SK30198A3 - Substituted phosphinic compounds and their use as pharmaceuticals - Google Patents

Abstract

A compound which is a substituted phosphinic acid of formula (I), or a salt or ester thereof, where R<1> is a monovalent aromatic or araliphatic group connected through a carbon atom thereof to the indicated carbon atom, R<2> is an unsubstituted or substituted hydrocarbyl group, R<x> is hydrogen or an unsubstituted or substituted hydrocarbyl group, R<y> is hydrogen, R<y>a or a NH-protecting group and R<y>a is an unsubstituted or substituted hydrocarbyl group.

Description

Technical field

The invention relates to chemical compounds which are substituted phosphinic acids or their salts or esters, their preparation and their use as medicaments.

BACKGROUND OF THE INVENTION

WO 94/22843 describes phosphinic acids of the general formula

Wherein R ¹ and R ² are both hydrogen, both methyl, or R ¹ and R ² together with the carbon atom to which they are attached form a cyclopentyl group. These compounds are said to act as antagonists.

SUMMARY OF THE INVENTION

More recently, it has been found that by preparing novel substituted morpholine ring containing phosphinic acids, compounds with remarkably high GABAg receptor binding affinity can be obtained.

Accordingly, the invention provides compounds that are substituted phosphinic acids of Formula I

Ο

in which

R ¹ represents a monovalent aromatic or araliphatic group attached to said carbon atom through its carbon atom,

R @ 1 represents an unsubstituted or substituted hydrocarbon group,

R ^x represents a hydrogen atom or an unsubstituted or substituted hydrocarbon group,

R represents H, R or _a protecting group NH, and

_And R represents an unsubstituted or substituted hydrocarbon radical, or salts or esters thereof.

The aromatic group may have up to 40 carbon atoms and may be an aryl group such as a phenyl, tolyl, xylyl or naphthyl group, or a heterocyclic aromatic group such as a thienyl, furyl, indolyl or pyridyl group, all of which may be be unsubstituted or substituted by one or more substituents such as halogen atoms, hydroxy, C 1 -C 4 alkoxy, carboxy, functionally modified carboxy groups, including esterified carboxy, amidated carboxy and kya 3 groups, carboxyalkyl groups of 1 to 8 carbon atoms, a functionally modified C 1 -C 8 carboxyalkyl group or an nitro group.

The aromatic group R @ ³ is preferably an aryl group having 6 to 15 carbon atoms, which may be. unsubstituted or substituted at one or more positions by substituents selected from the group consisting of halogen atoms, carboxy, functionally modified carboxy, carboxyalkyl of 1 to 8 carbon atoms in the alkyl moiety, functionally modified carboxyalkyl groups of 1 to 8 carbon atoms in the alkyl moiety, and nitro, or the aromatic group R ^{1 is a} 5- to 10-membered heterocyclic aromatic group containing one or two nitrogen atoms in the ring system. Even more preferably, an unsubstituted or substituted aryl group R ^{1 is a} phenyl group or a phenyl group substituted in one or more of the meta and para positions linked to its carbon atom and said morpholine ring by substituents selected from the group consisting of halogen atoms, carboxy , functionally modified carboxy and nitro groups. Examples of such substituted phenyl groups include phenyl groups mono- or disubstituted with substituents selected from the group consisting of a chlorine atom; a bromine atom; iodine atom; carboxy; -COOR where R ³ is C 1 -C 8 alkyl, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl, optionally substituted with halogen, hydroxy or C 1 -C 4 alkoxy alkyl; a carbamoyl group; N-alkylcarbamoyl groups having 1 to 4 carbon atoms in the alkyl moiety, such as methyl or ethylcarbamoyl groups; N, N-dialkylcarbamoyl groups having 1 to 4 carbon atoms in each alkyl moiety, such as dimethyl or diethylcarbamoyl groups; cyano; carboxyalkyl groups having 1 to 4 carbon atoms in the alkyl moiety, such as a carboxymethyl group; alkoxycarbonylalkyl groups having 1 to 8 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety such as methoxy4 or ethoxycarbonylmethyl; (C 1 -C 4) carbamoylalkyl; such as carbamoylmethyl; N-alkylcarbamoylalkyl groups having 1 to 4 carbon atoms in each alkyl moiety, such as a methyl or ethylcarbamoylmethyl group; N, N-dialkylcarbamoylalkyl having 1 to 4 carbon atoms in each alkyl moiety, such as dimethyl or diethylcarbamoylmethyl; (C 1 -C 4) cyanoalkyl such as cyanomethyl; and nitro. Even more preferably, the heterocyclic aromatic group R ^{1 is a} 5- to 10-membered heterocyclic group containing as the only ring heteroatom a nitrogen atom, for example a pyridyl or indolyl group.

The araliphatic group R ¹ may contain from 7 to 40 carbon atoms and may be a phenyl (lower) alkyl group such as a benzyl or 2-phenylethyl group, and, α-diphenyl (lower) alkyl group such as a diphenylmethyl group, or α-naphthyl (lower) alkyl, such as naphthylmethyl, all of which may be unsubstituted or substituted at one or more positions, which may be ortho, meta or para, by substituents selected from the groups specified above for an aromatic group in the meaning of the symbol R ¹ . Preferably, the araliphatic group R @ 1 is a C1 -C4 -phenylalkyl group in the alkyl moiety which is unsubstituted or substituted at one or more positions by substituents selected from the group consisting of halogen atoms, carboxy, functionally modified carboxy and nitro.

In particularly preferred compounds of the invention. R 1 represents phenyl, 3-iodophenyl, 3,4-dichlorophenyl,

3-carboxyphenyl, 3-cyanophenyl, 3- (methoxycarbonyl) phenyl, 3-nitrophenyl, benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl.

Unsubstituted or substituted hydrocarbon moieties as defined herein may generally contain 1 to 40 carbon atoms. It may be, for example, an alkyl, cycloalkyl, alkenyl or alkynyl group or an alkyl, cycloalkyl or alkenyl group substituted by one or more substituents such as halogen atoms, hydroxy, C 1 -C 8 alkoxy, thio, C 1 -C 8 alkylthio, cyano , acylamino, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl substituted by, for example, one or more substituents such as hydroxy, C 1 -C 8 alkoxy, thio or C 1 -C 8 alkylthio, cycloalkenyl C 3 -C 8 aryl, C 6 -C 15 aryl, C 6 -C 15 aryl substituted by, for example, one or more substituents such as hydroxy, C 1 -C 8 alkoxy, halogen, or trifluoromethyl, heteroaryl groups or heteroaryl groups substituted with one or more substituents such as halogen atoms.

p

Aliphatic radicals R are, for example, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, oxo (lower) alkyl groups, hydroxy- or dihydroxy (lower) alkyl groups, hydroxy (lower) alkenyl groups, mono-, di- or polyhalogen (lower) alkyl groups, mono- di- or polyhalogen (lower) alkenyl groups, mono- di- or polyhalogen (hydroxy) (lower) alkyl groups, mono- di- or polyhalogen (hydroxy) (lower) alkenyl groups, ( lower) alkoxy (lower) alkyl groups, di (lower) alkoxy (lower) alkyl groups, (lower) alkoxy (hydroxy) (lower) alkyl groups, (lower) alkoxy (halogen) (lower) alkyl groups, (lower) alkylthio (lower) alkyl groups and di (lower) alkylthio (lower) alkyl groups.

Cycloaliphatic radicals R are, for example, cycloalkyl, hydroxycycloalkyl, oxa-, dioxa-, thia and dithiacycloalkyl groups.

Cycloaliphatic-aliphatic residues in the meaning of the symbol o

R is, for example, cycloalkyl (lower) alkyl groups, cycloalkenyl (lower) alkyl groups, cycloalkyl (hydroxy) (lower) alkyl groups and ((lower) alkylthio) cycloalkyl (hydroxy) (lower) alkyl groups.

Araliphatic radicals are, for example, phenyl (lower) alkyl radicals which are unsubstituted or mono-, di- or trisubstituted by substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen atoms and / or trifluoromethyl, preferably α- phenyl (lower) alkyl groups substituted as above or unsubstituted α, α-diphenyl- or α-naphthyl (lower) alkyl groups.

Heteroarylaliphatic radicals R are, for example, thienyl, furyl, or pyridyl (lower) alkyl radicals which are unsubstituted or substituted, in particular mono- or disubstituted, by halogen, preferably unsubstituted α-thienyl, α-furyl or α. -pyridyl (lower) alkyl groups.

As used hereinabove and below, lower moieties and compounds are understood to be, for example, radicals and compounds containing up to 7 (inclusive) carbon atoms, preferably up to 4 (inclusive) carbon atoms.

A lower alkyl group is, for example, an alkyl group having from 1 to 7 carbon atoms, preferably an alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl or butyl, but may be. also isobutyl, sec-butyl or tert-butyl or alkyl of 5 to 7 carbon atoms, such as pentyl, hexyl or heptyl.

Lower alkenyl is, for example, C 2 -C 4 alkenyl, such as vinyl, allyl or but-2-enyl, but may also be C 5 -C 7 alkenyl, such as pentenyl, hexenyl or heptenyl.

Lower alkynyl is, for example, C 2 -C 7 alkynyl, preferably C 3 -C 5 alkynyl, which carries a triple bond at a higher position than the α, δ-position, for example 2-propynyl (propargyl), but-3- an in-1-yl, but-2-yn-1-yl or pent-3-ynyl group.

The oxo (lower) alkyl group carries the oxo group preferably at a higher position than in the α-position, and is, for example, an oxoalkyl group having 2 to 7 carbon atoms, especially an oxoalkyl group having 3 to 6 carbon atoms such as 2-oxopropyl, 2- or A 3-oxobutyl or 3-oxopentyl group.

Phenyl (lower) alkyl is, for example, benzyl,

1-phenylethyl, 2-phenylprop-2-yl or, secondly,

2-phenylethyl, 2-phenylprop-1-yl or 3-phenylprop-1-yl.

Thienyl-, furyl- or pyridyl- (lower) alkyl is, for example, thienyl-, furyl- or pyridylmethyl, Ι-thienyl-, 1-furyl- or 1-pyridylethyl, 2-thienyl-, 2-furyl- or 2- pyridylprop-2-yl or, secondly, 2-thienyl-, 2-furyl- or 2-pyridylethyl,

2-thienyl-, 2-furyl- or 2-pyridylprop-1-yl; or

3-thienyl-, 3-furyl or 3-pyridylprop-1-yl.

The hydroxy (lower) alkyl group bears the hydroxy group preferably in the α- or δ-position and is, for example, the corresponding hydroxyalkyl group having 2 to 7 carbon atoms, such as

1-hydroxyethyl, 1- or 2-hydroxypropyl, 2-hydroxyprop-2-yl, 1- or 2-hydroxybutyl, 1-hydroxyisobutyl or 2-hydroxy-3-methylbutyl.

A dihydroxy (lower) alkyl group carries hydroxy groups especially at the α, β-positions and is, for example, α, β-dihydroxyalkyl of 3 to 7 carbon atoms, such as 1,2-dihydroxyprop-2-yl.

The hydroxy (lower) alkenyl group carries a hydroxy group preferably at the α-position and the double bond preferably at the position higher than the α, β-position, and is, for example, the corresponding C 3 -C 5 α-hydroxyalkenyl group, for example 1-hydroxybut-2- enyl group.

A mono-, di- or polyhalogen (lower) alkenyl group is, for example, a mono-, di- or trifluoroalkenyl group having 2 to 5 carbon atoms, such as a 1-fluorobut-2-enyl group.

The mono-, di- or polyhalogen (hydroxy) (lower) alkyl group carries the hydroxy group preferably at the α-position and the halogen atoms preferably at the position higher than the α-position and is, for example, the corresponding mono-, di- or trifluoro-α-hydroxyalkyl group having 2 to 7 carbon atoms such as 4,4,4-trifluoro-1-hydroxybutyl.

A mono-, di- or polyhalogen (lower) alkyl group is, for example, a mono-, di- or trifluoroalkyl group having 2 to 5 carbon atoms, such as 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 1- or 2-fluorobutyl or 1,1-difluorobutyl.

Lower alkoxy is, for example, C 1 -C 7 alkoxy, preferably C 1 -C 4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, but may also be isobutoxy, alkoxy, tert-butoxy, tert-butoxy, tert-butoxy, tert-butoxy, tert-butoxy or tert-butoxy; C 5 to C 7 atoms such as pentyloxy, hexyloxy or heptyloxy.

An acylamino (lower) alkyl group is, for example, an alkylcarbonylaminoalkyl group having 1 to 4 carbon atoms in each alkyl moiety, such as an acetylaminopropyl group, or an arylcarbonylaminoalkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the alkyl moiety such as a benzoylaminomethyl group.

Cyano (lower) alkyl is, for example, cyanoalkyl having 1 to 4 carbon atoms in the alkyl moiety, such as cyanomethyl or 2-cyanoethyl.

The mono-, di- or polyhalogen (hydroxy) (lower) alkenyl group carries the hydroxy group preferably at the α-position and the halogen atoms preferably at the position higher than the α-position, and is, for example, the corresponding mono-, di- or trifluoro-α-hydroxyalkenyl a group having 2 to 5 carbon atoms, such as a 2-fluoro-1-hydroxybuten-2-yl group.

A (lower) alkoxy (lower) alkyl group is, for example, an alkoxyalkyl group having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, such as methoxy or ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxy or a 3-ethoxypropyl or 1- or 2-methoxybutyl group.

A di (lower) alkoxy (lower) alkyl group is, for example, a dialkoxyalkyl group having 1 to 4 carbon atoms in each alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, for example dimethoxymethyl, dipropoxymethyl, 1,1- or 2,2-diethoxyethyl, diisopropoxymethyl, dibutoxymethyl or 3,3-dimethoxypropyl.

A (lower) alkoxy (hydroxy) (lower) alkyl group is, for example, an alkoxy (hydroxy) alkyl group having 1 to 4 carbon atoms in the alkoxy moiety and 2 to 7 carbon atoms in the alkyl moiety such as 2-hydroxy-3-methoxyprop-2 -yl group.

A (lower) alkoxy (halogen) (lower) alkyl group is, for example, an alkoxy (halogen) alkyl group having 1 to 4 carbon atoms in the alkoxy moiety and 2 to 5 carbon atoms in the alkyl moiety such as a 2-fluoro-3-methoxybutyl group.

A (lower) alkylthio (lower) alkyl group is, for example, an alkylthioalkyl group having 1 to 4 carbon atoms in each alkyl moiety, such as methylthio or ethylthiomethyl,

2-methylthioethyl, 2-ethylthioethyl, 3-methylthio- or

A 3-ethylthiopropyl or 1- or 2-methylthiobutyl group.

A di (lower) alkylthio (lower) alkyl group is, for example, a dialkylthioalkyl group having 1 to 4 carbon atoms in each alkyl moiety, for example dimethylthiomethyl, dipropylthiomethyl, 1,1- or 2,2-diethylthioethyl, diisopropylthiomethyl, dibutylthiomethyl or 3,3-dimethylthiopropyl group.

Halogen is halogen having an atomic number of up to and including 53, i. fluorine, chlorine, bromine or iodine.

Cycloalkyl is, for example, cycloalkyl having 3 to 8 carbon atoms, in particular cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

A hydroxycycloalkyl group is, for example, an α-hydroxycycloalkyl group having 3 to 6 carbon atoms, such as a 1-hydroxycyclopropyl, 1-hydroxycyclobutyl or 1-hydroxycyclohexyl group.

An oxa- or tiacycloalkyl group is, for example, an oxa or thiacycloalkyl group having 3 to 8 carbon atoms, in particular an oxa- or tiacycloalkyl group having 3 to 6 carbon atoms, such as 2-oxacyclopropyl (oxiranyl), 2- or 3-oxacyclobutyl (oxetanyl), 2 - or a 3-thiacyclobutyl (tietanyl), 2- or 3-oxacyclopentyl (tetrahydrofuranyl), 2 or 3-thiacyclopentyl (thiolanyl) or 2-oxacyclohexyl (tetrahydropyranyl) group.

Dioxacycloalkyl is, for example, 1,3-dioxacycloalkyl of 3 to 8 carbon atoms, such as 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl.

Dithiacycloalkyl is, for example, 1,3-dithiacycloalkyl of 3 to 8 carbon atoms, such as 1,3-dithiolan-2-yl or 1,3-dithien-2-yl.

Cycloalkyl (lower) alkyl is, for example, cycloalkylalkyl of 3 to 8 carbon atoms in the cycloalkyl moiety and 1 to 4 atoms of the cycloalkylalkyl group of the cycloalkyl moiety and 1 to carbon in the alkyl moiety, in particular of 3 to 6 carbon atoms in the alkyl moiety, such as α- (cycloalkyl) alkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 4 carbon atoms in the alkyl moiety, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

Cycloalkenyl (lower) alkyl is, for example, cycloalkenylalkyl having 3 to 8 carbon atoms in the cycloalkenyl moiety and 1 to 4 carbon atoms in the alkyl moiety, especially cycloalkenylalkyl having 3 to 6 carbon atoms in the cycloalkenyl moiety and 1 to 4 carbon atoms in the alkyl moiety such as α- (cycloalkenyl) alkyl having 3 to 6 carbon atoms in the cycloalkenyl moiety and 1 to 4 carbon atoms in the alkyl moiety, for example, cyclopent-1-enylmethyl, cyclopent-2-enylmethyl, cyclopent-3-enylmethyl, cyclohexyl; 1-enylmethyl, cyclohex-2-enylmethyl or cyclohex-3-enylmethyl.

Cycloalkyl (hydroxy) (lower) alkyl is, for example, a cycloalkyl (hydroxy) alkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 4 carbon atoms in the alkyl moiety such as α- (cycloalkyl) -α-hydroxyalkyl group having 3 up to 6 carbon atoms in the cycloalkyl moiety and 1 to 4 carbon atoms in the alkyl moiety, for example cyclopropyl (hydroxy) methyl, for example cyclobutyl (hydroxy) methyl or cyclohexyl (hydroxy) methyl.

A (lower) alkylthiocycloalkyl (hydroxy) (lower) alkyl group is, for example, a 1- (alkylthiocycloalkyl) -1-hydroxyalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 4 carbon atoms in each alkyl moiety such as (2-methylthiocycloproprophenyl). 1-yl) hydroxymethyl group.

In preferred compounds of the invention, R ² is lower alkyl, lower alkenyl, lower alkynyl, oxo (lower) alkyl, hydroxy- or dihydroxy (lower) alkyl, hydroxy (lower) alkenyl, mono-, di- or a polyhalogen (lower) alkyl group, a monodi- or polyhalogen (lower) alkenyl group, a mono-, dialkyl or polyhalogen (hydroxy) (lower) alkyl group, a mono-, dialkyl or polyhalogen (hydroxy) (lower) alkenyl group, (lower) alkoxy ( lower) alkyl, di (lower) alkoxy (lower) alkyl, (lower) alkoxy (hydroxy) (lower) alkyl, (lower) alkoxy (halogen) (lower) alkyl, (lower) alkylthio (lower) alkyl a di- (lower) alkylthio (lower) alkyl group, a cyano (lower) alkyl group, an acylamino (lower) alkyl group, a cycloalkyl group, a hydroxycycloalkyl group, an oxa-, dioxa-, thia- or dithiacycloalkyl group, a cycloalkyl (lower) alkyl group, a cycloalkenyl (lower) alkyl group, a cycloalkyl (hydroxy) (lower) alkyl group, a ((lower) alkylthio) cycloalkyl (hydroxy) (lower) alkyl group, or a mono- or diphenyl (lower) alkyl group which is unsubstituted or mono-, di- or trisubstituted by lower alkyl, lower alkoxy, halogen, hydroxy and / or trifluoromethyl, naphthyl (lower) alkyl or unsubstituted or halo-substituted thienyl, furyl or pyridyl (lower).

In more preferred compounds of formula IR ² is C 1 -C 7 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl, and C 1 -C 4 -alkoxyalkyl in each alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, in particular a .alpha., .alpha.-dialkoxymethyl or a (C1 -C4) -ethyl group in each alkoxy moiety, such as a dimethoxy or diethoxymethyl or 1,1-diethoxyethyl group, a 1-cyanoalkyl group; C 1-4 alkyl atoms such as cyanomethyl or C 1-4 alkyl;

2-cyanoethyl, C 1 -C 5 acylaminoalkyl, such as acetylaminoethyl, acetylaminopropyl, acetylaminopentyl or benzoylaminomethyl, C 3 -C 6 cycloalkylalkyl and C 1 -C 4 alkyl, and C 1 -C 4 alkyl is cyclopropyl or cyclohexylmethyl, cycloalkenylalkyl having 3 to 6 carbon atoms in the cycloalkenyl moiety and 1 to 4 carbon atoms in the alkyl moiety, such as cyclohex-3-enylmethyl, or phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety, such as a benzyl group which is unsubstituted or mono-, di- or trisubstituted by a C1-C4 alkyl group such as a methyl group, a C1-C4 alkoxy group such as a methoxy group, a hydroxy group and / or a halogen such as fluorine, chlorine or iodine.

In even more preferred compounds of the invention, R ² is C 1 -C 5 alkyl, such as methyl, ethyl or butyl, and α, C 1 -C 4 -alkoxymethyl in each alkoxy moiety, such as dimethoxymethyl , α, α-dialkoxyethyl having 1 to 4 carbon atoms in each alkoxy moiety, such as 1,

1-diethoxyethyl, cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 4 carbon atoms in the alkyl moiety such as cyclopropylmethyl or cyclohexylmethyl, benzyl or 4-methoxybenzyl. In particularly preferred compounds of the invention, R is cyclohexylmethyl or 4-methoxybenzyl.

The unsubstituted or substituted hydrocarbon group denoted by R ^x may contain up to 40 carbon atoms and can either be an alkyl group having 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl having C 1 -C 13 aryl, C 6 -C 10 aryl or C 7 -C 13 aralkyl, any of which may be substituted with one or more substituents selected from the group specified above for R ¹ . R ^{@ 1} preferably represents a hydrogen atom, a lower alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 8 carbon atoms or an aralkyl group having 7 to 9 carbon atoms, in particular a hydrogen atom or an isopropyl group.

The unsubstituted or substituted hydrocarbon group RY in the meaning of the symbol RY may contain: up to 40 carbon atoms and may be: for example, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or an aralkyl group having 7 to 13 carbon atoms wherein any of these groups may be unsubstituted or substituted by hydroxy or alkoxy of 1 to 4 carbon atoms. The NH-protecting group in the meaning of the symbol RY may be. for example an acyl group such as acetyl, trifluoroacetyl, benzoyl or p-nitrobenzoyl group, or an alkoxycarbonyl group or an aralkoxycarbonyl group such as a tert-butoxycarbonyl or benzyloxycarbonyl group. Preferably, R Y is hydrogen, lower alkyl, C7 -C9 aralkyl, acetyl, benzoyl, tert-butoxycarbonyl or benzyloxycarbonyl, especially hydrogen, methyl, ethyl, benzoyl, tert-butoxycarbonyl or tert-butoxycarbonyl.

Particularly preferred compounds of the invention are those compounds of formula I wherein:

R ¹ represents phenyl, 3-iodophenyl, 3,4-dichlorophenyl,

3-cyanophenyl, 3- (methoxycarbonyl) phenyl, 3-carboxyphenyl, 3-nitrophenyl, benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl,

^R2 is cyclohexylmethyl or 4-methoxybenzyl,

R ^x represents a hydrogen atom or an isopropyl group, and

R y represents a hydrogen atom, a methyl or benzyloxycarbonyl group, and salts and esters thereof.

The compounds of formula I may be in the form of inner salts and may form both acid addition and base salts by conventional salt-forming reactions.

Acid addition salts of the compounds of formula I are, for example, their pharmaceutically acceptable salts with suitable mineral acids such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids. or N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates).

The salts of the compounds of the formula I with bases are, for example, their salts with pharmaceutically acceptable bases, such as non-toxic metal salts derived from metals of groups Ia, 1b, IIa and IIb, for example alkali metal salts, especially sodium or potassium salts, metal salts alkaline earths, especially calcium or magnesium salts, as well as ammonium salts with ammonia or organic amines or quaternary ammonium bases such as unsubstituted or C-hydroxylated aliphatic amines, in particular mono-, di- or tri (lower) -alkylamines, for example methyl- , ethyl- or diethylamine, mono-, dialkyl or tri (hydroxy (lower) alkyl) amines such as ethanol-, diethanol- or triethanolamine, tris (hydroxymethyl) methylamine or

2-hydroxy-tert-butylamine, or N- (hydroxy (lower) alkyl) -N, N-di (lower) alkylamines or N- (polyhydroxy (lower) alkyl) (lower) alkylamines such as 2- (dimethylamino) ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, for example tetrabutylammonium hydroxide.

Just as it can form salts with bases, the hydroxy group attached to the phosphorus atom of formula I can also be esterified. Accordingly, the invention includes compounds of formula I in the form of their esters with an alcohol which may be a C 1 -C 10 alkanol in which the alkyl moiety is unsubstituted or substituted, for example by halogen, cyano or C 1 -C 4 alkoxy, such as methanol , ethanol, isopropanol, isobutanol,

2-ethylhexanol, 2-chloroethanol, 2-cyanoethanol, 2-ethoxyethanol or 2-n-butoxyethanol, a C 3 -C 8 cycloaliphatic alcohol such as cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, methylcyclohexanol or cyclooctanol, or araliphatic an alcohol having 7 to 13 carbon atoms, such as benzyl alcohol.

When the asymmetric compounds of the invention are present in the form of racemates or in the form of optical antipodes.

carbon atoms, can be mixtures of isomers, especially in pure isomers, in particular

Preferred isomers of the compounds of formula I are those in which the group and the group are attached at the 2-position of said morpholine ring in the trans position relative to each other, i. isomers of formula IA

ABOUT

or of formula IB

Ο

Wherein R ¹ , R ² , R ^x and R Y are as defined above.

Other preferred isomers of the compounds of formula I are those in which the group and the group are attached at the 2-position of said morpholine ring in the cis position relative to each other, i. isomers of formula IC

(IC) or ID

wherein R ¹ , R ² , R ^x and R ^{y are} as defined above.

Examples of particular compounds of formula I include

- {(3R *, 6R *) - 6 - [(5-acetylaminopentyl) hydroxyphosphinoylmethyl] morpholin-3-yl} benzoic acid,

3 - {(3R *, 6R *) - 6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] morpholin-3-yl} benzoic acid,

- {(3R *, 6R *) - 6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] morpholin-3-yl} benzoic acid,

3 - [(3R, 6R) -6- (butylhydroxyphosphinoylmethyl) morpholin-3-yl] benzoic acid,

- {(3R *, 6R *) -6-C (diethoxymethyl) hydroxyphosphinoylmethyl] morpholin-3-yl] benzoic acid,

3 - [(3R *, 6R *) - 6-benzylhydroxyphosphinoylmethyl) morpholin-3-yl] benzoic acid, diethoxymethyl - {(2R *, 5R *) - 5 - [(3-methoxycarbonyl) phenyl] morpholin-2-ylmethyl } phosphinic acid, cyclohexylmethyl - [(2R *, 5R *) -5-phenylmorpholin-2-ylmethyl] phosphinic acid, diethoxymethyl - [(2R *, 5R *) -5- (3-nitrophenyl) morpholin-2-yl- methyl] phosphinic acid, butyl - [(2R *, 5R *) -5- (3-iodophenyl) morpholin-2-ylmethyl] phosphinic acid, [(2R *, 5R *) -5- (3-cyanophenyl) morpholine- 2-ylmethyl] phenylmethylphosphinic acid,

5-Acetylaminopentyl - [(2R *, 5R *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] phosphinic acid, cyclohexylmethyl - [(2R *, 5R *) - 5- (3,4-dichlorophenyl) (Morpholin-2-ylmethyl) phosphinic acid, butyl - [(2R *, 5R *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] phosphinic acid, benzyl - [(2R *, 5R *) - 5- (3,4-Dichlorophenyl) morpholin-2-ylmethyl] phosphinic acid, [(2R *, 5R *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] pyridin-2-ylmethylphosphinic acid, [ (2R *, 5R *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] diethoxymethylphosphinic acid, [(2R *, 5R *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] -4-methoxyphenylmethylphosphinic acid,

Ar [(2R, 5R) -5-Benzylmorpholin-2-ylmethyl] -4-methoxyphenylmethylphosphinic acid,

4 - {(3R *, 6R *) - 6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

4 - {(3R *, 6R *) - 6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

4 - [(3R *, 6R *) -6- (benzylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid,

4 - [(3R *, 6R *) - 6- (butylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid,

4 - {(3R *, 6R *) - 6 - [(diethoxymethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid, cyclohexylmethyl- [(2R *, 5R *) - 5- (4-iodobenzyl) morpholin-2- ylmethyl] phosphinic acid, [(2R *, 5R *) -5- (4-iodobenzyl) morpholin-2-ylmethyl] -4-methoxyphenylmethylphosphinic acid, cyclohexylmethyl - {(2R *, 5R *) - 5 - [(4- ethoxycarbonyl) phenylmethyl] morpholin-2-ylmethyl} phosphinic acid,

4 - [(3R *, 6R *) - 6- (butylhydroxyphosphinoylmethyl) -N-methylmorpholin-3-ylmethyl] benzoic acid,

4 - {(3R *, 6R *) - 6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] -N-benzyloxycarbonylmorpholin-3-ylmethyl} benzoic acid 3 - ((3R *, 6R *) - 6 - [(5-acetylaminopentyl) hydroxyphosphinoylmethyl] -3-Methylmorpholin-3-yl} benzoic acid

3 - {(3R *, 6R *) - 6 - [(diethoxymethyl) hydroxyphosphinoylmethyl] -3-methylmorpholin-3-yl} benzoic acid,

3 - [(3R *, 6R *) - 6- (butylhydroxyphosphinoylmethyl) -3-methylmorpholin-3-yl] benzoic acid;

3 - [(3R, 6R) -6- (Benzylhydroxyphosphinoylmethyl) -3-methylmorpholin-3-yl] benzoic acid,

3 - {(3R *, 6R *) - 6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] -3-methylmorpholin-3-yl] benzoic acid,

3 - {(3R *, 6R *) - 6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] -3-methylmorpholin-3-yl} benzoic acid,

5-Acetylaminopentyl-t (2R *, 5R *) -5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid, cyclohexylmethyl- [(2R *, 5R *) - 5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid, butyl - [(2R *, 5R *) - 5- (6-oxo-1,6-dihydropyridine- 3-yl) morfolin20

2-ylmethyl] phosphinic acid, benzyl - [(2R *, 5R *) -5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid;

4-methoxyphenylmethyl - [(2R, 5R) -5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid,

Kτ k Diethoxymethyl - [(2R, 5R) -5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid, cyclohexylmethyl- [(2R *, 5R *) - 5- (2-oxo-1,2-dihydropyridin-4-yl) morpholin-2-ylmethyl] phosphinic acid,

5-Acetylaminopentyl- [(2R *, 5R *) -5- (2-oxo-1,2-dihydropyridin-4-yl) morpholin-2-ylmethyl] phosphinic acid, butyl - [(2R *, 5R *) - 5- (2-oxo-1,2-dihydropyridin-4-yl) morpholin-2-ylmethyl] phosphinic acid, diethoxymethyl- [(2R *, 5R *) -5- (2-oxo-1,2-dihydropyridine- 4-yl) morpholin-2-ylmethyl] phosphinic acid, benzyl - [(2R *, 5R *) -5- (2-oxo-1,2-dihydropyridin-4-yl) morpholin-2-ylmethyl] phosphinic acid,

4-methoxyphenylmethyl - [(2R *, 5R *) -5- (2-oxo-1,2-dihydropyridin-4-yl) morpholin-2-ylmethyl] phosphinic acid,

2 - {(3R *, 6R *) - 6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

2 - {(3R *, 6R *) -6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

2 - {(3R *, 6R *) - 6 - [(diethoxymethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

2 - {(3R, 6R) -6 - [(5-acetylaminopentyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

2 - [(3R *, 6R *) - 6- (butylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid,

2 - [(3R *, 6R *) -6- (benzylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid,

3 - {(3R *, 6R *) -6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

- {(3R *, 6R *) - 6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

3 - {(3R *, 6R *) -6 - [(diethoxymethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

3 - {(3R *, 6R *) -6 - [(5-acetylaminopentyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

3 - [(3R, 6R) -6- (butylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid,

- [(3R *, 6R *) - 6- (benzylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid, benzyl - {(2R *, 5R *) - 5- [4 - ([1,3,4] oxadiazole- 2-yl) phenyl] morpholin-2-ylmethyl} phosphinic acid, butyl - {(2R *, 5R *) -5- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) phenyl] morpholin-2-ylmethyl} phosphinic acid,

1- (4 - {(3R *, 6R *) - 5 - [(4-methoxybenzyl) hydroxyphosphinoylmethyl] morpholin-3-yl} phenyl) -1H- [1,2,4] triazole-3-carboxylic acid, { (2R *, 5R *) -5- [4- (3-amino- [1,2,4] oxadiazol-5-yl) phenyl] morpholin-2-ylmethyl} cyclohexylmethylphosphinic acid, {(2R *, 5R *) -5- [3- (3-amino- [1,2,4] oxadiazol-5-yl) phenyl] morpholin-2-ylmethyl} cyclohexylmethylphosphinic acid, diethoxymethyl - {(2R *, 5R *) - 5- [3 - (1H-tetrazol-5-yl) phenyl] morpholin-2-ylmethyl} phosphinic acid,

3 - {(3R *, 6S *) - 6 - [(5-acetylaminopentyl) hydroxyphosphinoylmethyl] morpholin-3-yl} benzoic acid,

3 - {(3R *, 6S *) - 6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] morpholin-3-yl} benzoic acid,

3 - {(3R *, 6S *) -6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] morpholin-3-yl} benzoic acid,

3 - [(3R *, 6S *) - 6- (butylhydroxyphosphinoylmethyl) morpholin-3-yl] benzoic acid,

3 - {(3R *, 6S *) - 6 - [(diethoxymethyl) hydroxyphosphinoylmethyl] morpholin-3-yl} benzoic acid,

- [(3R *, 6S *) - 6- (benzylhydroxyphosphinoylmethyl) morpholin-3-yl] benzoic acid, diethoxymethyl -} (2R *, 5S *) - 5 - [(3-methoxycarbonyl) phenyl] morpholin-2-ylmethyl Phosphinic acid, cyclohexylmethyl - [(2R, 5S) -5-phenylmorpholin-2-ylmethyl] 22 phosphinic acid, diethoxymethyl - [(2R *, 5S *) -5- (3-nitrophenyl) morpholin-2-ylmethyl] phosphinic acid Acid, butyl - [(2R *, 5S *) -5- (3-iodophenyl) morpholin-2-ylmethyl] phosphinic acid, [(2R *, 5S *) -5- (3-cyanophenyl) morpholin-2-ylmethyl] ] -phenylmethylphosphinic acid,

5-Acetylaminopentyl- [(2R *, 5S *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] phosphinic acid, cyclohexylmethyl- [(2R *, 5S *) -5- (3,4-dichlorophenyl) (Morpholin-2-ylmethyl) phosphinic acid, butyl - [(2R *, 5S *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] phosphinic acid, benzyl [(2R *, 5S *) - 5- (3,4-Dichlorophenyl) morpholin-2-ylmethyl] phosphinic acid, [(2R *, 5S *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] pyridin-2-ylmethylphosphinic acid, [ (2R *, 5S *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] diethoxymethylphosphinic acid, [(2R *, 5S *) -5- (3,4-dichlorophenyl) morpholin-2-ylmethyl] 4-Methoxyphenylmethylphosphinic acid, N - [(2R, 5S) -5-benzylmorpholin-2-ylmethyl] -4-methoxyphenylmethylphosphinic acid,

4 - {(3R *, 6S *) - 6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

4 - {(3R *, 6S *) - 6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl] benzoic acid,

4 - [(3R *, 6S *) - 6- (benzylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid, * *

4 - [(3R, 6S) -6- (butylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid, k

4 - {(3R, 6S) -6 - [(diethoxymethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid, cyclohexylmethyl - [(2R *, 5S *) -5- (4-iodobenzyl) morpholin-2-ylmethyl] phosphinic acid, [(2R *, 5S *) -5- (4-iodobenzyl) morpholin-2-ylmethyl] -4-methoxyphenylmethylphosphinic acid, cyclohexylmethyl - {(2R, 5S) -5 - [(4-ethoxycarbonyl) phenylmethyl] 23 morpholin-2-ylmethyl} phosphinic acid,

4 - [(3R *, 6S *) - 6- (butylhydroxyphosphinoylmethyl) -N-methylmorpholine-3

-ylmethyl] benzoic acid,

4 - {(3R, 6S) -6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] -N-benzyloxycarbonylmorpholin-3-ylmethyl} benzoic acid 3 - {(3R *, 6S *) - 6 - [(5-acetylaminopentyl) hydroxyphosphinoylmethyl] - 3-methylmorpholin-3-yl} benzoic acid,

- {(3R *, 6S *) - 6 - [(diethoxymethyl) hydroxyphosphinoylmethyl] -3-methylmorpholin-3-yl} benzoic acid,

3 - [(3R *, 6S *) - 6- (butylhydroxyphosphinoylmethyl) -3-methylmorpholine-3

-yl] benzoic acid,

3 - [(3R *, 6S *) -6- (benzylhydroxyphosphinoylmethyl) -3-methylmorpholin-3-yl] benzoic acid,

3 - {(3R *, 6S *) - 6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] -3-methylmorpholin-3-yl} benzoic acid,

- {(3R *, 6S *) - 6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] -3-methylmorpholin-3-yl} benzoic acid,

5-Acetylaminopentyl - [(2R *, 5S *) - 5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid, cyclohexylmethyl - [(2R *, 5S *) - 5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid, butyl - [(2R *, 5S *) - 5- (6-oxo-1,6-dihydropyridine- 3-yl) morpholin-2-ylmethyl] phosphinic acid, benzyl - [(2R *, 5S *) -5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid,

4-Methoxyphenylmethyl - [(2R, 5S) -5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid, k] diethoxymethyl- [(2R, 5S) -5- (6-oxo-1,6-dihydropyridin-3-yl) morpholin-2-ylmethyl] phosphinic acid, cyclohexylmethyl - [(2R *, 5S *) -5- (2-oxo-1,2-dihydropyridine-4- yl) morpholin-2-ylmethyl] phosphinic acid,

5-Acetylaminopentyl - [(2R *, 5S *) -5- (2-oxo-1,2-dihydropyridin-4-yl) morpholin-2-ylmethyl] phosphinic acid, butyl - [(2R *, 5S *) - 5- (2-oxo-1,2-dihydropyridin-4-yl) morpholin-2-ylmethyl] phosphinic acid, diethoxymethyl - [(2R *, 5S *) -5- (2-oxo-1,2-dihydropyridine- 4-yl) 24-morpholin-2-ylmethyl] phosphinic acid, benzyl - [(2R *, 5S *) -5- (2-oxo-1,2-dihydropyridin-4-yl) morpholine

-2-ylmethyl] phosphinic acid,

4-Methoxyphenylmethyl - [(2R, 5S) -5- (2-oxo-1,2-dihydropyridin-4-yl) morpholin-2-ylmethyl] phosphinic acid,

2 - {(3R *, 6S *) -6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

2 - {(3R *, 6S *) - 6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

2 - {(3R *, 6S *) - 6 - [(diethoxymethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

2 - {(3R *, 6S *) - 6 - [(5-acetylaminopentyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

2 - [(3R *, 6S *) - 6- (butylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid,

2 - [(3R *, 6S *) -6- (benzylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid,

3 - {(3R *, 6S *) - 6 - [(cyclohexylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

3 - {(3R *, 6S *) - 6 - [(4-methoxyphenylmethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

3 - {(3R *, es *) -6- (diethoxymethyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

3 - {(3R *, 6S *) - 6 - [(5-acetylaminopentyl) hydroxyphosphinoylmethyl] morpholin-3-ylmethyl} benzoic acid,

3 - [(3R *, 6S *) - 6- (butylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid,

3 - [(3R *, 6S *) - 6- (benzylhydroxyphosphinoylmethyl) morpholin-3-ylmethyl] benzoic acid, benzyl - {(2R *, 5S *) - 5- [4 - ([1,3,4] oxadiazole) -2-yl) phenyl] morpholin-2-ylmethyl} phosphinic acid, butyl - {(2R *, 5S *) - 5- [4- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl)] phenyl] morpholin-2-ylmethyl ·} phosphinic acid,

1- (4 - {(3R *, 6S *) - 5 - [(4-methoxybenzyl) hydroxyphosphinoylmethyl] morpholin-3-yl} phenyl) -1H- [1,2,4] triazole-3-carboxylic acid, { (2R *, 5S *) -5- [4- (3-amino- [1,2,4] oxadiazol-5-yl) phenyl] morpholin-2-ylmethyl} cyclohexylmethylphosphinic acid, {(2R *, 5S *) -5- [3- (3-amino- [1,2,4] oxadiazol-5-yl) phenyl] morpholin-2-ylmethyl} cyclohexylmethylphosphinic acid, and diethoxymethyl - {(2R *, 5S *) - 5- [ 3- (1H-Tetrazol-5-yl) phenyl] morpholin-2-ylmethyl} phosphinic acid.

It has been found that the compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. They effectively bind to the GABAg receptor and have been found to be GABA (β-aminobutyric acid) antagonists at that receptor. With respect to this mechanism, antagonism at GABAg receptors may increase the release of fast stimulating amino acid transmitters, i.e. glutamate and aspartate, thereby improving the processing of information in the brain. This is consistent with the finding that the later post-synaptic inhibitory potential in the hippocampus attributed to the GABAg mechanism is disrupted by these antagonists, thereby allowing a faster sequence of nerve impulse transmission.

Chronic antidepressant treatment and repeated electrical shocks have also been found to increase the number of GABAg receptors in rat cerebral cortex. According to receptor theories, chronic treatment with GABAg antagonists should have the same effect. For this and other reasons, GABAg antagonists may accordingly act as antidepressants.

The GABAg antagonists of the invention interact on rat cerebral cortex membranes at the GABAg receptor with IC 50 values of ΙΟ do ⁷ to 10 ” ¹⁰ M (mol / liter). In contrast to GABAg antagonists, such as baclofen, they do not increase noradrenaline stimulation of adenylate cyclase on parts of the cerebral cortex but act as antagonists of baclofen action. Antagonists not only show antagonism to baclofen, but also exhibit independent action as endogenous GABA antagonists.

Because of their excellent GABAg antagonistic properties, the compounds of the invention are suitable for use in the treatment or prevention of conditions characterized by stimulation of GABAg receptors. Thus, they are suitable for use as nootropics, antidepressants and anxiolytics, for example for the treatment of central nervous system disorders such as anxiety, depression, cerebral insufficiency, epilepsy of the type small epileptic seizure (petit mal), i. j. absence of epilepsy in children and adolescents, atypical absences (sudden loss of consciousness or memory), such as Lennox-Gastant syndrome, for the treatment of conditions requiring increased cognitive activity and as an antidote against baclofen.

Compounds of formula I wherein R 1 is hydrogen may be prepared by reaction of a compound of formula II

OH

wherein R ⁴ is R ¹ as defined above, except that R ⁴ cannot be substituted with a carboxyl group, and R ^x is as defined above except that it cannot be substituted with a carboxyl group with a compound of formula III

OR ⁵ (III) wherein R 6 is as defined above, X represents a halogen atom, for example chlorine or bromine, and R ⁵ represents an alkyl group having 1 to 8 carbon atoms, for example n-hexyl or n-octyl, preferably alkyl C 1 -C 4, such as methyl, ethyl, isopropyl or isobutyl, especially ethyl in the presence of a base, to form a compound of formula IV

(IV) wherein R ⁴ and R ^{x have the} meanings defined for formula II, which reaction is followed, if necessary, by one or more substitution reactions altering the nature of the substituent in R ⁴ and / or R ^x and / or hydrolysis of the ester substituent in R ⁴ and / or R ^x to a carboxyl group, and / or the conversion of an ester group -OR 1 to a hydroxy group.

Depending on the choice of the base and the reaction conditions, the reaction of the compounds of formulas II and III in which the amino group is monoalkylated with subsequent cyclization can be carried out in one step. Preferably, in order to avoid complications due to dialkylation of the amino group, the reaction is carried out in two steps. In a first step, a weak base such as a hindered amine such as 1,8-diazabicyclo [5.4] is slowly added to a mixture of compounds of formulas II and III in a solvent, preferably a hydrocarbon such as benzene, toluene or xylene at 70-110 ° C. , 0] undec-7-ene (DBU), to give a novel intermediate of formula V

wherein R ² , R ⁴ , R ⁵ and R ^{x are} as defined above. This intermediate is then reacted with a base under harder conditions than those used in its formation, for example with a similar base at a higher temperature or preferably with a stronger base such as an alkali metal hydride at a temperature of from 10 to 50 ° C. The reaction of the intermediate with a base can be carried out in a solvent, preferably a hydrocarbon such as toluene, benzene or xylene.

The intermediate compounds of formula (V) may themselves be used as medicaments, for example for the treatment or prevention of a condition characterized by stimulation of the GABAg receptor, in particular in deesterified form, i.e. in the form in which the alkyl group R alkyl has been replaced by hydrogen and any esterified carboxylic acid present. the group in R ⁴ and / or R ^x has been converted to a carboxyl group. Accordingly, the invention includes novel compounds of formula VA

(VA)

OH wherein R ¹ , R ² and R ^{x are} as defined above, or salts or esters thereof.

The compounds of formula I or IV where ^Rx and / or R ¹ respectively R ⁴ has a substituent on an aryl or heteroaryl ring a cyano group, can be prepared by reacting an alkali metal cyanide with a compound of formula I or IV where ^Rx and / or R ¹ and R ^4, respectively, contain a halogen atom as a substituent on the aryl or heteroaryl ring, this compound may be prepared by diazotization and subsequent reaction with an alkali metal halide, from a compound of formula I or IV wherein R and / or R ¹ and R ⁴ respectively comprising the aryl or heteroaryl ring amino group, which compound may be prepared by reduction of a compound of formula I or IV in which ^Rx and / or R ¹ respectively R ⁴ has the aryl or heteroaryl ring nitro. All of these reactions can be carried out by known methods.

The compounds of formula I or IV in which ^Rx and / or R ¹ respectively R ⁴ substituent contains an esterified carboxy group, can also be prepared from other compounds of formula I, or IV..Možno thereof as prepared by the reaction of compounds of formula I or IV, wherein R ^x and / or R ¹ respectively R ⁴ has a substituent on an aryl or heteroaryl ring a halogen atom, with carbon monoxide and an alcohol in the presence of a palladium complex as catalyst, using known procedures.

The compounds of formula I, wherein R ^x and / or R ¹ contains as a substituent a carboxyl group, may be prepared by hydrolysis of a compound of formula I or IV in which ^Rx and / or R ¹ respectively R ⁴ has a substituent esterified carboxyl group, using conventional hydrolysis procedures.

If, in the compound of formula (IV) or (V), the radical R ⁴ contains an esterified carboxyl group, this group can be hydrolyzed to the free carboxyl group by conventional methods. If R ⁴ in the compound of formula IV contains a nitro group on the aryl or heteroaryl ring, this group can be successively converted by reduction to an amino group, diazotizing the amino group followed by reaction with an alkali metal halide to halogen, reacting halogen with alkali metal cyanide to cyano and cyano to hydrolysis to cyano carboxylic acid, wherein these reactions are conveniently carried out by known methods.

Conversion of the -OR4 ester moiety in a compound of formula IV or V to a hydroxy group may be accomplished by reaction with a suitable basic or acidic reagent such as an alkali metal hydroxide, for example sodium or lithium hydroxide, an alkali metal halide, especially an alkali metal bromide or iodide. such as lithium bromide or sodium iodide, thiourea, an alkali metal thiophenoxide such as sodium thiophenoxide, or a protonic acid or Lewis acid such as a mineral acid such as hydrochloric acid or a tri (lower) alkyl halosilane such as trimethylchlorosilane. This substitution reaction may be carried out either in the absence or presence of a solvent and, if necessary, by heating or cooling in a closed vessel and / or under an inert gas atmosphere.

The conversion of the group -OR 1 in a compound of formula IV or V into a hydroxy group can also be carried out by reaction with an acid under hydrolytic conditions, in particular a mineral acid such as a hydrohalic acid, for example hydrochloric acid, used in diluted or concentrated aqueous form, or with an organic silyl halide such as trimethylsilyl iodide or bromide and, if necessary, subsequent hydrolysis. This reaction is preferably carried out at elevated temperature, for example maintaining the temperature of the reaction mixture at reflux and, if appropriate, using an organic diluent in a closed vessel and / or an inert gas atmosphere.

Compounds of formula II are in some cases commercially available, for example, (R) - and (S) -phenylglycinols. Compounds of formula II may be prepared by reduction of an aminocarboxylic acid of formula R ⁴ C (R ^X ) (N 1 R ⁴ COOH, where R ⁴ and R ^{x are} as defined above for formula II) by reaction with borane-dimethylsulfide in the presence of boron trifluoride complex; such as boron trifluoride diethyl ether

In this way, the novel compounds of formula (II) in which (i) R ⁴ is iodobenzyl, especially 4-iodobenzyl, and R ^x is hydrogen, and (ii) R ⁴ is phenyl and R ^x may be prepared using known methods means an isopropyl group.

The compounds of formula II in which the radical R ⁴ substituted with nitro, can be prepared from amino carboxylic acid of formula R ⁴ C (R ^X) (NH 2) COOH, wherein R ⁴ otherwise unsubstituted by nitration to introduce a nitro group into ^R4, converting the amino group in the protected amino group product, for example by reaction with di-tert-butyl dicarbonate to form a tert-butylcarbamate group, esterifying the carboxyl group in the protected product with, for example, methyl ester, then reducing the ester group to -CH2OH by reaction with a suitable reducing agent such as alkali metal borohydride and finally removing the amino protecting group by reaction with an acid to regenerate the free amino group. These reactions can be carried out using known procedures or minor modifications thereof. A known compound of formula (II) in which R ⁴ is a nitrophenyl group can be prepared by this reaction procedure.

Compounds of formula II may also be prepared by Strecker synthesis, wherein an aldehyde or ketone of formula R ⁴ C (= O) R ^X , wherein R ⁴ and R ^{x are} as defined above, is reacted with a compound of formula R ⁶ NH ₂ wherein R ⁶ represents a hydrogen atom or a C 1 -C 8 alkyl group optionally substituted by a C 1 -C 10 aryl group which is unsubstituted or substituted, for example, a C 1 -C 4 hydroxy or alkoxy group and an alkali metal cyanide, to form a compound of formula VI

CN

R ⁴ -C-NHR ⁶ (VI) wherein R ⁴ , R ⁶ and R ^{x are} as defined above, a compound of formula VI is reacted with an alcohol of formula R OH, wherein R is an alkyl group of 1 to 10 carbon atoms, for example n-hexyl, 2-ethylhexyl, n-octyl or decyl, preferably alkyl of 1 to 4 carbon atoms such as methyl, ethyl, isopropyl or n-butyl, especially methyl or ethyl, in the presence of an acid to form a compound of formula VII

COOR ⁷

R ⁴ - _C ⁶ NHR

R ^x (VII) wherein R ⁴ , R ⁶ , R ⁷ and R ^{x are} as defined above, the R ⁶ group is removed from the compound of formula VII when it is other than hydrogen, for example using known procedures, to form a compound of formula VIII

COOR ⁷

R ⁴ C NH ₂ (VIII)

R ^x in which R, R and R are as defined above, for example, by, in the case where R is optionally substituted benzyl, catalytically hydrogenating an organic acid such as acetic acid, the compound of formula VIII as its salts with an organic acid, a compound of formula VIII is reacted with an amino protecting agent, such as tert-butyl dicarbonate, to convert the amino group to the protected amino group, an ester moiety

The -COOR in the protected compound is reduced to the -CH ₂ OH group by reaction with a suitable reducing agent, such as an alkali metal borohydride, and finally the protecting group is removed to form the free amino group. This sequence of reactions may be carried out using known procedures, or by minor modifications thereof. If the radical R ^{4 is} substituted with an esterified carboxyl group, the protected amino group formed should be a tert-butylcarbamate group that allows the reduction of the ester moiety in -COOR to -CH ₂ OH by maintaining the ester moiety in R ⁴ and then can be removed by reaction , for example in a non-aqueous medium in which the ester moiety in R ⁴ is retained.

In a modified Strecker synthesis as described above, a compound of formula VI can be subjected to acid hydrolysis, for example using conventional procedures, to convert said cyano group to a carboxyl group, and then the resulting aminocarboxylic acid can be reduced to a compound of formula II by reaction with borane-dimethylsulfide. in the presence of a boron trifluoride complex such as boron trifluoride diethyl ether, for example using known procedures.

Compounds of formula II, VI, VII or VIII in which R ⁴ represents a 3-methoxycarbonylphenyl group which can be prepared from an aldehyde or ketone of formula R ⁴ C (= O) R ^{X by the} sequence of reactions described above are new as such . Compounds of formula II or VIII wherein R ⁴ is 3,4-dichlorophenyl and R ⁷ is C 1 -C 10 alkyl are also novel.

Compounds of formula II in which R ⁴ represents a monovalent aromatic group as defined above and R ^x represents an unsubstituted or substituted hydrocarbon group are new, with the exception of compounds of formula II wherein R ⁴ represents a phenyl group and R ^x represents a methyl, chloromethyl, ethyl, - (C ^^ SCHj, an allyl group or a hydroxymethyl group, compounds of formula II wherein ^Rx is aminomethyl and ^R4 is phenyl, p-hydroxyphenyl or p-methoxyphenyl, compounds of formula II wherein R ^x is hydroxymethyl and R ⁴ is 4-decylphenyl or 5 - [(7-chloro-4-quinolyl) amino] -2-hydroxyphenyl; compounds of formula II wherein R ⁴ is 4-methoxyphenyl and R ^x denote ethyl and compounds of formula II wherein R ⁴ is 2,4-dichloro and R ^x is N-triazolylmethyl.

Compounds of formula II in which R ⁴ represents a monovalent araliphatic group as defined above and R ^x denotes an unsubstituted or substituted hydrocarbon group as defined above are new, with the exception of compounds of formula II in which R ^x represents methyl and R ⁴ is benzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 2-phenylethyl, 1,3-benzodioxole-5-methyl, 3-phenyl-1-aminopropyl, α-hydroxybenzyl, α a -hydroxy-α-methylbenzyl or α-hydroxy-α-methyl-4-nitrobenzyl group, and with the exception of compounds of formula II, wherein R ⁴ represents a benzyl group and R ^x represents an allyl group or a -C 1 - C 4 SCH 4 group.

The compounds of formula (II) in which R ⁴ represents an iodobenzyl group, in particular a 4-iodobenzyl group, and R ^x represents a hydrogen atom or an unsubstituted or substituted hydrocarbon group as defined above are also novel.

Compounds of formula III which are, with the exception of

S compounds in which R represents a methyl group and R is known as an ethyl group, new, especially those in which R represents a cycloalkylalkyl group such as a cyclohexylmethyl group, may be prepared by reaction of a compound of the general formula

IX

IX (IX)

R ²

OR ^J with a compound of formula X x-ch = ch-ch ₂ -x (X)

JC _x where the symbols R, R and X are as defined above, in the presence of a silylating agent such as bis (trialkylsilyl) derivát.amidu, the reagent is reacted with a compound of formula IX to form a silyl derivative of trivalent phosphorus, then is reacted with a compound of The reaction may be carried out at a temperature of from 0 to 50 ° C. Preferably, the reaction is carried out in a solvent such as a hydrocarbon such as toluene or a halogenated hydrocarbon such as dichloromethane.

Esters of formula IX can be prepared by reacting a protected phosphinic acid ester of formula XI wherein R ^{5 is} as defined above and Q is a PH functional group with a compound of formula XII

R ² Z (XII) in which R is as defined above and Z is a leaving group to form a compound of formula XIII

OR ⁵ and then replacing the protecting group Q in the compound of formula XIII with hydrogen.

The leaving group Z may be, for example, a halogen atom or an organic sulfonate moiety. Preferably Z represents a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate moiety. The reaction between the compounds of formulas XI and XII and the deprotection reaction of the compound of formula XIII can be carried out by known methods, for example as described in EP 0569333.

Protected phosphinic acid esters of formula XI can be prepared by known methods, for example as described in US 4 933 478. Compounds of formula XII are either commercially available or can be prepared by known methods.

Compounds of formula (X) are dihaloalkenes which are either commercially available or can be prepared by known methods.

The compounds of formula I where RY is may be prepared by reacting a compound of formula I where RY is hydrogen with a compound R ^ _and Z, wherein the symbols R _a and Z are as defined above, or by reductive alkylation using an aldehyde of of formula R RCHO where R kde is hydrogen or R ^ _a as defined above and a reducing agent that reduces imines and amines, for example sodium cyanoborohydride. Such reactions can be performed using conventional procedures.

Compounds of formula I in which NH is a protecting group may be prepared by reacting a compound of formula I in which R ^ represents a hydrogen atom with a reagent known to introduce the desired protecting group. For example, when the protecting group is an acyl group, a compound of formula I wherein R 1 is hydrogen can be reacted with an acyl halide or carboxylic acid anhydride such as acetyl chloride, acetic anhydride or benzoyl chloride, for example using known procedures. When the protecting group is an alkoxycarbonyl or aralkoxycarbonyl group, a compound of formula I in which R @ 1 is hydrogen may be reacted with an alkoxycarbonyl or aralkoxycarbonyl halide or an alkyl or aralkyldicarbonate such as benzyl chloroformate or di-tert-butyl carbonate, for example .

In general, compounds of formula I in which RT is R ^ _and NH or a protecting group NH may also be prepared as described above for the preparation of compounds of formula I in which R ^ represents a hydrogen atom in which the compound of formula II is replaced by a compound of formula IIA

OH

CH ₂ (HA) NHR ^y wherein R ⁴ and R ^{x have the} meanings defined above for formula (II) and R 'is R 1 _{and /} or a NH-protecting group, wherein the reaction of a compound of formula IIA with a compound of formula III Compounds of formula IVA are obtained directly from base treatment

0R ^J (IVA) wherein the symbols R ⁴ and R ^x are as defined in formula II, R ² and R ⁵ are as defined above and R is a group R _a as defined above, or a protecting group NH . This reaction can be carried out in a solvent, usually a hydrocarbon such as benzene, toluene or xylene, and is generally carried out under harder conditions than those used for the reaction of compounds of formulas II and III, for example using sodium hydride as the base and at 10 ° C. ° C to 70 ° C. This reaction may, if desired, be followed by one or more substitution reactions to change the nature of the substituent in R ⁴ and / or R ^x and / or hydrolysis of the ester moiety as a substituent in R ⁴ and / or R ^x to a carboxyl group and / OR4 to hydroxy.

Compounds of formula I may be prepared by reacting a compound of formula XIV

(XIV) to convert the present primary hydroxy group into a leaving group Z as defined above, thereby causing cyclization to give a compound of formula XV (XV)

wherein R ^, R ⁴ , R ^x and R R are as defined above and, if necessary, followed by the replacement of R ^y as an NH-protecting group by hydrogen and / or one or more substitution reactions to change the substituent nature of R ⁴ and / or R ^x and / or by hydrolyzing the ester moiety as a substituent in R ⁴ and / or R ^x to a carboxyl group and / or converting the ester moiety -OR ⁵ to a hydroxy group.

Conversion of the primary hydroxy group of the compound of formula (XIV) into the Z group can be accomplished by known methods. For example, when Z is an iodine atom, this conversion can be accomplished by reacting a compound of formula XIV with triphenylphosphine, imidazole and iodine in a solvent such as acetonitrile or tetrahydrofuran at 0 ° C to 50 ° C, and when Z is trifluoromethanesulfonate grouping, this conversion can be accomplished by reacting a compound of formula XIV with trifluoromethanesulfonic anhydride in pyridine at a temperature of -100 to 50 θθ.

Replacement of the group R.Y as an NH-protecting group with hydrogen can be accomplished using known procedures to remove the NH-protecting group. For example, when R1 is an acyl group such as acetyl or benzoyl, the replacement with hydrogen can be accomplished by reaction with aqueous hydrochloric acid, while when it is a trifluoroacetyl group, the replacement with hydrogen can be accomplished by reaction with aqueous potassium carbonate.

Further optional subsequent reactions of compounds of formula XV may be carried out as described above for the corresponding reactions of compounds of formula IV.

Compounds of formula XIV that are novel in themselves may be prepared by reacting a compound of formula II with a compound of formula XVI

(XVI) wherein R ² , R ⁵ and Z are as defined above, in the presence of a hindered base, to form a compound of formula XVII

(XVII) wherein R ² , R ⁴ , R ⁵ and R ^{x have} the same meanings as defined above, and by replacing the depicted hydrogen bonded to the nitrogen atom with an RY NH-protecting group as defined above, for example using known procedures such as those described higher. The reaction between the compounds of formula II and XVI may be carried out, for example, at a temperature of 20 to 100 ° C, preferably in an organic solvent such as an alcohol, in particular ethanol. The hindered base may be, for example, a diazabicyclo compound such as 1,5-diazabicyclo [4.3.0] non-5-ene or 1,8-diazabicyclo [5,4,0] undec-7-ene or preferably a tertiary amine such as is dicyclohexyl (ethyl) amine or especially diisopropylethylamine.

Compounds of formula XVI may be prepared using the procedures described in J. Med. Chem., 1995, 38, 3313.

The compounds of formula (XIV) or (XVII) may themselves be used as medicaments, for example, for the treatment or prevention of conditions characterized by stimulation of the GABAg receptor, especially in deesterified form, i.e. in the form of R ^{5 has been} replaced with hydrogen and any esterified carboxyl group in R ⁴ and / or R ^x has been converted to a carboxyl group using, for example, known methods. Accordingly, the invention includes novel compounds of formula XVIII

wherein R ¹ , R ² , R ^x and R 6 are as defined above, or salts or esters thereof.

As such, the compounds of the invention obtained in the form of salts can be converted into the free compounds in known manner, for example by reaction with a base such as an alkali metal hydroxide, metal carbonate or metal bicarbonate or ammonia, or any of the above salt-forming bases, or with an acid. , such as a mineral acid, for example hydrochloric acid or any of the aforementioned salt-forming acids.

The salts of the invention may as such be converted into other salts of the invention in a known manner, for example, acid addition salts may be converted by reaction with a suitable salt of another acid with a metal such as sodium, barium or silver in a suitable solvent in which the inorganic salt is present. which forms, insoluble, and is thus eliminated from the reaction equilibrium, and salts with bases can be converted into other salts by liberating the free acid and converting it again into a salt.

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

Due to the close similarity between the new compounds in free form and in the form of their salts with the higher and lower free compounds and their salts, the corresponding salts or free compounds, respectively, also optionally mean where appropriate and where the context permits.

In the case of compounds of formula I and intermediates V used in their preparation, diastereomeric mixtures and mixtures of racemates can be separated into pure diastereoisomers, respectively, in racemates in a manner known per se on the basis of physical chemical differences between the components, for example chromatographic processes and / or fractional crystallization.

The resulting racemates can also be resolved into the optical antipodes by known methods, for example, by recrystallization from an optically active solvent, by microorganisms, or by reaction of the resulting diastereomeric mixture or racemate with an optically active excipient, for example, depending on what acidic, basic or functionally modifiable the groups are present in the compounds of formula I, by reaction with an optically active acid, base or optically active alcohol, to form mixtures of diastereomeric salts or functional derivatives such as esters, and separating them into diastereoisomers from which the desired enantiomer can be liberated in conventional manner. Bases, acids and alcohols suitable for this purpose are, for example, optically active alkaloid bases _and bases such as strychnine, cinchonine or brucine, or D- or

L- (1-phenyl) ethylamine, 3-pipecoline, ephedrine, amphetamine and similar synthetically derived bases, optically active carboxylic or sulphonic acids such as quinic acid or D- or L-tartaric acid, D- or L-di-o toluoyltartaric acid, or L-malic acid, D- or L-mandelic acid or D- or L-camphorsulfonic acid, and optically active alcohols such as borneol or D- or L- (1-phenyl) ethanol.

Compounds of formula I, VA, or XVIII may be loaded with isotopes, particularly ¹¹ C, ¹⁴ C, ² H, ³ H or ¹²⁵ I, for use in diagnostic purposes.

The compounds of formula (I), (VA) or (XVIII) may, for example, be used in the form of pharmaceutical compositions containing therapeutically effective amounts of the active ingredient, if desired together with pharmaceutically acceptable carriers suitable for enteral, e.g. oral or parenteral administration. be solid or liquid and organic or inorganic. For example, tablets or gelatin capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or lubricants, for example silica gel, talc, stearic acid or its salts, such as magnesium or calcium stearate, and / or polyethylene glycol. The tablets may also contain binders, for example magnesium aluminum silicate, starches such as corn, wheat, rice or marzipan starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, for example starches, agar or its alginic acid. , for example, sodium alginate and / or effervescent mixtures, or absorbers, colorants, flavorings and sweeteners. The compounds of formula I may also be used in the form of compositions which can be administered parenterally or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions which, for example in the case of lyophilized formulations containing the active ingredient, alone or with a carrier, for example mannitol, may be prepared before use. The pharmaceutical compositions may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. These pharmaceutical compositions, which may contain, if desired, other pharmacologically active substances, may be prepared per se in a manner known per se, for example by conventional mixing, granulating, compression, dissolving or lyophilizing processes, and may contain from about 0.1% to 100%. in particular from about 1% to about 44%, and in the case of lyophilizers up to about 100%, the active ingredient.

The invention also relates to the use of the compounds of formula I, VA or XVIII, or salts or esters thereof, preferably in the form of pharmaceutical compositions.

The dose may depend on many factors such as the route of administration, the species, age and / or individual condition. Dosages administered daily for oral administration of from about 1 to about 50 mg / kg, in particular from 5 to about 25 mg / kg, in the case of warm-blooded animals with a body weight of about 70 kg may preferably be from about 70 mg to about 3500 mg, especially from about 350 mg to about 1750 mg, and conveniently subdivided into 2 to 6, for example 3 or 4, single doses.

Accordingly, the invention includes a method of treating or preventing a condition of a warm-blooded animal, particularly a human, characterized by stimulating GABAg receptors, comprising administering to said warm-blooded animal a compound of Formula I, VA or XVIII, or a pharmaceutically acceptable salt or ester thereof.

The following examples illustrate the invention. The abbreviation Boe used in the following formulas refers to tert-butoxycarbonyl.

DETAILED DESCRIPTION OF THE INVENTION

Compound D used in the Examples was prepared as follows:

g of phenylglycine is dissolved in 210 ml of concentrated sulfuric acid and the solution is cooled to 0 ° C. To the cooled solution was added dropwise 15.5 ml of fuming nitric acid over 30 minutes, stirred for an additional 30 minutes at 0 ° C and then for 18 hours at room temperature. The solution is poured into 1 liter of ice and the pH is adjusted to 7 by adding approximately 875 ml of 10M aqueous sodium hydroxide while maintaining the solution temperature below 20 ° C. The resulting mixture was stirred for 3 hours at room temperature and the precipitate was filtered off. This precipitate is washed three times with water and recrystallized from 1 liter of water to give 3-nitrophenylglycine, m.p. 165-166.

11.13 g of the mixture are heated to boiling. The resulting solution is cooled with g of 3-nitrophenylglycine, added to a mixture of 200 ml of methanol and 20 ml of triethylamine, and the mixture is stirred vigorously for 10 minutes at room temperature. The reaction mixture was refluxed for 2 hours at room temperature and then concentrated to dryness under reduced pressure to give a dark orange residue. This residue was purified by flash chromatography on silica gel eluting with 95% dichloromethane, 2.5% methanol, and 2.5% acetic acid to afford compound A as an orange foam.

Compound A ¹³ C-NMR (100 MHz, CDCl 3): δ ppm: 27.9 (q), 58.2 (d), 82.6 (s), 122.4 (d), 123.0 ( d, 129.5 (d),

133.0 (d), 140.4 (s), 148.2 (s), 156.8 (s), 172.1 (s)

A solution of 14.54 g of compound A and acid in 200 ml of methanol was stirred in the room. Ethyl acetate and sodium carbonate were added, the organic phase was magnesium sulfate and filtered under reduced pressure. The product obtained by flash chromatography on silica gel

1.87 g of p-toluenesulfone for 24 hours at room temperature, the saturated aqueous hydrogen phase is separated off, dried over and the filtrate is evaporated and purified by very much using 2: 1 hexane: ethyl acetate as the eluent to give compound B in yellow solid, m.p. 86 ° C.

Compound B

Analysis: for C 14 ^H 18 ^N 2 ^O 6 ^: calculated: 54.19% C, 5.85% H, 9.03% N; found: C 54.32, H 6.00, N 8.93.

To a stirred solution of 9.57 g of compound B in 120 ml of absolute ethanol at room temperature was added dropwise a solution of 2.3 3 g of sodium borohydride in 30 ml of absolute ethanol. The reaction mixture was stirred for 18 hours at room temperature and then the excess sodium borohydride was destroyed by the addition of glacial acetic acid. The solvents were removed under reduced pressure and the residue was triturated three times with 50 ml of ethyl acetate each time. The combined ethyl acetate phases are evaporated to dryness and the residue is then co-evaporated three times with 50 ml of toluene each time. The resulting residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / hexane (1: 1) to give compound C, mp 100 ° C.

Compound C

Analysis for ^c 13 ^H 18 ^N 2 ° 5 ^: calculated found:

55.31% C, 55.25% C,

H, 6.43; N, 9.92; H, 6.63; N, 9.76.

To a flask containing 5 g of compound C cooled to 0 ° C was added 60 mL of trifluoroacetic acid. The resulting solution was stirred for 20 minutes at 0 ° C, then allowed to warm to room temperature and stirred for an additional 3 hours. The solvent was removed under reduced pressure and the residue was purified by ion exchange chromatography on Dowex 50 WX 2-200 resin (in H ⁺ form) using 3% aqueous ammonium hydroxide as eluent to give compound D as a light brown foam.

NH,

NO.

OH compound D

Analysis for CgH-LQNgOg:

calculated: 52.74% C, found: 53.12% C,

H 5.53, H 5.75,

15.38% N; 15.07% N.

¹³ C-NMR (100 MHz, methanol): δ ppm: 58.0 (d), 68.2 (t), 122.8 (d), 123.1 (d), 130.4 (d) , 134.5 (d), 146.3 (s), 149.6 (s)

Compound G used in the examples was prepared as follows:

4.9 g (0.1 mol) of sodium cyanide and 5.88 g (0.11 mol) of ammonium chloride are stirred at room temperature in 20 ml of water. A solution of 17.5 g (0.1 mol) of 3,4-dichlorobenzaldehyde in 30 ml of methanol is added dropwise over 1 minute. 10 ml of 0.88 aqueous ammonia solution are added and the reaction mixture is stirred for 3 hours at room temperature. Ethyl acetate is added and the organic phase is separated, dried over magnesium sulphate48, filtered and evaporated. The residue was dissolved in ethyl acetate and extracted repeatedly with 2M hydrochloric acid. The pH of the combined aqueous layers is adjusted to 9 using aqueous ammonia solution and repeatedly back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to give an orange oil which was purified by flash chromatography on silica gel using hexane / ethyl acetate 1: 1 as eluent to give compound G with a melting point of 64 - 65 θ <3.

Analysis for C 8 H 8 Cl 2:

H, 3.01; N, 13.93. Found: C 47.81, H 2.99, N 13.92.

Compound J used in the Examples was prepared as follows:

Using essentially the same procedure described for the preparation of compound G, a mixture of 18.5 g (0.1 mol) of 3-bromobenzaldehyde, 4.9 g (0.1 mol) of sodium cyanide, 5.9 g (0.11 mol) of ammonium chloride and 10 ml of an aqueous 0.88 ammonia solution in a mixture of 30 ml of methanol and 20 ml of water are reacted for 24 hours at room temperature to give compound H as a reddish brown waxy solid.

Br 1 C-NMR (100 MHz, CDCl 3): δ ppm: 46.6 (d), 120.4 (s), 122.9 (s), 125.2 (d), 129.7 ( d), 130.5 (d), 132.1 (d), 138.3 (s)

A mixture of 10.5 g (49.8 mmol) of compound H in 200 ml of 6M hydrochloric acid was heated under reflux for 68 hours. The supernatant was decanted off, cooled to room temperature and the pH adjusted using an aqueous solution. The precipitated product is isolated by filtration, washed with water and dried. Trituration with ethyl acetate followed by drying afforded Compound J as a brown solid melting under decomposition at 201-204

COýrí

Br compound J ¹³ C-NMR (100 MHz, perdeuteromethanol): δ ppm: 56.9 (d), 124.0 (s), 128.1 (d), 132.2 (2 xd), 134, 0 (d),

136.0 (s), 170.1 (s)

Example 1

Compound 1

To a solution of 1.7 g (10.0 mmol) of 4-methoxybenzylamine hydrochloride and 0.490 g (10.0 mmol) of sodium cyanide in 10 ml of water was added 1.6 g (10.0 mmol) of 3-methoxycarbonylbenzaldehyde in 10 ml. methanol and the mixture was stirred at room temperature for 3 hours.

20 ml of water are added and the mixture is extracted with dichloromethane. The organic phase is washed with brine, dried over magnesium sulphate and evaporated to dryness to give an oil which is purified by chromatography on silica gel using 20% ethyl acetate in hexane as eluent. Compound 1 is obtained.

Analysis for ^C 18 ^H 18 ^N 2 ° ^3: Calculated: 69.66% C, 5.85% H, 9.03 Found: 69.40% C, 5.94% H, 8.73

N;

N.

C-NMR (100 MHz, CDCl3): δ ppm: 50.6 (t), 52.2 (q), 52.8 (d), 55.2 (q), 114.0 (d), 118.3 (s),

128.3 (d), 129.0 (d), 129.6 (d), 129.8 (s), 130.1 (d),

130.9 (s), 131.6 (d), 135.3 (s), 159.1 (s) 166.32 (s)

Example 2

and ₃ compound 2

A solution of 7 g (22.56 mmol) of 1 in 75 mL of methanol was cooled to 0 ° C and saturated with hydrogen chloride gas. Once saturated, store the reaction mixture at -20 ° C for 4 days and then concentrate under reduced pressure to a quarter of its original volume. Ethyl acetate and saturated aqueous sodium bicarbonate solution are added and the organic phase is separated, washed with water and brine, dried over magnesium sulfate, filtered and evaporated to an oil. Purification by flash chromatography on silica gel (hexane / ethyl acetate 1: 1) gave 2 as an oil.

¹³ C-NMR (100 MHz, CDCl 3): δ (t), 52.1 (q), 52.3 (q), 55.2 (q), 63.8

128.69 (d), 128.72 (d), 129.4 (d), 130.5

δ v ppm: 50.7 (d) 113.7 (d) (with) , 131.2 (with) ,

132.0 (d), 138.5 (s),

158.7 (s)

166.7 (s) 172.9 (s)

Example 3

compound 3

A mixture of compound 2 (8.0 g, 23.3 mmol) and palladium black (2.0 g) in glacial acetic acid (50 ml) and methanol (50 ml) was hydrogenated at room temperature for 4 hours. After checking that the reaction was complete, the mixture was filtered by thin layer chromatography and the filtrate was evaporated under reduced pressure. The residue was co-evaporated three times with 20 ml of toluene each and then purified by flash chromatography on silica gel using ethyl acetate as eluent to give compound 3 as a pale yellow oil.

Analysis for ^C 13 ^H 17 ^NO 6 ^:

calculated found: : 55.12% C, 55.46% C, H, 6.05; N, 4.94; H, 5.99; N, 5.05. ¹³ C-NMR (100 MHz, CDCl 3): values δ v ppm: 20.8 (q), 52.1 (q), 5.25 (q) 57.89 (d), 127.9 (d) 128.9 (d) 129.3 (d), 130.7 (s), 131.4 (d), 139.9 (with) , 166.6 (with) , 173.5 (s), 175.9 (s)

Example 4

COOCH ₃ Compound 4

Stage 1

To a vigorously stirred solution of 3.1 g (10.9 mmol) of compound 3 and 10 mL (71.75 mmol) of triethylamine in 40 mL of methanol was added a solution of 4.5 g (20.83 mmol) of di-tert-butyl dicarbonate in 10 mL of methanol. . The mixture was then heated to 60 ° C for 30 minutes, cooled to room temperature and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane / ethyl acetate 4: 1) to give compound E, mp 88-90 ° C.

cooch ₃

NHBoc compound E

COOCH ₃

Analysis for ^C 16 ^H 21 ^NO 6 ^: Calculated: C 59.43, H 6.55, N 4.33. found: C 59.54, H 6.72, N 4.32.

Stage 2

To a stirred solution of 3.2 g (9.9 mmol) of compound E in 50 mL of methanol was added sodium borohydride (800 mg, 21.2 mmol) in eight equal portions over 30 minutes. After completion of the reaction, which was verified by thin layer chromatography, the remaining sodium borohydride was quenched with glacial acetic acid and the reaction mixture was evaporated under reduced pressure to give an oily solid. This residue was co-evaporated twice with 20 ml of toluene each time and triturated with ethyl acetate. Evaporation of the ethyl acetate extracts under reduced pressure gave a colorless oil which was purified by flash chromatography on silica gel using hexane / ethyl acetate 1: 1 as the eluent to give compound F, mp 102-104 ° C.

Compound F

Analysis for ^C 15 ^H 21 ^{NO 5:} Calculated: 61.01% C, 7.17% H, 4.74% N; found: C 61.11, H 7.23, N 4.70.

Stage 3

To a stirred solution of Compound F (2.2 g, 7.45 mmol) in dry dichloromethane (25 mL) was added trifluoroacetic acid (3.0 mL, 39.17 mmol) at room temperature under argon. This mixture was stirred during completion of the reaction, which layer, the mixture was evaporated at room temperature for hours. It is verified by thin-layer chromatography without heating under reduced pressure and the residue is co-evaporated twice with 20 ml of chloroform. After drying under high vacuum, the residue was purified by ion exchange chromatography on Amberlyst A21 resin using water as eluent to give compound 4 as a colorless oil.

Analysis for C ^ HH ^N ^O ^. 0.5H ₂ O:

H, 6.91; N, 6.86. Found:% C, 59.98;% H, 6.73;% N, 6.53.

¹³ C-NMR (100 MHz, perdeuteromethanol): δ ppm: 52.6 (q), 58.1 (d), 67.4 (t), 129.1 (d), 129.8 (2 xd) ), 131.6 (s), 132.8 (d), 142.4 (s), 168.2 (s)

Example 5

A solution of Compound G (1.4 g, 5.98 mmol) in methanol (20 mL) was cooled to 0 ° C and saturated with hydrogen chloride gas. Once saturated, store the reaction at -20 ° C for 2 days. The solvent was removed under reduced pressure and the residue was co-evaporated three times with 20 ml of methanol each. The residue is suspended in ethyl acetate and the organic phase is washed successively with saturated aqueous sodium bicarbonate solution, water and brine. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil which is purified by flash chromatography on silica gel using hexane / ethyl acetate (1: 1) as the eluent to give the compound 5th

Analysis for CgHgCl ₂ NO: Calculated: 46.18 Found: 46.12% C, 3.88% C, 3.85% H, 5.98% N; % H, 6.09% N.

¹³ C-NMR (100 MHz, CDCl3): δ ppm: 52.5 (q), 57.5 (d), 126.2 (d), 128.9 (d), 130.8 (d) , 131.9 (s), 132.6 (s), 140.2 (s), 173.4 (s)

Example 6

Compound 6

6.0 g (25.63 mmol) of compound 5, 11.19 g (51.26 mmol) of di-tert-butyl dicarbonate and 20 ml (143.50 mmol) of triethylamine are reacted in 200 ml of methanol using essentially by the same procedure as described for the preparation of compound E in Example 4. The crude product was chromatographed on silica gel using 20% ethyl acetate in hexane as eluent to give compound 6 as a yellow solid, mp 90-92 ° C.

Analysis for C ₁₄ H ₁₇ Cl ₂ NO ₄ :

H, 5.13; N, 4.19. Found: C, 50.55; H, 5.16; N, 4.08.

Example 7

To a solution of 6.78 g (20.28 mmol) of compound 6 in 100 mL of absolute ethanol was added dropwise a solution of 1.15 g (30.43 mmol) of sodium borohydride in 30 mL of absolute ethanol. The reaction mixture was stirred for 6 hours at room temperature and then allowed to stand for 48 hours at room temperature. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel using hexane / ethyl acetate 1: 1 as eluent to give compound 7 as a white solid, mp 113-114 ° C.

Analysis for C ^ HH ^C ^NO- ^:

H, 5.60; N, 4.57. Found: C 51.21, H 5.69, N 4.43.

Example 8

NH ₂

OH compound 8

4.7 g (15.35 mmol) of compound 7 is reacted with 75 ml of trifluoroacetic acid using essentially the same procedure as described for the preparation of compound D from compound C. The crude product is purified by ion exchange chromatography on Dowex 50WX 2- resin 200 (in H ⁺ form) using 50% methanol, 47% water and 3% aqueous ammonia as eluent to give compound 8 as a cream colored solid, mp 65-67 ° C.

Analysis for C 8 H 8 Cl 2 NO:

H, 4.40; N, 6.80.

Found: C, 46.61; H, 4.37; N, 6.59.

Example 9

Compound 9

To a solution of 18.22 g of ethyl cyclohexylmethylphosphinate prepared as described in EP 0569333 in 100 ml of dry dichloromethane is added dropwise 28.51 ml of bis (trimethylsilyl) acedamide under argon. The solution was stirred at room temperature for 1 hour, then 13.42 ml of trimethyl phosphate was added, followed by 9.57 ml of a mixture of cis- and trans-isomers of 1,3-dibromopropene. The solution is stirred for 18 hours at room temperature, then poured into 100 ml of saturated aqueous sodium bicarbonate solution and stirred for 10 minutes. The product was extracted three times with 50 ml of dichloromethane each time, the combined organic extracts were washed with brine, then dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure, and the excess trimethyl phosphate is then removed by evaporation at 80 ° C at 60 Pa. The residue was purified by flash chromatography on silica gel using ethyl acetate as eluent to give compound 9 as a mixture of cis and trans isomers.

³¹ P-NT4R (162 and 52.2

MHz, deuterochloroform): δ values in ppm: 51.1

Example 10

Compound 10

A mixture of 0.88 g (6.47 mmol) of (R) -2-amino-2-phenylethanol and 1.0 g (3.23 mmol) of compound 9 in 10 ml of toluene was heated to reflux. At 30-minute intervals, 0.48 mL (3.23 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene is added to 10 parts. The reaction mixture was refluxed for an additional hour and allowed to stand overnight at room temperature. The mixture was filtered and the filtrate was evaporated under reduced pressure to give a yellow oil which was purified by flash chromatography on silica gel using 5% methanol in dichloromethane as eluent to give compound 10 as a mixture of diastereomers on phosphorus in a ratio of: 1: 1st

P-NMR (162 MHz, CDCl3): δ ppm: 43.49 and 43.55

Example 11

compound 11

2.66 g (19.4 mmol) of (S) -2-amino-2-phenylethanol, 3.0 g (9.7 mmol) of compound 9 and 1.40 g (9.7 mmol) of 1,8-diazabicyclo The [5,4,0] undec-7-ene is reacted in 30 ml of toluene using the procedure described for the preparation of compound 10. The crude product is purified by flash chromatography on silica gel using 5% methanol in dichloromethane as eluent to give Compound 11 is obtained as a 1: 1 mixture of diastereomers on phosphorus.

²¹ P-NMR (162 MHz, CDCl 3): δ values in ppm: 43.37 and 43.43

A mixture of Compound 4 (1.3 g, 6.66 mmol) and Compound 9 (2.06 g, 6.66 mmol) in toluene / tetrahydrofuran (1: 1, 25 ml) was heated to 80 ° C under argon. A solution of 1.52 g (9.95 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene in 15 ml of a 1: 1 mixture of toluene and tetrahydrofuran is added over 5 hours. The mixture was cooled to room temperature and allowed to stand for 18 hours. Then the mixture was filtered and the filtrate was evaporated under reduced pressure to give a yellow oil which was purified by flash chromatography on silica gel using 5% methanol in dichloromethane as eluent to give compound 12 as a mixture of diastereomers on phosphorus. 1: 1 ratio.

³¹ P-NMR (162 and 43.58)

MHz, deuterochloroform): δ values in ppm: 43.53

Example 13

OH

Compound 13

Using essentially the same procedure described for the preparation of 12, a mixture of 2.76 g (13.39 mmol) of 8 and 4.14 g (13.39 mmol) of 9 in a mixture of 50 mL of toluene and 4 mL of tetrahydrofuran at temperature 110 was treated with a solution of 2.03 g (13.39 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene in 6 mL of tetrahydrofuran to give 13 as a mixture of diastereomers on phosphorus in a ratio of 1: 1st

³¹ P-NMR (162 MHz, CDCl 3): δ values in ppm: 43.73 and 43.82

Using essentially the same procedure described for the preparation of 12, a mixture of 3.19 g (17.50 mmol) of D and 5.41 g (17.50 mmol) of 9 in a mixture of 50 mL of toluene and 4 mL of tetrahydrofuran at temperature 110 ° C was treated with a solution of 2.66 g (17.5 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene in 6 mL of tetrahydrofuran to give 14 as a mixture of diastereomers phosphfore ratio 1: 1.

³¹ P-NMR (162 MHz, CDCl 3): δ values in ppm: 43.60 and 43.66

Example 15

compound 15

A suspension of 0.079 g (3.31 mmol) of sodium hydride in 10 mL of dry toluene was stirred at 0 ° C. A solution of 1.1 g (3.01 mmol) of 10 in 20 mL of dry toluene is added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. 5 ml of saturated aqueous ammonium chloride solution were added and then the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 5% methanol in dichloromethane as eluent to give compound 15 as a mixture of diastereomers on phosphorus.

Mass Spectrometry (FAB (Fast Neutral Particle Ionization)): (m + 1) ⁺ m / z = 366

P-NMR (162 MHz, CDCl3): δ ppm: 54.05 and 54.63

Example 16

ABOUT

Compound 16

Using essentially the same procedure described for the preparation of 15, 1.20 g (3.28 mmol) of 11 and 0.086 g (3.61 mmol) of sodium hydride were reacted in 40 mL of toluene to give 16 as a mixture. diastereomers on the phosphorus.

Analysis for C ₂₀ H ₃₂ NO ₂ P.0.75H ₂ O:

calculated: 63.39% C, 8.91% H, found: 63.39% C, 8.75% H,

3.70% N; 3.70% N.

³¹ P-NMR (162 and 54.65)

MHz, deuterochloroform) δ values in ppm: 54.08

A solution of 50 mg (0.12 mmol) of 12 in 0.5 mL of dry toluene was stirred at room temperature. A suspension of 6.2 mg (0.26 mmol) of sodium hydride in 0.5 ml of toluene was added in one portion and the reaction mixture was stirred for 3 hours at room temperature. The reaction was then quenched by the addition of glacial acetic acid and the product was extracted with ethyl acetate. The combined organic phases are washed with water and brine, then dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 5% methanol in dichloromethane as eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 17, as a mixture of diastereomers on phosphorus.

³¹ P-NMR (162 and 54.64)

MHz, deuterochloroform): δ values in ppm: 54.06

Example 18

compound 18

Using essentially the same procedure described for the preparation of 15, 2.24 g (5.15 mmol) of 13 and 0.136 g (5.67 mmol) of sodium hydride were reacted in 80 mL of toluene to give racemic trans-2, A 5-disubstituted morpholine derivative, compound 18, in the form of a mixture of diastereomers on the phosphorus.

Analysis for ^C 20 ^H 30 ^Cl 2 ^NO 3 ^{P 1 O 5 H} 2 ° ^: calculated: 54.18% C, 7.05% H, found: 54.21% C, 7.08% H, ³¹ P-NMR (162 MHz, deuterochloroform) and 54.40

3.16% N; 3.11% N.

δ values in ppm: 53.80 i

Example .19

ABOUT

NO2 compound 19

Using essentially the same procedure described for the preparation of 15, 5.38 g (13.1 mmol) of 14 and 0.346 g (14.41 mmol) of sodium hydride were reacted in 150 mL of toluene to give racemic trans-2, 5-disubstituted morpholine derivative, compound 19, in the form of a mixture of diastereomers on the phosphorus.

³¹ P-NMR (162 MHz, CDCl 3): δ values in ppm: 53.73 and 54.33

Example 20 Compound 20

To a stirred solution of 650 mg (1.78 mmol) of 15 in 25 mL of dichloromethane was added 0.939 mL (7.12 mmol) of bromotrimethylsilane dropwise under argon. The reaction mixture was stirred for 24 hours at room temperature. The reaction was then quenched by the addition of 95: 5 methanol: water. The solvent was removed under reduced pressure to give an oily residue which was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in H ⁺ form) using 50% MeOH / 47% water / 3% aqueous ammonia solution. The resulting product was dried under high vacuum (at a pressure of less than 6.7 Pa) to give compound 20 as a white solid, m.p. &gt; 250 ° C.

[a] _D = +10.8 ⁰ (c = 1; in methanol)

Analysis for <3 ₁₈ Η ₂₈ ΝΟ ₃ Ρ:

H, 8.36; N, 4.15. Found:% C, 63.72;% H, 8.44;% N, 4.02.

³¹ P-NMR (162 MHz, deuterium oxide): δ ppm: 55.22

Example 21

ABOUT

Compound 21

Using the same procedure described for the preparation of compound 20, 670 mg (1.83 mmol) of compound 16 and 1.1 g (7.3 mmol) of bromotrimethylsilane were reacted in 20 mL of dichloromethane to give compound 21 with a melting point of more than 250 ° C.

[α] _D = -10.5 ⁰ (c = 1; in methanol) Analysis for C ₁₈ H ₂₈ NO ₃ P: calculated: 64.08 % H, 8.36; N, 4.15; found: 63.62 % H, 8.50; N, 4.05. ³¹ P-NMR (162 MHz, mixture) deuterium oxide and deuterium chloride)

δ values in ppm: 55.36

Example 22

Compound 22

Using the same procedure as described for the preparation of compound 20, 0.979 g (2.25 mmol) of compound 18 and 0.89 mL (6.76 mmol) of bromotrimethylsilane were reacted in 40 mL of dichloromethane to give racemic trans-2,5- a disubstituted morpholine derivative, compound 22, melting with decomposition at more than 200 ° C.

Analysis for (^ θ ^ ςΟ ^ ΝΟβΡ. 0,25H ₂ O:

H, 6.50; N, 3.41. found: C 52.45, H 6.53, N 3.29.

P-NMR (202.5 MHz, perdeuteroacetic acid) in ppm: 45.45 δ values

Sodium salt: ³¹ P-NMR (162 MHz, mixture of deuterium oxide and deuterium chloride): δ values in ppm: 41.89

Example 23

compound 23

Using the same procedure as described for the preparation of compound 20, 0.5 g (1.20 mmol) of compound 19 and 0.48 mL (3.65 mmol) of bromotrimethylsilane were reacted in 25 mL of dichloromethane to give racemic trans-2, 5-disubstituted morpholine derivative, compound 23, mp 128-130 ° C.

Analysis for ^C 18 ^H 27 ^N 2 · ^P ° 5 ° 2 ^H: Calculated: 53.99% C, 7.30% H, 7.00% N; found: C 54.23, H 7.25, N 6.93.

³¹ P-NMR (162 MHz, perdeuteromethanol): δ values in ppm: 37.64

Example 24

compound 24

A mixture of 2.98 g (7.26 mmol on activated carbon (0.5 g) was hydrogenated for 18 hours with compound 19 and 0.5 g of 10% palladium in 150 ml of absolute ethanol was filtered and the filtrate was evaporated. Flash chromatography on silica gel using 10% methanol in dichloromethane as eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 24, as a mixture of diastereomers on phosphorus, m.p. 115-118 ° (2). .

Analysis for C2qH ₃₃ N · 0.25 H ₂ P ₃ O _2:

calculated: 62.40% C, 8.77% H, found: 62.52% C, 8.88% H,

7.31% N; 7.18% N.

³¹ P-NMR (162 MHz, CDCl 3): δ values in ppm: 54.16 and 54.72

Example 25

To a stirred solution of 2.43 g (6.38 mmol) of compound 24 in 50 mL of concentrated hydrochloric acid was added 15 g of crushed ice and the resulting mixture was cooled to 0 ° C. A solution of 0.48 g (7.02 mmol) of sodium nitrite in 25 ml of water is added dropwise and the resulting mixture is stirred for 10 minutes at 0 ° C. The resulting solution was then added dropwise to a solution of 11.13 g (67.01 mmol) of potassium iodide in 200 mL of water. The reaction mixture was stirred for an additional 2.5 hours at room temperature and then allowed to stand overnight at room temperature. Ethyl acetate is added and the two phases are separated. The aqueous phase was neutralized by the addition of solid sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extracts are mixed with the original organic phase and the combined organic phases are washed with 10% aqueous sodium hydroxide solution, followed by 5% aqueous sodium bisulfite solution and then with water. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford the racemic trans-2,5-disubstituted morpholine derivative, compound 25, as a mixture of diastereomers on phosphorus.

MS (Cl (Chemical Ionization) / NH 4): (m + 1) ⁺ m / z = 492

P-NMR (162 MHz, CDCl3): δ ppm: 54.21 and 54.77

Example 26

ABOUT

Compound 26

Using essentially the same procedure described for the preparation of 20, 0.1 g (0.20 mmol) of 25 and 0.427 mL (3.20 mmol) of bromotrimethylsilane were reacted in 10 mL of dichloromethane for 78 hours at room temperature. The crude product was purified by Dowex 50WX 2-200 (in H ⁺ form) ion exchange chromatography using 50% methanol, 47% water and 3% aqueous ammonia as eluent and dried under high vacuum (at a vacuum). a pressure of less than 6.7 Pa) to give the racemic trans-2,5-disubstituted morpholine derivative, compound 26, melting with decomposition at a melting point greater than 230 ° C.

Analysis for ύ ₁₈ Η ₂₇ ΙΝΟ ₃ Ρ 1,2,2H ₂ O:

H, 6.11; N, 2.89. Found: C, 44.48; H, 5.70; N, 2.95.

³¹ P-NMR (162 MHz, mixture of perdeuteromethanol and deuterium chloride): δ values in ppm: 53.08

Example 27 Compound 27

CN

As described by S. L. Regen, S. Quici and S. J. Liaw in Journal Organic Chemistry, 1979, 44 (12), 2029, aluminum oxide impregnated with sodium cyanide (5 mmol sodium cyanide per gram alumina) was prepared. To a mixture of 0.17 g (0.18 mmol) of tris (dibenzylideneacetone) dipalladium (0), 4.7 g of alumina impregnated with sodium cyanide and 0.34 g (1.45 mmol) of tri- (2-furyl) f. Osfine was added, under argon, 0.89 g (1.8 mmol) of 25 in 50 mL dry degassed toluene. The reaction mixture is heated at 80 ° C for 12 hours. Check the progress of the reaction by thin layer chromatography and add 0.17 g (0.18 mmol) of tris (dibenzylideneacetone) dipalladium (0) and 0.34 g (1.45 mmol) of tri- (if necessary). 2-furyl) phosphine and the reaction mixture is again heated to 80 θ <2 for 8 hours. After completion of the reaction, the mixture was filtered and the solids were washed with ether. The combined filtrates were evaporated under reduced pressure and the residue purified by flash chromatography on silica gel using 10% methanol in ethyl acetate as eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 27, as a mixture of diastereomers to give the title compound. phosphorus.

Mass spectrometry (CI (chemical ionization) / NH ₃ ):

(M + 1) ⁺ m / z = 391 ³¹ P-NMR (162 and 54.57)

MHz, CDCl3) δ values in ppm: 53.95

Example 28 Compound 28

CN

Using essentially the same procedure described for the preparation of compound 20, 0.16 g (0.41 mmol) of compound 27 and 0.91 ml (6.14 mmol) of bromotrimethylsilane were reacted in dichloromethane to give racemic trans-2, 5-disubstituted morpholine derivative, compound 28.

Mass spectrometry (Cl (chemical ionization) / NH4):

M ⁺ m / z = 362 ³¹ P-NMR (162 MHz, deuterium oxide and deuterium chloride): δ values in ppm: 55.31

Example 29

ABOUT

COOH compound 29

A mixture of compound 27 (0.09 g, 0.23 mmol), 6M hydrochloric acid (10 mL) and ethanol (1 mL) was heated at reflux for 72 h. After completion of the reaction, which was verified by P-NMR, the solvent was removed under reduced pressure. The residue was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in H ⁺ -form) using 50% methanol, 47% water and 3% aqueous ammonia as eluent and the product dried under high vacuum (less pressure). or equal to 6.7 Pa) to give the racemic trans-2,5-disubstituted morpholine derivative, compound 29, with a melting point of more than 260 θθ.

P-NMR (162 MHz, deuterium oxide): δ ppm: 40.67

Example 30

A mixture of Compound 17 (0.50 g, 1.18 mmol), 6M hydrochloric acid (25 mL) and glacial acetic acid (5 mL) was heated at 100 ° C for 16 h. After completion of the reaction, which was verified by ³¹ P-NMR, the solvent was removed under reduced pressure. The residue is purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in H ⁺ form) using 50% methanol, 47% water and 3% aqueous ammonia as eluent and the product is dried under high vacuum (less pressure). or equal to 6.7 Pa) to give the racemic trans-2,5-disubstituted morpholine derivative, compound 29.

Analysis for C ₁₉ H ₂₅ NO ₅ P. 0.5H ₂ O:

H, 7.49; N, 3.59. Found:% C, 58.68;% H, 7.35;% N, 3.71.

³¹ P-NMR (162 MHz, deuterium oxide): δ ppm: 40.71

Example 31

A solution of 317 mg (0.83 mmol) of 29 in 20 mL of methanol was saturated with hydrogen chloride gas and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in H ⁺ form) using a mixture of 50% methanol, 47% water and 3% aqueous ammonia as eluent. The product is dried under high vacuum (less than or equal to 6.7 Pa) to give the racemic trans-2,5-disubstituted morpholine derivative, compound 30.

Analysis for C ₂₀ H ₃ θΝΟ ^ Ρ 0.25H ₂ O:

calculated: 60.01% C, 7.68% H, found: 60.26% C, 7.57% H,

3.50% N; 3.45% N.

³¹ P-NMR (162

MHz, perdeuteromethanol):

δ values in ppm: 37.21

Example 32

Compound 31

Using essentially the same procedure described for the preparation of compound 20, 90 mg (0.246 mmol) of compound 10 and 200 μΐ (1.57 mmol) of bromotrimethylsilane were reacted in 2 mL of dichloromethane to give compound 31.

[α] _D = -38.5 ⁰ (c = 0.6, in methanol) ³¹ P-NMR (162 MHz, perdeuteromethanol): δ values in ppm: 29.00

Example 33

Using essentially the same procedure described for the preparation of compound 20, 90 mg (0.246 mmol) of 11 and 200 μΐ (1.57 mmol) of bromotrimethylsilane were reacted in dichloromethane to give compound 32.

[a] q = +41.3 ⁰ (c = 0.6, in methanol)

3 µ_NMR (162 MHz, perdeuteromethanol): δ values in ppm: 28.84

Example 34

To a stirred solution of 100 mL (0.24 mmol) of 12 in 2 mL of dichloromethane was added 300 μim (2.4 mmol) of bromotrimethylsilane under argon and the reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was co-evaporated with a 1: 1 mixture of methanol and water. The resulting residue was then dissolved in 5 ml of a mixture of 6M hydrochloric acid and 0.3 ml of methanol, and the mixture was heated under reflux for 4 hours. The solvent was removed under reduced pressure and the residue was co-evaporated three times with water. The resulting residue was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in H ⁺ form) using 50% methanol, 47% water and 3% aqueous ammonia as eluent to afford compound 33.

P-NMR (162 MHz, CD): δ ppm: 29.28

Ί4.

Compound 34

Using essentially the same procedure described for the preparation of compound 20, 0.5 g (1.15 mmol) of compound 13 and 0.91 mL (6.9 mmol) of bromotrimethylsilane were reacted in 15 mL of dichloromethane to give compound 34.

³¹ P-NMR (162 MHz, perdeuteromethanol): δ values in ppm: 29.06

Example 36

Compound 35

Using essentially the same procedure described for the preparation of compound 20, 90 mg (0.219 mmol) of compound 14 and 200 μΐ (1.57 mmol) of bromotrimethylsilane were reacted in 2 mL of dichloromethane to give compound 35.

³¹ P-NMR (162 MHz, perdeuteromethanol): δ values in ppm: 29.57

Example 37

To a suspension of 2.9 g (10 mmol) of 2-amino-3- (4-iodophenyl) propionic acid in 10 ml of tetrahydrofuran was added dropwise 1.25 ml (10 mmol) of boron trifluoride ethyl ether over 20 minutes. The mixture was heated to reflux for 2 hours, then 1.1 mL (11 mmol) of borane-dimethylsulfide complex was added dropwise over 1 hour while maintaining reflux. The mixture was heated at reflux for an additional 5 hours and then stirred for 15 hours at room temperature.

20 ml of a 1: 1 mixture of water and tetrahydrofuran are added, followed by 7.5 ml of 5N sodium hydroxide solution. The reaction mixture was heated at reflux for 7 hours, cooled to room temperature and filtered. The filter cake is washed twice with 10 ml of tetrahydrofuran each time and the filtrate is evaporated to 25% of its original volume and then extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a pale yellow solid which was recrystallized from hexane / ethyl acetate (1: 1). 2 to give compound 36, mp 105-107 ° C.

Analysis for C 8 H 11 NO 3:

H, 4.37; N, 5.06. found: 38.69% C, 4.40% H, 4.92% N.

Example 38

Ο

Compound 37

Using essentially the same procedure described for the preparation of 12, a mixture of 2.40 g (8.66 mmol) of 36 and 2.7 g (8.66 mmol) of 9 in a mixture of 20 mL of toluene was treated at 75 ° C. by treatment with a solution of 1.30 g (8.66 mmol) of 1,8-diazabicyclo [5.4, Q] -undec-7-ene in 10 ml of tetrahydrofuran to give compound 37 as a 1: mixture of diastereomers on phosphorus. : 1 ..

³¹ P-NMR (202 MHz, CDCl 3): δ values in ppm: 43.69 and 43.72

Example 39

H

compound 38 compound 39 (trans) (cis)

To a stirred solution of compound 37 (2.0 g, 4.0 mmol) in dry toluene (25 mL) was added a suspension of sodium hydride (0.105 g, 4.4 mmol) in dry toluene (5 mL) over 30 seconds. The mixture is stirred for 30 minutes at 0 ° C and then for 3 hours at room temperature. 1 ml of glacial acetic acid was added and the reaction mixture was then diluted with 75 ml of ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution, water and then brine. The combined organic phases are dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 20% methanol in ethyl acetate as eluent to give the racemic trans-2,5-disulfated morpholine derivative, compound 38, and the racemic cis-2,5-disustituted morpholine derivative, compound 39, each in the form of a mixture of diastereomers on the phosphorus.

Compound 38: ⁵ * P-NMR (162 MHz, CDCl3): δ ppm: 53.93 and 54.60

Compound 39: ³¹ P-NMR (162 MHz, CDCl3): δ ppm: 54.25 and 54.82

Example 40 Compound 40

To a stirred solution of compound 38 (180 mL, 0.356 mmol) in dichloromethane (5 mL) was added bromotrimethylsilane (0.20 mL, 1.52 mmol) dropwise under argon. The reaction mixture was stirred for 20 hours at room temperature. The solvent was removed under reduced pressure and the residue was co-evaporated twice with 0.5 ml of 1: 1 water / methanol each time. The residue was purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in H ⁺ form) using a 1: 1 mixture of methanol and 2% sodium hydroxide solution to elute the product. The resulting product was further purified by gel filtration on a Bio-Gel P2 column using water as the eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 40, melting with decomposition at more than 250 ° C.

Analysis for C - ^^ glNONOPP. 3 ^ 0:

H, 6.10; N, 2.53. Found: C, 41.42; H, 5.40; N, 2.42.

P-NMR (161 MHz, deuterium oxide): δ ppm: 41.81

Example 41

A mixture of 0.180 g (0.36 mmol) of compound 38 and 0.200 g (0.28 mmol) of bistriphenylphosphine palladium (II) chloride in 2 mL of absolute ethanol and 1 mL of triethylamine was degassed by bubbling argon for 5 minutes. The mixture was heated to reflux and stirred vigorously under a carbon monoxide atmosphere for 3 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure to give an oily solid which was triturated with ethyl acetate. The combined ethyl acetate used for washing was evaporated under reduced pressure and the residue purified by flash chromatography on silica gel using 10% methanol in chloroform as eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 41, as mixtures of diastereomers on phosphorus.

³¹ P-NMR (161 and 54.60)

MHz, deuterochloroform): δ values in ppm: 53.93

Example 42

Na ^{@ +} .alpha

Compound 42

A mixture of 0.095 g (0.21 mmol) of compound 41 and 4 mL of 6M hydrochloric acid was heated to reflux for 20 hours. After completion of the ³¹ P-NMR reaction, the solvent was removed under reduced pressure and the residue was purified by Dowex 50WX 2-200 (in H ⁺ -form) ion exchange chromatography using a mixture of methanol and 2% sodium hydroxide solution. in a 1: 1 ratio to elute the product. The resulting product was further purified by gel filtration on a BIO-GEL P2 column using water as the eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 42, melting with decomposition at more than 250 ° C.

Analysis for C ₂₀ H ₂₈ NO ₅ P.Na ₂ H ₂ O:

calculated: 50.52% C, 6.79% H, found: 50.53% C, 7.40% H,

2.95% N; 2.96% N.

³¹ P-NMR (202 MHz, deuterium oxide):

δ values in ppm: 42.38

Example 43

Compound 43

Dissolve 1.8 g (21.4 mmol) of sodium acetate, 1.3 ml (22.7 mmol) of acetic acid and 7.0 ml (101 mmol) of a 40% aqueous formaldehyde solution in 5 ml of water to prepare a buffered formaldehyde stock solution . Add 10 mL of the above stock solution to a mixture of 0.10 g (0.262 mmol) of 29 in 2 mL of methanol and stir at room temperature for 10 minutes. 0.165 g (2.62 mmol) of sodium cyanoborohydride was added portionwise over 2 minutes. The mixture was stirred for 24 hours at room temperature. The solvent was removed under reduced pressure and the residue was purified by Dowex 50WX 2-200 (in H ⁺ form) ion exchange chromatography using a 1: 1 mixture of methanol and 2% sodium hydroxide solution to elute the product. The resulting product was further purified by gel filtration on a BIO-GEL P2 column using water as eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 43, melting with decomposition at more than 250 ° C.

Analysis for C2QH2gNO5P.2Na.H2O:

calculated: 52.52% C, 6.61% H, found: 52.60% C, 6.82% H,

3.06% N; 3.10% N.

³¹ P-NMR

02 MHz, deuterium oxide):

δ values in ppm: 41.93

Example 44

Compound 44

0.25 g (0.66 mmol) of 29 was dissolved in 4 mL of 1: 1 dioxane / water and the pH of the resulting solution was adjusted to 9 by addition of 0.1 M sodium hydroxide solution. The mixture was stirred vigorously and benzyl chloroformate (0.188 mL, 1.32 mmol) was added dropwise over 15 minutes. The pH of the mixture was adjusted to 9 by further addition of 0.1M sodium hydroxide solution and the mixture was stirred for 20 hours at room temperature. The mixture was concentrated under reduced pressure to one half of its original volume and acidified with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and the combined organic phases are washed with water and then with brine, dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 2% acetic acid, 10% methanol and 88% chloroform as eluent. The product is further purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in H ⁺ form) using a 3: 1 mixture of tetrahydrofuran and water as eluent. The resulting product was dissolved in 2.5 mL of 1% sodium hydroxide solution and purified by gel filtration on a BIO-GEL P2 column using water as eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 44, m.p. with decomposition above 250 ° C.

Analysis for C27H32NO7P.2Na.3H2O:

H, 6.24; N, 2.28. found: C 52.27, H 6.00, N 2.24.

³¹ P-NMR (161 MHz, deuterium oxide): δ ppm: 41.75

Example 45

To a suspension of 70.2 g (0.31 mol) of Compound J in 350 mL of tetrahydrofuran was added dropwise 75.0 mL (0.61 mol) of boron trifluoride ethyl ether over 20 min. The mixture was heated to reflux for 2 hours, then 57.9 ml (0.61 mol) of borane-dimethylsulfide complex was added dropwise over 1.5 hours while maintaining reflux. The mixture was heated to reflux for an additional hour and then allowed to stand for 18 hours at room temperature.

350 ml of a mixture of water and tetrahydrofuran (1 l) are added, followed by 350 ml of 5M sodium hydroxide solution. The reaction mixture was heated to reflux for 5 hours and then cooled to room temperature. The two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a brown oil.

This residue was triturated with diethyl ether / hexane and then recrystallized from ethyl acetate to give compound 45, mp 74-76 ° C.

Analysis for C 8 H 11 N 2 BrNO:

calculated: 44.46% C, 4.67% H, 6.48% N; found: C, 44.40; H, 4.67; N, 6.35.

Example 46

A mixture of 15.0 g (69.4 mmol) of 45 and 4.0 g (5.70 mmol) of bis (triphenylphosphine) palladium (II) chloride in 100 mL of methanol and 25 mL of triethylamine was degassed by bubbling argon for 5 minutes. The mixture is saturated with carbon monoxide and then pressurized to 210 kPa in a pressure vessel. The mixture is then slowly heated to 100 ° C, maintaining the pressure below 350 kPa for 5 hours. The mixture was cooled to room temperature, filtered and evaporated. The residue was triturated with ethyl acetate and the filtrate was evaporated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 10% to 20% methanol in chloroform to afford compound 4.

¹³ C-NMR (100 MKz, perdeuteromethanol): δ ppm: 52.6 (q), 58.3 (d), 68.1 (t), 129.0 (d), 129.5 (d) , 129.7 (d), 131.5 (s), 132.9 (d), 143.6 (s), 168.4 (s)

Example 47 f

> «

Compound 46

As described by A. H. Katz et al. in Journal Medicinal Chemistry, 1988, 31, 1244, (2R / S) -2-amino-2- (1H-indol-3-yl) ethanol is prepared.

Using essentially the same procedure described for the preparation of 12, a mixture of 0.39 g (2.21 mmol) of (2R / S) -2-amino-2- (1H-indol-3-yl) ethanol and 0.68 g (2.20 mmol) of compound 9 in a mixture of 10 mL of toluene and 15 mL of tetrahydrofuran at 75 was treated with a solution of 0.33 g (2.17 mmol) of 1,8-diazabicyclo [5.4.0] undec-7. -ene in 5 ml of toluene to give compound 46 as a 1: 1 mixture of diastereomers on phosphorus.

@ 1 H-NMR (162 MHz, CDCl3): .delta. In ppm: 43.25 and 43.43

Example 48

Compound 47

A suspension of 0.014 g (0.59 mmol) of sodium hydride in 10 ml of dry toluene is stirred at 0 ° C. A solution of 0.200 g (0.49 mmol) of 46 in 7 mL of dry toluene is added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred for 4 hours. The reaction was quenched by the addition of glacial acetic acid and then the mixture was filtered and evaporated. The residue was purified by flash chromatography on silica gel using 20% methanol in ethyl acetate as eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 47, as a mixture of diastereomers on phosphorus.

Mass spectrometry (Cl (chemical ionization) / NH 4): (M + 1) ⁺ m / z = 405 ³¹ P-NMR (162 MHz, CDCl 3): δ and 55.32 ppm: 54.44

Example 49

Compound 48

Using essentially the same procedure described for the preparation of compound 40, 0.115 g (0.28 mmol) of compound 47 and 0.15 mL (1.13 mmol) of bromotrimethylsilane were reacted in 5 mL of dichloromethane for 3 days at room temperature, whereby to give the racemic trans-2,5-disubstituted morpholine derivative, compound 48.

¹³ C-NMR (100 MHZ, Deuterium oxide): values of δ v ppm: 28.6 (t), 28.7 (t), 35.1 (d), 37.6 (t), 37.7 (t) 37.9 (t), 38.3 (t), 41.6 (t), 53.8 (d), 54.2 (t), 74.7 (t), 75.6

(d), 114.8 (d), 115.6 (s), 121.3 (d), 122.3 (d), 125.0 (d), 125.4 (d), 128.3 (d), s), 138.8 (s) ³¹ P-NMR (202 MHz, deuterium oxide): δ values in ppm: 42.6

Example 50

Using essentially the same procedure described in Example 37, 10.0 g (51.8 mmol) of DL-2-amino-3-methyl-2-phenylbutyric acid, 6.4 ml (51.8 mmol) of boron trifluoride ethyl etherate were used. and 4.9 mL (51.8 mmol) of borane-dimethylsulfide complex was reacted in 50 mL of dry tetrahydrofuran to give compound 49.

Mass spectrometry (Cl (chemical ionization) / NH ₃ ): (m + 1) ⁺ m / z = 180 ¹³ C-NMR (100 MHz, CDCl 3): δ values in ppm: 16.8 (q), 17.4 (q), 34.8 (d), 61.7 (s), 69.2 (t), 126.2 (d),

126.4 (d), 127.8 (d), 144.2 (s)

Example 51

Using essentially the same procedure described for the preparation of 12, a mixture of 1.07 g (6.0 mmol) of 49 and 1.86 g (6.0 mmol) of 9 in 20 mL of toluene was reacted at 75 ° C. with a solution of 1.1 g (7.2 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene in 5 ml of toluene to give the compound as a 1: 1 mixture of diastereomers on phosphorus. ·

Mass spectrometry (CI (chemical ionization) / NH 4): (m + 1) ⁺ m / z = 408 ³¹ P-NMR (202.5 MHz, and 44.25 deuterochloroform) of δ in ppm: 44.22

Example 52

compound 51 (2R *, 5R *) compound 52 (2R, 5S)

Using essentially the same procedure described in Example 39, 200 mg (0.49 mmol) of compound 50 and 12 mg (0.49 mmol) of sodium hydride were reacted in 3 mL of dry toluene. The crude product was purified by flash chromatography on silica gel using 10% methanol in ethyl acetate as eluent to give the racemic (2R, 5R) -morpholine derivative, compound 51, and racemic compound 52, each as a mixture.

Compound 51: ³¹ P-NMR (162 MHz, δ in ppm: 54.3 and 55.0)

Compound 52: ³¹ P-NMR (162 MHz, δ in ppm: 54.2 and 55.5 (2R, 5S) -morpholine derivative, phosphorus diastereomers).

deuterochloroform): values deuterochloroform): values

Example 53

Compound 53

H

Using essentially the same procedure described in Example 40, 40 mg (0.1 mmol) of compound 51 and 0.066 mL (0.5 mmol) of bromotrimethylsilane were reacted in 1 mL of dichloromethane to give racemic (2R *, 3R *) morpholine derivative, compound 53.

³¹ P-NMR (202.5 MHz, deuterium oxide): δ ppm: 42.5

Example 54

Compound 54

Using essentially the same procedure described in Example 40, 180 mg (0.2 mmol) of 52 and 0.132 mL (1.0 mmol) of bromotrimethylsilane were reacted in 2 mL of dry dichloromethane to give racemic (2R, 5S) - morpholine derivative, compound 54.

³⁴ P-NMR (202.5 MHz, deuterium oxide): δ values in ppm: 42.2

Example 55 ch ₃ o

compound 55 and ₂ ch ₃

To a solution of 5.25 g (25 mmol) of ethyl 1,1-diethoxyethylphosphinate in 30 ml of dry tetrahydrofuran cooled to -70 ° C is added dropwise 50 ml (25 mmol) of a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene. The mixture is stirred for 0.5 hour at -70 θ <2. The resulting solution was added dropwise to a cooled solution of 3.9 g (25 mmol) of 4-methoxybenzyl chloride in 30 mL of tetrahydrofuran over minutes. The resulting mixture was stirred for 1 hour at -70 ° C and then allowed to warm to room temperature. The reaction mixture was stirred for 18 hours at room temperature, then glacial acetic acid was added and the reaction mixture was evaporated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase is separated, washed with water and then with brine, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate / hexane (2: 1) as eluent to give compound 55.

³¹ P-NMR (162 MHz, CDCl 3): δ values in ppm: 44.6

Example 56

Compound 56

To a solution of Compound 55 (1.0 g, 3.03 mmol) in 9: 1 chloroform / ethanol (10 mL) was added chlorotrimethylsilane (3.8 mL, 30.3 mmol) and stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure and the residue co-evaporated with chloroform. After drying under high vacuum, the residue was purified by flash chromatography on silica gel using ethyl acetate as eluent to give compound 56 as a colorless oil.

Mass spectrometry (Cl (chemical ionization) / NHg):

(M + _NH4) ⁺ m / z = 232

P-NMR (162 MHz, CDCl3): δ ppm: 37.3

IN'

Example 57

compound 57 essentially with 0.5 g of the same (2.33 mmol) procedure as described for compound 56, 0.69 mL

Using Example 9 (2.80 mmol) bis (trimethylsilyl) acetamide, 0.33 mL (2.80 mmol) trimethyl phosphate and 0.23 mL (2.33 mmol) a mixture of cis- and trans-isomers of 1,3-dibromopropene and treated with 10 ml of dry dichloromethane to give compound 57 as a mixture of cis-trans isomers.

@ ³ H-NMR (162 MHz, CDCl3): .delta. In ppm: 47.2 and 48.1

Example 58

Using essentially the same procedure described in Example 12, a mixture of 0.193 g (0.99 mmol) of compound 4 and 0.330 g (0.99 mmol) of compound 57 in 10 mL of 4: 1 toluene / tetrahydrofuran at 80 was treated with by treatment with a solution of 1.181 g (1.19 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene in 2 mL of toluene to give compound 58 as a 1: 1 mixture of diastereomers on phosphorus.

Mass spectrometry (Cl (chemical ionization) / NH ₃ ): (m + 1) ⁺ m / z = 448 ³¹ P-NMR (162 and 39.49)

MHz, deuterochloroform) δ in ppm: 39,40

Example 59

COjCHj

Using essentially the same procedure described in Example 39, 200 mg (0.45 mmol) of compound 58 and 10.8 mg (0.45 mmol) of sodium hydride were reacted in 2 mL of toluene to give racemic trans-2.5. a disubstituted morpholine derivative, compound 59, in the form of a mixture of diastereomers on the phosphorus.

³¹ P-NMR (162 MHz, and 50.8 deuterochloroform): δ values in ppm: 50.0

Example 60

CO ' ₂ Na *

Compound 60

To a solution of 50 mg (0.11 dichloromethane) was added 0.074 mL mmol) of compound 59 in 1 mL (0.55 mmol) bromotrimethylsilane, and the reaction mixture was stirred for 24 hours at room temperature. The solvent was removed under reduced pressure and the residue was co-evaporated with a 1: 1 mixture of methanol and water. The resulting residue was dissolved in 2 ml of 6M hydrochloric acid and the mixture was heated under reflux for 4 hours. The solvent was removed under reduced pressure and the residue was co-evaporated three times with water. The resulting ion exchange chromatography on (in H ⁺ -form) using a 1: 1 mixture of methanol and 2% sodium hydroxide solution to elute the product. The resulting product was further purified by gel filtration on a BIO-GEL P2 column using water as eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 60.

the residue is purified with Dowex 50WX 2-200 resin

P-NMR (202.5 MHz, deuterium oxide): δ values in ppm: 37.4

Claims (37)

PATENT CLAIMS A compound which is a substituted phosphinic acid of the general formula I in which R ¹ represents a monovalent aromatic or araliphatic group attached to said carbon atom through its carbon atom, R ² represents an unsubstituted or substituted hydrocarbon group, R ^x represents a hydrogen atom or an unsubstituted or substituted hydrocarbon group, RT represents a hydrogen atom, an R ^ group or an NH-protecting group and represents an unsubstituted or substituted hydrocarbyl group, or a salt or ester thereof. A compound according to claim 1, wherein R ¹ represents an aryl group having 6 to 15 carbon atoms which is unsubstituted or substituted at one or more positions by substituents selected from the group consisting of halogen atoms, hydroxy, C 1 -C 4 alkoxy, carboxy, functionally modified carboxy, carboxyalkyl groups of 1 to 8 carbon atoms in the alkyl moiety, functionally modified carboxyalkyl groups of 1 to 8 carbon atoms in the alkyl moiety, and nitro, or R ¹ represents a 5- to 10-membered heterocyclic aromatic group containing one ring system or two nitrogen atoms. A compound according to claim 1, wherein R ¹ represents a phenyl group or a phenyl group substituted in one or more of the meta and para positions, based on its carbon atom attached to said morpholine ring, with substituents selected from the group consisting of halogen atoms, carboxy, functionally modified carboxy and nitro groups; represents a 5- to 10-membered heterocyclic aromatic group containing as the only ring heteroatom a nitrogen atom. A compound according to claim 1, wherein R ¹ represents phenyl (lower) alkyl, α, α-diphenyl (lower) alkyl, or α-naphthyl (lower) alkyl, which is unsubstituted or substituted in one or more positions with substituents selected from the group consisting of halogen atoms, hydroxy, C 1 -C 4 alkoxy, carboxy, functionally modified carboxy, carboxyalkyl of 1 to 8 carbon atoms in the alkyl moiety, functionally modified carboxyalkyl groups of 1 to 8 carbon atoms in the alkyl moiety and nitro. A compound according to claim 1, wherein R ¹ represents an a-phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety which is unsubstituted or substituted at one or more positions by substituents selected from the group consisting of halogen atoms, carboxy, functionally modified carboxy, and nitro. A compound according to claim 1 wherein R ¹ represents phenyl, 3-iodophenyl, 3,4-dichlorophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3- (methoxycarbonyl) phenyl, 3-nitrophenyl, benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl. A compound according to any one of claims 1 to 6, wherein R ² is lower alkyl, lower alkenyl, lower alkynyl, oxo (lower) alkyl, hydroxy- or dihydroxy (lower) alkyl, hydroxy (lower) alkenyl group, a mono-, di- or poly-halo (lower) alkyl a mono-, di- or polyhalogen (lower) alkenyl group, a mono-, di- or polyhalogen (hydroxy) (lower) alkyl group, a mono-, di- or polyhalogen (hydroxy) (lower) alkenyl group, (lower) alkoxy (lower) alkyl, di (lower) alkoxy (lower) alkyl, (lower) alkoxy (hydroxy) (lower) alkyl, (lower) alkoxy (halogen) (lower) alkyl, (lower) alkylthio (lower) alkyl, di- (lower) alkylthio (lower) alkyl, cyano (lower) alkyl, acylamino (lower) alkyl, cycloalkyl, hydroxycycloalkyl, oxa-, dioxa-, thia- or dithiacycloalkyl, cycloalkyl (lower) alkyl) , a cycloalkenyl (lower) alkyl group, a cycloalkyl (hydroxy) (lower) alkyl group, a ((lower) alkylthio) cycloalkyl (hydroxy) (lower) alkyl group, or a mono- or diphenyl (lower) alkyl group which is unsubstituted or mono -, di- or trisubstituted with substituents selected from the group consisting of lower alkyl groups, lower alkoxy groups, halogen atoms, hydroxy and / or trifluoromethyl groups, or naphthyl (lower) alkyl groups or unsubstituted or halo-substituted thienyl-, furyl- or pyridyl (lower) groups group. A compound according to claim 7, wherein R ² is C 1 -C 7 alkyl, C 1 -C 4 α-dialkoxyalkyl in each alkoxy moiety and C 1 -C 4 alkyl moieties, cyanoalkyl (C 1 -C 4) alkyl, (C 1 -C 5) acylaminoalkyl, (C 3 -C 6) cycloalkylalkyl, (C 1 -C 4) alkyl, (C 3 -C 6) cycloalkenylalkyl C 1 -C 4 -alkyl, or C 1 -C 4 -phenylalkyl, which is unsubstituted or mono-, di-or tri-substituted by C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy; C, hydrox, hydroxy and / or halogen. The compound of claim 7, wherein R ² is C 1 -C 5 alkyl, α, α-dialkoxymethyl of 1 to 4 carbon atoms in each alkoxy moiety, α, α-dialkoxyethyl of 1 to 4 carbon atoms in each alkoxy moiety, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 4 carbon atoms in the alkyl moiety, a benzyl group or a 4-methoxybenzyl group. A compound according to claim 7, wherein R represents a cyclohexylmethyl or 4-methoxybenzyl group. A compound according to any one of claims 1 to 10, wherein the unsubstituted or substituted hydrocarbon group R ^x is an alkyl group of 1 to 10 carbon atoms, an alkenyl group of 2 to 10 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms , (C 4 -C 13) cycloalkylalkyl, (C 6 -C 10) aryl or (C 7 -C 13) aralkyl group which are unsubstituted or substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxy, alkoxy groups of 1 up to 4 carbon atoms, carboxy, functionally modified carboxy groups, carboxyalkyl groups having 1 to 8 carbon atoms in the alkyl moiety, functionally modified carboxyalkyl groups having 1 to 8 carbon atoms in the alkyl moiety, and nitro. A compound according to any one of claims 1 to 11, wherein R ^x represents a hydrogen atom, a lower alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 8 carbon atoms or an aralkyl group having 7 to 9 carbon atoms. A compound according to claim 12, wherein R ^x represents a hydrogen atom or an isopropyl group. A compound according to any one of claims 1 to 13, wherein rT represents a group R 1 _a and represents an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or an aralkyl group having 7 to 13 carbon atoms which is unsubstituted or substituted by hydroxy or alkoxy having 1 to 4 carbon atoms. A compound according to any one of claims 1 to 13, wherein R ^y represents an NH-protecting group and represents an acyl group, an alkoxycarbonyl group or an aralkoxycarbonyl group. A compound according to any one of claims 1 to 13, wherein RY represents a hydrogen atom, a lower alkyl group, a C7 -C9 aralkyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group. The compound of claim 1, wherein R ¹ represents phenyl, 3-iodophenyl, 3,4-dichlorophenyl, 3-cyanophenyl, 3- (methoxycarbonyl) phenyl, 3-carboxyphenyl, 3-nitrophenyl, benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl, R is cyclohexylmethyl or 4-methoxybenzyl, R ^x represents a hydrogen atom or an isopropyl group, and R ^y represents a hydrogen atom, a methyl or a benzyloxycarbonyl group, A compound according to any one of claims IA, IB, IC or ID 1 to 17 wherein R ^{1 is} as defined in any one of claims 1 to 6, R ^{2 is} as defined in any one of claims 1 and 7 to 10, R ^{x is} as defined in any one of claims 1 to 11 and 13 and R 1 is as defined in any one of of claims 1 and 14 to 16. A compound of formula VA R ² (VA) OH wherein R ^{1 is} as defined in any one of claims 1 to 6, R ^{2 is} as defined in any one of claims 1 and 7 to 10 and R ^{x is} as defined in any one of claims 1 to 11 to 13, or a salt or ester thereof. A compound of formula III ABOUT OR ⁵ in which R ² is as defined in any one of claims 1 and 7 to 10, X represents a halogen atom, and R ⁵ represents an alkyl group having 1 to 8 carbon atoms, provided that R ² does not represent a methyl group when R ⁵ represents an ethyl group. A compound of formula (II), (VI), (VII) or (VIII) CN 4 I R-c-nhr ⁶ | (Vi) R ^x COOR ⁷ R ⁴ -C-NHR ⁶ I R ^x COOR ⁷ ₄ I R ⁴ -C-NH ₂ R ^x (VII) (VIII) wherein R ⁴ represents a 3-methoxycarbonylphenyl group, R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms which is unsubstituted or substituted by an unsubstituted or substituted aryl group having 6 to 10 carbon atoms, 100 R ⁷ represents an alkyl group having 1 to 10 carbon atoms, and R ^x represents a hydrogen atom or an unsubstituted or substituted hydrocarbon group, or a compound of formula II or VIII, wherein: R ⁴ is 3,4-dichlorophenyl, a * 7 R represents an alkyl group having 1 to 10 carbon atoms, or a compound of formula II wherein R ⁴ represents a monovalent aromatic group attached to said carbon atom via its carbon atom, and R ^x represents an unsubstituted or substituted hydrocarbon group, provided that when R ⁴ represents a phenyl group, R ^x does not represent a methyl group, an ethyl group, a - (CH 2 R 4 SCH 8), allyl or a hydroxymethyl group when R ^x represents an aminomethyl group, then R ^{4 is} not phenyl, p-hydroxyphenyl or p-methoxyphenyl, and when R ⁴ is 2,4-dichlorophenyl then R ^{x is} not N-triazolylmethyl, or a compound of formula II wherein R ⁴ represents an iodobenzyl group, and R ^x represents a hydrogen atom or an unsubstituted or substituted hydrocarbon group, or a compound of formula II wherein: 4 Ί R represents a monovalent araliphatic group R ¹ · as defined in any one of claims 1 and 4 to 6, and 101 R ^x represents an unsubstituted or substituted hydrocarbon group as defined in any one of claims 1 and 11 to 13 other than a hydroxymethyl group, provided that when R ^x represents a methyl group, then R ⁴ does not represent a benzyl, 4-chlorobenzyl, 3,4 -dichlorobenzyl, 3,4-dimethoxybenzyl, 2-phenylethyl, 1,3-benzodioxole-5-methyl, 3-phenyl-1-aminopropyl, α-hydroxybenzyl, α-hydroxy-α-methylbenzyl or α-hydroxy-α-methyl -4-nitrobenzyl, and when R ⁴ represents a benzyl group, then R ^{x is} not an allyl group or -C (CH 2) SCH-j. A compound of formula XVIII (XVIII) wherein R ^{1 is} as defined in any one of claims 1 to 6, R is as defined in any one of claims 1 and 7 to 10, R is as defined in any one of claims 1 to 11 and 13 and RY as defined in any one of claims 1 to 14 to 16, or a salt or ester thereof. A process for the preparation of a compound of formula I according to claim 1, wherein R Y represents a hydrogen atom, characterized in that the compound of formula II OH R ^x CH ₂ (II) Wherein R ⁴ is a group R 1 as defined in any one of claims 1 to 6, wherein R ⁴ is not substituted with a carboxyl group, and R ^x is as defined in any one of claims 1 and 11 to 13, with The compound of formula (III), which is not substituted by a carboxyl group, is reacted with a compound of formula III R ² (III) OR ⁵ wherein R ² is as defined in any one of claims 1 and 7 to 10, X represents a halogen atom, and R ³ represents an alkyl group having 1 to 8 carbon atoms, in the presence of a base, to form a compound of formula IV (IV) the symbols R and R are as defined in formula II, followed, if necessary, carrying out one or more substitution reactions to change the nature of a substituent in ^R4 and / or ^Rx and / or by hydrolysis of an ester substituent in ^R4 and / or R ^x to a carboxyl group and / or the conversion of the ester group -OR ⁵ to a hydroxy group. 24. The process of claim 23 wherein the reaction of compounds of formulas II and III is carried out by adding a weak base to a mixture of compounds of formulas II and III in a solvent to form an intermediate of formula V 103 wherein R ² , R ⁴ , R ⁵ and R ^{x have the} meanings defined in claim 23, and then subjecting the intermediate to a reaction with a base under harder conditions than those used in its formation. A process according to claim 23 or 24, wherein R ⁴ in the compound of formula IV contains a nitro group on the aryl or heteroaryl ring, and this group is gradually converted to an amino group by reduction, halogen by diazotization of the amino group and subsequent reaction with cyanide. alkali metal and then to the carboxyl group by hydrolysis of the cyano group. A process for the preparation of a compound of formula III according to claim 20, characterized in that the compound of formula IX HPR ² (IX) OR ³ is reacted with a compound of formula X x-ch = ch-ch ₂ -x (X) wherein R ² , R ⁵ and X are as defined in claim 20 in the presence of a silylating agent that reacts with a compound of formula IX to form a trivalent phosphorus silyl derivative which is then reacted with a compound of formula X. 104 A process for the preparation of a compound of formula II according to claim 21, characterized in that the aldehyde or ketone of formula R ⁴ C (= O) R ^X is reacted with an amine of formula r 6nh ₂ and an alkali metal cyanide to form a compound of formula VI CN R ^x and either (a) the compound of formula VI is reacted with an alcohol of formula R ⁷ OH in the presence of an acid to form a compound of formula VIIa COOR ⁷ 4 I R-NHR ° (VII) I R ^x from the compound of formula VII removes the group R 6, if other than hydrogen, to give a compound of formula VIII COOR ⁷ ₄ I R ⁴ -C -NH ₂ (VIII) I The R ^x compound of formula VIII is reacted with an amino protecting agent to convert the amino group to the protected amino group, the -COOR ⁷ ester moiety is reduced to the -CH ₂ OH group in the protected compound, and the protecting group is removed to form the free amino group. 105 the symbols R ⁴ , R ⁶ , R ⁷ and R ^x have the meanings defined in claim 21, or (b) the compound of formula VI is subjected to acid hydrolysis to convert said cyano group to a carboxyl group, and the resulting aminocarboxylic acid is then reduced by reaction with borane -dimethylsulfide in the presence of boron trioxide complex. A process for the preparation of a compound of formula II according to claim 21, characterized in that the aminocarboxylic acid of formula R ⁴ C (R ^X ) (NH ₂ ) COOH, wherein R ⁴ and R ^{x have the} meanings defined in claim 21, is reduced, by reaction with borane-dimethylsulfide in the presence of a boron trifluoride complex. A process for the preparation of a compound of formula I according to claim 1, wherein R ^y represents a group, characterized in that the compound of formula I according to claim 1, wherein R 1 represents a hydrogen atom, is reacted (a) with a compound of the general formula or (b) with an aldehyde of the formula R ^ CHO, wherein R ^yb is a hydrogen atom or a R ^ group as defined in claim 1 , and a reducing agent that reduces imines to amines. A process for the preparation of a compound of formula I according to claim 1, wherein R 1 represents an NH-functional group, characterized in that the compound of formula I according to claim 1, wherein R 1 represents a hydrogen atom with an acyl halide, carboxylic anhydride acid, alkoxycarbonyl or aralkoxycarbonyl halide or alkyl or aralkyldicarbonate. A process for the preparation of a compound of formula I according to claim 1, wherein R 1 is a group R 1 _a or a protecting group NH, characterized in that the compound of formula IIA 106 R ⁴ OH ch ₂ (II) NHR ^yl with a compound of formula III as defined in claim 23, in the presence of a base to form a compound of the formula IVA (IVA) as defined in claim 23 and R / is R _and / or a protecting group NH, as defined in any one of claims 1 to 14 to 16, followed by, if necessary, one or more substitution reactions to change the nature of the substituent in R ⁴ and / or R ^x and / or hydrolyzing the ester moiety as a substituent in R ⁴ or (a) R ^x to a carboxyl group, and / or the conversion of an ester group -OR 1 to a hydroxy group. A process for the preparation of a compound of formula I according to claim 1, characterized in that the compound of formula XIV (XIV) 107 undergoes a reaction to convert the present primary hydroxy group to a leaving group, causing cyclization to give a compound of formula XV (XV) wherein R ² , R ⁴ , R ^x and R ^{Y are} as defined in claim 1 and R ⁵ is as defined in of claim 23, and, if necessary, the R 6 group is subsequently replaced with a hydrogen protecting group and / or one or more substitution reactions are performed to change the nature of the substituent in R ⁴ and / or R ^x and / or hydrolyzing the ester moiety as a substituent in R ⁴ and / or R ^x to a carboxyl group and / or the conversion of the ester group -OR ⁵ to a hydroxy group. A process for the preparation of a compound of formula XIV according to claim 32, characterized in that the compound of formula II as defined in claim 23 is reacted with a compound of formula XVI (XVI). Wherein S and R are as defined in claim 32 and Z is a leaving group, in the presence of a hindered base, to form a compound of formula XVII H (XVII) 108 wherein R ² , R ⁴ , R ⁵ and R ^{x have the} meanings defined in claim 32, and the illustrated hydrogen atom attached to the nitrogen atom is replaced by an NH-protecting group. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19 or 22, optionally together with a pharmaceutically acceptable carrier. T " A compound according to any one of claims 1 to 19 or 22 for use in a therapeutic method of treating a warm-blooded animal. Use of a compound according to any one of claims 1 to 19 or 22 for the preparation of a medicament for the treatment or prevention of conditions characterized by GABAg receptor stimulation. 37. A method of treating or preventing a warm-blooded mammal condition characterized by stimulating a GABAg receptor, comprising administering to said mammal a compound according to any one of claims 1 to 19 or 22.