3.5 ml of
dichloromethane, and 0.7 ml (5.45 mmol) of trimethylbromosilane is added dropwise at
room temperaturç. The mixture is left to stand at room temperature for 24 hours, 3.5 ml of
ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is con-
centrated by evaporation in a rotary evaporator, the residue is dissolved in 2.4 ml of
ethanol, and a mixture of 0.6 ml of propylene oxide and 0.6 ml of ethanol is added. A
suspension forms, which is stirred for a further 2 hours at room temperature and for
2 hours with ice cooling and is then ~lltered with suction. 2-amino-6-fluoro-
4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222 (decomp.)
2~2~
- 29 -
is obtained.
The starting material can be prepared, for example, as follows:
2.4 g (26.6 rnrnol) of 4-fluorobutanal, 2.44 g (30.0 mmol) of dimethylammonium chloride
and 2.34 ml (31.1 mrnol) of 37 % forrnaldehyde solution are heated at 100 for 2 hours
with stirring. The mixture is allowed to cool and is extracted 3 times with diethyl ether.
The organic phases are washed with saturated sodium chloride solution, combined, dried
over sodium sulfate, filtered and concentrated to dryness by evaporat;on.
4-fluoro-2-methylenebutanal is obtained in the form of a yellowish oil which can be
reacted further without further purification.
1.43 g (14.0 mrnol) of 4-fluoro-2-methylenebutanal and 1.53 ml (14.0 mmol) of
isocyanoacetic acid ethyl ester are dissolved in 14 ml of toluene, and 40 mg of coppera)
oxide are added. When the exotherrnic reaction has subsided, the rnixture is stirred for a
further 2 hours, filtered over Hyflo~ and concentrated to dryness by evaporation. The
residue is taken up in 14 rnl of tetrahydrofuran, 3.1 rnl of water are added, and the mixture
is heated under reflux for 2 hours with stirring. The mixture is concentrated to dryness by
evaporation, toluene is added, and the rnixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethyl acetate (1:1) as eluant yields 6-fluoro-
2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the form of a
dark-yellow oil.
1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl
ester are dissolved in 14 ml of 1,2-dichloroethane, and 0.56 ml (7.2 mmol) of thionyl
bromide is added dropwise at room temperature. After 45 minutes, 12 ml of water are
added and the mixh~e is stirred vigorously for 15 minutes. The organic phase is separated
off, washed in succession with water, lN potassium hydrogen carbonate solution and
again with water, dried over sodium sulfate, filtered and concentrated by evaporation.
4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl es~er is obtained in the
form of a brownish-yellow oil.
1.43 g (4.82 mrnol) of 4-bromomethyl-6-fluoro~2-formylamino-hex-3-enoic acid ethyl
ester and 5.3 ml ~19 mmol) of triisopropyl phosphite (96 %) are heated to 80 and stirred
under a pressure of approximately 130 mbar for 18 hours. The excess triisopropylphosphite is distilled off under reduced pressure and the evaporation residue is purified by
~2~
- 30 -
chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-
6-fluoro-2-formylalr~ino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish
oil.
Example 7: 0.5 g (1.86 mrnol) of 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid
ethyl ester are heated under reflux ;n 4 ml of water for 17 hours. The reaction mixture is
concentrated by evaporation and separated with water on a strongly acidic ion-exchanger
(Dowex 50Wx8; H0 form). 2-amino-6-fluoro 4-phosphonomethyl-hex-3-enoic acid
having a melting point of 160-162C (decomp.) is obtained.
~xample 8: In a manner analogous to that described in Example 3,
2,10-diarnino-4-phosphonomethyl-dec-3-enoic acid dihydrochloride, m.p. 126, is
obtained, starting from 8-aminooctan-1-ol.
Example 9: 8.63 g (15.2 mmol) of 10-~N-benzyloxycarbonyl-
amino)-4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester are
dissolved in 22 ml of dichloromethane, and 9.82 ml (75.9 mmol) of trimethylbromosilane
are added dropwise at room temperature. The rr~ixture is s~red at room temperature for
22 hours, 22 ml of absolute ethanol are then added dropwise, and the mixture is stirred for
a further 22 hours and concentrated by evaporation in a rotary evaporator. 20 ml of
toluene are poured over the residue, and the mixture is concentrated by evaporation in
vacuo. This operation is repeated a further three times. The resulting pale yellow foam is
dissolved in 150 ml of absolute ethanol, and a solution of 7.5 ml of propylene oxide in
7.5 ml of ethanol is added dropwise within a period of 90 minutes. A crystallinesuspension forms, which is stiIred overnight at room temperature. The product is filtered
off and washed with ethanol and ether. Drying under a high vacuum at room temperature
yields 4~70 g of crude product in the form of pale yellow crystals. For further purification,
the product is stirred with 46 rnl of water. After a small amount (0.33 g) of undissolved
material has been filtered off, the clear pale yellow filtrate is completely concentrated by
evaporation in vacuo. 20 ml of ethanol and 20 ml of toluene are added to the residue, and
the mixture is again concentrated to dIyness by evaporation. This operation is repeated
twice more using toluene. After drying under a high vacuum, the residue is suspended in
150 ml of absolute ethanol, and a S-normal solution of hydrogen chloride gas in ethanol is
added dropwise, with stirring, until the rnixture gives an acid reaction to Congo red. A
mixture of 7.4 ml of propylene oxide in 7.4 ml of ethanol is added dropwise to the
resulting clear solution within a period of one hour. A crystalline suspension forms, which
. .
2 J~ ~ 3~
- 31 -
is stirred for a further 15 hours and then filtered with suction. After washing with ethanol
and ether, the product is dried under a high vacuum at 50 for 48 hours, yielding 2.86 g of
2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester, which begins to sinter at
157 and melts at 194 with decomposition.
This product contains as impurities approximately from 5 to 10 % by weight of the
corresponding compound that is N-benzylated in the 10-position and of the
N-(2-hydroxy)propylated compound.
The starting material is prepared as follows:
In a manner analogous to that described in Example 3, 8-(N-
benzyloxycarbonylamino)-2-methyleneoctanal is obtained, starting from
8-aminooctan-1-ol, via 8-(N-ben~yloxycarbonylamino)octan-l-ol and
8-~N-benzyloxycarbonylamino)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 and added
dropwise under argon, within a period of 75 minutes, to a suspension of 0.30 g of
copper(I) oxide in 76 ml of toluene. The mixture is then stirred for 90 minutes at 30,
cooled to room temperature and filtered, and the clear, bright red filtrate is introduced into
a column filled with 250 g of silica gel (particle size 0.04-0.063 mrn) and eluted with
hexane/ethyl acetate (2:1). Concentration of the suitable fractions by evaporation yields
8.15 g of 5-[8-(N-benzyloxycarbonylamino)oct-l-en-2-yl]-oxazoline-4-carboxylic acid
ethyl ester in the form of a colourless honey.
8.15 g (20.25 mmol) of 5-[8-(N-benzyloxycarbonylamino)oct-
l-en-2-ylJ-oxazoline-4-carboxylic acid ethyl ester are heated under reflux in 40 ml of
tetrahydrofuran and 20 ml of water for 4 hours with stirring. The reaction mixture is
concentrated to dryness by evaporation in vacuo at 45, and the honey-like residue is
concentrated by evaporation twice more after the addition of toluene. The crude produ~t
is dissolved in dichloromethane, dried with sodium sulfate, filtered and concentrated by
evaporation. Drying under a high vacuum at room temperature yields 9.03 g of
10-(N-benzyloxycarbonylamino)-2-fo~mylamino-3-hydroxy-4-methylene-decanoic acid
ethyl ester in the form of a yellowish honey.
- 32 -
To 13,70 g (32.60 mmol) of crude 10-(N-benzyloxycarbonyl-
arnino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in 137 ml of
tetrahydrofuran there are added, under argon, 18.5 ml (156.4 mmol) of hexa-1,5-diene and
then, dropwise at 10 within a period of 15 minutes, 6.1 ml (78.2 mmol) of thionyl
bromide. The mixture is stirred for one hour at 10 and for 2 hours at room temperature
and is then poured into 200 ml of ice-cold saturated sodium hydrogen carbonate solution;
the organic phase is separated off and re-extracted once with dichloromethane. The
organic phases are washed with ice-cold O.S-norrnal sodium hydrogen carbonate solution
and then with saturated sodium chloride solution, dri~d over sodium sulfate and
concentrated to dryness by evaporation in vacuo at 40. 64 ml (260 mmol) of triisopropyl
phosphite (96 %) are added immediately to the resulting crude
10-(N-benzyloxycarbonylam~no)-4-bromomethyl-2-forrnylamino-dec-3-enoic acid ethyl
es~er (27 g, yellow honey), and the mixture is stirred for 17 hours at 80 under a pressure
of approximately 100 mbar, the isopropyl bromide that forrns being captured in a cold trap
(CO2). The excess triisopropyl phosphite is then distilled off under reduced pressure and
the evaporation residue (23 g) is purified by chromatography on a column filled with
650 mg of silica gel (0.04-0.063 mm) with ethyl acetate/methanol (95:5). 8.73 g of
10-(N-benzyloxycarbonylamino)-4-diisopropylphosphonomethyl-2-formylamino-
dec-3-enoic acid ethyl ester are obtained in the form of a yellowish honey.
Example 10: 2.25 g (6.98 mmol) of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid
ethyl ester are dissolved under argon in 45 ml of 2-normal hydrochloric acid and stirred
for 17 hours at a bath temperature of 120. The clear, pale brown solution is concentrated
by evaporation in a rotary evaporator. The residue is dissolved in 20 ml of ethanol and,
after the addition of 30 ml of toluene, concentrated by evaporation in vacuo. This
operation is repeated a further three times. The resulting beige foam is dissolved in 75 ml
of absolute ethanol, and a solution of 15 ml of propylene oxide in 15 ml of ethanol is
added dropwise within a period of 35 minutes. The crystalline suspension that forrns,
which has a pH of 3, is filtered off after 1~ hours' stirring and washed thoroughly with
ethanol and ether. Drying in vacuo yields 1.65 g of beige crude product, which is
dissolved in the rninimum arnount of water (about 2 ml) and chrornatographed on a
column filled with 67 g of reversed-phase silica gel (Opti-Up Cl2, particle size 40 ~,lm),
using pure water as eluant, at a slight ove~pressure (0.2 bar). A pure fraction, Rf value on
silica gel = 0.37 with n-propanoVwater/pyridine/acetic acid (15:12:10:3) as eluant, and
several n~ixed fractions containing a by-product of Rf value = 0.48 are obtained.
Chromatography of those mixed fractions again and purification of the pure fractions,
l ~2~r,~,~
followed by Iyophilisation from water, yield 2,10-diamino-4-phosphonomethyl-dec-3-
enoic acid hemi-hydrochloride hydrate in the form of an amorphous glass which slowly
sinters at 134 and above and decomposes at 149 with foaming.
Example 11: 4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphos-
phonomethyl-2-formylamino-hept-3-enoic acid ethyl ester are dissolved in 25 ml of
dichloromethane, and 5.1 ml (39.5 mmol) of trimethylbromosilane are added dropwise at
room temperature. The mixture is left to stand at room temperature for 24 hours, 25 ml of
ethanol are added dropwise, the rnixture is left to stand for a further 24 hours and is
concentrated by evaporation, the residue is dissolved in 25 ml of ethanol, and a mixture of
25 ml of propylene oxide and 25 ml of ethanol is added dropwise. A suspension forrns,
which is stirred for one hour at room temperature and for one hour in an ice bath and is
then filtered with suction. Drying yields 2-amino-7-
hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester having a melting point of
210C (decomp.).
The starting material can be prepared, for example, as follows:
10 g (69.4 rnmol) of 5-acetoxypentanal, 6.37 g (78.~ mmol) of dimethylammonium
chloride and 6.1 ml (81.2 mmol) of 37 % formaldehyde solution are refluxed for 1 -~ hours
(bath temperature ~110C) with stirring. The mixture is allowed to cool and is extracted
three tirnes with ether; the organic phases are combined, dried over MgSO4, filtered and
concentrated by evaporation. 5-acetoxy-2-methylenepentanal is obtained in the forrn of a
yellowlsh oil which can be reac~od without further purification.
9.6 g (61.5 rnmol) of 5-acetoxy-2-methylenepentanal and 7.38 rnl (67.6 rnmol) ofisocyanoacetic acid ethyl ester are placed in 70 ml of toluene at room temperature, and
250 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the
rnixture is stirred for a further one hour and is filtered over Hyflo~3) and concentrated by
evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are
added, and the mixture is refluxed for 3 hours. The mixture is concen~rated to dryness by
evaporation, toluene is added, and the rnixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethyl acetate (4:1) yields
7-acetoxy-2-formylarnino-3-hydroxy-4-methylene-heptanoic acid ethyl ester in the form
of an orange oil.
2 ~ 3 ~
- 34 -
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 1.9 ml (24.6 mmol) of thionyl
bromide are added dropwise at room temperature. After one hour, 40 ml of water are
added asld the mixture is stirred vigorously for 10 minutes. The organic phase is separated
off, washed in succession Wit}l water, lN KHC03 solution and again with water, dried
over MgS04, filtered and concentrated by evaporation.
7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the
form of a b;own oil, which is reacted further in the crude state.
6.1 g (17.4 mmol) of 7-acetoxy-4-bromomethyl-2-formylaminohept-3-enoic acid ethyl
ester and 19.1 rïll (69.6 mmol) of tIiisopropyl phosphite (90 %) are heated to 80C and
stirred under a pressure of approximately 130 mbar for 18 hours. The excess trusopropyl
phosphite is distilled off and the residue is purified on silica gel with ethyl acetate. 7-
acetoxy4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester is
obtained in the form of a yellow oil.
Example 12: 1.1 g (3.9 mmol) of 2-asnino-7-hydroxy-4-phosphonomethyl-hept-3-enoic
acid ethyl ester in 8 ml of water are stirred at 13ûC for 18 hours in a bomb tube. The
dark reaction solution is treated with activated carbon and filtered over Hyflo~. The
colourless filtrate is concentrated to ~3 ml, and ~25 ml of ethanol are added. The resul-
ting suspension is filtered with suction and dried under a high vacuum at 50C.
2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid having a melting point from
190C and above (decomp.) is obtained.
Example 13: 8.2 g (18.9 mmol) of 6-(N-acetyl-N-methylan~ino)-
4-diisopropylphosphonomethyl-2-formylanino-hex-3-enoic acid ethyl ester are dissolved
in 40 ml of dichloromethane, and 9.8 ml (75.6 mmol) of trimethylbromosilane are added
dropwise at room temperatlLre. The mixture is left to stand at room temperature for
24 hours, 40 ml of ethanol are added dropwise, tne mixture is left to stand for a fur~er
24 hours and is concentrated by evaporation, the residue is dissolved in 40 ml of ethanol,
and a nixture of 40 ml of propylene oxide and 40 rnl of ethanol is added dropwise. A
suspension forms, which is stirred for a further one hour at room te nperature and for one
hour at 0 and is then filtered with suction. Drying yields
6-(N-acetyl-N-methylamino)-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester
having a melting point of 222-223C ~decomp.).
~,
35 ~2~a~
The starting material can be prepared, for example, as follows:
35.8 g (0.2 mol) of 4-aminobutyraldehyde-diethylacetal (90 %) are dissolved in 600 ml of
dichloromethaule, 300 ml of saturated sodium hydrogen carbonate solution are added, and
the mixture is cooled to 0C. 17 ml (0.24 mol) of acetyl chloride are added dropwise at
0-5C, and the mixture is stirred for a further 6 hours at 0-5C. The organic phase is
separated off and the aqueous phase is extracted twice more with dichloromethane. The
organic phases are combined, dried over MgS04, filtered and concentrated by evaporation
in a rotary evaporator. The residue is purified by chromatography on silica gel with ethyl
acetate. 4-(N-acetylamino)butyraldehyde-diethylacetal is obtained in the form of a
yellowish oil.
35 g (172.2 mmol) of 4-(N-acetylamino)butyraldehyde-diethylacetal are dissolved in
180 ml of dimethylforrnarnide, 8.3 g (206.6 mmol) of sodium hydride dispersion (60 % in
mineral oil) are added in portions, and the rnixture is stirred at room temperature for
45 minutes. 12.9 ml (206.6 mmol) of methyl iodide in 20 ml of dimethylformamide are
then added, and the mixture is subsequently stirred at room temperature for 4 hours.
Water/ice is added to the reaction mixture, and the batch is extracted three times with
ethyl acetate. The organic phases are washed with water and saturated sodium chloride
solution, combined, dried over MgSO4, filtered and concentrated by evaporation. The
residue is distilled under a high vacuum. 4-(N-acetyl-N-methylamino)butyraldehyde~
diethylacetal is obtained in the form of a colourless oil9 b.p.o I = 92-94.
30 g (138.2 mmol) of 4-(N-acetyl-N-methylamino)butyraldehydedlethylacetal, 12.6 g
(154.4 mmol) of dimethylammonium chloride and 12.1 ml (161.7 mmol) of 37 %
formaldehyde solution are refluxed for 45 minutes with st-irring. I he mixture is allowed to
cool and is extracted three times with dichloromethane. The organic phases are combined,
dried over MgSO4, filtered and concentrated by evaporation. 4-(N-
acetyl-N-methylamino)-2-methylene-butyraldehyde is obtained in the form of a yellowish
oil which can be reacted without further purification.
19.9 g (128.3 mmol) of 4-(N-acetyl-N-methylamino)-2-methylene-butanal and 15.4 ml
(141.1 mmol) of isocyanoacetic acid ethyl ester are placed at room temperature in ~0 ml
of toluene, and 500 mg of copper(I) oxide are added. When the exothermic reaction has
subsided, the mixture is stirred for a further one hour at room temperature, filtered over
Hyflo(g) and concentrated by evaporation. The residue is taken up in 60 ml of
2 ~ J '~3 ~ 3
- 36-
tetrahydrofuran, 20 ml of water are added, and the mixture is refluxed for 4 hours. The
mixture is concentrated by evaporation, toluene is added, and the rnixture is again
concentrated by evapor~tion. Chromatography on sllica gel with ethyl acetate/isopropanol
(7:1) yields 6-(N-acetyl-N-methylamino)-2-formylamino-3-hydroxy-4-
methylene-hexanoic acid ethyl ester in the forrn of a yellowish oil.
15.8 g (55.2 mmol) of 6-(N-acetyl-N-methylamino)-2-formyl-
amino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 150 ml ofdichloromethane, and 5.1 ml (66.2 mmol) of thionyl bromide are added dropwise at room
temperature. After one hour, 100 ml of water are added and the mixture is stirred
vigorously for 10 minutes. The organic phase is separated off, washed in succession with
water, lN KHCO3 solution and again with water, dried over MgSO4, filtered and
concentrated by evaporation. 6-(N-
acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is
obtained in the form of a yellowish-orange oil which is reacted further in the crude state.
16.0 g (45.8 mmol) of 6-(N-acetyl-N-methylamino)-4-bromo-
methyl-2-formylamino-hex-3-enoic acid ethyl ester and 50~3 ml (183.3 mmol) of
triisopropyl phosphite (90 %) are heated to 80 and stirred under a pressure of
approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off
and the residue is purified by chromatography on silica gel with ethyl acetate~lsopropanol
(7:2). 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-
3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Example 14: 3.3 g (6.82 mrnol) of 6-benzoyloxy-4-diisopropyl-
phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 20 ml of
dichloromethane, and 3.52 ml (27.3 rnmol) of trimethylbromosilane are added dropwise at
room temperature. The mixture is left to stand at room temperature for 22 hours, 20 ml of
ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is
concentrated by evaporation, the residue is dissolved in 20 ml of ethanol, and a r~ixture of
20 ml of propylene oxide and 20 rlll of ethanol is added dropwise. A suspension forms,
which is stirred for one hour at room temperature and for one hour at 0C and is then
filtered with suction. Drying yields 2-arnino-6-benzoyloxy-2-amino-4-phos-
phonom~thyl-hex-3-enoic acid ethyl ester having a melting point of 236-237C (decomp.).
The starting material can be prepared, for example, as follows:
~ ,323 v3~
- 37 -
10 g (52 mmol) of 4-benzoyloxybutanal, 4.78 g (58.6 mmol) of dimethylammonium
chloride and 4.6 ml (60.8 mmol) of formaldehyde solution (37 %) are refluxed for one
hour with stirring (bath temperature ~110C). The rnixture is allowed to cool and is
extracted three times with ether; the organic phases are combined, washed with saturated
sodium chloride solution, dried over MgS04, filtered and concentrated by evaporation.
4-benzoyloxy-2-methylenebutanal is obtained in the form of a yellowish oil which can be
reacted without further purification.
10 g (49 mmol) of 4-benzoyloxy-2-methylenebutanal and 5.3 ml (49 mmol) of
isocyanoacetic acid ethyl ester are placed at room temperature in 70 ml of toluene, and
200 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the
mixture is stirred for a further one hour, filtered over Hyflo(~) and concentrated by
evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are
added, and the rnixture is refluxed for 3 hours. The mixture is concentrated by
evaporation, toluene is again added, and the rnixture is again concentrated by evaporation.
Chrornatography on silica gel with toluene/ethyl acetate (3:2) yields
~benzoyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in theform of a brown oil.
8 g (23.9 rnmol) of 6-benzoyl-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl
ester are dissolved in 80 ml of dichloromethane, and 2.22 ml (28.6 mmol) of thionyl
bromide are added dropwise at room temperature. After 2 hours, 60 ml of water are added
and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off,
washed in succession with water, lN KHCS)3 solution and again with water, dried over
MgSO4, filtered and concentrated by evaporation.
6-benzoyloxy-4-bromomethyl-2-forrnyIarninc~hex-3-enoic acid ethyl ester is obtained in
the form of a brown oil which is reacted fur~er in the crude state.
8.4 g (21 mrnol) of 6-benzoyloxy-4-bromomethyl-2-formylamino-hex-3-enoic asid ethyl -
ester and 23 ml (84 mmol) of triisopropyl phosphite (90 %) are heated to 80C and stirred
under a pressure of ~130 mbar for 18 hours. The excess triisopropyl phosphite is distilled
off and the residue is purified by chromatography on silica gel with ethyl acetate. 6-
benzoyloxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is
obtained in the form of a brown oil.
2 ~ 2 ~
Example 15: 4.0 g (8.51 mmol) of 6-ben~yloxy-4-diisopropyl-
phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 24 ml of
dichloromethane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at
room temperature. The mixture is left to stand at room temperature for 22 hours, 24 ml of
ethanol are added dropwise and the mixture is left to stand for a further 24 hours and is
concentrated by evaporation in a rotary evaporator, the residue is dissolved in 24 ml of
ethanol, and a mixture of 24 ml of propylene oxide and 24 ml of ethanol is added drop-
wise. ~ suspension forms, which is stirred for a further one hour at room temperature and
for one hour at 0 and is then filtered with suction. Drying yields 2.2 g of a white crys-
talline product which is a mixture of 2-amino-6-benzyloxy-
4-phosphonomethyl-hex-3-enoic acid ethyl ester and 2-amin~
6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid. To obtain a uniform product, that
mixture is hydrolysed overnight at room temperature with 20 ml of N-sodium hydroxide
solution in 30 ml of ethanol, acidified with N-hydrochloric acid and neutralised with
propylene oxide. Since the product crystallises poorly, it is concentrated by evaporation in
a rotary evaporator, the residue is filtered in water over 20 g of silica gel, and the fractions
containing the desired product are concentrated by evaporation in a rotary evaporator. The
residue is dissolved with 10 ml of tert.-butanoVwater (1:1) and freeze-dried.
2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid is obtained in the form of a
lyophilisate.
The starting material can be prepared, for example, as follows:
6 g (0.2 mol) of a sodium hydride dispersion (80 % in white oil) are placed at room
temperature in 120 ml of absolute dimethylformamide, and 22.2 ml (0.25 mol) of
1,4-butanediol are added dropwise. When the addition is complete, the mixture is stirred
for a further 30 minutes at room ~emperature. 23.1 rnl (0.2 mol) of benzyl chloride are
then slowly added dropwise, a slight exothermic reaction being observed. The reaction
mixture is stirred overnight at room temperature, water/ice is added, and the mixture is
extracted twice with ether. The organic phases are washed with water and with saturated
sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by
evaporation. The residue is subjected to fractional distillation under a waterjet vacuum
over a 10 cm Yigreux column. 4-benzyloxybu~anol is obtained, b.p.22 = 161-162.
36.6 g (170 mmol) of pyridinium chlorochromate are placed at room temperature in120 ml of dichloromethane under N2, and a solution of 20.4 g (113 mmol) of
.,
~ ~ 2 s3 ~3 ~ ~
- 39 -
4-benzyloxybutanol in 20 ml of dichloromethane is added. The reaction mixture rapidly
becomes dark and the reaction is slightly exothermic. The reaction mixture is stirred at
room temperature for 3~ hours. The supernatant dichloromethane phase is decanted off
and concentrated by evaporation in a rotary evaporator. The residue is filtered over 100 g
of silica gel. The product fractions are concentrated by evaporation in a rotary evaporator
and distilled under a high vacuum over a 10 cm Vigreux column. 4-benzyloxybutanal is
obtained, b.p.o I = 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 rnrnol) of 37 % formaldehyde solution are kept at a bath
temperature of 110 for one hour with stirring. The mixture is allowed to cool and is
extracted ~hree times with ether. The organic phases are washed with saturated sodium
chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation.
4-benzyloxy-2-methylenebutanal is obtained in ~he form of a yellowish oil which can be
reacted further without further purification.
.
8.0 g (42 mrnol) of 4-benzyloxy-2-methylenebutanal and 4.57 ml (42 rnmol) of
isocyanoacetic acid ethyl ester are placed in 60 ml of toluene, and 200 mg of copper(I)
oxide are added. When the exothermic reaction has subsided, the mixture is sti~red for a
further 2 hours, filtered over Hyflo~ and concentrated by evaporation. The residue is
taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the mixture is refluxed
for 3 hours. The mixture is concentrated to dryness by evaporation, toluene is added, and
the mixture is again concentrated by evaporation. Chromatography on silica gel with
toluene/ethyl acetate (3:2) as eluant yields ~benzyloxy-2-formylarnino-3-hydroxy-4-
methylene-hexanoic acid ethyl ester in the form of a reddish-brown oil.
7.0 g (21.8 mmol) of 6-benzyloxy-2-formylamin~3-hydroxy-4-methylene-hexanoic acid
ethyl ester are dissolved in 70 ml of dichloromethane, and 2.0 ml (26.1 mmol) of thionyl
bromide are added dropwise at room temperature. After 2 hours, 40 ml of water are added
and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off,
washed in succession with water, N-KHC03 solution and again with water, dlied over
MgSO4, filtered and concentrated by evaporation.
~benzyloxy-4-bromomethyl-2-formylarnino-hex-3-enoic acid ethyl ester is obtained in
the form of a reddish-brown oil which can be reacted further without purification.
7.9 g (20.5 mmol) of 6-benzyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl
,,
~2w~
-40-
ester and 22.5 ml (82.2 mmol) of ~iisopropyl phosphite (90 %) are heated to 80 and
stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl
phosphite is distilled off in a rotary evaporator and the residue is puri~led bychromatography on silica gel with ethyl acetate. 6-benzoyl-4-diisopropyl-
phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a
yellowish oil.
Example 16: 3.15 g (6.84 mmol) of 4-(1-acetylpiperidin-4-yl)-
5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in
17 ml of dichloromethane, and 3.54 ml (27.3 mmol) of trimethylbromosilane are added
dropwise at room temperature. The rnixture is left to stand at room temperature for
16 hours, 17 ml of ethanol are added dropwise, the mixture is left to stand for a further
18 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved
in 12 ml of ethanol, and a mixture of 3 ml of propylene oxide and 3 ml of ethanol is added.
A suspension forms, which is stirred for a further 2 hours at room temperature and for
2 hours with ice cooling and is then filtered with suction. 2-amino-4-(1-acetyl-piperidin-4-yl)-5-phosphono-pent-3-enoic acid ethyl ester having a melting point of 225
(decomp.) is obtained.
The starting material can be prepared, for example, as follows:
3.95 g (23.3 mmol) of 2-(1-acetylpiperidin-4-yl)ethanol, 2.12 g (26.3 mmol) of
dimethylammonium chloride and 3 ml (40 mmol) of 37 % formaldehyde solution are
heated at 110C for 2 hours with sti~ing. The mixture is allowed to cool and is extracted
several times with diethyl ether. The organic phases are combined, washed with saturated
sodium ch!oride solution, d~ied over sodium sulfate, filtered and concentrated to dryness
by evaporation. 2-(1-acetylpiperidin-4-yl)propenal is obtained in the foml of a yellowish
oil which can be further reas~ted without further purification.
2.9 g (16.0 mmol) of 2-(1-acetylpiperidin-4-yl)propenal and 1.75 ml (16 mmol) ofisocyanoacetic acid ethyl ester are dissolved in 13 ml of toluene, and 46 mg of copper(I)
oxide are added. When the exotherrnic reaction has subsided, the mixture is stiIred for a
further 2 hours, filtered over Hyflo~) and concentrated to dryness by evaporation. The
residue is taken up in 13 ml of tetrahydrofuran, 6 rnl of water are added, and the rnixture is
heated under reflux for 2 hours with stirling. The mixture is concentrated to dryness by
evaporation, toluene is added, and the mixture is again concentrated by evaporation.
~2~
- 41 -
Chromatography on silica gel with ethyl acetate/methanol (9:1) as eluant yields 4-(1-
acetylpiperidin-4-yl)-2-formylarnino-3-hydroxy-pent-4-enoic acid ethyl ester in the form
of a yellowish-brown oil.
3.3 g (10.5 mmol) of 4-(1-acetylpiperidin-4-yl)-2-formylamino-3-hydroxy-pent-4-enoic
acid ethyl ester are dissolved in 25 ml of 1,2-dichloroethane, and 0.98 ml (12.6 mmol) of
thionyl bromide are added dropwise at room temperature. After 1~ hours, 20 ml of water
are added and the mixture is stirred vigorously for 15 minutes. The organic phase is
separated off, washed in succession with water, N-potassium hydrogen carbonate solution
and again with water, dried over sodium sulfate, filtered and concentrated by evaporation.
4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester is
obtained in the form of a reddish-brown oil.
2.68 g (7.14 mmol) of 4-(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 %) aIe heated to 80
and stirred under a pressure of approximately 130 mbar for 18 hours. The excess
triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is
purified by chromatography on silica gel with ethyl acetate/methanol (9:1).
4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-forrnylamino-pent-3-enoic acid ethyl
ester is obtained in the form of a yellowish oil.
Example 17: 1 g (2.17 mrnol) of 4-(1-acetylpiperidin-4-yl)-5-
diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester is heated under re~lux
in 20 ml of 6N hydrochloric acid for 8 hours. After concentration by evaporation, the
residue is dissolved in 25 ml of ethanol. 3 ml of propylene oxide are then added, ~e
mixture is stirred for 2 hours at room temperature and for one hour with ice cooling, and
then the suspension that has formed is filtered off with suction.
2-amino-4-(piperidin-4-yl)-5-phosphono-pent-3-enoic acid having a melting point of 212
(decomp.) is obtained.
Example 18: 0.68 g (1.49 mmol) of 5-benzyloxy-4-diisopropyl-
phosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is dissolved in 10 ml of
dichloromethane, and 0.8 ml (~ mmol) of trimethylbromosilane is added dropwise at room
temperature. The mixture is left to stand at room temperature for 6 hours, I0 ml of
ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is
concent~ated by evaporation, the residue is dissolved in 5 ml of ethanol, and a rnixture of
~2~ 38
- 42 -
S ml of propylene oxide and S ml of ethanol is added dropwise. A suspension forms,
which is stirred at room temperature for 2 hours and is then filtered with suction. Drying
yields 2-amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a
melting point of 218-220 (decomp.).
The starting material can be prepared, for example, as follows:
3.0 g (62.4 mmol) of 50 % sodism hydride dispersion in mineral oil are placed in 50 ml of
tetrahydrofuran and 40 ml of dimethylformarnide, a solution of 10.0 g (62.4 mrnol) of
3-hydroxy-2-methylenepropionaldehyde-diethylacetal in 10 ml of tetrahydrofuran is
slowly added dropwise at 0, and the mixture is stirred at 0 for 2 hours. The mixture is
diluted with 15 rnl of tetrahydrofuran and 10 ml of dimethylformamide and stiIred at room
temperature for a further 2 hours. 7.2 ml (62.4 mmol) of benzyl chlolide in 10 ml of
dimethylformamide are then added at 0, and the mixture is stirred at room temperature
for 18 hours. Water is added to the reaction mixture, which is then extracted three times
with ethyl acetate, and the organic phases are washed with saturated sodium chloride
solution. The organic phases are combined, dlied over Na2S04, filtered and concentrated
by evaporation. The residue is chromatographed on silica gel with methylene chloride,
yielding 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal in the form of a pale
yellowish liquid.
4.8 g (1~.1 mmol) of 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal and 0.36 g
(1.9 mmol) of p-toluenesulfonic acid monohydrate are stiITed for 3 hours in 60 ml of
acetone. The mixture is diluted with 400 ml of methylene chloride, extracted with
N-KHC03 solution and saturated sodium chloride solution, dried over Na2S04, filtered
and concentrated by evaporation. The 3-benzyloxy-2-methylenepropanol that remains
(yellow liquid) is placed at room temperature, without further purification, together with
2.1 ml (19 mmol) of isocyanoacetic acid ethyl ester, in 25 rnl of toluene, and 50 mg of
copper(I) oxide are added. When the exothermic reaction has subsided, the rnixture is
stirred for a further one hour at room temperature, filtered over Hyllo~) and concentrated
by evaporation. The residue is taken up in 25 ml of tetrahydrofuran, 5 ml of water are
added, and the rIuxture is refluxed for 4 hours. The mixture is concentrated by
evaporation, toluene is added, and the rnixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethyl acetate (1:1) and subsequent crystal-
Iisation from diethyl eth~r yield S-benzyloxy-2-formylamino-3-hydroxy-4-methylene-
pentanoic acid ethyl ester having a melting point of 112-114C.
~J~
- 43 -
1.0 g (3.25 mmol) of S-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid
ethyl ester are suspended in 30 ml of 1,2-dichloroethane, and 0.38 ml (4.9 mmol) of
thionyl chloride is added dropwise at room temperature. After 45 minutes, 20 ml of water
are added to the yellow solution, and the mixture is stirred vigorously for 15 minutes. The
organic phase is separated off, washed with saturated sodium chloride solution, dried over
Na2SO4, filtered and concentrated by evaporation.
S-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in
the form of a yellowish oil which is reacted further in the crude state.
1.14 g (3.1 mmol) of S-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl
ester and 10 rnl (38.5 mmol) of triisopropyl phosphite (95 %) are heated to 80C and
stirred under a pressure of approximately 130 mbar for 3~ hours. The excess triisopropyl
phosphite is distilled off and the residue is purified by chromatography on silica gel with
ethyl acetate. S-benzyloxy-4~iisopropylphosphonomethyl-2-formylamino-pent-3-enoic
acid ethyl ester is obtained in the form of a yellowish oil.
Example 19: 1.10 g (2.8 mrnol) of S-ethoxy-4-diisopropylphos-
phonomethyl-2-forrnylamino-pent-3-enoic acid ethyl ester are dissolved in 20 ml of
dichloromethane, and 1.6 ml (12.3 mmol) of trimethylsilane are added dropwise at room
temperature. The rnixeure is left to stand at room temperature for 7 hours, 20 rnl of
ethanol are added, the mixture is left to stand for a further 15 hours and is concentrated by
evaporation, the residue is dissolved in 10 rnl of ethanol, and a mixture of 10 ml of
propylene oxide and 10 ml of ethanol is added dropwise. A suspension folms, which is
stirred at room temperature for 2 hours and is then ~lltered with suction. Drying yields
5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting
point of 217-218C (decomp.).
The starting matenal can be prepared, for example, as follows:
50 g (283 mmol) of 3-ethoxypropionaldehyde-diethylacetal, 27.3 g (335 mmol) of
dimethylammonium chloride and 30 ml (392 mmol) of 36 % formaldehyde solution areheated at 110C for 2 hours with stirring. The mixture is allowed to cool and is extracted
~hree times with diethyl ether. The organic phases are washed with saturated sodium
chloride solution, combined, dried over sodium sulfate, filtered and concentrated to
dryness by evaporation. 2-ethoxypropanol is obtained in the form of a yellow liquid
3 rJ ,~
-44 -
which can be reacted -further without further purification.
4.2 g (36.1 mmol) of 2-ethoxypropanol and 4.4 ml (40 mmol) of isocyanoacetic acid ethyl
ester are dissolved in 50 ml of toluene, and 200 mg of copper(I) oxide are added. When
the exotherrnic reaction has subsided, the mixture is stirred for a further one hour, filtered
over Hyflo(~) and concentrated to dryness by evaporation. The residue is taken up in 50 ml
of tetrahydrofuran, 12 ml of water are added, and the mixture is heated under reflux for
one hour with stirring. The mixture is concentrated to dryness by evaporation, toluene is
added, and the mixture is again concentr~ted by evaporation. Chromatography on silica
gel with toluene/isopropanol (9:1) as eluant yields 5-ethoxy-2-formylamino-3-hydroxy-4-
methylene-pentanoic acid ethyl ester in the form of a yellow oil.
3.70 g (15.1 mrnol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid
ethyl ester are dissolved in 100 ml of 1,2-dichloroethane, and 1.8 rnl (22.8 mmol) of
thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water
are added and the rnixture is stirred vigorously for 15 minutes. The organic phase is
separated off, washed in succession with lN potassium hydrogen carbonate solution and
with brine, dried over sodium sulfate, filtered and concentrated by evaporation.5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the
form of a yellowish-brown oil which is reacted further in the crude state.
3.12 g (10.1 mmol) of 5-ethoxy-4-bromomethyl-2-formylanuno-pent-3-enoic acid ethyl
ester and 30 ml (118 mmol) of triisopropyl phosphite (90 %) are heated to 80C and
stirred under a pressure of approximately 130 mbar for 7 hours. The excess ~iisopropyl
phosphite is distilled off and the residue is purified by chromatography on silica gel with
methylene oxide/methanol (97:3 to 9S:S). 5-ethoxy-4-dihydropropylphos-
phonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a
yellow oil.
Example 20: Tablets, each containing 50 mg of 2-amino-6-
hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt,
thereof, can L~ prepared as follows:
Composi~ion (10LOOO tablets)
active ingredient 500.0 g
~; ~ 2 ~ 3 eJ ~
- 45 -
lactose 500.0 g
potato starch 352.0 g
gelatin 8.0 g
talcurn 60.0 g
magnesium stearate 10.0 g
silica (highly disperse) 20.0 g
ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture
is moistened with an ethanolic solution of the gelatin and granulated through a sieve.
After drying, the remaining potato starch, the magnesium stearate, the talsum and the
silica are mixed in and the mixture is compressed to form tablets which each weigh
145.0 mg and contain 50.0 mg of active ingredient, and which may, if desired, be provided
with dividing notches for finer adaptation of the dose.
Example 21. Coa~ed tablets, each containing 100 mg of 2-amino-
6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt,
thereof, can be prepared as follows:
Composition (for 1.000 coated tablets)
activeingredient 100.0 g
lactose 100.0 g
com starch ~0.0 g
talcum ~ 8.5 g
calciumstearate 1.5 g
hydroxypropylmethylcellulose 2.36 g
shellac 0.64 g
water q.s.
methylene chloride q.s.
The active ingredient, the lactose and 40 g of the corn starch are mixed, and the mixture is
moistened with a paste, prepared from 15 g of the corn starch and water (with heating),
and granulated. The granulate is dried, the remaining corn starch, the talcum and the
calcium stearate are added and mixed with the granulate. The rnixture is compressed to
fonn tablets (weight: 280 mg), which are coated with a solution of the
2~2~3~
- 46 -
hydroxypropylmethylcellulose and the shellac in methylene chloride. Final weight of the
coated tablet: 283 mg.
Example 22- Gelatin dry-filled capsules, containing 100 mg of active ingredient, for
example 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example
the sodium salt, thereof, can be prepared, for exarnple, as follows:
Composition (for 1~000 capsules)
activeingredierlt 100.0 g
lactose 250.0 g
microcrystalline cellulose 30.0 g
sodiumlaurylsulfate 2.0 g
magnesium stearate 8.0 g
The sodium lauryl sulfate is added to the Iyophilised active ingredient through a sieve
having a mesh size of 0.2 mm. The two components are intimately mixed. Then, first the
lactose is added through a sieve having a mesh size of 0.6 mm and then the
microcrystalline cellulose through a sieve having a mesh size of 0.9 mm. The mixture is
again intimately mixed for 10 minutes. Finally, the magnesium stearate is added through
a sieve having a mesh size of 0.8 mm. After further mixing for 3 minutes, size 0 gelatin
dry-fill capsules are each filled with 390 mg of the resulting formulation.
Example 23: A 0.2 % injection or infusion solution of
2-amino-~hydroxy-4-phosphonomethyl-hex-3-enoic acid or of a salt, for example the
sodium salt, thereof can be prepared, for example, as follows:
.
Composit on (for 11000 ampoules)
active ingredient 5.0 g
sodium chloride 22.5 g
phosphate buffer pH = 7.4 300.0 g
dernineralised water ad 2500.0 ml
The active ingredient and the sodium chloride are dissolved in 1000 ml of water and
filtered through a micro-filter. The buffer solution is added, and the mixture is made up to
,
.
2~2~3~
- 47 -
2500 ml with water. To prepare dosage unit forms, 1.0 or 2.5 ml are introduced into each
glass ampoule, which then contains 2.0 or 5.0 mg, respectively, of active ingredient.
Example 24: In a manner analogous to that described in Examples 1 to 10 also thefollowing compound can be m~nufactured:
2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid e~hyl ester, m.p. 230-233
(decomp.);
2-amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester,
m.p. 177-180, and
2-amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester, m.p. 243-244(decomp.).
Example 25: In a manner analogous to that described in Examples 20 to 23, it is also
possible to prepare pharmaceutical preparations containing a different compound of
formula I according to any one of Examples 1 to 19. and 24
