SI8812187A - Process for preparation of substituted propane-phosphinic acid compounds - Google Patents

Abstract

Compounds of Formula I wherein R is aliphatic, cycloaliphatic, cycloaliphatic aliphatic and an araliphatic radical of 2 or more carbon atoms and in which one of the groups R 1, R 2 and R 2 represents hydrogen or aliphatic, cycloaliphatic, araliphatic or aromatic the radical is the second of R1, R2 and R3 hydrogen, atoms, in the example R1 and R are hydroxy and the rest of R1, R2 and R3 are hydrogen, and their salts have antagonistic properties against GABAb and can be used as antagonists GABAb- They are obtained if in a compound of formula II in which R, R1, R2 and R3 have their precursors mean, Z represents -NH2 and R4 represents protective R5 is hydroxy or, if R1 and R3 are hydrogen and R2 is hydrogen or alkyl, is an alkali ion metal or ammonium ion R6 or Z represents protected or the latent amino group Z ° and R 4 is hydrogen or hydroxy protecting group R5, any R5 group or R 6 is replaced by hydrogen and / or any group Z ° is converted to -NH2.

Description

in which R is an aliphatic, cycloaliphatic, cycloaliphatic aliphatic and araliphatic radical of 2 or more carbon atoms and in which one of the groups R ¹ , R ² and R ^{2 is} hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical is the other of R ¹ , R ² and R ^{3 are} hydrogen, atoms, in the case of R ¹ and R, hydroxy and the remainder of R ¹ , R ² and R ^{3 are} hydrogen, and their salts have antagonistic properties against GABAb and can be used as GABAb antagonists. if in a compound of formula II

in which R, R ¹ , R ² and R ^{3 have} their previous meanings, Z represents -NH 2 and R ⁴ represents a protecting group R ⁵ for hydroxy or, if R ¹ and R ^{3 are} hydrogen and R ^{2 is} hydrogen or alkyl, means an alkali metal ion or an ammonium ion R ⁶ , or Z represents a protected or latent amino group Z ° and R ⁴ means hydrogen or a protecting group R ⁵ for hydroxy, any group R ⁵ or R ^{6 being} replaced by hydrogen and / or any group Z ° converted in -NH2.

CIBA-GEIGY AG

A process for the preparation of compounds of substituted propane-phosphinic acids

FIELD OF THE INVENTION

The invention is within the scope of the pharmaceutical industry and relates to a process for the preparation of compounds of formula I

wherein R represents an aliphatic, cycloaliphatic, or araliphatic cikloalifatskoalifatski -radikal with 2 or more carbon atoms, and in which represents one of the groups D, F, and R ^J is hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical,

3 12 is other than R, R and R hydrogen or, in the case of R and R,

2 3 is hydroxy and the residue of R, R and fi is hydrogen, provided that R is other than 1,1-di (C ₁ -C 4 -alkoxy) -C ₁ -C 4 -alkyl if

3 one of R, R and R represents hydrogen, C 1 -C 8 alkyl, C 1 -C 8 cycloalkyl, phenyl optionally substituted by halogen, C 1 -C 4 -alkyl, -C 1 -alkoxy and / or trifluoromethyl or C 1 -C 4 -phenylalkyl optionally substituted in the phenyl moiety by halogen, C 1 -C 4 -alkyl, -C 1 -alkoxy 1 2 3 and / or trifluoromethyl, and the other two being R, R and R are hydrogen, and to their salts, provided that they are salts of compounds of formula I in which R is an unsubstituted aliphatic, cycloaliphatic or araliphatic hydrocarbon radical, R ¹ and 3 2

R is hydrogen and R is hydrogen or alkyl, with bases other than alkali metal salts and ammonium salts.

The aliphatic radicals R are e.g. alkyl groups which may be interrupted by one or two spaced atoms selected from oxygen and sulfur and / or substituted by halogen or hydroxy, such as alkyl, alkyl mono-, di- or poly-substituted by halogen and / or hydroxy, alkyl interrupted by one or two spaced atoms torn between oxygen and sulfur, or alkyl interrupted by one or two spaced atoms selected from oxygen and sulfur and substituted by halogen and / or hydroxy, alkenyl groups which may be mono-, di- or poly-substituted by halogen and / or hydroxy, such as lower alkenyl or lower alkenyl, which is halogen substituted and / or hydroxy, or alkynyl groups, as lower alkynyl. The aliphatic radicals R1, R2, or r3 are e.g. lower alkyl groups.

The cycloaliphatic radicals R are e.g. cycloalkyl

- 3 groups which may be interrupted by one or two spaced atoms selected from oxygen and sulfur and / or substituted by hydroxy, such as cycloalkyl, cycloalkyl interrupted by one or two spaced atoms selected from oxygen and sulfur or cycloalkyl substituted with hydroxy. 12 3

The cycloaliphatic radicals R, R or R ^J are e.g. cycloalkyl groups.

The cycloaliphatic-aliphatic radicals R are e.g. cycloalkyl-lower alkyl groups which may be interrupted by one or two spaced atoms selected from oxygen and sulfur and / or substituted by hydroxy and / or lower alkylthio, such as cycloalkyl-lower alkyl, cycloalkyl-lower alkyl, which is interrupted by one or two spaced atoms selected from oxygen and sulfur, or cycloalkyl-lower alkyl which is substituted in the cycloalkyl moiety by hydroxy or lower alkylthio and / or in the alkylene moiety by hydroxy.

The araliphatic radicals R and / or r \ R ^ or R ^ are e.g. phenyl-lower alkyl or naphthyl-lower alkyl radicals which may be substituted in the aryl ring by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, and / or lower alkylene moiety by hydroxy, such as phenyl-lower alkyl, phenyl- ( 1-hydroxy-lower alkyl, naphthyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl.

3

The aromatic radicals R, R or R are e.g. phenyl, naphthyl or phenyl substituted with halogen, lower alkyl, lower alkoxy and / or trifluoromethyl.

In the compounds of formula I, the group R is bonded to the P atom via a carbon atom.

Alkyl, alkenyl and alkynyl R may contain up to and including 14, preferably 12 carbon atoms, represented by lower alkyl, lower alkenyl and lower alkynyl. Alkyl R may also be Cg-C ^ -, e.g. Cg-C ₁₂ alkyl such as octyl, enoic, decile, undecilna or dodecyl group, eg. decile or dodecyl group.

Alkyl or alkenyl which is mono-, di- or polysubstituted by halogen and / or hydroxy represent mono- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di- or polyhalogen-lower alkyl, mono-, di- or polyhalogen-lower alkenyl, mono-, di- or polychalogen-lower hydroxyalkyl and mono-, di- or polychalogen-lower hydroxyalkenyl.

Alkyl interrupted by one or two atoms selected from oxygen and sulfur represent lower alkoxy lower alkyl, lower alkylthio-lower alkyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, di lower alkoxy-lower alkyl, di-lower alkylthio-lower alkyl and lower alkoxy-lower alkylthio-lower alkyl.

Alkyl which is interrupted by one or two atoms selected from oxygen and sulfur and which is substituted by hydroxy and / or halogen represent lower alkoxy- (hydroxy) lower alkyl and lower alkoxy- (halogen) lower alkyl.

Cycloalkyl represents Cg-Cg-cycloalkyl.

Cycloalkyl substituted with hydroxy represents 1-hydroxy-Cg-Cg-cycloalkyl.

Cycloalkyl and cycloalkyl in cycloalkyl-lower alkyl, which in each case is interrupted by one or two atoms selected from oxygen and sulfur, represent oxa-Cg-Cg-cycloalkyl, thia-Cg-Cg-cycloalkyl, dioxa-Cg-Cgcycloalkyl, dithia-Cg-Cg-cycloalkyl and oxatia-Cg-Cg-cycloalkyl.

Cycloalkyl-lower alkyl substituted on the cycloalkyl moiety with hydroxy and / or lower alkylthio and / or in alkylene moiety with hydroxy represent lower alkylthiocycloalkyl-lower alkyl, cycloalkyl- (hydroxy) lower alkyl and lower alkylthiocycloalkyl- (hydroxy) lower .

The general definitions used herein have the following meanings within the scope of the present invention.

The term lower, spoken of more and less in relation to organic radicals. compounds, unless otherwise explicitly defined, such with up to and including 7, preferably with up to and including 4 carbon atoms.

Lower alkyl R represents C ₂ -C ₄ -alkyl, e.g. ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, (2-methyl) butyl, hexyl or heptyl. Lower alkyl other than R means e.g. C1-C4-alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl or tert-butyl.

Lower alkenyl means e.g. C ₂ -Cy-alkenyl, preferably

Cg-C ^ -alkenyl bearing a double bond in a position higher than the position "and is e.g. 2-propenyl (allyl), but-3-en-1-yl, (2-raethyl) prop-2-en-1-yl (isobutenyl) or (5-methyl) but-2-en-1-yl but it can also carry a double bond in position and can be e.g. vinyl, prop-1-enyl or but-1-enyl, or it may be C 1 -C 6 -alkenyl, such as a hexenyl or heptenyl group.

Lower alkynyl means e.g. C ₂ -C 4 -alkynyl, preferably C 1 -C 4 -alkynyl, bearing a triple bond in a position higher than the position <X, fS, and e.g. 2-propynyl (propargyl), but-3-in-1-yl, but-2-in-1-yl or pent-3-yn-1-yl.

C 1 -C 8 cycloalkyl preferably has 3 to 6 ring carbon atoms and is thus C 1 -C 8 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

C 1 -C 8 -cycloalkyl-lower alkyl preferably has 3 to 6 ring and 1 to 4 chain carbon atoms and is e.g. C 1 -C 8 -cycloalkyl-C 1 -C 6 alkyl such as cyclopropylmethyl, cyclobutylmethyl or cyclohexylmethyl.

Mono- or dihydroxy-lower alkyl preferably has one of the hydroxy groups in the O <1> position and is e.g. (X-hydroxy-C ₂ -Cyalkyl, such as <X -hydroxy-C 1 -C 4 -alkyl, e.g. 1-hydroxyethyl,

2- (2-hydroxy) propyl, 1-hydroxybutyl, 2- (2-hydroxy) butyl or 1- (1-hydroxy-2-methyl-propyl, or <1, β-dihydroxy-C 1 -C 6 alkyl, such as 1 , 2-dihydroxy-prop-2-yl, but may carry a single hydroxy group in a position higher than the position and means, for example, y- or ¢ 5-hydroxy-C 1 -C 4 -alkyl, e.g. -hydroxypropyl or 2-, 3- or 4-hydroxybutyl.

The hydroxy-lower alkenyl preferably carries a hydroxy group in position X and a double bond in a position higher than position (β), and corresponds to e.g. o -hydroxy-C 1 -C 4 -alkenyl, e.g.

1-hydroxybut-2-enyl.

Mono-, di-, or polyhalogen-lower alkyl is, for example, mono-, di-, or trifluoro-C1-C4-alkyl, e.g. 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 1- or 2-fluorobutyl or 1,1-difluorobutyl.

Mono-, di or polyhalogen-lower alkenyl is, for example, mono-, di or trifluoro-C1-C4-alkenyl, e.g. 2-fluorobut2-enyl.

Mono-, di- or polychalogen-lower hydroxyalkyl and mono-, di- or polychalogen-lower hydroxyalkenyl preferably carry a hydroxy group to the higher position of the halogen atom (s) of the halogen. " , and fits e.g. mono-, dial-trifluoro <* .- hydroxy-C ₂ -C? -alkilu or mono-, dial trifluoro-C ^ -C ^ -alkenilu, for example. 2-fluoro-1-hydroxybutyl, 2fluoro-1-hydroxy-but-2-en-1-yl or 4,4,4-trifluoro-1-hydroxy butyl.

Lower alkoxy-lower alkyl preferably has up to 10 carbon atoms and is e.g. C1-C4-alkoxy-C1-C4-alkyl, such as C1-C4-alkoxy-C1-C4-alkyl, e.g. methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl or 1- or

2-methoxybutyl.

Lower alkoxy is, for example, C ₁ -C 4 -alkoxy, e.g. methoxy, ethoxy, isopropoxy, propoxy, butoxy, sec.butoxy or tert.butoxy.

Lower alkoxy-lower alkoxy-lower alkyl is, for example, C ₁ -C 4 -alkoxy-C ₂ -C ₁₁ -alkoxy-C ₁ -C 4 -alkyl, e.g. 2-methoxyethoxymethyl.

Lower alkylthio-lower alkyl preferably has up to 10 carbon atoms and is, for example, C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, such as C - C ₃ - a 1 which 11 io - C 1 - C - a 1 ki 1, e.g. methylthiomethyl, ethylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl or 3-methylthiopropyl.

Lower alkanesulfinyl- and lower alkansulfonyl-lower alkyl preferably has up to 10 carbon atoms and is, for example, C ₁ -C 4 -alkanesulfinyl or -C 1 -alkanesulfonyl-C 1 -C 4 -alkyl, e.g. ethanesulfinylmethyl or ethanesulfonylmethyl.

The di-lower alkoxy-lower alkyl preferably has a total of 15 carbon atoms and is, for example, di-C 1 -C 4 -alkoxyC 1 -C 4 -alkyl, such as di-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, e.g. dimethoxymethyl, diethoxymethyl, dipropyloxymethyl, 1,1- or 2,2-diethoxyethyl, diisopropyloxymethyl, di-n-butoxymethyl or 3,3-dimethoxypropyl.

Di-lower alkylthio-lower alkyl preferably has a total of 15 carbon atoms and is, for example, di-C 1 -C 4 -alkylthioC 1 -C 6 -alkyl, such as di-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl , e.g. dimethylthiomethyl, diethylthiomethyl or 1,1- or 2,2-dimethylthioethyl.

Lower alkoxy- (hydroxy) lower alkyl is, for example, C 1 -C 4 -alkoxy-C 1 -C 6 - (hydroxy) alkyl, e.g. 2- (2-hydroxy-3methoxy) propyl.

Lower alkoxy- (halogen) lower alkyl is, for example, C 1 -C 4 -alkoxy-C 0 -0γ- (halogen) alkyl, e.g. 1- (2-Fluoro-1-methoxy) butyl.

Hydroxy-C1-C8-cycloalkyl is, for example, 1-hydroxy-C1-C8-cycloalkyl, e.g. 1-hydroxycyclobutyl.

Oxa or thia-C1-C8-cycloalkyl preferably has 2 to 6 ring carbon atoms and is, for example, 2-oxacyclopropyl (oxiranyl), 2- or 3-oxacyclobutyl (oxetanyl), 2- or

3-thacyclobutyl (thietanyl), 2- or 3-oxacyclopentyl (tetrahydrof uranyl), 2- or 3-thacyclopentyl (thiolanil) or 2-oxacyclohexyl (tetrahydropyranyl).

The dioxa-C 1 -C 8 cycloalkyl preferably has 3 to 5 ring carbon atoms and carries those two oxygen atoms in the intermediate position of 1,3 and represents e.g. 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl.

Dithia-C 1 -C 8 -cycloalkyl preferably has 3 to 5 ring carbon atoms and bears those two sulfur atoms in an intermediate position of 1,3 and represents e.g. 1,3-dithiolan-2-yl or 1,3-dithioxan-2-yl. Oxathio-C 1 -C 8 -cycloalkyl is, for example, 1,3-oxathiolan-2-yl or 1,3-oxathioxan-2-yl.

C 1 -C 8 -cycloalkyl-hydroxy-lower alkyl preferably has 3 to 6 ring and 1 to 4 chain carbon atoms and is, for example, cyclo-C 1 -C 8 -alkyl-C 1 -C 6 -alkyl, e.g. 1-cyclopropyl-1-hydroxymethyl or 1-hydroxy-1-cyclobutylmethyl. Lower alkylthio cycloalkyl- (hydroxy) lower alkyl is, for example, 1-hydroxy-1 H (2methylthiocyclopropyl).

Halogen is a substituent of aromatic and / or 1 2 3 araliphatic radicals R, R or R preferably chloro, but may also be fluoro, bromo or iodo.

The phenyl or naphthyl group may have one or more than one, preferably one or two, same or different substituents as defined above. Phenyl- or naphthyl-lower: 10- -: .- -: _ alkyl alkyl is e.g. benzyl, naphth-2-ylmethyl, 1- or 2-phenylethyl or 2- or 3-phenylpropyl, each optionally substituted as described above.

The salts of the compounds of formula I are, in particular, their pharmaceutically acceptable salts, as the corresponding addition salts with acids, as well as the salts with bases. Suitable acids for the formation of acid addition salts are e.g. mineral acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acid, or organic acids such as organic sulfonic acids, e.g. benzenesulfonic,

4-toluenesulfonic or methanesulfonic acid, and organic carboxylic acids such as acetic, lactic, palmitic, stearic, malic, maleic, fumaric, tartaric, ascorbic or citric acid. The salts with bases are e.g. alkali metal or alkaline earth metal salts, such as sodium, potassium, calcium or magnesium salts, or ammonium salts, such as salts with ammonia or suitable organic amines, e.g. diethylamine, di- (2-hydroxyethyl) -amine, or tri- (2-hydroxyethyl) -amine.

Compounds of formula I may also form internal salts.

Depending on the presence of asymmetric carbon atoms, the compounds of this invention may be in the form of a mixture of isomers, in particular racemates, or in the form of pure isomers, in particular optical antipodes.

The compounds of formula I and their salts are useful as active ingredients in the pharmaceutical industry.

A technical problem

There is an ongoing need to prepare novel compounds having an antagonistic effect on GABAg receptors, which would act as nootropic, antidepressant, and anxiolytic agents and would surpass compounds of similar effect, known in the art, by their pharmacological properties.

The state of the art

Compounds of formula I wherein R is

2

A C 1 -alkoxy) -C 1 -C 6 - alkyl group, denotes one of R, R m 0 I 7

R ^{3 is} hydrogen, C 1 -C 8 alkyl, C 8 -C 8 cycloalkyl, phenyl optionally substituted by halogen, C 1-6 alkyl,

-C 1 -alkoxy and / or trifluoromethyl, or C 1 -C 4 -phenylalkyl optionally substituted in the phenyl moiety by halogen,

C ₁ -C 1 -alkyl, -C 1 -alkoxy and / or trifluoromethyl, and the other two are hydrogen, are known as intermediates for the preparation of the corresponding compounds wherein R is hydrogen and their salts. Also known are salts of those compounds of formula I in which '1 3

R is a hydrocarbon radical, R and R are hydrogen and 2

R is hydrogen or alkyl, and have been proposed as flame retardants and surfactants.

0pi3 solutions to a technical problem with implementation examples

However, compounds of formula I wherein R is

1,1-di (C 1 -C 4 -alkoxy) -C 1 -C 6 -alkyl represents one of R 4 and

R 12 is hydroxy and R and the other of R and R are hydrogen, specific compounds of formula I in which R is diethoxymethyl, one of

2 3

R and R are p-chlorophenyl or methyl and the other and R are hydrogen, and compounds of formula I in which R is a group of formula CHCOR '', in which R 'represents C 1 -C 4 -alkyl, such as ethyl, propyl,

2 3 isopropyl or n-butyl, and R, R and R are hydrogen, and their salts have not been described in the art so far and are therefore considered new.

The invention therefore also relates to those generally and specifically novel compounds which are generally known as intermediates and to their pharmaceutically acceptable salts for use in the treatment of the human or animal body, and to the pharmaceutical preparation containing them, as well as to compounds of the formula I, '' Τ2 - 1 2 in which R is diethoxymethyl, one of R and R is p-chlorophenyl or methyl and the other and R are hydrogen, or in which R is a group of the formula -CH 1 OR '^ in which R' represents C ₁ -C 4 -alkyl,

2 as ethyl, propyl, isopropyl or n-butyl, and R, R and R are hydrogen, and salts thereof.

We have now found that the compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. They show effective binding to the GABAg receptor and have been found to act as antagonists at this receptor. Mechanistically, antagonism at GABAg receptors can increase the release of fast-acting excitatory amino acid transmitters, i.e. glutamate and aspartate, thereby improving information processing in the brain. Consistent with this is the finding that the delayed inhibitory postsynaptic potential in the guinea pig, which is attributed to the GABAg mechanism, is shortened by antagonists, thereby allowing a faster nerve impulse transmission sequence.

On the other hand, prolonged treatment with antidepressants and repetitive shocks has been shown to increase the number of GABA _n receptors in the rat cerebral cortex.

D

In accordance with receptor theories to long-term treatment with antagonists of GABA _n resulting in the same effect.

D

For these and other reasons, GABAg antagonists may therefore act as antidepressants.

The GABAg anatagonists of the present invention interact at the GABAg 'receptor with values of ΙΟ ^ θ, - 7 starting from about 10 M (moles / liter) in the rat brain cortex membranes. Unlike GABAg agonists, such as baclofen, they do not potentiate adenylate cyclase stimulation in the rat brain cortex with noradrenaline, but antagonize

-13 effects of baclofen. Baclofen antagonism has also been shown in electrophysiological models in vitro, such as the preparation with penicillin-induced epileptic lobe of the seahorse, in which it inhibits baclofen at a concentration of 6 / UM epilepsy-like electrical activity in pyramidal cells. The compounds of the invention antagonize the effects of baclofen at concentrations of from about 10 to about 100 µM. In vivo, antagonism was demonstrated by baclofen iontophoresis in the rat cerebral cortex and systemic administration of antagonists at doses of 10 to 100 mg / kg. At doses of about 30 mg / kg i.p. the muscle relaxant effects of baclofen measured in the rotarod model are also antagonized.

Not only do antagonists show antagonistic effects against baclofen, but, as expected (see above), they also have their own effects as antagonists of endogenous GABA ·. Thus, antagonists are active in behavioral models that are known in the art to exhibit antidepressant, anxiolytic and / or nootropic properties. The compounds of formula I were found to be active after oral administration in the Porsolt test, in the Geller test, in the single experiment, in the passive withdrawal test (modification for the single experiment) in the pre- and post-test conditions, in the two compartment test and in a complex maze. In addition, we have seen an increase in playfulness, exploration, cultivation of sociability and a reduction of anxiety in studying on Rhesus monkeys. Accordingly, compounds of formula I can be used as nootropic, antidepressant and anxiolytic agents. Of course, they can also be used as antipodes against baclofen.

The invention relates in particular to compounds of formula I in which R 2 has more or more carbon atoms and is alkyl, alkenyl, alkynyl, alkyl or alkenyl which is mono-, di- or polysubstituted by halogen and / or hydroxy, alkyl, is interrupted by one or two spaced atoms selected from oxygen and sulfur, alkyl interrupted by one or two spaced atoms selected from oxygen and sulfur and which is substituted by halogen and / or hydroxy, cycloalkyl, cycloalkyl substituted by hydroxy, wherein cycloalkyl is interrupted by one or two spaced atoms selected from oxygen and sulfur, cycloalkyl-lower alkyl, cycloalkyl-lower alkyl substituted in the cycloalkyl moiety by hydroxy or lower alkylthio and / or alkylene working with hydroxy, cycloalkyl-lower alkyl, interrupted in the cycloalkyl portion by one or two spaced atoms selected from oxygen and sulfur, phenyl-lower alkyl, naphthyl-lower alkyl or phenyls aftyl-lower alkyl ring-substituted with halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, or naphthyl-lower alkyl, and / or chain substituted with hydroxy, 12 3 m in which one of the groups R, R and R represents hydrogen, lower alkyl, cycloalkyl, phenyl or naphthyl, phenyl or naphthyl substituted with halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl portion with halogen, lower alkyl, lower alkoxy and / but trifluoromethyl, is the second of

3 12

R, R and R are hydrogen or in the case of R and R are hydroxy and is

1 2 3 Hydrogen residues of R, R and R, and salts thereof, in particular pharmaceutically acceptable salts, with the foregoing reservations ·

The invention relates to compounds of formula I in which R 2 has more or more carbon atoms and is lower alkyl, lower alkenyl, lower alkynyl, alkyl interrupted by one or two spaced atoms selected from oxygen and sulfur , and cycloalkyl, cycloalkyl interrupted by one or two spaced atoms selected from oxygen and sulfur, cycloalkyl or cycloalkyl-lower alkyl interrupted by one or two spaced atoms selected from oxygen and in 12 3 sulfur; and in which one of the groups R, R and R represents hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted with halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl lower alkyl or phenyl lower alkyl substituted in the phenyl moiety halogen, lower alkyl, lower alkoxy 1 2 and / or trifluoromethyl, or one of R and R is hydroxy 1 2 3 m the remaining two of R, R and R are hydrogen, and to their salts, in particular pharmaceutically acceptable salts, with the above reservations ·

The invention relates in particular to compounds of formula I in which R 2 has more or more carbon atoms and is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxycycloalkyl cycloalkyl-lower alkyl, cycloalkyl- (hydroxy) lower alkyl or lower alkylthiocycloalkyl- ( hydroxy) lower alkyl group having 3 to 6 ring carbon atoms, mono- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di or polyhalogen-lower

- 16 alkyl, mono-, di- or polyhalogen-lower alkenyl, mono-, dially polyhalogen- (hydroxy) lower alkyl, mono-, di- or polyhalogen- (hydroxy) lower acenyl, lower alkoxy-lower alkyl, lower alkylthio- lower alkyl, lower alkanesulfinyl-lower alkyl, lower alkansulfonyl-lower alkyl, di-lower alkoxy-lower alkyl, di-lower alkylthio-lower alkyl, lower alkoxy- (hydroxy) lower alkyl, lower alkoxy- (halogen) lower alkyl, phenyl lower alkyl, phenyl lower alkyl which is mono- or disubstituted by halogen, lower alkyl, lower alkoxy and / or trofluoromethyl in the phenyl moiety, naphthyl-lower alkyl, oxa- or thiocycloalkyl having 2 to 6 ring carbon atoms or dioxa- , oxa thia- or dithacycloalkyl having 3 to 5 ring carbon atoms, 12 3 and in which one of R, R and R represents hydrogen, lower alkyl, cycloalkyl having 3 to 6 ring carbon atoms, phenyl, phenyl being mono- or substituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or and phenyl-lower alkyl, which is mono- or disubstituted by halogen, lower alkyl, lower alkoxy and / or trifluoro12 3 1 methyl, is other than R, R and R is hydrogen or in the case of R

12 3 and R hydroxy; and the residue of R, R and R is hydrogen, and salts thereof, in particular pharmaceutically acceptable salts, with the foregoing reservations.

One embodiment of the invention consists of subgroup A of compounds of formula I in which R 2 has more or more carbon atoms and is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxycycloalkyl, cycloalkyl-lower alkyl, cycloalkyl (hydroxy) lower alkyl or lower alkylthiocycloalkyl - (hydroxy) lower alkyl group of 3 to 6 ring carbon atoms, hydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di- or polychalogen-lower alkyl, mono-, di- or polychalogen-lower alkenyl, mono-, di- or polyhalogen- (hydroxy) lower alkyl, mono-, di- or polyhalogen- (hydroxy) lower alkenyl, phenyl lower alkyl, phenyl-lower alkyl, which in the phenyl moiety is substituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, or naphthyl-lower alkyl, and 12 3 in which one of the groups R, R and R ^{J represents} hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted with halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl lower alkyl or phenyl lower alkyl substituted in the phenyl moiety by halogen, lower alkyl, lower alkoxy 12 3 and / or trifluoromethyl, the other of R, R and R is hydrogen or

12 is R and R is hydroxy; and the residue of R, R and R is hydrogen, and salts thereof, especially pharmaceutically acceptable salts.

The compounds of subgroup A are, for example, those in which R 2 has more or less carbon atoms and is lower alkenyl or '1 2 lower alkynyl and in which one of the groups R, R □

and R ^{1 is} hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted with halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl portion with halogen, lower alkyl, lower alkoxy 1 2 and / or trifluoromethyl, or one of R and R is hydroxy and

2 3 are the remaining two of R, R and R hydrogen, and salts thereof, in particular pharmaceutically acceptable salts.

Another embodiment of the invention consists of subgroup B of compounds of formula I wherein R is lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl-lower alkyl, di-lower alkoxy-lower alkyl, di- lower alkylthio-lower alkyl, lower alkoxy- (hydroxy) lower alkyl, lower alkoxy- (halogen) lower, oxa- or thiacycloalkyl with 2 to 6 ring carbon atoms or dioxa- or dithacycloalkyl with 3 to 5 ring carbon atoms, and v which represents one of the groups R, R and R ^{J is} hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety with halogen, lower alkyl, lower alkoxy 1 2 3 and / or trifluoromethyl, the other of R, R and R is hydrogen or o 12 is, in the case of R and R, hydroxy; and the rest of R, R and R ^{J is} hydrogen, provided that if one of R and R is hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl fracture , phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety by halogen, lower alkyl, lower alkoxy 12 3 and / or trifluoromethyl, and the other two of R, R and R are hydrogen, R other than 1,1-di (C 1 -C 4 -alkoxy) -C 1 -C 8 -alkyl, and salts thereof, in particular pharmaceutically acceptable salts, with the foregoing reservations.

The compounds of subgroup B are e.g. those in which R represents lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, di-lower alkoxy-lower alkyl, di-lower alkylthio-lower alkyl, lower alkoxy-lower alkylthio-lower alkyl, oxacycloalkyl thiocycloalkyl, dioxycycloalkyl and dithacycloalkyl and in

3. v ..

of which one of the groups R, R and R represents hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety by halogen, lower alkyl, lower alkoxy 1 2 and / or trifluoromethyl, or one of R and R is hydroxy; 12 3 and the remaining two of R, R and R are hydrogen ,; and salts thereof, in particular pharmaceutically acceptable salts thereof, with the foregoing reservations.

Preferred are compounds of formula I in which R 12 3 has a more defined meaning and in which one of the groups R, R and R represents hydrogen, lower alkyl, phenyl or phenyl substituted by halogen or lower alkyl, and the remaining two of R ¹ ,

3

R and R are hydrogen, and salts thereof, in particular pharmaceutically acceptable salts.

Further preferred are compounds of formula I wherein R is lower alkyl of 2 or more carbon atoms, lower '2 alkenyl or lower alkynyl, R represents hydrogen, lower alkyl, phenyl or phenyl substituted with halogen or lower 1-3 alkyl, and R m R is hydrogen, m are pharmaceutically acceptable salts thereof.

Equally preferred is a subgroup B 'of compounds of formula I wherein R is lower alkoxy-lower alkyl or mono- or dihydroxy-lower alkyl, R represents hydrogen, lower alkyl, phenyl or phenyl substituted by halogen or lower alkyl, and R is and R ^J is hydrogen with higher mentioned provisos, and the pharmaceutically acceptable salts thereof.

The invention relates in particular to compounds of formula I in which R is ^C 2 ' ^C 12' ^alkyl 'such as ethyl, butyl, isobutyl, pentyl or isopentyl, C ₂ -C? -Alkenyl, such as but-3-enyl, C ₂ -C1-alkynyl, such as pent-3-ynyl, mono- or dihydroxy-C1-C4-alkyl, such as 2- (2-hydroxy) propyl, 2- (1,2-dihydroxy) propyl, 2- (2- hydroxy butyl or 1-hydroxybutyl, mono-, di- or trihalogen-OC-hydroxy-C1-C4-alkyl, such as 1-hydroxy-4,4,4-trifluorobutyl, 04-saturated mono-, di- or trihalogen - o <-hydroxy-C2 “Cy-alkenyl, as

1-hydroxy-2-fluoro-but-2-enyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, such as 2-ethoxyethyl, di-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl such as diethoxymethyl, -hydroxy-C 1 -C 4 -cycloalkyl, such as 1-hydroxycyclobutyl,

C1-C8-cycloalkyl-C1-C4-alkyl, such as cyclopropylmethyl, C1-C4-cycloalkyl-λ-hydroxy-C1-C4-alkyl, such as 1-cyclobutyl-1-hydroxy methyl, or 1- C 1 -C 4 -alkylthiocycloalkyl-OC-hydroxy-C 1 -C 4 -alkyl such as (1-methylthiocyclopropyl) - (1-hydroxy) methyl, R represents hydrogen, hydroxy, C 1 -C 4 -alkyl, such as methyl , phenyl or phenyl substituted by halogen, such as chloro, or C ₁ -C 4 -alkyl, such as

12 is methyl, and R and R are hydrogen or represents one of R and R is hydroxy and represents the other as well as R is hydrogen, and to their salts, in particular pharmaceutically acceptable salts, with the foregoing reservations.

Even more preferred are the subgroups of A 'and / or B' compounds of formula I in which R is either C ₂ -C 1 -alkyl, C 1 -C 6 alkenyl or C 1 -C 4 -alkynyl or represents -C 1 -alkoxy -C 1 -C 4 -alkyl or di-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl or represents c 1 -, β-, f- or <RTI ID = 0.0> -hydroxy-C2-Cy-alkyl, or oi , β-dihydroxy-C 2 'C 1-6 alkyl, represents hydrogen, lower alkyl, phenyl or phenyl substituted by halogen or lower alkyl, and R and R ^{J are} hydrogen, with the foregoing reservations, and their pharmaceutically acceptable salts, with the above reservations.

Particularly preferred are compounds of formula I in which R is C 2 -C 4 -alkyl, such as ethyl, butyl, isobutyl, pentyl or isopentyl, S (-saturated C 8 -C 4 -alkenyl, such as but-3-enyl, o ( -saturated C8-C4-alkynyl, such as pent-3-ynyl, ot-, or

C 1 -hydroxy-C 2 -C 6 -alkyl, such as 2- (2-hydroxy) propyl or 1-hydroxybutyl, N-B-dihydroxy-N-C 1-6 alkyl, such as 2- (1,2-dihydroxy) propyl, mono-, di- or trifluoro-OC-hydroxy-Cg-C? -alkyl, such as 1-hydroxy4,4,4-trifluorobutyl, © (-saturated mono-, di- or trihalogenoo (-hydroxy-Cg-Cy-alkenyl) , such as 1-hydroxy-2-fluoro-but-2-enyl,

C ₁ -C 4 -alkoxy-C ₁ -C 6 -alkyl, such as 2-ethoxyethyl, di-C ₁ -C 4 -alkoxyC-C ₁ -C 6 -alkyl, C 1 -C 8 -cycloalkyl-C 1 -C 4 -alkyl _? such as cyclopropylmethyl, ck-hydroxy-Cg-Cg-cycloalkyl, such as 1-hydroxycyclobutyl, or

C8-C8-cycloalkyl-OC-hydroxy-C1-C4-alkyl, such as 1-cyclopropyl-11 2 R hydroxymethyl, and R, R and R are hydrogen, and salts thereof, especially pharmaceutically acceptable salts.

Very special prednotni both subgroup A and / or B of compounds of formula I in which Rc is _2-C ^ alkyl, C2 ~ C ^ -alkenii or C _2-C ^ -alkynyl, or C ^ -alkoxy-C ^ -C 1 -alkyl or di-C 1 -C 4 -C 12 alkoxy-C 1 -C 4 -alkyl and R, R and R are hydrogen, and the pharmaceutically acceptable salts thereof, with the foregoing reservations.

Most preferred in the subgroup (s) are A and / or B compounds of formula I in which R is C 1 -C 4 -alkyl

And R, R and R are hydrogen, and pharmaceutically acceptable salts thereof.

The invention specifically relates to the compounds of formula I described herein and examples of their salts, in particular pharmaceutically acceptable salts.

Although salts of the compounds of formula I are included in the above definitions of preferred compounds, the invention mainly relates to the free compounds of formula I.

A process for the preparation of compounds of formula I is characterized in that in a compound of formula II

(II),

2 3 in which R, R, R and R have their previous meanings, Z represents -NH ₂ and R represents a protecting group R for hydroxy in 13 2 or, if R and R are hydrogen and R is hydrogen or alkyl, is an alkali ion metal or ammonium ion R ^, or vv O 4

Z represents a protected or latent amino group Z and R represents hydrogen or a protecting group R for hydroxy, any 5 6 group R or R being replaced by hydrogen and / or any group Z ° converted to -NH ₂ ;

and optionally the resulting salt obtained by this process can be converted to the free compound or to another salt and / or optionally the resulting free compound converted to a salt corresponding to the above definition, and / or optionally the resulting mixture of isomers is separated into individual isomers.

- 23 Protected hydroxy groups, such as -OR2 groups, present in protected form in the starting materials of Formula II, e.g. ethereal hydroxy groups, such as hydroxy groups etched with aliphatic, cycloaliphatic or araliphatic alcohol, e.g. with lower alkanol, cycloalkanol or phenyl or diphenyl-lower alkanol, or hydroxy groups etched with aliphatic silanol, e.g. with tri-lower alkyl 5 silanol. The lower alkoxy, e.g. C ₁ -C 4 -alkoxy, mono- or diphenyl-lower alkoxy, e.g. 1-phenyl- or 1,1-diphenyl-C 1 -C 4 -alkoxy, and tri-lower alkylsilyloxy, e.g. tri-C 1-4 -alkyl-, such as trimethylsilyloxy.

The protected amino groups of Z ° in the starting materials of formula II are e.g. acylamino groups such as lower alkanoylamino e.g. acetylamino, or phthalimido, a lower alkoxycarbonylamino, which is unsubstituted or substituted by phenyl, e.g. benzyloxycarbonylamino or tert.butoxycarbonylamino groups, or 1-aryl-methylamino groups, e.g. benzylamino or 1-phenyl-lower alkylamino, silylated amino groups, such as tri-lower alkylsilylamino or in particular bis- (tri-lower alkylsilyl) amino, e.g. bis trimethylsilylamino. The latent amino group Z ° may be e.g. nitro or azido.

Preferred compounds of formula II are those of formula

Ila

(Ila) in which R represents a protecting group for hydroxy, e.g. -C ₁ -alkyl or C ₁ -C 4 -alkyl substituted with lower alkanoyloxy or with one or two, optionally substituted phenyl groups, such as 1-C ₂ -C 4 -alkanoyloxy-C ₁ -C ₁ -alkyl , e.g. pivaloyloxymethyl, or 1-phenyl- or 1,1-diphenyl-C 1 -C 6 alkyl, e.g. benzyl, but of formula Ilb

(Ilb) in which R represents a C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted group for hydroxy, e.g. one or two optionally substituted phenyl groups, such as 1-phenyl- or 1,1-diphenyl-C1-C4-alkyl, e.g. benzyl, or a silyl group such as tri-C 1 -C 4 -alkylsilyl, e.g. trimethylsilyl, and Z ° has a previous meaning and means e.g. -Cy-alkanoylamino, e.g. acetylamido, phthalimido or bis-silylamino, such as bis (tri-C 1 -C 4 -alkylsilylamino, e.g. bis (trimethylsilyl) amino, or of formula Ilc

in which Z ° has its previous meaning and means e.g. C 1-6 -Cyalkanoylamino, e.g. acetylamino, C ₁ -C 4 -alkoxycarbonylamino, e.g. tert-butyloxycarbonylamino, or phenyl-C 1 -C 4 -alkoxycarbonylamino, or of the formula wherein R is an alkali metal ion or an ammonium ion, 12 3 and in which in formulas Ha, 11b and Ilc R, R, R and R its previous meaning, whether in the formula Ud R stands for unsubstituted aliphatic, cycloaliphatic or araliphatic hydrocarbons

3 represents a residue, R and R represent hydrogen and R represents hydrogen or alkyl.

The substitution of the protecting group R in the compounds of formula II, Ha or 11b with hydrogen can be carried out by treatment with a suitable nucleophilic reagent such as an alkali metal hydroxide, e.g. sodium hydroxide or lithium hydroxide, an alkali metal halide, in particular bromide or iodide, such as lithium bromide or sodium iodide, thiourea, alkali metal thiophenolate, such as sodium thiophenolate. The substitution reaction can be carried out in the absence or presence of a solvent and, if necessary, during cooling or heating, in a closed container and / or under an inert gas atmosphere.

If C 1 -C 4 -alkyl substituted in position 1 by one or two phenyl groups, e.g. if R is benzyl, substitution of such a group in the compounds of formulas II, Iia or Ilb with hydrogen by hydrogenolysis may be carried out in the presence of a metal hydrogenation catalyst or by any other suitable mode of operation.

Alternatively, a protecting group substitution may be performed, e.g.

silyl or alkyl groups R in compounds of formulas II,

Iia or Ilb or an alkali metal or ammonium r6 ion in compounds of formulas II or Ud with hydrogen by treatment with an acid under hydrolytic conditions, in particular a mineral acid such as hydrochloric acid, e.g. hydrochloric acid for use in dilute or concentrated aqueous form, or by treatment with an organic silyl halide such as trimethylsilyl iodide or bromide, followed by hydrolysis if necessary.

The reaction is preferably carried out at elevated temperature, e.g.

during the reflux of the reaction mixture, and if necessary using an organic diluent, in a sealed container and / or under an atmosphere of 5 inert gas. The method of substitution of protecting group R depends, e.g. from the substituent R present in the compound of formula II, which is to be maintained when converting the compound of formula II to the compound of formula I. This substitution can be carried out e.g. according to the illustrative examples.

The protected amino groups or the latent amino groups Z ° in the compounds of formula II, 11b or Ilc can be converted to the free amino according to known methods, which are selected according to the characteristics of the protected or latent amino group to be converted to amino, as with solvolitic or hydrogenolytic modes of operation, e.g. hydrolysis in the presence of acid or base, acidolysis, e.g. treatment with trifluoroacetic acid, treatment with hydrazine, or by hydrogenolysis in the presence of a metal hydrogenation catalyst or by any other suitable working method.

Depending on the affected groups, substitution and conversion operations can be performed in any order or simultaneously using methods known per se.

It is advantageous to convert all protecting groups, converting R4 or R4 to H and Z ° to NH4, in a single step by treatment with an acid, preferably with hydrochloric acid, in particular hydrochloric acid, under hydrolytic conditions.

The compounds of formula II can be prepared e.g. by different methods according to the nature of the group X in formula V, defined below, e.g. by reacting in the presence of a basic catalyst or in the presence of free radical-forming agents a compound of formula IV

4 in which R and R have their previous meaning, which can be prepared by metabolizing a compound of formula R-PHal ₂ (IVa; Hal =

C halogen) with the alcohol R OH in the presence of tri-lower alkylamine, or more preferably by reacting the aqueous hypophosphoric acid with an orthoester of formula C (C 1 -C ₄ alkyl) (OR) g (IVb). wherein, in the second example, a compound of formula IV is obtained wherein R is C (C 1 -C ₄ -alkyl) (OR) ₂ , with a compound of formula V, v,,.

2 in which R and R have a previous meaning and X is capable of being converted to a group of formula wherein R and Z have their previous meanings that a compound of formula VI

(VI) group,

-CH (R ³ ) -Z, formed

2 4 in which R, R, R, R and X have their previous meanings, and o then convert the group X to a group of formula -CH (R) -Z.

The group X is primarily cyano, but may also represent carbamoyl, a group of the formula CH (R ³ ) -Z ° (Via), in which R ³ and Z ° have a previous meaning; or X is a group of the formula -C (R) = Y, in which R ^{J has} a previous meaning and -C = Y is a functionally modified carbonyl group, as appropriate, of the corresponding ketal or thioketal group, including the corresponding cyclic group.

If in a compound of formula IV R has a preliminary meaning and in the compound of formula V X is an activating group Xa, such as cyano or -C (R ^) = O, either a basic catalyst or an i-space catalyst can be used. However, if the same compounds of formula IV are reacted with compounds of formula V in which X is e.g. residue of the formula -CH (R ^) - Z °, space radical catalysts are required.

The base catalyst used in the first step may be e.g. An alkali metal C1-C4-alkoxide, e.g. sodium or potassium C ₁ -C 4 -alkoxide, in particular sodium methoxide, sodium ethoxide or potassium tert-butoxide, alkali metal or alkaline earth metal fluoride, such as potassium fluoride or cesium fluoride, or alkali metal hydride, such as sodium hydride. The reaction can be carried out with or without the use of an added solvent.

If a solvent is added, it is preferably an alcohol, in particular a C 1 -C 4 -alkanol, corresponding to the alkoxide used as the base catalyst. The reaction temperature may vary from 0 ° C to the boiling point of any solvent added.

The agents that form free radicals are, for example. compounds which can be converted to free radicals by ionization or ultraviolet radiation, preferably peroxy compounds, such as inorganic peroxy compounds, e.g. hydrogen peroxide or ammonium persulfate, or organic peroxides, e.g. benzoyl peroxide or tert.butyl peroxide, or organic azo compounds, e.g. azo-bis-isobutyronitrile. The reactions involving free radical-forming agents can be carried out as desired

- 30 in the presence of solvent and, where necessary, during cooling or heating, in a closed container and / or in an inert gas atmosphere.

• 3

Conversion of group X to group -CH (R) -Z is carried out according to known methods. Cyano and carbamoyl are converted to aminomethyl by reduction, cyano e.g. by hydrogenation in the presence of a suitable catalyst, e.g. Raney nickel, and solvents such as ethanol, which may preferably contain ammonia, and carbamoyl e.g. by treatment with a suitable hydride reducing agent such as borane in tetrahydrofuran.

Conversion of group X to compounds of formula VI, v

About which X is a group -C (R) = Y, in which Y is oxygen, to a group □ of formula -CH (R ^J ) -Z, is carried out by known reductive amination procedures, e.g. by treatment with sodium cyanoborohydride in the presence of ammonium acetate in a suitable solvent, such as dioxane, and during cooling, e.g. at about 0 ° C.

The compounds of formula IV are either known or can be prepared by several methods described. Specific examples of compounds of formula IV include iso-propyl (ethyl) phosphonite, isopropyl (n-propyl) phosphonite, iso-butyl (n-butyl) phosphonite, iso-butyl (iso-propyl) phosphonite, iso-butyl (iso-butyl) ) phosphonite and iso-butyl (sec.butyl) phosphonite.

Similarly, compounds of formula V are either known or can be prepared by methods well known.

Alternatively, the compound of Formula VII

R ⁵ -0s yo-Si (R ⁷⁾ 3

R '(VII), in which RC 1 -C 4 -alkyl or C 1 -C 4 -alkyl substituted with one or two phenyl radicals or an additional group -Si (R) g, each R is independently C 1 -C 8 -alkyl, preferably C1-C6-alkyl, in particular methyl, wherein the groups R and R are the same or different, can be reacted with a compound of the formulas or

U (Vlila), (VHIb), (Fork), (V) in which R, R, R, Z and X have their previous meanings, with X being primarily cyano or a group of formula □

C (R) = Y and Hal stands for halogen, such as iodine, bromo or chloro. Reaction with an epoxide of formula VHIb is preferably carried out in the presence of mild Lewis acid as anhydrous zinc chloride, while reactions with halides of formulas Vlila or Vilic are carried out preferably under Arbus method conditions, e.g. at a reaction temperature ranging from room temperature to elevated temperature, e.g. 16 ° C, removing the trialkyl silyl halide formed in the reaction.

Compounds of formula Ilb and / or Ilc can also be prepared by starting from a compound of formula IX

°) UUU r

H-NH ₂ (IX)

12 3. .

in which R, R and R have their previous meanings, m is metabolized, e.g. is acylated to give the compound of formula X

3 in which R, R and R have e.g. an acylated amino group, a hydroxyl group in a compound of formula XI (X), having its previous meaning and being Z ° and then protecting (acid) with formula X to form a compound

(XI),

OO λ in which R, R, R ^J and Z ° have their previous meanings and R ^ O is protected, e.g. esterified hydroxy. Alternatively, the starting material of formula IX can be reacted with a silylating agent, such as hexa-lower alkylsilazane or tri-lower alkyl halogenosilane, e.g. with hexamethyldisilazane or with trimethylchlorosilane in the presence of triethylamine to form a compound of the formula

R ⁵ _O 0. R ¹ R ² R ³

CH-CH-CH-Z ° (XI '),

R ⁵ o (I

5 in which Ro is a group R which denotes a tri-lower alkylsilyl, e.g. trimethylsilyl, and Z ° represents bis (tri-lower alkylsilyl) amino as bis (trimethylsilylamino).

with the compound

An intermediate of formula XI or XI 'is then reacted with the ability to convert the group

R ⁵ 0 or

R ⁵ (y in group a

in which R has a prior meaning to form a compound of formula 5b, wherein R has a previous meaning. Thus, the intermediate of formula XI can be reacted with an aliphatic, cycloaliphatic, cycloaliphatic or araliphatic aldehyde or ketone, e.g. of formula R'-C (R) = O (XIIa) corresponding to the group R of formula R'-CH (R) (OH) -, with a terminally unsaturated aliphatic, cycloaliphatic or araliphatic compound R '' '- H (XIIb) ), in which R '' is a group identical to R, except that it has at least one additional terminal double bond, or in the presence of a basic condensing agent, such as a three-lower alkyl amine, e.g. N-ethyl-N, N-diisopropyl-amine, with the corresponding halide, e.g. lower alkyl halide of the formula R-Hal (XIIc,

Hal = halogen), preferably under basic conditions.

The starting materials of Formula IX and their preparation have been described in U.S. Pat. 4656298, which describes in a compound of formula XIII '

C-Ce-cycloalkyl, phenyl, which is (XIII '), and R ³ is hydrogen, C.-C, _Q-alkyl, a &apos; 1 s is optionally substituted

- 34 with halogen, C ^ -alkyl, C ₁ -C-alkoxy and / or CF ^, or Cy-C ₁₀ -fenilalkil, which is optionally substituted in the phenyl moiety by halogen, C ^ -alkyl, C ₁ -C 4 -alkoxy

O 'v, and / or CF ^, m are the other two hydrogen, Z is a protected amino group, is hydrogen, C1-C4-alkyl or an alkali metal cation or ammonium cation, and Q is hydrogen or a protecting group, c

substitution of the group R ^ when alkyl, with hydrogen or a cation in an alkali metal or ammonium cation;

replacement of the group Q, if a protecting group, by hydrogen; and converting Z ° to NH ₂ to form a compound of formula IX.

In the U.S. 4656298 can be replaced by Q groups, e.g.

-CCC1 -C4-alkyl) (O R ^a ) (O R ^b ), preferably -CH (OR ^a ) (OR ^b ), wherein R ^a and R ^{b are} -C 4 -alkyl, in particular -CH (OC ₂ H ₂ ) ₂ and / or C 1 -C 5 alkyl group R with hydrogen by treating a compound of formula XIII 'with an acid under hydrolytic conditions; or by treatment with organic silyl halide, such as tri-methyl silyl iodide or bromide, followed by hydrolysis. In US 2656298 vv 5, it is preferred to replace the protecting groups Q and R with H hydrogen and convert Z ° to NH ₉ in compounds of formula XIII 'in a single step with an acid under hydrolytic conditions.

This known method has the disadvantage that under the described sharp reaction conditions, at the same time as the protecting group Q, the protecting group R 1 for hydroxy and the 1 protecting group for amino are removed.

We have now found that in a compound of formula

I

XIII or XIV

2 in which R, R, have the meaning of a suitable protective when treating the compound with anhydrous medium to give the compound of formula ⁰ (XIII) or (XIV),

R ^, Q _t χ i _n 2 ° its predecessor o 5 groups R and Z respectively. R and X retain, Formula XIII or XIV counterparts to form a compound of Formula XI, or

NLUH (xv).

Examples of such protic anhydrous media include anhydrous hydrogen chloride gas, or the anhydrous medium can be prepared from an organic compound with one or more Si-Cl bonds together with an agent, e.g. an alkanol capable of cleaving the Si-Cl bond to form an anhydrous protic medium in situ.

Preferred anhydrous protic media therefore include trimethyl silyl chloride in technical chloroform containing ethanol.

This new route has the advantage of avoiding levels of re-protection, e.g. IX- »X and X- * XI, which are required in known routes.

The invention therefore also relates to a process for compounds of formula (XV), wherein X is cyano, carbamoyl or a group of the formulas -CH (R ³ ) -Z ° (XVa) or -C (R ³ ) = Y (XVb ), in which Z ° represents a protected or latent amino group, as indicated above, Y means optionally acetylated, thioacetalized, ketalized or thioketalized oxo group, one of r \ R and R being hydrogen, hydroxy, C 1 -C 8 - alkyl, C 1 -C 8 -cycloalkyl, phenyl optionally substituted by halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and / or trifluoromethyl, or optionally substituted in ^C 7 ^C 10 ^{"f 'enyl' l 'which} ^' ^{in the} phenyl moiety by halogen, C ^ -C ^ -alkyl, C ^ -alkoxy 1 2 3, and / or trifluoromethyl and the other of R, R and R is hydrogen, and R5 is A C 1 -C 4 -alkyl radical, wherein the compound of formula XXV

(XIV), i 2 5 * in which R, R, R ³ , R ³ b and X have the meanings indicated above and Q 'represents a group of the formula -C (R ^) - C (OR ^) (OR ^) ( XIVa) in which R® is lower alkyl, and represents R ^ and R ¹⁰ independently of one another lower alkyl or together represent lower alkylene, is treated with an anhydrous protic medium * and the compound of formula XV, whenever it is prepared according to this procedure or in a the obvious chemical equivalent.

The new process is carried out at a temperature ranging from -80 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

While the relative molar ratios of reactants can be used, i.e. of reactant XIV against organic silyl chloride, varying over a wide range, it is preferable to use molar ratios of from 1 to 2 molar equivalent of the other to the molar equivalent of XIV.

In a preferred embodiment of the process of the invention, a compound of formula Ila is subjected ^to w

-NH ₂ (Ha),

12 in which R is lower alkyl and R, R, R and R have their previous meanings, which can be obtained e.g. according to the reaction sequences

IV + V -► VI - Ila;

VII + Fork -VI —- Ila;

VII + VHIb - (Ilb) - Ila or

XIV - XV - VI - Ila;

basic or acid hydrolysis, or treated with tri-lower alkyl halogenosilane.

- 38 Combination process indicated by the reaction sequence

XIV - XV - VI - Ila - I is a new and advantageous route to compounds of formula I.

In another preferred embodiment of the process of the invention, compounds of the formula Ilc in which R, R ¹ , R ² , R ⁴ , R ⁴ and Z ° have their previous meanings, which can be prepared e.g. via reaction sequences

IX

XI

Ilb or

IX —— XI '- Ilb, basic or acidic hydrolysis or treated with tri-lower alkyl halogenosilane, followed by treatment with water. With 5, a compound Ilb is prepared in which R is tri-lower alkylsilyl, Z ° is bis (lower alkylsilyl) amino and 12

R, R and R have their foregoing meanings, in situ, by reacting the compound of formula

with a silylating agent and then, preferably under basic conditions, with a compound of the formula R-Hal (XIIb; Hal-halogen), and

- 39 remove the protection according to the invention when processed under counter flow, e.g. water or water / alcohol conditions.

The aforementioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably those which are inert to the reagents and are solvents therefor, catalysts, condensation or reactants. said other agents and / or in inert atmospheres, at low temperatures, at room temperature or at elevated temperatures, preferably near the boiling point of the solvents used, at atmospheric or supra-atmospheric pressure.

The compounds of formula I, which can be obtained according to the process of the invention, can be converted into one another.

Thus, compounds of formula I in which R is substituted by hydroxy and / or R and R represents hydroxy can be converted to the corresponding hydroxy-free compounds, e.g. by treating them with thiocarbonyldiimidazole and treating the resulting imidazolylthiourethane in the presence of a radical initiator, such as azoisobutyronitrile, with three-lower alkylstannan, e.g. with (C ^ Hg) ^ SnH, e.g. in benzene at 60 to 80 ° C.

Also, the double and / or triple bonds present in group R can be reduced to single bonds, and triple bonds, therefore, to double bonds to give the corresponding less unsaturated compound of formula I.

The invention further encompasses any variant of the present processes in which an intermediate, which can be obtained at any stage of the process, is used as starting material and residual steps, or in which the starting materials are formed under reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes. Whenever desired, the above procedures are performed after first adequately protecting all potentially disruptive reactive functional groups, e.g. as explained here.

It is advantageous to use in these reactions those starting materials which lead to the formation of those compounds mentioned above as preferred.

Depending on the choice of starting materials and methods, new compounds may be in the form of one of the possible isomers, e.g. as diastereomers, as optical isomers (antipodes), as racemates or as mixtures thereof.

In the case of diastereomeric mixtures of the above compounds or intermediates, they can be separated into individual racemic or optically active isomers by methods known per se, e.g. by fractional distillation, crystallization or chromatography.

Racemic products of formula I or basic intermediates can be cleaved into optical antipodes, e.g. by separating their diastereomeric salts, e.g. by fractional crystallization of the d- or 1- (tartrate, dibenzoyltartrate, mandelate or camphrasulfonate) salts.

It is advantageous to isolate more active antipodes of the compounds of the invention.

The compounds of the invention are further obtained either in the free (amphoteric ion) form or as a salt thereof. For example, any resulting free compound can be converted to a suitable acid addition salt, preferably using a pharmaceutically acceptable acid or anion exchange preparation, salts with bases by treating the free compounds with bases or suitable cation exchange techniques, or the resulting salts can be converted to the corresponding free compounds , e.g. acid addition salts using a stronger base, such as metal or ammonium hydroxide, or any base salt, e.g. alkali metal hydroxide or carbonate, or cation exchange preparation, and salts with bases by treatment with suitable acidic reagents. These or other salts, e.g. picrates can also be used to purify the compounds obtained; the compounds are then first converted to salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, when referring to the compound in this connection, an appropriate salt is also meant, provided that it is possible or appropriate in these circumstances, and the term "salts should include, optionally free compounds when appropriate in meaning and purpose.

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

The present invention also relates to the use of the compounds of the invention for the preparation of pharmaceutical compositions, in particular pharmaceutical preparations having selective antagonistic activity against GABAg that can be used to treat e.g. cognitive and memory disorders, depressive mental states, and anxiety.

The pharmaceutical compositions according to the invention are those suitable for enteral, as oral or rectal, transdermal and parenteral administration to mammals, including humans for the treatment of diseases that respond to the above blocking GABAg receptors, comprising an effective amount of a compound of the invention, blocking GABAg receptors, alone or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are incorporated into effective pharmaceutical compositions

- 43 the amount thereof in association with or admixture with excipients or carriers suitable for either enteral or parenteral administration.

Preferred are tablets and gelatin capsules comprising the active ingredient more expensively with a) diluents, e.g.

t lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, fipr. silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets also c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; optionally d) disintegrants, e.g. starches, agars, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavorings and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are prepared advantageously from fat emulsions or suspensions. These preparations may be sterilized and / or may contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solubilizing agents, osmotic pressure regulating salts and / or buffers. In addition, the preparations may also contain other therapeutically valuable substances. These preparations are prepared in accordance with conventional methods for mixing, granulating or mixing. and containing, - 44 about 0.1 to 75%, preferably about 1 to 50% of the active ingredient.

Suitable preparations for transdermal use include an effective amount of a compound of the invention with a carrier. Advantageous carriers include pharmacologically acceptable solvents that can be absorbed to assist in passage through the host skin. Typically, transdermal agents are in the form of a bandage comprising a support member, a reservoir containing the compound, optionally with carriers, optionally a volume control barrier, to supply the compound to the host skin in a controlled and predetermined amount over a long period of time, and a means of fixing the agent to the skin.

The present invention also relates to the use of compounds of the invention having antagonistic properties against GABAg and to pharmaceutical compositions containing these compounds for the treatment of disorders responsive to selective blocking of GABAg receptors, in particular cognitive and memory disorders as well as depression and anxiety in mammals.

One aspect advantageously relates to a method for treating nootropic disorders in a mammal using an effective amount of a compound of the invention, preferably in the form of the above pharmaceutical preparations.

45Dosage of the active compound to be administered depends on the type of warm-blooded animal (mammal), body weight, age and individual condition and form of administration.

A mammal dosage unit of about 50 to 70 kg may contain between about 10 and 500 mg of active ingredient.

The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in centigrade degrees. Unless otherwise noted, all evaporations under reduced pressure, preferably between about 2 and 13 kPa, are performed. The structure of the end products, intermediates and starting materials is confirmed by analytical methods, e.g. microanalysis and spectroscopic characteristics (e.g., MS, IR, NMR). The compounds of formula I are denoted below

3

3-Amino-1-R -2-R -3-R -propyl (R) phosphinic acid.

EXAMPLE 1

To a solution of 1.0 g of ethyl 3-amino-2- (p-chlorophenyl) propyl (diethoxymethyl) phosphinate in 5 ml of methanol was added 2.5 ml of a 2N sodium hydroxide solution and the mixture was heated to 80 ° C for 5 hours. After this time, the reaction mixture was concentrated under reduced pressure and the oily residue was passed through an ion exchange resin (D0WEX ® 50Μ-Χ8 H ⁺ ) using deionized water as eluent. The ninhydrin positive fractions were combined and evaporated to give 3-amino-2- (4-chlorophenyl) propyl (diethoxymethyl) phosphinic acid, m.p. 175-185 ° (dec.) ³¹ P-NMR: S = + 31.6 ppm (D ₂ O).

EXAMPLE 2

0.5 g of ethyl 3-amino-2-hydroxy-propyl (diethoxymethyl) phosphinate are dissolved in 5 ml of ethanol and this solution is added to a solution of 0.14 g of sodium hydroxide in 2 ml of water. This mixture was then heated to 60 ° C for 3 hours, cooled to room temperature and the solvent was evaporated under reduced pressure. The oily residue was passed through an ion exchange resin (D0WEX ® 5OW-X8 H ⁺ ) using deionized water as eluent. The ninhydrin-positive fractions were combined and evaporated to give 3-amino-2-hydroxy-propyl (diethoxymethyl) phosphinic acid, m.p. 214-215 ° (dec.) ³¹ P-NMR: ό = + 30.9 ppm (D ₂ 0).

The starting material can be prepared as follows:

To a solution of 25.0 g of ethyl (trimethylsilyl) diethoxymethylphosphonite in 200 ml of dry tetrahydrofuran was added 19.2 g

2,3-epoxypropylphthalimide under a nitrogen atmosphere. A catalytic amount of dry zinc chloride was added to this mixture while stirring, and the mixture was then refluxed for 2 hours. After cooling, the solvent was evaporated under reduced pressure, the residue dissolved in 100 ml of chloroform and stirred vigorously for 50 hours with 50 ml of water. The organic layer was separated, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was heated at 6 Pa at 100 ° for 1 hour to leave as an oily residue ethyl 2-hydroxy-3-phthalimido-propyl (diethoxymethyl) phosphinate, P-NMR: <5 = +42.0 and +41.6 ppm ( CDCl ^).

To a solution of 1.0 g of ethyl 2-hydroxy-3-phthalimidopropyl (diethoxymethyl) phosphinate in 23 ml of isopropanol was added 4 ml of water. 0.47 g of sodium borohydride was added to this mixture and stirred at room temperature for 24 hours. After this time, 2.6 ml of glacial acetic acid is carefully added and the reaction mixture is heated to 80 ° for 2 hours. After this time, the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was passed through a silica column using a mixture of one part ethyl acetate and one part ethanol as eluent. Ethyl 3-amino-2-hydroxy-propyl (diethoxymethyl) phosphinate, ³¹ P = +45.8 and +45.2 ppm (CDCl2) was obtained as a colorless oil.

EXAMPLE 3:

A solution of 6.7 g of 3- (benzyloxycarbonylamino) propyl (n-butyl) phosphinic acid in 125 ml of 36% hydrochloric acid was refluxed for 1.5 hours. The mixture was evaporated to an oil and the oil was co-evaporated with water (2 x 50 ml) to give a white solid. This solid was then dissolved in 50 ml of dry methanol, 1 to 3 ml of propylene oxide was added and the solution was stirred at room temperature. The precipitated product was collected by filtration and dried to give 3-aminopropyl (n-butyl) phosphinic acid, m.p. 231-234 ° (dec.), ³¹ P-NMR: c) = +44.6 ppm (d ₂ o).

The starting material can be prepared as follows:

A solution of 5.0 g of 3-aminopropylphosphinic acid in 200 ml of water was cooled to 5 ° and the pH was adjusted to 9.5 with 2 molar sodium hydroxide solution. To this mixture was added

6.8 g of benzyl chloroformate while maintaining pH and temperature. When the addition is complete, the mixture is stirred for 3 hours at pH 9.5 at room temperature and allowed to stand overnight. The mixture was then extracted with 100 ml of ether and the aqueous layer was stirred at 5 ° with an equal volume of chloroform. The mixture was acidified to pH 2, the chloroform layer was separated, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The oily product was triturated with ether to give a white solid, 3- (N-benzyloxycarbonyl) propylphosphinic acid, m.p. 53-55 °, ³ Y-NMR: <S = + 36.6 ppm (CDCl 2).

To a solution of 3.0 g of 3- (N-benzyloxycarbonylamino) propylphosphinic acid in 50 ml of dry tetrahydrofuran was added 2.3 g of triethylamine. This mixture was stirred under a nitrogen atmosphere for 0.5 hours and then 2.5 g of trimethylchlorosilane were added. This solution was stirred for 1 hour and a precipitate formed during this time. After this time, 7.6 g of 1-bromobutane were added and the reaction mixture was refluxed for 24 hours. The mixture was then allowed to cool to room temperature, 50 ml of water was added and the whole was stirred for 1 hour. The mixture was extracted with 200 ml of chloroform, the organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The oily product was triturated with ether to give a white solid, which is 3- (N-benzyloxycarbonylamino) -propyl (n-butyl) phosphinic acid, m.p. 116-118 °, ³ ^ P = +58.6 ppm (CDCl 2).

EXAMPLE 4

A solution of 3.3 g of lithium hydroxide monohydrate in 40 ml of water was added to a solution of 20 g of ethyl 3-aminopropyl (diethoxymethyl) phosphinate in 75 ml of ethanol. The mixture was stirred and about 25 ml of water was added to give a clear solution. The solution was stirred at room temperature until the reaction was complete after about 48-31 hours. This can be monitored by P-NMR. The solution was then evaporated to give a cloudy oil, to which 50 ml of ethanol was added. The insoluble inorganic solid was removed by filtration and the filtrate was evaporated. The residual oily product containing a little solid was triturated with acetone and the resulting solid filtered off with ³ * P NMR: <5 = 33.98 ppm; D ₂ 0).

The resulting filtrate was evaporated and triturated again with a little acetone to give a second crop of the product. Both crops are combined and dissolved in water. The solution was concentrated and extracted with chloroform to remove traces of starting material, then treated with charcoal. The solution is filtered to remove charcoal and evaporated to low volume. This crude product is then chromatographed on an ion exchanger (DOWE! ® 50W-X8 H ⁺ form) using deionized water as eluent. Collect fractions of 150 ml. Fraction 44 and the following fractions contain 3-aminopropyl (diethoxymethyl) phosphinic acid, which is obtained after evaporation in pure form, m.p. 209-210 ° (dec.).

50 EXAMPLE 5

To a solution of 8.0 g of isopropyl 3-aminopropyl (t-butyl) phosphinate in 80 ml of chloroform was added 11.7 ml of triraethylsilyl bromide. The reaction mixture was stirred for 4 hours at 50 ° C and then overnight at room temperature. Removal of chloroform and excess trimethylsilyl bromide under reduced pressure give an oil which is taken up in ethanol. Propylene oxide was added and the white solid was filtered off and dried over phosphorus pentoxide to give 3-aminopropyl (t-butyl) -phosphinic acid x 0.15 H ₂ 0, m.p. 253-255 °.

The starting material is prepared as follows:

A mixture of 24.7 g of isopropanol and 17.2 g of triethylamine in 35 ml of diethyl ether was added dropwise to 30 g of t-butyldichlorophosphine in 100 ml of diethyl ether. The temperature is maintained between 5 and 10 °. The solid was filtered off and the filtrate was evaporated. The crude oil is purified by distillation to give t-butylphosphonic acid isopropyl ester! as oil® »boil. 82 ° / 2 kPa, n ²⁰ = 1.4222.

ί

To 15.7 g of t-butylphosphonic acid isopropyl ester in 6.3 ml of acrylonitrile was added 21 ml of sodium isopropylate (0.25 molar). After the exothermic reaction (the temperature rises to 100 °), the suspension is filtered, the filtrate is evaporated and the residue is distilled to give isopropyl 2-cyanoethyl (t-butyl) phosphinate as an oil, boiling. 121 ° / 8 Pa, n ^ ⁰ = 1.4480.

A mixture of 11.0 g of isopropyl 2-cyanoethyl (t-butyl) phosphinate, 17.0 g of ammonia and 1.7 g of Raney nickel in 110 ml of ethanol was hydrogenated for 5 hours. The catalyst was filtered off and the solvent

51 · Remove by evaporation. The crude oil was purified by distillation in a ball tube to give isopropyl 3-aminopropyl (t-butyl) phosphinate as a boiling oil. 155 ° / 1 Pa, η ^ θ = 1.4600.

EXAMPLE 6

7.0 g of isopropyl 3-aminopropyl (n-propyl) phosphinate and 40 ml of 20% hydrochloric acid are stirred at reflux overnight. The reaction mixture was evaporated to dryness, taken up in methanol and treated with propylene oxide. The white solid was filtered off and dried over phosphorus pentoxide to give 3-aminopropyl- (n-propyl) phosphinic acid x 0.1 H ₂ O as white crystals, m.p. 210-213 °.

3-Aminopropyl (n-propyl) phosphinic acid can also be prepared from the same starting material by silylation with trimethylsilyl bromide and subsequent treatment with propylene oxide in ethanol, m.p. 213-215 °.

Starting materials isopropyl 3-aminopropyl (n-propyl) phosphinate, ref. 155 ° / 6 Pa, n ^ ° = 1.4571; isopropyl 2-cyanoethyl (n-propyl) phosphinate, ref. 132 ° / 4O Pa, n ^ ⁰ = 1.4470; and n-propylphosphonic acid isopropyl ester, ref. 93 ° / 2.8 20 kPa; η _β = 1,424, was prepared in a similar manner as described in the previous example, starting from n-propyldichlorophosphine.

EXAMPLE 7

A mixture of 7.73 g of isopropyl 3-aminopropyl (ethyl) phosphinate and 40 ml of 20% hydrochloric acid was refluxed for 14 hours. The clear solution was evaporated to dryness and the residue was recrystallized from methanol / propylene oxide to give 3-aminopropyl (ethyl) phosphinic acid as a white solid, m.p. 233-239 °; ¹ H-NMR (D ₂ O): 0.4-1.8 (m, 9H, PCH ₂ CH ₂ in

PCH ₂ CH ₃ ); 2.7 (t, 2H, NCH ₂ ); 4.55 (s, 3H, OH, NHg).

The starting materials are prepared as follows:

To a solution of 262 g of ethyldichlorophosphine in 1200 ml of diethyl ether, a solution of 370 ml of isopropanol and 280 ml of triethylamine in 400 ml of diethyl ether was added while stirring and cooling with ice at 5 to 10 °. The reaction is exothermic. After stirring at 20 ° for 12 hours, the white precipitate was filtered off and the filtrate was fractionally distilled. · Ethylphosphonic acid isopropyl ester is obtained as a colorless liquid, boiling. 80 to 85 ° / 26 kPa.

To 34 g of ethylphosphonic acid isopropyl ester and 16.45 ml of acrylonitrile are added while stirring 40 ml of isopropanol containing 0.25 mol of sodium isopropylate. The reaction is exothermic. After stirring at 20 ° for 1 hour, the mixture was fractionated. Isopropyl 2-cyanoethyl (ethyl) phosphinate is obtained as a colorless oil, boiling. 102-104 ° / 10 Pa.

To 34.1 g of isopropyl 2-cyanoethyl (ethyl) phosphinate in 500 ml of isopropanol was added 60 ml of liquid ammonia and 6.8 g of Raney nickel. The mixture was heated to 80 ° and treated with hydrogen at 100 bar. After 1 1/2 hours, the hydrogen uptake stopped.

The reaction mixture was filtered and the filtrate distilled to give isopropyl 3-aminopropyl (ethyl) phosphinate as a colorless oil, boiling. 75 ° / 13 Pa.

EXAMPLE 8

A mixture of 14.76 g (0.12 mol) of 3-aminopropylphosphonic acid and 96.72 g (0.6 mol) of hexamethyldisilazane was refluxed under argon under stirring for 16 hours to form a solution. To this solution was added 60 ml of diethylene glycol dimethylether and reflux. reflux for another 2 hours.

The reaction mixture was cooled to 120 ° and 58.75 g (0.3 mol) of N-ethyl-diisopropyl-amine was added over 20 minutes, followed by the addition of 54.06 g (0.3 mol) of isobutyl iodide over 20 minutes. The reaction mixture was heated under stirring for 22 hours. After cooling to 10 °, the white precipitate was filtered off and the filtrate was evaporated under reduced pressure. The clear solution was cooled, diluted with dichloromethane (300 ml) and extracted three times with 2 N hydrochloric acid (3 x 100 ml). The combined extracts in hydrochloric acid were evaporated in vacuo to dryness and re-evaporated twice with water (2 x 100 ml) to give a white solid which was suspended in 600 ml of acetone and stirred for 1 hour at 20 °. 3-Aminopropyl (isobutyl) phosphinic acid hydrochloride (25.3 g), m.p. 149 ° to 155 °, isolated by filtration.

Recrystallization from n-propanol / acetone (200/100 ml) gave the pure hydrochloride of 3-aminopropyl (isobutyl) phosphinic acid from m.p. 154 -156 °. 15.4 g of 3-amino propyl (isobutyl) phosphinic acid hydrochloride are dissolved in 75 ml of methanol and 300 ml of propylene oxide are added while stirring. The white solid precipitates overnight at 4 °.

The precipitate was collected by filtration and recrystallized from n-propanol to give pure 3-aminopropyl (isobutyl) phosphinic acid, m.p. 250-253 ° (dec.).

EXAMPLE 9Analogously as described in Example 8, 3-aminopropyl (n-hexyl) phosphinic acid was obtained with n-bromohexane at 130 ° for 22 hours. 242-246 °, hydrochloride, m.p. 196-198 °.

EXAMPLE 10

Analogous to that described in Example 8, by reaction with allyl bromide at 60 °, for 16 hours, 3-aminopropyl (allyl) phosphinic acid, m.p. 230-234 ° (dec.), Hydrochloride: m.p. 140-142 °.

EXAMPLE 1-1

Analogous to that described in Example 8, obtained by reaction with n-bromopentane at 120 °, for 16 hours, 3-aminopropyl (npentyl) phosphinic acid, m.p. 232-236 °, hydrochloride: m.p. 192-194 °.

EXAMPLE 12

Analogous to that described in Example 8, obtained by reaction with n-bromoheptane at 120 °, 16 hours, 3-aminopropyl (nheptyl) phosphinic acid, m.p. 232-236 ° (dec.), Hydrochloride: m.p. 190-192 °.

EXAMPLE 13

Analogous to that described in Example 8, obtained by reaction with 4-bromo-1-butene at 95 °, 16 hours, 3-aminopropyl (but-3-enyl) phosphinic acid, m.p. 215-220 °, hydrochloride; m.p. 170-172 °.

EXAMPLE 1.4

Analogous to that described in Example 8, obtained by reaction with n-bromodecane at 120 °, for 20 hours, 3-aminopropyl (n-decyl) phosphinic acid, m.p. 225-230 °, hydrochloride: m.p. 185-190 °.

EXAMPLE 15

Analogous to that described in Example 8, obtained by reaction with 1-bromo-3-methylbutane at 120 °, 22 hours, 3-aminopropyl (isopentyl) phosphinic acid, m.p. 238-240 ° (dec.), Hydrochloride: m.p. 159-161 °.

EXAMPLE 16

Analogous to that described in Example 8, reaction with bromomethyl-cyclopropane at 100 °, 22 hours, gave 3-aminopropyl (cyclopropylmethyl) phosphinic acid x 0, 16 H 2 O, m.p. 235-238 ° (dec.), Hydrochloride: m.p. 144-146 °.

EXAMPLE 17

Analogous to that described in Example 8, reaction of 1-methyl-2-amino-propylphosphonic acid with n-butyl bromide at 100 ° for 48 hours yields (1-methyl-3-aminopropyl) (n-butyl) phosphinic acid x 0 , 2 H 2 O, mp.212-215 °, hydrochloride: mp.137-139 °.

- 56 EXAMPLE 18

Analogous to that described in Example 8, reaction with 5-iodopent-2-yn at 60 °, 16 hours gave 3-aminopropyl (pent-3-ynyl) phosphinic acid x 0.2 H / m, m.p. 220-224 ° (dec.), Hydrochloride: m.p. 174-176 °.

EXAMPLE rg

Analogous to that described in Example 8, obtained by reaction with 4-iodobut-1-yne at 90 °, 16 hours, 3-aminopropyl (but3-yl) phosphinic acid, m.p. 214-218 °, hydrochloride: m.p. 148-150 °.

EXAMPLE 20

Analogous to that described in Example 8, reaction with (2-bromoethoxy) ethane at 100 °, 16 hours, 3-aminopropyl (2-ethoxyethyl) phosphinic acid x 0.14 ^ 0, m.p. 202-208 °.

EXAMPLE 21

Analogous to that described in Example 8, reaction with 2-methylbutyliodide at 100 °, 16 hours, gave 3-aminopropyl (2-methylbutyl) -phosphinic acid x 0.1 and N, mp. 248-254 °.

2-methylbutyl iodide can be prepared as follows:

17.63 g (0.20 mol) of 2-methyl-butanone were added slowly over 20 minutes while stirring to a mixture of 43.3 g (0.227 mol) of toluene-p-sulfonyl chloride in 20 ml of dry pyridine, while maintaining by external cooling temperature below 25 °.

After stirring at 20 ° for 2 hours, the mixture was poured into ice water and extracted with ether. The ether layer was then washed with 2 N sulfur

- 57 Acid, water and saturated sodium hydrogen carbonate solution. After drying over sodium sulfate, filtration and evaporation in vacuo, 2-methylbutyl toluene-p-sulfonate is obtained as a yellow oil.

45.99 g (0.189 mol) of 2-methylbutyl toluene p-sulfonate were dissolved in 290 ml of acetone, 34.7 g (0.23 mol) of sodium iodide were added at 20 ° and the mixture was stirred for 2 hours under reflux. After cooling to 0 °, the separated sodium toluene-p-sulfo nat is removed by filtration and the solvent is evaporated through a 15 cm Vigreux column at atmospheric pressure. The crude product was dissolved in ether and washed with 10% sodium thiosulphate solution, dried over sodium sulfate and filtered. Evaporation of the solvent through a 15 cm Vigreux column followed by fractionated distillation to give 2-methylbutyl iodide; boil. 93 ° / 200 mbar.

EXAMPLE 22

Analogous to that described in Example 8, reaction with 2-ethoxypropyliodide at 130 °, 16 hours, gave 3-aminopropyl (3-ethoxypropyl) -phosphinic acid x 0.1 H ₂ O, m.p. 210-218 °; hydrochloride: m.p. 161-165 °.

The 3-ethoxypropyliodide can be prepared as follows:

20.8 g (0.20 mol) of 2-ethoxypropanol was added slowly over 20 minutes while stirring to a mixture of 43.3 g (0.227 mol) of toluene-p-sulfonyl chloride and 20 ml of dry pyridine. The temperature of the reaction mixture was maintained by external cooling at 20 °. After stirring at 20 ° for 2 hours, the mixture was poured into ice water and extracted with ether. The ether layer was washed with 2 N

- 58 Sulfuric acid, with water and with saturated sodium hydrogen carbonate solution. After drying over sodium sulfate, filtration and evaporation in vacuo, 2-ethoxypropyl toluene-p-sulfonate is obtained as a yellow oil.

A solution of 51.5 g (0.199 mol) of 2-ethoxypropyl toluene-p-sulfonate and 36.5 g (0.243 mol) of sodium iodide in 250 ml of acetone was stirred at reflux for 2 hours. After cooling to 10 °, the separated toluene p-sulfonate is removed by filtration and the solvent is evaporated through a 15 cm Vigreux column at atmospheric pressure. The crude product was dissolved in ether and washed with 10% (wt) sodium thiosulphate solution. Drying over sodium sulfate, filtration and evaporation of the solvent through a 15 cm Vigreux column followed by fractional distillation to give 3-ethoxypropyliodide boiling. 97 ° / 4O mbar.

EXAMPLE 23

Analogous to that described in Example 8, reaction with 2-methoxy-propylodide at 115 °, 40 hours gave 3-aminopropyl (3-methoxypropyl) phosphinic acid x 0.25 t ^ O, m.p. 197-203 °, hydrochloride: m.p. 146-148 °.

EXAMPLE 24

Analogous to that described in Example 8, reaction with 1-bromo-2-butyn at 90 °, 16 hours, gave 3-aminopropyl (but-2-ynyl) phosphinic acid x 1,2 1 ^ 0, m.p. 110-115 °, hydrochloride: m.p. 154-158 °.

EXAMPLE 25

Analogous to that described in Example 8, 3-aminopropyl / 2 (2-ethoxyethoxy) ethyl / phosphinic acid x 0.16 ^ 0, mp is obtained by reaction with (2- (2-ethoxyethoxy) -ethyl) iodide. 215 to 225 °.

EXAMPLE 26

Analogous to that described in Example 8,. is obtained by reaction with 4,4,4-trifluorobutyliodide at 95 ° for 16 hours,

3-Aminopropyl (4,4,4-trifluorobutyl) phosphinic acid, m.p. 237-141 ° (dec.), Hydrochloride: m.p. 144-146 °.

EXAMPLE 27

Analogous to that described in Example 8, reaction with 1-chloro-2-methylthio-ethane at 100 °, for 16 hours, gave 3-aminopropyl (2-methyl thioethyl) phosphinic acid.

EXAMPLE 28

Analogous to is described v case 8, is obtained by reaction with methylthiomethyl chloride at 75 θ 1 c, 1b hours, , 3- -arainopropyl (methylthiomethyl) phosphine acid. EXAMPLE 29 Analogous to is described v case 8, is obtained by

reaction with 2-phenylethyl bromide at 120 °, 16 hours, 3-aminopropyl (2-phenethyl) phosphinic acid, m.p. 265-270 °.

EXAMPLE go

Analogous to that described in Example 8,. is obtained by reaction with methylyl chloride at 63 °, 24 hours, 3-aminopropyl60 (2-methylallyl) phosphinic acid, m.p. 140-143 °.

EXAMPLE 31

A solution of 2.4 g of 3-benzyloxycarbonylaminopropyl (dodecyl) phosphinic acid in 50 ml of 36% hydrochloric acid was refluxed for 3 hours. During this time a white precipitate forms. After cooling to room temperature, the acid is removed by evaporation with 6 x 50 ml of water on a rotary evaporator.

The crude product was then dissolved in 50 ml of ethanol and mixed with 5 ml of propylene oxide. Filtration and drying gave 3-aminopropyl (dodecyl) phosphinic acid as a white solid, m.p. 175-177 °. ³¹ P-NMR = 43.0 ppm (NaOD).

The starting material can be prepared as follows:

A solution of 1.30 g added in 6 ml of dry toluene was heated under an argon atmosphere to 80 °. A suspension of 2.0 g of 3-benzyloxycarbonylaminopropylphosphonic acid in 30 ml of dry toluene containing 0.6 g of t-butylcyclohexylperdicarbonate was added to this solution over 15 minutes. The reaction mixture was then stirred at 80 ° for 2 hours. An additional 0.6 g of radical initiator is added and stirring is continued at 80 ° for 2 hours. The reaction mixture was then cooled to room temperature and the solvent was removed with a rotary evaporator. The residue was triturated with petroleum ether (60-80 °), filtered and dried to give 3-benzyloxycarbonylaminopropyl (dodecyl) phosphinic acid as a white solid, m.p. 115-116 °; ¹ P-NMR: S = +58.7 ppm (CDCl 2) EXAMPLE

To a solution of 5.7 g (0.0224 mol) of isopropyl 3-aminopropyl (benzyl) phosphinate in 50 ml of chloroform was added 9.91 ml

61 (0.0922 mol) of trimethylsilyl bromide, raising the temperature to 44 °. The reaction mixture was stirred for 4 hours at 50 ° C and then overnight at room temperature. Removal of chloroform and excess trimethylsilyl bromide under reduced pressure yielded an oil which was taken up in isopropanol and 20 ml of propylene oxide. After stirring for 10 minutes, a white solid precipitates. The solid was filtered off and dried over phosphorus pentoxide to give 3-arainopropyl (benzyl) phosphinic acid, m.p. 278-280 °.

The starting material can be prepared from benzyl dichloro phosphine via benzylphosphonic acid isopropyl ester, boiling point. 113 ° (1 rbar), isopropyl 2-cyanoethyl (benzyl) phosphinate, m.p. 69-72 °, and isopropyl 3-aminopropyl (benzyl) phosphinate, ref. 113 ° (1 rnbar).

EXAMPLE 33

A suspension of 1.23 g (10 mmol) of 3-aminopropylphosphonic acid in 10.4 ml (50 mmol) of hexamethyldisilazane was heated to reflux under argon for 24 hours. To the resulting clear solution was added 5 ml of diethylene glycol dimethyl ether and the mixture was heated for 2 hours and then cooled to 0 °. 8.5 ml (50 mmol) of N-ethyl-N, N-diisopropyl-amine are added, followed by the slow addition of 3.8 ml (50 mmol) of propargyl bromide over 40 minutes. The mixture was stirred for 1 hour at 0 ° and for 4 hours at room temperature filtered and evaporated under high vacuum. The residue was dissolved in 10 ml of dichloromethane and extracted with 3 x 10 ml of 1 N hydrochloric acid solution. The aqueous layer was evaporated under high vacuum and the resulting residue was dissolved in 4 ml of methanol at

0 °. 20 ml of propylene oxide were added over 1 hour, after which the crude product precipitated. Chromatography (Silicagel Merck 230-400 ASTM, methanol) followed by recrystallization (methanol / ether) to give 3-aminopropyl (propargyl) -phosphinic acid, m.p. 172-173 °.

EXAMPLE 34

To a solution of 0.90 g (4.0 mmol) of 3-aminopropyl (diethoxymethyl) phosphinic acid in 10 ml of glacial acetic acid at 0 ° is added 0.38 ml (4.4 mmol) of ethane-1,2-dithiol, followed by addition of 2 ml of concentrated hydrochloric acid over 5 minutes. The mixture was allowed to warm to room temperature and then stirred for 18 hours. After removal of acetic and hydrochloric acid under high vacuum, the residue is chromatographed (Opti-Up C-j 2 water) and recrystallized from methanol to give

3-Arainopropyl (1,3-dithiolan-2-yl) phosphinic acid, m.p. 272-274 °.

EXAMPLE 35K 590 mg (2.20 mmol) of lithium hydroxide monohydrate in 1.1 ml of water was added a solution of 2 mmol of ethyl

3-Aminobutyl (diethoxymethyl) phosphinate in 2.1 ml ethanol followed by 1 ml water. The mixture was stirred for 48 hours at room temperature and evaporated in vacuo. Add 3 ml of water to dissolve the resulting precipitate. Then, 85 mg of 84 (wt%) phosphoric acid are slowly added and the suspension is stirred for 18 hours at room temperature. Filtration of the precipitate through Celite, evaporation to dryness, chromatography (R) (Opti-Up ^ 50%, HgO) and recrystallization from ethanol gave 3-aminobutyl (diethoxymethyl) phosphinic acid, m.p. 225-228 °

The starting material can be obtained as follows:

A mixture of 2.7 g of ethyl trimethylsilyldiethoxymethylphosphonite and 0.7 g of methyl vinyl ketone was heated at 50 ° for 1 hour under a nitrogen atmosphere. Then 10 ml of water are added and the mixture is stirred for another 30 minutes. The residue was extracted three times with 50 ml of chloroform, the organic phases were combined, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was then distilled to give ethyl 3-oxobutyl (diethoxymethyl) phosphinate, boiling.

130-5 ° (13.6 mbar).

A mixture of 1.0 g of ethyl 3-oxobutyl (diethoxymethyl) phosphinate,

2.85 g of ammonium acetate and 0.16 g of sodium cyanoborohydride in 20 ml of methanol were stirred for 2.5 hours. Adjust the pH overnight with 2 N hydrochloric acid to pH 5.6.

The mixture was then evaporated to dryness. 20 ml of water was added and the mixture was washed three times with 20 ml of diethyl ether. The aqueous layer was adjusted with potassium hydroxide to pH 12 and extracted four times with 25 ml of chloroform. The organic layers were combined, dried, filtered and evaporated to dryness to give ethyl 3-aminobutyl (diethoxymethyl) phosphate, ³ ? P-NMR spectrum:? - +46.0 ppm (CDCl?).

EXAMPLE 36

Analogous to that described in Example 35, 3-amino-1- (p-chloro phenyl) -propyl (diethoxymethyl) -phosphinic acid as a yellow oil was obtained by soaping with lithium hydroxide in aqueous ethanol; ^Ί Η-ΝΜΠ (CDCl 2): 7.2-7.4 (m, 4), 4.1 (d, 1, J = 6.5 Hz), 3.7 (m, 2), 3.6 (m, 2), 3.3 (t, ¹ , J = 7.5 Hz), 3.1 (m, 2), 3.0 (m, 4), 2.7 (m, 2), 2 , 2 (broad, 2) 1.2 (m, 6).

64. The starting material, ethyl 3-amino-1- (p-chlorophenyl) propyl (diethoxymethyl) phosphinate, can be obtained as follows:

A mixture of 25.8 g ethyl diethoxymethylphosphinate, 18.0 g

4-Chlorocinamoyl nitrile and 100 ml of ethanol were added dropwise at 0 to 5 ° while stirring to a solution of 1.2 g of sodium hydride (50% suspension in mineral oil) in 30 ml of ethanol. Then the ethanol was evaporated, the residue was dissolved in 100 ml of chloroform and washed twice with 25 ml of water, the organic phase was dried over magnesium sulfate, filtered and evaporated to give 20 g of ethyl 1- (p-chlorophenyl) -2-cyano-ethyl (diethoxymethyl) phosphinate as an oil, ³¹ P-NMR: +37.8 and +37.9 ppm (CDC1 ₃ ).

A solution of 20.0 g of ethyl 1- (p-chlorophenyl) -2-cyano-ethyl (diethoxymethyl) phosphinate in 131 g of 8% w / w ethanol ammonia was mixed with 8.5 ml of Raney nickel in 85 ml of ethanol and hydrogenate until hydrogen uptake has ceased. Filtration and evaporation then gave ethyl 3-amino-1- (p-chlorophenyl) propyl (diethoxymethyl) phosphinate as an oil.

EXAMPLE 37

While stirring, a solution of 4.37 g of ethyl 3-aminopropyl (di-n-propyloxymethyl) phosphinate in 16.2 ml of ethanol was added to a solution of 0.05 g of lithium hydroxide monohydrate in 7.7 ml of water. A slightly exothermic reaction follows and the reaction mixture becomes cloudy. Add 2 ml of water and stir the clear solution at room temperature for 5 days. After this time, the mixture was concentrated in vacuo at 55 ° and the residue was redissolved in water and extracted with 3 x 10 acre of dichloromethane. The aqueous layer was re-evaporated to dryness and the residue was dissolved in 20 ml of water and treated with 0.51 ml of 85% phosphoric acid. After stirring overnight, the solid was removed by filtration. Evaporation of the filtrate and crystallization of the residue from ethanol / ether gave 3-aminopropyl (di-n-propyloxymethyl) phosphinic acid, m.p. 223-225 ° as a white solid.

The starting material can be prepared as follows:

A mixture of 6.6 g of hypophosphoric acid (95% solution in water) and 86 g of tri-n-propyl orthoformate was treated with 0.77 ml of trifluoroacetic acid. The biphasic mixture was stirred at room temperature for 48 to 72 hours until the reaction was complete. This 31 can be monitored by P-NMR or thin layer chromatography. The reaction mixture was diluted with 200 ml of dichloromethane and washed twice with 150 ml of saturated aqueous sodium bicarbonate solution. After drying the dichloromethane layer over anhydrous magnesium sulfate and removing the solvent in vacuo, a colorless oil is obtained which, after distillation, gives the n-propyl ester of M di-n-propyloxymethylphosphonic acid, boiling. 45/2 x 10 mbar.

A solution of sodium ethoxide in absolute ethanol (0.48 g of metallic sodium in 15 ml of absolute ethanol) is cooled to 0 ° under nitrogen or argon. A solution of 2.72 g of acrylonitrile and 12.2 g of di-n-propyloxymethylphosphonic acid n-propyl ester in 50 ml of absolute ethanol was added at such a rate that the temperature did not exceed 5 °. After the addition is complete, allow the solution to warm to room temperature and stir overnight. After Appendix 1 _; 22 g of glacial acetic acid

-66 Concentrate the reaction mixture in vacuo. The residue was partitioned between ethyl acetate and water and the organic phase separated. After drying over anhydrous magnesium sulfate, the solvent is evaporated in vacuo to give an oil. Silica gel chromatography afforded ethyl 2-cyanoethyl (di-n-propyloxymethyl) phosphinate as a colorless oil.

A mixture of 4.35 g of ethyl 2-cyanoethyl (di-n-propyloxymethyl) phosphinate, 10 g of ammonia and 2.3 g of Raney nickel in 170 ml of ethanol was hydrogenated for 10.5 hours. The catalyst was filtered off and the solvent was removed by evaporation. The crude oil was purified by distillation to give ethyl 3-aminopropyl (di-n-propyloxymethyl) phosphinate as a colorless oil.

EXAMPLE 38

Analogous to that described in Example 37, 3-aminopropyl (diisopropyloxymethyl) phosphinic acid, m.p. 175 ° C (dec).

Starting materials: diisopropyloxymethylphosphonic acid isopropyl ester, boiling point. 48 C, 2 x 10 mbar; Ethyl 2-cyanoethyl (diisopropyloxymethyl) phosphinate and ethyl 3-aminoppropyl (diisopropyloxymethyl) phosphinate were prepared as described in Example 37 from hypophosphoric acid and triisopropyl orthoformate.

EXAMPLE 39

Analogous to that described in Example 37, 3-aminopropyl (di-n-butyloxymethyl) phosphinic acid, m.p. 221-224 °.

- 67 Starting materials: n-butyl ester di-n-butyloxymethyl - 4 phosphonic acids, boiling point. 75, 2.0 x 15 mbar: ethyl 2-cyanoethyl (di-n-butyloxymethyl) phosphinate and ethyl 3-aminopropyl (di-n-butoxymethyl) phosphinate are prepared as described in Example 38 from hypophosphoric acid and tri- n-butyl orthoformate.

EXAMPLE ⁴ .Q

While stirring, a solution of 2.0 g of ethyl 3-aminopropyl (tetrahydrofuran-2-yl) phosphinate in 20 ml of ethanol is added to a solution of 0.57 g of lithium hydroxide monohydrate in 10 ml of water. A slightly exothermic reaction follows and the reaction mixture becomes cloudy. Add 5 ml of water and then stir the clear solution for 3 days at room temperature. After this time, the reaction mixture was concentrated in vacuo at 55 °. The residue was redissolved in water and washed with 3 x 10 acre of dichloromethane. The aqueous layer was evaporated again to dryness and the residue was dissolved in 10 ml of water and treated with 0.65 ml of 85% phosphoric acid in 2 ml of water. After stirring overnight, the solid was removed by filtration. Evaporation of the filtrate and crystallization of the residue from methanol / ether gave 3-aminopropyl (tetrahydrofuran-2-yl) phosphinic acid, m.p. 222-223 ° (dec.) As a white solid.

The starting material can be prepared from either diethoxymethyl or diethoxyethylphosphonic acid as follows: A solution of 12.7 g of diethoxymethylphosphonic acid ethyl ester and 6.95 g of 4-chlorobutanal in 10 ml of absolute ethanol is cooled to 0 ° under inert gas. Ethanol ethanol (1.5 g of metallic sodium and 20 ml of absolute ethanol) was added dropwise so that the temperature did not rise above 5 °. After the addition is complete, the reaction mixture is warmed to room temperature and stirred for 20 hours. After this time a suspension is formed and the solvent is removed in vacuo. The residue was dissolved in dichloromethane / water and the organic layer was separated and washed with a further 20 ml of water. Drying with anhydrous magnesium sulfate and removal of the solvent in vacuo gave O-ethyl-β-diethoxymethyl-O tetrahydrofuran-2-yl-phosphinate, boiling. 125/1 x 10 ”mbar.

A suspension of 5.32 g of O-ethyl-P-diethoxymethyltetrahydrofuran-2-yl-phosphinate in 50 ml of 6.0 M aqueous hydrochloric acid was heated at 100 ° for 16 hours. After this time the solution is evaporated to dryness in vacuo and the residue is co-evaporated in vacuo with 5 x 20 ml of water, then with 5 x 20 ml of water and then with 5 x 10 ml of absolute ethanol. Drying the residue over phosphorus pentoxide in high vacuum at room temperature afforded P-tetrahydrofuran-2-yl-phosphonic acid; &Lt; 1 &gt; H-NMR (CDCl3): &lt; 5 &gt; 11.24 (1 H, s alternated with D ₂ O), 6.97 (1 H, d, J = 557 Mz), 4.07 (1 H, a). 3.90 (2 H, t, CH ₂ O), 2.15 (2 H, m), 1.99 (2 H, m).

A solution of 2.6 g of P-tetrahydrofuran-2-yl-phosphonic acid in 20 ml of anhydrous dichloromethane was cooled to 5 ° under an inert gas and treated with 2.03 g of triethylamine. A dichloromethane solution of 2.17 g of ethyl chloroformate was added dropwise, followed by an exothermic reaction and gas evolution. The suspension was warmed to room temperature and stirred for 3 hours. The reaction mixture was then diluted with dichloromethane and washed with water. Drying the organic phase with anhydrous magnesium sulfate and removing the solvent in vacuo gave ethyl ester

- 69 P-Tetrahydrofuran-2-ylphosphonic acid, ref. 9 ° / 8 χ 10 mbar.

A mixture of 0.68 g of acrylonitrile and 2.11 g of ethyl tetrahydrofuran-2-yl phosphonic acid ethyl ester in 5 ml of absolute ethanol was cooled to 0 ° under argon and treated dropwise with an ethanolic solution of sodium ethoxide (0.15 g of metallic sodium and 15 ml of absolute ethanol) at such a rate that the temperature does not exceed 5 ° (extreme exothermic). After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes and 0.4 g of glacial acetic acid are added. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried with anhydrous magnesium sulfate and removed in vacuo to give ethyl 2-cyanoethyl (tetrahydrofuran-2-yl) phosphinate; 1 H-NMR (CDCl 2): δ 4.15 (3 H,

m), 3.90 (2 H, m), 2.72 (2 H, m, CH ₂ CN), 2.34-1.87 (6 H, m), 1.32 (3 H, m; CHp.

Ethyl 2-cyanoethyl (tetrahydrofuran-2-yl) phosphinate solution in absolute ethanol containing 10% by weight % ammonia, hydrogenated over Raney nickel for 2.5 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give ethyl 3-aminopropyl (tetrahydrofuran-2-yl) phosphinate;

¹ H-NMR (CDCl ₃ ): S 4.24 (4 H, m), 3.95 (1 H, m), 2.88 (2 H, sharpened by the addition of D ₂ O: CH ₂ NH ₂ ) , 2.40-1.75 (6 H, m), 1.32 (3 H, t).

A solution of 2.10 g of 1,1-diethoxyethylphosphonic acid ethyl ester and 1.06 g of 4-chlorobutanal in 10 ml of absolute ethanol is cooled to 0 ° under inert gas. Ethanol sodium

70 'ethoxide (from 0.23 g of metallic sodium and 20 ml of absolute ethanol) was added dropwise so that the temperature did not exceed 5 °. After complete addition, the reaction solution was warmed to room temperature and stirred for 20 hours. After this time a suspension is formed and the solvent is removed in vacuo. The residue was dissolved in dichloromethane / water and the organic layer was separated and washed with a further 20 ml of water. After drying the organic phase with anhydrous magnesium sulfate and evaporating in vacuo, ethyl 1,1-diethoxyethyltetrahydrofuran-2-yl) phosphinate is obtained as a clear oil, boiling. 110 ° / 1 x 10 “ ² mbar.

A solution of 1 g of ethyl 1,1-diethoxyethyltetrahydrofuran2-yl) phosphinate in 10 ml of dichloromethane containing 1 wt. % ethanol, treated with 0.71 g trimethylsilyl chloride. The slightly cloudy solution was stirred overnight at room temperature, and after that time, thin layer chromatography showed the end of the reaction. Removal of the solvent in vacuo gave a colorless oil which, after distillation, caused the ethyl ester of P-tetrahydrofuran-2-yl-phosphonic acid to boil. 9 ° / 8 χ 10 ^-2 mbar.

Further conversion of the P-tetrahydrofuran2-yl-phosphonic acid ethyl ester into ethyl 2-cyanoethyl (tetrahydrofuran2-yl) phosphinate and ethyl 3-aminopropyl (tetrahydrofuran-2-yl) phosphinate proceeds as described in Example 41.

EXAMPLE 41

A suspension of 2.46 g of 3-aminopropylphosphonic acid in 20 ml of hexamethyldisilazane was heated to reflux under an inert gas for 24 hours. The resulting clear solution was cooled to room temperature and 14.8 g of freshly distilled n-butyraldehyde was added

An exothermic reaction follows and the reaction temperature rises to about 60 ° C. The reaction mixture was stirred for 1 hour at a temperature between 10 ° and 60 °. After cooling to room temperature, the volatiles are removed in vacuo to give a colorless oil. This oil was dissolved in water and stirred at room temperature for 1 hour and the water layer was evaporated to dryness at 55 °. A semi-solid residue was obtained which was dissolved in 50 ml of 2.0 M aqueous hydrochloric acid and washed with dichloromethane (3 x 100 ml) and ether (1 x 100 ml). After removal of the water, co-evaporate the white solid with water (10 x 50 ml) and then with 10 x 50 ml absolute ethanol. Crystallization of the ethanol residue to give 3-aminopropyl (1-hydroxybutyl) phosphinic acid hydrochloride, m.p. 154 to 160 °. Treatment of hydrochloride with propylene oxide / ethanol or passage through an ion exchange column D0We / ^ 50 W x 8 (14-40 mesh) gives as a white solid 3-aminopropyl (1-hydroxybutyl) phosphinic acid, m.p. 187-188 °.

EXAMPLE 42

Analogous to that described in Example 41, 3-arainopropyl (1-hydroxyisobutyl) phosphinic acid hydrochloride is obtained by one-hour reaction with isobutyraldehyde at 40-60 ° C. 105 ° (dec.) And 3-aminopropyl (1-hydroxyisobutyl) phosphinic acid, m.p. 122-123 °.

EXAMPLE 43

Analogous to that described in Example 41, a 1-hour reaction with acetaldehyde at 0-15 ° can be obtained with 3-aminopropyl (1-hydroxyethyl) phosphinic acid hydrochloride, m.p. 153-154 °, and 3-aminopropyl (1-hydroxyethyl) phosphinic acid, m.p. 255256 °.

EXAMPLE 44

Analogous to that described in Example 41, · obtained by 1-hour reaction with freshly distilled benzaldehyde at 40-60 ° hydrochloride 3-aminopropyl (1-hydroxybenzyl) phosphinic acid, m.p. 173-174 °, and 3-arainopropyl (1-hydroxybenzyl) phosphinic acid, m.p. 139-140 °.

EXAMPLE 45

Analogous to that described in Example 41, obtained by 1-hour reaction with 4,4,4-trifluorobutanal · at 20 ° hydrochloride 3-aminopropyl (1-hydroxy-4,4,4-trifluoro-butyl) phosphinic acid, m.p. 139.5-140 °, and 3-aminopropyl (1-hydroxy-4,4,4trifluorobutyl) phosphinic acid, m.p. 226-227 °.

EXAMPLE 46

Analogous to that described in Example 41, obtained by 1-hour reaction with (Z) -2-fluorochrotonaldehyde at 0 ° (very exothermic) hydrochloride 3-aminopropyl / 1-hydroxy- (Z) -2fluoro-but-2-enyl / phosphinic acids, m.p. 110-112 °, and 3-arainopropyl (1-hydroxy-2-fluoro- (Z) but-2-enyl) phosphinic acid, m.p. 121-122 °.

EXAMPLE 47

Analogous to that described in Example 41, a 1-hour reaction with 1-formyl cyclopropane at 20 ° gave 3-aminopropyl (1-hydroxy-1-cyclopropylmethyl) phosphinic acid hydrochloride

-73 tal. 135-136 °, and 3-aminopropyl (1-hydroxy-1-cyclopropylmethyl) phosphinic acid, glass: N (1 H-NMR, D ₂ O); 2.90 (3 H, d and t, CHOH, CH ₂ NH ₂ ), 1.77 (4 H, m), 0.89 (2 H, m, CH), 0.49 (2 H, m, CH ₂ ), 0.22 (2 H, m, CH ₂ ).

EXAMPLE 48

Analogous to that described in Example 41, obtained by 1-hour reaction with 1-formyl-1-methylthiocyclopropane at 40-60 ° 3-aminopropyl / 1-hydroxy-1- (2-methylthiocyclopropyl) methyl / phosphinic acid hydrochloride, m.p. 100 ° (dec.), And 3-aminopropyl / 1-hydroxy-1- (2-methylcyclopropyl) methyl / phosphinic acid, m.p. 105-106 °.

EXAMPLE 49

Analogous to that described in Example 41, a 1-hour reaction with 1-formylcyclobutanor at 40-60 ° was obtained with 3-aminopropyl (1-hydroxy-1-cyclobutylmethyl) phosphinic acid hydrochloride, m.p. 167-168 °, and 3-aminopropyl (1-hydroxy-1-cyclobutylmethyl) phosphinic acid, m.p. 225-226 °.

EXAMPLE 50

A suspension of 2.46 g of 3-aminopropylphosphonic acid in 20 ml of hexamethyldisilazane was heated to reflux under an inert gas for 24 hours, then a clear solution was obtained. Excess hexamethyldisilazane is removed by distillation at atmospheric pressure under a slightly positive pressure of an inert gas to give a colorless oil. The oil was cooled to about 40 ° and treated with 0.64 g of anhydrous zinc iodide and 25 ml of 1,2-epoxybutane. An exothermic reaction occurs and epoxybutane refluxes. Z

- 74 reflux was continued for 6 hours and after that time thin-layer chromatography indicated that the reaction was complete. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo at 40 °. The residue was dissolved in water and stirred at room temperature for 1 hour and the water removed in vacuo to give an oily solid. This was dissolved in some 2.0 M aqueous hydrochloric acid and washed with dichloromethane and ether. Removal of water at 40 ° in vacuo afforded a brown solid which was purified by ion exchange chromatography on DOWe / 50 W x 8 (14-40 mesh) to give 3-aminopropyl (-2-hydroxybutyl) phosphinic acid, m.p. 184-185 ° as a white solid.

EXAMPLE 51

Analogous to that described in Example 50, obtained by reaction with (R) - (-) - 1,2-epoxy-3-methylbutane at 70 ° 3-aminopropyl / 2- (r) -hydroxy-3-methylbutyl / phosphinic acid , tal. 187-189 °.

EXAMPLE 52

A suspension of 2.46 g of 3-aminopropylphosphonic acid in 20 ml of hexamethyldisilazane was heated to reflux under an inert gas for 24 hours. The resulting clear solution was cooled to 15 ° and 2.0 ml of cyclobutanone was added. The following is an exothermic reaction. The reaction mixture was stirred until the temperature dropped to room temperature (about 1 hour). Water was added and the volatiles were removed in vacuo to give a semi-solid. This was dissolved in 2.0 M aqueous hydrochloric acid and washed with 2 x 100 ml of dichloromethane. The aqueous layer was evaporated in vacuo to give a solid which was passed through a DOWE) P ^ 50 W x 8 (14-40 mesh) ion exchange column to give 3-aminopropyl (1-hydroxycyclobutyl) phosphinic acid, m.p. 174-175 ° (dec.).

EXAMPLE 53

A mixture of 3.0 g of 3-aminopropyl (benzyl) phosphinic acid hydrochloride and 0.6 g of Nishimura's catalyst in 30 ml of methanol was hydrogenated for 4 hours. The catalyst was filtered off and the solvent was removed by evaporation. The residue was dissolved in 20 ml of methanol and 10 ml of propylene oxide were added to the solution. Stirring for 3 hours gave a white solid which was filtered off and dried over phosphorus pentoxide to give 3-aminopropyl (cyclohexylmethyl) phosphinic acid, m.p. 230 ° (dec.).

EXAMPLE 54

A solution of 1 g of 3-aminopropyl (but-3-enyl) phosphinic acid in 25 ml of water is treated with 0, 1 g of 5% palladium on charcoal and hydrogenated at room temperature until hydrogen uptake ceases. The catalyst was removed by filtration of the reaction mixture through Celite and the filtrate was evaporated to dryness to give 3-aminopropyl (butyl) phosphinic acid, m.p. 231-234 ° (dec.). -NMR (D ^ O): c) +44.6 ppm.

EXAMPLE 55

A suspension of 25.7 g of 3- (N-benzyloxycarbonylaminopropyl) phosphonic acid in 150 ml of anhydrous dichloromethane was cooled to 5 ° under an inert gas and 11.1 g of triethylamine was added. A slight exothermic reaction follows and all the solid dissolves. The solution was again cooled to 0 ° and a solution of 11.94 g of ethyl chloroformate in 100 ml of anhydrous dichloromethane was added dropwise over 15 to 30 minutes while maintaining the temperature at 10 °. The reaction is exothermic and gas evolution is observed along with the formation of a white precipitate. The white suspension was stirred for 1 hour at room temperature, diluted with 500 ml of dichloromethane and washed with 2 x 200 ml of water. After drying the organic phase with anhydrous magnesium sulfate and evaporating the solvent in vacuo, 3- (N-benzyloxycarbonylaminopropyl) phosphonic acid ethyl ester is obtained as a colorless viscous oil

¹ H- NMR: d (CDCl 3; 7.35 (5 H, m, Ph), 7.13 (1 H, d, J = 530 Hz, P-h), 5.08 (2H, m , CH ₂ Ph), 4.13 (2 H, m, P · -och ₂ ). , 3.27 (2 H, wide, sharpen after the addition d ₂ o, ch ₂ , NH ₂ ), 1.82 (4 H, m, 2 x CH ₂ ), 1.35 (3 H, t, ch ₃ ).

A solution of 2.85 g of 3- (N-benzyloxycarbonylaminopropyl) phosphonic acid ethyl ester in 25 ml of anhydrous tetrahydrofuran is cooled to 0 ° under an inert gas and 2.22 g of triethylamine are added and a solution of 2.39 g is added dropwise over 15 minutes. trimethylsilyl chloride in 25 ml of anhydrous tetrahydrofuran. A slight exothermic reaction follows and a white precipitate is observed. The suspension was stirred at room temperature for 20 hours and filtered under inert gas. The solid was washed with a further 50 ml of anhydrous tetrahydrofuran under an inert gas and the combined organic filtrate was evaporated to dryness in vacuo to give a slightly cloudy colorless oil. This oil is treated with 10 to 15 ml of freshly distilled n-butyraldehyde while maintaining an inert atmosphere. An exothermic reaction follows and the temperature rises to about 35 °. Allow the mixture to cool to room temperature, dilute it with 100 ml of dichloromethane and wash with water, 0.1 ml of aqueous hydrochloric acid and then with water. Drying the solvent and removing dichloromethane in vacuo gave ethyl 3- (N-benzyloxycarbonylaminopropyl) (1-hydroxybutyl) phosphinate as a mixture of diastereoisomers:

¹ H-NMR: δ (CDCl 2); 7.35 (5H, m), 5.10 (1H, n), 4.25-3.98 (1

H, m, CHOH), 3.28 (2 H, t, CH ₂ NH ₂ ), 1.97-1.44 (4 H, m),

I, 40-1.21 (4 H, m), 0.95 (3 H, t, CH 2).

A solution of 0.714 g of ethyl 3- (N-benzyloxycarbonylamino propyl) - (1-hydroxybutyl) phosphinate in 10 ml of anhydrous dichloromethane is treated at room temperature with 0.712 g

N, N'-thiocarbonyl diimidazole. The red solution was stirred for 20 hours at room temperature, diluted with dichloromethane and washed with cold 1.0 M aqueous hydrochloric acid (2 x 30 ml), water * and saturated aqueous sodium bicarbonate solution. The organic layer was dried and the solvent removed in vacuo to give ethyl 3- (N-benzyloxycarbonylaminopropyl) - / 1- (O-thiocarbonylimidazyl-oxy) -butyl / phosphinate as a pale yellow oil: δ ¹ H-NMR:

(CDC1); 8.46 (1 H, d, t), 7.47 (1 H, d, t), 7.35 (5 H, m, Ph), 7.07 (1 H, m), 6.12 ( 1 H, m, CHO), 5.10 (2 H, CH ₂ Ph), 4.25-3.98 (2 H, m, CH ₂ OP), 3.25 (2 H, t, CH ₂ NH) ₂ ), 1.97-1.44 (2 H, m, 2 x CH ₂ ), 1.42-1.20 (4 H, m), 0.96 (3, H, t, CH 2).

A solution of ethyl 3- (N-benzyloxycarbonylaminopropyl) / 1- (O-thiocarbonylimidaz-1-yloxy) butyl / phosphinate in 10 ml of anhydrous degassed benzene was treated with 0.291 g of tri-n-butyl tin hydride. The clear solution is brought to reflux

- 78 plus 0.08 g of azobisisobutyronitrile. The reflux was continued for 1 hour, after which time thin-layer chromatography showed that the reaction was complete. The reaction mixture was cooled to room temperature and the volatile material was removed in vacuo to give a pale yellow oil. The oil was partitioned between acetonitrile and methane and the acetonitrile layer was separated and washed with a further 2 x 20 ml of hexane. Evaporation of acetonitrile in vacuo and chromatography of the remaining silica gel oil gave ethyl 3- (N-benzyloxycarbonylaminopropyl) (n-butyl) phosphinate as an oil; saponification of this oil with lithium hydroxide followed by acidification with phosphoric acid to give 3- (N-benzyloxycarbonylamino) propyl (n-butyl) phosphinic acid, m.p. 116-118 °, described in Example 3, which gives 3-aminopropyl (n-butyl) phosphinic acid, m.p. 231-234 ° (dec.).

EXAMPLE 56

A mixture of 2.0 g of ethyl 3-aminopropyl (1-hydroxybutyl) phosphinate and 20.0 ml of 2 M aqueous hydrochloric acid was refluxed for 2 hours and then evaporated to dryness. Dissolve the remaining oil in 10 ml of water and evaporate again. The residue was dissolved in 20 ml of ethanol and treated with propylene oxide to give 1.5 g of 3-aminopropyl (1-hydroxybutyl) phosphinic acid, m.p. 188 °.

The starting material is prepared as follows:

A mixture of 24.5 g of ethyl (1,1-diethoxyethyl) phosphinate and 40 g of hexamethyldisilazane was heated at 148 ° under an inert gas for 3 hours. The reaction mixture was cooled to room temperature and 6 g of acrylonitrile was added. The mixture was stirred for 2 hours. The reaction mixture was evaporated, dissolved in aqueous methanol and re-evaporated to give 25.7 g of ethyl 2-cyanoethyl (1,1-diethoxyethyl) phosphinate ( ³¹ P-NMR: ci = N 44 ppm).

This oil is treated with 25.7 g of trimethylsilyl chloride in 150 ml of commercially available chloroform (containing 1 to 5 wt% ethanol) at room temperature for 6 hours under argon. The reaction mixture was evaporated, the oil dissolved in methanol and re-evaporated to give ethyl 2-cyanoethylphosphinate.

A mixture of 2.5 g of ethyl 2-cyanoethylphosphinate and 4.96 g of hexamethyl disilazane was treated at 140 ° for 1 hour. The mixture was cooled to 50 ° and 2.45 g of n-butyraldehyde was added. After 15 minutes, the mixture was evaporated to an oil which was co-evaporated with 10 ml of aqueous ethanol to give 3.7 g of ethyl 2-cyanoethyl (1-hydroxybutyl) phosphinate.

Dissolve this oil in 50 ml of ethanol containing 0.58 g of ammonia and 0.5 g of Raney nickel and hydrogenate for 10 hours. The catalyst was filtered off and the solvent was removed by evaporation to give 2.0 g of ethyl 3-aminopropyl (1-hydroxybutyl-n-butyl) phosphinate.

EXAMPLE 57

A suspension of 1.23 g of 3-aminopropylphosphonic acid in 25 ml of hexamethyldisilazane was heated to reflux under an inert gas for 20 hours. After this time, a clear solution is formed and the reaction mixture is cooled to room temperature under an inert gas and 50 acres of anhydrous acetone are added; followed by an exothermic reaction. The reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo to give a clear oil. Dissolve this oil in 50 ml of aqueous 2.0 M hydrochloric acid and wash with 2 x 100 ml of dichloromethane and 1 x

100 ml of ether. The aqueous layer was evaporated to dryness to give a semi-solid residue which was co-evaporated with water (10 x 20 ml) and absolute ethanol (10 x 20 ml) to give the hydrochloride 3-aminopropyl (2hydroxyprop-2-yl) phosphinic acid, m.p. 159-161 ° as a white solid. This is suspended in absolute ethanol and treated with propylene oxide. Filtration and drying of the solid gave 3-aminopropyl (2-hydroxyprop-2-yl) phosphinic acid, m.p. 243-244 °.

EXAMPLE 58

Analogous to that described above in Example 57i can be obtained by reacting for 20 hours with 1-O-tert-butyldimethylsilyloxymethyl propan-2-one at 70 ° hydrochloride 3-aminopropyl (1,2dihydroxyprop-2-yl) phosphinic acid, m.p. . 175-179 °, and 3-aminopropyl- (1,2-dihydroprop-2-yl) -phosphinic acid, m.p. 209-210 ° (dec.).

The starting material can be obtained as follows:

To a solution of 6.8 g of imidazole in 20 ml of anhydrous dimethylformamide was added at 10 ° under an inert gas 7.5 g of tert-butyldimethylsilyl chloride in the same solvent. The clear solution was stirred for 15 minutes at 10 ° before 20 ml of anhydrous dimethylformamide solution of 3.7 g of hydroxy acetone was added. A slightly exothermic reaction follows and the reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction mixture was then diluted with ether and washed with water. After drying the organic phase with anhydrous magnesium sulfate and removing the ether in vacuo, the clear oil is distilled to give 1-0-tert-butyldimethylsilyloxymethyl propan-2-one; boil. 84-85 ° / 24 mbar.

EXAMPLE 59

Analogous to that described in Example 50, the reaction of n-propylphosphonic acid ethyl ester with epoxypropylphthalimide 3-amino-2-hydroxy-propyl (n-propyl) phosphinic acid and its hydrochloride can be prepared.

EXAMPLE 60

Analogous to that described in Example 8, the reaction of n-propylphosphonic acid ethyl ester with 1-phthalimido 2- (p-chlorophenyl) -3-bromopropane 3-amino-2- (p-chlorophenyl) propyl (n-propyl) phosphin can be prepared acid and its hydrochloride.

EXAMPLE 61

Analogous to that described in Example 4V, it can be prepared by reaction of 3- (benzyloxycarbonylamino) propanal with n-propylphosphonic acid ethyl ester 3-amino-1-hydroxy-propyl (n-propyl) phosphinic acid and its hydrochloride.

EXAMPLE 62

Analogous to that described in Example 31, the reaction of 3-aminopropylphosphonic acid and 4-hydroxybutyl-1-3-aminopropyl (4-hydroxybutyl) phosphinic acid and its hydrochloride can be obtained. The same method can also be obtained by reaction

3- Aminopropylphosphonic acid and 3-hydroxybut-1-one

3-Aminopropyl (3-hydroxybutyl) phosphinic acid and its hydrochloride.

EXAMPLE 63

Analogous to that described in Example 8, obtained by a 16-hour reaction with (S) - (+) - 2-ethylbutyl iodide at 120 ° 3 aminopropyl/2- (S) -methylbutyl / phosphinic acid, m.p. 252-255 ° (dec) / cx / _{365 nm} with +20.5; / «/ ^ _Nm = +13.8 = +8;

/ «/ | Θθ = + 6.6 ° and / <x / | gg = 6.1 ° (c = 0.95 in water).

EXAMPLE -64

Preparation of 10,000 tablets, each containing 100 mg of active ingredient with the following composition: 3-amino-2-hydroxy-propyl (diethoxymethyl) phosphinic acid 1,000.00 g Lactose 257.00 g Corn starch 75.00 g Polyethylene glycol 6.000 75, 00 g Magnesium stearate 18,00 g Purified water qs

Procedure: Sift all powders through a sieve with apertures of 0.6 mm. Then in a suitable blender mix the drug substance, lactose, magnesium stearate and half of the starch. The other half of the starch was suspended in 40 ml of water and the suspension was added to a boiling solution of polyethylene glycol in 150 ml of water. The resulting paste is added to the granulated powders, with additional water if necessary. Dry the granulate overnight at 35 °, crush on a sieve with apertures of 1.2 mm, and compress into 12.8 mm diameter tablets with a split notch above.

- 83 EXAMPLE 65

Preparation of 10,000 capsules, each containing 25 mg of active ingredient with the following composition:

3-amino-2-hydroxypropyl (diethoxymethyl) phosphinic acid 250.0 g

Lactose 1,750.0 g

Procedure: All powders are sieved through a 0.6 mm sieve. Then place the drug substance in a suitable mixer and mix with lactose until homogeneous. Using the capsule filling machine, fill the capsules no. 3 with 200 mg.

EXAMPLE 66

In the same way as described in Examples 65 and 66, tablets and capsules comprising 10 to 100 mg of other compounds of the invention, e.g. as described in Examples 1 to 64.

Claims (73)

PATENT APPLICATIONS A new process for the preparation of compounds of formula wherein R is an aliphatic, cycloaliphatic, cycloaliphatic aliphatic or araliphatic radical of 2 or more carbon atoms 12 3 and in which one of the groups R, R and R is hydrogen or aliphatic, cycloaliphatic, araliphatic or aromatic radical, 12 3 12 is other than R, R and R hydrogen or is, in the case of R and R 1 2 3 is hydroxy and the residue of R, R and R is hydrogen, provided that R is other than 1,1-di (C 1 -C 4 -alkoxy) -C 1 -C 4 -alkyl if 1 2 3 one of R, R and R represents hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical and the other 12 3 two of R, R and R are hydrogen, and salts thereof, provided that they are salts of compounds of formula I in which R is an unsubstituted aliphatic, cycloaliphatic or araliphatic hydrocarbon 13 radical, R and R are hydrogen and R is hydrogen or alkyl, with bases other than alkali metal salts and ammonium salts; and salts thereof, characterized in that in the compound of formula II (II), 12 3 in which R, R, R and R have their previous meanings, Z 4 - - -5 represents -NH ₂ and 8 represents a protecting group R for hydroxy - 85 - 1 3 2 or, if R and R are hydrogen and R is hydrogen or alkyl, it is an alkali metal ion or an ammonium ion R ^, or _in v. Q 2l Z represents a protected or latent amino group Z and R represents hydrogen or a protecting group R for hydroxy, any 5 6 group R or R being replaced by hydrogen and / or any group Z ° converted to -NH ₂ ; and optionally the resulting salt obtained by this process can be converted to the free compound or to another salt and / or optionally the resulting free compound converted to a salt corresponding to the above definition, and / or optionally the resulting mixture of isomers is separated into individual isomers. A method according to claim 1, characterized in that I prepare compounds of formula I in which R 2 has more or more carbon atoms and is alkyl, alkenyl, alkynyl, alkyl or alkenyl substituted by halogen and / or hydroxy, alkyl interrupted by one or two spaced atoms, selected from oxygen and sulfur, alkyl interrupted by one or two spaced atoms selected from oxygen and sulfur and which is substituted by halogen and / or hydroxy, cycloalkyl, cycloalkyl substituted by hydroxy, cycloalkyl interrupted with one or two spaced atoms selected from oxygen and sulfur, cycloalkyl-lower alkyl, cycloalkyl-lower alkyl substituted in the cycloalkyl moiety by hydroxy or lower alkylthio and / or in the alkylene moiety by hydroxy, cycloalkyl alkyl which is in cycloalkyl part interrupted by one or two spaced atoms selected from oxygen and sulfur, phenyl or naphthyl-lower alkyl or phenyl- or - 86 -...... naphthyl-lower alkyl, halogen-substituted and / or chain-substituted by hydroxy, lower alkyl, lower alkoxy and / or trifluoromethyl, and in which one 12 3 of the groups R, R and R are hydrogen, lower alkyl, cycloalkyl, phenyl or naphthyl, phenyl or naphthyl substituted with halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety having halogen, lower alkyl, lower alkoxy and / or trifluoro12 3 1 methyl, the other of R, R and R is hydrogen or, in the case of R, 2 12 3 and R, hydroxy and the remaining of R, R and R are hydrogen or salts thereof. 3- Process according to claim 1, characterized in that compounds of formula I are prepared in which R 2 has more than one carbon atom and is lower alkyl, lower alkenyl, lower alkynyl, alkyl interrupted by one or two spaced apart atoms selected from oxygen and sulfur, cycloalkyl, cycloalkyl interrupted by one or two spaced atoms selected from oxygen and sulfur, cycloalkyl or cycloalkyl-lower alkyl interrupted by one or two spaced apart in the cycloalkyl moiety atoms selected from oxygen and sulfur; and in which 12 3 represents one of the groups R, R and R hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety with halogen, lower alkyl, lower alkoxy and / or trifluoro1 2 methyl, or one of R and R is hydroxy and the remaining 1 2 3 two of R, fi and R are hydrogen, or salts thereof. 874. The process of claim 1, wherein the compounds of formula I are prepared, wherein R has 2 or more carbon atoms and is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxycycloalkyl, cycloalkyl-lower alkyl, cycloalkyl- (hydroxy) lower alkyl or lower alkylthiocycloalkyl- (hydroxy) lower alkyl group of 3 to 6 ring carbon atoms, mono- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di- or polychalogen-lower alkyl, mono-, dially polyhalogen-lower alkenyl, mono-, di- or polychalogen (hydroxy) lower alkyl, mono-, di or polyhalogen- (hydroxy) lower alkenyl, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl lower alkyl, di-lower alkoxy-lower alkyl, di-lower alkylthionyl alkyl, lower alkoxy- (hydroxy) lower alkyl, lower alkoxy- (halogen) lower alkyl, phenyl-lower alkyl, phenyl-lower hydroxyalkyl, phenyl-lower alkyl or phenyl-lower hydroxyalkyl which is mon o- or disubstituted in the phenyl moiety by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, naphthyl-lower alkyl, oxa- or thiacycloalkyl having 2 to 6 ring carbon atoms, or dioxa-, oxathia- or dithacycloalkyl with 3 to 5 ring carbon atoms and in which one of R ¹ , R ² , R ^{3 represents} hydrogen, lower alkyl, cycloalkyl having 3 to 6 ring carbon atoms, phenyl, phenyl which is mono- or disubstituted by halogen, lower alkyl, lower alkoxy and / or trifluoronethyl, phenyl-lower alkyl or phenyl-lower alkyl which is mono- or disubstituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, the other of R ¹ , R ² and R ^{J is} hydrogen or, in the case of R and R, hydroxy; and is residual 1 2 3 of R, R and R hydrogen, or salts thereof. 88 The process of claim 1, wherein the compounds of formula I are prepared wherein R has 2 or more carbon atoms and is lower alkenyl, lower alkynyl, cycloalkyl, hydroxycycloalkyl, cycloalkyl-lower alkyl, cycloalkyl (hydroxy) lower an alkyl or lower alkylthiocycloalkyl- (hydroxy) lower alkyl group having 3 to 6 ring carbon atoms, mono- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono- or polyhalogen-lower alkyl, mono-, di- or polyhalogen- lower alkenyl, mono-, di- or polyhalogen (hydroxy) lower alkyl, mono-, di- or polyhalogen- (hydroxy) lower alkenyl, phenyl-lower alkyl, phenyl-lower hydroxyphenyl, phenyl-lower alkyl which is mono- or disubstituted in the phenyl moiety by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, or naphthyl-lower alkyl, and in which one of the groups R, R and R ^{J represents} hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted by halogen , lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety by halogen lower alkyl, lower alkoxy and / or trifluoromethyl, is 12 3 12 the other of R, R and R is hydrogen or, in the case of R m R, is hydroxy 12 1 and the residue of R, R and R is hydrogen, or salts thereof. A process according to claim 1, characterized in that compounds of formula I are prepared in which R 2 has more or more carbon atoms and is lower alkyl, lower alkenyl or lower 1 2 3 alkynyl, and in which one of the groups R, R and R are hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl portion by halogen, lower alkyl, lower alkoxy - 39 - 1 2 and / or trifluoromethyl, or one of R and R is hydroxy, and 1 2 3 are the other two of R, R and 'R are hydrogen or salts thereof. Process according to claim 1, characterized in that compounds of formula I are prepared in which R represents lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl-lower alkyl, di-lower alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkoxy- (hydroxy) lower alkyl, lower alkoxy- (halogen) lower oxa- or thiacycloalkyl having 2 to 6 ring carbon atoms or dioxa- or dithacycloalkyl with 3 to 5 ring 1 2 carbon atoms and in which one of the groups R, R and R4 represents hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety by halogen, lower alkyl, lower alkoxy 1 2 3 and / or trifluoromethyl, the other of R, R and R is hydrogen or is, in 12 12 3 the case of R and R, hydroxy; and is the residual of R, R and R 1 2 is hydrogen, provided that if one of R and R is hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted with halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety by halogen, lower alkyl, lower alkoxy 1 2 3 and / or trifluoromethyl, and the other two are R, R and R hydrogen, R is other than hydroxy, R is other than 1,1-di ( C 1 -C 4 -alkoxyD-C 1 -C 4 -alkyl groups, and salts thereof. A process according to claim 3, wherein the compounds of formula I are prepared in which R represents lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, di-lower alkoxy-lower alkyl, di-lower alkylthio-lower alkyl, lower 90alkoxy-lower alkylthio-lower alkyl, oxacycloalkyl, thiacycloalkyl, dioxacycloalkyl and dithacycloalkyl, and in which one of 12, of the groups R, R and R represents hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy and / or trifluoromethyl, phenyl-lower alkyl or phenyl-lower alkyl substituted in the phenyl moiety by halogen, lower alkyl, lower alkoxy and / or trifluoro-1-methyl, or one of R and R is hydroxy; and the remaining 12 3 are two of R, R and R are hydrogen, or salts thereof. A process according to any one of claims 1 to 8, characterized in that compounds of formula I are prepared in which R is as defined herein and in which one of 12 3 groups R, R and Ir is hydrogen, lower alkyl, phenyl or phenyl substituted with halogen or lower alkyl, and the remaining 12 3 are two of R, R and R hydrogen, or salts thereof. A process according to any one of claims 1 to 8, characterized in that compounds of formula I are prepared in which R is lower alkyl of 2 or more carbon atoms, lower alkenyl '2 or lower alkynyl, R represents hydrogen, lower alkyl, phenyl or phenyl substituted with halogen or lower alkyl, and 1 and 3 are R and R are hydrogen or salts thereof. A process according to claim 1, characterized in that compounds of formula I are prepared in which R is lower alkoxy _in - 2 lower alkyl or mono- or dihydroxy-lower alkyl, R represents hydrogen, lower alkyl, phenyl or phenyl. substituted with halogen or lower alkyl, and R and ^{RJ are} hydrogen, and salts thereof. The method of claim 1,. characterized in that compounds of formula I are prepared in which RC _{2 is} C ₁ -C 6 -alkyl, -'91 C ₂ -C ₇ -alkenyl, C ₁ -C ₄ -alkynyl, mono- or dihydroxy-C 1 -C 6 -alkyl, mono-, di- or trihalogen-C 1 -hydroxy-C 1 -C 4 - alkyl, N-saturated mono-, di- or trihalogeno-OG-hydroxy-C 1 -C 4 -alkenyl, C 1 -C 4 alkoxy-C 1 -C 4 -alkyl, di-C 1 -C 4 -alkoxy -C 1 -C 4 -alkyl, N-hydroxyC 1 -C 8 -cycloalkyl, C 1 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, C 1 -C 8 -cycloalkyl-1L-hydroxy-C 1 -C 4 -alkyl or (2-C ₁ -C 4 -alkylthiocycloalkyl) -e <2 hydroxy-C ₁ -C 4 -alkyl, R represents hydrogen, hydroxy, C 1 -C 4 alkyl, phenyl or phenyl substituted by halogen or C 1 -C 12 alkyl and R and R 4 are hydrogen or represents one of R and R is hydroxy and represents the other as well as R is hydrogen, or salts thereof. A process according to claim 1, characterized in that compounds of formula I are prepared in which R is tx-, β-, f- or N -hydroxy- or N, β-dihydroxy-C ₂ -C ₇ -alkyl, R 4 represents hydrogen, hydroxy, C 1 -C 4 -alkyl, phenyl. or phenyl substituted by 1 3 with halogen or C 1 -C 4 -alkyl, and R and R are hydrogen or 1 2 represents one of R and R is hydroxy and R 3 is hydrogen or the salts thereof. A process according to claim 3, characterized in that compounds of formula I are prepared in which R is C 1 -C 4 -alkyl, C ₂ -C ₇ -alkenyl or C ₁ -C ₄ -alkynyl, R represents hydrogen, lower alkyl, phenyl, or phenyl substituted with halogen or lower 1-3 alkyl, and R and R are hydrogen or salts thereof. A process according to claim 3, characterized in that compounds of formula I are prepared in which R is C 1 -C 4 -alkoxy C 1 -C 4 -alkyl, R represents hydrogen, lower alkyl, phenyl or phenyl substituted by halogen or lower alkyl, 1 3 R and R are hydrogen, or salts thereof. and sta 9216. The process of claim 1, wherein the compounds of formula I are prepared in which R is C 1 -C 4 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 3 -C 4 - alkynyl, ok-, β-, f- ^or -hydroxy-C ₂ -C 4 -alkyl, -dihydroxy-C ₂ -Cy-alkyl, mono-, di- or trifluoro- -hydroxy-C 1 -C 4 -alkyl , cx.-saturated mono-, di- or trifluoro-OC-hydroxy-C1-C4-alkenyl, C1-6-alkoxy C 1 -C 6 alkyl 1, C 1 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, C 1 -C 6 hydroxy-C 1 -C 8 cycloalkyl or C 1 -C 8 -cycloalkyl-C 3 -hydroxy-C 1 -C 4 -alkyl 12 3 represent R, R and R hydrogen, or salts thereof. A process according to claim 6, characterized in that compounds of formula I are prepared in which R is either C ₂ -Cyalkyl, C ₂ -Cy-alkenyl, C ₂ -Cy-alkynyl or -C 1 -alkoxy-C- C 1-3 alkyl and R, R and R are hydrogen, or salts thereof. A process according to claim 6, characterized in that compounds of formula I are prepared wherein R is C 1 -C 4 -alkyl and 1 2 3 are R, R and R are hydrogen, or salts thereof. A process according to claim 1 in which 3-amino-2-hydroxy-propyl (diethoxymethyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (n-butyl) phosphinic acid or a salt thereof is prepared. 21. The method of claim 1, wherein 3-amino-propyl (ethyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein the hydrochloride of 3-amino-propyl (isobutyl) phosphinic acid or a salt thereof is prepared. The method of claim 1, wherein the preparation is 93 3-Amino-propyl (allyl) phosphinic acid or a salt thereof. A process according to claim 1 in which 3-amino-propyl (n-pentyl) phosphinic acid or a salt thereof is prepared. A process according to claim 1 in which 3-amino-propyl (but-3-enyl) phosphinic acid or a salt thereof is prepared. 26. The process of claim 1, wherein 3-amino-propyl (isopentyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (cyclopropylmethyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 1-methyl-3-amino-propyl (n-butyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (pent-3-ynyl) phosphinic acid or a salt thereof is prepared. 30. The process of claim 1, wherein 3-amino-propyl (but-3-ynyl) phosphinic acid or a salt thereof is prepared. A process according to claim 1 in which 3-amino-propyl (2-methylallyl) phosphinic acid or a salt thereof is prepared. A process according to claim 1, in which 3-amino-propyl (2-ethoxyethyl) phosphinic acid or a salt thereof is prepared. 33- The process of claim 1, wherein 3-amino-propyl (2-methylbutyl) -phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl- (3-ethoxypropyl) -phosphinic acid or a salt thereof is prepared. - 94 The process of claim 1, wherein 3-amino-propyl (3-methoxypropyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (but-2-ynyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl / 2- (2-ethoxyethoxy) ethyl / phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (4,4,4-trifluorobutyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (benzyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, in which 3-amino-propyl (n-heptyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, in which 3-amino-propyl (2-phenylethyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, in which 3-amino-propyl (dodecyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (propargyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, in which 3-amino-propyl (1,3-dithiolan-2-yl) phosphinic acid or a salt thereof is prepared. A process according to claim 1 in which 3-amino-propyl (tetrahydrofuran-2-yl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (1-hydroxybutyl) phosphinic acid or a salt thereof is prepared. A process according to claim 1 in which 3-amino-propyl (1-hydroxyisobutyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (1-hydroxyethyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (1-hydroxybenzyl) phosphinic acid or a salt thereof is prepared. A process according to claim 1 in which 3-amino-propyl (1-hydroxy-4,4,4-trifluoro-butyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (1-hydroxy-2- (Z) -fluoro-but-2-enyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (1-hydroxy-1-cyclopropylmethyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl / 1-hydroxy-1- (2-methylthiocyclopropyl) -methyl / -phosphinic acid or a salt thereof is prepared. The process of claim 1, in which 3-amino-propyl (cyclohexylmethyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (1-hydroxy-1-cyclobutyl-methyl) phosphinic acid or a salt thereof is prepared. The method of claim 1, wherein the preparation is made 3-amino-propyl / 2- (R) hydroxy-3-ethylbutyl / phosphinic acid or a salt thereof. The process of claim 1, in which 3-amino-propyl (2-hydroxyprop-2-yl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-propyl (1,2-dihydroxyprop-2-yl) phosphinic acid or is prepared. its salt. The process of claim 1, in which 3-amino-propyl (2-hydroxybutyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, wherein 3-amino-2-hydroxy-propyl (propyl) phosphinic acid or a salt thereof is prepared. A process according to claim 1 in which 3-amino-1-hydroxy-propyl (propyl) phosphinic acid or a salt thereof is prepared. The process of claim 1, in which 3-amino-propyl (4-hydroxybutyl) phosphinic acid or a salt thereof is prepared. 63- The process of claim 1, wherein 3-amino-propyl (3-hydroxybutyl) phosphinic acid or a salt thereof is prepared. 64. The process of claim 1, wherein 3 amino- propyl (2- (S) -methylbutyl) phosphinic acid or a salt thereof is prepared. A method according to claim 1, characterized in that it is prepared vimo compounds of formula I ^H \ IF ff Jp - CH - CH - CH - NH ₂ R (I), in which H is diethoxymethyl, one of and R ² is p-chlorophenyl or methyl and R ³ and the other of R ¹ and 2 hydrogen; or in which R is a group of the formula -CH (OR ') ₂ , v which R ' represents 1 2 C 1 -C 4 -alkyl and R 1, R 3 are as defined and R ³ hydrogen or theirs salts. 66. The process of claim 1, in which 3-amino-2- (p-chlorophenyl) propyl (diethoxymethyl) phosphinic acid or a salt thereof is prepared. 67. The process of claim 1, in which 3-aminopropyl (diethoxynethyl) phosphinic acid or a salt thereof is prepared. 68. The process of claim 1, wherein 3-amino-1- (p-chlorophenyl) propyl (diethoxymethyl) phosphinic acid or a salt thereof is prepared. 69. The process of claim 1, wherein 3-amino-propyl (di-n-propyloxymethyl) phosphinic acid or a salt thereof is prepared. A process according to claim 1 in which 3-amino-propyl (diisopropyloxymethyl) phosphinic acid or a salt thereof is prepared. - 98 The process of claim 1, in which 3-aminobutyl (diethoxymethyl) phosphinic acid or a salt thereof is prepared. 72. The process of claim 1, wherein 3-aminopropyl (di-n-butyloxymethyl) phosphinic acid or a salt thereof is prepared. 73. A process for the preparation of pharmaceutical preparations, characterized in that the compound of formula I f f f CH-CH-CH-NH ₂ (I), R ^Z in which R represents an aliphatic, cycloaliphatic, cycloaliphatic or aliphatic radical having 2 or more carbon atoms 1 2 3 and in which one of the groups R, R and R represents hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, 12 3 12 is other than R, R and R hydrogen or, in the case of R and R, 12 3 is hydroxy and the residue of R, R and R is hydrogen, or a pharmaceutically acceptable salt thereof is admixed with a conventional pharmaceutical carrier system. 74. A process for the preparation of pharmaceutical compositions in which the compound obtainable according to any one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 16, 22 to 64 and 65 to 67 is mixed with the conventional pharmaceutical carrier system. A method for the preparation of pharmaceutical preparations, wherein the compound according to any one of claims 3, 6, 8 to 10, 14, 15, 17, 18 to 21 and 68 to 72 are admixed to a conventional pharmaceutical carrier system. A method according to any one of claims 73 to 75 for the preparation of nootropic, ahtidepressive and / or anti-epileptic drugs.