CZ66498A3 - Substituted phosphinic acids, processes of their preparation, pharmaceutical composition containing thereof and their use - 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

(57) Annotation:

The compounds of general formula I are described, in which R ¹ is a monovalent aromatic or araliphatic group attached to the mentioned carbon atom through its carbon atom, R ² is unsubstituted or substituted hydrocarbyl, R ^x is CO hydrogen or unsubstituted or substituted hydrocarbyl, R ^y Is hydrogen, R ^y a or a group protecting the NH function, and R ^y a is unsubstituted or substituted hydrocarbyl, and salts or esters thereof. The methods of their preparation and the intermediates used in these methods, the pharmaceutical composition containing them, and their use are described.

664-98 •0 0000

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0·

00 0 0 0 0 0 • ·00 00 0#00 0 0 0 0 0 00 ·0 ·♦

175,765/KB

Substituted phosphinic acids, methods of their preparation, pharmaceutical composition containing them and their use

Field of technology

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

Current state of the art

WO 94/22843 describes phosphinic acids of the general formula

in which the symbols R _x and R ₂ are both hydrogen atoms, both methyl groups or R _x and R ₂ together with the carbon atom to which they are attached form a cyclopentyl group. These compounds are reported to act as GABA _g antagonists.

The essence of the invention

It has now been found that by preparing new substituted phosphonic acids containing a morpholine ring, compounds with a remarkably high binding affinity to the GABA _b receptor can be obtained.

Accordingly, the invention describes compounds which are substituted phosphinic acids of general formula I

- d2

OH (i:

and*

V • 0 ·00· 0 ♦ 4

V 0«0· « · · * » * • 9 ♦ ·« «000 «9 » 0 0 • ·· « 4 • 0 « • * ·· in which

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

R ² means an unsubstituted or substituted hydrocarbyl group,

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

R ^y means a hydrogen atom, a group R ^y a or a group protecting the function NH, a

R/ represents an unsubstituted or substituted hydrocarbyl group, or their salts or esters.

The aromatic group in the meaning of the symbol R ¹ can contain up to 40 carbon atoms and can 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 these groups can be unsubstituted or substituted by one or more substituents such as halogen atoms, hydroxy group, 1- to 4-carbon alkoxy groups, carboxy group, functionally modified carboxy groups including esterified carboxy groups, amidated carboxy groups and cyano groups, carboxyalkyl groups with 1 to 8 carbon atoms in alkyl part, a functionally modified carboxyalkyl group with 1 to 8 carbon atoms in the alkyl part or a nitro group.

An aromatic group in the meaning of the symbol R ¹ is preferably an aryl group with 6 to 15 carbon atoms, which can be unsubstituted or substituted in one or more positions by substituents selected from the group including halogen atoms, a carboxy group, functionally modified carboxy groups, * 999

9999

9 9 9 9

9999 9 9

9 9 9 9 9

9 9 9 9 9

9 99 9 9 • 9 9 9 carboxyalkyl groups with 1 to 8 carbon atoms in the alkyl part, functionally modified carboxyalkyl groups with 1 to 8 carbon atoms in the alkyl part and a nitro group, or the aromatic group in the meaning of the symbol R ¹ is a five- to ten-membered heterocyclic an aromatic group containing one or two nitrogen atoms in the ring system. Even more preferably, an unsubstituted or substituted aryl group in the meaning of the symbol R ¹ is a phenyl group or a phenyl group substituted in one or more of the meta- and para-positions. referred to its carbon atom attached to said morpholine { ring, substituents selected from the group comprising * halogen atoms, carboxy group, functionally modified carboxy group and nitro group. Examples of such substituted phenyl groups include phenyl groups with mono- or disubstituted substituents selected from the group consisting of a chlorine atom; bromine atom; iodine atom; carboxy group, - COOR ³ group, where R ³ represents an alkyl group with 1 to 8 carbon atoms, such as a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl group, which is optionally substituted by a halogen, a hydroxy group or an alkoxy group with 1 to 4 carbon atoms; a carbamoyl group; N-alkylcarbamoyl groups having 1 to 4 carbon atoms in the alkyl part, such as methyl or ethylcarbamoyl; N,N-dialkylcarbamoyl groups having 1 to 4 carbon atoms in each alkyl moiety, such as dimethyl or diethylcarbamoyl; cyano group; carboxyalkyl groups having 1 to 4 carbon atoms in the alkyl moiety, such as the carboxymethyl group of alkoxycarbonylalkyl groups having 1 to 8 carbon atoms in

1 alkoxy part and 1 to 4 carbon atoms in the alkyl part, such as { is a methoxy- or ethoxycarbonylmethyl group; carbamoyl*' alkyl groups having 1 to 4 carbon atoms in the alkyl moiety, such as carbamoylmethyl; N-alkylcarbamoylalkyl groups having 1 to 4 carbon atoms in each alkyl moiety, such as methyl or ethylcarbamoylmethyl; N,N-dialkylcarbamoylalkyl groups with 1 to 4 carbon atoms in each alkyl ·* • 4 444* 44 4444 4« *4« «4 4 44*4 «44* « · 4 4 44« β 4 *4* 4 « 4 4444 * ¥ 4 4 «4*4 «44

4« «4« 4« 44 «4 4-4 moieties such as a dimethyl- or diethylcarbamoylmethyl group; cyanoalkyl groups having 1 to 4 carbon atoms in the alkyl moiety, such as cyanomethyl group; and a nitro group. Even more preferably, a heterocyclic aromatic group in the meaning of the symbol R ¹ is a five- to ten-membered heterocyclic group containing a nitrogen atom as the only ring heteroatom, for example a pyridyl or indolyl group.

The araliphatic group in the meaning of the symbol R ¹ can contain 7 to 40 carbon atoms and can be a phenyl(lower)alkyl group, for example a benzyl or 2-phenylethyl group, an α,α-diphenyl(lower)alkyl group, such as a diphenylmethyl group, or an α-naphthyl (lower) alkyl group such as a naphthylmethyl group, all of which may be unsubstituted or substituted in one or more positions, which may be ortho, meta, or para, substituents selected from the groups specified above in, in the case of aromatic groups in the meaning of the symbol R ¹ . Preferably, the araliphatic group in the meaning of the symbol R ¹ is an α-phenylalkyl group with 1 to 4 carbon atoms in the alkyl part, which is unsubstituted or substituted in one or more positions by substituents selected from the group including halogen atoms, carboxy group, functionally modified carboxy groups and nitro group.

In particularly preferred compounds according to 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-ylol group.

An unsubstituted or substituted hydrocarbyl group in the meaning of the symbol R ² can generally contain 1 to 40 carbon atoms. It can be, for example, an alkyl, cycloalkyl, alkenyl or alkynyl group or an alkyl, cycloalkyl or alkenyl group substituted by one or more

4 4 4 4»

Ml* » 4 4 > 4 · ·

4 4« 4

4 4

4 4

4 4 4 * « 4 • 4 4.4 substituents such as halogen atoms, hydroxy group, alkoxy groups with 1 to 8 carbon atoms, thio group, alkylthio groups with 1 to 8 carbon atoms, cyano group, acylamino groups, cycloalkyl groups with 3 to 8 carbon atoms, cycloalkyl groups with 3 to 8 carbon atoms substituted, for example, by one or more substituents such as a hydroxy group, 1 to 8 carbon atom alkoxy groups, a 1 to 8 carbon atom thio group or an alkylthio group with 1 to 8 carbon atoms, a 3 to 3 carbon atom cycloalkenyl group, a 6 to 15 carbon atom aryl group of carbon, aryl groups with 6 to 15 carbon atoms substituted for example by one or more substituents such as a hydroxy group, alkoxy groups with 1 to 8 carbon atoms, halogen atoms or a trifluoromethyl group, heteroaryl groups or heteroaryl groups substituted by one or more substituents such as halogen atoms.

Aliphatic radicals in the meaning of the symbol R ² 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 polyhalo(lower)alkyl groups, mono-, di- or polyhalo(lower)alkenyl groups, mono-, di- or polyhalo(hydroxy)(lower)alkyl groups, mono-, di- or polyhalo(hydroxy) (lower ) alkenyl groups, (lower) alkoxy (lower) alkyl groups, di (lower) alkoxy (lower) alkyl groups, (lower) hydroxy (hydroxy) (lower) alkyl groups, (lower) alkoxy (halogen) (lower) alkyl groups, (lower)alkylthio(lower)alkyl groups and di(lower)alkylthio(lower)alkyl groups.

Cycloaliphatic residues in the meaning of the symbol R ² are, for example, cycloalkyl, hydroxycycloalkyl, oxa-, dioxa-, thia- and dithiacycloalkyl groups.

Cycloaliphatic-aliphatic residues in the meaning of the symbol R ² are, for example, cycloalkyl(lower)alkyl groups, cycloalkenyl(lower)alkyl groups, cycloalkyl(hydroxy)(lower)alkyl• 4 • ·

4 · *4 4*4

4 4 4 « 4 4 4 r · 4 * « 4 · 4 *4 4 · ol groups and ((lower)alkylthio)cycloalkyl(hydroxy)(lower)alkyl groups.

Araliphatic radicals in the meaning of the symbol R ² are, for example, phenyl (lower) alkyl radicals, which are unsubstituted or mono-, di- or tri-substituted substituents selected from the group comprising lower alkyl groups, lower alkoxy groups, a hydroxy group, halogen atoms and/or a trifluoromethyl group, preferably α-phenyl(lower)alkyl groups substituted as above or unsubstituted α,α-diphenyl- or α-naphthyl(lower)alkyl groups.

Heteroarylaliphatic radicals in the meaning of the symbol R ² are, for example, thienyl-, furyl- or pyridyl(lower) alkyl radicals, which are unsubstituted or substituted, especially mono- or disubstituted, by halogen, preferably unsubstituted α-thienyl-, α-furyl- or α- pyridyl (lower) alkyl groups.

Above and below in this text, lower residues and compounds mean, for example, residues 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 with 1 to 7 carbon atoms, preferably an alkyl group with 1 to 4 carbon atoms, such as a methyl, ethyl, propyl, isopropyl or butyl group, but it can also be isobutyl, sec-butyl or tert-butyl group or an alkyl group having 5 to 7 carbon atoms, such as a pentyl, hexyl or heptyl group.

A lower alkenyl group is, for example, an alkenyl group with 2 to 4 carbon atoms, such as a vinyl, allyl or but-2-enyl group, but it can also be an alkenyl group with 5 to 7 carbon atoms, such as a pentenyl, hexenyl or heptenyl group.

A lower alkynyl group is, for example, alkynyl

4 4·4 «

4444 a group with 2 to 7 carbon atoms, preferably an alkynyl group with 3 to 5 carbon atoms, which carries a triple bond in a higher position than in the α,β-position, for example 2-propynyl (propargyl), but-3-yn-1 -yl, but-2-yn-1-yl or pent-3-yn-1-yl group.

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

A phenyl (lower) alkyl group is, for example, benzyl,

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

2-phenylethyl, 2-phenylpropyl-1-yl or 3-phenylpropyl-1-yl group.

A thienyl-, furyl- or pyridyl(lower)alkyl group is, for example, a thienyl·-, furyl- or pyridylmethyl group, a Ι-thienyl-, 1-furyl- or 1-pyridylethyl group, a 2-thienyl-, 2-furyl- or 2 -pyridylprop-2-yl group, or, secondarily, 2-thienyl-, 2-furyl- or 2-pyridylethyl group, 2-thienyl-, 2-furyl- or 2-pyridylprop-i-yl group, or 3- thienyl=, 3-furyl- or 3-pyridylprop-1-yl group.

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

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

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

9«·*»1

9 » β 9 ··· * · ·

9 · «· · ··

Μ »·Μ 9 · 9 « · 9

M 9 *

9 9 ·

9 9 <9

A hydroxy(lower)alkenyl group carries a hydroxy group preferably in the α-position and a double bond preferably in a position higher than the α,β-position, and is for example the corresponding α-hydroxyalkenyl group with 3 to 5 carbon atoms, for example 1-hydroxybut-2- an enyl group.

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

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

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

A lower alkoxy group is, for example, an alkoxy group with 1 to 7 carbon atoms, preferably an alkoxy group with 1 to 4 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a butoxy group, but it can also be an isobutoxy group, sec. 5 to 7 carbon atoms such as pentyloxy, hexyloxy or heptyloxy.

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

··*· « »

4 4 4 • 4 * ♦

4 44 ·♦ 4444 *4 *

• 44 4 4 4

A cyano(lower)alkyl group is, for example, a cyanoalkyl group with 1 to 4 carbon atoms in the alkyl part, such as a cyanomethyl or 2-cyanoethyl group.

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

(Lower)Alkoxy(Lower)alkyl group is, for example, an Alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxy part and 1 to 4 carbon atoms in the alkyl part, such as methoxy- or ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxy - or 3-ethoxypropyl or 1- or

2-methoxybutyl group.

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

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

(Lower)Alkoxy(halo)(Lower)alkyl is, for example, an alkoxy(halo)alkyl group with 1 to 4 carbon atoms in the alkoxy part and 2 to 5 carbon atoms in the alkyl part, such as 2-fluoro-3-methoxybutyl.

A (lower)alkylthio(lower)alkyl group is, for example, an alkylthioalkyl group with 1 to 4 carbon atoms in each alkyl part, such as methylthio- or ethylthiomethyl, • · • · · ·· · • · * « · * ·· • · · · • « · ν· · · * ·· « * · • « ♦ · • * · *« > · · 4 ř · · * ··· · 4

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

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

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

A halogen is a halogen with an atomic number up to and including 53, i.e. fluorine, chlorine, bromine or iodine.

A cycloalkyl group is, for example, a cycloalkyl group with 3 to 8 carbon atoms, especially a cycloalkyl group with 3 to 6 carbon atoms, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

A hydroxycycloalkyl group is, for example, an α-hydroxycycloalkyl group having 3 to 6 carbon atoms, such as

1-hydroxycyclopropyl, 1-hydroxycyclobutyl or 1-hydroxycyclohexyl group.

An oxa- or thiacycloalkyl group is, for example, an oxane or thiacycloalkyl group with 3 to 8 carbon atoms, especially an oxa- or thiacycloalkyl group with 3 to 6 carbon atoms, such as 2-oxacyclopropyl (oxiranyl), 2- or

3-oxacyclobutyl (oxetanyl), 2- or 3-thiacyclobutyl (thietanyl), 2- or 3-oxacyclopentyl (tetrahydrofuranyl), 2- or 3-thiacyclopentyl (thiolanyl), or

2- oxacyclohexyl (tetrahydropyranyl) group.

The dioxacycloalkyl group is, for example, a 1,3-dioxacycloalkyl group having 3 to 8 carbon atoms, such as 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl.

A dithiacycloalkyl group is, for example, a 1,3-dithiacycloalkyl group with 3 to 8 carbon atoms, such as ♦ · * ♦ 0 · 0 « « ·

00«· 0 « 0 0 «0« » ♦ « 0 ^J 0 ·· 0000 0 90 · *000 0«0

0« «« ·« «« 0« 00

1,3-dithiolan-2-yl or 1,3-dithian-2-yl group.

A cycloalkyl (lower) alkyl group is, for example, a cycloalkylalkyl group with 3 to 8 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkyl part, especially a cycloalkylalkyl group with 3 to 6 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkyl part , such as an α-(cycloalkyl) alkyl group with 3 to 6 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkyl part, for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

A cycloalkenyl (lower) alkyl group is, for example, a cycloalkenylalkyl group with 3 to 8 carbon atoms in the cycloalkenyl part and 1 to 4 carbon atoms in the alkyl part, especially a cycloalkenylalkyl group with 3 to 6 carbon atoms in the cycloalkenyl part and 1 to 4 carbon atoms in the alkyl part , such as an α-(cycloalkenyl) alkyl group with 3 to 6 carbon atoms in the cycloalkenyl part and 1 to 4 carbon atoms in the alkyl part, for example cyclopent-1-enylmethyl, cyclopent-2-enylmethyl, cyclopent-3-enylmethyl, cyclohex- 1-enylmethyl, cyclohex-2-enylmethyl or cyclohex-3-enylmethyl group.

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

A (lower)alkylthiocycloalkyl(hydroxy)(lower)alkyl group is, for example, a 1-(alkylthiocycloalkyl)-1-hydroxyalkyl group with 3 to 6 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in each alkyl part, such as (2•9 ··*

9 9 * 9 «99

Φ ♦'

9 9 ♦ 9,999

-methylthiocycloprop-1-yl)hydroxymethyl group.

In the preferred compounds according to the invention, R ² means a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an oxo(lower)alkyl group, a hydroxy or dihydroxy(lower)alkyl group, a hydroxy(lower)alkenyl group, a mono-, di- or polyhalogen ( lower}alkyl group, mono-, di- or polyhalo(lower)alkenyl group, mono-, di- or polyhalo(hydroxy)(lower)alkyl group, mono-, di- or polyhalo(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 group, di(lower)alkylthio(lower)alkyl group, cyano(lower)alkyl group, acylamino(lower)alkyl group, cycloalkyl group, hydroxycycloalkyl group, oxa-, dioxa-, thi.or dithiacycloalkyl group , cycloalkyl(lower)alkyl, cycloalkenyl(lower}alkyl, cycloalkyl(hydroxy)(lower)alkyl, ((lower)alkylthio)cycloalkyl(hydroxy)(lower)alkyl, or mono- or diphenyl(lower)alkyl a group which is unsubstituted or mono-, di- or tri-substituted by a lower alkyl group, a lower alkoxy group, a halogen, a hydroxy group and/or a trifluoromethyl group, a naphthyl (lower) alkyl group or an unsubstituted or halogen substituted thienyl-, furyl- or pyridyl (lower) alkyl group.

In the more preferred compounds of the general formula IR ² represents an alkyl group with 1 to 7 carbon atoms, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl group, an α,α-dialkoxyalkyl group with 1 to 4 carbon atoms in each alkoxy part and 1 to 4 carbon atoms in the alkyl moiety, especially an α,α-dialkoxymethyl or -ethyl group with 1 to 4 carbon atoms in each alkyl moiety, such as dimethoxy- or diethoxymethyl • · »»**1, t« ·«· · » · ····* ., *'£ * · • » Μ ·ή » · · ·. 9 9 » · ^ι • * ·** * 4 » · *4

4 4 ·

41' 4 4 4

44 4 4

4 4

4 4 9 or 1,1-diethoxyethyl group, cyanoalkyl group of 1 to 4 carbon atoms in the alkyl part, such as cyanomethyl or 2-cyanoethyl group, acylaminoalkyl group·' with 1 to 5 carbon atoms in the alkyl part, such as -acetylaminoethyl, an acetylaminopropyl, acetylaminopentyl or benzoylaminomethyl group, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkyl part, such as a cyclopropyl or cyclohexylmethyl group, a cycloalkenylalkyl group having 3 to 6 » carbon atoms in the cycloalkenyl part and 1 to 4 carbon atoms in the ^K alkyl part, such as a cyclohex-3-enylmethyl " group, ^f - or a phenylalkyl group with 1 to 4 carbon atoms in the alkyl » ' ( · . part., such. is a benzyl group, which is unsubstituted or mono-, di- or tri-substituted by an alkyl group having 1' to 4 carbon atoms, such as a methyl group, an oxy group having 1 to 4 carbon atoms, such as a methoxy group, a hydroxy group, and/or a halogen such as fluorine, chlorine or iodine.

In even more preferred compounds according to the invention, R ² represents an alkyl group having 1 to 5 carbon atoms; such as a methyl, ethyl or butyl group, · an α,α-dialkyloxymethyl group of 1 to 4 carbon atoms in each *alkyl moiety, such as a dimethoxymethyl group, ^; ' ⁱⁿ ''a, ct-dialkoxyethyl group sl· to -4 atoms . of carbon ^: in each* alkoxy part, such as 1,1-diethoxyethyl group, cycloalkylalkyl group with 3 to 6 carbon atoms* cycloalkyl part and 1 to 4 carbon atoms in the alkyl · part', such as/is* cyclopropylmethyl or ¹ cyclohexylmethyl' group, <>. a benzyl c group or a 4-methoxybenzyl group.*In particularly preferred ₂ compounds according to the invention, R represents a cyclohexylmethyl v or a 4-methoxybenzyl group.

An unsubstituted or substituted hydrocarbyl group in the meaning of the symbol R* can contain up to 40 carbon atoms and can be an alkyl group with 1 to 10 carbon atoms, an alkenyl group with 2 to 10 carbon atoms; cycloalkyl • 0 0000 0 0 · * 0 000 • · * · 4 *· 0··

0*40

0 0

0 0 0 4 0 « 4 0 0 »· «0 ·< 00 4 « 4 · • 4 00 »«· · · 0 0 ·

0» ·· a group of 3 to 8 carbon atoms, a cycloalkylalkyl group of 4 to 13 carbon atoms, an aryl group of 6 to 10 carbon atoms or an aralkyl group of 7 to 13 carbon atoms, any of these groups may be substituted by one or more substituents selected from the group specified above in the case of R ¹ . R ^x preferably means a hydrogen atom, a lower alkyl group, a cycloalkyl group with 3 to 6 carbon atoms, an aryl group with 6 to 8 carbon atoms or an aralkyl group with 7 to 9 carbon atoms, especially a hydrogen atom or an isopropyl group.

The unsubstituted or substituted hydrocarbyl group Ry in the meaning of the symbol can contain up to 40 carbon atoms and can be, for example, an alkyl group with 1 to 10 carbon atoms, a cycloalkyl group with 3 to 8 carbon atoms or an aralkyl group with 7 to 13 carbon atoms, while any of these groups may be unsubstituted or substituted by a hydroxy group or an alkoxy group having 1 to 4 carbon atoms. The group protecting the NH function in the meaning of the symbol R ^y can be, for example, an acyl group, such as an acetyl, trifluoroacetyl, benzoyl or p-nitrobenzoyl group, or an alkoxycarbonyl group or an armethoxycarbonyl group, such as a tert-butoxycarbonyl or benzyloxycarbonyl group. R ^y preferably means a hydrogen atom, a lower alkyl group, an aralkyl group with 7 to 9 carbon atoms, an acetyl group, a benzoyl group, a tert.butoxycarbonyl s-group or a benzyloxycarbonyl group, especially a hydrogen atom, methyl, ethyl, benzoyl, butoxycarbonyl or benzyloxycarbonyl group.

Particularly preferred compounds according to the invention are compounds of general formula I in which

R ¹ represents phenyl, 3-iodophenyl, 3,4-dichlorophenyl, 3-cyanophenyl, 3-(methoxycarbonyl)phenyl,

3-carboxyphenyl, 3-nitrophenyl, benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonyl« · ih t £ ' t «: « *·

01.

00« * ·» » • 0 • 0 «

0' 0 0' • 0

0

0 0 ♦' * 000 0 0 «

0

O» benzyl or indol-3-yl group,

R ² means cyclohexylmethyl or 4-methoxybenzyl group,

R* represents a hydrogen atom or an isopropyl group, and

R ^v represents a hydrogen atom, a methyl or benzyloxycarbonyl group,

;.· V and their salts and esters.

The compounds of the general formula I- can be in the form of internal salts and can form both addition salts with acids and salts with bases by conventional reactions for the formation of salts. . .

Acid addition salts of the compounds of general 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, sulphates, hydrogen sulphates or phosphates, or salts with suitable aliphatic or aromatic sulphonic acids or by N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-tor luenesulfonates or N-cyclohexylsulfamates (cyclamates).

''-, - · · · ^v i '·

Salts of the compounds of general formula I with bases are, for example, their salts with pharmaceutically acceptable bases, such as non-toxic salts with metals derived from, metals of groups la, Ib, Ha and lib, for example salts with alkaline metals, especially ⁺ sodium or potassium salts, , salts of alkaline earth metals, « especially calcium or magnesium salts, and also ammonium salts , ^with ammonia or organic, amines or quaternary * ammonium bases, such as unsubstituted or C-hydroxy ¹ lated aliphatic amines, especially mono-, di - or tri(lower)_ ¹ * alkylamines, for example methyl-, ethyl- or diethylamine, mono-, di- or tri(hydroxy(lower)alkyl)amines, such as ethanol-, diethanol-,· or triethanolamine, tris( hydroxymethyl) methylamine.or' 2-hydroxytert.butylamine, or N-(hydroxy0 0 0 * 0 ··· « 0 0

0 ·

000

0-0 0 • »„ « «

Ί| 0 « · • 0 0 0

0« t 0 0 ·

0 00

0 0 0 0 0

0 0 (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 in the general formula I can also be esterified. The invention thus includes compounds of the general formula I in the form of their esters with an alcohol, which may be a C1-C10 alkanol in which the alkyl radical is unsubstituted or substituted, for example, by halogen, cyano or C1-4 alkoxy, such as methanol, ethanol, isopropanol, isobutanoo,

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

If asymmetric carbon atoms are present, the compounds according to the invention can be in the form of mixtures of isomers, especially in the form of racemates, or in the form of pure isomers, especially optical antipodes.

Preferred isomers of the compounds of the general formula I are those isomers in which the group R ¹ and the group bound in the 2-position of the indicated riiophorolinic ring are in the 'reciprocal position* trans, i.e. the isomers of the general formula IA

OH (IA)

R ^y or general formula IB

90 • · « *

4' 4 4«

·. «, 044 0 4

4 9 • 0 4«

- 17 00 0000 </ · 0 '·, 0 ··· . ·. « • i 4 4' ,· ·!Ι « • · * 0 · · 4

4· ··« 4· ·«

4000 ♦I. 0 0

Ο

(ΙΒ) where the symbols R ¹ , R ² , R* and R ^y have the meanings defined above.

Other preferred isomers of the compounds of general formula I are those in which the group R ¹ and the group bound in position 2 of the mentioned morpholine ring are in the mutual cis position, i.e. isomers of general formula IC

R\ or of the general formula ID 'N

Ry

OH

^R2 (IC)

ID) where the symbols R ¹ , R ² , R* and R ^y have the meanings defined above.

Examples of specific compounds of general formula I include:

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

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

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

- [ (3R*,6R*)-6-(butylhydroxyphosphinoylmethyl)morpholin-3-yl]·« »·«» ·· ·«·( «· ·« • t · · * · * * · · i ♦ , 1 · ·«· ·:,·« * · ·« » ί· ·' ,»·· »;ι · ·,'») ··· · · * * 4 4 » · 4 4* • 4 »· · *4 ·« »4 44 benzoic acid,

3-{(3R*,6R*)-6-[(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-ylmethyl ]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, [(2R*,5R*)-5-benzylmorpholin-2-ylmethyl]-4-methoxyphenylmethylphosphinic acid,

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

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

fl

E · · ' A ·«* '·' fl ¹ • « > · · · « »} ·;

• ·« ·« ' · »» » • · *« «

A. * ··

·. «ι ··· · · • # · · «· «·

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

- [ (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-[(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-dihydropyridin- 3-yl)morpholin-2-ylmethyl]phosphinic acid, *9 9999 99 9999 99 99 • · * ♦; · · · 9 · ♦ t

9 9 99, Β 9 9 . 9 9 99

9' ♦, «I 9 9 9, 9 ₍ 9·· 9 9 · 9 9 9 9 999

999 9· 99 99 99 benzyl-[(2R* , 5R*)-5-(β-οχο-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, 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]phosphonic acid, diethoxymethyl- [ (2R* , 5R* )-5-(2-oxo-1,2-dihydropyri' din-4-yl)morpholin-2-ylmethyl]phosphinic acid, benzyl-[(2R*,5R*)-5-(2-oxo-1,2-dihydropyridin-4-yl)morpholin-2-ylmethyl]phosphinic acid 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 Jbenzoic 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,

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

- 21 44 444 • · 4 4 4 « 4 44

4.. 4; 4 44 4 4 • 4 4 · •4 44 44

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,

3- [ (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,

3- [ (3R*,6S*)-6-(benzylhydroxyphosphinoylmethyl)morpholin-3-yl]benzoic acid, diethoxymethyl-{(2R*,5S*)-5-[(3-methoxycarbonyl)phenyl]9··· 99 «9 • 9 9 · 9

9 , · 9 9

9. 9 «« 9 9,

9 >99 •9 9 9 99

- 22 • 9 9999 «« • 9·. 9 9 • 9 9 9 9ι · 9 • · 9 9 9 i • 9 ·. 9.9

9' > 9·· · «« morpholin-2-ylmethyl}phosphinic acid, cyclohexylmethyl-[(2R*,5S*)-5-phenylmorpholin-2-ylmethyl]phosphinic acid, diethoxymethyl-[(2R*,5S*} -5-(3-nitrophenyl)morpholin-2-ylmethyl]phosphinic acid, butyl·-[(2R*,5S*)-5-(3-iodophenyl)morpholin-2-ylmethyl]phosphinic acid

- .i -r-> - - -ji >

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 ¹ acid, [ (2R*,5S*)-5-(3,4-dichlorophenyl)morpholin-2-ylmethyl]pyridine, -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, [ (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)hydroxyphosphinoyl, methyl] 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,

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

9999 « * « « 9 fl ♦· flfl · • fl fl flfl ··« fl • fl fl · flfl flflfl fl fl •

• · • fl • fl flfl fl flfl · • · flfl • flflfl fl flfl fl • fl flfl 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]morpholine-2 -ylmethyl}phosphinic acid,

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

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

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

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

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

3-{(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-dihydropyridin- 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, diethoxymethyl-[(2R*,5S*)- 5-(6-oxo-1,6-dihydropyridin-3-yl)24 • 1 ·«·· ·· ···» «« ··· « * · · · • · ··· · · · · · ·· « · · « · · · · ··· « • · ···«· »» ·· ··* ·· «· »· ·· morpholin-2-ylmethyl]phosphinic acid, cyclohexylmethyl-[(2R *,5S*)-5-(2-oxo-1,2-dihydropyridin-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-dihydropyridin- 4-yl)morpholin-2-ylmethyl]phosphinic acid, benzyl-[(2R*,5S*)-5-(2-oxo-1,2-dihydropyridin-4-yl)morpholin-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,

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

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

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

44 ···· · ···· 4« 44 • • • • • • * 4 4 4 • 4 ··· • • • 4 4 44 • • • 4· • • 4 444 4 4 • • • • • * 4 4 4 4 44 ··· 4* 44 • 4 44

methyl]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*,63*)-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*,53*)-5- [3-(1H-tetrazol-5-yl)phenyl]morpholin-2-ylmethyl}phosphinic acid.

The compounds of general formula I and their pharmaceutically acceptable salts have been found to exhibit valuable pharmacological properties. They bind effectively to the GABA _b receptor and have been found to be GABA (γ-aminobutyric acid) antagonists at this receptor. Regarding this mechanism, antagonism at GABA receptors _may increase the release of fast excitatory amino acid transmitters (transmitters), namely glutamate and aspartate, thereby improving information processing in the brain. This is consistent with the finding that the late post-synaptic inhibitory potential in the hippocampus, which is attributed to the GABA _S mechanism, is disrupted by these antagonists, allowing a faster sequence of nerve impulse transmission.

Chronic treatment with antidepressants and repeated electric shocks have also been found to increase the number of GABA _B receptors in the cerebral cortex of rats. Consistent with receptor theories, chronic treatment with a GABA _b antagonist should have the same effect. For this and other reasons, GABA _b antagonists may in accordance with ·* 0000

000 0« « 000«

0000 0 0 0 »000 • « 00« 0 «0 «00* « ·· · 0000 000

00000 0« 00 00 00

- 26 thus act as antidepressants.

The GABA ₆ antagonists according to the invention interact on the membranes of the cerebral cortex of rats at the GABA _b receptor with IC _SO values from 10' ⁷ to 10' ¹⁰ M . (mol/liter) . Unlike a GABA _S agonist such as baclofen, they do not increase noradrenaline stimulation of adenylate cyclase in parts of the rat cerebral cortex, but act as antagonists to the action of baclofen. The antagonists not only show antagonism to baclofen, but also show independent action as antagonists of endogenous GABA.

Due to the excellent antagonistic properties towards GABA _S, the compounds according to the invention are suitable for use in the treatment or prevention of conditions characterized by stimulation of GABA _S receptors. They are therefore 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 small epileptic seizure type (petit mal), i.e. absence epilepsy of children and adults, atypical absences (sudden loss of consciousness or memory) such as Lennox-Gastant syndrome, to treat conditions requiring increased cognitive activity and as an antidote to baclofen.

Compounds of general formula I, in which R ^y represents a hydrogen atom, can be prepared by reacting compounds of general formula II

OH

(II) with the difference that R ⁴ cannot be substituted by a carboxyl group, and R ^x has the meaning defined above with the fact that it cannot be substituted by a carboxyl group, with the compound of the general

4«

4 * 4 4 ·

4 4 4 4 44

4 44 4444 4

4*4 · 4 4

44 44 44

formulas III o

(III)

OR ⁵ where R ² has the meaning defined above, X means a halogen atom, for example chlorine or bromine, and R ⁵ represents an alkyl group with 1 to 8 carbon atoms, for example an n-hexyl or n-octyl group, preferably an alkyl group with 1 to 4 atoms carbon, such as a methyl, ethyl, isopropyl or isobutyl group, especially an ethyl group, in the presence of a base, to form a compound of general formula IV o

(IV) where the symbols R ⁴ and R ^x have the meanings defined in general formula II, this reaction being followed, if necessary, by one or more substitution reactions changing the nature of the substituent in R ⁴ or/and R ^x or/and hydrolysis of the ester substituent in R ⁴ or/and R ^x to a carboxyl group or/and conversion of an ester group -OR ⁵ to a hydroxy group.

With an appropriate choice of base and reaction conditions, the reaction of compounds of general formulas II and III, in which monoalkylation of the amino group with subsequent cyclization takes place, can be carried out in one step. Preferably, to avoid complications due to dialkylation of the amino group, the reaction is carried out in two steps. In the first stage, to a mixture of compounds of the general formulas II and III in a solvent, preferably a hydrocarbon such as benzene, toluene or xylene, at a temperature of 70 to 110° C slowly ·4·4 » 4 4 » · 4 44

4444 44 44

4 4 4 4 4 4

4 4 4 4 4 4 • 4 44 6444 4 • 6 4 4 « 4 4

44 44 44 adds a weak base, for example a hindered amine such as 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU)·, to form a new intermediate product of general formula V

in which the symbols R ³ , R ⁴ , R ⁵ and R ^x have the meanings defined above. This intermediate is then reacted with a base under harsher 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. of the intermediate with the base can be carried out in a solvent, preferably a hydrocarbon such as toluene, benzene or xylene.

The intermediate compounds of general formula V can also be used as drugs themselves, for example to treat or prevent a condition characterized by stimulation of GABA _S receptors, especially in a de-esterified form, i.e. in a form in which the alkyl group in the meaning of the symbol R ⁵ has been replaced by a hydrogen atom and any present esterified the carboxyl group in R ⁴ or/and R ^x has been converted into a carboxyl group. Accordingly, the invention includes novel compounds of formula VA

H (VA)

OH in which the symbols R ¹ , R ² and R ^x have the meanings defined above, or their salts or esters.

Compounds of general formula I or IV in which R ^: •0 0000

0 0 00 0 0 0 0 00»

0 00» » 0« 0000 0 0· · 0000 00« *0 0*0 0» 00 »0 0»

- 29 or/and R ¹ or R ⁴ respectively contains a cyano group as a substituent on the aryl or heteroaryl ring, can be prepared by reacting an alkali metal cyanide with a compound of general formula I or IV, in which R* or/and R ¹ or R ⁴ respectively contains a substituent on aryl or heteroaryl rings, a halogen atom, which compound can be prepared by diazotization and subsequent reaction with an alkali metal halide, from a compound of general formula I or IV, in which R ^x or/and R ¹ or R ⁴ respectively contains an amino group on the aryl or heteroaryl ring, which compound can in turn be prepared by reduction of a compound of general formula I or IV, in which R ^x or/and R ¹ or R ⁴ respectively contains a nitro group on the aryl or heteroaryl ring. All of these reactions can be carried out using known procedures.

Compounds of the general formula I or IV, in which R ^x or/and R ¹ or R ⁴ respectively contains an esterified carboxyl group as a substituent, can also be prepared from other compounds of the general formula I or IV. They can be prepared, for example, by reacting a compound of general formula I or IV, in which R* or/and R ¹ or R ⁴ respectively contains a halogen atom as a substituent on the aryl or heteroaryl ring, with carbon monoxide and alcohol in the presence of a palladium complex as a catalyst, under using known procedures.

Compounds of general formula I, in which R ^x or/and R ¹ contains a carboxyl group as a substituent, can be prepared by hydrolysis of a compound of general formula I or IV, in which R ^x or/and R ¹ or R ⁴ respectively contains an esterified carboxyl group as a substituent, for using conventional hydrolysis procedures.

If in the compound of general formula IV or V the residue R ⁴ contains an esterified carboxyl group, this group can be hydrolyzed to a free carboxyl group using conventional methods. If R ⁴ in the compound of general formula IV contains a nitro group on the aryl or heteroaryl ring,

- 30, this group can be gradually converted by reduction to an amino group, diazotization of the amino group and subsequent reaction with an alkali metal halide to a halogen atom, a reaction of a halogen with an alkali metal cyanide to a cyano group and a cyano group by hydrolysis to a carboxyl group, while these reactions are expediently carried out using known procedures.

The conversion of the ester group -OR ⁵ in the compound of general formula IV or V into a hydroxy group can be carried out by reaction with a suitable basic or acidic reagent, such as an alkali metal hydroxide, for example sodium hydroxide or lithium hydroxide, an alkali metal halide, especially an alkali metal bromide or iodide a metal such as lithium bromide or sodium iodide, thiourea, an alkali metal thiophenoxide such as sodium thiophenoxide or a protonic or Lewis acid such as a mineral acid such as hydrochloric acid or a tri(lower)alkylhalosilane such as trimethylchlorosilane. This substitution reaction can be carried out in the absence or presence of a solvent, and if necessary with heating or cooling in a closed vessel and/or in an inert gas atmosphere.

Conversion of the -OR ⁵ group in a compound of general formula IV or V to a hydroxy group can also be carried out by reaction with an acid under hydrolytic conditions, in particular with a mineral acid such as a hydrohalic acid, for example hydrochloric acid, which is used in dilute or concentrated aqueous form, or by reaction with an organic silyl halide such as trimethylsilyl iodide or -bromide and, if necessary, subsequent hydrolysis. This reaction is preferably carried out at an 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 in an inert gas atmosphere.

Compounds of general formula II are in some cases commercially available, for example (R)- and (S)-phenyl«9 · ··* «9 «999 • 9999 « 9 · 9 999

9 99* 9 99 9999 9 ·* 9 9999 999

999 99 99 99 99

- 31 glycinols. Compounds of the general formula II can be prepared by reducing an aminocarboxylic acid of the general formula R ⁴ C(R ^X ) (NHJCOOH, where the symbols R ⁴ and R ^x have the meanings defined above for the general formula II, by reaction with borane-dimethylsulfide in the presence of a boron fluoride complex such as boron trifluoride-diethyl etherate. This reaction can be carried out using known procedures. In this way, new compounds of general formula II can be prepared in which (i) R ⁴ is an iodobenzyl group, and R* is a hydrogen atom, and (ii ) R ⁴ represents a phenyl group and R ^x represents an isopropyl group.

Compounds of general formula II, in which the residue R ⁴ is substituted by a nitro group, can be prepared from an aminocarboxylic acid of the general formula R ⁴ C(R ^Z ) (NHJCOOH, where R ⁴ is otherwise unsubstituted, by nitration to introduce a nitro group into R ⁴ , by converting the amino group in the product to a protected amino group, for example by reaction with di-tert-butyl dicarbonate to form a tert-butyl carbamate group, by esterification of the carboxyl group in the protected product, for example by conversion to a methyl ester, then by reduction of the ester group to a -CH ₂ OH group by reaction with a suitable reducing agent such as an alkali metal borohydride, and finally by removing the protecting group of the amine function by reaction with acid to re-form the free amino group.

These reactions can be carried out using known procedures or with minor modifications thereof. This reaction procedure can be used to prepare the known compound of general formula II, in which R ⁴ represents a nitrophenyl group.

Compounds of the general formula II can also be prepared by the Strecker synthesis, in which an aldehyde or ketone of the general formula R ⁴ C(=O)R ^X , where the symbols R ⁴ and R ^x have the meanings defined above, is subjected to a reaction with a compound of the general formula R ⁶ NH ₂ , where.. ..R ^s means a hydrogen atom or an -alkyl group with 1 to 8 carbon atoms, optionally a substituted aryl group with 6 to 10 carbon atoms, which is not substituted in <4 •0 0·0·

0 0 0

0 000 0

0 *00 • 0 · 0

0 00 0

0« 0000 «

• 0 0 0 0 0 0 0 0 « • 00 0000

0 0 0 0 00 00 00 4 tuated or substituted, for example, with a hydroxy or C 1 -C 4 alkoxy group, and an alkali metal cyanide, to form a compound of general formula VI

CN

NHR°;vi:

in which the symbols R ⁴ , R ^s and R* have the meanings defined above, the compound of the general formula VI is subjected to a reaction with an alcohol of the general formula R ⁷ OH, where R ⁷ means an alkyl group with 1 to 10 carbon atoms, for example n-hexyl, 2 - an ethylhexyl, n-octyl or decyl group, preferably an alkyl group with 1 to 4 carbon atoms, such as a methyl, ethyl, isopropyl or n-butyl group, especially a methyl or ethyl group, in the presence of an acid, to form a compound of general formula VII

COOR ⁷

NHR ^C (VII) in which the symbols R ⁴ , ??, R ⁷ and R* have the meanings defined above, the group R ^s is removed from the compound of the general formula VII, if it has a meaning other than a hydrogen atom, for example using known procedures, for formation of the compound of general formula VIII

COOR ⁷

NHi (VIII) ** *··· »· 4444 44 99 • 99 «4 4 4 4 4 4 · ··· * · 4 « 4 44 • · «4« 4 4 « «444 4

4 4444 444 ·· 444 44 44 44 44

- 33 in which the symbols R ⁴ , R ¹ and R ^:< have the meanings defined above, for example, in the case that Pd represents an optionally substituted benzyl group, catalytic hydrogenation is carried out in the presence of an organic acid, for example acetic acid, to form the compound of formula VIII in the form of its salt with an organic acid, the compound of formula VIII is reacted with an amino protecting agent such as tert-butyl dicarbonate to convert the amino group into a protected amino group, the ester group -CO0R ⁷ in the protected compound is reduced to the group -CH2OH by reaction with a suitable reducing agent such as an alkali metal borohydride, and finally the protecting group is removed to form a free amino group. This sequence of reactions can be carried out using known procedures or their minor modifications. If the R ⁴ residue is substituted with an esterified carboxyl group, the protected amino group formed should be a group such as tert-butyl carbamate, which allows the reduction of the ester group -COOR ⁷ to the -CH2OH- group while preserving the _ester group in R", and can then be removed by reaction , for example in a non-aqueous environment in which the ester group in R ⁴ is preserved.

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 the resulting aminocarboxylic acid can then be reduced to a compound of formula II by reaction with borane- dimethyl sulfide in the presence of a boron fluoride complex such as boron trifluoride-diethyl etherate, for example using known procedures.

Compounds of the general 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 the general formula R ⁴ C(=O)R ^x by the sequence of reactions as described above, are new as such . Compounds of general formula II or VIII, in which • 0 4400 00 0000 00 00 *04 40 0 0004 * 4000 0 » 0 004 • · 000 0 0 · 0000 0 • 0 · 0000 000 ·· ·0· 00 04 00 00

- 34 R ⁴ means a 3,4-dichlorophenyl group and R ⁷ represents an alkyl group with 1 to 10 carbon atoms, they are also new.

The compounds of general formula IX in which R ⁴ represents a monovalent aromatic group as defined above and R ^x represents an unsubstituted or substituted hydrocarbyl group are new, except for the compounds of general formula II in which R ⁴ represents a phenyl group and R* means a methyl group, a chloromethyl group, an ethyl group, a -(CH ₂ ) ₃ SCH ₃ group, an allyl group or a hydroxymethyl group, compounds of general formula II, in which R ^x represents an aminomethyl group and R ⁴ means phenyl, p-hydroxyphenyl or p- methoxyphenyl group, compounds of general formula II, in which R* represents a hydroxymethyl group and R ⁴ means '4-decylphenyl or 5-[(7-chloro-4-quinolyl)amino]-2-hydroxyphenyl group, compounds of general formula ΙΪ, in which. R ⁴ represents a 4-methoxyphenyl group and R ^x represents an ethyl group and compounds of general formula II in which R ⁴ represents a 2,4-dichlorophenyl group and R ^x represents an N-triazolylmethyl group.

Compounds of formula II in which R ⁴ represents a monovalent araliphatic group as defined above and R" represents an unsubstituted or substituted hydrocarbyl group as defined above are novel, except for compounds of formula II in which R* represents methyl group and R ⁴ means 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 group, and with the exception of compounds of general formula II, in which R ⁴ represents a benzyl group and R* denotes an allyl group or a -CH ₂ CH ₂ SCH ₃ group.

Compounds of general formula II, in which R ⁴ represents 35 ** ···· ·« ···· ·· ·· • · · · · · · · · · * · ··· » * · · ··· • · ♦·'« · · · ·»· · · • · · · · · ♦ « · » ·· · · · · · · 99 · is an iodobenzyl group, especially a 4-iodobenzyl group, and R ^x is a hydrogen atom or an unsubstituted or substituted hydrocarbyl group as defined above are also novel.

Compounds of general formula III which are, with the exception of the compound in which R ² represents a methyl group and R ⁵ represents an ethyl group, new, especially those in which R ² represents a cycloalkylalkyl group such as cyclohexyl.. a methyl group, can be prepared by reaction compounds of the general formula IX;

H -p- R ² (IX)

OR ⁵ with a compound of general formula X

X-CH=CH-CH ₂ -X (X) where the symbols R ² , R ⁵ and X have the meanings defined above, in the presence of a silylating agent, such as a bis(trialkylsilyl) amide derivative, which agent reacts with the compound of general formula IX to form a silyl derivative of trivalent phosphorus, which then reacts with a compound of general formula X. The reaction can be carried out at a temperature from 0 to 50° C. The reaction is preferably carried out in a solvent, for example a hydrocarbon such as toluene, or a halogenated hydrocarbon such as dichloromethane.

Esters of the general formula . IX can be prepared by reacting a protected phosphinic acid ester of general formula XI

O

-- p OR ⁵ (xi)

0000 • * • 000

0» 0000

00 « · 0 0 0 0 0

0 * 0 · · 0

0 «04 0 0· 0000 0

0 0000 000 00 400 00 0 0 00 00

- 36 in which R ⁵ has the meaning defined above and Q represents a group protecting the PH function, with a compound of general formula XII

R ² Z (XII) where R ² has the meaning defined above and Z represents a leaving group, forming a compound of general formula XIII

OR ³ and then replacing the protecting group Q in the compound of general formula XIII with hydrogen.

The leaving group Z can be, for example, a halogen atom or an organic sulfonate group. Preferably, Z represents a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate group. The reaction between the compounds of general formulas XI and XII and the reaction to remove the protecting group from the compound of general formula XIII can be carried out using known procedures, for example as described in EP 0569333.

Protected phosphinic acid esters of formula XI can be prepared by known procedures, for example as described in US 4,933 4,78.. Compounds of formula XII' are either commercially available or can be prepared by known procedures.

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

Compounds of the general formula I, in which R ^y represents the group R ^y a, can be prepared by reacting a compound of the general formula I, where R ^y is a hydrogen atom, with the compound R ^y aZ, where they have

- 37 •4 4444 « · · • 4 4 4·

4 4 « 4

444

4« 4·«4

4 4

4 4

4 4 4

44

4« «·

4 4 4

4 44 «44 4V

4 4

4 4 symbols R ^y aa Z the meanings defined above, or by reductive alkylation using an aldehyde of the general formula R ^y bCHO, where R ^y b represents a hydrogen atom or a group R ^y a , as defined above, and a reducing agent that reduces imines to amines , for example sodium cyanoborohydride. Such reactions can be carried out using conventional procedures.

Compounds of formula I in which R ^y represents an NH protecting group can be prepared by reacting a compound of formula I where R ^y is hydrogen with a reagent known to introduce the desired protecting group. For example, when the protecting group is an acyl group, the compound of general formula I in which R ^y 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 aralkylcarbonyl group, the compound of general formula I in which R ^y is hydrogen can be reacted with an alkoxycarbonyl or aralkylcarbonyl halide or an alkyl or aralkyl dicarbonate such as benzyl chloroformate or di-tert-butyl dicarbonate, for example using known procedures.

In general, the compounds of general formula I, in which R ^y denotes the group R ^y and or the group protecting the NH function, can also be prepared in the manner described above for the preparation of compounds of general formula·. I., in. in which R^ represents - a hydrogen atom, - in which the compound of the general formula II is replaced by the compound of the general formula IIA

0* 000« • · 0 0 • 0 000 « « 0 0 0 « • 0 0« «0 00« «0·« «0·0 «0 0« • « «000 • * 0 0 00 0 ·« * »· 0 «

0 0 0 0 « «« «0 0« 00 where the symbols R ⁴ and R* have the meanings defined above in the general formula II and R ^y means the group R ^y and or the group protecting the NH function, while the reaction of the compound of the general formula IIA with the compound of general formula III in the presence of a base, the compound of general formula IVA is directly obtained

(IVA) where, the symbols R ⁴ and R ^x have the meanings defined in the case of general formula II, R ^J and R ^s have the meanings defined above and R ^y means the group R ^y a as defined above or a group protecting the NH function. This reaction can be carried out in a solvent, usually a hydrocarbon such as benzene, toluene or xylene, and is generally carried out under harsher conditions than those used for the reaction of compounds of general formulas II and III, for example using sodium hydride as a base and at a temperature of 10° C to 70° C. If necessary, this reaction may be followed by one or more substitution reactions to change the nature of the substituent in R ⁴ or/and R* or/and hydrolysis of the ester group as a substituent in R ⁴ or/and R* to a carboxyl group or /a conversion of the ester group -OR ⁵ to a hydroxy group.

Compounds of general formula I by reaction of compounds of general formula XIV o

can also be prepared

OR ^J (XIV) to convert the primary hydroxy group present to the leaving group 2 as defined above, thereby causing the cyclization • · ···· to form the compound of general formula XV o

*0 · 0« 0 0 0

0 0 00

0 * 0 «·· «· 00 0 0 0

0·0

Β #00 0 I

(XV) where the symbols R ² , R ⁴ , R ⁵ , R ^x and R ^y have the meanings defined above, and if necessary, with the following replacement of the group R ^y as a group protecting the NH function by hydrogen or/and one or more substitution reactions for changing the nature of the substituent in R ⁴ or/and R ^x or/and by hydrolysis of the ester group as a substituent in R ⁴ or/and R ^x to a carboxyl group or/and by converting the ester group -OR ^s to a hydroxy group.

The conversion of the primary hydroxy group in the compound of general formula XIV to the Z group can be carried out using known procedures. For example, when Z represents an iodine atom, this conversion can be carried out by reacting a compound of general formula XIV with triphenylphosphine, imidazole and iodine in a solvent such as acetonitrile or tetrahydrofuran at a temperature of 0°C to 50°C, and in the case where Z represents a trifluoromethanesulfonate group, this conversion can be carried out by reacting the compound of general formula XIV with trifluoromethanesulfonic acid anhydride in pyridine at a temperature of -100°C to 50°C.

Substitution of the R ^y group as a protecting group for the function. NH with hydrogen can. performed using known procedures for removing the NH protecting group. For example, when R ^y represents an acyl group such as an acetyl or benzoyl group, hydrogen replacement can be accomplished by reaction with aqueous hydrochloric acid, while when R ^y represents a trifluoroacetyl group, hydrogen replacement can be accomplished by reaction with aqueous potassium carbonate .

Other possible subsequent reactions of compounds of general formula XV can be carried out as described above for the corresponding reactions of compounds of general formula IV. and

Λ ť <\ ft r.· C ? c r : r : p 6

Č b· Cl' ;· í· < '

O C í.fl c

Compounds of general formula XIV, which are themselves new, can be prepared by reacting a compound of general formula II with <· ' .7 t:

compound of general formula XVI ,· f

(XVI) where the symbols R\ have R and Z above. defined meanings, in the presence of a hindered base, for formulas XVII of the formation of a general compound

About . - ·· · - ·* •-.ιϊ?3 ‘•'ii

OR ³ (XVII) ϊ' £

4- -rt tr where the symbols R ² , R', R ⁵ and R ^x are as defined above, and by replacing the depicted hydrogen bonded to the nitrogen atom with a group R ^y protecting the NH function as defined above, for example using known procedures such as are the procedures described above. The reaction between the compounds of general formulas II and XVI can be carried out, for example, at a temperature of 20 to 100° C., preferably in an organic solvent, such as alcohol. especially _: ethanol. The hindered base can be, for example, a diazabicyclo compound such as 1,5-diazabicyclo [4,3,0] non-5-ene ^1, ! or 1, .8-diazabicyclo[5,4,0]undec-7-ene * or . preferably a tertiary amine such as dicyclohexyl(ethyl)amine or especially diisopropylethylamine.

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

Compounds of general formula XIV or XVII can themselves be used as drugs/ for example to treat or prevent conditions characterized by . with > stimulation·, GABA receptors/; especially in ··· * · 0 0 0·· ♦ 0··· · · 0 00·· · 000 0 00 00·« 0 · 0 · 0 · · · ·

000 00 00 00 00 de-esterified form, i.e. in the form where the alkyl group in the meaning of the symbol R ^s has been replaced by hydrogen and any present esterified carboxyl group in R ⁴ or/and R ^x has been converted into a carboxyl group, for example using known procedures. Accordingly, the invention now includes compounds of general formula XVIII

(XVIII) in which the symbols R ¹ , R ² , R ^x and R ^y have the meanings defined above, or their salts or esters.

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

Salts according to the invention can be converted into other salts according to the invention in a manner known per se, for example addition salts with acids can 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 which is formed, is insoluble, and is thus excluded from the reaction equilibrium, and salts with bases can be converted into other salts by releasing the free acid and converting it back into a salt.

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

Due to the close similarity between the new compounds ·· * · » · • · · · • · • * · · · · ···· *► ···«···«···· • · · · · · · · ··· · · • · · ···· · · * _ 42 - .............

in the free form and in the form of their salts above and below, the free compounds and their salts also mean the corresponding salts and free compounds, respectively, where appropriate and where the context allows.

In the case of compounds of general formula I and intermediates used in their preparation, diastereoisomeric mixtures and racemate mixtures can be divided into pure diastereoisomers and racemates in a known manner on the basis of physicochemical differences between the components, for example by chromatographic procedures and/or fractional crystallization.

The resulting racemates can also be resolved into optical antipodes using known procedures, for example by recrystallization from an optically active solvent, using microorganisms, or by reacting the resulting diastereoisomeric mixture or racemates with an optically active auxiliary compound, for example, depending on how acidic, basic or functionally modifiable groups are present in the compounds of general formula I, by reaction with an optically active acid, base or optically active alcohol, to form mixtures of diastereoisomeric salts or functional derivatives such as esters, and their separation into diastereoisomers, from which the desired enantiomer can be released in a conventional manner. Bases, acids and alcohols suitable for this purpose are, for example, optically active alkaloid bases such as strychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases, optically active carboxylic or sulfonic acids such as quinic acid or D- or L-tartaric acid, D- or

L-di-o-toluoyltartaric acid, D- or L-malic acid, D- or L-mandelic acid or D- or L-camphorsulfonic acid, and optically active alcohols such as borriol or D- or L-(1-phenyl)ethanol.

Compounds of general formula I, VA or XVIII can be isotopically labeled, especially with ^1L C, ¹⁴ C, ^: H, ³ H or ¹²⁵ I, for

0» 0000 0 0 0 • » 0 0 0 • 0 0 0 •0 0 »0 » » »

0000 00 *0 • · · 0 0 0 · 0 · 0 0 0 0» · »» 0 » 0 0 0 » 0 0 » 0 0« » 00 00 00

- 43 uses for diagnostic purposes.

The compounds of general formula I, VA or XVIII can be used, for example, in the form of pharmaceutical compositions containing a therapeutically effective amount of the active substance, if necessary together with pharmaceutically acceptable carriers that are suitable for enteral, for example oral, or parenteral administration, which carriers may be solid or liquid and organic or inorganic. Tablets or gelatin capsules are used, for example, which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or sliding substances (lubricants), for example silica gel, talc, stearic acid or its salts, such as is magnesium or calcium stearate and/or polyethylene glycol. Tablets may also contain binders, for example magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if necessary disintegrants, for example starches, agar, alginic acid or its salts, for example sodium alginate and/or effervescent mixtures, or absorbers, dyes, flavorings and sweeteners.

The compounds of general formula I can also be used in the form of compositions that 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 preparations containing the active substance, alone or with a carrier, for example mannitol, can be prepared before use. Pharmaceutical preparations can be sterilized and/or may contain excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizing additives, salts for regulating osmotic pressure and/or buffers.

These pharmaceutical compositions, which may, if desired, contain other pharmacologically active substances, can be prepared in a known manner, for example by conventional methods of mixing, granulation, compression, dissolution or lyophilization, and ·· 4444 44 4444 44 44 • 44 4 4 4 4 *44 • 4444 4 4 4 · 444 • 4 4«4 4 4· 4444 ·

4 4444 444 ·44 44 44 44 44 may contain from approximately 0.1% to 100%, in particular from approximately 1% to approximately 50%, and in the case of lyophilizates up to approximately 100%, active substances.

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

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

Accordingly, the invention includes a method of treating or preventing a condition in warm-blooded animals, especially humans, characterized by stimulation of GABA _S receptors, in which said warm-blooded animal is administered a compound of general formula I, VA or XVIII, or a pharmaceutically acceptable salt or ester thereof.

The following examples illustrate the invention. The abbreviation Bac used in the following formulas denotes tert-butoxycarbonyl.

Examples of the embodiment of the invention

Compound D used in the examples is prepared as follows:

g of phenylglycine is dissolved in 210 ml of concentrated sulfuric acid and the solution is cooled to a temperature of 0° C. To the cooled solution is added dropwise over the course of 30 minutes

15.5 ml of fuming nitric acid, the mixture is stirred for a time

- 45 «0 ···* «0 000 0 • 0 · 0 0 0 • · ·* « · · • · · · · · • 0 «00* 00 000 *0 «0 «· *«

0 «0 0*0 0 0 «« 0 • 0 « « another 30 minutes at 0°C and then for 18 hours at room temperature. The resulting solution is poured into 1 liter of ice and the pH is carefully adjusted to 7 by adding approximately 875 ml of 10 M aqueous sodium hydroxide while keeping the solution temperature below 20° C. The resulting mixture is stirred for 3 hours at room temperature and the precipitate is filtered off. This precipitate is washed three times with water and recrystallized from 1 liter of water to give 3-nitrophenylglycine with a melting point of 165-166°C.

g of 3-nitrophenylglycine is added to a mixture of 200 ml of methanol and 20 ml of triethylamine and this mixture is vigorously stirred for 10 minutes at room temperature. 11.13 g of di-tert-butyl dicarbonate are added and the reaction mixture is heated to reflux for 2 hours. The resulting solution was cooled to room temperature and then concentrated to dryness under reduced pressure to give a dark orange residue. This

The residue is also purified using very fast chromatography on silica gel using a mixture containing 95% dichloromethane,

2.5% methanol and 2.5% acetic acid as eluent to give compound A as an orange foam.

ⁿ C-NMR (100 MHz, deuterochloroform); δ values in 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 (sj

A solution of 14.54 g of compound A and 1.87 g of p-toluenesulfonic acid in 200 ml of methanol was stirred for 24 hours at room temperature. Ethyl acetate and saturated aqueous sodium bicarbonate are added, the organic phase is separated and dried

- 46 ·· ♦♦·· 44 4444 «« 44 • · · · · · ···· • 4 44» * 4 « 4 4·« * · ·44 4 44 4444 4 «· · 4 4 4 4 444 ·· 444 44 ·« «4 44 over magnesium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The product obtained is purified by flash chromatography on silica gel using a mixture of hexane and ethyl acetate in a ratio of 2:1 as the eluent to give compound B as a yellow solid with a melting point of 86°C.

Ι[»

compound B

Analysis for C ₁₄ H _ia N ₂ O _s :

calcd: 54.19% C, 5.85% H, 9.03% N;

' found: 54.32% C, 6.00% H, 8.93% N.

A solution of 2.33 g of sodium borohydride in 30 ml of absolute ethanol is added dropwise at room temperature to a stirred solution of 9.57 g of compound B in 120 ml of absolute ethanol. The reaction mixture was stirred for 18 h at room temperature and then the excess sodium borohydride was quenched by addition of glacial acetic acid. The solvents are removed under reduced pressure and the residue is 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 is purified by flash chromatography on silica gel using a mixture of ethyl acetate and hexane in a ratio of 1:1 as eluent to give compound C with a melting point of 100°C.

- 47 «· KU 9* 9999

9 9 «9 9 • 9 999 9 * 9 • 9 9 9 9 9 9 • 9 9 9 9 9 9 • 9 999 99 99

99

9 9 9

9 · 9

999 9 9

9 9

99

Analysis for C ₁₃ H ₁₈ N ₂ O _S :

calcd: 55.31% C, 6.43% H, 9.92% N; found: 55.25% C, 6.63% H, 9.76% N.

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

compound D

Analysis for C _e H ₁₀ N ₂ O ₃ :

calculated: 52.74% C, 5.53 % H, 15.38% N; found: 53.12% C, 5.75 % H, 15.07% N. C-NMR (100 MHz, methanol): О values in ppm: 58.0 (d), 68.2 (t), 122.8 (d), 123.1 (d) , 130.4 (d), 134.5 (d), 146.3 (s), 149.6 (WITH) Compound G used in the examples se will prepare

as follows:

4.9 g (0.1 mol) of sodium cyanide and 5.88 g (0.11 mol) of ammonium chloride are mixed 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 the course of 1 minute. 10 ml of aqueous ammonia solution with a density of 0.88 is added and the reaction mixture is stirred for 3 hours at

- 48 »4 ·«*« » · ·

I 4 4·«

I · · « » * 4 • 4 · · 4

4444 ·4

P 4 4 <

• 4 4· «4 room temperature. Ethyl acetate was added and the organic phase was separated, dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in ethyl acetate and repeatedly extracted with 2M hydrochloric acid. The pH of the mixed aqueous layers is adjusted to 9 using an 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 eluting with 1:1 hexane/ethyl acetate to give the compound G with a melting point of 64 - 65° C.

compound G

Analysis for C _and H _with Cl ₂ N ₂ ·.

calcd: 47.79% C, 3.01% H, 13.93% N; found: 47.81% C, 2.99% H, 13.92

N.

Compound as follows:

J used in the examples will be prepared

Using essentially the same procedure as 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 ammonia solution with a density of 0.88 in a mixture of 30 ml. of methanol and 20 ml of water was allowed to react for 24 hours at room temperature to give compound H as a red-brown waxy solid.

NH,

Br compound H fit· 17 r.C ftcrc speech <; c c : r r.f.<· ie c- « i· C c: c c C «· : fc c, f e c c íj c oc,ft re r,c η r ’· <' c · c ť < tt Cl < ít' kl

V* ¹³ C-NMRt (100 MHz, deuterochloroform) ·. δ values in 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 ·;} ; _ t , ;

of hydrochloric acid is heated to boiling under reflux, l.i. ' i ' refrigerator for 68 hours. The liquid above the deposit is decanted/ cooled to room temperature and the pH is adjusted using aqueous ammonia ³ to a value of 7? The expressed product is »isolated by filtration, ^: washed. gets watered and dried. Trituration with ethyl acetate and subsequent drying gives compound J as a brown solid melting on decomposition

compound J ⁿ C-NMR (100 MHz, perdeuteromethanol): δ values in 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 <

{ í compound 1

K solution of 1.7 g (10.0 mmol) of 4-methoxybenzylamine hydrochloride and 0.490 g (IQ'.0 mmol) of sodium cyanide in 10 ml of water. 1.6 g (10.0, mmol) of -3-methoxycarbonylbenzaldehyde in 10 mL of methanol is added and the mixture is stirred at room temperature for

4·· » » 0 w 4 » · 4«

4 4 4 4 4

4 4 4 4 44 > 4 4 4 4 4 4 4 4

4 4 4 4 4 4

4« 44 44 4 4 hrs. 20 ml of water are added and the mixture is extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness to give an oil which was purified by chromatography on silica gel using 20¾ ethyl acetate in hexane as eluent. Compound 1 is obtained.

Analysis for C ₁₈ H _ia N ₂ O ₃ :

calculated: 6 9.66% C, 5.85% H, 9.03 % N; found: 69.40% C, 5.94% H, 8.73 %N. ¹³ C-NMR (100 MHz, deuterochloroform): values of δ v ppm: 50.6 (t) , , 52.2 (q) , 52)8 (d), 55.2 (q> , 114.0 (d), 118.3 (with) . 128.3 (d), 129.0 (d), 129.6 (d) , 129.8 (S), 130.1 (d) , 130.9 (s), 131.6 (d), 135.3 (with) 159.1 1 )s), 166.32

Example 2 cooch ₃

oh ₃ compound 2

A solution of 7 g (22.56 mmol) of compound 1 in 75 ml. of methanol is cooled to a temperature of 0° C and saturated with hydrogen chloride gas. Once the reaction mixture is saturated, it is stored for 4 days at -20°C and then concentrated under reduced pressure to a quarter of its original volume. It will be added. ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic phase was separated, washed with water and brine, dried over magnesium sulfate, filtered and evaporated to an oil. Purification by flash chromatography on silica gel using a mixture of hexane and ethyl acetate in the ratio

- 51 «4 I··» * · 4 4

4,444 4

4 4 4 4 · 4 4

4 44

4444

4444 44 44 • 4 4 4 4 4

4 4 4 44

4 4 444 4 » • « 4 4 4 4 >4 44 44 44 : 1 as eluent, compound 2 is obtained as an oil.

¹³ C-NMR (100 MHz, deuterochloroform): δ values in ppm: 50.7 (t), 52.1 (q), 52.3 (q) , 55.2 (q) , 63.8 <d) , 113.7 (d) , 128.69 (d) , 128.72 (d) , '129.4 (d) , 130.5 (s), 131.2 (S), 132.0 (d) , 138.5 (s) , 158.7 (s), 166.7 (s), 172.9 (s)

Example 3

compound 3

A mixture of 8.0 g (23.3 mmol) of compound 2 and 2.0 g of palladium black in 50 mL of glacial acetic acid and 50 mL of methanol was hydrogenated for 4 h at room temperature. After checking that the reaction was complete by thin layer chromatography, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was co-evaporated three times with 20 mL of toluene and then purified by flash chromatography on silica gel eluting with ethyl acetate to give compound 3 as a pale yellow oil. Analysis for C ₁₃ H ₁₇ NO ₆ :

calculated: found:

55.12% C, 6.05% H, 4.94% N; 55.46% C, 5.99% H, 5.05% N.

³ C-NMR (100 MHz, deuterochloroform): δ values in 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 (with) 175.9 (s)

00··

- 52 00 0000 • 0 · 0 0

0 0 00 0 0 0

0 · 0 · 0

0 0 0 0 0

0 0 0 0« 00

00

0 0 « « 00

0 0 0 0

0 * «0

Example 4

Grade A

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 is purified by flash chromatography on silica gel using a mixture of hexane and ethyl acetate in a ratio of 4 to 1 as eluent, thereby obtaining compound E with a melting point of 88-90°C.

compound E

Analysis for C _1S H _2L NO ₆ :

calcd: 59.43% C, 6.55% H, found: 59.54% C, 6.72% H,

4.33% N; 4.32%N.

Level 2

To a stirred solution of 3.2 g (9.9 mmol) of compound E in 50 ml of methanol is added 800 mg (21.2 mmol) of sodium borohydride in eight equal portions at 30-minute intervals. After completion of the reaction, which is verified by thin layer chromatography, the remaining sodium borohydride is decomposed with glacial acid

- 53 »4 4*44 • 4 4 * 4 4 4 4

4 ·

4 · ·· 44 4 •4 ·4·4 ·4

4 4

4« 44

4 4 4

4 44

4 · 4 4

4 4'

4» 44 acetic acid and the reaction mixture was evaporated under reduced pressure to give an oily solid. This residue is co-evaporated twice with 20 ml of toluene each time and triturated with ethyl acetate. Evaporation of the ethyl acetate extracts under reduced pressure gives a colorless oil, which is purified by very fast chromatography on silica gel using a mixture of hexane and ethyl acetate in a ratio of 1 to 1 as eluent, thereby obtaining ' κ* ·· compound F with a melting point of ^102 ^1 104° _C_

Analysis for C ₁₅ H ₂₁ NO ₅ :

calculated: 61.01% C, 7.17 % H, 4.74% N; found: 61.11% C, 7.23 % H, 4.70% N. Level 3 To the mixed solution 2, .2 g (7.45 mmol) compounds F in

ml of dry dichloromethane, 3.0 ml (39.17 mmol) of trifluoroacetic acid is added in an atmosphere of argon at room temperature. This mixture was stirred for 5 hours at room temperature. After completion of the reaction, which was verified by thin layer chromatography, the mixture was evaporated without heating under reduced pressure and the residue was co-evaporated twice with 20 ml of chloroform each time. After drying under high vacuum, the residue was purified by ion exchange chromatography on Amberlyst A21 resin using water as eluent to afford compound 4 as a colorless oil.

Analysis for C ₁₀ phi ₁₃ NO ₃ . 0 , 5H _: O:

calcd: 58.8% C, 6.91% H, 6.86% N; found: 59.98% C, 6.73% H, 6.53% N.

·· ···· ·· ···· flt flfl • · · fl « · ♦ · fl · « · ··· · · · flflfl· ί» · fl · · · · « flflflfl · flfl « flflflfl flflfl · « flfls ·· ·· ·· ·· ⁿ C-NMR (100 MHz, perdeuteromethanol): δ values in 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

compound 5

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

Analysis for C^ClzNO:

calcd: 46.18% C, 3.88% H, 5.98% N;

found: 46.12% C, 3.85% H, 6.09% N.

¹³ C-NMR (100 MHz, deuterochloroform): δ values in 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,

h;

.4 '4 •i'

SC ¢. Λ <\ β cce fc fc O Λ C bto· ¹ (? t fc or rv o ř:

f>4 ťVfc-GÉi rc to tol c ř ti nr _r

In ϊ> c it,'

OC fit?

rr, f <r to to) not c <;· r. ¹ < to r to v

Oto «fp 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 were reacted in 200 ml of methanol. using essentially the same procedure as that described for the preparation of compound E in Example 4. The crude product was purified by flash chromatography on silica gel using 20% ethyl acetate in hexane as the eluent to give compound 6v. in the form of a yellow solid with a melting point of 90 - 92° C.

Analysis for C ₁₄ H ₁₇ C1 ₂ NO ₄ :

calculated found:

50.32% C, 5.13% H, 50.55% C, 5.16% H,

4.19% N; 4.08% N. '.

A solution of 1.15 g is added dropwise to a solution of 6.78 g (20.28 mmol) of compound 6 in 100 ml of absolute ethanol }

(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 is removed under reduced pressure and the residue is purified by flash chromatography on k-1

4 4 4 4 4

4444« 44 4

4 4 « · 6 . · 6·4

444 44 4 ·

4 4 4

44

4*4 4

4 «

44 silica gel using a mixture of hexane and ethyl acetate in a ratio of 1:1 as an eluent, thus obtaining compound 7 in the form of a white solid with a melting point of 113-114°C.

Analysis for C ₁₃ H ₁₇ C1 ₂ NO ₃ :

calcd: 51.00% C, 5.60% H, 4.57% N; found: 51.21% C, 5.69% H, 4.43% N.

Example 8

4.7 g (15.35 mmol) of compound 7 was treated 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 was purified by ion exchange chromatography on Dowex 5QWX 2 resin. -200 (in øV-form) using a mixture of 50% methanol, 47% water and 3% aqueous ammonia solution as an eluent, thus obtaining compound 8 in the form of a cream-colored solid, melting at 65-67°C.

Analysis for C ₈ H,C1 ₂ NO:

calculated found:

6., 63 46.61% C,

4..,.4 0 Λ H.,_. 6.8.0% N; 4.37% Η, 6.59% N.

Example 9

O

compound 9 oc ₂ h ₅

- 57 «4 4 444 *4 «4*4 • 4 · 4 · * 4 V · « • •44* «4 · 4 · 44

4 · 4 4 4 *4 4 * 4 « 4

4 4 4 4 * · «44 • · 44 4· 4 4 *4 44

To a solution of 18.22 g of ethyl cyclohexylmethylphosphinate, prepared as described in EP 0569333, in 100 ml of dry dichloromethane, 28.51 ml of bis(trimethylsilyl)acetamide is added dropwise in an argon atmosphere. 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 was stirred for 18 hours at room temperature, then poured into 100 ml of saturated aqueous sodium bicarbonate solution and the mixture was stirred for 10 minutes. The product is extracted three times with 50 ml each of dichloromethane, the combined organic extracts are washed with sodium chloride solution, then dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure, the excess trimethyl phosphate is then removed by evaporation at a temperature of 80° C. under a pressure of 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.

¹¹ P-NMR (162 MHz, deuterochloroform): δ values in ppm: 51.1. and 52.2

Example 10

Γβΐ'

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. 0.48 mL (3.23 mmol) of 1,8-diazabicyclo(5,4,0]undec-7-ene) is added in 10 portions at 30-minute intervals. The reaction mixture is heated to reflux for a further hours and allowed to stand overnight at room temperature.The mixture is filtered and the filtrate is evaporated at ·· ···· ·· 9449 9« ··

4» « · * 4 · · · »··«· · · · ··

4 * 9 4 4 ♦ * · » · · 9 «4 4 9 4 ·· · ·

9» ··* ·· ·« «9 4·

- 58 under reduced pressure to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane to give compound 10 as a 1:1 mixture of diastereomers on phosphorus.

^3l P-NMR (162 MHz, deuterochloroform): δ values in ppm: 43.49 and 43.55

Example 11

compound 11

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

³¹ P-NMR (162 MHz, deuterochloroform): S values in ppm: 43.37 and 43.43

Example 12

compound 12

A mixture of 1.3 g (6.66 mmol) of compound 4 and 2.06 g «9 99·9 *« ···* «* «9

9 9 9» · 9 9 · 9

9 999 » · 9 9 99 • 9 999 · 9 · 9999 9

9 9 9 9 9 999 «9* 19 99 99 99

- 59 (6.66 mmol) of compound 9 in 25 ml of a mixture of toluene and tetrahydrofuran in a ratio of 1:1 is heated to a temperature of 80° C in an argon atmosphere. Over the course of 5 hours, a solution of 1.52 g (9.95 mmol) is added 1,8-diazabicyclo[5,4,0]undec-7-ene in 15 ml of a 1:1 mixture of toluene and tetrahydrofuran. The mixture was cooled to room temperature and allowed to stand for 18 hours. The mixture was then filtered and the filtrate evaporated under reduced pressure to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane to give compound 12 as a mixture of diastereomers at phosphorus in a ratio of 1:1.

^J1 P-NMR (162 MHz, deuterochloroform): 6 values in ppm: 43.53 and 43.58

Example 13

OH

compound 13

Using essentially the same procedure as described for the preparation of compound 12, a mixture of 2.76 g (13.39 mmol) of compound 8 and 4.14 g (13.39 mmol) of compound 9 in a mixture of 50 mL of toluene and 4 mL of tetrahydrof of uranium at a temperature of 110°C is reacted 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 compound 13 as a mixture diastereomers on phosphorus in a ratio of 1:1.

^K P-NMR (162 MHz, deuterochloroform): δ values in ppm: 43.73 and 43.82

- 60 • 4 «444 ·· 9-444 44 «· • · · 4« * 4 4 4 »

9*444 9 · 9 · 4 4· » 4 4 « » » « 44 4 4 4 • · · 4449 4 4 4

444 44 44 *4 ·4

Example 14

compound 14

Using essentially the same procedure as described for the preparation of compound 12, a mixture of 3.19 g (17.50 mmol) of compound D and 5.41 g (17.50 mmol) of compound 9 in a mixture of 50 mL of toluene and 4 mL of tetrahydrofuran at at a temperature of 110°C is subjected to a reaction 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, thereby obtaining compound 14 in the form of a mixture of diastereomers on phosphorus in a ratio of 1:1.

³¹ P-NMR (162 MHz, deuterochloroform): 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 is stirred at 0° C. A solution of 1.1 g (3.01 mmol) of compound 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 was added and then the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate,

- 61 *0 0000 ·· ·*·« ·· 0« 000 «0 · 0000 • 0000 0 0 0 0 0 00 0 0 000 0 00 0000 0 00 0 000« 000 «0 000 00 00 «0 ·0 will filter and evaporate. The residue was purified by flash chromatography on silica gel using 5% methanol in dichloromethane as eluant to give compound 15 as a mixture of phosphorous diastereomers.

Mass Spectrometry (FAB (Fast Neutral Particle Ionization)); (m+1)' m/z = 366 ³¹ P-NM_R (162 MHz, deuterochloroform) ·. δ values in ppm: 54.05 and 54.63

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

Analysis for C ₂₀ H ₃₂ NO ₃ P . 0.75H ₂ O :

Calcd: 63.39% C, 8.91% H, 3.70% Not found: 63.39-% C, 8.75% H, 3.70% N.

^By P-NMR (162 MHz, deuterochloroform): δ values in ppm: 54.08 and 54.65

Example 17

N

H

OC2H5 compound 17

0« 0000

- 62 0« 0000 • «0

0 0 · · • 0 « • · 0'

0*0 · · *09 9 9 0 « 0

0* 00

00

0 0 » « 0 ·9

0 0 0 *

0 0 • 0 ·4

A solution of 50 mg (0.12 mmol) of compound 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 all at once and the reaction mixture was stirred for 3 hours at room temperature. The reaction is then quenched by the addition of glacial acetic acid and the product is extracted with ethyl acetate. The combined organic phases are washed with water and sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 5% methanol in dichloromethane as eluant to give the racemic trans-2,5-disubstituted morpholine derivative, compound 17, as a mixture of phosphorus diastereomers.

^3l P-NMR (162 MHz, 54.64 deuterochloroform) δ values in ppm: 54.06 and

Example 18

compound 18

Using essentially the same procedure as described for the preparation of compound 15 , 2.24 g (5.15 mmol) of compound 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, as a mixture of phosphorus diastereomers.

Analysis for C ₂₀ H5 ₀ Cl ₂ NO ₃ P. 0.5H ₂ O:

calcd: 54.18% C, 7.05% H, 3.16% N; found:· 54.21% C, 7.08% H, 3.11% N.

- 63 ·· «999 ♦ 99 9

9,999 9

9 * 9 9

9999

9

9

9 » 9

9« 99

99 » 9 9 « ► 9· 99

999 9 « • 9 « «9 99 ³¹ P-NMR {162 MHz, deuterochioroform) : δ values in ppm;· 53.80 and 54.40

Example 19

compound 19

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

T ³¹ P-NMR (162 MHz, deuterochioroform): δ values in ppm: 53.73 and

54.33

Example 20

compound 20

To a stirred solution of 650 mg (1.78 mmol) of compound 15 in 25 mL of dichloromethane, 0.939 mL (7.12 mmol) of bromotrimethylsilane was added dropwise under an argon atmosphere. The reaction mixture was stirred for 24 hours at room temperature. The reaction is then terminated by adding a mixture of methanol and water in the ratio of 95:5. The solvent is removed under reduced pressure to obtain ♦ · flfl»· fl· flflbfl ·· flfl flflfl · · · «··« fl · ·«· · ♦ fl «fl·· flfl · A· > ·« ««fl · « • fl ·' ··»!· ··· ·· ··· ·· ·· ·« ·· an oily residue that is cleaned 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 resulting product is dried under high vacuum (less than 6.7 Pa) to give r>.

compound 20 in form of white firmly substances about melting point more than 250°C. ία] _D = +10.8° (c = 1; in methanol) Analysis for C _XS H ₂₈ NO ₃ P : calculated: 64.08% C, 8.36% H, 4.15 % N; found: 63.72% C, 8.44% H, 4.02 %N.

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

Example 21

compound 21

Using the same procedure as 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.

[a] _D = -10.5° (c = 1; in methanol)

Analysis for C _xe H ₂₀ NO ₃ P:

calculated: 64.08 %C, 8.36 % H, 4.15% N; found: 63.62 %C, 8.50 % H, 4.05%N. ⁿ P-NMR (162 MHz, mixture deuterium oxide and deuterium chloride) values of δ v ppm: 55,36

*.*

Example 22

Cl

O

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, A 5-disubstituted morpholine derivative, compound 22, melting with decomposition above 200°C.

Analysis for Ο ₁₃ Η ₂₆ <Ζ1 ₂ ΝΟ ₃ Ρ. 0.25H ₂ O :

calcd: 52.63% C, 6.50% H, 3.41% N; found: 52.45% C, 6.53% H, 3.29% N.

³¹ P-NMR (202.5 MHz, perdeuteroacetic acid): δ values in ppm: 45.45

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

Example 23'

H

II

OH compound 23

No

Using the same procedure as described for the preparation of ·'··· • · «

0 ··♦

0000 0 * ♦ ·Ι · '

0 0-00 I 0 0 0 0 0 0 ·· 000 00 00

00 ♦ * 0 0 0 0'. 0 00 · «000 0 • 0 0 «0 Compound 20 was reacted with 0.50 g (1.20 mmol) of Compound 19 and 0.48 mL (3.65 mmol) of bromotrimethylsilane in 25 mL of dichloromethane to give the racemic trans -2,5-disubstituted morpholine derivative, compound 23, melting point 128 to 130°C.

Analysis for C _ia H ₂₇ N ₂ O ₅ P. H ₂ O:

calculated: found ·.

53.99% C, 7.30% H, 7.00% N; 54.23% C, 7.25% H, 6.93% N.

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

Example 24

compound 24'

A mixture of 2.98 g (7.26 mmol) of compound 19 and 0.5 g of 10% palladium on activated carbon (0.5 g) in 150 ml of absolute ethanol was hydrogenated for 18 h·. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluant to give the racemic trans-2,5-disubstituted morpholine derivative compound 24 as a mixture of diastereomers on phosphorus, mp 115 to 118°C.

Analysis for C ₂₀ H ₃₃ N ₂ O ₃ P. 0.25H ₂ O :

calcd: 62.40% C, 8.77

H, 7.31% N; 62.52% C, 8.88% H, 7.18% N.

found:

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

- 67 44 444*. 44 ···· 44 44

444 44 4 4 · 4 4

44444 4 4 4 · · >·

4444 44 4 4 4. « 4

4,444 4',444

444 4* .44 44 44

Example 25

15 g of crushed ice is added to a stirred solution of 2.43 g (6.38 mmol) of compound 24 in 50 ml of concentrated hydrochloric acid, and the resulting mixture is cooled to 0° C. A solution of 0.48 g (7, 02 mmol) of sodium nitrite in 25 ml of water and the resulting mixture is stirred for 10 minutes at 0° C. The resulting solution is 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 is neutralized by 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 a 10% aqueous solution of sodium hydroxide, then with a 5% aqueous solution of sodium bisulfite and then with water. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using 10% methanol in ethyl acetate as eluant to afford the racemic trans-2,5-disubstituted morpholine derivative compound 25 as a mixture of diastereomers at phosphorus.

Mass spectrometry (Cl (chemical ionization)/NH ₃ ) : (m+l)* m/z = 4.92

·«·· 9« «999 •99 9 ·. 9. 9 ··· 9 9k ·

9 9 9 9 IÍ' 9

9 9 9 9 9 9

9« 9*9 9* «9 ^3l P-NMR (162 MHz, deuterochloroform) 54.77 δ values in ppm: 54.21 and

Example 26

compound 25

Using essentially the same procedure as described for the preparation of compound 20, 0.1 g (0.20 mmol) of compound 25 and 0.427 mL (3.20 mmol) of bromotrimethylsilane were reacted in 10 mL of dichloromethane for 73 h at room temperature. The crude product is purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in ϊΓ-form) using a mixture of 50% methanol, 47% water and 3% aqueous ammonia as eluent and the product is dried under high vacuum (at a pressure of less than 6.7 Pa), yielding a racemic trans-2,5-disubstituted morpholine derivative, compound 26, melting with decomposition at more than 230°C.

Analysis for C _ia H ₂₇ INO ₃ P. 1,2H ₂ O:

calculated: found: 44.59 44,48 % c % c 6.11% H, 5.70% H, 2.89% N; 2.95%N. ³¹ P~NMR (162 MHz, mixture perdeuteromethanol and deuterium chloride ridu): δ values in ppm: 53.08 Example 27 0 11 j year Y ϊΎ γ ν' w i Y oc ₂ h ₅ and compound 27

CN

4« 444«

4-4 4 4

4

4 ··

4 4 4

4» 4

4« *

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

Mass spectrometry (Cl (chemical ionization)/NH ₃ ) : (M+1)' m/z = 391 ³¹ P-NMR (162 MHz,' deuterochloroform) : δ values in ppm: 53.95 and

54,57

Example 28 compound 28

CN

0000

- 70 •0 0000 0 · * * 0·«0

0 * 0 « 0

00 0

0»

0 0

0*0

0» 0«

00 0 «00 0 B 00

0 0 0 0 0 «0 0

0 00.

Using essentially the same procedure as described for the preparation of compound 20 , 0.16 g (0.41 mmol) of compound 27 and 0.81 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) /NH ₃ ),:

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

Example 29

compound 29

A mixture of 0.09 g (0.23 mmol) of compound 27, 10 mL of 6M hydrochloric acid solution, and 1 mL of ethanol was heated to reflux for 72 hours. After completion of the reaction, which is verified by ³¹ P-NMR, the solvent is removed under reduced pressure. The residue is 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 and the product is dried under high vacuum (at a pressure of less or equal to 6.7 Pa), giving a racemic trans-2,5-disubstituted morpholine derivative, compound 29, with a melting point of more than 260°C.

³¹ P-NMR (162 MHz, deuterium oxide): δ values in ppm: 40.67

4« »444 ·» ·»»· 44 ·« • · * 4 · 4 4444

44444 4 4 · 4444

4 4 4 4 4 44 4444 4

4 4 · 4 * 4 444

4444« 44 44 44 4'4

Example 30

A mixture of 0.50 g (1.18 mmol) of compound 17, 25 mL of 6M hydrochloric acid solution, and 5 mL of glacial acetic acid was heated for 16 h at 10 0° C. After completion of the reaction, which was verified by ³ⁱ P- NMR, the solvent is removed under reduced pressure. The residue is purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in the H* form) using a mixture of 50% methanol, 47% water and 3% aqueous ammonia as eluent and the product is dried under high vacuum (2a pressure less or equal to 6.7 Pa), giving the racemic trans-2,5-disubstituted morpholine derivative, compound 29.

Analysis for C^H^NOsP . 0.5H ₂ O :

Calcd: 58.45% C, 7.49% H, 3.59% Not found: 58.68% C, 7.35% H, 3.71% N.

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

Example 31

A solution of ∼317 mg (0.83 mmol) of compound 29 in 20 mL of methanol was saturated with hydrogen chloride gas and the reaction mixture was stirred for 16 h at room temperature. The solvent is removed under reduced pressure and the residue is purified by ion exchange chromatography on Dowex 50WX 2-200 resin (in the H'-form) using a mixture of 50% methanol, 47% water and 3% aqueous ammonia as eluent. The product se

9999 99 V·»· · «9 9 • * 999 9 9 9

9 9 9 9 9 9·

9 · 9 9 9 9 *»9 999 99 99

dried under high vacuum (at a pressure of 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 <,NO;P. 0.25H ₂ O :

calcd: 60.01% C, 7.68% H, 3.50% N; found: 60.26% C, 7.57% H, 3.45% N.

³¹ P-NMR (162 MHz, perdeuteromethanol): δ values in ppm: 37.21 )

Example 32

compound 31

2a using essentially the same procedure as 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.

[ct] _D = -38.5° (c = 0.6, in methanol) ³¹ P-NMR (162 MHz, perdeuteromeethanol): δ values in ppm: 29.00

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

·· ···· ·· ···· »· ·· ··· ·· · ···* * · ··· · · · « · «* • · ··· · * ··· · · • · ····· ··· ·· »»· ·· ·· «· ·· [a] _D = +41.3° (c = 0.6, in methanol} ³¹ P-NMR (162 MHz , perdeuteromethanol): δ values in ppm: 28.84

Example 34

compound 33

To a stirred solution of 100 mg (0.24 mmol) of compound 12 in ml of dichloromethane, 300 μΐ (2.4 mmol) of bromotrimethylsilane was added under an argon atmosphere, 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 then dissolved in 5 mL of a mixture of 6M hydrochloric acid and 0.3 mL of methanol and the mixture was refluxed for for 4 hours. The solvent is removed under reduced pressure and the residue is co-evaporated three times with water. The resulting residue was purified by ion exchange chromatography on Dowex 50WX 2-200 resin using a mixture of 50% methanol, 47% water, and % aqueous ammonia as eluent to afford compound 33.

P-NMR (162 MHz, perdeuteromethanol): δ values in ppm: 29.28

Example 35

compound 34

Cl ·· φ · φ · φ* · · · · · « «···'' · φ · • φ «·· φ ······ ^ • φ · · ·· · . m · φ ·· ι·· · · ··

Using essentially the same procedure as 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 .

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

Example 36

Using essentially the same procedure as 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

_NH2

OH compound 36

To a suspension of 2.9 g (10 mmol) of 2-amino-3-(4-iodophenyl)propionic acid in 10 ml of tetrahydrofuran, 1.25 ml (10 mmol) of boron trifluoride ethyl etherate is added dropwise over the course of 20 minutes. The mixture was heated to reflux for 2 h, then 1.1 mL (11 mmol) of borane-dimethylsulfide complex was added dropwise over 1 h while refluxing. The mixture is heated to reflux for an additional 5 hours and then stirred for 15 « *·♦»

9 9 • 9 9

9 · Β 9 9

9 9

9 9 9 hours at room temperature.

Add 20 ml of a 1:1 mixture of water and tetrahydrofuran, followed by 7.5 ml of 5N sodium hydroxide solution. The reaction mixture is refluxed 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 a 1:2 mixture of hexane and ethyl acetate to give compound 36, mp 105 - 107° C.

Analysis for C ₃ H ₁₂ INO:

calcd: 39.01% C, 4.37% H, 5.06% N; found·- 38.69% C, 4.'40% H, 4.92% N.

Example 38

II compound 37

Using essentially the same procedure as described for the preparation of compound 12, a mixture of 2.40 g (8.66 mmol) of compound 36 and 2.7 g (8.66 mmol) of compound 9 in 20 mL of toluene at 75° C. reaction with a solution of 1.30 g (8.66 mmol) of 1,8-diazabicyclo[5,4,0]undec-7-ene in 10 ml of tetrahydrofuran gives compound 37 as a mixture of phosphorus diastereomers in a ratio of 1: 1.

³¹ P-NMR (202 MHz, deuterochloroform): δ values in ppm.· 43.69 a

43.72 »· · ·· I • * • · ··

·· · ·

Example 39

compound 38 (trans) compound 39 (cis)

To a stirred solution of 2.0 g (4.0 mmol) of compound 37 in 25 ml of dry toluene, a suspension of 0.105 g (4.4 mmol) of sodium hydride in 5 ml of dry toluene was added portionwise over the course of 30 seconds. The mixture was stirred for 30 minutes at 0°C, 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 with sodium chloride solution. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 20% methanol in ethyl acetate as eluant to give the racemic trans-2,5-disubstituted morpholine derivative, compound 38, and the racemic cis-2,5-disubstituted morpholine derivative, compound 39, always in the form of a mixture of diastereomers on phosphorus.

Compound 38: ³¹ P-NMR (162 MHz, in ppm: 53.93 and 54.60 deuterochloroform) δ 'fl values,

Compound'39: ³¹ P-NMR (162 MHz, in ppm: 54.25 and 54.82 deuterochloroform) δ values

Example 40

compound 40· • · 4 • 4 ·· » *· Μ

To a stirred solution of 130 mg (0.356 mmol) of compound 38 in ml of dichloromethane, 0.20 ml (1.52 mmol) of bromotrimethylsilane was added dropwise in an argon atmosphere. 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 a 1:1 mixture of water and methanol. The residue is 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 2a column using water as the eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 40, melting with decomposition at a temperature greater than 250°C.

Analysis for C ₁₉ H ₃₀ INO ₃ P.Na . 3H ₂ O :

calcd: 41.20% C, 6.10% H, 2.53% N; found: 41.42% C, 5.40% H, 2.42% N.

^3l P-NMR (161 MHz, deuterium oxide): δ values in ppm: 41.81

Example 41

compound 41

Mixture. 0.180 g (0.36 mmol) of compound 38 and 0.200 g (0.28 mmol) of bistriphenylphosphinepalladium(II) chloride in 2 mL of absolute ethanol and 1 mL of triethylamine were degassed by bubbling with argon for 5 min. The mixture was heated under reflux and vigorously stirred under carbon monoxide 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.

- 78 ··· 4 4 · · 4 · · • 4444 4 · · · 444

9 999 4 44 4444 4 • 4 6 4 4 464 • 6 444 64 44 44 44

The combined ethyl acetate used for washing was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel using 10% methanol in chloroform as the eluent to give the racemic trans-2,5-disubstituted morpholine derivative, compound 41, as diastereomer mixtures on phosphorus.

³¹ P-NMR (161 MHz, deuterochloroform): δ values in ppm: 53.93 and 54.60

Example 42

compound 42

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

Analysis for C2 ₀ H _2B NO ₅ P.Na . 2H ₂ O:

calculated·. 50.52% C, 6.79% H, 2.95% N; found: 50.53% C, 7.40% H, 2.96% N.

^r 'P-NMR (202 MHz, deuterium oxide): δ values in ppm: 42.38 • ·

Example 43

O

O

compound 43

CO ₂ -Na ⁺

A buffered formaldehyde stock solution is prepared by dissolving 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 40¾ aqueous formaldehyde solution in 5 mL of water. 10 mL of the above stock solution was added to a mixture of 0.10 g (0.262 mmol) of compound 29 in 2 mL of methanol and the mixture was stirred for 10 min at room temperature. 0.165 g (2.62 mmol) of sodium cyanoborohydride is added portionwise over the course of 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 ion exchange chromatography on Dowex 50WX 2-200 resin (in ff-form) using a 1:1 mixture of methanol and 2% sodium hydroxide solution to elute the product. The resulting product is 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 43, melting with decomposition at a temperature greater than 250°C.

Analysis for C ₂₀ H ₂₆ NO _S P . 2 On. H ₂ 0:

calcd: 52.52% C, 6.61% H, 3.06% N; found: 52.60% C, 6.82% H, 3.10% N.

³¹ P-NMR (202 MHz, deuterium oxide): δ values in ppm: 41.93 <1

Example 44

O

• · · · · « * · • ···

compound 44

0.25 g (0.66 mmol) of compound 29 is dissolved in 4 ml of a 1:1 mixture of dioxane and water, and the pH of the resulting solution is adjusted to 9 by adding 0.1 M sodium hydroxide solution. The mixture is stirred intensively and 0.188 ml (1.32 mm) of benzyl chloroformate is added dropwise over the course of 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 is concentrated under reduced pressure to one half of its original volume and acidified with concentrated hydrochloric acid. The mixture is then extracted with ethyl acetate and the combined organic phases are washed with water and then with sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel using a mixture of % acetic acid, 10% methanol and 88% chloroform as eluent. The product is further purified by means of ion exchange chromatography on Dowex 50WX 2-200 resin (in H*-form) using a mixture of tetrahydrofuran and water in the ratio: 1 as eluent. The resulting product is 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, melting on decomposition at more than 250°C.

9« 9999

99

999 99 · 9999

9999 9 9 9 9 9 «

9 9*9 9 * · »999 9 • 9 9 9··* 999

999 9« 99 99 99

Analysis for C ₂₇ H ₃₂ NO ₇ P.2Na.3H ₂ O:

calculated-. 52.85% C, 6.24% H, 2.28% N;

found: 52.27% C, 6.00% H, 2.24% N.

^In P-NMR (161 MHz, deuterium oxide): δ values in ppm: 41.75 Example 45 ,OH ΓΊΤ ^nh ₂ Y compound 45 Bro TO suspension 70.2 g (0.31 mol) of compound J in 350 ml tetrahydrofuran with in progress After 20 minutes, he adds drops

75.0 mL (0.61 mol} of boron trifluoride-ethyl etherate. The mixture was heated to reflux for 2 hours, then 57.9 mL (0 .61 mol) of borane complex with dimethylsulfide.The mixture was heated to reflux for an additional 3 hours and then allowed to stand for 18 hours at room temperature.

Add 350 ml of a 1:1 mixture of water and tetrahydrofuran 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 is triturated with a mixture of diethyl ether and hexane and then recrystallized from ethyl acetate to give compound 45 with a melting point of 74-76°C.

- 82 4« «4·· •4 4444

4 4 4 4

444· 4 >

4 4 4 4 4

4 4 4 4 4 •4 444 44

44

4 4 4 4 • 4 4 4 4

4 44« 4 4 • ·44

44 44

Analysis for C ₈ H _l0 BrNO;

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

Example 46

compound 4

A mixture of 15.0 (5.70 mmol) of bis(triphenylphosphine)palladium(II) chloride in 100 mL of methanol and 25 mL of triethylamine was degassed by bubbling with argon for 5 min. The mixture is saturated with carbon monoxide and then pressurized to 210 kPa in the pressure vessel. The mixture is then slowly heated to 100° C. while maintaining the pressure below 350 kPa for 5 hours. The mixture was cooled to room temperature, filtered and evaporated. The residue is triturated with ethyl acetate and the filtrate is 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 .

COjCHj g (69.4 mmol) of compound 45 and 4.0 g ¹³ C-NMR (100 MHz, perdeuteromethanol): (q) , 58.3 (d) , 68.1 (t) , 129.0 (d) , 131.5 (s), 132.9 (d), 143.6 .δ values in ppm: 52.6 (d) , 129.5 (d) , 129.7 (s), 168.4 (s )

Example 47

compound 46

- 83 • fl ···· ·· ···· ·· ·· • flfl * · fl fl··· • flfl··' fl fl · · flfl· • · ··· fl flfl ···· flfl · flfl·· ··« • fl flflfl flfl ·· flfl ··

By the procedure 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 as described for the preparation of compound 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 a temperature of 75° C is subjected to a reaction with a solution of 0.33 g (2.17 mmol) of 1,8-diazabicyclo(5,4,0] of undec-7-ene in 5 mL of toluene to give compound 46 as a 1:1 mixture of phosphorus diastereomers.

³¹ P-NMR (162 MHz, 43.43 deuterochloroform): δ values in ppm, 43.25 and

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 compound 46 in 7 ml of dry toluene is added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of glacial acetic acid and then the mixture is filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 20% methanol in ethyl acetate to afford the racemic trans-2,5-disubstituted morpholine derivative compound 47 as a mixture of phosphorus diastereomers.

«4 ·»♦· »4 4 49 4

4 4 44..4+4 * t*4 4 9 4

9 4444 44 4»»4“ • 4 4 9 4 4 4 gn* 4

444 4« 44

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

(M+1)* m/z = 405 ³¹ P-NMR (162 MHz, deuterochloroform): δ values in ppm: 54.44 and 55.32

Example 49

compound 48

Using essentially the same procedure as 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, This gives the racemic trans-2,5-disubstituted morpholine derivative, compound 48.

^l3 C-NMR (100 MHz, deuterium oxide): δ values in 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 Cd) , 125.0 (d) ,

125.4 (d), 128.3 (s), 138.8 (s) ^3L P-NMR (202 MHz, deuterium oxide) : δ values in ppm: 42.6

Example 50

compound 49

Using essentially the same procedure as described in Example 37, 10.0 g (51.8 mmol) of DL-2-amino-3-methyl-2-phe-

• 4 4444 II 4444

44 4 4 4 .: · w * » itftf |

4 444 4 4 4 <·4»«44 «4 4*4* 4B g 444 4|

4 4 4 4 4 4 «| • 4,444 44 4« ««| nylbutyric acid, 6.4 mL (51.8 mmol) of boron trifluoride-ethyl etherate, and 4.9 mL (51.8 mmol) of borane-dimethylsulfide complex were reacted in 50 mL of dry tetrahydrofuran to give compound 49.

Mass spectrometry (Cl (chemical ionization)/NH ₃ ) (m+l) ⁺ m/z = 180 ¹³ C-NMR (100 MHz, deuterochloroform): δ values in ppm: 16.8 (q), 17.4 ( q), 34.8 (d), 61.7 (s), 69.2 (t), 126.2 i), 126.4 (d), 127.8 (d), 144.2 (s)

Example 51

Using essentially the same procedure as described for the preparation of compound 12, a mixture of 1.07 g (6.0 mmol) of compound 49 and 1.86 g (6.0 mmol) of compound 9 in 20 mL of toluene at 75° C. reaction 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 compound 50 as a mixture of phosphorus diastereomers in a ratio of 1: 1.

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

(m+l) ^f m/z = 408 ³¹ P-NMR (202.5 MHz, deuterochloroform): δ values in ppm: 44.22 and 44.25

Example 52

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

• · • I * »

- 86 • lil

Using essentially the same procedure as 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 the racemic (2R*,5S*)-derivative morpholine, compound 52, always in the form of a mixture of phosphorus diastereomers.

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

Compound 52: ¹¹ P-NMR (162 MHz, deuterochloroform): δ values in ppm: 54.2 and 55.5

Example 53

compound 53

Using essentially the same procedure as 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 the racemic (2R*,3R* }-morpholine derivative, compound 53.

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

Example 54

O

Chi

O'Na ⁺ compound 54 • fl ···* » fl · t flflfl* flfl · * » · · *· >·«

- 87 tfl ··*·

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

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

Example 55 ch ₃ oo ch ₃

och ₂ ch ₃ och ₂ ch ₃ och ₂ ch ₃ compound 55

To a solution of 5.25 g (25 mmol) of ethyl 1,1-diethoxyethylphosphinate in 30 ml of dry tetrahydrofuran cooled to -70°C, 50 ml (25 mmol) of a 0.5 M solution of potassium bis(trimethylsilyl)amide is added dropwise in toluene. The mixture is stirred for 0.5 hours at a temperature of -70° C. The resulting solution is added dropwise over the course of 10 minutes to a cooled solution of 3.9 g (25 mmol) of 4-methoxybenzyl chloride in 30 ml of tetrahydrofuran. The resulting mixture is stirred for 1 hour at a temperature of -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. The organic phase se. separated, washed with water and then with sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a 2:1 mixture of ethyl acetate and hexane as the eluent to afford compound 55.

ⁿ P-NMR (162 MHz, deuterochloroform): δ values in ppm: 44.6 « · 0 • ·

0 » · 0

0 0« t 0 « »0 00 «

Example 56

compound 56

To a solution of 1.0 g (3.03 mmol) of compound 55 in 10 ml of a 9:1 mixture of chloroform and ethanol was added 3.8 ml (30.3 mmol) of chlorotrimethylsilane and the mixture was stirred for 18 hours at room temperature . The mixture was evaporated under reduced pressure and the residue was 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 afford compound 56 as a colorless oil.

Mass spectrometry (CI (chemical (m+NHj ⁺ m/z = 232 ionization)/NHJ :

³¹ P-NMR (162 MHz, deuterochloroform): δ values in ppm: 37.3

Example 57

Br compound 57

Using essentially the same procedure as described in Example 9, 0.5 g (2.33 mmol) of compound 56, 0.69 mL (2.80 mmol) of bis(trimethylsilyl)acetamide, 0.33 mL (2.80 mmol) of trimethyl phosphate and 0.23 mL (2.33 mmol) of a mixture of cis- and trans-isomers of 1,3-dibromoproperine are reacted in 10 mL of dry dichloromethane to give compound 57 as a mixture of cis- and trans-isomers.

• 9

- 89 *9 « · 9 9 • 9 9 « 9 9 9 9 h ¥ a

99 9

9

9 ·

9

9 9

9* O

99

9 «

9 9

9 9 9 1 ³¹ P-NMR (162 MHz, deuterochloroform) 48.1 δ values in ppm: 47.2 a

Example 58

compound 58

Using essentially the same procedure as 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 a 4:1 mixture of toluene and tetrahydrofuran at room temperature 80°C react with a solution of 0.181 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 mixture of phosphorus diastereomers in the ratio 1:1.

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

(m+l)* m/z = 448 ³¹ P-NMR (162 MHz, deuterochloroform): δ values in ppm: 39.40 and 39.49

Using essentially the same procedure as 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,

0 «0 0« · 0 0

0 · · · * 0 • 0 0 0*00 '· 0« 0 0·· · * 0 » *0 0' ·0 ·« 00

giving the racemic trans-2,5-disubstituted morpholine derivative, compound 59, as a mixture of phosphorus diastereomers.

³¹ P-NMR (162 MHz, deuterochloroform); values of 6 in ppm: 50.0 and 50.8

Example 60 fa:

. *)ι

O

compound 60 and ₃

CO' ₂ Na ⁺

To a solution of 50 mg (0.11 mmol) in dichloromethane was added 0.074 mL (0. compound 59 in 1 mL mmol) of 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 refluxed for 4 hours. The solvent is removed under reduced pressure and the residue is co-evaporated three times with water. The resulting residue is 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 60.

Claims (37)

PATENT CLAIMS 1. A compound in which the acid of general formula I is substituted phosphinic R ^y (I) in which R ^l represents a monovalent aromatic or araliphatic group attached to said carbon atom through its carbon atom, R ^: means an unsubstituted or substituted hydrocarbyl group, R ^x represents a hydrogen atom or an unsubstituted or substituted hydrocarbyl group, R ^y means a hydrogen atom, a group R ^y a or a group protecting the function NH, a R ^y a represents an unsubstituted or substituted hydrocarbyl group, or a sul or ester thereof. 2. The compound according to claim 1, in which R ¹ represents an aryl group with 6 to 15 carbon atoms, which is unsubstituted or substituted in one or more positions by substituents selected from the group consisting of halogen atoms, a hydroxy group, an alkoxy group with 1 to 4 carbon atoms, a carboxy group , functionally modified carboxy groups, carboxyalkyl groups with 1 to 8 carbon atoms in the alkyl part, functionally modified carboxyalkyl groups with 1 to 8 atoms • 4 «444 «4 4444 44 4« 44* *4 4 ♦ · · » ♦ 44>· 4 4 · · ^44 4 4 4 · 4 4 · 4 4*4 4 4 4 4 4*4* * 4 4 444*4 *« *· *4 V* - 92 carbons in the alkyl part and a nitro group, or R ¹ represents a five- to ten-membered heterocyclic aromatic group containing one or two nitrogen atoms in the ring system. 3. The compound according to claim 1, in which 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 the said morpholine ring, substituents selected from the group including halogen atoms, carboxy group , functionally modified carboxy groups and a nitro group, or R ¹ represents a five- to ten-membered heterocyclic aromatic group containing a nitrogen atom as the only ring heteroatom. 4. A compound according to claim 1, in which R ¹ represents a phenyl(lower)alkyl group, an α,α-diphenyl(lower)alkyl group or an α-naphthyl(lower)alkyl group, which group is unsubstituted or substituted in one or more positions substituents selected from the group consisting of halogen atoms, hydroxy group, 1- to 4-carbon alkoxy group, carboxy group, functionally modified carboxy group, carboxyalkyl group with 1 to 8 carbon atoms in the alkyl part, functionally modified carboxyalkyl group with 1 to 8 carbon atoms in the alkyl part, and intragroup. 5. The compound according to claim 1, in which R ¹ represents an α-phenylalkyl group with 1 to 4 carbon atoms in the alkyl part, which is unsubstituted or substituted in one or more positions by substituents selected from the group comprising halogen atoms, a carboxy group, functionally modified carboxy groups and a nitro group. 6. The compound according to claim 1, in which R ¹ represents phenyl, 3-iodophenyl, 3,4-dichlorophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3-(methoxycarbonyl)phenyl, 9 9' 9 b 9 9 ··» • 9 9 • 9 9 9 9 9 9 9 9 9 9 « 9 9 «9 9999 • 9 9 9 9 · «9 9« 99 9 I* ··«♦ - 93 3-nitrophenyl, benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl group. 7. A compound according to any one of claims 1 to 6, in which R ² represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an oxo(lower)alkyl group, a hydroxy- or dihydroxy(lower)alkyl group, a hydroxy(lower)alkenyl group group, mono-, di- or polyhalo(lower)alkyl group, mono-, di- or polyhalo(lower)alkenyl group, mono-, di- or polyhalo(hydroxy)(lower)alkyl group, mono-, di- or polyhalo(hydroxy)(lower)alkenyl group, (lower)alkyl(lower)alkyl group, di(lower)alkyl(lower)alkyl group, (lower)alkyl(hydroxy)(lower)alkyl group, (lower)alkyl(halogen )(lower)alkyl group, (lower)alkylthio(lower)alkyl group, di(lower)alkylthio(lower}alkyl group, cyano(lower)alkyl group, acylamino(lower)alkyl group, cycloalkyl group, hydroxycycloalkyl group , oxa-, dioxa-, thia- or dithiacycloalkyl group, cycloalkyl(lower)alkyl group, cycloalkenyl(lower)alkyl group, cycloalkyl(hydroxy)(lower)alkyl group, ((lower)alkylthio)cycloalkyl(hydroxy)(lower) an alkyl group, or a mono- or diphenyl (lower) alkyl group which is unsubstituted or mono-, di- or tri-substituted by substituents selected from the group comprising lower alkyl groups, lower alkoxy groups, halogen atoms, a hydroxy group and/or a trifluoromethyl group, or naphthyl ( a lower)alkyl group or an unsubstituted or halogen-substituted thienyl-, furyl- or pyridyl(lower)alkyl group. 8. A compound according to claim 7, in which R ² represents an alkyl group with 1 to 7 carbon atoms, an α,α-dialkoxyalkyl group with 1 to 4 carbon atoms in each alkoxy part - 94 • 0 0000 * 0 0 » 0 0 00 * » ♦ 0 0 0 0 0 00 0 «I ·000 * 0 0 0*0 0 0 < 0 0 e b 0 0 and · • * 0* 0 0·· 0 • 0 « 0 0 0* and 1 to 4 carbon atoms in the alkyl part, a cyanoalkyl group with 1 to 4 carbon atoms in the alkyl part, an acylaminoalkyl group with 1 to 5 carbon atoms in the alkyl part, a cycloalkylalkyl group with 3 to 6 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkyl part, a cycloalkenylalkyl group with 3 to 6 carbon atoms in the cycloalkenyl part and 1 to 4 carbon atoms in the alkyl part, or a phenylalkyl group with 1 to 4 carbon atoms in the alkyl part, which is unsubstituted or · mono- , di- or trisubstituted by an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, a hydroxy group and/or a halogen. 9. The compound according to claim 7, in which R ² represents an alkyl group ε 1 to 5 carbon atoms, an α,α-dialkoxymethyl group with 1 to 4 carbon atoms in each alkyl·'..·' part, an α,α-dialkoxyethyl group with 1 to 4 carbon atoms in , each alkoxy part, a cycloalkylalkyl group with 3 to 6 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkyl part, a benzyl group or a 4-methoxybenzyl +·· * group. 10. A compound according to claim 7, in which R ² represents a cyclohexylmethyl or 4-methoxybenzyl group. 11. A compound according to any one of claims 1 to 10, in which the unsubstituted or substituted hydrocarbyl group in the meaning of the symbol R ^x is an alkyl group with 1 to 10'* carbon atoms, an alkenyl group with 2 to 10 carbon atoms, a cycloalkyl group with 3 to 8 carbon atoms, cycloalkylalkyl A group with 4 to 13 carbon atoms, an aryl group se 6 to 10 carbon atoms or an aralkyl group with 7 to 13 carbon atoms, wherein these groups are unsubstituted or substituted by at least one substituent selected from the group comprising halogen atoms, a hydroxy group, an alkoxy group with 1 to 4 carbon atoms, a carboxy group, functionally modified • · 4 * · 9 · · ♦ · » b 4 * · 4 · ·. b *9· 9 b 4 · 4 4 9 9 · » ·· 4 4« » b · · b 494 4 4 ««9 »·'# · ··' ·*' »4 carboxy groups, carboxyalkyl groups with 1 to 8 carbon atoms h in the alkyl part, functionally modified carboxyalkyl groups with 1 to 8 carbon atoms in the alkyl part and a nitro group. 12. A compound according to any 2 of claims 1 to 11, in which R ^x represents a hydrogen atom, a lower alkyl group, a cycloalkyl group with 3 to 6 carbon atoms, an aryl group with 6 to 8 carbon atoms or an aralkyl group with 7 to 9 carbon atoms. 13. The compound according to claim 12, in which R ^x represents a hydrogen atom or an isopropyl group. 14. A compound according to any one of claims 1 to 13, in. wherein R ^y represents the group R ^y aa means an alkyl group of 1 to 10 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms or an aralkyl group of 7 to 13 carbon atoms, which group is unsubstituted or substituted by a hydroxy group or an alkoxy group of 1 to 4 atoms carbon. 15. The compound according to any one of claims 1 to 13, in which R ^y represents a group protecting the NH function and denotes an acyl group, an alkoxycarbonyl group or an armethoxycarbonyl group. 16. The compound according to any one of claims 1 to 13, in which R ^y represents a hydrogen atom, a lower alkyl group, an aralkyl group with 7 to 9 carbon atoms, a tert.butoxycarbonyl group or a benzyloxycarbonyl group. 17. 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. « ti 6 4 * 6 · 4 4 4' 4 4 4 . 6 6 4 6 6 6 • 6 «44 66 4 ·6 i 4 64 44 4 6 4> 6 4 4 4 6 4 4 . 6: 6 4 4 6 6 4 * ·« 4 * 4 • 6 4 6 6 4 4 6.4 4 4 « 4 6 4 -iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl group, R ² means cyclohexylmethyl or 4-methoxybenzyl group, R ^x represents a hydrogen atom or an isopropyl group, and R ^Y represents a hydrogen atom, methyl or benzyloxycarbonyl group. 4' 18. A compound according to any one of claims 1 to 17 of the general formula ΙΑ, IB, IC or.ID *) (IA) (IB) (IC) (ID) - 97 4 4' 4 4 ·· * 4 ·) 4 44 4: ♦ 4, 4 • · « 4« 4 4 4 4 4 * »·. 4 4 « 4 · · · 4 4 · 4 4 *« 4 4' 4 4 4 4 4. « 4 4 4 4 4 ¹ 4, 4 4 ·« ·· 4b 4 4 where R ¹ has the meaning defined in any of claims 1 to 6, R ² has the meaning defined in any of claims 1 and 7 to 10, R ^x has the meaning defined in any of claims 1 and 11 to 13 and R ^y the meaning defined in any of claims 1 and 14 to 16.. 19. Compound of general formula VA (VA) OH in which R ¹ has the meaning defined in any of claims 1 to 6, R ² has the meaning defined in any of claims 1 and 7 to 10' and R* has the meaning defined in any of claims 1 and 11 to 13, or a salt thereof or ester. 20. Compound of general formula III O OR ⁵ in which R ² has the meaning defined in any of claims 1 and 7 to 10; X represents a halogen atom, and R ⁵ means an alkyl group with 1 to 8 carbon atoms, with the proviso that R ² does not mean a methyl group if R ⁵ represents an ethyl group. 21. A compound of general formula II, VI, VII or VIII CN r ⁴ - c-NHR ⁶ ( ^VI ) R* COOR ⁷ R ⁴ - _C -NHR ⁶ (VII) R* COOR ⁷ (VIII) R ⁴ -C-NH ₂ R* where « 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 unsubstituted or substituted aryl 44 4444 44 ·Μ· ·· I* 4*4 *4 * 4 * * * • * 4 44 4 4 4 4 4 4« 4 4 444 4 «· »44 4 4 4 4 4 4 4 4 »' , 4' 4 4 44 444 «· 4« 44 «« group with 6 to 10 carbon atoms, R ⁷ represents an alkyl group with 1 to 10 carbon atoms, and R ^x represents a hydrogen atom or an unsubstituted or substituted hydrocarbyl group, or a compound of general formula II or VIII, where R ⁴ represents a 3,4-dichlorophenyl group, and R ⁷ means an alkyl group with 1 to 10 carbon atoms, or a compound of general formula II, where R ⁴ represents a monovalent aromatic group attached to the mentioned carbon atom through its carbon atom, and R ^x represents an unsubstituted or substituted hydrocarbyl group, with the proviso that if R ⁴ represents a phenyl group, then R ^x does not represent a methyl group, an ethyl group, a group:. - (CH _Z )-jSCH ₃ , an allyl group or a hydroxymethyl group,:; if R* represents an aminomethyl group, then R ⁴ '¹;. does not mean a phenyl, p-hydroxyphenyl or p-methoxyphenyl group, and if R ⁴ represents a 2,4-dichlorophenyl group, then R* does not mean an N-triazolylmethyl group, or a compound of general formula II where R ⁴ represents an iodobenzyl group, and R* represents a hydrogen atom or an unsubstituted or substituted hydrocarbyl group, or a compound of general formula II, where R ⁴ represents a monovalent araliphatic group R ¹ as defined in any one of claims 1 and 4 to 6, and R ^x is an unsubstituted or substituted hydrocarbyl group as defined in any z 00 0000 00 «0 0 0 0 0 0 0 0 0 0 0 0 · 00 0 0 0 0 #0 0' 0 0 0 0 « 0 0 0 0 0« 00 00 00 00 0*00 * 0 0 0 ♦ 000 • 0 0 « 0 0 00,000 100 ¢) i of claims 1 and 11 to 13 other than a hydroxymethyl group, with the proviso that if R* represents a methyl group, then R ⁴ does not mean 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 group, and if R ⁴ represents a benzyl group, then R ^x does not represent an allyl group or a -CHjCHjSCHj group. 22. A compound of general formula XVIII in which R ¹ has the meaning defined in any of claims 1 to 6, R ² has the meaning defined in any of claims 1a to 7 to 10, R ^x has the meaning defined in any of claims 11a13aR ^Y has the meaning defined in any one of claims 1 and 14 to 16, or a salt or ester thereof. 23. Method for preparing the compound of general formula I according to claim 1. in which R ^y represents a hydrogen atom, characterized by the fact that the compound of general formula II OH R ^l ch ₂ v (II) • 9 «99« 99 9··9 99 »9 99« ** 9 · · · 9 • 9 9 99 9 · 9 9 9 99 9 9 9 * 9 9 ♦»»»»· 9 9 9 9 · 9 ^! · 9 9 9 9 9» 999 9· 99 9 9/ «9 101 wherein R ⁴ represents a group R ¹ as defined in any of claims 1 to 6, provided that R ⁴ is not substituted by a carboxyl group, and R* is as defined in any of claims 1 and 11 to 13, provided , that is not substituted by a carboxyl group, undergoes a reaction with a compound of general formula III (III) OR ⁵ where R ² has the meaning defined in any of claims 1 and 7 to 10, X represents a halogen atom, and R ⁵ represents an alkyl group with 1 to 8 carbon atoms, in the presence of a base, to form a compound of general formula IV Where the symbols R ⁴ and R ^x have the meanings defined in the general formula II, and subsequently, if necessary, one or more substitution reactions are performed changing the nature of the substituent in R ⁴ or/and R ^x or/and the hydrolysis of the ester group as a substituent in R ⁴ or/aR ^x to a carboxyl group or/and conversion of an ester group -OR ⁵ to a hydroxy group. 24. The method according to claim 23. characterized in that the reaction of compounds of general formulas II and III is carried out by adding a weak base to a mixture of compounds of general formulas II and III in a solvent, forming an intermediate of general formula V - 102 flfl flflflfl flfl flflflfl flfl flfl flflfl flfl fl fl flflfl • ·. flflfl flflfl fll. ·' flfl fl fl flfl' fl · flfl flflflfl · flfl fl fl »’ · ·' fl'· fl fl flfl flflfl flfl flfl) ·· flfl °„ C 1 r.4 3 — - R ² R H (IN) OR ⁵ in which the symbols R ² , R ⁴ , ^Rs and R ³ meanings defined in of claim 23, and then subjecting this intermediate reaction with base under harsher conditions than those used in its creation. 25. The method according to claim 23 or 24, characterized in that R' in the compound of general formula IV contains a nitro group on an aryl or heteroaryl ring, and this group is gradually converted to an amino group by reduction, to a halogen by diazotization of the amino group and subsequent reaction with alkali metal cyanide and then to the carboxyl group by hydrolysis of the cyano group. 26. Method for preparing the compound of general formula III according to claim 2C, characterized in that the compound of general formula IX o OR ⁵ undergoes a reaction with a compound of general formula X X-CH=CH-CH ₂ -X (X) where the symbols R ² , R ⁵ and X have the meanings defined in claim 20, in the presence of a silylating agent which reacts with the compound of general formula IX to form a silyl derivative. of trivalent phosphorus, which then reacts with the compound of general formula X. • 9 999· 99 ·**9 99 99 9 9 9 «.9 9 ·'♦' 9 9 » 9 9*9 9 9 9 * « 9« * »: · · 9 9. 9 9' ·· · 9 9 « 9 9 9 9 9 9 ¹ » 9 9 99 999 99 9 9l 9 9 99 103 27. A method for preparing a compound of general formula II according to claim 21, characterized in that an aldehyde or ketone of the general formula R ⁴ C(=O)R* is subjected to a reaction with an amine of the general formula R ⁶ NH ₂ and an alkali metal cyanide to form the compound of general formula VI CN ₄ í R -c-NHR ^Ď | (VI) R ^x a be (a) a compound of general formula VI. undergoes a reaction with an alcohol of the general formula R ⁷ 0H, in the presence of an acid, to form a compound of the general formula VII COOR ⁷ I (VII) R* from the compound of the general formula VII, the group R ^s , if it has a meaning other than a hydrogen atom, is removed to give the compound of the general formula VIII COOR ⁷ R' compound of general formula VIII is subjected to reaction with an amino-protecting agent to convert the amino group into a protected amino group, . the ester group -COOR ⁷ is reduced to the group -CH ₂ 0H in the protected compound, and the protecting group is removed to form a free amino group, wherein the symbols R ⁴ , R ⁶ , R ⁷ and R ^x have the meanings defined in claim 21, or ( b) subject the compound of general formula VI to acid hydrolysis Φ·φΦ «« »φ Φ ΦΦΦΦ φ Φ' . ·'· ·' ΦΦ • φι ΦΦ ' ν φ φ' φ φ φ φ νφ· ·· ΦΦ' ΦΦ·Φ Φ· i Φ Φ *' φ· φ φ φ · · φ * • φ * φ* φ « . Φ · Φ φ: Φ · • Φ Φ·· ·Φ 104 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 fluoride complex. 28. A method for preparing a compound of general formula II according to claim 21, characterized in that an aminocarboxylic acid of the general formula R ⁴ C(R*) (NH ₂ )COOH is reduced, where the symbols R ⁴ and R ^:< have the meanings defined in claim 21 , by reaction with borane-dimethylsulfide in the presence of a boron fluoride complex. 29. A method for preparing a compound of general formula I according to claim 1, in which R ^y represents the group R ^y a , characterized in that the compound of general formula I according to claim 1, in which R ^y represents a hydrogen atom, is subjected to reaction (a) with a compound of the general formula R ^y aZ, where R ^y a has the meaning defined in claim 1 and Z represents a leaving group, or (b) with an aldehyde of the general formula R ^y bCHO, where R ^y b represents a hydrogen atom or a group R ^y a , as as defined in claim 1, and a reducing agent that reduces imines to amines. 30. Method for preparing the compound of general formula I according to claim 1, in which R ^y represents a group protecting the NH function, characterized in that the compound of general formula I according to claim 1, in which R ^y denotes a hydrogen atom, with acyl halide, carboxylic anhydride acid, an alkoxycarbonyl or aralkylcarbonyl halide or an alkyl or aralkyl dicarbonate. 31. Method for preparing the compound of general formula I according to claim 1, in which R ^y represents the group R ^y and or the group protecting the NH function, characterized in that the compound of general formula IIA - 105 OH »· 9 91»· • 9 9 9 · 9·· • 9 9 »' 9 9 9 • 9 * in · • 9 9*9·' *9 9 9 9 9 9 9 9. 9 9 9 · ·- 9! «1/9 9. · 9 9J 9 9 ·. 9 9 9.99/9 9 9 9 • 9 *9 99 99 (XIA) R ⁴ NHR ^y reacts with a compound of formula III as defined in claim 23 in the presence of a base to form a compound of formula IVA IVA) where the symbols R ⁴ , R ^x , R ² and R ⁵ have the meanings defined in claim 23 and R ^y means a group R ^y and or a group protecting the NH function as defined in any of claims 1 and 14 to 16, and subsequently if necessary, one or more substitution reactions are carried out to change the nature of the substituent in R ⁴ or/and R ^x or/and the hydrolysis of the ester group as a substituent in R ⁴ or/and R ^K to a carboxyl group or/and the conversion of the ester group - OR ⁵ to the hydroxy group. 32. Method for preparing the compound of general formula I according to claim 1, characterized in that the compound of general formula XIV About (XIV) 106 44 4··· ·* ·*♦» ** ·« 9 9 9 4 4 4 4' 4 · 4 * *·* * * · *< · 4«. * t 4 4 · 4 4. 4 4.·4 4 « 9 4 4 4 4 4/ 4 4 4 ft 4 · 4 · · 44 44 44 4« undergoes a reaction to convert the present primary hydroxy group Hyna into a leaving group, which causes cyclization to form the compound of general formula XV Where the symbols R ² , R", R ^x and R ^y have the meanings defined in claim 1a, R ⁵ has the meaning defined in claim 23, and if necessary, the group R ^y is subsequently replaced as a group protecting the NH function by hydrogen or/and one or more substitution reactions to change the nature of the substituent in R ⁴ or/and R ^x or/hydrolysis of the ester group as a substituent in R ⁴ or/and R ^x to a carboxyl group or/and the conversion of the ester group -OR ⁵ to a hydroxy group. 33. A method for preparing a compound of the general formula XIV according to claim 32, characterized in that the compound of the general formula II, as defined in claim 23, is subjected to a reaction with a compound of the general formula XVI where the symbols R ² and R ⁵ have the meanings defined in claim 32 and Z represents a leaving group, in the presence of a protected base, to form a compound of general formula XVII H (XVII) 107 • 4 ··»* «· ···* ·· Μ 4 · 4 · · 4 ···· 4 4·*· 4 4 0 *··· 0 « · · 0 « 4* Mil · 44 4 ·-<·,· fc « * »« «·· «<·. 4·00 * where the symbols R ² , R ⁴ , R ⁵ and R ^x have the meanings defined in claim 32, and the shown hydrogen atom attached to the nitrogen atom is replaced by a group protecting the NH function. 34. Pharmaceutical composition, characterized in that it contains therapeutically effective compounds according to any one of claims 1 to 19, optionally together with a pharmaceutically acceptable carrier in an amount or 22, 35. A compound according to any one of claims 1 to 19 or 22 for use in the therapeutic method of treating a warm-blooded animal. 36. 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 stimulation of the GABA _α receptor. 37. A method of treating or preventing conditions in an arterial mammal characterized by stimulation of GABA _and , characterized in that the mammal is administered a s-totcherin according to any of claims 1 to 19 or 22.